WO2019106605A1 - Polythérapie pour le traitement du cancer - Google Patents

Polythérapie pour le traitement du cancer Download PDF

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Publication number
WO2019106605A1
WO2019106605A1 PCT/IB2018/059475 IB2018059475W WO2019106605A1 WO 2019106605 A1 WO2019106605 A1 WO 2019106605A1 IB 2018059475 W IB2018059475 W IB 2018059475W WO 2019106605 A1 WO2019106605 A1 WO 2019106605A1
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WO
WIPO (PCT)
Prior art keywords
methyl
morpholinyl
amino acid
benzimidazole
acid sequence
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PCT/IB2018/059475
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English (en)
Inventor
Patrick Hwu
Weiyi PENG
Niranjan YANAMANDRA
Original Assignee
Board Of Regents, The University Of Texas System
Glaxosmithkline Intellectual Property Development Limited
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Application filed by Board Of Regents, The University Of Texas System, Glaxosmithkline Intellectual Property Development Limited filed Critical Board Of Regents, The University Of Texas System
Publication of WO2019106605A1 publication Critical patent/WO2019106605A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2878—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39541—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against normal tissues, cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/75—Agonist effect on antigen

Definitions

  • the present invention relates, in part, to a method of treating a cancer in a mammal.
  • 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.
  • ABSP anti-OX40 antigen binding protein
  • 0X40 binding protein such as an antibody (e.g., agonist antibody) to human 0X40
  • a PI3Kb inhibitor for treating a cancer, such as a PTEN deficient cancer.
  • 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.
  • 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.
  • 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).
  • a subject e.g., patient
  • a subject e.g., mammal, e.g., human
  • the subject to be treated with an anti-OX40 agonist ABP and a PI3Kb inhibitor e.g., therapeutically effective amounts thereof
  • 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.
  • 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).
  • an anti-OX40 ABP e.g., an agonist anti-OX40 ABP
  • a PI3Kb inhibitor e.g., therapeutically effective amounts thereof
  • the cancer e.g., the PTEN deficient cancer (e.g., the PTEN deficient tumor).
  • 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).
  • a cancer e.g., a PTEN deficient cancer (e.g., a PTEN deficient tumor)
  • a subject e.g., patient
  • mammal e.g., human
  • 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
  • a medicament for the treatment of a cancer e.g., a PTEN deficient cancer (e.g., a PTEN deficient tumor).
  • 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).
  • 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).
  • a PI3Kb inhibitor 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).
  • 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).
  • 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.
  • a mammal e.g., a human
  • a PI3Kb inhibitor e.g., a therapeutically effective amount thereof
  • 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.
  • a mammal e.g., human
  • administering e.g., an anti-OX40 antigen binding protein
  • a PI3Kb inhibitor e.g., a therapeutically effective amount thereof
  • the cancer is a solid tumor.
  • the cancer is a PTEN deficient cancer.
  • the mammal has a PTEN deficient cancer.
  • the mammal or a cancer from the mammal is identified as having a PTEN deficient cancer.
  • the mammal or a cancer from the mammal is selected on the basis of having a PTEN deficient cancer.
  • the mammal or a cancer from the mammal is evaluated to determine whether the cancer is PTEN deficient.
  • the evaluation comprises Q-PCR.
  • the evaluation comprises an ELISA.
  • the cancer is selected from the group consisting of: breast cancer, thyroid cancer, glioblastoma, endometrial cancer, prostate cancer, and melanoma.
  • the cancer is a prostate cancer.
  • the cancer is a melanoma.
  • the anti-OX40 antigen binding protein and the PI3Kb inhibitor are administered at the same time.
  • the anti-OX40 antigen binding protein is administered after the PI3Kb inhibitor is administered.
  • the anti-OX40 antigen binding protein is administered before the PI3Kb inhibitor is administered.
  • the anti-OX40 antigen binding protein is administered systemically.
  • the anti-OX40 antigen binding protein is administered intratu morally.
  • the PI3Kb inhibitor is administered systemically.
  • the PI3Kb inhibitor is administered orally.
  • 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.
  • the anti-OX40 antigen binding protein binds to human 0X40.
  • the PI3Kb inhibitor is a compound of Formula (II):
  • R1 is selected from H, Ci-ealkyl, alkoxy, hydroxy, halogen, -CN, -NH 2 , -NHC(0)Ra, -NHS0 2 Ra, -CO2H, -CC Ra, -CONHRb, -CONH 2 , -CH 2 OH, and heteroaryl wherein the heteroaryl may be substituted by one or two Ci-3alkyl groups;
  • R2 is selected from H, -NHRa, alkoxy, halogen, -CF 3 , -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, -CF 3 , and hydroxy; and n is 0-2,
  • the heteroaryl of R1 is selected from the group consisting of: pyrazolyl, triazolyl, tetrazolyl, oxazolyl and imidazolyl.
  • the aryl or heteroaryl of R3 are selected from phenyl, naphthyl, benzothienyl, quinolinyl, isoquinolinyl, and quinazolinyl.
  • each Rc is independently Ci-3alkyl, F or Cl, and n is 0.
  • each Rc is independently CF 3 or F, and n is 0.
  • the PI3Kb inhibitor is a compound having the Formula
  • each of R6, R7, and R8 is independently selected from Ci- 3 alkyl, halogen, -CF 3 , 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;
  • the PI3Kb inhibitor is a compound having the Formula
  • the PI3Kb inhibitor is a compound having the Formula
  • each of R6 and R7 is independently selected from Ci- 3 alkyl, halogen, -CF 3 , and hydroxyl.
  • the PI3Kb inhibitor is:
  • 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.
  • 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.
  • 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.
  • 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;
  • 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.
  • 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.
  • VL light chain variable region
  • 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.
  • VH heavy chain variable region
  • 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.
  • VL light chain variable region
  • 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.
  • VH heavy chain variable region
  • 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.
  • 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.
  • VL light chain variable region
  • 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.
  • VH heavy chain variable region
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the method further comprises administering at least one antineoplastic agent to the mammal in need thereof.
  • 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.
  • 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.
  • 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.
  • 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.
  • an anti-OX40 antigen binding protein e.g., a therapeutically effective amount thereof
  • a PI3Kb inhibitor e.g., a therapeutically effective amount thereof
  • the cancer is a solid tumor.
  • the cancer is a PTEN deficient cancer.
  • the mammal has a PTEN deficient cancer.
  • the mammal or a cancer from the mammal is identified as having a PTEN deficient cancer.
  • the mammal or a cancer from the mammal is selected on the basis of having a PTEN deficient cancer.
  • the mammal or a cancer from the mammal is evaluated to determine whether the cancer is PTEN deficient.
  • the evaluation comprises Q-PCR.
  • the evaluation comprises an ELISA.
  • the cancer is selected from the group consisting of: breast cancer, thyroid cancer, glioblastoma, endometrial cancer, prostate cancer, and melanoma.
  • the cancer is a prostate cancer.
  • the cancer is a melanoma.
  • the anti-OX40 antigen binding protein and the PI3Kb inhibitor are administered at the same time.
  • the anti-OX40 antigen binding protein is administered after the PI3Kb inhibitor is administered.
  • 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.
  • the anti-OX40 antigen binding protein is administered intratu morally.
  • the PI3Kb inhibitor is administered systemically.
  • the PI3Kb inhibitor is administered orally.
  • the mammal is human.
  • 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.
  • the anti-OX40 antigen binding protein binds to human 0X40.
  • the PI3Kb inhibitor is a compound of Formula (II):
  • R1 is selected from H, Ci-ealkyl, alkoxy, hydroxy, halogen, -CN, -NH 2 , -NHC(0)Ra, -NHS0 2 Ra, -CO 2 H, -CC Ra, -CONHRb, -CONH 2 , -CH 2 OH, and heteroaryl wherein the heteroaryl may be substituted by one or two Ci- 3 alkyl groups;
  • R2 is selected from H, -NHRa, alkoxy, halogen, -CF 3 , -CFIF 2 , 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- 3 alkyl
  • Rb is selected from FI, Ci- 3 alkyl, and SChMe;
  • each Rc is independently selected from Ci- 3 alkyl, halogen, -CF 3 , and hydroxy; and n is 0-2,
  • the heteroaryl of R1 is selected from the group consisting of: pyrazolyl, triazolyl, tetrazolyl, oxazolyl and imidazolyl.
  • the aryl or heteroaryl of R3 are selected from phenyl, naphthyl, benzothienyl, quinolinyl, isoquinolinyl, and quinazolinyl.
  • each Rc is independently Ci-3alkyl, F or Cl, and n is 0.
  • each Rc is independently CF 3 or F, and n is 0.
  • the PI3Kb inhibitor is a compound having the Formula
  • each of R6, R7, and R8 is independently selected from Ci-3alkyl, halogen, -CF 3 , 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;
  • the PI3Kb inhibitor is a compound having the Formula
  • the PI3Kb inhibitor is a compound having the Formula
  • each of R6 and R7 is independently selected from Ci- 3 alkyl, halogen, -CF 3 , and hydroxyl.
  • the PI3Kb inhibitor is:
  • 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.
  • 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.
  • 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.
  • 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.
  • 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;
  • 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.
  • 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.
  • VL light chain variable region
  • 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.
  • VH heavy chain variable region
  • 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.
  • VL light chain variable region
  • 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.
  • VH heavy chain variable region
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the method further comprises administering at least one antineoplastic agent to the mammal in need thereof.
  • 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.
  • 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.
  • 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.
  • 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
  • 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).
  • an anti-OX40 antigen binding protein e.g., a therapeutically effective amount thereof
  • a PI3Kb inhibitor e.g., a therapeutically effective amount thereof
  • the cancer is a PTEN deficient cancer.
  • the mammal has a PTEN deficient cancer.
  • the mammal or a cancer from the mammal is identified as having a PTEN deficient cancer.
  • 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.
  • 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;
  • 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.
  • VL light chain variable region
  • 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.
  • VH heavy chain variable region
  • 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.
  • 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.
  • 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.
  • the PI3Kb inhibitor is a compound of Formula (II):
  • R1 is selected from H, Ci-ealkyl, alkoxy, hydroxy, halogen, -CN, -NH 2 , -NHC(0)Ra, -NHS0 2 Ra, -CO 2 H, -CChRa, -CONHRb, -CONH 2 , -CH 2 OH, and heteroaryl wherein the heteroaryl may be substituted by one or two Ci- 3 alkyl groups;
  • R2 is selected from H, -NHRa, alkoxy, halogen, -CF 3 , -CHF 2 , 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- 3 alkyl
  • Rb is selected from FI, Ci- 3 alkyl, and SChMe;
  • each Rc is independently selected from Ci- 3 alkyl, halogen, -CF 3 , and hydroxy; and n is 0-2,
  • the PI3Kb inhibitor is a compound having the Formula
  • each of R6, R7, and R8 is independently selected from Ci- 3 alkyl, halogen, -CF 3 , 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;
  • the PI3Kb inhibitor is a compound having the Formula
  • the PI3Kb inhibitor is a compound having the Formula
  • each of R6 and R7 is independently selected from Ci- 3 alkyl, halogen, -CF 3 , and hydroxyl.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a mammal e.g., human
  • a PI3Kb inhibitor e.g., a therapeutically effective amount thereof
  • the tumor comprises a PTEN deficient cancer.
  • the mammal has a PTEN deficient cancer.
  • the mammal or a cancer from the mammal is identified as having a PTEN deficient cancer.
  • 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.
  • 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;
  • 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.
  • 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.
  • VH heavy chain variable region
  • 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.
  • 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.
  • 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.
  • the PI3Kb inhibitor is a compound of Formula (II):
  • R1 is selected from H, Ci-ealkyl, alkoxy, hydroxy, halogen, -CN, -NH 2 , -NHC(0)Ra, -NHS0 2 Ra, -CO 2 H, -CChRa, -CONHRb, -CONH 2 , -CH 2 OH, and heteroaryl wherein the heteroaryl may be substituted by one or two Ci- 3 alkyl groups;
  • R2 is selected from H, -NHRa, alkoxy, halogen, -CF 3 , -CHF 2 , 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- 6 alkyl
  • each Ra is independently selected from Ci- 3 alkyl
  • Rb is selected from FI, Ci- 3 alkyl, and SChMe;
  • each Rc is independently selected from Ci- 3 alkyl, halogen, -CF 3 , and hydroxy; and n is 0-2,
  • the PI3Kb inhibitor is a compound having the Formula
  • each of R6, R7, and R8 is independently selected from Ci- 3 alkyl, halogen, -CF 3 , 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;
  • the PI3Kb inhibitor is a compound having the Formula
  • the PI3Kb inhibitor is a compound having the Formula
  • each of R6 and R7 is independently selected from Ci- 3 alkyl, halogen, -CF 3 , and hydroxyl.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • a mammal e.g., human having a cancer.
  • 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
  • a PI3Kb inhibitor e.g., a therapeutically effective amount thereof.
  • the tumor comprises a PTEN deficient cancer.
  • 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.
  • the mammal or a tumor from the mammal is selected on the basis of having a PTEN deficient cancer.
  • the mammal or a tumor from the mammal is evaluated to determine whether the cancer is PTEN deficient.
  • the evaluation comprises Q-PCR.
  • the evaluation comprises an ELISA.
  • the cancer is selected from the group consisting of: breast cancer, thyroid cancer, glioblastoma, endometrial cancer, prostate cancer, and melanoma.
  • cancer is a prostate cancer.
  • the cancer is a melanoma.
  • 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.
  • 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;
  • 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.
  • VL light chain variable region
  • 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.
  • VH heavy chain variable region
  • 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.
  • 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.
  • 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.
  • the PI3Kb inhibitor is a compound of Formula (II):
  • R1 is selected from H, Ci-ealkyl, alkoxy, hydroxy, halogen, -CN, -INH 2 , -NHC(0)Ra, -NHSChRa, -CO 2 H, -CChRa, -CONHRb, -CONH 2 , -CH 2 OH, and heteroaryl wherein the heteroaryl may be substituted by one or two Ci- 3 alkyl groups;
  • R2 is selected from H, -NHRa, alkoxy, halogen, -CF 3 , -CFIF 2 , 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- 3 alkyl
  • Rb is selected from FI, Ci- 3 alkyl, and SCbMe;
  • each Rc is independently selected from Ci- 3 alkyl, halogen, -CF 3 , and hydroxy; and n is 0-2,
  • the PI3Kb inhibitor is a compound having the Formula
  • each of R6, R7, and R8 is independently selected from Ci- 3 alkyl, halogen, -CF 3 , 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;
  • the PI3Kb inhibitor is a compound having the Formula
  • the PI3Kb inhibitor is a compound having the Formula
  • each of R6 and R7 is independently selected from Ci-3alkyl, halogen, -CF 3 , and hydroxyl.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a mammal e.g., human having a cancer
  • the tumor comprises a PTEN deficient cancer.
  • the mammal has a PTEN deficient cancer.
  • the mammal or a tumor from the mammal is identified as having a PTEN deficient cancer.
  • the mammal or a tumor from the mammal is selected on the basis of having a PTEN deficient cancer.
  • the mammal or a tumor from the mammal is evaluated to determine whether the cancer is PTEN deficient.
  • the evaluation comprises Q-PCR.
  • the evaluation comprises an ELISA.
  • the cancer is selected from the group consisting of: breast cancer, thyroid cancer, glioblastoma, endometrial cancer, prostate cancer, and melanoma.
  • cancer is a prostate cancer.
  • the cancer is a melanoma.
  • the anti-OX40 antigen binding protein and the PI3Kb inhibitor are administered at the same time.
  • the anti-OX40 antigen binding protein is administered after the PI3Kb inhibitor is administered.
  • the anti-OX40 antigen binding protein is administered before the PI3Kb inhibitor is administered.
  • the anti-OX40 antigen binding protein is administered systemically.
  • the anti-OX40 antigen binding protein is administered intratu morally.
  • the PI3Kb inhibitor is administered systemically.
  • the PI3Kb inhibitor is administered orally.
  • the mammal is human.
  • 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.
  • the anti-OX40 antigen binding protein binds to human 0X40.
  • the PI3Kb inhibitor is a compound of Formula (II):
  • R1 is selected from H, Ci-ealkyl, alkoxy, hydroxy, halogen, -CN, -NH 2 , -NHC(0)Ra, -NHS0 2 Ra, -CO 2 H, -C0 2 Ra, -CONHRb, -CONH 2 , -CH 2 OH, and heteroaryl wherein the heteroaryl may be substituted by one or two Ci- 3 alkyl groups;
  • R2 is selected from H, -NHRa, alkoxy, halogen, -CF 3 , -CHF 2 , 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- 3 alkyl
  • Rb is selected from FI, Ci- 3 alkyl, and SChMe;
  • each Rc is independently selected from Ci- 3 alkyl, halogen, -CF 3 , and hydroxy; and n is 0-2,
  • the heteroaryl of R1 is selected from the group consisting of: pyrazolyl, triazolyl, tetrazolyl, oxazolyl and imidazolyl.
  • the aryl or heteroaryl of R3 are selected from phenyl, naphthyl, benzothienyl, quinolinyl, isoquinolinyl, and quinazolinyl.
  • each Rc is independently Ci- 3 alkyl, F or Cl, and n is 0.
  • each Rc is independently CF 3 or F, and n is 0.
  • the PI3Kb inhibitor is a compound having the Formula
  • each of R6, R7, and R8 is independently selected from Ci- 3 alkyl, halogen, -CF 3 , 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;
  • the PI3Kb inhibitor is a compound having the Formula
  • the PI3Kb inhibitor is a compound having the Formula
  • each of R6 and R7 is independently selected from Ci- 3 alkyl, halogen, -CF 3 , and hydroxyl.
  • the PI3Kb inhibitor is:
  • 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.
  • 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.
  • 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.
  • 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;
  • 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.
  • 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.
  • VL light chain variable region
  • 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.
  • VH heavy chain variable region
  • 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.
  • VL light chain variable region
  • 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.
  • VH heavy chain variable region
  • 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.
  • 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.
  • VL light chain variable region
  • 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.
  • VH heavy chain variable region
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the method further comprises administering at least one antineoplastic agent to the mammal in need thereof.
  • 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.
  • 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.
  • 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.
  • 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.
  • an anti-OX40 antigen binding protein e.g., a therapeutically effective amount thereof
  • a PI3Kb inhibitor e.g., a therapeutically effective amount thereof
  • the tumor comprises a PTEN deficient cancer.
  • the mammal has a PTEN deficient cancer.
  • the mammal or a tumor from the mammal is identified as having a PTEN deficient cancer.
  • the mammal or a tumor from the mammal is selected on the basis of having a PTEN deficient cancer.
  • the mammal or a tumor from the mammal is evaluated to determine whether the cancer is PTEN deficient.
  • the evaluation comprises Q-PCR.
  • the evaluation comprises an ELISA.
  • the cancer is selected from the group consisting of: breast cancer, thyroid cancer, glioblastoma, endometrial cancer, prostate cancer, and melanoma.
  • cancer is a prostate cancer.
  • the cancer is a melanoma.
  • 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.
  • 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;
  • 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.
  • VL light chain variable region
  • 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.
  • VH heavy chain variable region
  • 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.
  • 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.
  • 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.
  • the PI3Kb inhibitor is a compound of Formula (II):
  • R1 is selected from H, Ci-ealkyl, alkoxy, hydroxy, halogen, -CN, -NH 2 , -NHC(0)Ra, -NHS0 2 Ra, -CO 2 H, -C0 2 Ra, -CONHRb, -CONH 2 , -CH 2 OH, and heteroaryl wherein the heteroaryl may be substituted by one or two Ci- 3 alkyl groups;
  • R2 is selected from H, -NFIRa, alkoxy, halogen, -CF 3 , -CFIF 2 , 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- 3 alkyl
  • Rb is selected from FI, Ci -3 alkyl, and SChMe;
  • each Rc is independently selected from Ci -3 alkyl, halogen, -CF 3 , and hydroxy; and n is 0-2,
  • the PI3Kb inhibitor is a compound having the Formula
  • each of R6, R7, and R8 is independently selected from Ci- 3 alkyl, halogen, -CF 3 , 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;
  • the PI3Kb inhibitor is a compound having the Formula
  • the PI3Kb inhibitor is a compound having the Formula
  • each of R6 and R7 is independently selected from Ci-3alkyl, halogen, -CF 3 , and hydroxyl.
  • 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.
  • 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.
  • 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.
  • 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.
  • the disclosure provides a kit for use in the treatment of cancer comprising:
  • an anti-OX40 antigen binding protein e.g., a therapeutically effective amount thereof (e.g., an anti-OX40 antigen binding protein described herein);
  • a PI3Kb inhibitor e.g., a therapeutically effective amount thereof (e.g., a PI3Kb inhibitor described herein);
  • the anti-OX40 antigen binding protein and the PI3Kb inhibitor are each individually formulated with one or more pharmaceutically acceptable carriers.
  • the kit is for use in a mammal has a cancer that is a PTEN deficient cancer.
  • the instructions include identifying the mammal or a cancer from the mammal as having a PTEN deficient cancer.
  • the instructions include selecting the mammal or a cancer from the mammal on the basis of having a PTEN deficient cancer.
  • 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.
  • the disclosure provides a kit for use in the treatment of cancer comprising:
  • an anti-OX40 antigen binding protein e.g., a therapeutically effective amount thereof (e.g., an anti-OX40 antigen binding protein described herein);
  • instructions for use in the treatment of cancer when combined with a PI3Kb inhibitor e.g., a therapeutically effective amount thereof
  • a PI3Kb inhibitor e.g., a therapeutically effective amount thereof
  • a PI3Kb inhibitor described herein e.g., a PI3Kb inhibitor described herein.
  • the anti-OX40 antigen binding protein and the PI3Kb inhibitor are each individually formulated with one or more pharmaceutically acceptable carriers.
  • the kit is for use in a mammal has a cancer that is a PTEN deficient cancer.
  • 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.
  • 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.
  • the disclosure provides a kit for use in the treatment of cancer, where the kit comprises:
  • a PI3Kb inhibitor e.g., a therapeutically effective amount thereof (e.g., a PI3Kb inhibitor described herein);
  • instructions for use in the treatment of cancer when combined with an anti- 0X40 antigen binding protein e.g., a therapeutically effective amount thereof
  • an anti-OX40 antigen binding protein e.g., an anti-OX40 antigen binding protein described herein.
  • the anti-OX40 antigen binding protein and the PI3Kb inhibitor are each individually formulated with one or more pharmaceutically acceptable carriers.
  • the kit is for use in a mammal has a cancer that is a PTEN deficient cancer.
  • the instructions include identifying the mammal or a cancer from the mammal as having a PTEN deficient cancer.
  • the instructions include selecting the mammal or a cancer from the mammal on the basis of having a PTEN deficient cancer.
  • 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.
  • the disclosure provides a kit for use in reducing tumor size in a mammal (e.g., a mammal with cancer) comprising:
  • an anti-OX40 antigen binding protein e.g., a therapeutically effective amount thereof (e.g., an anti-OX40 antigen binding protein described herein);
  • a PI3Kb inhibitor e.g., a therapeutically effective amount thereof (e.g., a PI3Kb inhibitor described herein);
  • the anti-OX40 antigen binding protein and the PI3Kb inhibitor are each individually formulated with one or more pharmaceutically acceptable carriers.
  • the kit is for use in a mammal has a tumor that comprises a PTEN deficient cancer.
  • the instructions include identifying the mammal or a tumor from the mammal as having a PTEN deficient cancer.
  • the instructions include selecting the mammal or a tumor from the mammal on the basis of having a PTEN deficient cancer.
  • 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.
  • the disclosure provides a kit for use in reducing tumor size in a mammal (e.g., a mammal with cancer):
  • an anti-OX40 antigen binding protein e.g., a therapeutically effective amount thereof (e.g., an anti-OX40 antigen binding protein described herein);
  • instructions for use in reducing tumor size in a mammal when combined with a PI3Kb inhibitor e.g., a therapeutically effective amount thereof
  • a PI3Kb inhibitor e.g., a therapeutically effective amount thereof
  • a PI3Kb inhibitor described herein e.g., a PI3Kb inhibitor described herein.
  • the anti-OX40 antigen binding protein and the PI3Kb inhibitor are each individually formulated with one or more pharmaceutically acceptable carriers.
  • the kit is for use in a mammal has a tumor that comprises a PTEN deficient cancer.
  • the instructions include identifying the mammal or a tumor from the mammal as having a PTEN deficient cancer.
  • the instructions include selecting the mammal or a tumor from the mammal on the basis of having a PTEN deficient cancer.
  • 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.
  • 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
  • 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
  • an anti-OX40 antigen binding protein e.g., a therapeutically effective amount thereof
  • the anti-OX40 antigen binding protein and the PI3Kb inhibitor are each individually formulated with one or more pharmaceutically acceptable carriers.
  • the kit is for use in a mammal has a tumor that comprises a PTEN deficient cancer.
  • the instructions include identifying the mammal or a tumor from the mammal as having a PTEN deficient cancer.
  • the instructions include selecting the mammal or a tumor from the mammal on the basis of having a PTEN deficient cancer.
  • 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.
  • 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.
  • 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.
  • 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:
  • an antigen binding protein that binds 0X40 e.g., a therapeutically effective amount thereof
  • the antigen binding protein that binds 0X40 is as described herein
  • a PI3Kb inhibitor e.g., a therapeutically effective amount thereof
  • the mammal e.g., human
  • the mammal has cancer, as described herein.
  • 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.
  • 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:
  • an antigen binding protein that binds 0X40 e.g., a therapeutically effective amount thereof
  • the antigen binding protein that binds 0X40 is as described herein
  • a PI3Kb inhibitor e.g., a therapeutically effective amount thereof
  • the mammal e.g., human
  • the mammal has cancer, as described herein.
  • 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.
  • a PI3Kb inhibitor e.g., a therapeutically effective amount thereof
  • an antigen binding protein that binds 0X40 e.g., a therapeutically effective amount thereof
  • a PI3Kb inhibitor e.g., a therapeutically effective amount thereof
  • 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.
  • IFN-g protein levels e.g., IFN-g serum levels
  • a mammal e.g., human
  • a PI3Kb inhibitor e.g., a therapeutically effective amount thereof
  • the mammal e.g., human
  • cancer as described herein.
  • 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.
  • an antigen binding protein that binds 0X40 e.g., a therapeutically effective amount thereof
  • a PI3Kb inhibitor e.g., a therapeutically effective amount thereof
  • a subject in need of cancer treatment preferably a human
  • administering 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.
  • an anti-OX40 ABP and a PI3Kb inhibitor e.g., a therapeutically effective amount of each
  • 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.
  • 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. 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.
  • 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).
  • loss of the PTEN tumor suppressor e.g., loss of function or loss of expression (e.g., mRNA or protein)
  • a PTEN deficient cancer e.g., a PTEN deficient tumor.
  • T cell co-stimulatory molecules e.g., 0X40.
  • 0X40 e.g., human 0X40 (hOX40) or hOX40R
  • hOX40 human 0X40
  • hOX40R hOX40R
  • OX40L The ligand for 0X40 (OX40L) is expressed by activated antigen-presenting cells.
  • 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.
  • the anti-OX40 ABPs of a combination of the invention, or a method or use thereof bind and engage 0X40.
  • the anti-OX40 ABPs of a combination of the invention, or a method or use thereof modulate 0X40.
  • the ABPs of a combination of the invention, or a method or use thereof modulate 0X40 by mimicking OX40L.
  • the anti-OX40 ABPs of a combination of the invention, or a method or use thereof modulate 0X40 and cause proliferation of T cells.
  • 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.
  • 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.
  • 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.
  • 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.
  • the anti-OX40 ABPs of a combination of the invention, or a method or use thereof enhance effector T cell function.
  • 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.
  • any of the preceding effects occur in a tumor microenvironment.
  • Tregs T regulatory cells
  • TGF- B Transforming Growth Factor
  • IL-10 interleukin-10
  • Tregs a key immune pathogenesis of cancer can be the involvement of Tregs that are found in tumor beds and sites of inflammation.
  • 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.
  • 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.
  • modulators may be agonists or antagonists.
  • 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.
  • 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.
  • 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.
  • an agonist anti-OX40 ABP inhibits the suppressive effect of Treg cells on other T cells, e.g., within the tumor environment.
  • 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.
  • 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.
  • cancer As used herein, the terms “cancer,” “neoplasm,” and “tumor,” are used
  • a malignant transformation refers 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
  • the definition of a cancer cell includes not only a primary cancer cell, but any cell derived from a cancer cell ancestor.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • terapéuticaally 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.
  • a therapeutically effective amount of the combinations of the invention 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.
  • 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.
  • suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal, and parenteral (including intratumoral, subcutaneous,
  • intramuscular, intraveneous, intradermal, intrathecal, and epidural may vary with, for example, the condition of the recipient of the combination and the cancer to be treated.
  • 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.
  • 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.
  • 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.
  • all of the components of a combination of the invention are administered systemically, e.g., intravenously.
  • all of the components of the combination of the invention are administered intratumorally.
  • the components of the invention are administered as one or more
  • Antigen Binding Protein 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.
  • 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
  • an ABP also includes antigen binding fragments of such antibodies or other molecules.
  • 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.
  • the antigen that the 0X40 antigen binding protein (ABP) binds is 0X40 (e.g., human 0X40).
  • 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.
  • 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.
  • 0X40 e.g., human 0X40
  • antibody 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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).
  • ELISA enzyme-linked immunoabsorbent assay
  • RIA radioimmunoassay
  • kinetics e.g., BIACORE analysis
  • the BIACORE methods known in the art may be used to measure binding affinity.
  • the ABP of the invention binds its target (e.g., 0X40) with high affinity.
  • 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.
  • 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.
  • the antibody binds 0X40, preferably human 0X40, with a KD of less than lOOnM.
  • KD The reciprocal of KD (i.e. 1/KD) is the equilibrium association constant (KA) having units M 1 .
  • KA equilibrium association constant
  • 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.
  • 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.
  • the competition assay is carried out by BIACORE.
  • 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.
  • 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.
  • 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.
  • CDR 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.
  • CDR refers 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;
  • the CDRs are referred to as "CDR1,” “CDR2,” “CDR3" of the variable light chain and “CDR1,””CDR2,” and “CDR3” of the variable heavy chain.
  • the numbering convention is the Kabat convention.
  • CDR variant 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.
  • each CDR that can be modified may be modified alone or in combination with another CDR.
  • the modification is a substitution, particularly a conservative substitution, for example as shown in Table A.
  • 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.
  • the CDRs from a mouse antibody may be humanized for administration to humans.
  • 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).
  • 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.,
  • 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.
  • the humanized antibody has a human antibody constant region that is an IgG.
  • the IgG is a sequence as disclosed in any of the above references or patent publications.
  • nucleotide and amino acid sequences 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 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.
  • 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.
  • a query amino acid sequence may be described by an amino acid sequence identified in one or more claims 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.
  • 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.
  • 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.
  • ABPs that bind human 0X40 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”).
  • anti-OX40 ABP an anti-OX40 ABP
  • 0X40 antigen binding protein or "0X40 binding protein”
  • 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.
  • 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.
  • 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.
  • the 0X40 antigen binding protein is ANTIBODY 106-222 (HC of SEQ ID NO: 48 and LC of SEQ ID NO:49).
  • 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.
  • 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.
  • VH or 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.
  • the 0X40 antigen binding protein is ANTIBODY 119-122.
  • 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.
  • 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.
  • 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.
  • the 0X40 antigen binding protein is ANTIBODY 119-43-1.
  • 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.
  • 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.
  • the 0X40 antigen binding protein is MEDI6469; MEDI6383; MEDI0562; MOXR0916 (RG7888); PF-04518600; BMS986178; or INCAGN01949.
  • 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.
  • 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.
  • the 0X40 antigen binding protein is MEDI6469.
  • 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.
  • 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.
  • the 0X40 antigen binding protein is MEDI6383.
  • 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.
  • 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.
  • the 0X40 antigen binding protein is MEDI0562.
  • 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.
  • 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.
  • the 0X40 antigen binding protein is MOXR0916 (RG7888).
  • 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.
  • 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.
  • the 0X40 antigen binding protein is PF-04518600.
  • 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.
  • 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.
  • the 0X40 antigen binding protein is BMS986178.
  • 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.
  • 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.
  • the 0X40 antigen binding protein is INCAGN01949.
  • 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.
  • 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.
  • the 0X40 antigen binding protein is one disclosed in
  • 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.
  • 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%
  • the 0X40 antigen binding protein is one disclosed in
  • 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.
  • 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%
  • the 0X40 antigen binding protein is one disclosed in
  • 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.
  • 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
  • VH or 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.
  • the 0X40 antigen binding protein is one disclosed in WO2013/028231 (PCT/US2012/024570), international filing date 9 February 2012.
  • the antigen binding protein comprises the CDRs of an antibody disclosed in WO2013/028231 (PCT/US2012/024570), international filing date 9 February
  • 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.
  • 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. 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.
  • 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 GenBank database
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • any one of the anti-OX40 ABPs described in this paragraph are humanized.
  • any one of the ABPs described in this paragraph are engineered to make a humanized antibody.
  • 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.
  • 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.
  • the anti-OX40 ABP of a combination of the invention 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.
  • the anti-OX40 ABP of a combination of the invention 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.
  • 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.
  • 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.
  • 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.
  • VL light chain variable region
  • 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.
  • VH heavy chain variable region
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • 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.
  • 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.
  • the PI3Kb inhibitor is a compound of Formula (II):
  • R1 is selected from H, Ci-ealkyl, alkoxy, hydroxy, halogen, -CN, -NH 2 , -NHC(0)Ra, - NHSChRa, -CO 2 H, -C0 2 Ra, -CONHRb, -CONH 2 , -CH 2 OH, and heteroaryl wherein the heteroaryl may be substituted by one or two Ci- 3 alkyl groups;
  • R2 is selected from H, -NHRa, alkoxy, halogen, -CF 3 , -CHF 2 , 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- 3 alkyl
  • Rb is selected from FI, Ci- 3 alkyl, and SChMe;
  • each Rc is independently selected from Ci- 3 alkyl, halogen, -CF 3 , and hydroxy; and n is 0-2,
  • the heteroaryl of R1 is selected from the group consisting of: pyrazolyl, triazolyl, tetrazolyl, oxazolyl and imidazolyl.
  • the aryl or heteroaryl of R3 are selected from phenyl, naphthyl, benzothienyl, quinolinyl, isoquinolinyl, and quinazolinyl.
  • the each Rc is independently Ci- 3 alkyl, F or Cl, and n is 0.
  • the each Rc is independently CF 3 or F, and n is 0.
  • the PI3Kb inhibitor has the Formula (II)(C):
  • each of R6, R7, and R8 is independently selected from Ci- 3 alkyl, halogen, - CF 3 , 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;
  • the PI3Kb inhibitor has the Formula (II)(D):
  • the PI3Kb inhibitor has the Formula (II)(E):
  • each of R6 and R7 is independently selected from Ci-3alkyl, halogen, -CF 3 , and hydroxyl.
  • the PI3Kb inhibitor is:
  • 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.
  • 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).
  • Phosphatase and tensin homolog 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.
  • PTEN protein has both protein phosphatase and lipid phosphatase activity.
  • 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.
  • most types of tumors with PTEN alteration also carry other genetic changes, making the role of PTEN more ambiguous.
  • 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.
  • PI3Kb selective RI3Kb
  • 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).
  • a subject e.g., patient
  • 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).
  • 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).
  • 0X40 e.g., agonistic engagement, e.g., with an agonist antibody, e.g., an agonist antibody described herein
  • 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).
  • 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.
  • 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.
  • NM_000314.4 the protein sequence is NCBI Accession No. AAH05821.1.
  • 0X40 e.g., human 0X40
  • agonistic engagement e.g., with an agonist antibody, e.g., an agonist antibody described herein
  • PI3Kb inhibition e.g., with a PI3Kb inhibitor described herein
  • 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).
  • 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 cancer comprises a PTEN deficient cancer.
  • a subject or a cancer from the subject is identified as having a PTEN deficient cancer.
  • a subject or a cancer from the subject is selected on the basis of having a PTEN deficient cancer.
  • a subject or a cancer from the subject is evaluated to determine whether the cancer is PTEN deficient.
  • the evaluation comprises Q-PCR.
  • 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.
  • 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
  • the cancer comprises a PTEN deficient cancer.
  • a subject or a cancer from the subject is identified as having a PTEN deficient cancer.
  • a subject or a cancer from the subject is selected on the basis of having a PTEN deficient cancer.
  • a subject e.g., patient
  • a cancer from the subject is evaluated to determine whether the cancer is PTEN deficient.
  • the evaluation comprises Q-PCR.
  • 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).
  • 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 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).
  • 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 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 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)
  • 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).
  • 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).
  • 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 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 remedial, 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 disorder e.g., for the treatment of a cancer, e.g., a cancer with loss of
  • 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).
  • 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 cancer is a solid cancer, e.g, a tumor, e.g., a PTEN deficient solid cancer or a PTEN deficient tumor.
  • 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.
  • the cancer is a solid tumor.
  • the cancer is selected from the group consisting of: breast, thyroid, glioblastoma, endometrial, and prostate cancer, and melanoma.
  • the cancer is a liquid tumor.
  • 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.
  • the PI3Kb inhibitor is administered systemically, e.g., intravenously.
  • the antigen binding protein that binds 0X40 is administered intratumorally.
  • the antigen binding protein that binds OX40 is administered systemically, e.g., intravenously.
  • 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.
  • the combination may be synergistic.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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;
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the mammal has increased survival when treated with a
  • the methods further comprise administering at least one anti-neoplastic agent to the mammal in need thereof.
  • compositions 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).
  • an antigen binding protein that binds 0X40 e.g., an agonist antibody to human 0X40 described herein
  • a PI3Kb inhibitor e.g., a PI3Kb inhibitor described herein
  • two pharmaceutical compositions for use in a combination 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).
  • an antigen binding protein that binds 0X40 e.g., an agonist antibody to human 0X40 described herein
  • a PI3Kb inhibitor e.g., a PI3Kb inhibitor described herein
  • 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%,
  • 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
  • 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- ⁇ [
  • 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.
  • 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).
  • an agonist antibody to human 0X40 e.g., an agonist antibody to human 0X40 described herein
  • a PI3Kb inhibitor e.g., a PI3Kb inhibitor described herein
  • 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.
  • 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 lympho

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Abstract

La présente invention concerne une méthode de traitement impliquant la combinaison d'une protéine de liaison à l'antigène OX40 (par exemple, un anticorps agoniste anti-OX40) et un inhibiteur de PI3Kb destinée à être utilisée dans le traitement du cancer, notamment un cancer déficient en PTEN.
PCT/IB2018/059475 2017-12-01 2018-11-29 Polythérapie pour le traitement du cancer WO2019106605A1 (fr)

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WO2021028081A1 (fr) 2019-08-12 2021-02-18 Interna Technologies B.V. Nouveaux traitements impliquant le miarn-193a
WO2021102372A1 (fr) * 2019-11-20 2021-05-27 Abvision, Inc. Anticorps monoclonaux ciblant l'ox40 humaine
WO2021170786A1 (fr) 2020-02-28 2021-09-02 Interna Technologies B.V. Miarn-193a pour favoriser la mort cellulaire immunogène

Citations (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0054951A1 (fr) 1980-12-24 1982-06-30 Chugai Seiyaku Kabushiki Kaisha Dibenzo(b,f)(1,4)oxazépines, leur procédé de préparation et les compositions pharmaceutiques les contenant
WO1986001533A1 (fr) 1984-09-03 1986-03-13 Celltech Limited Production d'anticorps chimeriques
EP0239400A2 (fr) 1986-03-27 1987-09-30 Medical Research Council Anticorps recombinants et leurs procédés de production
US5681835A (en) 1994-04-25 1997-10-28 Glaxo Wellcome Inc. Non-steroidal ligands for the estrogen receptor
US6268391B1 (en) 1997-08-06 2001-07-31 Glaxo Wellcome Inc. Benzylidene-1,3-dihydro-indol-2-one derivatives a receptor tyrosine kinase inhibitors, particularly of Raf kinases
US20050053973A1 (en) 2001-04-26 2005-03-10 Avidia Research Institute Novel proteins with targeted binding
US20050089932A1 (en) 2001-04-26 2005-04-28 Avidia Research Institute Novel proteins with targeted binding
US20050164301A1 (en) 2003-10-24 2005-07-28 Avidia Research Institute LDL receptor class A and EGF domain monomers and multimers
WO2012027328A2 (fr) 2010-08-23 2012-03-01 Board Of Regents, The University Of Texas System Anticorps anti-ox40 et leurs procédés d'utilisation
WO2012047538A1 (fr) 2010-10-06 2012-04-12 Glaxosmithkline Llc Dérivés de benzimidazole utilisés comme inhibiteurs de pi3 kinase
WO2013028231A1 (fr) 2011-08-23 2013-02-28 Board Of Regents, The University Of Texas System Anticorps anti-ox40 et leurs procédés d'utilisation
WO2013038191A2 (fr) 2011-09-16 2013-03-21 Bioceros B.V. Anticorps anti-cd134 (ox40) et leurs utilisations
WO2015153513A1 (fr) 2014-03-31 2015-10-08 Genentech, Inc. Anticorps anti-ox40 et procédés d'utilisation correspondants
WO2015168599A1 (fr) * 2014-05-02 2015-11-05 The Wistar Institute Of Anatomy And Biology Polythérapies ciblant des mitochondries pour une cancérothérapie
WO2016200836A1 (fr) * 2015-06-08 2016-12-15 Genentech, Inc. Méthodes de traitement du cancer au moyen d'anticorps anti-ox40
WO2017021913A1 (fr) * 2015-08-04 2017-02-09 Glaxosmithkline Intellectual Property Development Limited Traitements de combinaison et utilisations et procédés associés

Patent Citations (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0054951A1 (fr) 1980-12-24 1982-06-30 Chugai Seiyaku Kabushiki Kaisha Dibenzo(b,f)(1,4)oxazépines, leur procédé de préparation et les compositions pharmaceutiques les contenant
WO1986001533A1 (fr) 1984-09-03 1986-03-13 Celltech Limited Production d'anticorps chimeriques
EP0239400A2 (fr) 1986-03-27 1987-09-30 Medical Research Council Anticorps recombinants et leurs procédés de production
US5681835A (en) 1994-04-25 1997-10-28 Glaxo Wellcome Inc. Non-steroidal ligands for the estrogen receptor
US5877219A (en) 1994-04-25 1999-03-02 Glaxo Wellcomeinc. Non-steroidal ligands for the estrogen receptor
US6207716B1 (en) 1994-04-25 2001-03-27 Glaxo Wellcome Inc. Non-steroidal ligands for the estrogen receptor
US6268391B1 (en) 1997-08-06 2001-07-31 Glaxo Wellcome Inc. Benzylidene-1,3-dihydro-indol-2-one derivatives a receptor tyrosine kinase inhibitors, particularly of Raf kinases
US20050089932A1 (en) 2001-04-26 2005-04-28 Avidia Research Institute Novel proteins with targeted binding
US20050053973A1 (en) 2001-04-26 2005-03-10 Avidia Research Institute Novel proteins with targeted binding
US20050164301A1 (en) 2003-10-24 2005-07-28 Avidia Research Institute LDL receptor class A and EGF domain monomers and multimers
WO2012027328A2 (fr) 2010-08-23 2012-03-01 Board Of Regents, The University Of Texas System Anticorps anti-ox40 et leurs procédés d'utilisation
WO2012047538A1 (fr) 2010-10-06 2012-04-12 Glaxosmithkline Llc Dérivés de benzimidazole utilisés comme inhibiteurs de pi3 kinase
US8435988B2 (en) 2010-10-06 2013-05-07 Glaxosmithkline Llc Benzimidazole derivatives as P13 kinase inhibitors
WO2013028231A1 (fr) 2011-08-23 2013-02-28 Board Of Regents, The University Of Texas System Anticorps anti-ox40 et leurs procédés d'utilisation
WO2013038191A2 (fr) 2011-09-16 2013-03-21 Bioceros B.V. Anticorps anti-cd134 (ox40) et leurs utilisations
WO2015153513A1 (fr) 2014-03-31 2015-10-08 Genentech, Inc. Anticorps anti-ox40 et procédés d'utilisation correspondants
WO2015168599A1 (fr) * 2014-05-02 2015-11-05 The Wistar Institute Of Anatomy And Biology Polythérapies ciblant des mitochondries pour une cancérothérapie
WO2016200836A1 (fr) * 2015-06-08 2016-12-15 Genentech, Inc. Méthodes de traitement du cancer au moyen d'anticorps anti-ox40
WO2017021913A1 (fr) * 2015-08-04 2017-02-09 Glaxosmithkline Intellectual Property Development Limited Traitements de combinaison et utilisations et procédés associés

Non-Patent Citations (56)

* Cited by examiner, † Cited by third party
Title
"GenBank", Database accession no. AAB39944
"GenBank", Database accession no. AAI05071
"GenBank", Database accession no. CAE11757
"NCBI", Database accession no. AAH05821.1
"NCBI", Database accession no. NM_000314.4
"NCBI", Database accession no. NP_003317
"Tyrosine Kinase Signalling in Breast cancer:erbB Family Receptor Tyrosine Kinases", BREAST CANCER RES., vol. 2, no. 3, 2000, pages 176 - 183
ABRAHAM, R.T., CURRENT OPINION IN IMMUNOLOGY, vol. 8, no. 3, 1996, pages 412 - 8
AGUISSA-TOURE ET AL., CELLULAR AND MOLECULAR LIFE SCIENCES, vol. 69, 2012, pages 1475 - 1491
ASHBY, M.N., CURRENT OPINION IN LIPIDOLOGY, vol. 9, no. 2, 1998, pages 99 - 102
BIOCHIM. BIOPHYS. ACTA, vol. 1423, no. 3, pages 19 - 30
BOLEN, J.B.; BRUGGE, J.S., ANNUAL REVIEW OF IMMUNOLOGY, vol. 15, 1997, pages 371 - 404
BREKKEN, R.A. ET AL.: "Selective Inhibition of VEGFR2 Activity by a monoclonal Anti-VEGF antibody blocks tumor growth in mice", CANCER RES., vol. 60, 2000, pages 5117 - 5124, XP002340113
BRODT, P; SAMANI, A.; NAVAB, R., BIOCHEMICAL PHARMACOLOGY, vol. 60, 2000, pages 1101 - 1107
C DRAHL: "Liveblogging First-Time Disclosures From #ACSSanDiego - The HaystackLiveblogging First-Time Disclosures From #ACSSanDiego - The Haystack | The Haystack", 24 March 2012 (2012-03-24), XP055565036, Retrieved from the Internet <URL:http://cenblog.org/the-haystack/2012/03/liveblogging-first-time-disclosures-from-acssandiego/> [retrieved on 20190306] *
CANMAN, C.E.; LIM, D.S., ONCOGENE, vol. 17, no. 25, 1998, pages 3301 - 3308
CHOTHIA ET AL., NATURE, vol. 342, 1989, pages 877 - 883
D MACAULEY ET AL: "AMERICAN ASSOCIATION FOR CANCER RESEARCH (AACR) 103RD ANNUAL MEETING", DRUGS OF THE FUTURE, vol. 37, 1 January 2012 (2012-01-01), pages 451 - 455, XP055565025, DOI: 10.1358/dof.2012.37.6.1820866 *
EINZIG, PROC. AM. SOC. CLIN. ONCOL., vol. 20, pages 46
FORASTIRE, SEM. ONCOL., vol. 20, 1990, pages 56
GREEN, M.C. ET AL.: "Monoclonal Antibody Therapy for Solid Tumors", CANCER TREAT. REV., vol. 26, no. 4, 2000, pages 269 - 286, XP009019784, DOI: doi:10.1053/ctrv.2000.0176
HOCHMAN, J. ET AL., BIOCHEMISTRY, vol. 12, 1973, pages 1130 - 1135
HODGSON ET AL., BIO/TECHNOLOGY, vol. 9, 1991, pages 421
HOLMES ET AL., J. NAT. CANCER INST., vol. 83, 1991, pages 1797
HOSFORD SARAH R ET AL: "Combined Inhibition of Both p110 alpha and p110 beta Isoforms of Phosphatidylinositol 3-Kinase Is Required for Sustained Therapeutic Effect in PTEN-Deficient, ER+ Breast Cancer", CLINICAL CANCER RESEARCH, THE AMERICAN ASSOCIATION FOR CANCER RESEARCH, US, vol. 23, no. 11, 20 November 2017 (2017-11-20), pages 2795 - 2805, XP009505270, ISSN: 1078-0432, DOI: 10.1158/1078-0432.CCR-15-2764 *
IGNOFF, R.J., CANCER CHEMOTHERAPY POCKET GUIDE, 1998
JACKSON, S.P., INTERNATIONAL JOURNAL OF BIOCHEMISTRY AND CELL BIOLOGY, vol. 29, no. 7, 1997, pages 935 - 8
JOAQUIN MATEO ET AL: "A First-Time-in-Human Study of GSK2636771, a Phosphoinositide 3 Kinase Beta-Selective Inhibitor, in Patients with Advanced Solid Tumors", CLINICAL CANCER RESEARCH, vol. 23, no. 19, 1 October 2017 (2017-10-01), US, pages 5981 - 5992, XP055565051, ISSN: 1078-0432, DOI: 10.1158/1078-0432.CCR-17-0725 *
JUNGHANS ET AL., CANCER RES., vol. 50, 1990, pages 1495
KABAT ET AL.: "Sequences of Proteins of Immunological Interest", 1987, U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
KABAT ET AL.: "Sequences of Proteins of Immunological Interests", 1991, U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
KATH, JOHN C., EXP. OPIN. THER. PATENTS, vol. 10, no. 6, 2000, pages 803 - 818
KEARNS, C.M., SEMINARS IN ONCOLOGY, vol. 3, no. 6, 1995, pages 16 - 23
LACKEY, K. ET AL., BIOORGANIC AND MEDICINAL CHEMISTRY LETTERS, vol. 10, 2000, pages 223 - 226
LOFTS, F. J. ET AL.: "New Molecular Targets for Cancer Chemotherapy", 1994, CRC PRESS, article "Growth factor receptors as targets"
MARKMAN ET AL., YALE JOURNAL OF BIOLOGY AND MEDICINE, vol. 64, 1991, pages 583
MARTINEZ-IACACI, L. ET AL., INT. J. CANCER, vol. 88, no. 1, 2000, pages 44 - 52
MASSAGUE, J.; WEIS-GARCIA, F., CANCER SURVEYS, vol. 27, 1996, pages 41 - 64
MCGUIRE ET AL., ANN. INTEM, MED., vol. 111, 1989, pages 273
PENG ET AL., CANCER DISCOVERY, vol. 6, 2016, pages 202 - 216
PHILIP, P.A.; HARRIS, A.L., CANCER TREATMENT AND RESEARCH, vol. 78, 1995, pages 3 - 27
POWIS, G.; KOZIKOWSKI A.: "New Molecular Targets for Cancer Chemotherapy ed.", 1994, CRC PRESS
QUEEN ET AL., PROC. NATL ACAD SCI USA, vol. 86, 1989, pages 10029 - 10032
ROSANIA ET AL., EXP. OPIN. THER. PATENTS, vol. 10, no. 2, 2000, pages 215 - 230
ROUSSEAUX ET AL., METH. ENZYMOL., vol. 121, 1986, pages 663 - 69
SAKR ET AL., APPL IMMUNOHISTOCHEM MOL MORPHOL., vol. 18, 2010, pages 371 - 374
SCHAROVSKY, O.G.; ROZADOS, V.R.; GERVASONI, S.I.; MATAR, P., JOURNAL OF BIOMEDICAL SCIENCE, vol. 7, no. 4, 2000, pages 292 - 8
SHARON, J. ET AL., BIOCHEMISTRY, vol. 15, 1976, pages 1591 - 1594
SHAWVER ET AL., DDT, vol. 2, no. 2, February 1997 (1997-02-01)
SINH, S.; COREY, S.J., JOURNAL OF HEMATOTHERAPY AND STEM CELL RESEARCH, vol. 8, no. 5, 1999, pages 465 - 80
SMITHGALL, T.E., JOURNAL OF PHARMACOLOGICAL AND TOXICOLOGICAL METHODS, vol. 34, no. 3, 1995, pages 125 - 32
WAHL ET AL., J. NUC. MED., vol. 24, 1983, pages 316 - 325
WEIYI PENG ET AL: "Abstract 4938: OX40 agonist antibody-based combination therapy with PI3K[beta] selective inhibitor enhances T cell immunity", CANCER RESEARCH, vol. 78, no. 13 Supplement, 1 July 2018 (2018-07-01), US, pages 4938 - 4938, XP055564793, ISSN: 0008-5472, DOI: 10.1158/1538-7445.AM2018-4938 *
WOO, NATURE, vol. 368, 1994, pages 750
YAMAMOTO, T.; TAYA, S.; KAIBUCHI, K., JOURNAL OF BIOCHEMISTRY, vol. 126, no. 5, 1999, pages 799 - 803
ZHONG, H. ET AL., CANCER RES, vol. 60, no. 6, 2000, pages 1541 - 1545

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WO2021028081A1 (fr) 2019-08-12 2021-02-18 Interna Technologies B.V. Nouveaux traitements impliquant le miarn-193a
WO2021102372A1 (fr) * 2019-11-20 2021-05-27 Abvision, Inc. Anticorps monoclonaux ciblant l'ox40 humaine
WO2021170786A1 (fr) 2020-02-28 2021-09-02 Interna Technologies B.V. Miarn-193a pour favoriser la mort cellulaire immunogène

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