WO2019106605A1

WO2019106605A1 - Combination treatment for cancer

Info

Publication number: WO2019106605A1
Application number: PCT/IB2018/059475
Authority: WO
Inventors: Patrick Hwu; Weiyi PENG; Niranjan YANAMANDRA
Original assignee: Board Of Regents, The University Of Texas System; Glaxosmithkline Intellectual Property Development Limited
Priority date: 2017-12-01
Filing date: 2018-11-29
Publication date: 2019-06-06

Abstract

Disclosed herein is a method of treatment involving the combination of an OX40 antigen binding protein (e.g., an anti-OX40 agonist antibody) and a PI3Kb inhibitor for use in treating a cancer, such as a PTEN deficient cancer.

Description

Combination Treatment for Cancer

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Application Serial No. 62/593,414, filed on December 1, 2017. The disclosure of the prior application is considered part of (and is incorporated by reference in) the disclosure of this application.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on November 27, 2018, is named PU66486_PCT_SL.txt and is 59,247 bytes in size.

FIELD OF THE INVENTION

The present invention relates, in part, to a method of treating a cancer in a mammal. In particular, the present invention relates to a combination of an anti-OX40 antigen binding protein (ABP), also known as an 0X40 binding protein, such as an antibody (e.g., agonist antibody) to human 0X40, and a PI3Kb inhibitor for treating a cancer, such as a PTEN deficient cancer.

BACKGROUND OF THE INVENTION

0X40 is a potent co-stimulatory receptor that can potentiate T-cell receptor signaling on the surface of T lymphocytes, leading to their activation by a specifically recognized antigen. In particular, 0X40 engagement by ligands present on dendritic cells dramatically increases the proliferation, effector function and survival of T cells. Preclinical studies have shown that 0X40 agonists increase anti-tumor immunity and improve tumor-free survival.

SUMMARY OF THE INVENTION

The disclosure relates, in part, to the ability of an anti-OX40 agonist ABP and a PI3Kb inhibitor (e.g., therapeutically effective amounts thereof) (e.g., a combination of an anti- 0X40 agonist ABP and a PI3Kb inhibitor) to treat a cancer in a subject (e.g., patient) (e.g., mammal, e.g., human). In some aspects, the subject to be treated with an anti-OX40 agonist ABP and a PI3Kb inhibitor (e.g., therapeutically effective amounts thereof) (e.g., a combination of an anti-OX40 agonist ABP and a PI3Kb inhibitor) has a cancer with loss of expression of the PTEN tumor suppressor (e.g., a subject with a PTEN deficient cancer, e.g., a PTEN deficient tumor).

Provided herein is a method of treating a cancer, e.g., a PTEN deficient cancer (e.g., a PTEN deficient tumor) in a subject, the method comprising administering an anti-OX40 ABP, e.g., an agonist anti-OX40 ABP, and a PI3Kb inhibitor (e.g., therapeutically effective amounts thereof) (e.g., a combination of an anti-OX40 agonist ABP and a PI3Kb inhibitor) to the subject, thereby treating the cancer, e.g., the PTEN deficient cancer (e.g., the PTEN deficient tumor).

Provided herein are combinations comprising an anti-OX40 ABP, e.g., an agonist anti-OX40 ABP and a PI3Kb inhibitor (e.g., therapeutically effective amounts thereof) for treating a cancer, e.g., a PTEN deficient cancer (e.g., a PTEN deficient tumor), e.g., in a subject (e.g., patient) (e.g., mammal, e.g., human).

Further provided is an anti-OX40 ABP, e.g., an agonist anti-OX40 ABP (e.g., a therapeutically effective amount thereof) to and a PI3Kb inhibitor, in combination

(simultaneously or sequentially (e.g., in any order)), for use in the manufacture of a medicament for the treatment of a cancer, e.g., a PTEN deficient cancer (e.g., a PTEN deficient tumor).

Further provided is an anti-OX40 ABP, e.g., an agonist anti-OX40 ABP (e.g., a therapeutically effective amount thereof), for use in the manufacture of a medicament for the treatment of a cancer, e.g., a PTEN deficient cancer (e.g., a PTEN deficient tumor) in combination (simultaneously or sequentially (e.g., in any order)) with a PI3Kb inhibitor (e.g., a therapeutically effective amount thereof).

Further provided is a PI3Kb inhibitor (e.g., a therapeutically effective amount thereof), for use in the manufacture of a medicament for the treatment of a cancer, e.g., a PTEN deficient cancer (e.g., a PTEN deficient tumor) in combination (simultaneously or sequentially (e.g., in any order)) with an anti-OX40 ABP, e.g., an agonist anti-OX40 ABP (e.g., a therapeutically effective amount thereof).

Also provided are methods of treating a cancer, e.g., a PTEN deficient cancer (e.g., a PTEN deficient tumor in a subject (e.g., patient) (e.g., mammal, e.g., human) comprising administering a combination of the invention, and uses of the combinations for therapy, preferably for therapy for a cancer, e.g., a PTEN deficient cancer (e.g., a PTEN deficient tumor).

In some aspects, the disclosure provides a method of treating a cancer in a mammal (e.g., a human) in need thereof, the method comprising: administering to the mammal an anti-OX40 antigen binding protein (e.g., a therapeutically effective amount thereof) and a PI3Kb inhibitor (e.g., a therapeutically effective amount thereof), thereby treating the cancer.

In some aspects, the disclosure provides a method of treating a cancer in a mammal (e.g., human) in need thereof, the method comprising: administering to the mammal an anti-OX40 antigen binding protein (e.g., a therapeutically effective amount thereof) and a PI3Kb inhibitor (e.g., a therapeutically effective amount thereof), thereby treating the cancer.

In some embodiments, the cancer is a solid tumor.

In some embodiments, the cancer is a PTEN deficient cancer.

In some embodiments, the mammal has a PTEN deficient cancer.

In some embodiments, the mammal or a cancer from the mammal is identified as having a PTEN deficient cancer.

In some embodiments, the mammal or a cancer from the mammal is selected on the basis of having a PTEN deficient cancer.

In some embodiments, the mammal or a cancer from the mammal is evaluated to determine whether the cancer is PTEN deficient. In some embodiments, the evaluation comprises Q-PCR. In some embodiments, the evaluation comprises an ELISA.

In some embodiments, the cancer is selected from the group consisting of: breast cancer, thyroid cancer, glioblastoma, endometrial cancer, prostate cancer, and melanoma.

In some embodiments, the cancer is a prostate cancer.

In some embodiments, the cancer is a melanoma.

In some embodiments, the anti-OX40 antigen binding protein and the PI3Kb inhibitor are administered at the same time.

In some embodiments, the anti-OX40 antigen binding protein is administered after the PI3Kb inhibitor is administered.

In some embodiments, the anti-OX40 antigen binding protein is administered before the PI3Kb inhibitor is administered.

In some embodiments, the anti-OX40 antigen binding protein is administered systemically.

In some embodiments, the anti-OX40 antigen binding protein is administered intratu morally.

In some embodiments, the PI3Kb inhibitor is administered systemically.

In some embodiments, the PI3Kb inhibitor is administered orally.

In some embodiments, the mammal is human. In some embodiments, the size of the cancer in the mammal is reduced by more than the additive amount by which the size is reduced with treatment with the anti-OX40 antigen binding protein used as a monotherapy and the PI3Kb inhibitor used as a monotherapy.

In some embodiments, the anti-OX40 antigen binding protein binds to human 0X40.

In some embodiments, the PI3Kb inhibitor is a compound of Formula (II):

wherein

R1 is selected from H, Ci-ealkyl, alkoxy, hydroxy, halogen, -CN, -NH₂, -NHC(0)Ra, -NHS0₂Ra, -CO2H, -CC Ra, -CONHRb, -CONH₂, -CH₂OH, and heteroaryl wherein the heteroaryl may be substituted by one or two Ci-3alkyl groups;

R2 is selected from H, -NHRa, alkoxy, halogen, -CF₃, -CFIF2, and Ci-ealkyl;

R3 is selected from aryl and heteroaryl, wherein said aryl or heteroaryl may be substituted by one to three Rc;

R4 is selected from FI or Ra;

each R5 is independently selected from Ci-ealkyl;

each Ra is independently selected from Ci-3alkyl;

Rb is selected from FI, Ci-3alkyl, and SChMe;

each Rc is independently selected from Ci-3alkyl, halogen, -CF₃, and hydroxy; and n is 0-2,

or a pharmaceutically acceptable salt thereof.

In some embodiments, the heteroaryl of R1 is selected from the group consisting of: pyrazolyl, triazolyl, tetrazolyl, oxazolyl and imidazolyl.

In some embodiments, the aryl or heteroaryl of R3 are selected from phenyl, naphthyl, benzothienyl, quinolinyl, isoquinolinyl, and quinazolinyl.

In some embodiments, each Rc is independently Ci-3alkyl, F or Cl, and n is 0.

In some embodiments, each Rc is independently CF₃ or F, and n is 0.

In some embodiments, the PI3Kb inhibitor is a compound having the Formula

(H)(C):

wherein

each of R6, R7, and R8 is independently selected from Ci-₃alkyl, halogen, -CF₃, and hydroxyl, or R6 and R7 combine to form a bi-cyclic aryl or heteroaryl, or R7 and R8 combine to form a bi-cyclic aryl or heteroaryl;

In some embodiments, the PI3Kb inhibitor is a compound having the Formula

(H)(D):

(ID(D).

In some embodiments, the PI3Kb inhibitor is a compound having the Formula

(P)(E):

wherein

each of R6 and R7 is independently selected from Ci-₃alkyl, halogen, -CF₃, and hydroxyl.

In some embodiments, the PI3Kb inhibitor is:

2-(l-methylethyl)-6-(4-morpholinyl)-l-(l-naphthalenylmethyl)-lH-benzimidazol-4-ol,

2-ethyl-6-(4-morpholinyl)-l-(l-naphthalenylmethyl)-lH-benzimidazol-4-ol, l-[(2,3-dichlorophenyl)methyl]-2-(l-methylethyl)-6-(4-morpholinyl)-lH-benzimidazol-

4-ol,

l-[(2,3-dichlorophenyl)methyl]-4-fluoro-2-methyl-6-(4-morpholinyl)-lH- benzimidazole,

1-[(2,3-dichlorophenyl)methyl]-2-ethyl-6-(4-morpholinyl)-lH-benzimidazol-4-ol,

4-fluoro-2-methyl-6-(4-morpholinyl)-l-(l-naphthalenylmethyl)-lH-benzimidazole,

2-ethyl-4-fluoro-6-(4-morpholinyl)-l-(l-naphthalenylmethyl)-lH-benzimidazole,

2-methyl-6-(4-morpholinyl)-l-(l-naphthalenylmethyl)-lH-benzimidazole-4-carboxylic acid,

1-[(2,3-dichlorophenyl)methyl]-2-ethyl-4-fluoro-6-(4-morpholinyl)-lH-benzimidazole,

2-methyl-6-(4-morpholinyl)-l-(l-naphthalenylmethyl)-4-(lH-pyrazol-5-yl)-lH- benzimidazole,

l-[(2,3-dichlorophenyl)methyl]-2-methyl-6-(4-morpholinyl)-lH-benzimidazole-4- carboxylic acid,

1-[(2,3-dichlorophenyl)methyl]-2-methyl-6-(4-morpholinyl)-4-(lH-pyrazol-5-yl)-lH- benzimidazole,

2-methyl-6-(4-morpholinyl)-l-(l-naphthalenylmethyl)-4-(lH-l,2,4-triazol-3-yl)-lH- benzimidazole,

methyl 2-methyl-6-(4-morpholinyl)-l-(l-naphthalenylmethyl)-lH-benzimidazole-4- carboxylate,

1-[(2,3-dichlorophenyl)methyl]-2-methyl-6-(4-morpholinyl)-lH-benzimidazole-4- carboxamide,

methyl l-[(2-fluoro-3-methylphenyl)methyl]-2-methyl-6-(4-morpholinyl)-lH- benzimidazole-4-carboxylate,

2-methyl-6-(4-morpholinyl)-l-(l-naphthalenylmethyl)-lH-benzimidazole-4- carbonitrile,

l-[(2,3-dichlorophenyl)methyl]-2-methyl-6-(4-morpholinyl)-lH-benzimidazole-4- carbonitrile, methyl 2-methyl-l-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)- lH-benzimidazole-4-carboxylate,

2-methyl-l-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-lH- benzimidazole-4-carboxylic acid,

1-[(2-fluoro-3-methylphenyl)methyl]-2-methyl-6-(4-morpholinyl)-lH-benzimidazole- 4-carboxylic acid,

2-methyl-6-(4-morpholinyl)-l-(l-naphthalenylmethyl)-lH-benzimidazole-4- carboxamide,

1-[(2,3-dichlorophenyl)methyl]-2-methyl-6-(4-morpholinyl)-4-(lH-l,2,4-triazol-3-yl)- lH-benzimidazole,

methyl 2-methyl-6-(4-morpholinyl)-l-(5-quinolinylmethyl)-lH-benzimidazole-4- carboxylate,

2-methyl-6-(4-morpholinyl)-l-(5-quinolinylmethyl)-lH-benzimidazole-4-carboxylic acid,

1-[(3,4-dimethylphenyl)methyl]-2-methyl-6-(4-morpholinyl)-lH-benzimidazole-4- carboxylic acid,

2-methyl-6-(4-morpholinyl)-l-(2-naphthalenylmethyl)-lH-benzimidazole-4-carboxylic acid,

1-[(3,4-dichlorophenyl)methyl]-2-methyl-6-(4-morpholinyl)-lH-benzimidazole-4- carboxylic acid,

2-methyl-l-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-4-(lH- l,2,4-triazol-3-yl)-lH-benzimidazole,

2-methyl-4-(3-methyl-lH-l,2,4-triazol-5-yl)-6-(4-morpholinyl)-l-(l- naphthalenylmethyl)-lH-benzimidazole,

1-[2-methyl-6-(4-morpholinyl)-l-(l-naphthalenylmethyl)-lH-benzimidazol-4- yl]ethanone,

[2-methyl-6-(4-morpholinyl)-l-(l-naphthalenylmethyl)-lH-benzimidazol-4- yl]methanol,

2-methyl-N-(methylsulfonyl)-6-(4-morpholinyl)-l-(l-naphthalenylmethyl)-lH- benzimidazole-4-carboxamide,

methyl 5-(4-morpholinyl)-2-(trifluoromethyl)-lH-benzimidazole-7-carboxylate, methyl l-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-2- (trifluoromethyl)-lH-benzimidazole-4-carboxylate,

l-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-2- (trifluoromethyl)-lH-benzimidazole-4-carboxylic acid, 6-(4-morpholinyl)-l-(l-naphthalenylmethyl)-2-(trifluoromethyl)-lH-benzimidazole-4- carboxylic acid,

methyl l-[(3-chloro-2-methylphenyl)methyl]-6-(4-morpholinyl)-2-(trifluoromethyl)- lH-benzimidazole-4-carboxylate,

l-[(2,3-dichlorophenyl)methyl]-6-(4-morpholinyl)-2-(trifluoromethyl)-lH- benzimidazole-4-carboxylic acid,

l-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-2-

(trifluoromethyl)-lH-benzimidazole-4-carboxamide,

methyl 6-(4-morpholinyl)-l-(l-naphthalenylmethyl)-2-(trifluoromethyl)-lH- benzimidazole-4-carboxylate,

methyl l-[(2,3-dichlorophenyl)methyl]-6-(4-morpholinyl)-2-(trifluoromethyl)-lH- benzimidazole-4-carboxylate,

l-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-4-(lH-l,2,4- triazol-3-yl)-2-(trifluoromethyl)-lH-benzimidazole,

l-[(3-chloro-2-methylphenyl)methyl]-6-(4-morpholinyl)-2-(trifluoromethyl)-lH- benzimidazole-4-carboxylic acid,

l-[(2,3-dichlorophenyl)methyl]-6-(4-morpholinyl)-4-(lH-l,2,4-triazol-3-yl)-2-

(trifluoromethyl)-lH-benzimidazole,

1-[(3-chloro-2-methylphenyl)methyl]-6-(4-morpholinyl)-4-(lH-l,2,4-triazol-3-yl)-2- (trifluoromethyl)-lH-benzimidazole,

2-methyl-6-(4-morpholinyl)-l-(l-naphthalenylmethyl)-4-(lH-tetrazol-5-yl)-lH- benzimidazole,

[2-methyl-l-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-lH- benzimidazol-4-yl]methanol,

1-[(3-chloro-2-methylphenyl)methyl]-2-methyl-6-(4-morpholinyl)-lH-benzimidazole- 4-carboxylic acid,

2-methyl-l-[(2-methylphenyl)methyl]-6-(4-morpholinyl)-lH-benzimidazole-4- carboxylic acid,

ethyl 2-methyl-l-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-lH- benzimidazole-4-carboxylate,

4-bromo-2-methyl-6-(4-morpholinyl)-lH-benzimidazole,

4-bromo-2-methyl-l-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)- lH-benzimidazole,

2-methyl-l-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-4-(l,3- oxazol-2-yl)-lH-benzimidazole, methyl 2-chloro-5-(4-morpholinyl)-lH-benzimidazole-7-carboxylate, methyl 2-chloro-l-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)- lH-benzimidazole-4-carboxylate,

2-chloro-l-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-lH- benzimidazole-4-carboxylic acid

methyl 2-(difluoromethyl)-5-(4-morpholinyl)-lH-benzimidazole-7-carboxylate,

2-(difluoromethyl)-6-(4-morpholinyl)-l-(l-naphthalenylmethyl)-lH-benzimidazole-4- carboxylic acid,

2-(difluoromethyl)-l-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)- lH-benzimidazole-4-carboxylic acid,

l-[(2,3-dichlorophenyl)methyl]-2-(difluoromethyl)-6-(4-morpholinyl)-lH- benzimidazole-4-carboxylic acid,

l-[(3-chloro-2-methylphenyl)methyl]-2-(difluoromethyl)-6-(4-morpholinyl)-lH- benzimidazole-4-carboxylic acid,

l-(l-benzothien-7-ylmethyl)-2-methyl-6-(4-morpholinyl)-lH-benzimidazole-4- carboxylic acid,

l-[(2,3-dimethylphenyl)methyl]-2-methyl-6-(4-morpholinyl)-lH-benzimidazole-4- carboxylic acid,

l-[(3-fluoro-2-methylphenyl)methyl]-2-methyl-6-(4-morpholinyl)-lH-benzimidazole- 4-carboxylic acid,

2,4-dimethyl-l-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-lH- benzimidazole,

1-[l-(3-chloro-2-methylphenyl)ethyl]-2-methyl-6-(4-morpholinyl)-lH-benzimidazole- 4-carboxylic acid,

2-methyl-l-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-4-(l,3- thiazol-2-yl)-lH-benzimidazole,

4-(2-furanyl)-2-methyl-l-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4- morpholinyl)-lH-benzimidazole or

2-methyl-4-[(methyloxy)methyl]-l-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-

(4-morpholinyl)-lH-benzimidazole,

or a pharmaceutically acceptable salt thereof.

In some embodiments, the PI3Kb inhibitor is 2-methyl-l-{[2-methyl-3- (trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-lH-benzimidazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof. In some embodiments, the PI3Kb inhibitor is 2-methyl-l-{[2-methyl-3- (trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-lH-benzimidazole-4-carboxylic acid 2- amino-2-(hydroxymethyl)-l, 3-propanediol salt.

In some embodiments, the anti-OX40 antigen binding protein comprises: a heavy chain variable region CDR1 comprising an amino acid sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:l or 13; a heavy chain variable region CDR2 comprising an amino acid sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO:2 or 14; and/or a heavy chain variable region CDR3 comprising an amino acid sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO:3 or 15.

In some embodiments, the anti-OX40 antigen binding protein comprises a light chain variable region CDR1 comprising an amino acid sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO:7 or 19; a light chain variable region CDR2 comprising an amino acid sequence with at least at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO:8 or 20 and/or a light chain variable region CDR3 comprising an amino acid sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO:9 or 21.

In some embodiments, the anti-OX40 antigen binding protein comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:l; (b) a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:2; (c) a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:3;

(d) a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:7;

(e) a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:8; and (f) a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:9.

In some embodiments, the anti-OX40 antigen binding protein comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 13; (b) a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 14; (c) a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:15; (d) a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 19; (e) a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:20; and (f) a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:21.

In some embodiments, the anti-OX40 antigen binding protein comprises a light chain variable region ("VL") comprising an amino acid sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 10, 11, 22 or 23.

In some embodiments, the anti-OX40 antigen binding protein comprises a heavy chain variable region ("VH") comprising an amino acid sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO:4, 5, 16 or 17.

In some embodiments, the anti-OX40 antigen binding protein comprises a light chain variable region ("VL") comprising an amino acid sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: ll.

In some embodiments, the anti-OX40 antigen binding protein comprises a heavy chain variable region ("VH") comprising an amino acid sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 5.

In some embodiments, the anti-OX40 antigen binding protein comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:5 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:ll.

In some embodiments, the anti-OX40 antigen binding protein comprises a light chain variable region ("VL") comprising an amino acid sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO:23.

In some embodiments, the anti-OX40 antigen binding protein comprises a heavy chain variable region ("VH") comprising an amino acid sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 17.

In some embodiments, the anti-OX40 antigen binding protein comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 17 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:23.

In some embodiments, the anti-OX40 antigen binding protein comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: ll or 23, or an amino acid sequence with at least 90% sequence identity to the amino acid sequences of SEQ ID NO:ll or 23.

In some embodiments, the anti-OX40 antigen binding protein comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:5 or 17, or an amino acid sequence with at least 90% sequence identity to the amino acid sequences of SEQ ID NO:5 or 17.

In some embodiments, the anti-OX40 antigen binding protein comprises a heavy chain comprising an amino acid sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO:48 and a light chain comprising an amino acid sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO:49.

In some embodiments, the anti-OX40 antigen binding protein comprises a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO:48 and a light chain comprising an amino acid sequence as set forth in SEQ ID NO:49.

In some embodiments, the mammal has increased survival when treated with a therapeutically effective amount of an anti-OX40 antigen binding protein in combination with a PI3Kb inhibitor compared with a mammal who received the anti-OX40 antigen binding protein as a monotherapy or the PI3Kb inhibitor as a monotherapy.

In some embodiments, the method further comprises administering at least one antineoplastic agent to the mammal in need thereof.

In some embodiments, the PI3Kb inhibitor is 2-methyl-l-{[2-methyl-3- (trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-lH-benzimidazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof and the anti-OX40 antigen binding protein comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:l; (b) a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:2; (c) a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:3; (d) a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:7; (e) a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:8; and (f) a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:9.

In some embodiments, the PI3Kb inhibitor is 2-methyl-l-{[2-methyl-3- (trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-lH-benzimidazole-4-carboxylic acid 2- amino-2-(hydroxymethyl)-l, 3-propanediol salt and the anti-OX40 antigen binding protein comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:5 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:ll.

In some embodiments, the PI3Kb inhibitor is 2-methyl-l-{[2-methyl-3- (trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-lH-benzimidazole-4-carboxylic acid 2- amino-2-(hydroxymethyl)-l, 3-propanediol salt and the anti-OX40 antigen binding protein comprises a heavy chain comprising an amino acid sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO:48 and a light chain comprising an amino acid sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO:49.

In some aspects, the disclosure provides a combination of an anti-OX40 antigen binding protein (e.g., a therapeutically effective amount thereof) and a PI3Kb inhibitor (e.g., a therapeutically effective amount thereof) for use (e.g., for simultaneous or sequential use) in treating a cancer in a mammal.

In some embodiments, the cancer is a solid tumor.

In some embodiments, the cancer is a PTEN deficient cancer.

In some embodiments, the mammal has a PTEN deficient cancer.

In some embodiments, the cancer is a prostate cancer.

In some embodiments, the cancer is a melanoma.

In some embodiments, the anti-OX40 antigen binding protein is administered before the PI3Kb inhibitor is administered. In some embodiments, the anti-OX40 antigen binding protein is administered systemically.

In some embodiments, the PI3Kb inhibitor is administered systemically.

In some embodiments, the PI3Kb inhibitor is administered orally.

In some embodiments, the mammal is human.

In some embodiments, the size of the cancer in the mammal is reduced by more than the additive amount by which the size is reduced with treatment with the anti-OX40 antigen binding protein used as a monotherapy and the PI3Kb inhibitor used as a monotherapy.

In some embodiments, the anti-OX40 antigen binding protein binds to human 0X40.

In some embodiments, the PI3Kb inhibitor is a compound of Formula (II):

wherein

R1 is selected from H, Ci-ealkyl, alkoxy, hydroxy, halogen, -CN, -NH₂, -NHC(0)Ra, -NHS0₂Ra, -CO₂H, -CC Ra, -CONHRb, -CONH₂, -CH₂OH, and heteroaryl wherein the heteroaryl may be substituted by one or two Ci-₃alkyl groups;

R2 is selected from H, -NHRa, alkoxy, halogen, -CF₃, -CFIF₂, and Ci-ealkyl;

R4 is selected from FI or Ra;

each R5 is independently selected from Ci-ealkyl;

each Ra is independently selected from Ci-₃alkyl;

Rb is selected from FI, Ci-₃alkyl, and SChMe;

each Rc is independently selected from Ci-₃alkyl, halogen, -CF₃, and hydroxy; and n is 0-2,

or a pharmaceutically acceptable salt thereof. In some embodiments, the heteroaryl of R1 is selected from the group consisting of: pyrazolyl, triazolyl, tetrazolyl, oxazolyl and imidazolyl.

In some embodiments, each Rc is independently Ci-3alkyl, F or Cl, and n is 0.

In some embodiments, each Rc is independently CF₃ or F, and n is 0.

In some embodiments, the PI3Kb inhibitor is a compound having the Formula

(H)(C):

wherein

each of R6, R7, and R8 is independently selected from Ci-3alkyl, halogen, -CF₃, and hydroxyl, or R6 and R7 combine to form a bi-cyclic aryl or heteroaryl, or R7 and R8 combine to form a bi-cyclic aryl or heteroaryl;

In some embodiments, the PI3Kb inhibitor is a compound having the Formula

(H)(D):

(ID(D).

In some embodiments, the PI3Kb inhibitor is a compound having the Formula

(P)(E):

(P)(E)

wherein

In some embodiments, the PI3Kb inhibitor is:

4-ol,

1-[(2,3-dichlorophenyl)methyl]-2-ethyl-6-(4-morpholinyl)-lH-benzimidazol-4-ol, 4-fluoro-2-methyl-6-(4-morpholinyl)-l-(l-naphthalenylmethyl)-lH-benzimidazole,

2-ethyl-4-fluoro-6-(4-morpholinyl)-l-(l-naphthalenylmethyl)-lH-benzimidazole, 2-methyl-6-(4-morpholinyl)-l-(l-naphthalenylmethyl)-lH-benzimidazole-4-carboxylic acid,

2-methyl-6-(4-morpholinyl)-l-(l-naphthalenylmethyl)-4-(lH-l,2,4-triazol-3-yl)-lH- benzimidazole, methyl 2-methyl-6-(4-morpholinyl)-l-(l-naphthalenylmethyl)-lH-benzimidazole-4- carboxylate,

1-[(2,3-dichlorophenyl)methyl]-2-methyl-6-(4-morpholinyl)-lH-benzimidazole-4- carbonitrile,

methyl 2-methyl-l-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)- lH-benzimidazole-4-carboxylate,

2-methyl-4-(3-methyl-lH-l,2,4-triazol-5-yl)-6-(4-morpholinyl)-l-(l- naphthalenylmethyl)-lH-benzimidazole, 1-[2-methyl-6-(4-morpholinyl)-l-(l-naphthalenylmethyl)-lH-benzimidazol-4- yl]ethanone,

l-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-2- (trifluoromethyl)-lH-benzimidazole-4-carboxylic acid,

6-(4-morpholinyl)-l-(l-naphthalenylmethyl)-2-(trifluoromethyl)-lH-benzimidazole-4- carboxylic acid,

l-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-2-

(trifluoromethyl)-lH-benzimidazole-4-carboxamide,

l-[(2,3-dichlorophenyl)methyl]-6-(4-morpholinyl)-4-(lH-l,2,4-triazol-3-yl)-2-

(trifluoromethyl)-lH-benzimidazole,

[2-methyl-l-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-lH- benzimidazol-4-yl]methanol, 1-[(3-chloro-2-methylphenyl)methyl]-2-methyl-6-(4-morpholinyl)-lH-benzimidazole- 4-carboxylic acid,

4-bromo-2-methyl-6-(4-morpholinyl)-lH-benzimidazole,

2-methyl-l-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-4-(l,3- oxazol-2-yl)-lH-benzimidazole,

methyl 2-chloro-5-(4-morpholinyl)-lH-benzimidazole-7-carboxylate,

methyl 2-chloro-l-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)- lH-benzimidazole-4-carboxylate,

methyl 2-(difluoromethyl)-5-(4-morpholinyl)-lH-benzimidazole-7-carboxylate,

l-[l-(3-chloro-2-methylphenyl)ethyl]-2-methyl-6-(4-morpholinyl)-lH-benzimidazole- 4-carboxylic acid, 2-methyl-l-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-4-(l,3- thiazol-2-yl)-lH-benzimidazole,

(4-morpholinyl)-lH-benzimidazole,

or a pharmaceutically acceptable salt thereof.

In some embodiments, the PI3Kb inhibitor is 2-methyl-l-{[2-methyl-3- (trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-lH-benzimidazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof.

In some embodiments, the PI3Kb inhibitor is 2-methyl-l-{[2-methyl-3- (trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-lH-benzimidazole-4-carboxylic acid 2- amino-2-(hydroxymethyl)-l, 3-propanediol salt.

In some embodiments, the anti-OX40 antigen binding protein comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:l; (b) a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:2; (c) a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:3; (d) a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:7;

In some embodiments, the anti-OX40 antigen binding protein comprises a light chain variable region ("VL") comprising an amino acid sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO:10, 11, 22 or 23.

In some embodiments, the anti-OX40 antigen binding protein comprises a light chain variable region ("VL") comprising an amino acid sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO:ll.

In some embodiments, the anti-OX40 antigen binding protein comprises a light chain variable region ("VL") comprising an amino acid sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO:23. In some embodiments, the anti-OX40 antigen binding protein comprises a heavy chain variable region ("VH") comprising an amino acid sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 17.

In some embodiments, the anti-OX40 antigen binding protein comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:ll or 23, or an amino acid sequence with at least 90% sequence identity to the amino acid sequences of SEQ ID NO:ll or 23.

In some embodiments, the PI3Kb inhibitor is 2-methyl-l-{[2-methyl-3- (trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-lH-benzimidazole-4-carboxylic acid 2- amino-2-(hydroxymethyl)-l, 3-propanediol salt and the anti-OX40 antigen binding protein comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:5 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: ll.

In some aspects, the disclosure provides use of an anti-OX40 antigen binding protein (e.g., a therapeutically effective amount thereof) and a PI3Kb inhibitor (e.g., a

therapeutically effective amount thereof) in the manufacture of a medicament for the treatment of a cancer.

In some aspects, the disclosure provides use of an anti-OX40 antigen binding protein (e.g., a therapeutically effective amount thereof) in the manufacture of a medicament for treating a cancer in a mammal (e.g., human) in combination (simultaneously or sequentially) with a PI3Kb inhibitor (e.g., a therapeutically effective amount thereof).

In some embodiments, the cancer is a PTEN deficient cancer.

In some embodiments, the mammal has a PTEN deficient cancer.

In some embodiments, the mammal or a cancer from the mammal is selected on the basis of having a PTEN deficient cancer. In some embodiments, the mammal or a cancer from the mammal is evaluated to determine whether the cancer is PTEN deficient. In some embodiments, the evaluation comprises Q-PCR. In some embodiments, the evaluation comprises an ELISA.

In some embodiments, the PI3Kb inhibitor is a compound of Formula (II):

wherein

R1 is selected from H, Ci-ealkyl, alkoxy, hydroxy, halogen, -CN, -NH₂, -NHC(0)Ra, -NHS0₂Ra, -CO₂H, -CChRa, -CONHRb, -CONH₂, -CH₂OH, and heteroaryl wherein the heteroaryl may be substituted by one or two Ci-₃alkyl groups;

R2 is selected from H, -NHRa, alkoxy, halogen, -CF₃, -CHF₂, and Ci-ealkyl;

R4 is selected from FI or Ra;

each R5 is independently selected from Ci-ealkyl;

each Ra is independently selected from Ci-₃alkyl;

Rb is selected from FI, Ci-₃alkyl, and SChMe;

or a pharmaceutically acceptable salt thereof.

In some embodiments, the PI3Kb inhibitor is a compound having the Formula

(H)(C):

wherein

In some embodiments, the PI3Kb inhibitor is a compound having the Formula

(H)(D):

(ID(D).

In some embodiments, the PI3Kb inhibitor is a compound having the Formula

(P)(E):

wherein

In some embodiments, the PI3Kb inhibitor is 2-methyl-l-{[2-methyl-3- (trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-lFI-benzimidazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof.

In some embodiments, the PI3Kb inhibitor is 2-methyl-l-{[2-methyl-3- (trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-lFI-benzimidazole-4-carboxylic acid 2- amino-2-(hydroxymethyl)-l, 3-propanediol salt. In some embodiments, the PI3Kb inhibitor is 2-methyl-l-{[2-methyl-3- (trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-lH-benzimidazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof and the anti-OX40 antigen binding protein comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: l; (b) a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:2; (c) a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:3; (d) a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:7; (e) a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:8; and (f) a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:9.

In some aspects, the disclosure provides a combination for reducing tumor size in a mammal (e.g., human) having a cancer, the combination comprising: administering an anti- 0X40 antigen binding protein (e.g., a therapeutically effective amount thereof) and a PI3Kb inhibitor (e.g., a therapeutically effective amount thereof) to the mammal.

In some embodiments, the tumor comprises a PTEN deficient cancer.

In some embodiments, the mammal has a PTEN deficient cancer.

In some embodiments, an amino acid sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO:ll.

In some embodiments, the PI3Kb inhibitor is a compound of Formula (II):

wherein

R2 is selected from H, -NHRa, alkoxy, halogen, -CF₃, -CHF₂, and Ci-ealkyl;

R4 is selected from FI or Ra;

each R5 is independently selected from Ci-₆alkyl;

each Ra is independently selected from Ci-₃alkyl;

Rb is selected from FI, Ci-₃alkyl, and SChMe;

or a pharmaceutically acceptable salt thereof.

In some embodiments, the PI3Kb inhibitor is a compound having the Formula

(H)(C):

wherein

In some embodiments, the PI3Kb inhibitor is a compound having the Formula

(H)(D):

(ID(D).

In some embodiments, the PI3Kb inhibitor is a compound having the Formula

(II)(E):

wherein

In some embodiments, the PI3Kb inhibitor is 2-methyl-l-{[2-methyl-3- (trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-lFI-benzimidazole-4-carboxylic acid or a In some embodiments, the PI3Kb inhibitor is 2-methyl-l-{[2-methyl-3- (trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-lFI-benzimidazole-4-carboxylic acid 2- amino-2-(hydroxymethyl)-l, 3-propanediol salt. In some embodiments, the PI3Kb inhibitor is 2-methyl-l-{[2-methyl-3- (trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-lH-benzimidazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof and the anti-OX40 antigen binding protein comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: l; (b) a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:2; (c) a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:3; (d) a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:7; (e) a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:8; and (f) a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:9.

therapeutically effective amount thereof) in the manufacture of a medicament for reducing tumor size in a mammal (e.g., human) having a cancer.

In some aspects, the disclosure provides use of an anti-OX40 antigen binding protein (e.g., a therapeutically effective amount thereof) in the manufacture of a medicament for reducing tumor size in a mammal (e.g., human) having a cancer in combination

(simultaneously or sequentially) with a PI3Kb inhibitor (e.g., a therapeutically effective amount thereof).

In some embodiments, the tumor comprises a PTEN deficient cancer.

In some embodiments, the mammal has a PTEN deficient cancer. In some embodiments, the mammal or a tumor from the mammal is identified as having a PTEN deficient cancer.

In some embodiments, the mammal or a tumor from the mammal is selected on the basis of having a PTEN deficient cancer.

In some embodiments, the mammal or a tumor from the mammal is evaluated to determine whether the cancer is PTEN deficient. In some embodiments, the evaluation comprises Q-PCR. In some embodiments, the evaluation comprises an ELISA.

In some embodiments, cancer is a prostate cancer.

In some embodiments, the cancer is a melanoma.

In some embodiments, the size of the tumor in the mammal is reduced by more than the additive amount by which the size is reduced with treatment with the anti-OX40 antigen binding protein used as a monotherapy and the PI3Kb inhibitor used as a monotherapy.

In some embodiments, the PI3Kb inhibitor is a compound of Formula (II):

wherein

R1 is selected from H, Ci-ealkyl, alkoxy, hydroxy, halogen, -CN, -INH₂, -NHC(0)Ra, -NHSChRa, -CO₂H, -CChRa, -CONHRb, -CONH₂, -CH₂OH, and heteroaryl wherein the heteroaryl may be substituted by one or two Ci-₃alkyl groups;

R2 is selected from H, -NHRa, alkoxy, halogen, -CF₃, -CFIF₂, and Ci-ealkyl;

R4 is selected from FI or Ra;

each R5 is independently selected from Ci-ealkyl;

each Ra is independently selected from Ci-₃alkyl;

Rb is selected from FI, Ci-₃alkyl, and SCbMe;

or a pharmaceutically acceptable salt thereof.

In some embodiments, the PI3Kb inhibitor is a compound having the Formula

(H)(C):

wherein

In some embodiments, the PI3Kb inhibitor is a compound having the Formula

(H)(D):

(ID(D).

In some embodiments, the PI3Kb inhibitor is a compound having the Formula

(P)(E):

wherein

each of R6 and R7 is independently selected from Ci-3alkyl, halogen, -CF₃, and hydroxyl.

In some embodiments, the PI3Kb inhibitor is 2-methyl-l-{[2-methyl-3- (trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-lH-benzimidazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof and the anti-OX40 antigen binding protein comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: l; (b) a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:2; (c) a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:3; (d) a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:7; (e) a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:8; and (f) a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:9.

In some aspects, the disclosure provides a method of reducing tumor size in a mammal (e.g., human) having a cancer, the method comprising: administering to the mammal an anti-OX40 antigen binding protein (e.g., a therapeutically effective amount thereof) and a PI3Kb inhibitor (e.g., a therapeutically effective amount thereof), thereby reducing tumor size in the mammal.

In some embodiments, the tumor comprises a PTEN deficient cancer.

In some embodiments, the mammal has a PTEN deficient cancer.

In some embodiments, the mammal or a tumor from the mammal is identified as having a PTEN deficient cancer.

In some embodiments, cancer is a prostate cancer.

In some embodiments, the cancer is a melanoma.

In some embodiments, the PI3Kb inhibitor is administered systemically.

In some embodiments, the PI3Kb inhibitor is administered orally.

In some embodiments, the mammal is human.

In some embodiments, the anti-OX40 antigen binding protein binds to human 0X40.

In some embodiments, the PI3Kb inhibitor is a compound of Formula (II):

wherein

R1 is selected from H, Ci-ealkyl, alkoxy, hydroxy, halogen, -CN, -NH₂, -NHC(0)Ra, -NHS0₂Ra, -CO₂H, -C0₂Ra, -CONHRb, -CONH₂, -CH₂OH, and heteroaryl wherein the heteroaryl may be substituted by one or two Ci-₃alkyl groups;

R2 is selected from H, -NHRa, alkoxy, halogen, -CF₃, -CHF₂, and Ci-ealkyl;

R4 is selected from FI or Ra;

each R5 is independently selected from Ci-ealkyl;

each Ra is independently selected from Ci-₃alkyl;

Rb is selected from FI, Ci-₃alkyl, and SChMe;

or a pharmaceutically acceptable salt thereof.

In some embodiments, each Rc is independently Ci-₃alkyl, F or Cl, and n is 0.

In some embodiments, each Rc is independently CF₃ or F, and n is 0.

In some embodiments, the PI3Kb inhibitor is a compound having the Formula

(H)(C):

wherein

In some embodiments, the PI3Kb inhibitor is a compound having the Formula

(H)(D):

In some embodiments, the PI3Kb inhibitor is a compound having the Formula

(P)(E):

wherein

In some embodiments, the PI3Kb inhibitor is:

4-ol,

1-[(2,3-dichlorophenyl)methyl]-2-ethyl-6-(4-morpholinyl)-lH-benzimidazol-4-ol,

4-fluoro-2-methyl-6-(4-morpholinyl)-l-(l-naphthalenylmethyl)-lH-benzimidazole,

2-ethyl-4-fluoro-6-(4-morpholinyl)-l-(l-naphthalenylmethyl)-lH-benzimidazole,

l-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-2-

(trifluoromethyl)-lH-benzimidazole-4-carboxamide,

l-[(2,3-dichlorophenyl)methyl]-6-(4-morpholinyl)-4-(lH-l,2,4-triazol-3-yl)-2-

(trifluoromethyl)-lH-benzimidazole,

4-bromo-2-methyl-6-(4-morpholinyl)-lH-benzimidazole,

methyl 2-(difluoromethyl)-5-(4-morpholinyl)-lH-benzimidazole-7-carboxylate,

(4-morpholinyl)-lH-benzimidazole,

or a pharmaceutically acceptable salt thereof.

In some embodiments, the anti-OX40 antigen binding protein comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:ll or 23, or an amino acid sequence with at least 90% sequence identity to the amino acid sequences of SEQ ID NO: ll or 23.

In some aspects, the disclosure provides a combination of an anti-OX40 antigen binding protein (e.g., a therapeutically effective amount thereof) and a PI3Kb inhibitor (e.g., a therapeutically effective amount thereof) for use in reducing tumor size in a mammal (e.g., human) having a cancer.

In some embodiments, the tumor comprises a PTEN deficient cancer.

In some embodiments, the mammal has a PTEN deficient cancer.

In some embodiments, cancer is a prostate cancer.

In some embodiments, the cancer is a melanoma.

(d) a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:7; (e) a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:8; and (f) a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:9.

In some embodiments, the anti-OX40 antigen binding protein comprises a heavy chain comprising an amino acid sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO:48 and a light chain comprising an amino acid sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to amino acid sequence as set forth in SEQ ID NO:49.

In some embodiments, the PI3Kb inhibitor is a compound of Formula (II):

wherein

R1 is selected from H, Ci-ealkyl, alkoxy, hydroxy, halogen, -CN, -NH₂, -NHC(0)Ra, -NHS0₂Ra, -CO₂H, -C0₂Ra, -CONHRb, -CONH₂, -CH₂OH, and heteroaryl wherein the heteroaryl may be substituted by one or two Ci-₃alkyl groups; R2 is selected from H, -NFIRa, alkoxy, halogen, -CF₃, -CFIF₂, and Ci-ealkyl;

R4 is selected from FI or Ra;

each R5 is independently selected from Ci-ealkyl;

each Ra is independently selected from Ci-₃alkyl;

Rb is selected from FI, Ci_-3alkyl, and SChMe;

each Rc is independently selected from Ci_-3alkyl, halogen, -CF₃, and hydroxy; and n is 0-2,

or a pharmaceutically acceptable salt thereof.

In some embodiments, the PI3Kb inhibitor is a compound having the Formula

(H)(C):

wherein

In some embodiments, the PI3Kb inhibitor is a compound having the Formula

(H)(D):

In some embodiments, the PI3Kb inhibitor is a compound having the Formula

(P)(E):

wherein

In some embodiments, the PI3Kb inhibitor is 2-methyl-l-{[2-methyl-3- (trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-lFI-benzimidazole-4-carboxylic acid 2- amino-2-(hydroxymethyl)-l, 3-propanediol salt.

In some embodiments, PI3Kb inhibitor is 2-methyl-l-{[2-methyl-3- (trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-lFI-benzimidazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof and the anti-OX40 antigen binding protein comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: l; (b) a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:2; (c) a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:3; (d) a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:7; (e) a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:8; and (f) a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:9.

In some embodiments, the PI3Kb inhibitor is 2-methyl-l-{[2-methyl-3- (trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-lFI-benzimidazole-4-carboxylic acid 2- amino-2-(hydroxymethyl)-l, 3-propanediol salt and the anti-OX40 antigen binding protein comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:5 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:ll.

In some aspects, the disclosure provides a kit for use in the treatment of cancer comprising:

(i) an anti-OX40 antigen binding protein (e.g., a therapeutically effective amount thereof) (e.g., an anti-OX40 antigen binding protein described herein);

(ii) a PI3Kb inhibitor (e.g., a therapeutically effective amount thereof) (e.g., a PI3Kb inhibitor described herein); and

(iii) instructions for use in the treatment of cancer.

In some embodiments, the anti-OX40 antigen binding protein and the PI3Kb inhibitor are each individually formulated with one or more pharmaceutically acceptable carriers.

In some embodiments, the kit is for use in a mammal has a cancer that is a PTEN deficient cancer.

In some embodiments, the instructions include identifying the mammal or a cancer from the mammal as having a PTEN deficient cancer.

In some embodiments, the instructions include selecting the mammal or a cancer from the mammal on the basis of having a PTEN deficient cancer.

In some embodiments, the instructions include evaluating the mammal or a cancer from the mammal to determine whether the cancer is a PTEN deficient cancer. In further embodiments, the instructions indicate that the treatment is for a mammal who has a cancer that is a PTEN deficient cancer. In some embodiments, the evaluation comprises Q- PCR. In some embodiments, the evaluation comprises an ELISA.

(i) an anti-OX40 antigen binding protein (e.g., a therapeutically effective amount thereof) (e.g., an anti-OX40 antigen binding protein described herein); and

(ii) instructions for use in the treatment of cancer when combined with a PI3Kb inhibitor (e.g., a therapeutically effective amount thereof) (e.g., a PI3Kb inhibitor described herein).

In some embodiments, the instructions include identifying the mammal or a cancer from the mammal as having a PTEN deficient cancer. In some embodiments, the instructions include selecting the mammal or a cancer from the mammal on the basis of having a PTEN deficient cancer.

In some aspects, the disclosure provides a kit for use in the treatment of cancer, where the kit comprises:

(i) a PI3Kb inhibitor (e.g., a therapeutically effective amount thereof) (e.g., a PI3Kb inhibitor described herein); and

(ii) instructions for use in the treatment of cancer when combined with an anti- 0X40 antigen binding protein (e.g., a therapeutically effective amount thereof) (e.g., an anti-OX40 antigen binding protein described herein).

In some aspects, the disclosure provides a kit for use in reducing tumor size in a mammal (e.g., a mammal with cancer) comprising:

(iii) instructions for use in reducing tumor size in a mammal. In some embodiments, the anti-OX40 antigen binding protein and the PI3Kb inhibitor are each individually formulated with one or more pharmaceutically acceptable carriers.

In some embodiments, the kit is for use in a mammal has a tumor that comprises a PTEN deficient cancer.

In some embodiments, the instructions include identifying the mammal or a tumor from the mammal as having a PTEN deficient cancer.

In some embodiments, the instructions include selecting the mammal or a tumor from the mammal on the basis of having a PTEN deficient cancer.

In some embodiments, the instructions include evaluating the mammal or a tumor from the mammal to determine whether the tumor comprises a PTEN deficient cancer. In further embodiments, the instructions indicate that the treatment is for a mammal who has a tumor that comprises a PTEN deficient cancer. In some embodiments, the evaluation comprises Q-PCR. In some embodiments, the evaluation comprises an ELISA.

In some aspects, the disclosure provides a kit for use in reducing tumor size in a mammal (e.g., a mammal with cancer):

(ii) instructions for use in reducing tumor size in a mammal when combined with a PI3Kb inhibitor (e.g., a therapeutically effective amount thereof) (e.g., a PI3Kb inhibitor described herein).

In some aspects, the disclosure provides a kit for use in reducing tumor size in a mammal (e.g., a mammal with cancer), where the kit comprises: (i) a PI3Kb inhibitor (e.g., a therapeutically effective amount thereof) (e.g., a PI3Kb inhibitor described herein); and

(ii) instructions for use in reducing tumor size in a mammal when combined with an anti-OX40 antigen binding protein (e.g., a therapeutically effective amount thereof) (e.g., an anti-OX40 antigen binding protein described herein).

In some embodiments, the PI3Kb inhibitor is 2-methyl-l-{[2-methyl-3- (trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-lH-benzimidazole-4-carboxylic acid 2- amino-2-(hydroxymethyl)-l, 3-propanediol salt and the anti-OX40 antigen binding protein comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:5 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: ll. In some aspects, the disclosure provides a method for increasing CCL4 protein levels (e.g., CCL4 serum levels) (e.g., determined as described herein) in a mammal (e.g., human) (e.g., subject, e.g., patient), the method comprising:

administering to the mammal an antigen binding protein that binds 0X40 (e.g., a therapeutically effective amount thereof), wherein the antigen binding protein that binds 0X40 is as described herein, and a PI3Kb inhibitor (e.g., a therapeutically effective amount thereof), wherein the PI3Kb inhibitor is as described herein, e.g., both administered as described herein. E.g., wherein the mammal (e.g., human) has cancer, as described herein. Also provided herein is an antigen binding protein that binds 0X40 (e.g., a therapeutically effective amount thereof) and a PI3Kb inhibitor (e.g., a therapeutically effective amount thereof), both as described herein, for use in increasing CCL4 protein levels (e.g., CCL4 serum levels) in the mammal. Also provided herein is use of an antigen binding protein that binds 0X40 (e.g., a therapeutically effective amount thereof) and a PI3Kb inhibitor (e.g., a therapeutically effective amount thereof), both as described herein, for the preparation of a medicament for increasing CCL4 protein levels (e.g., CCL4 serum levels) in the mammal.

In some aspects, the disclosure provides a method for increasing CXCL10 protein levels (e.g., CXCL10 serum levels) (e.g., determined as described herein) in a mammal (e.g., human) (e.g., subject, e.g., patient), the method comprising:

administering to the mammal an antigen binding protein that binds 0X40 (e.g., a therapeutically effective amount thereof), wherein the antigen binding protein that binds 0X40 is as described herein, and a PI3Kb inhibitor (e.g., a therapeutically effective amount thereof), wherein the PI3Kb inhibitor is as described herein, e.g., both administered as described herein. E.g., wherein the mammal (e.g., human) has cancer, as described herein. Also provided herein is an antigen binding protein that binds 0X40 (e.g., a therapeutically effective amount thereof) and a PI3Kb inhibitor (e.g., a therapeutically effective amount thereof), both as described herein, for use in increasing CXCL10 protein levels (e.g., CXCL10 serum levels) in the mammal. Also provided herein is use of an antigen binding protein that binds 0X40 (e.g., a therapeutically effective amount thereof) and a PI3Kb inhibitor (e.g., a therapeutically effective amount thereof), both as described herein, for the preparation of a medicament for increasing CXCL10 protein levels (e.g., CXCL10 serum levels) in the mammal.

In some aspects, the disclosure provides a method for increasing IFN-g (IFN-g) protein levels (e.g., IFN-g serum levels) (e.g., determined as described herein) in a mammal (e.g., human) (e.g., subject, e.g., patient), the method comprising: administering to the mammal an antigen binding protein that binds 0X40 (e.g., a therapeutically effective amount thereof), wherein the antigen binding protein that binds 0X40 is as described herein, and a PI3Kb inhibitor (e.g., a therapeutically effective amount thereof), wherein the PI3Kb inhibitor is as described herein, e.g., both administered as described herein. E.g., wherein the mammal (e.g., human) has cancer, as described herein. Also provided herein is an antigen binding protein that binds 0X40 (e.g., a therapeutically effective amount thereof) and a PI3Kb inhibitor (e.g., a therapeutically effective amount thereof), both as described herein, for use in increasing IFN-g protein levels (e.g., IFN-g serum levels) in the mammal. Also provided herein is use of an antigen binding protein that binds 0X40 (e.g., a therapeutically effective amount thereof) and a PI3Kb inhibitor (e.g., a therapeutically effective amount thereof), both as described herein, for the preparation of a medicament for increasing IFN-g protein levels (e.g., IFN-g serum levels) in the mammal.

Further provided are methods for modulating the immune response of a subject in need of cancer treatment, preferably a human, comprising administering to said subject an effective amount of the combination of an anti-OX40 ABP and a PI3Kb inhibitor (e.g., a therapeutically effective amount of each), both as described herein, e.g., in one or more pharmaceutical compositions.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1-12 show sequences of anti-OX40 ABPs. FIG.l includes a disclosure of residues 1-30, 36-49, 67-98, and 121-131 of SEQ ID NO:70. X61012 is disclosed as SEQ ID NO: 70. FIG. 2 includes a disclosure of residues 1-23, 35-49, 57-88, and 102-111 of SEQ ID NO:71. AJ388641 is disclosed as SEQ ID NO:71. FIG. 3 includes a disclosure of the amino acid sequence as SEQ ID NO:72. FIG. 4 includes a disclosure of the amino acid sequence as SEQ ID NO:73. FIG. 5 includes a disclosure of residues 17-46, 52-65, 83-114, and 126-136 of SEQ ID NO:74. Z14189 is disclosed as SEQ ID NO:74. FIG. 6 includes a disclosure of residues 21-43, 55-69, 77-108, and 118-127 of SEQ ID NO:75. M29469 is disclosed as SEQ ID NO:75. FIG. 7 includes a disclosure of the amino acid sequence as SEQ ID NO:76. FIG.

8 includes a disclosure of the amino acid sequence as SEQ ID NO:77.

FIG. 13A-E show the synergistic effect of GSK2636771B and an anti-OX40 antibody in control of PTEN deficient tumors.

FIG. 14 shows the combination of GSK2636771B and an anti-OX40 antibody enhances the serum concentrations of CCL4, CXCL10 and IFN-g in mice bearing PTEN deficient tumors. FIG. 15 shows GSK2636771B plus anti-OX40 antibody treatment does not impair the proliferation of antigen-specific T cells in peripheral blood from vaccinated mice.

DETAILED DESCRIPTION OF THE INVENTION

The combination of an anti-OX40 agonist ABP and a PI3Kb inhibitor can be effective in treating a cancer. The combination can be effective in treating a cancer with loss of the PTEN tumor suppressor (e.g., loss of function or loss of expression (e.g., mRNA or protein)) (e.g., a PTEN deficient cancer, e.g., a PTEN deficient tumor).

Compositions and Combinations

An emerging immunotherapeutic strategy is to target T cell co-stimulatory molecules, e.g., 0X40. 0X40 (e.g., human 0X40 (hOX40) or hOX40R) is a tumor necrosis factor receptor family member that is expressed, among other cells, on activated CD4 and CD8 T cells. One of its functions is in the differentiation and long-term survival of these cells. The ligand for 0X40 (OX40L) is expressed by activated antigen-presenting cells. Not wishing to be bound by theory, the anti-OX40 ABPs (agonist anti-OX40 ABPs) of a combination of the invention, or a method or use thereof, modulate 0X40 and promote growth and/or differentiation of T cells and increase long-term memory T-cell populations, e.g., in overlapping mechanisms as those of OX40L, by "engaging" 0X40. The anti-OX40 ABPs of the invention may be agonist antibodies. Thus, in one embodiment of the ABPs of a combination of the invention, or a method or use thereof, bind and engage 0X40. In another embodiment, the anti-OX40 ABPs of a combination of the invention, or a method or use thereof, modulate 0X40. In a further embodiment, the ABPs of a combination of the invention, or a method or use thereof, modulate 0X40 by mimicking OX40L. In another embodiment, the anti-OX40 ABPs of a combination of the invention, or a method or use thereof, modulate 0X40 and cause proliferation of T cells. In a further embodiment, the anti-OX40 ABPs of a combination of the invention, or a method or use thereof, modulate 0X40 and improve, augment, enhance, or increase proliferation of CD4 T cells. In another embodiment, the anti-OX40 ABPs of a combination of the invention, or a method or use thereof, improve, augment, enhance, or increase proliferation of CD8 T cells. In a further embodiment, the anti-OX40 ABPs of a combination of the invention, or a method or use thereof, improve, augment, enhance, or increase proliferation of both CD4 and CD8 T cells. In another embodiment, the anti-OX40 ABPs of a combination of the invention, or a method or use thereof, enhance T cell function, e.g., of CD4 or CD8 T cells, or both CD4 and CD8 T cells. In a further embodiment, the anti-OX40 ABPs of a combination of the invention, or a method or use thereof, enhance effector T cell function. In another embodiment, the anti- 0X40 ABPs of a combination of the invention, or a method or use thereof, improve, augment, enhance, or increase long-term survival of CD8 T cells. In further embodiments, any of the preceding effects occur in a tumor microenvironment.

Not being bound by theory, of equal importance is the blockade of a potentially robust immunosuppressive response at the tumor site by mediators produced both by T regulatory cells (Tregs) as well as the tumor itself (e.g., Transforming Growth Factor (TGF- B) and interleukin-10 (IL-10)). Not wishing to be bound by theory, a key immune pathogenesis of cancer can be the involvement of Tregs that are found in tumor beds and sites of inflammation. In general, Treg cells occur naturally in circulation and help the immune system to return to a quiet, although vigilant state, after encountering and eliminating external pathogens. They help to maintain tolerance to self antigens and are naturally suppressive in function. They are phenotypically characterized as CD4+, CD25+, FOXP3+ cells. Not wishing to be bound by theory, in order to break tolerance to effectively treat certain cancers, one mode of therapy is to eliminate Tregs preferentially at tumor sites. Targeting and eliminating Tregs leading to an antitumor response has been more successful in tumors that are immunogenic compared to those that are poorly immunogenic. Many tumors secrete cytokines, e.g., TGF-B that may hamper the immune response by causing precursor CD4+25+ cells to acquire the FOXP3+ phenotype and function as Tregs.

"Modulate" as used herein, for example with regard to a receptor or other target means to change any natural or existing function of the receptor, for example it means affecting binding of natural or artificial ligands to the receptor or target; it includes initiating any partial or full conformational changes or signaling through the receptor or target, and also includes preventing partial or full binding of the receptor or target with its natural or artificial ligands. Also included in the case of membrane bound receptors or targets are any changes in the way the receptor or target interacts with other proteins or molecules in the membrane or change in any localization (or co-localization with other molecules) within membrane compartments as compared to its natural or unchanged state. Modulators are therefore compounds or ligands or molecules that modulate a target or receptor. Modulate includes agonizing, e.g., signaling, as well as antagonizing, or blocking signaling or interactions with a ligand or compound or molecule that happen in the unchanged or unmodulated state. Thus, modulators may be agonists or antagonists. Further, one of skill in the art will recognize that not all modulators will have absolute selectivity for one target or receptor, but are still considered a modulator for that target or receptor; for example, a modulator may also engage multiple targets. As used herein the term "agonist" refers to an antigen binding protein including but not limited to an antibody, which upon contact with a co-signalling receptor causes one or more of the following (1) stimulates or activates the receptor, (2) enhances, increases or promotes, induces or prolongs an activity, function or presence of the receptor (3) mimics one or more functions of a natural ligand or molecule that interacts with a target or receptor and includes initiating one or more signaling events through the receptor, mimicking one or more functions of a natural ligand, or initiating one or more partial or full conformational changes that are seen in known functioning or signaling through the receptor and/or (4) enhances, increases, promotes or induces the expression of the receptor. Agonist activity can be measured in vitro by various assays know in the art such as, but not limited to, measurement of cell signalling, cell proliferation, immune cell activation markers, and cytokine production. Agonist activity can also be measured in vivo by various assays that measure surrogate end points such as, but not limited to the measurement of T cell proliferation or cytokine production.

As used herein the term "antagonist" refers to an antigen binding protein including but not limited to an antibody, which upon contact with a co-signalling receptor causes one or more of the following (1) attenuates, blocks or inactivates the receptor and/or blocks activation of a receptor by its natural ligand, (2) reduces, decreases or shortens the activity, function or presence of the receptor and/or (3) reduces, descrease, abrogates the expression of the receptor. Antagonist activity can be measured in vitro by various assays know in the art such as, but not limited to, measurement of an increase or decrease in cell signalling, cell proliferation, immune cell activation markers, cytokine production. Antagonist activity can also be measured in vivo by various assays that measure surrogate end points such as, but not limited to the measurement of T cell proliferation or cytokine production.

Thus, in one embodiment, an agonist anti-OX40 ABP inhibits the suppressive effect of Treg cells on other T cells, e.g., within the tumor environment.

Accumulating evidence suggests that the ratio of Tregs to T effector cells in the tumor correlates with anti-tumor response. Therefore, in one embodiment, the 0X40 ABPs (anti-OX40 ABPs) of a combination of the invention, or a method or use thereof, modulate 0X40 to augment T effector number and function and inhibit Treg function.

Enhancing, augmenting, improving, increasing, and otherwise changing the antitumor effect of 0X40 is an object of a combination of the invention, or a method or use thereof. Described herein are combinations of an anti-OX40 ABP, or a method or use thereof, and another therapy for cancer, e.g., a PI3Kb inhibitor described herein. Thus, as used herein the term "combination of the invention" refers to a combination comprising an anti-OX40 ABP, suitably an agonist anti-OX40 ABP, and another treatment described herein, suitably a PI3Kb inhibitor as described herein.

As used herein, the terms "cancer,” "neoplasm," and "tumor," are used

interchangeably and in either the singular or plural form, refer to cells that have undergone a malignant transformation or undergone cellular changes that result in aberrant or unregulated growth or hyperproliferation. Such changes or malignant transformations usually make such cells pathological to the host organism, thus precancers or precancerous cells that are or could become pathological and require or could benefit from intervention are also intended to be included. Primary cancer cells (that is, cells obtained from near the site of malignant transformation) can be readily distinguished from non-cancerous cells by well-established techniques, particularly histological examination. The definition of a cancer cell, as used herein, includes not only a primary cancer cell, but any cell derived from a cancer cell ancestor. This includes metastasized cancer cells, and in vitro cultures and cell lines derived from cancer cells. When referring to a type of cancer that normally manifests as a solid tumor, a "clinically detectable" tumor is one that is detectable on the basis of tumor mass; e.g., by procedures such as CAT scan, MR imaging, X-ray, ultrasound or palpation, and/or which is detectable because of the expression of one or more cancer- specific antigens in a sample obtainable from a patient. In other words, the terms herein include cells, neoplasms, cancers, and tumors of any stage, including what a clinician refers to as precancer, tumors, in situ growths, as well as late stage metastatic growths. Tumors may be hematopoietic tumors, for example, tumors of blood cells or the like, meaning liquid tumors. Specific examples of clinical conditions based on such a tumor include leukemia such as chronic myelocytic leukemia or acute myelocytic leukemia; myeloma such as multiple myeloma; lymphoma and the like.

As used herein the term "agent" is understood to mean a substance that produces a desired effect in a tissue, system, animal, mammal, human, or other subject. Accordingly, the term "anti-neoplastic agent" is understood to mean a substance producing an antineoplastic effect in a tissue, system, animal, mammal, human, or other subject. It is also to be understood that an "agent" may be a single compound or a combination or composition of two or more compounds.

By the term "treating" and derivatives thereof as used herein, is meant therapeutic therapy. In reference to a particular condition, treating means: (1) to ameliorate the condition or one or more of the biological manifestations of the condition; (2) to interfere with (a) one or more points in the biological cascade that leads to or is responsible for the condition or (b) one or more of the biological manifestations of the condition; (3) to alleviate one or more of the symptoms, effects or side effects associated with the condition or one or more of the symptoms, effects or side effects associated with the condition or treatment thereof; (4) to slow the progression of the condition or one or more of the biological manifestations of the condition and/or (5) to cure said condition or one or more of the biological manifestations of the condition by eliminating or reducing to undetectable levels one or more of the biological manifestations of the condition for a period of time considered to be a state of remission for that manifestation without additional treatment over the period of remission. One skilled in the art will understand the duration of time considered to be remission for a particular disease or condition. Prophylactic therapy is also contemplated. The skilled artisan will appreciate that "prevention" is not an absolute term. In medicine, "prevention" is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof.

Prophylactic therapy is appropriate, for example, when a subject is considered at high risk for developing cancer, such as when a subject has a strong family history of cancer or when a subject has been exposed to a carcinogen.

As used herein, the term "effective amount" means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.

Furthermore, the term "therapeutically effective amount" means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.

The administration of a therapeutically effective amount of the combinations of the invention (or therapeutically effective amounts of each of the components of the combination) are advantageous over the individual component compounds in that the combinations provide one or more of the following improved properties when compared to the individual administration of a therapeutically effective amount of a component compound: i) a greater anticancer effect than the most active single agent, ii) synergistic or highly synergistic anticancer activity, iii) a dosing protocol that provides enhanced anticancer activity with reduced side effect profile, iv) a reduction in the toxic effect profile, v) an increase in the therapeutic window, or vi) an increase in the bioavailability of one or both of the component compounds. The invention further provides pharmaceutical compositions, which include one or more of the components herein, and one or more pharmaceutically acceptable carriers, diluents, or excipients. The combination of the invention may comprise two pharmaceutical compositions, one comprising an anti-OX40 ABP of the invention, suitably an agonist anti- 0X40 ABP, and the other comprising a PI3Kb inhibitor, each of which may have the same or different carriers, diluents or excipients. The carrier(s), diluent(s) or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation, capable of pharmaceutical formulation, and not deleterious to the recipient thereof.

The components of the combination of the invention, and pharmaceutical compositions comprising such components may be administered in any order, and in different routes; the components and pharmaceutical compositions comprising the same may be administered simultaneously.

In accordance with another aspect of the invention there is also provided a process for the preparation of a pharmaceutical composition including admixing a component of the combination of the invention and one or more pharmaceutically acceptable carriers, diluents or excipients.

The components of the invention may be administered by any appropriate route.

For some components, suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal, and parenteral (including intratumoral, subcutaneous,

intramuscular, intraveneous, intradermal, intrathecal, and epidural). It will be appreciated that the preferred route may vary with, for example, the condition of the recipient of the combination and the cancer to be treated. It will also be appreciated that each of the agents administered may be administered by the same or different routes and that the components may be compounded together or in separate pharmaceutical compositions.

In one embodiment, one or more components of a combination of the invention are administered systemically. In one embodiment, one or more components of a combination of the invention are administered parenterally. In one embodiment, one or more components of a combination of the invention are administered intravenously. In another embodiment, one or more components of a combination of the invention are administered intratumorally. In one embodiment, one or more components of a combination of the invention are administered orally. In another embodiment, one or more components of a combination of the invention are administered systemically, e.g., intravenously, and one or more other components of a combination of the invention are administered intratumorally.

In another embodiment, one or more components of a combination of the invention are administered systemically, e.g., orally, and one or more other components of a combination of the invention are administered intratumorally. In another embodiment, all of the components of a combination of the invention are administered systemically, e.g., intravenously. In an alternative embodiment, all of the components of the combination of the invention are administered intratumorally. In any of the embodiments, e.g., in this paragraph, the components of the invention are administered as one or more

pharmaceutical compositions.

Antigen Binding Proteins

"Antigen Binding Protein (ABP)" means a protein that binds an antigen, including antibodies or engineered molecules that function in similar ways to antibodies. Such alternative antibody formats include triabody, tetrabody, miniantibody, and a minibody. Also included are alternative scaffolds in which the one or more CDRs of any molecules in accordance with the disclosure can be arranged onto a suitable non-immunoglobulin protein scaffold or skeleton, such as an affibody, a SpA scaffold, an LDL receptor class A domain, an avimer (see, e.g., U.S. Patent Application Publication Nos. 2005/0053973, 2005/0089932, 2005/0164301) or an EGF domain. An ABP also includes antigen binding fragments of such antibodies or other molecules. Further, an ABP of a combination of the invention, or a method or use thereof, may comprise the variable heavy chain (VH) and variable light chain (VL) regions formatted into a full-length antibody, a (Fab')2 fragment, a Fab fragment, a bispecific or biparatopic molecule or equivalent thereof (such as scFV, bi- tri- or tetra-bodies, Tandabs etc.), when paired with an appropriate light chain. The ABP may comprise an antibody that is an IgGl, IgG2, IgG3, or IgG4; or IgM; IgA, IgE or IgD or a modified variant thereof. The constant domain of the antibody heavy chain may be selected accordingly.

The light chain constant domain may be a kappa or lambda constant domain. The ABP may also be a chimeric antibody of the type described in WO86/01533 which comprises an antigen binding region and a non-immunoglobulin region.

Flerein, the antigen that the 0X40 antigen binding protein (ABP) binds is 0X40 (e.g., human 0X40). The following terms are used herein interchangeably to mean an antigen binding protein that binds to 0X40: an anti-OX40 binding protein, an 0X40 ABP, an anti- 0X40 antigen binding protein, an anti-OX40 ABP, an 0X40 antigen binding protein, an antigen binding protein to 0X40, an ABP to 0X40.

Thus, herein an anti-OX40 ABP of a combination, or a method or use thereof, of the invention is one that binds 0X40 (e.g., human 0X40), and in preferred embodiments does one or more of the following: modulate signaling through 0X40, modulates the function of 0X40, agonize 0X40 signalling, stimulate 0X40 function, or co-stimulate 0X40 signaling. One of skill in the art would readily recognize a variety of well known assays to establish such functions.

The term "antibody" as used herein refers to molecules with an antigen binding domain, and optionally an immunoglobulin-like domain or fragment thereof and includes monoclonal (for example IgG, IgM, IgA, IgD or IgE and modified variants thereof), recombinant, polyclonal, chimeric, humanized, biparatopic, bispecific and heteroconjugate antibodies, or a closed conformation multispecific antibody. An "antibody" includes xenogeneic, allogeneic, syngeneic, or other modified forms thereof. An antibody may be isolated or purified. An antibody may also be recombinant, i.e. produced by recombinant means; for example, an antibody that is 90% identical to a reference antibody may be generated by mutagenesis of certain residues using recombinant molecular biology techniques known in the art. Thus, the antibodies of the present invention may comprise heavy chain variable regions and light chain variable regions of a combination of the invention, or a method or use thereof, which may be formatted into the structure of a natural antibody or formatted into a full length recombinant antibody, a (Fab 2 fragment, a Fab fragment, a bi-specific or biparatopic molecule or equivalent thereof (such as scFV, bi- tri- or tetra-bodies, Tandabs etc.), when paired with an appropriate light chain. The antibody may be an IgGl, IgG2, IgG3, or IgG4 or a modified variant thereof. The constant domain of the antibody heavy chain may be selected accordingly. The light chain constant domain may be a kappa or lambda constant domain. The antibody may also be a chimeric antibody of the type described in WO86/01533 which comprises an antigen binding region and a non-immunoglobulin region.

One of skill in the art will recognize that the anti-OX40 ABPs of a combination herein, or method or use therof, of the invention bind an epitope of 0X40. The epitope of an ABP is the region of its antigen to which the ABP binds. Two ABPs bind to the same or overlapping epitope if each competitively inhibits (blocks) binding of the other to the antigen. That is, a lx, 5x, lOx, 20x or lOOx excess of one antibody inhibits binding of the other by at least 50% but preferably 75%, 90% or even 99% as measured in a competitive binding assay compared to a control lacking the competing antibody (see, e.g., Junghans et al., Cancer Res. 50:1495, 1990, which is incorporated herein by reference). Alternatively, two antibodies have the same epitope if essentially all amino acid mutations in the antigen that reduce (e.g., by 50% 75%, 90% or even 99%, as compared to the level prior to making the mutation(s)) or eliminate binding of one antibody reduce or eliminate binding of the other. Also the same epitope may include "overlapping epitopes" e.g., if some amino acid mutations that reduce (e.g., by 50% 75%, 90% or even 99%, as compared to the level prior to making the mutation(s)) or eliminate binding of one antibody reduce (e.g., by 50% 75%, 90% or even 99%, as compared to the level prior to making the mutation(s)) or eliminate binding of the other.

The strength of binding may be important in dosing and administration of an ABP of the combination, or method or use thereof, of the invention. Affinity is the strength of binding of one molecule, e.g., an antibody of a combination of the invention, or a method or use thereof, to another, e.g., its target antigen, at a single binding site. The binding affinity of an antibody to its target may be determined by equilibrium methods (e.g., enzyme-linked immunoabsorbent assay (ELISA) or radioimmunoassay (RIA)), or kinetics (e.g., BIACORE analysis). For example, the BIACORE methods known in the art may be used to measure binding affinity. In one embodiment, the ABP of the invention binds its target (e.g., 0X40) with high affinity. For example, when measured by BIACORE, the antibody binds to 0X40, preferably human 0X40, with a KD of 1-lOOOnM or 500nM or less or a KD of 200nM or less or a KD of lOOnM or less or a KD of 50 nM or less or a KD of 500pM or less or a KD of 400pM or less, or 300pM or less. In a further aspect, the antibody binds to 0X40, preferably human 0X40, when measured by Biacore with a KD of between about 50nM and about 200nM or between about 50nM and about 150nM. In one aspect of the present invention the antibody binds 0X40, preferably human 0X40, with a KD of less than lOOnM. A skilled person will appreciate that the smaller the KD numerical value, the stronger the binding.

The reciprocal of KD (i.e. 1/KD) is the equilibrium association constant (KA) having units M ¹. A skilled person will appreciate that the larger the KA numerical value, the stronger the binding.

Avidity is the sum total of the strength of binding of two molecules to one another at multiple sites, e.g., taking into account the valency of the interaction.

The dissociation rate constant (kd) or "off-rate" describes the stability of the complex of the ABP on one hand and target (e.g., 0X40 or PD-1, preferably human 0X40) on the other hand, i.e., the fraction of complexes that decay per second. For example, a kd of 0.01 s ¹ equates to 1% of the complexes decaying per second. In an embodiment, the dissociation rate constant (kd) is lxlO ³ s ¹ or less, lxlO ⁴ s ¹ or less, lxlO ⁵ s ¹ or less, or lxlO ⁶ s ¹ or less. The kd may be between lxlO ⁵ s ¹ and lxlO ⁴ s ¹; or between lxlO ⁴ s ¹ and lxlO ³ s ¹.

Competition between an anti-OX40 ABP of a combination of the invention, or a method or use thereof, and a reference antibody, e.g., for binding 0X40 (e.g., human 0X40), an epitope of 0X40, or a fragment of the 0X40, may be determined by competition ELISA, FMAT or BIACORE. In one aspect, the competition assay is carried out by BIACORE. There are several possible reasons for this competition: the two proteins may bind to the same or overlapping epitopes, there may be steric inhibition of binding, or binding of the first protein may induce a conformational change in the antigen that prevents or reduces binding of the second protein.

"Binding fragments" as used herein means a portion or fragment of the ABPs of a combination of the invention, or a method or use thereof, that include the antigen-binding site and are capable of binding 0X40 as defined herein.

Functional fragments of the ABPs of a combination of the invention, or a method or use thereof, are contemplated herein.

Thus, "binding fragments" and "functional fragments" may be an Fab and F(ab')2 fragments which lack the Fc fragment of an intact antibody, clear more rapidly from the circulation, and may have less non-specific tissue binding than an intact antibody (Wahl et al., J. Nuc. Med. 24:316-325 (1983)). Also included are Fv fragments (Flochman, J. et al. Biochemistry 12:1130-1135 (1973); Sharon, J. et al. Biochemistry 15: 1591-1594 (1976)). These various fragments are produced using conventional techniques such as protease cleavage or chemical cleavage (see, e.g., Rousseaux et al., Meth. Enzymol., 121 :663-69 (1986)).

"Functional fragments" as used herein means a portion or fragment of the ABPs of a combination of the invention, or a method or use thereof, that include the antigen-binding site and are capable of binding the same target as the parent ABP, e.g., but not limited to binding the same epitope, and that also retain one or more modulating or other functions described herein or known in the art.

As the ABPs of the present invention may comprise heavy chain variable regions and light chain variable regions of a combination of the invention, or a method or use thereof, which may be formatted into the structure of a natural antibody, a functional fragment is one that retains binding or one or more functions of the full length ABP as described herein. A binding fragment of an ABP of a combination of the invention, or a method or use thereof, may therefore comprise the VL or VH regions, a (Fab')2 fragment, a Fab fragment, a fragment of a bi-specific or biparatopic molecule or equivalent thereof (such as scFV, bi- trior tetra-bodies, Tandabs etc.), when paired with an appropriate light chain.

The term "CDR" as used herein, refers to the complementarity determining region amino acid sequences of an antigen binding protein. These are the hypervariable regions of immunoglobulin heavy and light chains. There are three heavy chain and three light chain CDRs (or CDR regions) in the variable portion of an immunoglobulin. It will be apparent to those skilled in the art that there are various numbering conventions for CDR sequences; Chothia (Chothia et al. Nature 342:877-883 (1989)), Kabat (Kabat et al., Sequences of Proteins of Immunological Interest, 4th Ed., U.S. Department of Health and Human Services, National Institutes of Health (1987)), AbM (University of Bath) and Contact (University College London). The minimum overlapping region using at least two of the Kabat, Chothia, AbM and contact methods can be determined to provide the "minimum binding unit". The minimum binding unit may be a subportion of a CDR. The structure and protein folding of the antibody may mean that other residues are considered part of the CDR sequence and would be understood to be so by a skilled person. It is noted that some of the CDR definitions may vary depending on the individual publication used.

Unless otherwise stated and/or in absence of a specifically identified sequence, references herein to "CDR", "CDRL1" (or "LC CDR1"), "CDRL2" (or "LC CDR2"), "CDRL3" (or "LC CDR3"), "CDRH1" (or "HC CDR1"), "CDRH2" (or "HC CDR2"), "CDRH3" (or "HC CDR3") refer to amino acid sequences numbered according to any of the known conventions;

alternatively, the CDRs are referred to as "CDR1," "CDR2," "CDR3" of the variable light chain and "CDR1,""CDR2," and "CDR3" of the variable heavy chain. In particular embodiments, the numbering convention is the Kabat convention.

The term "CDR variant" as used herein, refers to a CDR that has been modified by at least one, for example 1, 2 or 3, amino acid substitution(s), deletion(s) or addition(s), wherein the modified antigen binding protein comprising the CDR variant substantially retains (e.g., by 50% 75%, 90% or even 99%, as compared to the level prior to making the modification(s)) the biological characteristics of the antigen binding protein pre-modification. It will be appreciated that each CDR that can be modified may be modified alone or in combination with another CDR. In one aspect, the modification is a substitution, particularly a conservative substitution, for example as shown in Table A.

Table A

For example, in a variant CDR, the amino acid residues of the minimum binding unit may remain the same, but the flanking residues that comprise the CDR as part of the Kabat or Chothia definition(s) may be substituted with a conservative amino acid residue. Such antigen binding proteins comprising modified CDRs or minimum binding units as described above may be referred to herein as "functional CDR variants" or "functional binding unit variants".

The antibody may be of any species, or modified to be suitable to administer to a cross species. For example the CDRs from a mouse antibody may be humanized for administration to humans. In any embodiment, the antigen binding protein is optionally a humanized antibody.

A "humanized antibody" refers to a type of engineered antibody having its CDRs derived from a non-human donor immunoglobulin, the remaining immunoglobulin-derived parts of the molecule being derived from one (or more) human immunoglobulin(s). In addition, framework support residues may be altered to preserve binding affinity (see, e.g., Queen et al., Proc. Natl Acad Sci USA, 86:10029-10032 (1989), Hodgson et al.,

Bio/Technology, 9:421 (1991)). A suitable human acceptor antibody may be one selected from a conventional database, e.g., the KABAT® database, Los Alamos database, and Swiss Protein database, by homology to the nucleotide and amino acid sequences of the donor antibody. A human antibody characterized by a homology to the framework regions of the donor antibody (on an amino acid basis) may be suitable to provide a heavy chain constant region and/or a heavy chain variable framework region for insertion of the donor CDRs. A suitable acceptor antibody capable of donating light chain constant or variable framework regions may be selected in a similar manner. It should be noted that the acceptor antibody heavy and light chains are not required to originate from the same acceptor antibody. The prior art describes several ways of producing such humanised antibodies - see for example EP-A-0239400 and EP-A-054951.

In yet a further embodiment, the humanized antibody has a human antibody constant region that is an IgG. In another embodiment, the IgG is a sequence as disclosed in any of the above references or patent publications.

For nucleotide and amino acid sequences, the term "identical" or "identity" indicates the degree of identity between two nucleic acid or two amino acid sequences when optimally aligned and compared with appropriate insertions or deletions.

The percent sequence identity between two sequences is a function of the number of identical positions shared by the sequences (i.e., % identity = number of identical positions/total number of positions multiplied by 100), taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences. The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm, as described below.

Percent identity between a query nucleic acid sequence and a subject nucleic acid sequence is the "Identities" value, expressed as a percentage, which is calculated by the BLASTN algorithm when a subject nucleic acid sequence has 100% query coverage with a query nucleic acid sequence after a pair-wise BLASTN alignment is performed. Such pairwise BLASTN alignments between a query nucleic acid sequence and a subject nucleic acid sequence are performed by using the default settings of the BLASTN algorithm available on the National Center for Biotechnology Institute's website with the filter for low complexity regions turned off. Importantly, a query nucleic acid sequence may be described by a nucleic acid sequence identified in one or more claims herein.

Percent identity between a query amino acid sequence and a subject amino acid sequence is the "Identities" value, expressed as a percentage, which is calculated by the BLASTP algorithm when a subject amino acid sequence has 100% query coverage with a query amino acid sequence after a pair-wise BLASTP alignment is performed. Such pairwise BLASTP alignments between a query amino acid sequence and a subject amino acid sequence are performed by using the default settings of the BLASTP algorithm available on the National Center for Biotechnology Institute's website with the filter for low complexity regions turned off. Importantly, a query amino acid sequence may be described by an amino acid sequence identified in one or more claims herein.

In any embodiment of a combination of the invention, or a method or use thereof, herein, the ABP may have any one or all CDRs, VH, VL, heavy chain (HC), light chain (LC), with 99, 98, 97, 96, 95, 94, 93, 92, 91, or 90, or 85, or 80, or 75, or 70 percent identity to the sequence shown or referenced, e.g., as defined by a SEQ ID NO disclosed herein.

With respect to an antibody, the percent identity can be over the entire VL or LC sequence or the percent identity can be confined to the framework regions, while the sequences that correspond to CDRs have 100% identity to the disclosed CDRs within the VL or LC.

With respect to an antibody, the percent identity can be over the entire VH or HC sequence or the percent identity can be confined to the framework regions, while the sequences that correspond to CDRs have 100% identity to the disclosed CDRs within the VH or HC. Antigen Binding Proteins that Bind 0X40

ABPs that bind human 0X40 (also referred to as human 0X40 receptor) are provided herein (i.e., an anti-OX40 ABP and an anti-human 0X40 receptor (hOX-40R) ABP, sometimes referred to herein as an "anti-OX40 ABP" or "0X40 antigen binding protein" or "0X40 binding protein", such as an "anti- 0X40 antibody"). These ABPs, such as antibodies, are useful in the treatment or prevention of acute or chronic diseases or conditions whose pathology involves 0X40 signalling, e.g., an increase or decrease thereof, e.g., a decrease thereof. In one aspect, an antigen binding protein, or isolated human antibody or functional fragment of such protein or antibody, that binds to human 0X40 and is effective as a cancer treatment or treatment as otherwise described herein, for example in combination with another compound such as a PI3Kb inhibitor, e.g, a PI3Kb inhibitor described herein. Any of the antigen binding proteins or antibodies disclosed herein may be used as a medicament. Any one or more of the antigen binding proteins or antibodies may be used in the methods or compositions to treat cancer, e.g., those disclosed herein. The anti-OX40 ABPs are agonist ABPs, e.g., agonist antibodies, e.g., agonists of 0X40 (i.e., of 0X40 receptor (OX40R)).

The isolated ABPs, such as antibodies, as described herein bind to 0X40, and may bind to 0X40 encoded from the following genes: NCBI Accession Number NP_003317, Genpept Accession Number P23510, or genes having 90 percent homology or 90 percent identity thereto. The isolated antibody provided herein may further bind to 0X40 (0X40 receptor) having one of the following Gen Bank Accession Numbers: AAB39944, CAE11757, or AAI05071.

Antigen binding proteins such as antibodies that bind and/or modulate 0X40 (OX-40 receptor, 0X40 receptor, human 0X40, human 0X40 receptor) are known in the art.

Exemplary anti-OX40 ABPs of a combination of the invention, or a method or use thereof, are disclosed, for example in International Publication No. WO2013/028231

(PCT/US2012/024570), international filing date 9 February 2012, and WO2012/027328 (PCT/US2011/048752), international filing date 23 August 2011, each of which is incorporated by reference in its entirety herein (To the extent any definitions conflict, this instant application controls).

In one embodiment, the 0X40 antigen binding protein is ANTIBODY 106-222 (HC of SEQ ID NO: 48 and LC of SEQ ID NO:49). In another embodiment, the antigen binding protein comprises the CDRs (SEQ ID NOS: 1-3 and 7-9) of ANTIBODY 106-222, or CDRs with at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the CDR sequences thereof. In a further embodiment the antigen binding protein comprises a VH (SEQ ID NO: 5), a VL (SEQ ID NO: 11), or both of ANTIBODY 106-222 (i.e. humanized 106-222), or a VH or a VL with at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the VH or VL sequences thereof.

In one embodiment, the 0X40 antigen binding protein is ANTIBODY 119-122. In another embodiment, the antigen binding protein comprises the CDRs of ANTIBODY 119- 122 (SEQ ID NOS: 13-15 and 19-21), or CDRs with at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the CDR sequences thereof. In a further embodiment the antigen binding protein comprises a VH (SEQ ID NO:17), a VL (SEQ ID NO:23), or both of ANTIBODY 119-122, or a VH or a VL with at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the VH or VL sequences thereof. In a further embodiment the antigen binding protein comprises a humanized VH, a VL, or both of ANTIBODY 119-122, or a VH or a VL with at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the humanized VH or VL sequences thereof.

In one embodiment, the 0X40 antigen binding protein is ANTIBODY 119-43-1. In another embodiment, the antigen binding protein comprises the CDRs of ANTIBODY 119-43- 1 (SEQ ID NOS:25-27 and 32-34), or CDRs with at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the CDR sequences thereof. In a further embodiment the antigen binding protein comprises a VH, a VL, or both of ANTIBODY 119-43-1, or a VH or a VL with at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the VH or VL sequences thereof.

In one embodiment, the 0X40 antigen binding protein is MEDI6469; MEDI6383; MEDI0562; MOXR0916 (RG7888); PF-04518600; BMS986178; or INCAGN01949. In another embodiment, the antigen binding protein comprises the CDRs of MEDI6469; MEDI6383; MEDI0562; MOXR0916 (RG7888); PF-04518600; BMS986178; or INCAGN01949, or CDRs with at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the CDR sequences thereof. In a further embodiment the antigen binding protein comprises a VH, a VL, or both of MEDI6469; MEDI6383; MEDI0562; MOXR0916 (RG7888); PF-04518600; BMS986178; or INCAGN01949, or a VH or a VL with at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the VH or VL sequences thereof.

In one embodiment, the 0X40 antigen binding protein is MEDI6469. In another embodiment, the antigen binding protein comprises the CDRs of MEDI6469, or CDRs with at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the CDR sequences thereof. In a further embodiment the antigen binding protein comprises a VH, a VL, or both of MEDI6469, or a VH or a VL with at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the VH or VL sequences thereof.

In one embodiment, the 0X40 antigen binding protein is MEDI6383. In another embodiment, the antigen binding protein comprises the CDRs of MEDI6383, or CDRs with at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the CDR sequences thereof. In a further embodiment the antigen binding protein comprises a VH, a VL, or both of MEDI6383, or a VH or a VL with at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the VH or VL sequences thereof.

In one embodiment, the 0X40 antigen binding protein is MEDI0562. In another embodiment, the antigen binding protein comprises the CDRs of MEDI0562, or CDRs with at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the CDR sequences thereof. In a further embodiment the antigen binding protein comprises a VH, a VL, or both of MEDI0562, or a VH or a VL with at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the VH or VL sequences thereof.

In one embodiment, the 0X40 antigen binding protein is MOXR0916 (RG7888). In another embodiment, the antigen binding protein comprises the CDRs of MOXR0916 (RG7888), or CDRs with at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the CDR sequences thereof. In a further embodiment the antigen binding protein comprises a VH, a VL, or both of MOXR0916 (RG7888), or a VH or a VL with at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the VH or VL sequences thereof.

In one embodiment, the 0X40 antigen binding protein is PF-04518600. In another embodiment, the antigen binding protein comprises the CDRs of PF-04518600, or CDRs with at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the CDR sequences thereof. In a further embodiment the antigen binding protein comprises a VH, a VL, or both of PF-04518600, or a VH or a VL with at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the VH or VL sequences thereof.

In one embodiment, the 0X40 antigen binding protein is BMS986178. In another embodiment, the antigen binding protein comprises the CDRs of BMS986178, or CDRs with at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the CDR sequences thereof. In a further embodiment the antigen binding protein comprises a VH, a VL, or both of BMS986178, or a VH or a VL with at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the VH or VL sequences thereof.

In one embodiment, the 0X40 antigen binding protein is INCAGN01949. In another embodiment, the antigen binding protein comprises the CDRs of INCAGN01949, or CDRs with at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the CDR sequences thereof. In a further embodiment the antigen binding protein comprises a VH, a VL, or both of INCAGN01949, or a VH or a VL with at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the VH or VL sequences thereof.

In one embodiment, the 0X40 antigen binding protein is one disclosed in

WO2015/153513. In another embodiment, the antigen binding protein comprises the CDRs of an antibody disclosed in WO2015/153513, or CDRs with at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the disclosed CDR sequences. In a further embodiment the antigen binding protein comprises a VH, a VL, or both of an antibody disclosed in WO2015/153513, or a VH or a VL with at least 90%

(e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the disclosed VH or VL sequences.

In one embodiment, the 0X40 antigen binding protein is one disclosed in

W02013/038191. In another embodiment, the antigen binding protein comprises the CDRs of an antibody disclosed in W02013/038191, or CDRs with at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the disclosed CDR sequences. In a further embodiment the antigen binding protein comprises a VH, a VL, or both of an antibody disclosed in W02013/038191, or a VH or a VL with at least 90%

In one embodiment, the 0X40 antigen binding protein is one disclosed in

WO2012/027328 (PCT/US2011/048752), international filing date 23 August 2011. In another embodiment, the antigen binding protein comprises the CDRs of an antibody disclosed in WO2012/027328 (PCT/US2011/048752), international filing date 23 August 2011, or CDRs with at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the disclosed CDR sequences. In a further embodiment the antigen binding protein comprises a VH, a VL, or both of an antibody disclosed in WO2012/027328 (PCT/US2011/048752), international filing date 23 August

2011, or a VH or a VL with at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the disclosed VH or VL sequences.

In another embodiment, the 0X40 antigen binding protein is one disclosed in WO2013/028231 (PCT/US2012/024570), international filing date 9 February 2012. In another embodiment, the antigen binding protein comprises the CDRs of an antibody disclosed in WO2013/028231 (PCT/US2012/024570), international filing date 9 February

2012, or CDRs with at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,

98%, 99%, or 100%) sequence identity to the disclosed CDR sequences. In a further embodiment the antigen binding protein comprises a VH, a VL, or both of an antibody disclosed in WO2013/028231 (PCT/US2012/024570), international filing date 9 February 2012, or a VH or a VL with at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the disclosed VH or VL sequences.

Figures 1-12 show sequences of the anti-OX40 ABPs of a combination of the invention, or a method or use thereof, e.g., CDRs and VH and VL sequences of the ABPs. In another embodiment, the anti-OX40 ABP of a combination of the invention, or a method or use thereof, comprises one or more of the CDRs or VH or VL sequences, or sequences with at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity thereto, shown in the Figures herein. FIG.l includes a disclosure of residues 1-30, 36-49, 67-98, and 121-131 of SEQ ID NO:70. X61012 is disclosed as SEQ ID NO: 70. FIG. 2 includes a disclosure of residues 1-23, 35-49, 57-88, and 102-111 of SEQ ID NO:71. AJ388641 is disclosed as SEQ ID NO:71. FIG. 3 includes a disclosure of the amino acid sequence as SEQ ID NO:72. FIG. 4 includes a disclosure of the amino acid sequence as SEQ ID NO:73. FIG. 5 includes a disclosure of residues 17-46, 52-65, 83-114, and 126-136 of SEQ ID NO:74. Z14189 is disclosed as SEQ ID NO:74. FIG. 6 includes a disclosure of residues 21-43, 55-69, 77-108, and 118-127 of SEQ ID NO:75. M29469 is disclosed as SEQ ID NO:75. FIG. 7 includes a disclosure of the amino acid sequence as SEQ ID NO:76. FIG.

8 includes a disclosure of the amino acid sequence as SEQ ID NO:77.

FIG. 1 shows the alignment of the amino acid sequences of murine 106-222, humanized 106-222 (Hul06), and human acceptor X61012 (Gen Bank accession number) VH sequences. Amino acid residues are shown in single letter code. Numbers above the sequences indicate the locations according to Kabat et al. (Sequences of Proteins of Immunological Interests, Fifth edition, NIH Publication No. 91-3242, U.S. Department of Health and Human Services, 1991). In FIG. 1, CDR sequences defined by Kabat et al.

(1991) are underlined in 106-222 VH. CDR residues in X61012 VH are omitted in the figure. Human VH sequences homologous to the 106-222 VH frameworks were searched for within the GenBank database, and the VH sequence encoded by the human X61012 cDNA (X61012 VH) was chosen as an acceptor for humanization. The CDR sequences of 106-222 VH were first transferred to the corresponding positions of X61012 VH. Next, at framework positions where the three-dimensional model of the 106-222 variable regions suggested significant contact with the CDRs, amino acid residues of mouse 106-222 VH were substituted for the corresponding human residues. These substitutions were performed at positions 46 and 94 (underlined in Hul06 VH). In addition, a human framework residue that was found to be atypical in the corresponding V region subgroup was substituted with the most typical residue to reduce potential immunogenicity. This substitution was performed at position 105 (double-underlined in Hul06 VH).

FIG. 2 shows alignment of the amino acid sequences of murine 106-222, humanized 106-222 (Hul06), and human acceptor AJ388641 (GenBank accession number) VL sequences. Amino acid residues are shown in single letter code. Numbers above the sequences indicate the locations according to Kabat et al. (1991). CDR sequences defined by Kabat et al. are underlined in 106-222 VH. CDR residues in AJ388641 VL are omitted in the figure. Human VL sequences homologous to the 106-222 VL frameworks were searched for within the GenBank database, and the VL sequence encoded by the human AJ388641 cDNA (AJ388641 VL) was chosen as an acceptor for humanization. The CDR sequences of 106-222 VL were transferred to the corresponding positions of AJ388641 VL. No framework substitutions were performed in the humanized form.

FIG. 3 shows the nucleotide sequence of the Hul06 VH gene flanked by Spel and Hindlll sites (underlined) along with the deduced amino acid sequence. Amino acid residues are shown in single letter code. The signal peptide sequence is in italic. The N- terminal amino acid residue (Q) of the mature VH is double-underlined. CDR sequences according to the definition of Kabat et al. (1991) are underlined. The intron sequence is in italic.

FIG. 4 shows the nucleotide sequence of the Hul06-222 VL gene flanked by Nhel and EcoRI sites (underlined) along with the deduced amino acid sequence. Amino acid residues are shown in single letter code. The signal peptide sequence is in italic. The N- terminal amino acid residue (D) of the mature VL is double-underlined. CDR sequences according to the definition of Kabat et al. (1991) are underlined. The intron sequence is in italic.

FIG. 5 shows the alignment of the amino acid sequences of 119-122, humanized 119-122 (Hull9), and human acceptor Z14189 (GenBank accession number) VH sequences. Amino acid residues are shown in single leter code. Numbers above the sequences indicate the locations according to Kabat et al. (Sequences of Proteins of Immunological Interests, Fifth edition, NIH Publication No. 91-3242, U.S. Department of Health and Human Services, 1991). CDR sequences defined by Kabat et al. (1991) are underlined in 119-122 VH. CDR residues in Z14189 VH are omited in the figure. Human VH sequences homologous to the 119-122 VH frameworks were searched for within the GenBank database, and the VH sequence encoded by the human Z14189 cDNA (Z14189 VH) was chosen as an acceptor for humanization. The CDR sequences of 119-122 VH were first transferred to the

corresponding positions of Z14189 VH. Next, at framework positions where the three- dimensional model of the 119-122 variable regions suggested significant contact with the CDRs, amino acid residues of mouse 119-122 VH were substituted for the corresponding human residues. These substitutions were performed at positions 26, 27, 28, 30 and 47 (underlined in the Hull9 VH sequence) as shown on the figure.

FIG. 6 shows the alignment of the amino acid sequences of 119-122, humanized 119-122 (Hull9), and human acceptor M29469 (GenBank accession number) VL sequences. Amino acid residues are shown in single leter code. Numbers above the sequences indicate the locations according to Kabat et al. (1991). CDR sequences defined by Kabat et al. (1) are underlined in 119-122 VL. CDR residues in M29469 VL are omitted in the sequence. Human VL sequences homologous to the 119-122 VL frameworks were searched for within the GenBank database, and the VL sequence encoded by the human M29469 cDNA (M29469 VL) was chosen as an acceptor for humanization. The CDR sequences of 119-122 VL were transferred to the corresponding positions of M29469 VL. No framework substitutions were needed in the humanized form.

FIG. 7 shows the nucleotide sequence of the Hull9 VH gene flanked by Spel and Hindlll sites (underlined) along with the deduced amino acid sequence. Amino acid residues are shown in single leter code. The signal peptide sequence is in italic. The N- terminal amino acid residue (E) of the mature VH is double-underlined. CDR sequences according to the definition of Kabat et al. (1991) are underlined. The intron sequence is in italic.

FIG. 8 shows the nucleotide sequence of the Hull9 VL gene flanked by Nhel and EcoRI sites (underlined) along with the deduced amino acid sequence. Amino acid residues are shown in single leter code. The signal peptide sequence is in italic. The N-terminal amino acid residue (E) of the mature VL is double-underlined. CDR sequences according to the definition of Kabat et al. (1991) are underlined. The intron sequence is in italic. FIG. 9 shows the nucleotide sequence of mouse 119-43-1 VH cDNA along with the deduced amino acid sequence. Amino acid residues are shown in single letter code. The signal peptide sequence is in italic. The N-terminal amino acid residue (E) of the mature VH is double-underlined. CDR sequences according to the definition of Kabat et al. (Sequences of Proteins of Immunological Interests, Fifth edition, NIH Publication No. 91-3242, U.S. Department of Health and Human Services, 1991) are underlined.

FIG. 10 shows the nucleotide sequence of mouse 119-43-1 VL cDNA along with the deduced amino acid sequence. Amino acid residues are shown in single letter code. The signal peptide sequence is in italic. The N-terminal amino acid residue (D) of the mature VL is double-underlined. CDR sequences according to the definition of Kabat et al. (1991) are underlined.

FIG. 11 shows the nucleotide sequence of the designed 119-43-1 VH gene flanked by Spel and Hindlll sites (underlined) along with the deduced amino acid sequence. Amino acid residues are shown in single letter code. The signal peptide sequence is in italic. The N-terminal amino acid residue (E) of the mature VH is double-underlined. CDR sequences according to the definition of Kabat et al. (1991) are underlined. The intron sequence is in italic.

FIG. 12 shows the nucleotide sequence of the designed 119-43-1 VL gene flanked by Nhel and EcoRI sites (underlined) along with the deduced amino acid sequence. Amino acid residues are shown in single letter code. The signal peptide sequence is in italic. The N- terminal amino acid residue (D) of the mature VL is double-underlined. CDR sequences according to the definition of Kabat et al. (1991) are underlined. The intron sequence is in italic.

In one embodiment, the anti-OX40 ABP of a combination of the invention, or a method or use thereof, comprises the CDRs of the 106-222 antibody, e.g., CDRH1, CDRH2, and CDRH3 having the amino acid sequence as set forth in SEQ ID NOS:l, 2, and 3, and e.g., CDRL1, CDRL2, and CDRL3 having the sequences as set forth in SEQ ID NOS:7, 8, and 9 respectively. In one embodiment, the ABP of a combination of the invention, or a method or use thereof, comprises the CDRs of the 106-222, Hul06 or Hul06-222 antibody as disclosed in WO2012/027328 (PCT/US2011/048752), international filing date 23 August 2011.

As described herein, ANTIBODY 106-222 is a humanized monoclonal antibody that binds to human 0X40 as disclosed in WO2012/027328 and described herein as an antibody comprising CDRH1, CDRH2, and CDRH3 having the amino acid sequence as set forth in SEQ ID NOS:l, 2, and 3, and e.g., CDRL1, CDRL2, and CDRL3 having the sequences as set forth in SEQ ID NOS:7, 8, and 9, respectively and an antibody comprising VH having an amino acid sequence as set forth in SEQ ID NO: 5 and a VL having an amino acid sequence as set forth in SEQ ID NO: 11.

In a further embodiment, the anti-OX40 ABP of a combination of the invention, or a method or use thereof, comprises the VH and VL regions of the 106-222 antibody as shown in FIG. 6 and FIG. 7 herein, e.g., a VH having an amino acid sequence as set forth in SEQ ID NO:4 and a VL having an amino acid sequence as set forth in SEQ ID NO:10. In another embodiment, the ABP of a combination of the invention, or a method or use thereof, comprises a VH having an amino acid sequence as set forth in SEQ ID NO: 5, and a VL having an amino acid sequence as set forth in SEQ ID NO: ll. In a further embodiment, the anti-OX40 ABP of a combination of the invention, or a method or use thereof, comprises the VH and VL regions of the 106-222 antibody or the Hul06 antibody as disclosed in

WO2012/027328 (PCT/US2011/048752), international filing date 23 August 2011. In a further embodiment, the anti-OX40 ABP of a combination of the invention, or a method or use thereof, is 106-222, Hul06-222 or Hul06, e.g., as disclosed in WO2012/027328 (PCT/US2011/048752), international filing date 23 August 2011. In a further embodiment, the ABP of a combination of the invention, or a method or use thereof, comprises CDRs or VH or VL or antibody sequences with at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the sequences in this paragraph.

In another embodiment, the anti-OX40 ABP of a combination of the invention, or a method or use thereof, comprises the CDRs of the 119-122 antibody, e.g., CDRH1, CDRH2, and CDRH3 having the amino acid sequence as set forth in SEQ ID NOs: 13, 14, and 15 respectively. In another embodiment, the anti-OX40 ABP of a combination of the invention, or a method or use thereof, comprises the CDRs of the murine 119-122 or Hull9 or Hull9- 222 antibody as disclosed in WO2012/027328 (PCT/US2011/048752), international filing date 23 August 2011. In a further embodiment, the anti-OX40 ABP of a combination of the invention, or a method or use thereof, comprises a VH having an amino acid sequence as set forth in SEQ ID NO: 16, and a VL having the amino acid sequence as set forth in SEQ ID NO:22. In another embodiment, the anti-OX40 ABP of a combination of the invention, or a method or use thereof, comprises a VH having an amino acid sequence as set forth in SEQ ID NO: 17 and a VL having the amino acid sequence as set forth in SEQ ID NO:23. In a further embodiment, the anti-OX40 ABP of a combination of the invention, or a method or use thereof, comprises the VH and VL regions of the murine 119-122 or Hull9 or Hull9- 222 antibody as disclosed in WO2012/027328 (PCT/US2011/048752), international filing date 23 August 2011. In a further embodiment, the ABP of a combination of the invention, or a method or use thereof, is murine 119-222 or Hull9 or Hull9-222 antibody, e.g., as disclosed in WO2012/027328 (PCT/US2011/048752), international filing date 23 August 2011. In a further embodiment, the ABP comprises CDRs or VH or VL or antibody sequences with at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the sequences in this paragraph.

In another embodiment, the anti-OX40 ABP of a combination of the invention, or a method or use thereof, comprises the CDRs of the 119-43-1 antibody as disclosed in WO2013/028231 (PCT/US2012/024570), international filing date 9 February 2012. In another embodiment, the anti-OX40 ABP of a combination of the invention, or a method or use thereof, comprises the CDRs of the 119-43-1 antibody as disclosed in WO2013/028231 (PCT/US2012/024570), international filing date 9 February 2012. In a further embodiment, the anti-OX40 ABP of a combination of the invention, or a method or use thereof, comprises one of the VH and one of the VL regions of the 119-43-1 antibody. In a further

embodiment, the anti-OX40 ABP of a combination of the invention, or a method or use thereof, comprises the VH and VL regions of the 119-43-1 antibody as disclosed in

WO2013/028231 (PCT/US2012/024570), international filing date 9 February 2012. In a further embodiment, the anti-OX40 ABP of a combination of the invention, or a method or use thereof, is murine 119-43-1 or 119-43-1 chimeric. In a further embodiment, the anti- 0X40 ABP of a combination of the invention, or a method or use thereof, as disclosed in WO2013/028231 (PCT/US2012/024570), international filing date 9 February 2012. In further embodiments, any one of the anti-OX40 ABPs described in this paragraph are humanized. In further embodiments, any one of the ABPs described in this paragraph are engineered to make a humanized antibody. In a further embodiment, the anti-OX40 ABP of a combination of the invention, or a method or use thereof, comprises CDRs or VH or VL or antibody sequences with at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the sequences in this paragraph.

In another embodiment, further embodiment, any mouse or chimeric sequences of any anti-OX40 ABP of a combination of the invention, or a method or use thereof, are engineered to make a humanized antibody.

In one embodiment, the anti-OX40 ABP of a combination of the invention, or a method or use thereof, comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:l; (b) a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:2; (c) a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:3; (d) a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:7; (e) a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:8; and (f) a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:9.

In another embodiment, the anti-OX40 ABP of a combination of the invention, or a method or use thereof, comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 13; (b) a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 14; (c) a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 15; (d) a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 19; (e) a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:20; and (f) a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:21.

In another embodiment, the anti-OX40 ABP of a combination of the invention, or a method or use thereof, comprises: a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:l or 13; a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:2 or 14; and/or a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:3 or 15, or a heavy chain variable region CDR having 90 percent identity thereto.

In another embodiment, the anti-OX40 ABP of a combination of the invention, or a method or use thereof, comprises: a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:7 or 19; a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:8 or 20 and/or a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:9 or 21, or a heavy chain variable region having 90 percent identity thereto.

In another embodiment, the anti-OX40 ABP of a combination of the invention, or a method or use thereof, comprises: a light chain variable region ("VL") comprising the amino acid sequence of SEQ ID NO: 10, 11, 22 or 23, or an amino acid sequence with at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the amino acid sequences of SEQ ID NO: 10, 11, 22 or 23. In another embodiment, the anti-OX40 ABP of a combination of the invention, or a method or use thereof, comprises a heavy chain variable region ("VH") comprising the amino acid sequence of SEQ ID NO:4, 5, 16 or 17, or an amino acid sequence with at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the amino acid sequences of SEQ ID NO:4, 5, 16 or 17. In another embodiment, the anti- 0X40 ABP of a combination of the invention, or a method or use thereof, comprises a variable heavy sequence of SEQ ID NO: 5 and a variable light sequence of SEQ ID NO: 11, or a sequence having 90 (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) percent sequence identity thereto. In another embodiment, the anti-OX40 ABP of a combination of the invention, or a method or use thereof, comprises a variable heavy sequence of SEQ ID NO: 17 and a variable light sequence of SEQ ID NO:23 or a sequence having 90 (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) percent sequence identity thereto.

In another embodiment, the anti-OX40 ABP of a combination of the invention, or a method or use thereof, comprises a variable light chain encoded by the nucleic acid sequence of SEQ ID NO: 12, or 24, or a nucleic acid sequence with at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the nucleotide sequences of SEQ ID NO: 12 or 24. In another embodiment, the anti-OX40 ABP of a combination of the invention, or a method or use thereof, comprises a variable heavy chain encoded by a nucleic acid sequence of SEQ ID NO:6 or 18, or a nucleic acid sequence with at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to nucleotide sequences of SEQ ID NO:6 or 18.

Also provided herein are monoclonal antibodies. In one embodiment, the monoclonal antibodies comprise a variable light chain comprising the amino acid sequence of SEQ ID NO:10 or 22, or an amino acid sequence with at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the amino acid sequences of SEQ ID NO: 10 or 22. Further provided are monoclonal antibodies comprising a variable heavy chain comprising the amino acid sequence of SEQ ID NO:4 or 16, or an amino acid sequence with at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the amino acid sequences of SEQ ID NO:4 or 16.

In one embodiment, the monoclonal antibodies comprise a variable light chain comprising the amino acid sequence of SEQ ID NO: 11 or 23, or an amino acid sequence with at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the amino acid sequences of SEQ ID NO:ll or 23. Further provided are monoclonal antibodies comprising a variable heavy chain comprising the amino acid sequence of SEQ ID NO:5 or 17, or an amino acid sequence with at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the amino acid sequences of SEQ ID NO:5 or 17.

In one embodiment, the monoclonal antibodies comprise a variable light chain comprising the amino acid sequence of SEQ ID NO: 11, or an amino acid sequence with at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the amino acid sequence of SEQ ID NO:ll. Further provided are monoclonal antibodies comprising a variable heavy chain comprising the amino acid sequence of SEQ ID NO:5, or an amino acid sequence with at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the amino acid sequences of SEQ ID NO:5.

Further provided are monoclonal antibodies comprising a variable light chain comprising the amino acid sequence of SEQ ID NO: 11, or an amino acid sequence with at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the amino acid sequences of SEQ ID NO: ll, and a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 5, or an amino acid sequence with at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the amino acid sequences of SEQ ID NO:5.

In one embodiment, the monoclonal antibodies comprise a light chain comprising the amino acid sequence of SEQ ID NO:49, or an amino acid sequence with at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the amino acid sequences of SEQ ID NO:49. Further provided are monoclonal antibodies comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:48, or an amino acid sequence with at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the amino acid sequences of SEQ ID NO:48.

Further provided are monoclonal antibodies comprising a ight chain comprising the amino acid sequence of SEQ ID NO:49, or an amino acid sequence with at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the amino acid sequence of SEQ ID NO:49, and a heavy chain comprising the amino acid sequence of SEQ ID NO:48, or an amino acid sequence with at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to the amino acid sequences of SEQ ID NO:48.

Heavy Chain of ANTIBODY 106-222:

QVQLVQSGSELKKPGASVKVSCKASGYTFTDYSMHWVRQAPGQGLKWMGWINTETGEP

TYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCANPYYDYVSYYAMDYWGQGTTVT

VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ

SSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLG

GPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY

NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDE LTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:48)

Light Chain of ANTIBODY 106-222:

DIQMTQSPSSLSASVGDRVTITCKASQDVSTAVAWYQQKPGKAPKLLIYSASYLYTGVPSR FSGSGSGTDFTFTISSLQPEDIATYYCQQHYSTPRTFGQGTKLEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:49)

Heavy Chain Variable Region of ANTIBODY 106-222:

QVQLVQSGSELKKPGASVKVSCKASGYTFTDYSMHWVRQAPGQGLKWMGWINTETGEP TYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCANPYYDYVSYYAMDYWGQGTTVT VSS (SEQ ID NO:5)

Light Chain Variable Region of ANTIBODY 106-222:

DIQMTQSPSSLSASVGDRVTITCKASQDVSTAVAWYQQKPGKAPKLLIYSASYLYTGVPSR FSGSGSGTDFTFTISSLQPEDIATYYCQQHYSTPRTFGQGTKLEIK (SEQ ID NO:11)

CDR sequences of ANTIBODY 106-222:

HC CDR1 : Asp Tyr Ser Met His (SEQ ID NO:1)

HC CDR2: Trp lie Asn Thr Glu Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe Lys Gly (SEQ ID NO:2)

HC CDR3: Pro Tyr Tyr Asp Tyr Val Ser Tyr Tyr Ala Met Asp Tyr (SEQ ID NO:3)

LC CDR1 : Lys Ala Ser Gin Asp Val Ser Thr Ala Val Ala (SEQ ID NO:7)

LC CDR2: Ser Ala Ser Tyr Leu Tyr Thr (SEQ ID NO:8)

LC CDR3: Gin Gin His Tyr Ser Thr Pro Arg Thr (SEQ ID NO:9)

PI3Kb Inhibitors

PI3Kb inhibitors (also referred to as RI3Kb inhibitors) are provided herein. These PI3Kb inhibitors are useful in the treatment or prevention of acute or chronic diseases or conditions whose pathology involves PI3Kb activity. In one aspect, a PI3Kb inhibitor effective as a cancer treatment or treatment against disease is described, for example in combination with another agent such as an anti-OX40 ABP, suitably an agonist anti-OX40 ABP, e.g., an agonist anti-OX40 ABP described herein. Any of the PI3Kb inhibitors disclosed herein may be used as a medicament. Any one or more of the PI3Kb inhibitors may be used in the methods or compositions to treat cancer, e.g., those disclosed herein. See also PCT Publication No. WO 2012/047538 and U.S. Patent No. 8,435,988.

In some aspects, the PI3Kb inhibitor is a compound of Formula (II):

wherein

R1 is selected from H, Ci-ealkyl, alkoxy, hydroxy, halogen, -CN, -NH₂, -NHC(0)Ra, - NHSChRa, -CO₂H, -C0₂Ra, -CONHRb, -CONH₂, -CH₂OH, and heteroaryl wherein the heteroaryl may be substituted by one or two Ci-₃alkyl groups;

R2 is selected from H, -NHRa, alkoxy, halogen, -CF₃, -CHF₂, and Ci-ealkyl;

R4 is selected from FI or Ra;

each R5 is independently selected from Ci-ealkyl;

each Ra is independently selected from Ci-₃alkyl;

Rb is selected from FI, Ci-₃alkyl, and SChMe;

or a pharmaceutically acceptable salt thereof.

In some embodiments, the the aryl or heteroaryl of R3 are selected from phenyl, naphthyl, benzothienyl, quinolinyl, isoquinolinyl, and quinazolinyl.

In some embodiments, the each Rc is independently Ci-₃alkyl, F or Cl, and n is 0.

In some embodiments, the each Rc is independently CF₃ or F, and n is 0.

In some embodiments, the PI3Kb inhibitor has the Formula (II)(C):

wherein

each of R6, R7, and R8 is independently selected from Ci-₃alkyl, halogen, - CF₃, and hydroxyl, or R6 and R7 combine to form a bi-cyclic aryl or heteroaryl, or R7 and R8 combine to form a bi-cyclic aryl or heteroaryl;

In some embodiments, the PI3Kb inhibitor has the Formula (II)(D):

(II)(D).

In some embodiments, the PI3Kb inhibitor has the Formula (II)(E):

wherein

In some embodiments, the PI3Kb inhibitor is:

4-ol,

1-[(2,3-dichlorophenyl)methyl]-2-ethyl-6-(4-morpholinyl)-lH-benzimidazol-4-ol,

4-fluoro-2-methyl-6-(4-morpholinyl)-l-(l-naphthalenylmethyl)-lH-benzimidazole,

2-ethyl-4-fluoro-6-(4-morpholinyl)-l-(l-naphthalenylmethyl)-lH-benzimidazole,

l-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-2-

(trifluoromethyl)-lH-benzimidazole-4-carboxamide,

l-[(2,3-dichlorophenyl)methyl]-6-(4-morpholinyl)-4-(lH-l,2,4-triazol-3-yl)-2-

(trifluoromethyl)-lH-benzimidazole,

4-bromo-2-methyl-6-(4-morpholinyl)-lH-benzimidazole,

methyl 2-(difluoromethyl)-5-(4-morpholinyl)-lH-benzimidazole-7-carboxylate,

(4-morpholinyl)-lH-benzimidazole,

or a pharmaceutically acceptable salt thereof.

In some embodiments, the PI3Kb inhibitor is 2-methyl-l-{[2-methyl-3- (trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-lH-benzimidazole-4-carboxylic acid (GSK2636771), or a pharmaceutically acceptable salt thereof. In some embodiments, the PI3Kb inhibitor is 2-methyl-l-{[2-methyl-3- (trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-lH-benzimidazole-4-carboxylic acid 2- amino-2-(hydroxymethyl)-l, 3-propanediol salt (GSK2636771B).

PTEN

Phosphatase and tensin homolog (PTEN) is 47-kDa protein and was first identified as a candidate tumor suppressor gene in 1997 after its positional cloning from a region of chromosome 10q23 known to exhibit loss in a wide spectrum of tumor types. Since then, mutations of PTEN have been detected in a variety of human cancers including breast, thyroid, glioblastoma, endometrial, and prostate cancer, and melanoma. Inherited mutations in this gene also predispose carriers to develop Cowden's disease, a heritable cancer risk syndrome, and several related conditions. PTEN is classified as a tumor suppressor because its activity is lost by deletion, mutation, or through epigenetic changes. Molecular mechanistic studies of PTEN have provided a great deal of insight into the basis for its involvement in tumor suppression. The PTEN protein has both protein phosphatase and lipid phosphatase activity. Although the tumor suppressive function of PTEN has mainly been attributed to its lipid phosphatase activity, a role for PTEN protein phosphatase activity in cell-cycle regulation and inhibition of cell invasion in vitro has been suggested as well. Loss of PTEN function seems to be responsible for many of the phenotypic features of melanoma, thus PTEN may serve as a potential target for drug development. However, most types of tumors with PTEN alteration also carry other genetic changes, making the role of PTEN more ambiguous. As discussed below, PTEN homozygous deletions and missense mutations alone are sufficient to cause tumorigenesis in certain tissues but not in others. However, even when mutation of PTEN alone has minimal effects, it frequently contributes to tumorigenesis in the context of other genetic alterations. See Aguissa-Toure et al., Cellular and Molecular Life Sciences 69: 1475-1491 (2012).

T cell-mediated immunotherapies are promising cancer treatments. However, many patients still fail to respond to these therapies. The molecular determinants of immune resistance are poorly understood. Loss of PTEN in tumor cells in preclinical models of melanoma inhibits T cell-mediated tumor killing and decreases T-cell trafficking into tumors. In patients (e.g., subjects), PTEN loss correlates with decreased T-cell infiltration at tumor sites, reduced likelihood of successful T-cell expansion from resected tumors, and inferior outcomes with PD-1 inhibitor therapy. PTEN loss in tumor cells increased the expression of immunosuppressive cytokines, resulting in decreased T-cell infiltration in tumors, and inhibited autophagy, which decreased T cell-mediated cell death. Treatment with a selective RI3Kb (PI3Kb) inhibitor can improve the efficacy of both anti-PD-1 and anti-CTLA-4 antibodies in murine models. These findings demonstrate that PTEN loss promotes immune resistance and support the rationale to explore combinations of immunotherapies and PI3K- AKT pathway inhibitors. See Peng et al., Cancer Discovery 6:202-216 (2016).

The PI3K pathway plays a critical role in cancer by regulating several critical cellular processes, including proliferation and survival. One of the most common ways that this pathway is activated in cancer is by loss of expression of the tumor suppressor PTEN, which is a lipid phosphatase that dampens the activity of PI3K signaling. Loss of PTEN corresponds with increased activation of the PI3K-AKT pathway in multiple tumor types. Loss of PTEN occurs in up to 30% of melanomas, frequently in tumors with a concurrent activating BRAF mutation. Id.

A combination of an anti-OX40 agonist ABP and a PI3Kb inhibitor can be useful to treat a cancer in a subject (e.g., patient) (e.g., mammal, e.g., human). In some aspects, the subject to be treated with a combination of an anti-OX40 agonist ABP and a PI3Kb inhibitor has a cancer with loss of expression of the PTEN tumor suppressor (e.g., a subject with a PTEN deficient cancer, e.g., a PTEN deficient tumor).

PTEN deficiency and assays for PTEN deficiency determination

The combinations of the invention are believed to have utility in disorders wherein the engagement of 0X40 (e.g., agonistic engagement, e.g., with an agonist antibody, e.g., an agonist antibody described herein) and/or PI3Kb inhibition is beneficial, e.g., for the treatment of a cancer with loss of expression of the PTEN tumor suppressor (e.g., a PTEN deficient cancer, e.g., a PTEN deficient tumor).

As used herein, "PTEN deficient" or "PTEN deficiency" refers to a cancer with a deficiency of the tumor suppressor function of PTEN, e.g., loss of expression of the PTEN tumor supporessor. Such deficiency includes mutation in the PTEN gene, reduction or absence of PTEN protein when compared to PTEN wild-type, or mutation or absence of other genes that cause suppression of PTEN function. It includes PTEN activity or expression lost by deletion, mutation, or through epigenetic changes. Multiple mechanisms exist for the regulation of PTEN, including transcription, mRNA stability, microRNA (miRNA) targeting, translation, and protein stability. PTEN is transcriptionally silenced by promoter methylation in endometrial, gastric, lung, thyroid, breast and ovarian tumors, as well as glioblastoma. Mutations resulting in the loss of function or reduced levels of PTEN, as well as PTEN deletions or alteration are found in many sporadic tumors. See Aguissa-Toure et al., supra. PTEN deficiency can be determined by methods such as Q-PCR or ELISA or immunohistochemistry. Human PTEN qPCR primer pairs are commercially available, e.g., from Sino Biological and Genecopoeia. A PTEN (Human) ELISA kit is commercially available, e.g., from BioVision and Abeam. An immunohistochemistry protocol is provided, e.g., in Sakr et al., Appl Immunohistochem Mol Morphol. 18:371-374 (2010)_and Peng et al., supra. Antibodies are commercially available, e.g., from Abeam and Sino Biological.

For reference, the human PTEN mRNA sequence is NCBI Accession No.

NM_000314.4; the protein sequence is NCBI Accession No. AAH05821.1.

Methods of Treatment

The combinations of the invention are believed to have utility in disorders wherein the engagement of 0X40 (e.g., human 0X40) (e.g., agonistic engagement, e.g., with an agonist antibody, e.g., an agonist antibody described herein) and/or PI3Kb inhibition (e.g., with a PI3Kb inhibitor described herein) is beneficial, e.g., for the treatment of a cancer, e.g., a cancer with loss of expression of the PTEN tumor suppressor (e.g., a PTEN deficient cancer, e.g., a PTEN deficient tumor).

The present invention thus also provides an anti-OX40 agonist ABP and a PI3Kb inhibitor, e.g., a combination of the invention, for use in therapy, particularly in the treatment of disorders wherein the engagement of 0X40 (e.g., human 0X40) (e.g., agonistic engagement, e.g., with an agonist antibody, e.g., an agonist antibody described herein) and/or PI3Kb inhibition is beneficial, e.g., for the treatment of a cancer, e.g., a cancer with loss of expression of the PTEN tumor suppressor (e.g., a PTEN deficient cancer, e.g., a PTEN deficient tumor).

In some aspects, the cancer comprises a PTEN deficient cancer.

In some aspects, a subject or a cancer from the subject (e.g., patient) (e.g., mammal, e.g., human) is identified as having a PTEN deficient cancer.

In some aspects, a subject or a cancer from the subject (e.g., patient) (e.g., mammal, e.g., human) is selected on the basis of having a PTEN deficient cancer.

In some aspects, a subject or a cancer from the subject (e.g., patient) (e.g., mammal, e.g., human) (e.g., in a sample) is evaluated to determine whether the cancer is PTEN deficient. In some embodiments, the evaluation comprises Q-PCR. In some embodiments, the evaluation comprises an ELISA.

A further aspect of the invention provides a method of treatment of a disorder (e.g., for the treatment of a cancer, a cancer with loss of expression of the PTEN tumor suppressor (e.g., a PTEN deficient cancer, e.g., a PTEN deficient tumor) wherein engagement of 0X40 (e.g., agonistic engagement, e.g., with an agonist antibody, e.g., an agonist antibody described herein) and/or PI3Kb inhibition is beneficial, comprising administering an anti-OX40 agonist ABP and a PI3Kb inhibitor, e.g., a combination of the invention.

In some aspects, the cancer comprises a PTEN deficient cancer.

In some aspects, a subject or a cancer from the subject (e.g., patient) (e.g., mammal, e.g., human) (e.g., in a sample) is selected on the basis of having a PTEN deficient cancer.

In some aspects, a subject (e.g., patient) (e.g., mammal, e.g., human) or a cancer from the subject is evaluated to determine whether the cancer is PTEN deficient. In some embodiments, the evaluation comprises Q-PCR. In some embodiments, the evaluation comprises an ELISA.

A further aspect of the present invention provides the use of an anti-OX40 agonist ABP and a PI3Kb inhibitor, e.g., a combination of the invention in the manufacture of a medicament for the treatment of a disorder wherein engagement of 0X40 (e.g., agonistic engagement, e.g., with an agonist antibody, e.g., an agonist antibody described herein) and/or PI3Kb inhibition, is beneficial, e.g., for the treatment of a cancer, e.g., a cancer with loss of expression of the PTEN tumor suppressor (e.g., a PTEN deficient cancer, e.g., a PTEN deficient tumor).

An anti-OX40 agonist ABP and a PI3Kb inhibitor, e.g., the combinations of the invention are believed to have utility in disorders wherein the engagement of 0X40 (e.g., agonistic engagement, e.g., with an agonist antibody, e.g., an agonist antibody described herein) and/or PI3Kb inhibition (e.g., with an inhibitor described herein), is beneficial, e.g., for the treatment of a cancer, e.g., a cancer with loss of expression of the PTEN tumor suppressor (e.g., a PTEN deficient cancer, e.g., a PTEN deficient tumor).

The present invention thus also provides an anti-OX40 agonist ABP and a PI3Kb inhibitor, e.g., a combination of the invention, for use in therapy, particularly in the treatment of disorders wherein the engagement of 0X40 (e.g., agonistic engagement, e.g., with an agonist antibody, e.g., an agonist antibody described herein) and/or PI3Kb inhibition (e.g., with an inhibitor described herein), is beneficial, e.g., for the treatment of a cancer, e.g., a cancer with loss of expression of the PTEN tumor suppressor (e.g., a PTEN deficient cancer, e.g., a PTEN deficient tumor).

A further aspect of the invention provides a method of treatment of a disorder (e.g., for the treatment of a cancer, e.g., a cancer with loss of expression of the PTEN tumor suppressor (e.g., a PTEN deficient cancer, e.g., a PTEN deficient tumor)) wherein engagement of 0X40 (e.g., agonistic engagement, e.g., with an agonist antibody, e.g., an agonist antibody described herein) and/or PI3Kb inhibition (e.g., with an inhibitor described herein), is beneficial, comprising administering an anti-OX40 agonist ABP and a PI3Kb inhibitor, e.g., a combination of the invention.

A further aspect of the present invention provides the use of an anti-OX40 agonist ABP and a PI3Kb inhibitor, e.g., a combination of the invention in the manufacture of a medicament for the treatment of a disorder engagement of 0X40 (e.g., agonistic engagement, e.g., with an agonist antibody, e.g., an agonist antibody described herein) and/or PI3Kb inhibition (e.g., with an inhibitor described herein), is beneficial, e.g., for the treatment of a cancer, e.g., a cancer with loss of expression of the PTEN tumor suppressor (e.g., a PTEN deficient cancer, e.g., a PTEN deficient tumor).

The combinations of the invention are believed to have utility in disorders wherein the engagement of 0X40 (e.g., agonistic engagement, e.g., with an agonist antibody, e.g., an agonist antibody described herein) and/or PI3Kb inhibition (e.g., with an inhibitor described herein), is beneficial, e.g., for the treatment of a cancer, e.g., a cancer with loss of expression of the PTEN tumor suppressor (e.g., a PTEN deficient cancer, e.g., a PTEN deficient tumor).

The present invention thus also provides a combination of the invention, for use in therapy, particularly in the treatment of disorders wherein the engagement of 0X40 (e.g., agonistic engagement, e.g., with an agonist antibody, e.g., an agonist antibody described herein) and/or PI3Kb inhibition (e.g., with an inhibitor described herein), is beneficial, e.g., for the treatment of a cancer, e.g., a cancer with loss of expression of the PTEN tumor suppressor (e.g., a PTEN deficient cancer, e.g., a PTEN deficient tumor).

A further aspect of the invention provides a method of treatment of a disorder (e.g., for the treatment of a cancer, e.g., a cancer with loss of expression of the PTEN tumor suppressor (e.g., a PTEN deficient cancer, e.g., a PTEN deficient tumor)) wherein engagement of 0X40 (e.g., agonistic engagement, e.g., with an agonist antibody, e.g., an agonist antibody described herein) and/or PI3Kb inhibition (e.g., with an inhibitor described herein) is benefical, e.g., for the treatment of a cancer, e.g., a cancer with loss of expression of the PTEN tumor suppressor (e.g., a PTEN deficient cancer, e.g., a PTEN deficient tumor), comprising administering a combination of the invention.

A further aspect of the present invention provides the use of a combination of the invention in the manufacture of a medicament for the treatment of a disorder engagement of 0X40 (e.g., agonistic engagement, e.g., with an agonist antibody, e.g., an agonist antibody described herein) and/or PI3Kb inhibition (e.g., with an inhibitor described herein) is beneficial, e.g., for the treatment of a cancer, e.g., a cancer with loss of expression of the PTEN tumor suppressor (e.g., a PTEN deficient cancer, e.g., a PTEN deficient tumor).

In some embodiments, the cancer is a solid cancer, e.g, a tumor, e.g., a PTEN deficient solid cancer or a PTEN deficient tumor.

In one embodiment, the present invention provides methods of treating cancer in a mammal in need thereof comprising administering a therapeutically effective amount of an antigen binding protein that binds 0X40 and a PI3Kb inhibitor. In some aspects, the cancer is a solid tumor. The cancer is selected from the group consisting of: breast, thyroid, glioblastoma, endometrial, and prostate cancer, and melanoma. In another aspect the cancer is a liquid tumor.

In one embodiment, the antigen binding protein that binds 0X40 and the PI3Kb inhibitor are administered at the same time. In another embodiment, the antigen binding protein that binds 0X40 and the PI3Kb inhibitor are administered sequentially, in any order. In one aspect, the antigen binding protein that binds 0X40 and/or the PI3Kb inhibitor are administered systemically, e.g., intravenously or orally. In another aspect, the antigen binding protein that binds 0X40 and/or the PI3Kb inhibitor are administered intratumorally. In another aspect, the PI3Kb inhibitor is administered orally. In another aspect, the PI3Kb inhibitor is administered intratumorally. In another aspect, the PI3Kb inhibitor is administered systemically, e.g., intravenously. In another aspect, the antigen binding protein that binds 0X40 is administered intratumorally. In another aspect, the antigen binding protein that binds OX40is administered systemically, e.g., intravenously.

In one embodiment, the mammal is human.

Methods are provided wherein the tumor size of the cancer in said mammal is reduced by more than an additive amount compared with treatment with the antigen binding protein to 0X40 or the PI3Kb inhibitor as used as a monotherapy. Suitably the combination may be synergistic.

In one embodiment, the antigen binding protein that binds 0X40 binds to human 0X40. In one embodiment, the antigen binding protein that binds 0X40 is a humanized monoclonal antibody. In one embodiment, the antigen binding protein that binds 0X40 is a fully human monoclonal antibody.

In one embodiment, the antigen binding protein that binds 0X40 is an antibody with an IgGl isotype or variant thereof. In one embodiment, the antigen binding protein that binds 0X40 is an antibody with an IgG4 isotype or variant thereof. In one aspect, the antigen binding protein that binds 0X40 is an agonist antibody. Suitably, the antigen binding protein that binds 0X40 comprises: a heavy chain variable region CDR1 comprising an amino acid sequence with at least 90% 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:l or 13; a heavy chain variable region CDR2 comprising an amino acid sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO:2 or 14; and/or a heavy chain variable region CDR3 comprising an amino acid sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO:3 or 15.

Suitably, the antigen binding protein that binds 0X40 comprises a light chain variable region CDR1 comprising an amino acid sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO:7 or 19; a light chain variable region CDR2 comprising an amino acid sequence with at least at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO:8 or 20 and/or a light chain variable region CDR3 comprising an amino acid sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO:9 or 21.

Suitably, the antigen binding protein that binds 0X40 comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:l; (b) a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:2; (c) a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:3; (d) a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:7; (e) a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:8; and (f) a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:9.

Suitably, the antigen binding protein that binds 0X40 comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 13; (b) a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 14; (c) a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 15; (d) a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 19;

(e) a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:20; and (f) a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:21.

Suitably, the antigen binding protein that binds 0X40 comprises a light chain variable region ("VL") comprising an amino acid sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO:10, 11, 22 or 23. Suitably, the antigen binding protein that binds 0X40 comprises a heavy chain variable region ("VH") comprising an amino acid sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO:4, 5, 16 or 17. Suitably, the antigen binding protein that binds 0X40 comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 5 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:ll.

Suitably, the antigen binding protein that binds 0X40 comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 17 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:23.

Suitably, the antigen binding protein that binds 0X40 comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 11 or 23, or an amino acid sequence with at least 90% sequence identity to the amino acid sequences of SEQ ID NO: 11 or 23. Suitably, the antigen binding protein that binds 0X40 comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:5 or 17, or an amino acid sequence with at least 90% sequence identity to the amino acid sequences of SEQ ID NO:5 or 17.

In one aspect, the mammal has increased survival when treated with a

therapeutically effective amount of an antigen binding protein to 0X40 and a therapeutically effective amount of a PI3Kb inhibitor compared with a mammal who received the antigen binding protein to 0X40 as a monotherapy or the PI3Kb inhibitor as monotherapy. In one aspect, the methods further comprise administering at least one anti-neoplastic agent to the mammal in need thereof.

In one embodiment, pharmaceutical compositions are provided comprising a therapeutically effective amount of an antigen binding protein that binds 0X40 (e.g., an agonist antibody to human 0X40 described herein) and a therapeutically effective amount of a PI3Kb inhibitor (e.g., a PI3Kb inhibitor described herein). In one embodiment, two pharmaceutical compositions for use in a combination described herein (e.g., in a method of treatment or use described herein) are provided; the first pharmaceutical composition of the combination comprising a therapeutically effective amount of an antigen binding protein that binds 0X40 (e.g., an agonist antibody to human 0X40 described herein) and the second pharmaceutical composition of the combination comprising a therapeutically effective amount of a PI3Kb inhibitor (e.g., a PI3Kb inhibitor described herein). In one embodiment, the pharmaceutical compositions comprise, or the first pharmaceutical composition comprises, an antibody comprising an antigen binding protein that binds 0X40 comprising a CDRH1 having an amino acid sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: l, a CDRH2 having an amino acid sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO:2, a CDRH3 having an amino acid sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO:3, a CDRL1 having an amino acid sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%,

97%, 98%, 99% or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO:7, a CDRL2 having an amino acid sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO:8, a CDRL3 having an amino acid sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO:9; and the pharmaceutical compositions further comprise, or the second pharmaceutical composition comprises, a PI3Kb inhibitor described herein, e.g., 2-methyl-l-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4- morpholinyl)-lH-benzimidazole-4-carboxylic acid, or a pharmaceutically acceptable salt thereof, such as 2-methyl-l-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4- morpholinyl)-lH-benzimidazole-4-carboxylic acid 2-amino-2-(hydroxymethyl)-l,3- propanediol salt.

In one embodiment, the pharmaceutical compositions comprise, or the first pharmaceutical composition comprises, an antibody comprising a VH region having a sequence at least with a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO:4 or 5 and VL having a sequence at least with a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO: 10 or 11, and the pharmaceutical compositions further comprise, or the second pharmaceutical composition comprises, a PI3Kb inhibitor described herein, e.g., 2-methyl-l-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-lH- benzimidazole-4-carboxylic acid, or a pharmaceutically acceptable salt thereof, such as 2- methyl-l-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-lH-benzimidazole- 4-carboxylic acid 2-amino-2-(hydroxymethyl)-l, 3-propanediol salt. Also provided in the present invention is the use of a combination or pharmaceutical compositions of this invention in the manufacture of a medicament for the treatment of cancer. Also provided are the use of pharmaceutical compositions of the present invention for treating cancer. The present invention also provides a combination kit comprising pharmaceutical compositions of the invention together with one or more pharmaceutically acceptable carriers.

In one embodiment methods and uses are provided for reducing tumor size in a human having cancer comprising administering a therapeutically effective amount of an agonist antibody to human 0X40 (e.g., an agonist antibody to human 0X40 described herein) and a therapeutically effective amount of a PI3Kb inhibitor (e.g., a PI3Kb inhibitor described herein).

Examples of cancers that are suitable for treatment with a combination of the invention include, but are limited to, both primary and metastatic forms of head and neck, breast, lung, colon, ovary, and prostate cancers. Suitably the cancer is selected from: brain (gliomas), glioblastomas, astrocytomas, glioblastoma multiforme, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, inflammatory breast cancer, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid, lymphoblastic T cell leukemia, Chronic myelogenous leukemia, Chronic lymphocytic leukemia, Hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, AML, Chronic neutrophilic leukemia, Acute lymphoblastic T cell leukemia, plasmacytoma, Immunoblastic large cell leukemia, Mantle cell leukemia, Multiple myeloma Megakaryoblastic leukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia, Erythroleukemia, malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, lung cancer, vulval cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer,

nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor) and testicular cancer.

Additionally, examples of a cancer to be treated include Barret's adenocarcinoma; billiary tract carcinomas; breast cancer; cervical cancer; cholangiocarcinoma; central nervous system tumors including primary CNS tumors such as glioblastomas, astrocytomas (e.g., glioblastoma multiforme) and ependymomas, and secondary CNS tumors (i.e., metastases to the central nervous system of tumors originating outside of the central nervous system); colorectal cancer including large intestinal colon carcinoma; gastric cancer; carcinoma of the head and neck including squamous cell carcinoma of the head and neck; hematologic cancers including leukemias and lymphomas such as acute lymphoblastic leukemia, acute myelogenous leukemia (AML), myelodysplastic syndromes, chronic myelogenous leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, megakaryoblastic leukemia, multiple myeloma and erythroleukemia; hepatocellular carcinoma; lung cancer including small cell lung cancer and non-small cell lung cancer; ovarian cancer; endometrial cancer; pancreatic cancer; pituitary adenoma; prostate cancer; renal cancer; sarcoma; skin cancers including melanomas; and thyroid cancers.

Suitably, the present invention relates to a method for treating or lessening the severity of a cancer selected from the group consisting of: brain (gliomas), glioblastomas, astrocytomas, glioblastoma multiforme, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast cancer, colon cancer, head and neck cancer, kidney cancer, lung cancer, liver cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma and thyroid cancer.

Suitably, the present invention relates to a method for treating or lessening the severity of a cancer selected from the group consisting of: ovarian, breast cancer, pancreatic cancer and prostate cancer.

Suitably, the present invention relates to a method for treating or lessening the severity of non-small cell lung carcinoma (NSCLC), small cell lung cancer (SCLC), bladder cancer or metastatic hormone-refractory prostate cancer.

Suitably, the present invention relates to a method for treating or lessening the severity of breast, thyroid, glioblastoma, endometrial, or prostate cancer, or melanoma.

Suitably, the present invention relates to a method for treating or lessening the severity of melanoma.

Suitably, the present invention relates to a method for treating or lessening the severity of prostate cancer.

Suitably, the present invention relates to a method for treating or lessening the severity of lung cancer.

Suitably the present invention relates to a method for treating or lessening the severity of pre-cancerous syndromes in a mammal, including a human, wherein the pre- cancerous syndrome is selected from: cervical intraepithelial neoplasia, monoclonal gammapathy of unknown significance (MGUS), myelodysplastic syndrome, aplastic anemia, cervical lesions, skin nevi (pre-melanoma), prostatic intraepithleial (intraductal) neoplasia (PIN), Ductal Carcinoma in situ (DCIS), colon polyps and severe hepatitis or cirrhosis. In each case, the cancer to be treated may be characterized by loss of expression of the PTEN tumor suppressor (e.g., a PTEN deficient cancer, e.g., a PTEN deficient tumor).

The combination of the invention may be used alone or in combination with one or more other therapeutic agents. The invention thus provides in a further aspect a further combination comprising a combination of the invention with a further therapeutic agent or agents, compositions and medicaments comprising the combination and use of the further combination, compositions and medicaments in therapy, in particular in the treatment of diseases susceptible engagement of 0X40 (e.g., agonism of 0X40) and PI3Kb inhibition.

In the embodiment, the combination of the invention may be employed with other therapeutic methods of cancer treatment (e.g., another (e.g., further) anti-cancer therapy). In particular, in anti-neoplastic therapy, combination therapy with other chemotherapeutic, hormonal, antibody agents as well as surgical and/or radiation treatments other than those mentioned above are envisaged. Combination therapies according to the present invention thus include the administration of an anti-OX40 ABP of a combination, or method or use thereof, of the invention and a PI3Kb inhibitor of a combination, or method or use thereof, of the invention as well as optional use of other therapeutic agents including other antineoplastic agents. The term "combination" refers to the use of the two or more therapies to treat the same patient (subject) for a reason(s) related to the same indication (e.g., the therapies of the combination are used to treat the same indication or an indication and side effect(s) or symptom(s) related thereto), wherein the use or actions of the therapies overlap in time. The therapies can be administered at the same time (e.g., as a single formulation that is administered to a patient or as two (or more) separate formulations or treatments administered concurrently) or sequentially in any order. Sequential administrations are administrations that are given at different times. The time between administration of the one therapy and another therapy can be minutes, hours, days, or weeks. For example, the time between administration of the one therapy and another therapy is 12, 24, 36, 48, 60, 72, 84, or 96 hours. For example, the time between administration of an anti-OX40 ABP and radiotherapy is 12, 24, 36, 48, 60, 72, 84, or 96 hours. For example, an anti-OX40 ABP can be administered 12, 24, 36, 48, 60, 72, 84, or 96 hours after a PI3Kb inhibitor is administered. As another example, a PI3Kb inhibitor can be administered 12, 24, 36, 48,

60, 72, 84, or 96 hours after an anti-OX40 ABP is administered.

A further anti-cancer therapy can be administered with the anti-OX40 ABP and the PI3Kb inhibitor (simultaneously or sequentially, in any order).

In one embodiment, the further anti-cancer therapy is surgical therapy (e.g., surgery) and/or radiotherapy. In one embodiment, the further anti-cancer therapy is surgery.

In some embodiments, the futher anti-cancer therapy is radiotherapy (also referred to as irradiation and radiation therapy). In some embodiments, the radiation therapy used in combination with an anti-OX40 ABP (e.g., an agonist antibody, e.g., an agonist antibody described herein) and a PI3Kb inhibitor (e.g., a PI3Kb inhibitor described herein) includes Stereotactic Body Radiation Therapy ("SBRT"). In some embodiments, the radiation therapy includes external beam radiotherapy (EBRT or XRT) or teletherapy, brachytherapy or sealed source radiotherapy, or systemic radioisotope therapy or unsealed source radiotherapy. In some embodiments, the radiation therapy includes conventional external beam

radiotherapy, stereotactic radiation therapy (e.g., Axesse, Cyberknife, Gamma Knife, Novalis, Primatom, Synergy, X-Knife, TomoTherapy or Trilogy), Intensity-Modulated Radiation Therapy, particle therapy (e.g., proton therapy), brachytherapy, delivery of radioisotopes, intraoperative radiotherapy, Auger therapy, Volumetric modulated arc therapy (VMAT), Virtual simulation, 3-dimensional conformal radiation therapy, or intensity-modulated radiation therapy. In some embodiments, the radiation therapy includes external-beam radiation therapy; internal radiation therapy (brachytherapy), or systemic radiation therapy. In some embodiments, the radiation therapy includes external-beam radiation therapy and includes: Intensity-modulated radiation therapy (IMRT), Image-guided radiation

therapy (IGRT), Tomotherapy, Stereotactic radiosurgery, Stereotactic body radiation therapy, Proton therapy, or other charged particle beams. In some embodiments, the radiation therapy includes Stereotactic radiosurgery ("SRS"). In some embodiments, the radiation therapy includes Intraoperative Radiation Therapy ("IORT").

In one embodiment, the further anti-cancer therapy is at least one additional antineoplastic agent.

In one embodiment, the pharmaceutical combination includes an anti-OX40 ABP, suitably an agonist anti-OX40 ABP, and a PI3Kb inhibitor, and optionally at least one additional anti-neoplastic agent for use (simultaneously or sequentially, in any order). In one embodiment, the pharmaceutical combination includes an anti-OX40 ABP, suitably an agonist anti-OX40 ABP and an anti-PD-1 ABP, and a PI3Kb inhibitor, and optionally at least one additional anti-neoplastic agent for use (simultaneously or sequentially, in any order).

In one embodiment, the pharmaceutical combination includes an anti-OX40 ABP, suitably an agonist anti-OX40 ABP, and and a PI3Kb inhibitor, and optionally at least one additional antineoplastic agent.

In one embodiment, the further anti-cancer therapy is at least one additional antineoplastic agent. Any anti-neoplastic agent that has activity versus a susceptible tumor being treated may be utilized in the combination. Typical anti-neoplastic agents useful include, but are not limited to, anti-microtubule agents such as diterpenoids and vinca alkaloids; platinum coordination complexes; alkylating agents such as nitrogen mustards, oxazaphosphorines, alkylsulfonates, nitrosoureas, and triazenes; antibiotic agents such as anthracyclins, actinomycins and bleomycins; topoisomerase II inhibitors such as epipodophyllotoxins; anti metabolites such as purine and pyrimidine analogues and anti-folate compounds;

topoisomerase I inhibitors such as camptothecins; hormones and hormonal analogues; signal transduction pathway inhibitors; non-receptor tyrosine angiogenesis inhibitors;

immunotherapeutic agents; proapoptotic agents; and cell cycle signaling inhibitors.

Anti-microtubule or anti-mitotic agents: Anti-microtubule or anti-mitotic agents are phase specific agents active against the microtubules of tumor cells during M or the mitosis phase of the cell cycle. Examples of anti-microtubule agents include, but are not limited to, diterpenoids and vinca alkaloids.

Diterpenoids, which are derived from natural sources, are phase specific anti -cancer agents that operate at the G2/M phases of the cell cycle. It is believed that the diterpenoids stabilize the b-tubulin subunit of the microtubules, by binding with this protein. Disassembly of the protein appears then to be inhibited with mitosis being arrested and cell death following. Examples of diterpenoids include, but are not limited to, paclitaxel and its analog docetaxel.

Paclitaxel, 5p,20-epoxy-l,2a,4,7p,10p,13a-hexa-hydroxytax-ll-en-9-one 4,10- diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine; is a natural diterpene product isolated from the Pacific yew tree Tax us b re vi folia and is commercially available as an injectable solution TAXOL®. It is a member of the taxane family of terpenes. Paclitaxel has been approved for clinical use in the treatment of refractory ovarian cancer in the United States (Markman et al., Yale Journal of Biology and Medicine, 64:583, 1991; McGuire et al., Ann. Intern, Med., 111 :273,1989) and for the treatment of breast cancer (Holmes et al., J. Nat. Cancer Inst., 83: 1797,1991.) It is a potential candidate for treatment of neoplasms in the skin (Einzig et. al., Proc. Am. Soc. Clin. Oncol., 20:46) and head and neck carcinomas (Forastire et. al., Sem. Oncol., 20:56, 1990). The compound also shows potential for the treatment of polycystic kidney disease (Woo et. al., Nature, 368:750. 1994), lung cancer and malaria. Treatment of patients with paclitaxel results in bone marrow suppression (multiple cell lineages, Ignoff, RJ. et. al, Cancer Chemotherapy Pocket Guide^ 1998) related to the duration of dosing above a threshold concentration (50nM) (Kearns, C.M. et. al., Seminars in Oncology, 3(6) p.16-23, 1995). Docetaxel, (2R,3S)- N-carboxy-3-phenylisoserine,N-fe/f-butyl ester, 13-ester with 5b- 20-epoxy-l,2a,4,7p,10p,13a-hexahydroxytax-ll-en-9-one 4-acetate 2-benzoate, trihydrate; is commercially available as an injectable solution as TAXOTERE®. Docetaxel is indicated for the treatment of breast cancer. Docetaxel is a semisynthetic derivative of paclitaxel q.v., prepared using a natural precursor, 10-deacetyl-baccatin III, extracted from the needle of the European Yew tree.

Vinca alkaloids are phase specific anti-neoplastic agents derived from the periwinkle plant. Vinca alkaloids act at the M phase (mitosis) of the cell cycle by binding specifically to tubulin. Consequently, the bound tubulin molecule is unable to polymerize into

microtubules. Mitosis is believed to be arrested in metaphase with cell death following. Examples of vinca alkaloids include, but are not limited to, vinblastine, vincristine, and vinorelbine.

Vinblastine, vincaleukoblastine sulfate, is commercially available as VELBAN® as an injectable solution. Although, it has possible indication as a second line therapy of various solid tumors, it is primarily indicated in the treatment of testicular cancer and various lymphomas including Hodgkin's Disease; and lymphocytic and histiocytic lymphomas.

Myelosuppression is the dose limiting side effect of vinblastine.

Vincristine, vincaleukoblastine, 22-oxo-, sulfate, is commercially available as ONCOVIN® as an injectable solution. Vincristine is indicated for the treatment of acute leukemias and has also found use in treatment regimens for Hodgkin's and non-Hodgkin's malignant lymphomas. Alopecia and neurologic effects are the most common side effect of vincristine and to a lesser extent myelosupression and gastrointestinal mucositis effects occur.

Vinorelbine, 3',4'-didehydro -4'-deoxy-C'-norvincaleukoblastine [R-(R*,R*)-2,3- dihydroxybutanedioate (l:2)(salt)], commercially available as an injectable solution of vinorelbine tartrate (NAVELBINE®), is a semisynthetic vinca alkaloid. Vinorelbine is indicated as a single agent or in combination with other chemotherapeutic agents, such as cisplatin, in the treatment of various solid tumors, particularly non-small cell lung, advanced breast, and hormone refractory prostate cancers. Myelosuppression is the most common dose limiting side effect of vinorelbine.

Platinum coordination complexes: Platinum coordination complexes are non-phase specific anti-cancer agents, which are interactive with DNA. The platinum complexes enter tumor cells, undergo, aquation and form intra- and interstrand crosslinks with DNA causing adverse biological effects to the tumor. Examples of platinum coordination complexes include, but are not limited to, oxaliplatin, cisplatin and carboplatin. Cisplatin, cis-diamminedichloroplatinum, is commercially available as PLATINOL® as an injectable solution. Cisplatin is primarily indicated in the treatment of metastatic testicular and ovarian cancer and advanced bladder cancer.

Carboplatin, platinum, diammine [l,l-cyclobutane-dicarboxylate(2-)-0,0'], is commercially available as PARAPLATIN® as an injectable solution. Carboplatin is primarily indicated in the first and second line treatment of advanced ovarian carcinoma.

Alkylating agents: Alkylating agents are non-phase anti-cancer specific agents and strong electrophiles. Typically, alkylating agents form covalent linkages, by alkylation, to DNA through nucleophilic moieties of the DNA molecule such as phosphate, amino, sulfhydryl, hydroxyl, carboxyl, and imidazole groups. Such alkylation disrupts nucleic acid function leading to cell death. Examples of alkylating agents include, but are not limited to, nitrogen mustards such as cyclophosphamide, melphalan, and chlorambucil; alkyl sulfonates such as busulfan; nitrosoureas such as carmustine; and triazenes such as dacarbazine.

Cyclophosphamide, 2-[bis(2-chloroethyl)amino]tetrahydro-2H-l,3,2- oxazaphosphorine 2-oxide monohydrate, is commercially available as an injectable solution or tablets as CYTOXAN®. Cyclophosphamide is indicated as a single agent or in

combination with other chemotherapeutic agents, in the treatment of malignant lymphomas, multiple myeloma, and leukemias.

Melphalan, 4-[bis(2-chloroethyl)amino]-L-phenylalanine, is commercially available as an injectable solution or tablets as ALKERAN®. Melphalan is indicated for the palliative treatment of multiple myeloma and non-resectable epithelial carcinoma of the ovary. Bone marrow suppression is the most common dose limiting side effect of melphalan.

Chlorambucil, 4-[bis(2-chloroethyl)amino]benzenebutanoic acid, is commercially available as LEUKERAN® tablets. Chlorambucil is indicated for the palliative treatment of chronic lymphatic leukemia, and malignant lymphomas such as lymphosarcoma, giant follicular lymphoma, and Hodgkin's disease.

Busulfan, 1,4-butanediol dimethanesulfonate, is commercially available as

MYLERAN® tablets. Busulfan is indicated for the palliative treatment of chronic

myelogenous leukemia.

Carmustine, l,3-[bis(2-chloroethyl)-l-nitrosourea, is commercially available as single vials of lyophilized material as BiCNU®. Carmustine is indicated for the palliative treatment as a single agent or in combination with other agents for brain tumors, multiple myeloma, Hodgkin's disease, and non-Hodgkin's lymphomas.

Dacarbazine, 5-(3,3-dimethyl-l-triazeno)-imidazole-4-carboxamide, is commercially available as single vials of material as DTIC-Dome®. Dacarbazine is indicated for the treatment of metastatic malignant melanoma and in combination with other agents for the second line treatment of Hodgkin's Disease.

Antibiotic anti-neoplastics: Antibiotic anti-neoplastics are non-phase specific agents, which bind or intercalate with DNA. Typically, such action results in stable DNA complexes or strand breakage, which disrupts ordinary function of the nucleic acids leading to cell death. Examples of antibiotic anti-neoplastic agents include, but are not limited to, actinomycins such as dactinomycin, anthrocyclins such as daunorubicin and doxorubicin; and bleomycins.

Dactinomycin, also know as Actinomycin D, is commercially available in injectable form as COSMEGEN®. Dactinomycin is indicated for the treatment of Wilm's tumor and rhabdomyosarcoma.

Daunorubicin, (8S-cis-)-8-acetyl-10-[(3-amino-2,3,6-trideoxy-a-L-lyxo- hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,ll-trihydroxy-l-methoxy-5,12

naphthacenedione hydrochloride, is commercially available as a liposomal injectable form as DAUNOXOME® or as an injectable as CERUBIDINE®. Daunorubicin is indicated for remission induction in the treatment of acute non lymphocytic leukemia and advanced HIV associated Kaposi's sarcoma.

Doxorubicin, (8S, 10S)-10-[(3-amino-2,3,6-trideoxy-a-L-lyxo-hexopyranosyl)oxy]-8- glycoloyl, 7,8,9,10-tetrahydro-6,8,ll-trihydroxy-l-methoxy-5,12 naphthacenedione hydrochloride, is commercially available as an injectable form as RUBEX® or ADRIAMYCIN RDF®. Doxorubicin is primarily indicated for the treatment of acute lymphoblastic leukemia and acute myeloblastic leukemia, but is also a useful component in the treatment of some solid tumors and lymphomas.

Bleomycin, a mixture of cytotoxic glycopeptide antibiotics isolated from a strain of Streptomyces verticMus, is commercially available as BLENOXANE®. Bleomycin is indicated as a palliative treatment, as a single agent or in combination with other agents, of squamous cell carcinoma, lymphomas, and testicular carcinomas.

Topoisomerase II inhibitors: Topoisomerase II inhibitors include, but are not limited to, epipodophyllotoxins.

Epipodophyllotoxins are phase specific anti-neoplastic agents derived from the mandrake plant. Epipodophyllotoxins typically affect cells in the S and G₂ phases of the cell cycle by forming a ternary complex with topoisomerase II and DNA causing DNA strand breaks. The strand breaks accumulate and cell death follows. Examples of

epipodophyllotoxins include, but are not limited to, etoposide and teniposide. Etoposide, 4'-demethyl-epipodophyllotoxin 9[4,6-0-(R )-ethylidene-p-D- glucopyranoside], is commercially available as an injectable solution or capsules as

VePESID® and is commonly known as VP-16. Etoposide is indicated as a single agent or in combination with other chemotherapy agents in the treatment of testicular and non-small cell lung cancers.

Teniposide, 4'-demethyl-epipodophyllotoxin 9[4,6-0-(R )-thenylidene-p-D- glucopyranoside], is commercially available as an injectable solution as VUMON® and is commonly known as VM-26. Teniposide is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia in children.

Antimetabolite neoplastic agents: Anti metabolite neoplastic agents are phase specific anti-neoplastic agents that act at S phase (DNA synthesis) of the cell cycle by inhibiting DNA synthesis or by inhibiting purine or pyrimidine base synthesis and thereby limiting DNA synthesis. Consequently, S phase does not proceed and cell death follows. Examples of anti metabolite anti-neoplastic agents include, but are not limited to, fluorouracil, methotrexate, cytarabine, mecaptopurine, thioguanine, and gemcitabine.

5-fluorouracil, 5-fluoro-2,4- (1H,3H) pyrimidinedione, is commercially available as fluorouracil. Administration of 5-fluorouracil leads to inhibition of thymidylate synthesis and is also incorporated into both RNA and DNA. The result typically is cell death. 5-fluorouracil is indicated as a single agent or in combination with other chemotherapy agents in the treatment of carcinomas of the breast, colon, rectum, stomach and pancreas. Other fluoropyrimidine analogs include 5-fluoro deoxyuridine (floxuridine) and 5-fluorodeoxyuridine monophosphate.

Cytarabine, 4-amino-l-p-D-arabinofuranosyl-2 (lH)-pyrimidinone, is commercially available as CYTOSAR-U® and is commonly known as Ara-C. It is believed that cytarabine exhibits cell phase specificity at S-phase by inhibiting DNA chain elongation by terminal incorporation of cytarabine into the growing DNA chain. Cytarabine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. Other cytidine analogs include 5-azacytidine and 2',2'-difluorodeoxycytidine (gemcitabine).

Mercaptopurine, l,7-dihydro-6H-purine-6-thione monohydrate, is commercially available as PURINETHOL®. Mercaptopurine exhibits cell phase specificity at S-phase by inhibiting DNA synthesis by an as of yet unspecified mechanism. Mercaptopurine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. A useful mercaptopurine analog is azathioprine. Thioguanine, 2-amino-l,7-dihydro-6H-purine-6-thione, is commercially available as TABLOID®. Thioguanine exhibits cell phase specificity at S-phase by inhibiting DNA synthesis by an as of yet unspecified mechanism. Thioguanine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia.

Other purine analogs include pentostatin, erythrohydroxynonyladenine, fludarabine phosphate, and cladribine.

Gemcitabine, 2'-deoxy-2', 2'-difluorocytidine monohydrochloride (b-isomer), is commercially available as GEMZAR®. Gemcitabine exhibits cell phase specificity at S-phase and by blocking progression of cells through the Gl/S boundary. Gemcitabine is indicated in combination with cisplatin in the treatment of locally advanced non-small cell lung cancer and alone in the treatment of locally advanced pancreatic cancer.

Methotrexate, N-[4[[(2,4-diamino-6-pteridinyl) methyl]methylamino] benzoyl]-L- glutamic acid, is commercially available as methotrexate sodium. Methotrexate exhibits cell phase effects specifically at S-phase by inhibiting DNA synthesis, repair and/or replication through the inhibition of dyhydrofolic acid reductase which is required for synthesis of purine nucleotides and thymidylate. Methotrexate is indicated as a single agent or in combination with other chemotherapy agents in the treatment of choriocarcinoma, meningeal leukemia, non-Hodgkin's lymphoma, and carcinomas of the breast, head, neck, ovary and bladder.

Topoisomerase I inhibitors: Camptothecins, including, camptothecin and

camptothecin derivatives are available or under development as Topoisomerase I inhibitors. Camptothecins cytotoxic activity is believed to be related to its Topoisomerase I inhibitory activity. Examples of camptothecins include, but are not limited to irinotecan, topotecan, and the various optical forms of 7-(4-methylpiperazino-methylene)-10,ll-ethylenedioxy-20- camptothecin described below.

Irinotecan HCI, (4S)-4,ll-diethyl-4-hydroxy-9-[(4-piperidinopiperidino) carbonyloxy]- lH-pyrano[3',4',6,7]indolizino[l,2-b]quinoline-3,14(4H,12H)-dione hydrochloride, is commercially available as the injectable solution CAMPTOSAR®. Irinotecan is a derivative of camptothecin which binds, along with its active metabolite SN-38, to the topoisomerase I - DNA complex. It is believed that cytotoxicity occurs as a result of irreparable double strand breaks caused by interaction of the topoisomerase I : DNA : irintecan or SN-38 ternary complex with replication enzymes. Irinotecan is indicated for treatment of metastatic cancer of the colon or rectum.

Topotecan HCI, (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-lH- pyrano[3',4',6,7]indolizino[l,2-b]quinoline-3,14-(4H,12H)-dione monohydrochloride, is commercially available as the injectable solution HYCAMTIN®. Topotecan is a derivative of camptothecin which binds to the topoisomerase I - DNA complex and prevents religation of singles strand breaks caused by Topoisomerase I in response to torsional strain of the DNA molecule. Topotecan is indicated for second line treatment of metastatic carcinoma of the ovary and small cell lung cancer.

Hormones and hormonal analogues: Hormones and hormonal analogues are useful compounds for treating cancers in which there is a relationship between the hormone(s) and growth and/or lack of growth of the cancer. Examples of hormones and hormonal analogues useful in cancer treatment include, but are not limited to, ad renocorticosteroids such as prednisone and prednisolone which are useful in the treatment of malignant lymphoma and acute leukemia in children; aminoglutethimide and other aromatase inhibitors such as anastrozole, letrazole, vorazole, and exemestane useful in the treatment of adrenocortical carcinoma and hormone dependent breast carcinoma containing estrogen receptors; progestrins such as megestrol acetate useful in the treatment of hormone dependent breast cancer and endometrial carcinoma; estrogens, androgens, and antiandrogens such as flutamide, nilutamide, bicalutamide, cyproterone acetate and 5a- reductases such as finasteride and dutasteride, useful in the treatment of prostatic carcinoma and benign prostatic hypertrophy; anti-estrogens such as tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfene, as well as selective estrogen receptor modulators (SERMS) such those described in U.S. Patent Nos. 5,681,835, 5,877,219, and 6,207,716, useful in the treatment of hormone dependent breast carcinoma and other susceptible cancers; and gonadotropin-releasing hormone (GnRH) and analogues thereof which stimulate the release of leutinizing hormone (LH) and/or follicle stimulating hormone (FSH) for the treatment prostatic carcinoma, for instance, LHRH agonists and antagagonists such as goserelin acetate and luprolide.

Signal transduction pathway inhibitors: Signal transduction pathway inhibitors are those inhibitors, which block or inhibit a chemical process which evokes an intracellular change. As used herein this change is cell proliferation or differentiation. Signal tranduction inhibitors useful in the present invention include inhibitors of receptor tyrosine kinases, nonreceptor tyrosine kinases, SH2/SH3 domain blockers, serine/threonine kinases, phosphotidyl inositol-3 kinases, myo-inositol signaling, and Ras oncogenes.

Several protein tyrosine kinases catalyse the phosphorylation of specific tyrosyl residues in various proteins involved in the regulation of cell growth. Such protein tyrosine kinases can be broadly classified as receptor or non-receptor kinases.

Receptor tyrosine kinases are transmembrane proteins having an extracellular ligand binding domain, a transmembrane domain, and a tyrosine kinase domain. Receptor tyrosine kinases are involved in the regulation of cell growth and are generally termed growth factor receptors. Inappropriate or uncontrolled activation of many of these kinases, i.e. aberrant kinase growth factor receptor activity, for example by over-expression or mutation, has been shown to result in uncontrolled cell growth. Accordingly, the aberrant activity of such kinases has been linked to malignant tissue growth. Consequently, inhibitors of such kinases could provide cancer treatment methods. Growth factor receptors include, for example, epidermal growth factor receptor (EGFr), platelet derived growth factor receptor (PDGFr), erbB2, erbB4, ret, vascular endothelial growth factor receptor (VEGFr), tyrosine kinase with immunoglobulin-like and epidermal growth factor identity domains (TIE-2), insulin growth factor -I (IGFI) receptor, macrophage colony stimulating factor (cfms), BTK, ckit, cmet, fibroblast growth factor (FGF) receptors, Trk receptors (TrkA, TrkB, and TrkC), ephrin (eph) receptors, and the RET protooncogene. Several inhibitors of growth receptors are under development and include ligand antagonists, antibodies, tyrosine kinase inhibitors and anti-sense oligonucleotides. Growth factor receptors and agents that inhibit growth factor receptor function are described, for instance, in Kath, John C., Exp. Opin. Ther.

Patents (2000) 10(6):803-818; Shawver et al DDT Vol 2, No. 2 February 1997; and Lofts, F. J. et al, "Growth factor receptors as targets", New Molecular Targets for Cancer

Chemotherapy, ed. Workman, Paul and Kerr, David, CRC press 1994, London.

Tyrosine kinases, which are not growth factor receptor kinases are termed nonreceptor tyrosine kinases. Non-receptor tyrosine kinases useful in the present invention, which are targets or potential targets of anti-cancer drugs, include cSrc, Lck, Fyn, Yes, Jak, cAbl, FAK (Focal adhesion kinase), Brutons tyrosine kinase, and Bcr-Abl. Such non-receptor kinases and agents which inhibit non-receptor tyrosine kinase function are described in Sinh, S. and Corey, S J., (1999) Journal of Hematotherapy and Stem Cell Research 8 (5): 465 - 80; and Bolen, J.B., Brugge, J.S., (1997) Annual review of Immunology. 15: 371-404.

SH2/SH3 domain blockers are agents that disrupt SH2 or SH3 domain binding in a variety of enzymes or adaptor proteins including, PI3-K p85 subunit, Src family kinases, adaptor molecules (She, Crk, Nek, Grb2) and Ras-GAP. SH2/SH3 domains as targets for anti-cancer drugs are discussed in Smithgall, T.E. (1995), Journal of Pharmacological and Toxicological Methods. 34(3) 125-32.

Inhibitors of Serine/Threonine Kinases including MAP kinase cascade blockers which include blockers of Raf kinases (rafk), Mitogen or Extracellular Regulated Kinase (MEKs), and Extracellular Regulated Kinases (ERKs); and Protein kinase C family member blockers including blockers of PKCs (alpha, beta, gamma, epsilon, mu, lambda, iota, zeta). IkB kinase family (IKKa, IKKb), PKB family kinases, akt kinase family members, and TGF beta receptor kinases. Such Serine/Threonine kinases and inhibitors thereof are described in Yamamoto, T., Taya, S., Kaibuchi, K., (1999), Journal of Biochemistry. 126 (5) 799-803; Brodt, P, Samani, A., and Navab, R. (2000), Biochemical Pharmacology, 60. 1101-1107; Massague,

J., Weis-Garcia, F. (1996) Cancer Surveys. 27:41-64; Philip, P.A., and Harris, A.L. (1995), Cancer Treatment and Research. 78: 3-27, Lackey, K. et al Bioorganic and Medicinal Chemistry Letters, (10), 2000, 223-226; U.S. Patent No. 6,268,391; and Martinez-Iacaci, L., et al, Int. J. Cancer (2000), 88(1), 44-52.

Inhibitors of Phosphotidyl inositol-3 Kinase family members including blockers of PI3-kinase, ATM, DNA-PK, and Ku are also useful in the present invention. Such kinases are discussed in Abraham, R.T. (1996), Current Opinion in Immunology. 8 (3) 412-8; Canman, C.E., Lim, D.S. (1998), Oncogene 17 (25) 3301-3308; Jackson, S.P. (1997), International Journal of Biochemistry and Cell Biology. 29 (7):935-8; and Zhong, H. et al, Cancer res, (2000) 60(6), 1541-1545.

Also useful in the present invention are Myo-inositol signaling inhibitors such as phospholipase C blockers and Myoinositol analogues. Such signal inhibitors are described in Powis, G., and Kozikowski A., (1994) New Molecular Targets for Cancer Chemotherapy ed., Paul Workman and David Kerr, CRC press 1994, London.

Another group of signal transduction pathway inhibitors are inhibitors of Ras Oncogene. Such inhibitors include inhibitors of farnesyltransferase, geranyl-geranyl transferase, and CAAX proteases as well as anti-sense oligonucleotides, ribozymes and immunotherapy. Such inhibitors have been shown to block ras activation in cells containing wild type mutant ras , thereby acting as antiproliferation agents. Ras oncogene inhibition is discussed in Scharovsky, O.G., Rozados, V.R., Gervasoni, S.I. Matar, P. (2000), Journal of Biomedical Science. 7(4) 292-8; Ashby, M.N. (1998), Current Opinion in Lipidology. 9 (2) 99 - 102; and BioChim. Biophys. Acta, (19899) 1423(3): 19-30.

As mentioned above, antibody antagonists to receptor kinase ligand binding may also serve as signal transduction inhibitors. This group of signal transduction pathway inhibitors includes the use of humanized antibodies to the extracellular ligand binding domain of receptor tyrosine kinases. For example Imclone C225 EGFR specific antibody (see Green, M.C. et al, Monoclonal Antibody Therapy for Solid Tumors, Cancer Treat. Rev., (2000),

26(4), 269-286); HERCEPTIN ® erbB2 antibody (see Tyrosine Kinase Signalling in Breast cancenerbB Family Receptor Tyrosine Kinases, Breast cancer Res., 2000, 2(3), 176-183); and 2CB VEGFR2 specific antibody (see Brekken, R.A. et al, Selective Inhibition of VEGFR2 Activity by a monoclonal Anti-VEGF antibody blocks tumor growth in mice, Cancer Res. (2000) 60, 5117-5124). Anti-angiogenic agents: Anti-angiogenic agents including non- receptorMEKngiogenesis inhibitors may alo be useful. Anti-angiogenic agents such as those which inhibit the effects of vascular edothelial growth factor, (for example the anti-vascular endothelial cell growth factor antibody bevacizumab [Avastin™], and compounds that work by other mechanisms (for example linomide, inhibitors of integrin anb3 function, endostatin and angiostatin);

Immunotherapeutic agents: Agents used in immunotherapeutic regimens may also be useful in combination with an anti-OX40 ABP (e.g., an agonist antibody, e.g., an agonist antibody described herein) and a PI3Kb inhibitor (e.g., a PI3Kb inhibitor described herein). Immunotherapy approaches, including for example ex-vivo and in-vivo approaches to increase the immunogenecity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.

Proapoptotoc agents: Agents used in proapoptotic regimens (e.g., bcl-2 antisense oligonucleotides) may also be used in the combination of the present invention.

Cell cycle signalling inhibitors: Cell cycle signalling inhibitors inhibit molecules involved in the control of the cell cycle. A family of protein kinases called cyclin dependent kinases (CDKs) and their interaction with a family of proteins termed cyclins controls progression through the eukaryotic cell cycle. The coordinate activation and inactivation of different cyclin/CDK complexes is necessary for normal progression through the cell cycle. Several inhibitors of cell cycle signalling are under development. For instance, examples of cyclin dependent kinases, including CDK2, CDK4, and CDK6 and inhibitors for the same are described in, for instance, Rosania et al, Exp. Opin. Ther. Patents (2000) 10(2):215-230.

In one embodiment, the combination of the present invention comprises an anti- 0X40 ABP and a PI3Kb inhibitor optionally with a PD-1 modulator (e.g., anti-PD-1 ABP, e.g., pembrolizumab or nivolumab).

In one embodiment, the combination of the present invention comprises an anti- 0X40 ABP and a PI3Kb inhibitor and at least one anti-neoplastic agent selected from antimicrotubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, and cell cycle signaling inhibitors. In one embodiment, the combination of the present invention comprises an anti- 0X40 ABP and a PI3Kb inhibitor and at least one anti-neoplastic agent selected from antimicrotubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, and cell cycle signaling inhibitors.

In one embodiment, the combination of the present invention comprises an anti- 0X40 ABP and a PI3Kb inhibitor and at least one anti-neoplastic agent which is an antimicrotubule agent selected from diterpenoids and vinca alkaloids.

In a further embodiment, the at least one anti-neoplastic agent agent is a diterpenoid.

In a further embodiment, the at least one anti-neoplastic agent is a vinca alkaloid.

In one embodiment, the combination of the present invention comprises an anti- 0X40 ABP and a PI3Kb inhibitor and at least one anti-neoplastic agent, which is a platinum coordination complex.

In a further embodiment, the at least one anti-neoplastic agent is paclitaxel, carboplatin, or vinorelbine.

In a further embodiment, the at least one anti-neoplastic agent is carboplatin.

In a further embodiment, the at least one anti-neoplastic agent is vinorelbine.

In a further embodiment, the at least one anti-neoplastic agent is paclitaxel.

In one embodiment, the combination of the present invention comprises an anti- 0X40 ABP and a PI3Kb inhibitor and at least one anti-neoplastic agent which is a signal transduction pathway inhibitor.

In a further embodiment the signal transduction pathway inhibitor is an inhibitor of a growth factor receptor kinase VEGFR2, TIE2, PDGFR, BTK, erbB2, EGFr, IGFR-1, TrkA, TrkB, TrkC, or c-fms.

In a further embodiment the signal transduction pathway inhibitor is an inhibitor of a serine/threonine kinase rafk, akt, or PKC-zeta.

In a further embodiment the signal transduction pathway inhibitor is an inhibitor of a non- receptor tyrosine kinase selected from the src family of kinases. In a further embodiment the signal transduction pathway inhibitor is an inhibitor of c-src.

In a further embodiment the signal transduction pathway inhibitor is an inhibitor of Ras oncogene selected from inhibitors of farnesyl transferase and geranylgeranyl transferase.

In a further embodiment the signal transduction pathway inhibitor is an inhibitor of a serine/threonine kinase such as PI3K, such as PI3Kb.

In a further embodiment the signal transduction pathway inhibitor is a dual

EGFr/erbB2 inhibitor, for example N-{3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl}-6-[5-({[2- (methanesulphonyl) ethyl]amino}methyl)-2-furyl]-4-quinazolinamine (structure below):

Formula I

In one embodiment, the combination of the present invention comprises a compound of formula I or a salt or solvate thereof and at least one anti-neoplastic agent which is a cell cycle signaling inhibitor.

In further embodiment, cell cycle signaling inhibitor is an inhibitor of CDK2, CDK4 or

CDK6.

In one embodiment the mammal in the methods and uses of the present invention is a human.

As indicated, therapeutically effective amounts of the combinations of the invention (an anti-OX40 ABP and a PI3Kb inhibitor) are administered to a human. Typically, the therapeutically effective amount of the administered agents of the present invention will depend upon a number of factors including, for example, the age and weight of the subject, the precise condition requiring treatment, the severity of the condition, the nature of the formulation, and the route of administration. Ultimately, the therapeutically effective amount will be at the discretion of the attendant physician.

The following examples are intended for illustration only and are not intended to limit the scope of the invention in any way. EXAMPLES

Example 1. Preparation of 2-methyl-l-{[2-methyl-3- (trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-lH-benzimidazole-4- carboxylic acid (GSK2636771)

An aqueous solution of 2 N LiOH (1.2 mL) was added to a solution of methyl 2- methyl-l-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-lH-benzimidazole- 4-carboxylate (180 mg, 0.4 mmol) in THF (10 mL) and stirred at 50° C for 1 h. When TLC showed no starting material remaining, the mixture was cooled to rt and THF was removed under reduced pressure. The pH of the mixture was acidified to pH 3. The suspension was filtered and the filtrate was collected, and washed with water (lOmL) to give the product as a white solid (152 mg, yield 88%). ^XH NMR (300 MHz, DMSO-de): d ppm 2.46 (s, 3H), 2.54 (s, 3H), 3.10 (t, 4H, J=4.8 Hz), 3.73 (t, 4H, J=4.8 Hz), 5.63 (s, 2H), 6.37 (d, 1H, J=7.8 Hz), 7.26 (t, 1H, J=7.8 Hz), 7.35 (d, 1H, J=2.4 Hz), 7.44 (d, 1H, J=2.4 Hz), 7.62 (d, 1H, J=7.8 Hz); LC-MS: m/e = 434 [M+l]⁺ .

See also PCT Publication No. WO 2012/047538 and U.S. Patent No. 8,435,988, in particular Example 31.

Example 2. Preparation of 2-methyl-l-{[2-methyl-3- (trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-lH-benzimidazole-4- carboxylic acid 2-amino-2-(hydroxymethyl)-l, 3-propanediol salt

(GSK263677 IB)

Seed crystal preparation - Batch 1 : To the 2-methyl-l-{[2-methyl-3- (trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-lH-benzimidazole-4-carboxylic acid (52.9 mg, 0.122 mmol), methanol (2.0 mL) was added. To the slurry, tromethamine (2-amino-2- (hydroxymethyl)-l, 3-propanediol) (3.0 M solution in water, 1.0 equivalent) was added. The slurry was heated to 60°C and kept stirring at 60°C for 3 hours. The slurry was then cooled slowly (O.lC/min) to 20°C. Once the temperature of the slurry reached 20°C, the slurry was kept stirring at 20°C for 8 hours. The crystalline solids were isolated by vacuum filtration. The yield of the desired salt was 57.2 mg (85% yield).

Seed crystal preparation - Batch 2: To the 2-methyl-l-{[2-methyl-3- (trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-lH-benzimidazole-4-carboxylic acid (353.0 mg), methanol (14.0 mL) was added. The slurry was heated to 60°C and tromethamine (3.0 M solution in water, 1.0 equivalent) was added in four aliquots over 15 minutes followed by the addition of crystalline seeds of crystalline tromethamine salt from batch 1. The slurry was stirred at 60°C for 3 hours, cooled (lC/min) to 20°C, and stirred at 20°C for 8 hours. The solids were isolated by vacuum filtration, dried at 60°C under vacuum for 5 hours. The yield of the tromethamine salt was 401.5 mg (~88.9% yield).

Batch 3: 2-methyl-l-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)- lH-benzimidazole-4-carboxylic acid (40.0 g, 92 mmol) was suspended in Methanol (1.6 L) in a 3L rounded-bottom flask. The resulting slurry was heated to 60°C mixing on a buchii rotary evaporator water bath and tris(hydroxymethyl)aminomethane (3M solution in water) (0.031 L, 92 mmol) was added in four aliquots over 15 minutes followed by the addition of seed crystals (108 mg). This slurry was stirred (flask rotated on buchii rotovap) at 60 °C for 3 hours, then cooled (~1 °C/min) to 20 °C (room temperature), then finally magnetically stirred at 20 °C (room temperature) for 8 hours. The resulting white solid was isolated by vacuum filtration, dried under vacuum at 60 °C for 8 hours to provide 2-methyl-l-{[2- methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-lH-benzimidazole-4-carboxylic acid - 2-amino-2-(hydroxymethyl)-l, 3-propanediol (1:1) (47.76 g, 86 mmol, 93 % yield) as a white solid. Both proton NMR and LCMS are consistent with the proposed structure. 1H NMR (400 MHz, DMSO-d6) d ppm 7.61 (d, J=7.83 Hz, 1 H) 7.37 (d, J=2.27 Hz, 1 H) 7.17 - 7.33 (m, 2 H) 6.33 (d, J=7.83 Hz, 1 H) 5.59 (s, 2 H) 3.66 - 3.80 (m, 4 H) 2.98 - 3.15 (m, 4 H) 2.50 - 2.58 (m, 10 H) 2.43 (s, 3 H); LCMS m/z MH+ =434.3.

See also PCT Publication No. WO 2012/047538 and U.S. Patent No. 8,435,988, in particular Example 86.

Example 3. 0X40 agonist antibody-based combination therapy with RI3Kb selective inhibitor enhances T cell immunity.

0X40 (CD134), a tumor necrosis factor (TNF) receptor family member, plays a critical role in initiating signaling cascades required for full activation of tumor-reactive T cells. Due to its distinct mechanism of action, the use of 0X40 agonist-based combinations is emerging as a novel avenue to improve the effectiveness of cancer treatments. Our recently published studies demonstrate that oncogenic activation of the PI3K pathway by loss of the expression of tumor suppressor PTEN, imposes an immunosuppressive microenvironment in favor of tumor immune evasion. These results highlight the therapeutic potential of combinational therapy using 0X40 agonists and PI3K inhibitors (PI3Ki) in cancer patients.

See Peng et al., supra.

In this study, we sought to evaluate the antitumor efficacy of the combination of an 0X40 agonist antibody and a PI3Kb selective inhibitor, GSK2636771B, in tumors with PTEN loss. By using a genetically engineered mouse (GEM) model of melanoma, which can spontaneously develop tumors with PTEN loss (PTEN deficient tumors), we observed that combination therapy using an anti-OX40 mAb and GSK2636771B significantly delayed tumor growth and improved survival time of mice bearing PTEN loss tumors (FIG. 13A-C). This combinational treatment was also well tolerated in experimental mice. Unlike the combination of GSK2636771B and immune checkpoint blockers, this combinational treatment did not result in an increase in the number of CD8⁺ tumor-infiltrating T cells, but significantly enhanced the percentage of Ki67⁺ CD8⁺ T cells at the tumor site when compared to either treatment alone (FIG. 13D-E). These results suggest that GSK2636771B treatment can synergize with 0X40 agonists to augment effector functions of tumor-reactive T cells. To further confirm this synergistic effect, we measured serum levels of 45 cytokines/chemokines in tumor-bearing mice receiving an anti-OX40 antibody alone or in combination with GSK2636771B. Serum levels of CCL4, CXCL10 and IFN-g (IFN-g) which are mainly produced by memory and/or effector T cells, were significantly increased in mice in the combination cohort in comparison to the monotherapy cohorts (FIG. 14). More importantly, using a vaccine mouse model, we demonstrate that GSK2636771B in combination with anti-OX40 did not significantly impair the generation and maintenance of memory T cells (FIG. 15).

Taken together, our results suggest that the combinational approach of an 0X40 agonist antibody and GSK2636771B, may induce robust and durable antitumor T cell immunity. Our study also provides a rationale to explore the clinical activity of an 0X40 agonist antibo dy in combination with GSK2636771B in cancer patients with PTEN deficient tumors.

For the results shown in FIG. 13A-E, melanoma was initiated in a group of

TynCreER; PTENIOJ^IOX; BRAF V600E/+ mice. Mice with measureable tumors were randomly treated with either vehicle plus control antibody, GSK2636771B (30mg/kg/d), anti-OX40 (50 mg), or the combination of GSK2636771B and anti-anti-OX40. (A) A schematic diagram depicts the treatment schedule. (B) Tumor size in each of the treatment groups. Tumor growth was monitored every 3 days. (C) Kaplan-Meier survival curves of mice treated with GSK2636771B and/or anti-OX40. Log-rank test demonstrates statistical significance (P<0.05): GSK2636771B+anti-OX40 vs control, GSK2636771B alone and anti-OX40 alone. (D) The numbers of tumor-infiltrating T cells and (E) the percentage of Ki67+ T cells in tumors from mice treated with GSK2636771B and/or anti-OX40. 7 days after treatment, tumor tissues were harvested and weighed. Single cell suspensions from tumor tissues were made for Ki67, CD8 and CD4 staining. One-Way ANOVA test demonstrates statistical significance (* P<0.05).

For the results shown in FIG. 14, TynCreER; PTENIox/lox; BRAF V600E/+ mice were treated with 4-hydroxytamoxifen to induce tumor development. Mice with measureable tumors were randomly treated with either vehicle plus control antibody, GSK2636771B (30mg/kg/d), anti-OX40 (50 mg), or the combination of both GSK2636771B and anti-anti- 0X40. 7 days after treatment, serum samples were collected from experimental mice. The serum levels of cytokines/chemokines were determined by the MILLIPLEX MAP Mouse Cytokine/Chemokine Magnetic Bead Panel I, II and III. N.D. stands for not detected. One- Way ANOVA test demonstrates statistical significance (* P<0.05; ** P<0.01;

****P<0.0001).

For the results shown in FIG. 15, C57BL/6 mice were transferred with the splenocytes from Pmel-Thyl.l mice, followed by gplOO peptide vaccination, intraperitoneal injection of 100,000 IU rhIL-2 protein and topical application of 50 mg of imiquimod cream 5% on the vaccination site. Vaccinated mice received either vehicle, GSK2636771B (30mg/kg/d) and/or anti-OX40 (50mg) for 5 days. After 28 days, mice were boosted with gplOO peptide vaccine. Schematic representation of vaccine, the PI3Ki and anti-OX40 antibody treatment protocols was shown. The numbers of antigen-specific T cells in peripheral blood from vaccinated mice. Thyl.l, a congenic marker for transferred Pmel T cells, was used to determine the number of gplOO-specific T cells.

In experiments that employed an anti-OX40 antibody, the 0X86 (rat anti-murine 0X40 antibody) antibody (commercially available: clone name OX-86 from BioXcell) was used.

Example 4. CyTOF analysis.

The results of CyTOF analysis revealed the differential effects of anti-OX40 mAb alone and in combination with PI3Kbi (GSK2636771B) in vivo. Spleen tissues were collected from mice receiving mock treatment, anti-OX40 mAb alone or in combination with GSK2636771B. To access the activation and proliferation of immune cells, single cell suspensions from these samples were analyzed by CyTOF to measure Ki67 levels in different immune cell populations. High-dimensional visualization of changes of Ki67 expression in response to treatment was generated by SPADE software (data not shown). These data confirmed that the combination treatment can further enhance the proliferation of tumor- infiltrating T cells.

Example 5. Linear mixed model analysis.

Linear mixed model analysis showed statistically significant interaction between GSK2636771B and anti-OX40 mAb (P = 0.0004). To determine the interaction between

GSK2636771B and anti-OX40 mAb, mean tumor size of each mouse across six time points in different treatment groups were used for linear mixed model analysis. The data are represented as mean±standard error (SE) (data not shown). A P value < 0.05 for the interaction of two drugs was considered as statistical synergy. The analysis was conducted using R program software (R version 3.3.2).

Claims

We claim:

1. A method of treating a cancer in a mammal in need thereof, the method comprising : administering to the mammal an anti-OX40 antigen binding protein and a PI3Kb inhibitor, thereby treating the cancer.

2. Use of an anti-OX40 antigen binding protein and a PI3Kb inhibitor in the manufacture of a medicament for the treatment of a cancer.

3. Use of an anti-OX40 antigen binding protein in the manufacture of a medicament for treating a cancer in a mammal in combination with a PI3Kb inhibitor.

4. A combination of an anti-OX40 antigen binding protein and a PI3Kb inhibitor for use in treating a cancer in a mammal.

5. A method of reducing tumor size in a mammal having a cancer, the method comprising: administering to the mammal an anti-OX40 antigen binding protein and a PI3Kb inhibitor, thereby reducing the tumor size in the mammal.

6. Use of an anti-OX40 antigen binding protein and a PI3Kb inhibitor in the manufacture of a medicament for reducing tumor size in a mammal having a cancer.

7. Use of an anti-OX40 antigen binding protein in the manufacture of a medicament for reducing tumor size in a mammal having a cancer in combination with a PI3Kb inhibitor.

8. A combination of an anti-OX40 antigen binding protein and a PI3Kb inhibitor for use in reducing tumor size in a mammal having a cancer.

9. The method of claim 1 or 5, the use of any one of claims 2, 3, 6, or 7, or the combination of any one of claims 4 or 8, wherein the PI3Kb inhibitor is a compound of Formula (II):

wherein

R1 is selected from H, Ci-₆alkyl, alkoxy, hydroxy, halogen, -CN, -NH₂, -NHC(0)Ra, -NHS0₂Ra, -CO₂H, -C0₂Ra, -CONHRb, -CONH₂, -CH₂OH, and heteroaryl wherein the heteroaryl may be substituted by one or two Ci-₃alkyl groups;

R2 is selected from H, -NHRa, alkoxy, halogen, -CF₃, -CHF₂, and Ci-ealkyl;

R4 is selected from FI or Ra;

each R5 is independently selected from Ci-ealkyl;

each Ra is independently selected from Ci-₃alkyl;

Rb is selected from FI, Ci-₃alkyl, and SChMe;

or a pharmaceutically acceptable salt thereof.

10. The method of claim 1 or 5, the use of any one of claims 2, 3, 6, or 7, or the combination of any one of claims 4 or 8, wherein the heteroaryl of R1 is selected from the group consisting of: pyrazolyl, triazolyl, tetrazolyl, oxazolyl and imidazolyl.

11. The method of claim 1 or 5, the use of any one of claims 2, 3, 6, or 7, or the combination of any one of claims 4 or 8, wherein the aryl or heteroaryl of R3 are selected from phenyl, naphthyl, benzothienyl, quinolinyl, isoquinolinyl, and quinazolinyl.

12. The method of claim 1 or 5, the use of any one of claims 2, 3, 6, or 7, or the combination of any one of claims 4 or 8, wherein each Rc is independently Ci-₃alkyl, F or Cl, and n is 0.

13. The method of claim 1 or 5, the use of any one of claims 2, 3, 6, or 7, or the combination of any one of claims 4 or 8, wherein each Rc is independently CF₃ or F, and n is 0.

14. The method of claim 1 or 5, the use of any one of claims 2, 3, 6, or 7, or the combination of any one of claims 4 or 8, wherein the PI3Kb inhibitor is a compound having the Formula (II)(C):

wherein

15. method of claim 1 or 5, the use of any one of claims 2, 3, 6, or 7, or the combination of any one of claims 4 or 8, wherein the PI3Kb inhibitor is a compound having the

Formula (II)(D):

16. The method of claim 1 or 5, the use of any one of claims 2, 3, 6, or 7, or the combination of any one of claims 4 or 8, wherein the PI3Kb inhibitor is a compound having the Formula (II)(E):

wherein

17. The method of claim 1 or 5, the use of any one of claims 2, 3, 6, or 7, or the combination of any one of claims 4 or 8, wherein the PI3Kb inhibitor is:

2-(l-methylethyl)-6-(4-morpholinyl)-l-(l-naphthalenylmethyl)-lFI-benzimidazol-4-ol,

2-ethyl-6-(4-morpholinyl)-l-(l-naphthalenylmethyl)-lFI-benzimidazol-4-ol,

l-[(2,3-dichlorophenyl)methyl]-2-(l-methylethyl)-6-(4-morpholinyl)-lFI-benzimidazol-4-ol, l-[(2,3-dichlorophenyl)methyl]-4-fluoro-2-methyl-6-(4-morpholinyl)-lFI-benzimidazole,

1-[(2,3-dichlorophenyl)methyl]-2-ethyl-6-(4-morpholinyl)-lFI-benzimidazol-4-ol,

4-fluoro-2-methyl-6-(4-morpholinyl)-l-(l-naphthalenylmethyl)-lFI-benzimidazole,

2-ethyl-4-fluoro-6-(4-morpholinyl)-l-(l-naphthalenylmethyl)-lFI-benzimidazole,

2-methyl-6-(4-morpholinyl)-l-(l-naphthalenylmethyl)-lFI-benzimidazole-4-carboxylic acid,

1-[(2,3-dichlorophenyl)methyl]-2-ethyl-4-fluoro-6-(4-morpholinyl)-lFI-benzimidazole,

2-methyl-6-(4-morpholinyl)-l-(l-naphthalenylmethyl)-4-(lFI-pyrazol-5-yl)-lFI-benzimidazole, l-[(2,3-dichlorophenyl)methyl]-2-methyl-6-(4-morpholinyl)-lFI-benzimidazole-4-carboxylic acid,

1-[(2,3-dichlorophenyl)methyl]-2-methyl-6-(4-morpholinyl)-4-(lFI-pyrazol-5-yl)-lFI- benzimidazole,

2-methyl-6-(4-morpholinyl)-l-(l-naphthalenylmethyl)-4-(lFI-l,2,4-triazol-3-yl)-lFI- benzimidazole, methyl 2-methyl-6-(4-morpholinyl)-l-(l-naphthalenylmethyl)-lH-benzimidazole-4- carboxylate,

methyl l-[(2-fluoro-3-methylphenyl)methyl]-2-methyl-6-(4-morpholinyl)-lH-benzimidazole- 4-carboxylate,

2-methyl-6-(4-morpholinyl)-l-(l-naphthalenylmethyl)-lH-benzimidazole-4-carbonitrile,

1-[(2,3-dichlorophenyl)methyl]-2-methyl-6-(4-morpholinyl)-lH-benzimidazole-4-carbonitrile, methyl 2-methyl-l-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-lH- benzimidazole-4-carboxylate,

1-[(2-fluoro-3-methylphenyl)methyl]-2-methyl-6-(4-morpholinyl)-lH-benzimidazole-4- carboxylic acid,

2-methyl-6-(4-morpholinyl)-l-(l-naphthalenylmethyl)-lH-benzimidazole-4-carboxamide,

1-[(2,3-dichlorophenyl)methyl]-2-methyl-6-(4-morpholinyl)-4-(lH-l,2,4-triazol-3-yl)-lH- benzimidazole,

methyl 2-methyl-6-(4-morpholinyl)-l-(5-quinolinylmethyl)-lH-benzimidazole-4-carboxylate,

1-[(3,4-dimethylphenyl)methyl]-2-methyl-6-(4-morpholinyl)-lH-benzimidazole-4-carboxylic acid,

1-[(3,4-dichlorophenyl)methyl]-2-methyl-6-(4-morpholinyl)-lH-benzimidazole-4-carboxylic acid,

2-methyl-l-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-4-(lH-l,2,4- triazol-3-yl)-lH-benzimidazole,

2-methyl-4-(3-methyl-lH-l,2,4-triazol-5-yl)-6-(4-morpholinyl)-l-(l-naphthalenylmethyl)-lH- benzimidazole,

1-[2-methyl-6-(4-morpholinyl)-l-(l-naphthalenylmethyl)-lH-benzimidazol-4-yl]ethanone, [2-methyl-6-(4-morpholinyl)-l-(l-naphthalenylmethyl)-lH-benzimidazol-4-yl]methanol,

2-methyl-N-(methylsulfonyl)-6-(4-morpholinyl)-l-(l-naphthalenylmethyl)-lH-benzimidazole- 4-carboxamide,

methyl 5-(4-morpholinyl)-2-(trifluoromethyl)-lH-benzimidazole-7-carboxylate,

methyl l-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-2- (trifluoromethyl)-lH-benzimidazole-4-carboxylate, l-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-2-(trifluoromethyl)-lH- benzimidazole-4-carboxylic acid,

methyl l-[(3-chloro-2-methylphenyl)methyl]-6-(4-morpholinyl)-2-(trifluoromethyl)-lH- benzimidazole-4-carboxylate,

l-[(2,3-dichlorophenyl)methyl]-6-(4-morpholinyl)-2-(trifluoromethyl)-lH-benzimidazole-4- carboxylic acid,

l-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-2-(trifluoromethyl)-lH- benzimidazole-4-carboxamide,

methyl 6-(4-morpholinyl)-l-(l-naphthalenylmethyl)-2-(trifluoromethyl)-lH-benzimidazole-4- carboxylate,

1-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-4-(lH-l,2,4-triazol-3-yl)-

2-(trifluoromethyl)-lH-benzimidazole,

l-[(2,3-dichlorophenyl)methyl]-6-(4-morpholinyl)-4-(lH-l,2,4-triazol-3-yl)-2-

(trifluoromethyl)-lH-benzimidazole,

2-methyl-6-(4-morpholinyl)-l-(l-naphthalenylmethyl)-4-(lH-tetrazol-5-yl)-lH-benzimidazole, [2-methyl-l-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-lH- benzimidazol-4-yl]methanol,

1-[(3-chloro-2-methylphenyl)methyl]-2-methyl-6-(4-morpholinyl)-lH-benzimidazole-4- carboxylic acid,

2-methyl-l-[(2-methylphenyl)methyl]-6-(4-morpholinyl)-lH-benzimidazole-4-carboxylic acid, ethyl 2-methyl-l-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-lH- benzimidazole-4-carboxylate,

4-bromo-2-methyl-6-(4-morpholinyl)-lH-benzimidazole,

4-bromo-2-methyl-l-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-lH- benzimidazole,

2-methyl-l-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-4-(l,3-oxazol-2- yl)-lH-benzimidazole, methyl 2-chloro-5-(4-morpholinyl)-lH-benzimidazole-7-carboxylate,

methyl 2-chloro-l-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-lH- benzimidazole-4-carboxylate,

methyl 2-(difluoromethyl)-5-(4-morpholinyl)-lH-benzimidazole-7-carboxylate,

2-(difluoromethyl)-l-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-lH- benzimidazole-4-carboxylic acid,

l-[(2,3-dichlorophenyl)methyl]-2-(difluoromethyl)-6-(4-morpholinyl)-lH-benzimidazole-4- carboxylic acid,

l-(l-benzothien-7-ylmethyl)-2-methyl-6-(4-morpholinyl)-lH-benzimidazole-4-carboxylic acid, l-[(2,3-dimethylphenyl)methyl]-2-methyl-6-(4-morpholinyl)-lH-benzimidazole-4-carboxylic acid,

l-[(3-fluoro-2-methylphenyl)methyl]-2-methyl-6-(4-morpholinyl)-lH-benzimidazole-4- carboxylic acid,

1-[l-(3-chloro-2-methylphenyl)ethyl]-2-methyl-6-(4-morpholinyl)-lH-benzimidazole-4- carboxylic acid,

2-methyl-l-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-4-(l,3-thiazol-2- yl)-lH-benzimidazole,

4-(2-furanyl)-2-methyl-l-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)- lH-benzimidazole or

2-methyl-4-[(methyloxy)methyl]-l-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4- morpholinyl)-lH-benzimidazole,

or a pharmaceutically acceptable salt thereof.

18. The method of claim 1 or 5, the use of any one of claims 2, 3, 6, or 7, or the combination of any one of claims 4 or 8, wherein the PI3Kb inhibitor is 2-methyl-l-{[2- methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-lH-benzimidazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof.

19. The method of claim 1 or 5, the use of any one of claims 2, 3, 6, or 7, or the combination of any one of claims 4 or 8, wherein the PI3Kb inhibitor is 2-methyl-l-{[2- methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-lH-benzimidazole-4-carboxylic acid 2-amino-2-(hydroxymethyl)-l, 3-propanediol salt.

20. The method of claim 1 or 5, the use of any one of claims 2, 3, 6, or 7, or the combination of any one of claims 4 or 8, wherein the anti-OX40 antigen binding protein comprises: a heavy chain variable region CDR1 comprising an amino acid sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:l or 13; a heavy chain variable region CDR2 comprising an amino acid sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO:2 or 14; and/or a heavy chain variable region CDR3 comprising an amino acid sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO:3 or 15.

21. The method of claim 1 or 5, the use of any one of claims 2, 3, 6, or 7, or the combination of any one of claims 4 or 8, wherein the anti-OX40 antigen binding protein comprises a light chain variable region CDR1 comprising an amino acid sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO:7 or 19; a light chain variable region CDR2 comprising an amino acid sequence with at least at least 90%, 91%, 92%, 93%,

94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO:8 or 20 and/or a light chain variable region CDR3 comprising an amino acid sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO:9 or 21.

22. The method of claim 1 or 5, the use of any one of claims 2, 3, 6, or 7, or the combination of any one of claims 4 or 8, wherein the anti-OX40 antigen binding protein comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:l; (b) a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:2; (c) a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:3; (d) a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:7; (e) a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:8; and (f) a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:9.

23. The method of claim 1 or 5, the use of any one of claims 2, 3, 6, or 7, or the combination of any one of claims 4 or 8, wherein the anti-OX40 antigen binding protein comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 13; (b) a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 14; (c) a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 15; (d) a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 19; (e) a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:20; and (f) a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:21.

24. The method of claim 1 or 5, the use of any one of claims 2, 3, 6, or 7, or the combination of any one of claims 4 or 8, wherein the anti-OX40 antigen binding protein comprises a light chain variable region ("VL") comprising an amino acid sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO:ll.

25. The method of claim 1 or 5, the use of any one of claims 2, 3, 6, or 7, or the combination of any one of claims 4 or 8, wherein the anti-OX40 antigen binding protein comprises a heavy chain variable region ("VH") comprising an amino acid sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO:5.

26. The method of claim 1 or 5, the use of any one of claims 2, 3, 6, or 7, or the combination of any one of claims 4 or 8, wherein the anti-OX40 antigen binding protein comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:5 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:ll.

27. The method of claim 1 or 5, the use of any one of claims 2, 3, 6, or 7, or the combination of any one of claims 4 or 8, wherein the anti-OX40 antigen binding protein comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 17 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:23.

28. The method of claim 1 or 5, the use of any one of claims 2, 3, 6, or 7, or the combination of any one of claims 4 or 8, wherein the anti-OX40 antigen binding protein comprises a heavy chain comprising an amino acid sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO:48 and a light chain comprising an amino acid sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO:49.

29. The method of claim 1 or 5, the use of any one of claims 2, 3, 6, or 7, or the combination of any one of claims 4 or 8, further comprising administering at least one antineoplastic agent to the mammal in need thereof.

30. The method of claim 1 or 5, the use of any one of claims 2, 3, 6, or 7, or the combination of any one of claims 4 or 8, wherein the PI3Kb inhibitor is 2-methyl-l-{[2- methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-lH-benzimidazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof and wherein the anti-OX40 antigen binding protein comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: l; (b) a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:2; (c) a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:3; (d) a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:7; (e) a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:8; and (f) a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:9.

31. The method of claim 1 or 5, the use of any one of claims 2, 3, 6, or 7, or the combination of any one of claims 4 or 8, wherein the PI3Kb inhibitor is 2-methyl-l-{[2- methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-lH-benzimidazole-4-carboxylic acid 2-amino-2-(hydroxymethyl)-l, 3-propanediol salt and wherein the anti-OX40 antigen binding protein comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:5 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 11.

32. A kit for use in the treatment of cancer comprising:

(i) an anti-OX40 antigen binding protein;

(ii) a PI3Kb inhibitor; and

(iii) instructions for use in the treatment of cancer.

33. A kit for use in the treatment of cancer comprising:

(i) an anti-OX40 antigen binding protein; and

(ii) instructions for use in the treatment of cancer when combined with a PI3Kb inhibitor.

34. A kit for use in the treatment of cancer comprising:

(i) a PI3Kb inhibitor; and

(ii) instructions for use in the treatment of cancer when combined with an anti-OX40 antigen binding protein.

35. A kit of any one of claims 32 to 34, wherein the anti-OX40 antigen binding protein and the PI3Kb inhibitor are each individually formulated with one or more pharmaceutically acceptable carriers.

36. The kit of any one of claims 32 to 34, wherein the PI3Kb inhibitor is 2-methyl-l-{[2- methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-lH-benzimidazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof and wherein the anti-OX40 antigen binding protein comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:l; (b) a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:2; (c) a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:3; (d) a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:7; (e) a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:8; and (f) a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:9.

37. The kit of any one of claims 32 to 34, wherein the PI3Kb inhibitor is 2-methyl-l-{[2- methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-lH-benzimidazole-4-carboxylic acid 2-amino-2-(hydroxymethyl)-l, 3-propanediol salt and wherein the anti-OX40 antigen binding protein comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:5 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 11.