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WO2020030570A1 - Combinaisons d'un anticorps ox40 et d'un modulateur de tlr4 et leurs utilisations - Google Patents

Combinaisons d'un anticorps ox40 et d'un modulateur de tlr4 et leurs utilisations Download PDF

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WO2020030570A1
WO2020030570A1 PCT/EP2019/070978 EP2019070978W WO2020030570A1 WO 2020030570 A1 WO2020030570 A1 WO 2020030570A1 EP 2019070978 W EP2019070978 W EP 2019070978W WO 2020030570 A1 WO2020030570 A1 WO 2020030570A1
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agonist
dose
crx
binding protein
administered
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Bruce A HUG
Christopher J MATHENY
Elaine Marie PAUL
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GlaxoSmithKline Intellectual Property Development Ltd
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GlaxoSmithKline Intellectual Property Development Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7008—Compounds having an amino group directly attached to a carbon atom of the saccharide radical, e.g. D-galactosamine, ranimustine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • 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
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • 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 to a method of treating cancer in a mammal and to combinations useful in such treatment.
  • the present invention relates to combinations of an 0X40 binding protein and one or more TLR4 agonist.
  • cancer results from the deregulation of the normal processes that control cell division, differentiation and apoptotic cell death and is characterized by the proliferation of malignant cells which have the potential for unlimited growth, local expansion and systemic metastasis.
  • Deregulation of normal processes includes abnormalities in signal transduction pathways and response to factors that differ from those found in normal cells.
  • Immunotherapies are one approach to treat hyperproliferative disorders.
  • a major hurdle that scientists and clinicians have encountered in the development of various types of cancer immunotherapies has been to break tolerance to self antigen (cancer) in order to mount a robust anti-tumor response leading to tumor regression.
  • cancer self antigen
  • immunotherapies target cells of the immune system that have the potential to generate a memory pool of effector cells to induce more durable effects and minimize recurrences.
  • 0X40 is a co-stimulatory molecule involved in multiple processes of the immune system.
  • Antigen binding proteins and antibodies that bind 0X40 receptor and modulate 0X40 signaling are known in the art and are disclosed as immunotherapy, for example, for cancer.
  • Aminoalkyl glucosaminide phosphates are synthetic ligands of Toll-like
  • TLR4 Receptor 4
  • kits for treating cancer in a human with the compositions of the invention and uses of the combinations for therapy, such as therapy for cancer.
  • methods for modulating the immune response of a subject in need of cancer treatment, such as a human comprising administering to said subject an effective amount of the combination, e.g., in one or more pharmaceutical compositions.
  • the disclosure is drawn to a method of treatment of a subject with cancer, the method comprising: administering to the subject an agonist 0X40 binding protein and a TLR4 agonist, wherein the agonist 0X40 binding protein is administered at a dose of about 8 mg to about 24 mg and the TLR4 agonist is administered at a dose of about 5 ng to about 1000 ng.
  • the TLR4 agonist is administered at a dose of about 50 ng to about 250 ng.
  • the disclosure is drawn to an agonist 0X40 binding protein and a TLR4 agonist for simultaneous or sequential use in treating cancer, wherein the agonist 0X40 binding protein is to be administered at a dose of about 8 mg to about 24 mg and the TLR4 agonist is to be administered at a dose of about 5 ng to about 1000 ng. In an embodiment, the TLR4 agonist is to be administered at a dose of about 50 ng to about 250 ng.
  • the disclosure is drawn to an agonist 0X40 binding protein for use in treating cancer, wherein the agonist 0X40 binding protein is to be administered at a dose of about 8 mg to about 24 mg and is to be administered simultaneously or sequentially with a TLR4 agonist at a dose of about 5 ng to about 1000 ng. In an embodiment, the TLR4 agonist is to be administered at a dose of about 50 ng to about 250 ng. In some aspects, the disclosure is drawn to a TLR4 agonist for use in treating cancer, wherein the TLR4 agonist is to be administered at a dose of about 5 ng to about 1000 ng and is to be administered simultaneously or sequentially with an agonist 0X40 binding protein at a dose of about 8 mg to about 24 mg. In an embodiment, the TLR4 agonist is to be administered at a dose of about 50 ng to about 250 ng.
  • the disclosure is drawn to use of an agonist 0X40 binding protein in the manufacture of a medicament for treating cancer, wherein the 0X40 binding protein is to be administered at a dose of about 8 mg to about 24 mg and is to be administered simultaneously or sequentially with a TLR4 agonist at a dose of about 5 ng to about 1000 ng.
  • the TLR4 agonist is to be administered at a dose of about 50 ng to about 250 ng.
  • the disclosure is drawn to use of a TLR4 agonist in the manufacture of a medicament for treating cancer, wherein the TLR4 agonist is to be administered at a dose of about 5 ng to about 1000 ng and is to be administered simultaneously or sequentially with an agonist 0X40 binding protein at a dose of about 8 mg to about 24 mg. In an embodiment, the TLR4 agonist is to be administered at a dose of about 50 ng to about 250 ng.
  • the disclosure is drawn to a pharmaceutical kit comprising about 8 mg to about 24 mg of an agonist 0X40 binding protein and about 5 ng to 1000 ng of a TLR4 agonist.
  • the TLR4 agonist is to be administered at a dose of about 50 ng to about 250 ng.
  • the agonist 0X40 binding protein is administered intravenously.
  • the TLR4 agonist is administered intravenously.
  • the TLR4 agonist is administered subcutaneously.
  • the TLR4 agonist is administered intratumorally.
  • the agonist 0X40 binding protein is administered intravenously and the TLR4 agonist is administered intravenously. In some embodiments, the agonist 0X40 binding protein is administered at a dose of about 8 mg.
  • the agonist 0X40 binding protein is administered at a dose of about 24 mg. In some embodiments, the TLR4 agonist is administered at a dose of about 5 ng to about 1000 ng.
  • the TLR4 agonist is administered at a dose of about 50 ng to about 250 ng.
  • the TLR4 agonist is administered at a dose of about 50 ng. In some embodiments, the TLR4 agonist is administered at a dose of about 100 ng.
  • the TLR4 agonist is administered at a dose of about 150 ng.
  • the TLR4 agonist is administered at a dose of about 200 ng.
  • the TLR4 agonist is administered at a dose of about 250 ng.
  • the TLR4 agonist is administered at a dose of about 300 ng. In some embodiments, the TLR4 agonist is administered at a dose of about 350 ng.
  • the TLR4 agonist is administered at a dose of about 400 ng.
  • the TLR4 agonist is administered at a dose of about 450 ng.
  • the TLR4 agonist is administered at a dose of about 500 ng.
  • the TLR4 agonist is administered at a dose of about 550 ng. In some embodiments, the TLR4 agonist is administered at a dose of about 600 ng.
  • the TLR4 agonist is administered at a dose of about 600 ng to about 1000 ng.
  • the agonist 0X40 binding protein comprises (a) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: l ; (b) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO:2; (c) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO:3; (d) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO:7; (e) a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 8; and (f) a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO:9.
  • the agonist 0X40 binding protein comprises a heavy chain variable region comprising the amino acid sequence as set forth in SEQ ID NO:5; and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: l l .
  • the agonist 0X40 binding protein is a humanized monoclonal antibody.
  • the agonist 0X40 binding protein comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:48 and a light chain comprising the amino acid sequence set forth in SEQ ID NO:49.
  • the TLR4 agonist is selected from the group consisting of: CRX- 601; CRX-547; CRX-602; and CRX-527.
  • the TLR4 agonist is CRX-527.
  • the TLR4 agonist is CRX-601.
  • the cancer comprises a solid tumor.
  • the cancer comprises squamous cell carcinoma of head and neck (SCCHN).
  • SCCHN squamous cell carcinoma of head and neck
  • the SCCHN is recurrent, locally advanced, or metastatic.
  • the TLR4 agonist and the agonist 0X40 binding protein are both periodically administered. In some embodiments, the TLR4 agonist and the agonist 0X40 binding protein are both administered to the subject every three weeks.
  • the TLR4 agonist is administered for a two-week run in period (e.g. , the TLR4 agonist is administered on day 1 and 8) prior to administering the agonist 0X40 binding protein.
  • the TLR4 agonist is administered for a two-week run in period (e.g., the TLR4 agonist is administered on day 1 and 8), and following the run in period, the TLR4 agonist and the agonist 0X40 binding protein are both administered to the subject, e.g., every three weeks, e.g. starting on day 15.
  • Figure 1A is a graph showing dose-dependent anti-tumor activity (as measured by tumor growth inhibition over time) of TLR4 agonist (CRX-527) in a CT-26 syngeneic mouse model of colon cancer. Results are the mean of 10 animals.
  • Figure IB is a graph showing dose-dependent anti-tumor activity (as measured by tumor growth inhibition over time) of a rat anti-mouse 0X40 receptor antibody (clone OX-86) in a CT-26 syngeneic mouse model of colon cancer. Results are the mean of 10 animals; control treatments in Figure 1A are the same as those in FigurelB.
  • Figure 2 is a graph showing anti-tumor activity (as measured by tumor growth inhibition over time) of a rat anti-mouse 0X40 receptor antibody (clone OX-86), 5 pg of TLR4 agonist (CRX-527), and the combination of both in a CT-26 syngeneic mouse model of colon cancer. Results are the mean of 10 animals.
  • Figure 3 is a graph showing dose-dependent anti-tumor activity (as measured by tumor growth inhibition over time) of a rat anti-mouse 0X40 receptor antibody (clone OX-86), 25 pg of TLR4 agonist (CRX-527), and the combination of both in a CT-26 syngeneic mouse model of colon cancer measured over 38 days. Results are the mean of 10 animals; control treatments in Figure 2 represent identical animals as those in Figure 3.
  • Figures 4A-4F are graphs showing dose-dependent anti-tumor activity (as measured by tumor growth inhibition over time) in individual mice of a control antibody (IgG), rat anti-mouse 0X40 receptor antibody (clone OX-86), 5 or 25 pg of TLR4 agonist (CRX- 527), and the combination of 0X86 and CRX-527 in a group of mice in a CT-26 syngeneic mouse model of colon cancer measured over 42 days.
  • the average group tumor volume for mice remaining on study in Figures 4A-4F were used to generate the plots in Figures 2-3.
  • Figure 5 is a graph showing dose-dependent anti-tumor activity (as measured by tumor growth inhibition over time) of 4, 20, or 100 pg of TLR4 agonist (CRX-601) in a CT-26 syngeneic mouse model of colon cancer.
  • Figures 6-12 show sequences of the ABPs and antibodies of the invention, e.g., CDRs and VH and VL sequences.
  • Figures 13-17 show sequences of ABPs and antibodies of the invention, e.g., CDRs and VH and VL sequences.
  • Figure 18 is a graph showing dose-dependent anti-tumor activity (as measured by tumor growth inhibition over time) of the TLR4 agonist CRX-601 dosed intratumoral in a CT- 26 syngeneic mouse tumor model.
  • Figure 19 is a graph showing survival curves of mice treated with the TLR4 agonist CRX-601 intratumoral dosed intratumoral in a CT-26 syngeneic mouse tumor model. (*p-values ⁇ 0.05).
  • Figure 20 is a graph showing dose-dependent anti-tumor activity (as measured by tumor growth inhibition over time) of the TLR4 agonist CRX-601 in a CT-26 syngeneic mouse tumor model. (*p-values ⁇ 0.05)
  • Figure 21 is a graph showing survival curves of mice treated with the TLR4 agonist CRX-601 dosed intravenous in a CT-26 syngeneic mouse tumor model (*p- values ⁇ 0.05).
  • Figure 22 is a graph showing anti-tumor activity (as measured by tumor growth inhibition over time) of 25 pg/mouse of a rat anti-mouse 0X40 antibody clone OX-86, dosed Anti-tumor activity (as measured by tumor growth inhibition over time) of 25 pg/mouse of a rat anti-mouse 0X40 antibody clone OX-86, dosed via intraperitoneal injection twice per week for 6 doses total, 10 pg or 25 pg/mouse of TLR4 agonist CRX- 601 dosed intravenous lx/week for 3 doses total, and the combination of both in a CT-26 syngeneic mouse model.
  • Figure 23 is a graph showing survival curves of mice treated with 25 pg/mouse of a rat anti-mouse 0X40 receptor antibody (clone OX-86), dosed via intraperitoneal injection twice per week for 6 doses total, 10 pg or 25 pg of TLR4 agonist CRX-601 dosed intravenous lx/week for 3 doses total, and the combination of both in a CT-26 syngeneic mouse model. (*p-values ⁇ 0.05)
  • Figure 24 is a graph showing anti-tumor activity (as measured by tumor growth inhibition over time) of 25 pg/mouse of a rat anti-mouse 0X40 receptor antibody (clone OX-86), dosed via intraperitoneal injection twice per week for 6 doses total, or 25 pg/mouse of TLR4 agonist CRX-601 dosed intravenous lx/week for 3 doses total, and the combination of both in a CT-26 syngeneic mouse model. (*p-values ⁇ 0.05)
  • Figure 25 shows survival curves of mice treated with 25 pg/mouse of a rat anti-mouse 0X40 receptor antibody (clone OX-86), dosed via intraperitoneal injection twice per week for 6 doses total, or 25 pg/mouse of TLR4 agonist CRX-601 dosed intravenous lx/week for 3 doses total, and the combination of both in a CT-26 syngeneic mouse model. (*p-values ⁇ 0.05)
  • Figures 26 A-C are graphs showing increase of leukocytes and immune-activation in mice treated with 10 pg of TLR4 agonist CRX-601, 25 pg of a rat anti-mouse 0X40 receptor antibody (clone OX-86), and the combination of both in a CT-26 syngeneic mouse model of colon cancer measured at 8 days post-dosing.
  • Figures 27 A-B are graphs showing increases of immune-activating cytokines TNF alpha (A) and IL-l2p70 (B) in mice treated with 10 pg of TLR4 agonist CRX-601 , a rat anti mouse OX40R receptor antibody (clone OX-86), and the combination of both in a CT-26 syngeneic mouse model of colon cancer measured at 1 and 8 days post dosing.
  • Figure 28 is a graph showing anti-tumor activity (as measured by tumor growth inhibition over time) of 25 pg/mouse of a rat anti-mouse 0X40 receptor antibody (clone OX-86), dosed via intraperitoneal injection twice per week for 6 doses total, or 25 pg/mouse of TLR4 agonist CRX-601 dosed intravenous lx/week for 3 doses total, and the combination of both in a CT-26 syngeneic mouse model. (0.5% Glycerol/4%
  • Figure 29 is a graph showing anti-tumor activity (as measured by tumor growth inhibition over time) of 25 pg/mouse of a rat anti-mouse 0X40 receptor antibody (clone OX-86), dosed via intraperitoneal injection twice per week for 6 doses total, or 25 pg/mouse of TLR4 agonist CRX-601 dosed intratumoral lx/week for 3 doses total, and the combination of both in a CT-26 syngeneic mouse model. (0.5% Glycerol/4%
  • Figure 30 is a graph showing survival curves of mice treated with 25 pg/mouse of a rat anti-mouse 0X40 antibody (clone OX-86), dosed via intraperitoneal injection twice per week for 6 doses total, or 25 pg/mouse of TLR4 agonist CRX-601 dosed intravenous lx/week for 3 doses total, and the combination of both in a CT-26 syngeneic mouse model. (0.5% Glycerol/4% Dextrose vehicle used for CRX-601) (*p-values ⁇ 0.05)
  • Figure 31 is a graph showing survival curves of mice treated with 25 pg/mouse of a rat anti-mouse 0X40 receptor antibody (clone OX-86), dosed via intraperitoneal injection twice per week for 6 doses total, or 25 pg/mouse of TLR4 agonist CRX-601 dosed intratumoral lx/week for 3 doses total, and the combination of both in a CT-26 syngeneic mouse model. (0.5% Glycerol/4% Dextrose vehicle used for CRX-601) Cp- values ⁇ 0.05)
  • Figure 32 is a graph showing CT-26 tumor re-challenge of tumor- free mice in study 6.
  • tumor-free mice were re-challenged with CT-26 tumor cells.
  • Naive control mice were also included. While tumors grew as expected in the control naive mice, tumors were rejected and no tumors grew in the treatment groups.
  • Figure 33 is a graph showing anti-tumor activity (as measured by tumor growth inhibition over time) of 25 pg/mouse of a rat anti-mouse 0X40 receptor antibody (clone OX-86), dosed via intraperitoneal injection twice per week for 6 doses total, or 25 pg/mouse of TLR4 agonist CRX-601 dosed intravenous lx/week for 3 doses total, and the combination of both in a CT-26 syngeneic mouse model. (0.5% Glycerol/4%
  • Figure 34 is a graph showing anti-tumor activity (as measured by tumor growth inhibition over time) of 25 pg/mouse of a rat anti-mouse 0X40 receptor antibody (clone OX-86), dosed via intraperitoneal injection twice per week for 6 doses total, or 25 pg/mouse of TLR4 agonist CRX-601 dosed intratumoral lx/week for 3 doses total, and the combination of both in a CT-26 syngeneic mouse model. (DOPC/CHOL Liposome formulation used for CRX-601 intratumoral dosing) (*p- values ⁇ 0.05).
  • Figure 35 is a graph showing survival curves of mice treated with 25 pg/mouse of a rat anti-mouse 0X40 receptor antibody (clone OX-86), dosed via intraperitoneal injection twice per week for 6 doses total, or 25 pg/mouse of TLR4 agonist CRX-601 dosed intravenous lx/week for 3 doses total, and the combination of both in a CT-26 syngeneic mouse model. (0.5% Glycerol/4% Dextrose vehicle used for CRX-601 intravenous dosing) (*p-values ⁇ 0.05).
  • Figure 36 is a graph showing survival curves of mice treated with 25 pg/mouse of a rat anti-mouse 0X40 receptor antibody (clone OX-86), dosed via intraperitoneal injection twice per week for 6 doses total, or 25 pg/mouse of TLR4 agonist CRX-601 dosed intravenous lx/week for 3 doses total, and the combination of both in a CT-26 syngeneic mouse model. (0.5% Glycerol/4% Dextrose vehicle used for CRX-601 intravenous dosing) (*p-values ⁇ 0.05).
  • Figure 37 is a graph showing CT-26 tumor re-challenge of tumor-free mice in study 7.
  • FIG. 38 is a graph showing tumor growth of individual mice of Group 7: CRX-601 25 pg/mouse (in 0.5% glycerol/4% dextrose) dosed intravenous once per week for 3 doses total + 0X86 25 pg/mouse dosed intraperontoneal twice per week for 6 doses total.
  • Figure 39 is a graph showing tumor growth of individual mice of Group 8: CRX-601 25 pg/mouse (in 0.5% glycerol/4% dextrose) dosed intratumoral once per week in the left flank tumor for 3 doses total + 0X86 25 pg/mouse dosed intraperontoneal twice per week for 6 doses total.
  • Figure 40 is a graph showing tumor growth of individual mice of Group 12: CRX-601 25 pg/mouse (in DOPC/CHOL Liposome) dosed intratumoral once per week in the left flank tumor for 3 doses total + 0X86 25 pg/mouse dosed intraperontoneal twice per week for 6 doses total
  • Figure 41A-4D are graphs showing survival curves for all treatment groups in Study 8. Mice remaining on study by day 60 were completely tumor-free.
  • Figure 42A-C are graphs showing upregulation of 0X40 expression induced by CRX601 treatment with a range of concentrations (0.01 - 1000 ng/ml) on human CD4+ T cells (A), dendritic cells (B), and monocytes (C) at 24 hours in in vitro cell culture.
  • Figure 43 is a graph showing CT-26 tumor growth in Balb/c mice treated with CRX-601 (TLR4 agonist) and/or 0X86 (mouse surrogate for 0X40) agonist.
  • Figure 44 is a graph showing survival of Balb/c mice implanted with CT-26 tumors and treated with CRX-601 (TLR4 agonist) and/or 0X86 agonist.
  • Figure 45 is a graph showing Median Receptor Occupancy Profiles for Varying Doses of ANTIBODY 106-222.
  • compositions and Combinations Improved function of the immune system is a goal of immunotherapy for cancer. While not being bound by theory, it is thought that for the immune system to be activated and effectively cause regression or eliminate tumors, there must be efficient cross-talk among the various compartments of the immune system as well as at the tumor bed.
  • the tumoricidal effect is dependent on one or more steps, e.g., the uptake of antigen by immature dendritic cells and presentation of processed antigen via MHC I and II by mature dendritic cells to naive CD8 (cytotoxic) and CD4 (helper) lymphocytes, respectively, in the draining lymph nodes.
  • Naive T cells express molecules, such as CTLA-4 and CD28, that engage with co-stimulatory molecules of the B7 family on antigen presenting cells (APCs) such as dendritic cells.
  • APCs antigen presenting cells
  • B7 on APCs preferentially binds to CTLA-4, an inhibitory molecule on T lymphocytes.
  • TCR T cell receptor
  • MHC Class I or II receptors MHC Class I or II receptors
  • the co stimulatory molecule disengages from CTLA-4 and instead binds to the lower affinity stimulatory molecule CD28, causing T cell activation and proliferation.
  • This expanded population of primed T lymphocytes retains memory of the antigen that was presented to them as they traffic to distant tumor sites.
  • cytolytic mediators such as granzyme B and perforins.
  • This apparently simplistic sequence of events is highly dependent on several cytokines, co-stimulatory molecules and check point modulators to activate and differentiate these primed T lymphocytes to a memory pool of cells that can eliminate the tumor.
  • an emerging immunotherapeutic strategy is to target T cell co-stimulatory molecules, e.g., 0X40.
  • 0X40 e.g., hOX40 or hOX40R
  • hOX40R a tumor necrosis factor receptor family member that is expressed, among other cells, on activated CD4 and CD8 T cells.
  • One of its functions is in the differentiation and long-term survival of these cells.
  • the ligand for 0X40 (OX40L) is expressed by activated antigen-presenting cells.
  • the ABPs and antibodies of the invention 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 ABPs and antibodies of the invention bind and engage 0X40.
  • the ABPs and antibodies of the invention modulate 0X40.
  • the ABPs and antibodies of the invention modulate 0X40 by mimicking OX40L.
  • the ABPs and antibodies of the invention are agonist antibodies.
  • the ABPs and antibodies of the invention modulate 0X40 and cause proliferation of T cells.
  • the ABPs and antibodies of the invention modulate 0X40 and improve, augment, enhance, or increase proliferation of CD4 T cells.
  • the ABPs and antibodies of the invention improve, augment, enhance, or increase proliferation of CD8 T cells.
  • the ABPs and antibodies of the invention improve, augment, enhance, or increase proliferation of both CD4 and CD8 T cells.
  • the ABPs and antibodies of the invention enhance T cell function, e.g., of CD4 or CD8 T cells, or both CD4 and CD8 T cells.
  • the ABPs and antibodies of the invention enhance effector T cell function.
  • the ABPs and antibodies of the invention improve, augment, enhance, or increase long term survival of CD8 T cells. In further embodiments, any of the preceding effects occur in a tumor microenvironment.
  • Tregs T regulatory cells
  • TGF-b Transforming Growth Factor
  • IL-10 interleukin- 10
  • An important 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.
  • Treg cells help to maintain tolerance to self antigens and are naturally suppressive in function, and they phenotypically characterized as CD4+, CD25+, FOXP3+ cells.
  • one mode of therapy is to eliminate Tregs preferentially at tumor sites. Targeting and eliminating Tregs leading to an anti-tumor response has been more successful in tumors that are immunogenic compared to those that are poorly
  • cytokines e.g., TGF-b that may hamper the immune response by causing precursor CD4+25+ cells to acquire the FOXP3+ phenotype and function as Tregs.
  • “Modulate” as used herein, for example, with regard to a receptor or other target means to change any natural or existing function of the receptor, for example it means affecting binding of natural or artificial ligands to the receptor or target; it includes initiating any partial or full conformational changes or signaling through the receptor or target, and also includes preventing partial or full binding of the receptor or target with its natural or artificial ligands. Also included in the case of membrane bound receptors or targets are any changes in the way the receptor or target interacts with other proteins or molecules in the membrane or change in any localization (or co-localization with other molecules) within membrane compartments as compared to its natural or unchanged state.
  • Modulators are, therefore, compounds or ligands or molecules that modulate a target or receptor.“Modulate” includes agonizing, e.g., signaling, as well as antagonizing, or blocking signaling or interactions with a ligand or compound or molecule that happen in the unchanged or unmodulated state. Thus, modulators may be agonists or antagonists. Further, one of skill in the art will recognize that not all modulators will have absolute selectivity for one target or receptor, but are still considered a modulator for that target or receptor; for example, a TLR4 modulator may also engage another TLR, but still be considered a TLR4 modulator. Other modulators are known to have multiple
  • TLR7/8 modulators that modulate both TLR7 and TLR8. Molecules with such known double or multiple specificities are considered a modulator of each of its target; that is, a TLR7/8 modulator is a TLR7 modulator as used herein and likewise a TLR7/8 modulator is a TLR8 modulator as used herein.
  • the term“agonist” refers to an antigen binding protein, including but not limited to an antibody, which upon contact with a co-signaling 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 signaling, cell proliferation, immune cell activation markers, 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.
  • the 0X40 binding protein or antibody inhibits the suppressive effect of Treg cells on other T cells, e.g., within the tumor environment.
  • the 0X40 binding proteins or antibodies of the invention modulate 0X40 to augment T effector number and function and inhibit Treg function.
  • Enhancing, augmenting, improving, increasing, and otherwise changing the anti-tumor effect of 0X40 is an object of the invention. Described herein are combinations of an 0X40 binding protein such as an antibody and another compound, such as a TLR modulator described herein.
  • the term“combination of the invention” refers to a combination comprising an 0X40 binding protein, such as an antibody, and a TLR4 modulator, such as an AGP, each of which may be administered separately or simultaneously as described herein.
  • cancer As used herein, the terms“cancer”,“neoplasm”, and“tumor”, are used interchangeably and in either the singular or plural form, refer to cells that have undergone a malignant transformation or undergone cellular changes that result in aberrant or unregulated growth or hyperproliferation. Such changes or malignant transformations usually make such cells pathological to the host organism, thus precancers or pre-cancerous 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
  • a cancer cell includes not only a primary cancer cell, but any cell derived from a cancer cell ancestor. This includes metastasized cancer cells, and in vitro cultures and cell lines derived from cancer cells.
  • 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.
  • tumors may be hematopoietic tumor, 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” means a substance that produces a desired effect in a tissue, system, animal, mammal, human, or other subject.
  • the term,“anti neoplastic agent”, means a substance producing an anti-neoplastic effect in a tissue, system, animal, mammal, human, or other subject.
  • the term,“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; or (4) to slow the progression of the condition or one or more of the biological manifestations of the condition.
  • “prevention” means the prophylactic administration of a drug, such as an agent, 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.
  • a drug such as an agent
  • “prevention” is not an absolute term. 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 agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term “effective amount” means that amount of a drug or agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term “effective amount” means that amount of a drug or agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term
  • “therapeutically effective amount” means any amount that, as compared to a
  • an 0X40 binding protein and/or a TLR4 modulator can be administered to a subject or used in an effective amount (such as a therapeutically effective amount), e.g., in the methods and uses described herein.
  • combination kit means the pharmaceutical composition or compositions that are used to administer Compound A, or a pharmaceutically acceptable salt thereof, and Compound B, or a pharmaceutically acceptable salt thereof, according to the invention.
  • the combination kit can contain Compound A, or a pharmaceutically acceptable salt thereof, and
  • the combination kit will contain Compound A, or a pharmaceutically acceptable salt thereof, and Compound B, or a pharmaceutically acceptable salt thereof, in separate pharmaceutical compositions.
  • the combination kit can comprise Compound A, or a pharmaceutically acceptable salt thereof, and Compound B, or a pharmaceutically acceptable salt thereof, in separate pharmaceutical compositions in a single package or in separate pharmaceutical compositions in separate packages.
  • the invention provides a combination kit comprising the
  • Compound A e.g ., an OX-40 binding protein, e.g., at a dose of about 8 mg to about 24 mg, at a dose of about 8 mg, or at a dose of about 24 mg), or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier; and
  • Compound B e.g., a TLR4 agonist, e.g., at a dose of about 50 ng to about 250 ng
  • a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable carrier.
  • the combination kit comprises the following components:
  • Compound A e.g., an OX-40 binding protein, e.g., at a dose of about 8 mg to about 24 mg, at a dose of about 8 mg, or at a dose of about 24 mg), or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier; and
  • Compound B e.g., a TLR4 agonist, e.g., at a dose of about 50 ng to about 250 ng
  • a pharmaceutically acceptable carrier e.g., a pharmaceutically acceptable carrier
  • the combination kit comprises: a first container comprising Compound A (e.g., an OX-40 binding protein, e.g., at a dose of about 8 mg to about 24 mg, at a dose of about 8 mg, or at a dose of about 24 mg), or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier; and a second container comprising Compound B (e.g ., a TLR4 agonist, e.g., at a dose of about 50 ng to about 250 ng), or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier, and a container means for containing said first and second containers.
  • Compound A e.g., an OX-40 binding protein, e.g., at a dose of about 8 mg to about 24 mg, at a dose of about 8 mg, or at a dose of about 24 mg
  • Compound B e.g ., a TLR4 agonist, e.g., at a dose of about 50 ng to
  • The“combination kit” can also be provided by instruction, such as dosage and administration instructions.
  • dosage and administration instructions can be of the kind that is provided to a doctor, for example by a drug product label, or they can be of the kind that is provided by a doctor, such as instructions to a patient.
  • Compound A 2 means a monoclonal antibody to human OX-40 or the antigen binding portion thereof.
  • Compound A 2 means a humanized monoclonal antibody having a heavy chain variable region as set forth in SEQ ID NO:5 and a light chain variable region as set forth in SEQ ID NO: 1 1.
  • Compound A 2 can mean a humanized monoclonal antibody having a heavy chain as set forth in SEQ ID NO:48 and a light chain as set forth in SEQ ID NO:49.
  • Compound B 2 means a TLR4 agonist of Formula I or Formula la.
  • Compound B 2 means the TLR4 agonist CRX-601.
  • Compound B 2 means the TLR4 agonist CRX-527.
  • the combinations of this invention are administered within a“specified period”.
  • specified period and grammatical variations thereof, as used herein, means the interval of time between the administration of one of Compound A 2 and Compound B 2 and the other of Compound A 2 and Compound B 2 .
  • the specified period can include simultaneous administration.
  • the specified period refers to administration of Compound A 2 and Compound B 2 during a single day.
  • the specified period will be about 24 hours.; suitably they will both be administered within about 12 hours of each other - in this case, the specified period will be about 12 hours; suitably they will both be administered within about 1 1 hours of each other - in this case, the specified period will be about 11 hours; suitably they will both be administered within about 10 hours of each other - in this case, the specified period will be about 10 hours; suitably they will both be administered within about 9 hours of each other - in this case, the specified period will be about 9 hours; suitably they will both be administered within about 8 hours of each other - in this case, the specified period will be about 8 hours; suitably they will both be administered within about 7 hours of each other - in this case, the specified period will be about 7 hours; suitably they will both be administered within about 6 hours of each other - in this case, the specified period will be about 6 hours; suitably they will be about 6 hours; suitably they will be about 6 hours; suitably they will be about 6 hours; suitably they will be about 6 hours; suitably they will
  • the compounds when the combination of the invention is administered for a“specified period”, the compounds will be co-administered for a“duration of time”.
  • duration of time and grammatical variations thereof, as used herein means that both compounds of the invention are administered for an indicated number of consecutive days. Unless otherwise defined, the number of consecutive days does not have to commence with the start of treatment or terminate with the end of treatment, it is only required that the number of consecutive days occur at some point during the course of treatment.
  • both compounds will be administered within a specified period for at least one day - in this case, the duration of time will be at least one day; suitably, during the course to treatment, both compounds will be administered within a specified period for at least 3 consecutive days - in this case, the duration of time will be at least 3 days; suitably, during the course to treatment, both compounds will be administered within a specified period for at least 5 consecutive days - in this case, the duration of time will be at least 5 days; suitably, during the course to treatment, both compounds will be administered within a specified period for at least 7 consecutive days - in this case, the duration of time will be at least 7 days; suitably, during the course to treatment, both compounds will be administered within a specified period for at least 14 consecutive days - in this case, the duration of time will be at least 14 days; suitably, during the course to treatment, both compounds will be administered within a specified period for at least 30 consecutive days - in this case, the duration of time will be at least 30 days.
  • both compounds are administered within a specified period (e.g ., within one day, e.g., at least an hour between administration of the two compounds) which specified period occurs every three weeks.
  • the compounds are not administered during a specified period, they are administered sequentially.
  • sequential administration and grammatical derivates thereof, as used herein is meant that one of Compound A 2 and Compound B 2 is administered once a day for two or more consecutive days and the other of Compound A 2 and Compound B 2 is subsequently administered once a day for two or more consecutive days.
  • a drug holiday utilized between the sequential administration of one of Compound A 2 and Compound B 2 and the other of Compound A 2 and Compound B 2 .
  • a drug holiday is a period of days after the sequential administration of one of Compound A 2 and Compound B 2 and before the administration of the other of Compound A 2 and Compound B 2 where neither Compound A 2 nor Compound B 2 is administered.
  • the drug holiday will be a period of days selected from: 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 1 1 days, 12 days, 13 days and 14 days.
  • one of Compound A 2 and Compound B 2 is administered for from 1 to 30 consecutive days, followed by an optional drug holiday, followed by administration of the other of Compound A 2 and Compound B 2 for from 1 to 30 consecutive days.
  • one of Compound A 2 and Compound B 2 is administered for from 1 to 21 consecutive days, followed by an optional drug holiday, followed by administration of the other of Compound A 2 and Compound B 2 for from 1 to 21 consecutive days.
  • one of Compound A 2 and Compound B 2 is administered for from 1 to 14 consecutive days, followed by a drug holiday of from 1 to 14 days, followed by administration of the other of Compound A 2 and Compound B 2 for from 1 to 14 consecutive days.
  • one of Compound A 2 and Compound B 2 is administered for from 1 to 7 consecutive days, followed by a drug holiday of from 1 to 10 days, followed by administration of the other of Compound A 2 and Compound B 2 for from 1 to 7 consecutive days.
  • Compound B 2 will be administered first in the sequence, followed by an optional drug holiday, followed by administration of Compound A 2 .
  • Compound B 2 will be administered first in the sequence, followed by an optional drug holiday, followed by administration of Compound A 2 .
  • Compound B 2 is administered for from 3 to 21 consecutive days, followed by an optional drug holiday, followed by administration of Compound A 2 for from 3 to 21 consecutive days.
  • Compound B 2 is administered for from 3 to 21 consecutive days, followed by a drug holiday of from 1 to 14 days, followed by administration of
  • Compound A 2 for from 3 to 21 consecutive days.
  • Compound B 2 is
  • Compound B 2 is administered for 21 consecutive days, followed by an optional drug holiday, followed by administration of Compound A 2 for 14 consecutive days.
  • Compound B 2 is administered for 14 consecutive days, followed by a drug holiday of from 1 to 14 days, followed by administration of Compound A 2 for 14 consecutive days.
  • Compound B 2 is administered for 7 consecutive days, followed by a drug holiday of from 3 to 10 days, followed by administration of
  • Compound A 2 for 7 consecutive days is administered for 3 consecutive days, followed by a drug holiday of from 3 to 14 days, followed by administration of Compound A 2 for 7 consecutive days.
  • Compound B 2 is administered for 3 consecutive days, followed by a drug holiday of from 3 to 10 days, followed by administration of Compound A 2 for 3 consecutive days.
  • administration can be followed by repeat dosing or can be followed by an alternate dosing protocol, and a drug holiday may precede the repeat dosing or alternate dosing protocol.
  • the methods of the present invention may also be employed with other therapeutic methods of cancer treatment.
  • compositions Accordingly, the invention further provides pharmaceutical compositions, which include Compound A 2 and/or Compound B 2 , and one or more pharmaceutically acceptable carriers.
  • the combinations of the present invention are as described above.
  • the carrier(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.
  • a process for the preparation of a pharmaceutical formulation including admixing Compound A 2 and/or Compound B 2 with one or more
  • pharmaceutically acceptable carriers As indicated above, such elements of the pharmaceutical combination utilized may be presented in separate pharmaceutical compositions or formulated together in one pharmaceutical formulation.
  • compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose.
  • amount of active ingredient per dose will depend on the condition being treated, the route of administration and the age, weight and condition of the
  • Preferred unit dosage formulations are those containing a daily dose or sub-dose, or an appropriate fraction thereof, of an active ingredient. Furthermore, such
  • compositions may be prepared by any of the methods well known in the pharmacy art.
  • Compound A 2 and Compound B 2 may be administered by any appropriate route
  • Suitable routes include oral, rectal, nasal, topical (including buccal and
  • intramuscular, intravenous, 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 Compound A 2 and Compound B 2 may be compounded together in a pharmaceutical composition/formulation.
  • 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 anti-cancer effect than the most active single agent; ii) synergistic or highly synergistic anti-cancer activity; iii) a dosing protocol that provides enhanced anti-cancer 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 ABP or antibody of the invention, and the other comprising a TLR4 modulator, 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 formulation may be aqueous or liposomal.
  • the liposomal formulation may be a DOPC/CHOL Liposome formulation.
  • 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 subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural).
  • the preferred route 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 the components may be compounded together or in separate pharmaceutical compositions.
  • 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 another embodiment, one or more components of a combination of the invention are administered systemically, e.g., intravenously, and one or more other components of a combination of the invention are administered intratumorally. In another embodiment, all of the components of a combination of the invention are administered systemically, e.g., intravenously. In an alternative embodiment, all of the components of the combination of the invention are administered intratumorally. In any of the embodiments, e.g., in this paragraph, the components of the invention are administered as one or more pharmaceutical
  • the two compounds are administered intravenously.
  • the 0X40 ABP is administered by intravenous infusion.
  • the TLR4 agonist is administered by intravenous injection.
  • the 0X40 ABP is administered by intravenous infusion and the TLR4 agonist is administered by intravenous injection.
  • the TLR4 agonist is administered by intratumoral injection.
  • Antigen Binding Protein means a protein that binds an antigen, and includes 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,
  • An ABP also includes antigen binding fragments of such antibodies or other molecules.
  • an ABP may comprise the VH regions of the invention formatted into a full length antibody, a (Fab')2 fragment, a Fab fragment, a bi-specific or biparatopic molecule or equivalent thereof (such as scFV, bi- tri- or tetra-bodies, Tandabs, etc.), when paired with an appropriate light chain.
  • the 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.
  • an ABP of the invention or an 0X40 binding protein is one that binds 0X40, and in some embodiments, does one or more of the following: modulate signaling through 0X40, modulates the function of 0X40, agonize 0X40 signaling, stimulate 0X40 function, or co-stimulate 0X40 signaling.
  • Example 1 of FT.S. Patent 9,006,399 discloses an 0X40 binding assay.
  • One of skill in the art would readily recognize a variety of other well-known assays to establish such functions.
  • 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., produced by recombinant means; for example, an antibody that is 90% identical to a reference antibody may be generated by mutagenesis of certain residues using recombinant molecular biology techniques known in the art.
  • the antibodies of the present invention may comprise heavy chain variable regions and light chain variable regions of the invention which may be formatted into the structure of a natural antibody or formatted into a full length recombinant antibody, a (Fab')2 fragment, a Fab fragment, a bi-specific or biparatopic molecule or equivalent thereof (such as scFV, bi- tri- or tetra- bodies, Tandabs etc.), when paired with an appropriate light chain.
  • the antibody may be an IgGl, IgG2, IgG3, or IgG4 or a modified variant thereof.
  • the constant domain of the antibody heavy chain may be selected accordingly.
  • the light chain constant domain may be a kappa or lambda constant domain.
  • the antibody may also be a chimeric antibody of the type described in WO86/01533 which comprises an antigen binding region and a non- immunoglobulin region.
  • the ABPs such as antibodies, of the invention bind an epitope of 0X40.
  • the epitope of an ABP is the region of its antigen to which the ABP binds.
  • Two ABPs bind to the same or overlapping epitope if each competitively inhibits (blocks) binding of the other to the antigen. That is, a lx, 5x, lOx, 20x or lOOx excess of one antibody inhibits binding of the other by at least 50%, 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 ah, Cancer Res. 50: 1495, 1990.
  • two antibodies have the same epitope if essentially all amino acid mutations in the antigen that reduce 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 or eliminate binding of one antibody reduce or eliminate binding of the other.
  • the ABP of the invention binds to 0X40, preferably human 0X40, with high affinity.
  • KD Equilibrium affinity or equilibrium dissociation constant
  • the ABP binds to 0X40, preferably human 0X40, with KD (equilibrium affinity or equilibrium dissociation constant) of 1 to 1000 nM, or 500 nM or less, or an affinity of 200 nM or less, or an affinity of 100 nM or less, or an affinity of 50 nM or less, or an affinity of 500 pM or less, or an affinity of 400 pM or less, or 300 pM or less.
  • the ABP binds to 0X40, preferably human 0X40, when measured by surface plasmon resonance of between about 50 nM and about 200 nM, or between about 50 nM and about 150 nM. In one aspect of the present invention the ABP binds 0X40, preferably human 0X40, with an affinity of less than 100 nM.
  • binding is measured by BIACORE.
  • Affinity is the strength of binding of one molecule, e.g., an ABP of the invention, to another, e.g., its target antigen, at a single binding site.
  • the binding affinity of an ABP to its target may be determined by equilibrium methods (e.g., enzyme-linked immunoabsorbent assay (ELISA) or radioimmunoassay (RIA)), or kinetics (e.g., BIACORE SPR data analyzed with a kinetic model).
  • ELISA enzyme-linked immunoabsorbent assay
  • RIA radioimmunoassay
  • kinetics e.g., BIACORE SPR data analyzed with a kinetic model.
  • the BIACORE methods known in the art may be used to measure binding affinity and measure kinetic binding parameters.
  • 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 equilibrium dissociation constant (K D ) of the ABP of the invention and 0X40, preferably human 0X40, interaction is 100 nM or less, 10 nM or less, 2 nM or less or 1 nM or less.
  • the K D may be between 5 and 10 nM; or between 1 and 2 nM.
  • the K D may be between 1 pM and 500 pM; or between 500 pM and 1 nM.
  • the reciprocal of K D i.e., 1/Kn
  • K A equilibrium association constant having units M 1 .
  • K A numerical value the stronger the binding.
  • the dissociation rate constant (ka) or“off-rate” describes the stability of the complex of an ABP on one hand and 0X40, preferably human 0X40 on the other hand, i.e., the fraction of complexes that decay per second. For example, a ka of 0.01 s 1 equates to 1% of the complexes decaying per second.
  • the dissociation rate constant (ka) 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 ka 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 ABP e.g., 0X40 binding protein of the invention
  • a reference antibody e.g., for binding 0X40, an epitope of 0X40, or a fragment of the 0X40
  • competition ELISA FMAT (fluorometric microvolume assay technology) 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 the invention that include the antigen-binding site and are capable of binding 0X40 as defined herein, e.g., but not limited to capable of binding to the same epitope of the parent or full length antibody.
  • “binding fragments” and“functional fragments” may be Fab and F(ab')2 fragments that 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 (Hochman, et al., Biochemistry 12: 1130-1135 (1973); Sharon, 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 the invention 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 the invention 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 the invention 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- tri- or 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 (ABP). 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.
  • CDR sequences Chothia (Chothia el al. (1989) Nature 342: 877-883), Rabat (Rabat 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 Rabat, 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.
  • references herein to“CDR”,“CDRL1”,“CDRL2”,“CDRL3”,“CDRH1”,“CDRH2”,“CDRH3” refer to amino acid sequences numbered according to any of the known conventions; alternatively, the CDRs are referred to as“CDR1 ,”“CDR2,”“CDR3” of the variable light chain and“CDR1,”“CDR2,” and“CDR3” of the variable heavy chain.
  • the numbering convention is the Rabat 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 the biological characteristics of the antigen binding protein pre-modification. It will be appreciated that each CDR that can be modified may be modified alone or in combination with another CDR. In one aspect, the modification is a substitution, particularly a conservative substitution, for example as shown in Table 1. Table 1
  • 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 Rabat or Chothia definition(s) may be substituted with a conservative amino acid residue.
  • 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 antigen binding protein 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 ah, Proc. Natl Acad Sci USA, 86: 10029-10032 (1989), Hodgson, et ah, Bio/Technology, 9:421 (1991)).
  • a suitable human acceptor antibody may be one selected from a conventional database, e.g., the RABAT 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.
  • the humanized antibody has a human antibody constant region that is an IgGl .
  • 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 pair-wise 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 pair-wise 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, with 100, 99, 98, 97, 96, 95, 94, 93, 92, 91, or 90 percent identity to the sequence shown or referenced, e.g., as defined by a SEQ ID NO disclosed herein.
  • ABPs that bind human 0X40 are provided herein (e.g., an 0X40 ABP, or 0X40 binding protein, or 0X40 antigen binding protein, or an anti human 0X40 receptor (hOX40R) antibody, sometimes referred to herein as an“anti- 0X40 ABP” or“an anti- 0X40 antibody” and/or other variations of the same).
  • 0X40 receptor also known as 0X40 receptor
  • antigen binding proteins are useful in the treatment or prevention of acute or chronic diseases or conditions whose pathology involves 0X40 signaling.
  • an antigen binding protein such as an isolated human antibody or functional fragment of such protein or antibody, that binds to human OX40R and is effective as a cancer treatment or treatment against disease is described, for example in combination with another compound such as a TLR4 modulator or TLR4 agonist.
  • Any of the antigen binding proteins such as anti-OX40 antibodies disclosed herein may be used as a medicament. Any one or more of the antigen binding proteins such as anti-OX40 antibodies may be used in the methods or compositions to treat cancer, e.g., those disclosed herein.
  • the isolated antigen binding proteins such as antibodies, as described herein bind to 0X40, and may bind to 0X40 encoded from the following genes: NCBI Accession Number NP_0033l7, Genpept Accession Number P23510, or genes having 90 percent homology or 90 percent identity thereto.
  • the isolated antigen binding proteins provided herein may further bind to the 0X40 receptor having one of the following GenBank Accession Numbers: AAB39944, CAE 11757, or AAI05071.
  • Antigen binding proteins such as antibodies, that bind and/or modulate 0X40 receptor are known in the art.
  • Exemplary ABPs and antibodies of the invention are disclosed, for example in International Publication No. WO2013/028231 (PCT/US2012/024570), international filing date 9 Feb. 2012, and WO2012/027328 (PCT/US201 1/048752), international filing date 23 August 2011. (To the extent any definitions conflict, this instant application controls).
  • 0X40 antibodies of the present invention are disclosed in ETS Patent No. 9,163,085.
  • the 0X40 binding protein is one disclosed in WO2012/027328 (PCT/US2011/048752), international filing date 23 August 2011. In another embodiment, the 0X40 binding protein is one disclosed in WO2012/027328 (PCT/US2011/048752), international filing date 23 August 2011. In another embodiment, the 0X40 binding protein is one disclosed in WO2012/027328 (PCT/US2011/048752), international filing date 23 August 2011. In another
  • the antigen binding protein comprises the CDRs of an antibody disclosed in WO2012/027328 (PCT/US201 1/048752), international filing date 23 August 2011 , or CDRs with 90% 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/US201 1/048752), international filing date 23 August 2011 , or a VH or a VL with 90% identity to the disclosed VH or VL sequences.
  • the 0X40 binding protein is an agonist.
  • the 0X40 binding protein is disclosed in WO2013/028231 (PCT/US2012/024570), international filing date 9 Feb. 2012.
  • the antigen binding protein comprises the CDRs of an antibody disclosed in
  • 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 Feb. 2012 or a VH or a VL with 90% identity to the disclosed VH or VL sequences.
  • the 0X40 binding protein of the invention comprises one or more of the CDRs or VH or VL sequences, or sequences with 90% identity thereto, shown in the Figures herein.
  • the ABP of the invention comprises the CDRs of the 106-222 antibody, e.g., of Figures 6-7 herein, e.g. , CDRH1, CDRH2, and CDRH3 having the amino acid sequence as set forth in SEQ ID NOs 1 , 2, and 3, as disclosed in Figure 6, and e.g.,CDRLl, CDRL2, and CDRL3 having the sequences as set forth in SEQ ID NOs 7, 8, and 9 respectively as disclosed in Figure 7.
  • the ABP of the invention comprises the CDRs of the 106-222, Hul06 or Hul 06-222 antibody as disclosed in WO2012/027328 (PCT/US201 1/048752), international filing date 23 August 2011.
  • the 0X40 binding protein of the invention comprises the VH and VL regions of the 106-222 antibody as shown in Figures 6-7 herein, e.g., a VH having an amino acid sequence as set forth in SEQ ID NO:4 and a VL as in Figure 7 having an amino acid sequence as set forth in SEQ ID NO: 10.
  • the ABP of the invention comprises a VH having an amino acid sequence as set forth in SEQ ID NO:5 in Figure 6 herein, and a VL having an amino acid sequence as set forth in SEQ ID NO: 11 in Figure 7 herein.
  • the 0X40 binding protein of the invention comprises the VH and VL regions of the Hul 06-222 antibody or the 106-222 antibody or the Hul06 antibody as disclosed in WO2012/027328 (PCT/US201 1/048752), international filing date 23 August 2011.
  • the 0X40 binding protein of the invention is 106-222, Hul06-222 or Hul06, e.g., as disclosed in
  • the ABP of the invention comprises CDRs or VH or VL or antibody sequences with 90% identity to the sequences in this paragraph.
  • the 0X40 binding protein of the invention comprises the CDRs of the 1 19-122 antibody, e.g., of Figures 10-11 herein, e.g., CDRH1, CDRH2, and CDRH3 having the amino acid sequence as set forth in SEQ ID NOs 13, 14, and 15 respectively.
  • the 0X40 binding protein of the invention comprises the CDRs of the 119-122 or Hul 19 or Hul 19-222 antibody as disclosed in WO2012/027328 (PCT/US201 1/048752), international filing date 23 August 2011.
  • the 0X40 binding protein of the invention comprises a VH having an amino acid sequence as set forth in SEQ ID NO: 16 in Figure 10 herein, and a VL having the amino acid sequence as set forth in SEQ ID NO: 22 as shown in Figure 11 herein.
  • the 0X40 binding protein of the invention 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 0X40 binding protein of the invention comprises the VH and VL regions of the 119-122 or Hul 19 or Hul 19-222 antibody as disclosed in WO2012/027328 (PCT/US201 1/048752), international filing date 23 August 2011.
  • the ABP of the invention is 119-222 or Hul 19 or Hul 19-222 antibody, e.g., as disclosed in
  • the ABP of the invention comprises CDRs or VH or VL or antibody sequences with 90% identity to the sequences in this paragraph.
  • the 0X40 binding protein of the invention comprises the CDRs of the 1 19-43-1 antibody, e.g., as shown in Figures 14-15 herein.
  • the 0X40 binding protein of the invention comprises the CDRs of the 1 19-43-1 antibody, e.g., as shown in Figures 14-15 herein.
  • the 0X40 binding protein or antibody of the invention comprises the CDRs of the 1 19-43-1 antibody as disclosed in WO2013/028231 (PCT/US2012/024570), international filing date 9 Feb. 2012.
  • the 0X40 binding protein of the invention comprises one of the VH and one of the VL regions of the 1 19-43-1 antibody as shown in Figures 14-17.
  • the 0X40 binding protein of the invention comprises the VH and VL regions of the 119-43-1 antibody as disclosed in WO2013/028231 (PCT/US2012/024570), international filing date 9 Feb. 2012.
  • the 0X40 binding protein of the invention is 119-43-1 or 119-43-1 chimeric as disclosed in Figures 14-17 herein.
  • the ABP of the invention as disclosed in WO2013/028231 (PCT/US2012/024570), international filing date 9 Feb. 2012.
  • any one of the ABPs described in this paragraph are humanized.
  • any one of the any one of the ABPs described in this paragraph are engineered to make a humanized antibody.
  • the ABP of the invention comprises CDRs or VH or VL or antibody sequences with 90% identity to the sequences in this paragraph.
  • the 0X40 binding protein is an 0X40 agonist.
  • any mouse or chimeric sequences of any 0X40 binding protein of the invention are engineered to make a humanized antibody.
  • the 0X40 binding protein of the invention comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 1 ; (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 0X40 binding protein 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:2l .
  • the 0X40 binding protein of the invention 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% identity thereto.
  • the 0X40 binding protein of the invention 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 0X40 binding protein of the invention comprises: a light chain variable region (“Vi”) comprising the amino acid sequence of SEQ ID NO: 10, 11, 22 or 23, or an amino acid sequence with at least 90 percent identity to the amino acid sequences of SEQ ID NO: 10, 1 1, 22 or 23.
  • the 0X40 binding protein of the invention comprises a heavy chain variable region (“V H ”) comprising the amino acid sequence of SEQ ID NO:4, 5, 16 and 17, or an amino acid sequence with at least 90 percent identity to the amino acid sequences of SEQ ID NO:4, 5, 16 and 17.
  • the 0X40 binding protein of the invention comprises a variable heavy chain sequence of SEQ ID NO:5, or a sequence having 90 percent identity thereto, and a variable light chain sequence of SEQ ID NO: 1 1 , or a sequence having 90 percent identity thereto.
  • the 0X40 binding protein of the invention comprises a variable heavy chain sequence of SEQ ID NO: 17, or a sequence having 90 percent identity thereto, and a variable light chain sequence of SEQ ID NO:23 or a sequence having 90 percent identity thereto.
  • the 0X40 binding protein of the invention 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 percent identity to the nucleotide sequences of SEQ ID NO: 12 or 24.
  • the 0X40 binding protein of the invention 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 percent 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 percent identity to the amino acid sequences of SEQ ID NO: 10 or 22. Further provided are monoclonal antibodies comprising a variable heavy chain comprising the amino acid sequence of SEQ ID NO:4 or 16, or an amino acid sequence with at least 90 percent identity to the amino acid sequences of SEQ ID NO:4 or 16.
  • the 0X40 binding protein of the invention comprises a variable heavy chain sequence of SEQ ID NO:5 and a variable light chain sequence of SEQ ID NO: l l .
  • the 0X40 binding protein or antibody of the invention is an antibody that comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:48 and a light chain comprising the amino acid sequence set forth in SEQ ID NO:49.
  • Trp lie Asn Thr Glu Thr Gly Glu Pro Thr Tyr Ala Asp Asp
  • LC CDR2 Ser Ala Ser Tyr Leu Tyr Thr (SEQ ID NO: 8)
  • TLR4 Agonists comprise TLR4 agonists, that is, molecules that agonize TLR4, for example, by binding and initiating conformational changes or signaling by engaging TLR4.
  • TLR4 agonists bind to TLR4 and activate the receptor, triggering signaling to initiate a TLR4 signaling pathway response.
  • TLR4 modulators are aminoalkyl glucosaminide phosphate compounds (AGPs). TLR4 recognizes bacterial LPS (lipopolysaccharide) and when activated initiates an innate immune response.
  • AGPs are a monosaccharide mimetic of the lipid A protein of bacterial LPS and have been developed with ether and ester linkages on the“acyl chains” of the compound. Processes for making these compounds are known and disclosed, for example, in WO 2006/016997, U.S. Patent Nos. 7,288,640 and 6,113,918, and WO 01/90129. Other AGPs and related processes are disclosed in U.S. Patent No. 7,129,219, U.S. Patent No. 6,525,028 and U.S. Patent No 6,911,434. AGPs with ether linkages on the acyl chains employed in the composition of the invention are known and disclosed in WO 2006/016997.
  • the AGP compounds set forth and described according to Formula (III) at paragraphs [0019] through [0021] in WO 2006/016997 may be employed in the presently claimed methods and combinations.
  • AGP compounds employed in the present invention have the structure set forth in Formula 1 as follows:
  • n 0 to 4;
  • X is O or S, preferably O;
  • Y is O or NH
  • Z is O or H
  • each Ri, R 2 , R3 is selected independently from the group consisting of a Cl -20 acyl and a Cl -20 alkyl;
  • R 4 is H or Me
  • R5 is selected independently from the group consisting of -H, -OH, -(C1-C4) alkoxy, -PO3R8R9, -OPO3R8R9, -SO3R8, -OSO3R8, -NR8R9, -SRs, -CN, -N0 2 , - CHO, -C0 2 R 8 , and -CONR8R9, wherein Rs and R9 are each independently selected from H and (C1-C4) alkyl; and
  • each Re and R 7 is independently H or P0 3 H 2 .
  • the configuration of the 3' stereogenic centers to which the normal fatty acyl residues (that is, the secondary acyloxy or alkoxy residues, e.g., RiO, R 2 0, and R 3 0) are attached is R or S, preferably R (as designated by Cahn-Ingold-Prelog priority rules).
  • Configuration of aglycon stereogenic centers to which R 4 and R5 are attached can be R or S. All stereoisomers, both enantiomers and diastereomers, and mixtures thereof, are considered to fall within the scope of the present invention.
  • the number of carbon atoms between heteroatom X and the aglycon nitrogen atom is determined by the variable“n”, which can be an integer from 0 to 4, or an integer from 0 to 2.
  • the chain length of normal fatty acids Ri, R 2 , and R3 can be from about 6 to about 16 carbons, or from about 9 to about 14 carbons.
  • the chain lengths can be the same or different. Some embodiments include chain lengths where Ri, R 2 and R3 are 6 or 10 or 12 or 14.
  • R5 is an acidic group capable of salt formation; the phosphate can be either on 4- or 6- position of the glucosamine unit, preferably, is in the 4-position.
  • R 5 is CO 2 H
  • Re is PO 3 H 2
  • R 7 is H.
  • This AGP compound is set forth as the structure in Formula la as follows:
  • X is O or S; Y is O or NH; Z is O or H; each Ri, R 2 , R 3 is selected independently from the group consisting of a Cl -20 acyl and a Cl -20 alkyl; and R 4 is H or methyl.
  • Formula la encompasses L/D-seryl, -threonyl, -cysteinyl ether or ester lipid AGPs, both agonists and antagonists.
  • CRX-601 and CRX-527 are compounds of Formula 1. Their structures are set forth as follows:
  • CRX-547 having the structure shown.
  • Still other embodiments include AGPs, such as CRX-602 or CRX-526 providing increased stability to AGPs having shorter secondary acyl or alkyl chains.
  • the TLR4 modulator is an agonist.
  • the TLR4 modulator that is an agonist is selected from the group consisting of: CRX-601, CRX-547, and CRX-527.
  • the composition comprising a TLR4 modulator, such as an AGP is buffered using a zwitterionoic buffer.
  • the zwitterionic buffer is an aminoalkanesulfonic acid or suitable salt. Examples of amninoalkanesulfonic buffers include, but are not limited, to HEPES, HEPPS/EPPS, MOPS, MOBS and PIPES.
  • the buffer is a pharmaceutically acceptable buffer, suitable for use in humans, such as in for use in a commercial injection product.
  • the buffer is HEPES.
  • the disclosure is drawn to a method of treatment of a subject with cancer, wherein an agonist 0X40 binding protein and a TLR4 agonist are administered to the subject, wherein the agonist 0X40 binding protein is administered at a dose of about 8 mg to about 24 mg and the TLR4 agonist is administered at a dose of about 50 ng to about 250 ng.
  • the disclosure is drawn to a method of treatment of a subject with cancer, wherein an agonist 0X40 binding protein and a TLR4 agonist are administered to the subject, wherein the agonist 0X40 binding protein is administered at a dose of about 24 mg and the TLR4 agonist is administered at a dose of about 50 ng to about 250 ng.
  • the disclosure is drawn to an agonist 0X40 binding protein and a TLR4 agonist for simultaneous or sequential use in treating cancer, wherein the agonist 0X40 binding protein is to be administered at a dose of about 8 mg to about 24 mg and the TLR4 agonist is to be administered at a dose of about 50 ng to about 250 ng.
  • the disclosure is drawn to an agonist 0X40 binding protein and a TLR4 agonist for simultaneous or sequential use in treating cancer, wherein the agonist 0X40 binding protein is to be administered at a dose of about 24 mg and the TLR4 agonist is to be administered at a dose of about 50 ng to about 250 ng.
  • the disclosure is drawn to an agonist 0X40 binding protein for use in treating cancer, wherein the agonist 0X40 binding protein is to be administered at a dose of about 8 mg to about 24 mg and is to be administered simultaneously or sequentially with a TLR4 agonist at a dose of about 50 ng to about 250 ng.
  • the disclosure is drawn to an agonist 0X40 binding protein for use in treating cancer, wherein the agonist 0X40 binding protein is to be administered at a dose of about 24 mg and is to be administered simultaneously or sequentially with a TLR4 agonist at a dose of about 50 ng to about 250 ng.
  • the disclosure is drawn to a TLR4 agonist for use in treating cancer, wherein the TLR4 agonist is to be administered at a dose of about 50 ng to about 250 ng and is to be administered simultaneously or sequentially with an agonist 0X40 binding protein at a dose of about 8 mg to about 24 mg.
  • the disclosure is drawn to a TLR4 agonist for use in treating cancer, wherein the TLR4 agonist is to be administered at a dose of about 50 ng to about 250 ng and is to be administered simultaneously or sequentially with an agonist 0X40 binding protein at a dose of about 24 mg.
  • the disclosure is drawn to use of an agonist 0X40 binding protein in the manufacture of a medicament for treating cancer, wherein the 0X40 binding protein is to be administered at a dose of about 8 mg to about 24 mg and is to be administered simultaneously or sequentially with a TLR4 agonist at a dose of about 50 ng to about 250 ng-
  • the disclosure is drawn to use of an agonist 0X40 binding protein in the manufacture of a medicament for treating cancer, wherein the 0X40 binding protein is to be administered at a dose of about 24 mg and is to be administered simultaneously or sequentially with a TLR4 agonist at a dose of about 50 ng to about 250 ng.
  • the disclosure is drawn to use of a TLR4 agonist in the manufacture of a medicament for treating cancer, wherein the TLR4 agonist is to be administered at a dose of about 50 ng to about 250 ng and is to be administered simultaneously or sequentially with an agonist 0X40 binding protein at a dose of about 8 mg to about 24 mg.
  • the disclosure is drawn to use of a TLR4 agonist in the manufacture of a medicament for treating cancer, wherein the TLR4 agonist is to be administered at a dose of about 50 ng to about 250 ng and is to be administered simultaneously or sequentially with an agonist 0X40 binding protein at a dose of about 24 mg.
  • the disclosure is drawn to a pharmaceutical kit comprising about 8 mg to about 24 mg of an agonist 0X40 binding protein and about 50 ng to 250 ng of a TLR4 agonist.
  • the disclosure is drawn to a pharmaceutical kit comprising about 24 mg of an agonist 0X40 binding protein and about 50 ng to 250 ng of a TLR4 agonist.
  • the agonist 0X40 binding protein is administered intravenously (e.g ., intravenous infusion).
  • the TLR4 agonist is administered intravenously (e.g., intravenous injection).
  • the TLR4 agonist is administered intratumorally (e.g., by intratumoral injection).
  • the agonist 0X40 binding protein is administered intravenously (e.g., intravenous infusion) and the TLR4 agonist is administered intravenously (e.g., intravenous injection).
  • the agonist 0X40 binding protein is administered at a dose of about 8 mg.
  • the agonist 0X40 binding protein is administered at a dose of about 24 mg.
  • the TLR4 agonist is administred in a dose in the range of about 5 ng to about 1000 ng.
  • the TLR4 agonist is to be administered at a dose of about 50 ng to about 250 ng.
  • the TLR4 agonist is administered at a dose of about 50 ng.
  • the TLR4 agonist is administered at a dose of about 450 ng.
  • the TLR4 agonist is administered at a dose of about 500 ng.
  • the TLR4 agonist is administered at a dose of about 550 ng.
  • the TLR4 agonist is administered at a dose of about 600 ng.
  • the TLR4 agonist is administered at a dose of about 600 ng to about 1000 ng.
  • the agonist 0X40 binding protein comprises (a) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: l ; (b) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO:2; (c) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO:3; (d) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO:7; (e) a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 8; and (f) a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO:9.
  • the agonist 0X40 binding protein comprises a heavy chain variable region comprising the amino acid sequence as set forth in SEQ ID NO:5; and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: l l .
  • the agonist 0X40 binding protein is a humanized monoclonal antibody.
  • the agonist 0X40 binding protein comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:48 and a light chain comprising the amino acid sequence set forth in SEQ ID NO:49.
  • the TLR4 agonist is selected from the group consisting of: CRX- 601; CRX-547; CRX-602; and, CRX-527.
  • the TLR4 agonist is CRX-527. In some embodiments, the TLR4 agonist is CRX-601.
  • the cancer comprises a solid tumor.
  • the cancer comprises squamous cell carcinoma of head and neck (SCCHN).
  • SCCHN squamous cell carcinoma of head and neck
  • the SCCHN is recurrent, locally advanced, or metastatic.
  • the TLR4 agonist e.g ., CRX-601
  • the agonist 0X40 binding protein e.g. , an agonist 0X40 binding protein that comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:48 and a light chain comprising the amino acid sequence set forth in SEQ ID NO:49
  • the TLR4 agonist e.g ., CRX-601
  • the agonist 0X40 binding protein e.g. , an agonist 0X40 binding protein that comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:48 and a light chain comprising the amino acid sequence set forth in SEQ ID NO:49
  • the TLR4 agonist e.g., CRX-601
  • the TLR4 agonist is administered for a two-week run in period (e.g., the TLR4 agonist is administered on day 1 and 8 of the run in period) prior to administering the agonist 0X40 binding protein (e.g. , an agonist 0X40 binding protein that comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:48 and a light chain comprising the amino acid sequence set forth in SEQ ID NO:49).
  • the agonist 0X40 binding protein e.g. , an agonist 0X40 binding protein that comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:48 and a light chain comprising the amino acid sequence set forth in SEQ ID NO:49.
  • the TLR4 agonist e.g., CRX-601
  • the agonist 0X40 binding protein e.g., an agonist 0X40 binding protein that comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:48 and a light chain comprising the amino acid sequence set forth in SEQ ID NO:49
  • the TLR4 agonist e.g., CRX-601
  • the agonist 0X40 binding protein e.g., an agonist 0X40 binding protein that comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:48 and a light chain comprising the amino acid sequence set forth in SEQ ID NO:49
  • the TLR4 agonist e.g., CRX-601
  • the TLR4 agonist is administered for a two-week run in period (e.g., the TLR4 agonist is administered on day 1 and day 8 of the two-week run in period), and following the run in period, the TLR4 agonist and the agonist 0X40 binding protein (e.g. , an agonist 0X40 binding protein that comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:48 and a light chain comprising the amino acid sequence set forth in SEQ ID NO:49) are both administered to the subject, e.g., every three weeks.
  • the combinations of the invention are believed to have utility in disorders wherein the engagement of 0X40 and/or TLR4, is beneficial.
  • 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 and/or TLR4, is beneficial, particularly cancer.
  • the present invention provides methods of treating cancer in a patient with the combination of a TLR4 agonist, such as CRX-601, with a humanized monoclonal 0X40 antibody, wherein the humanized 0X40 antibody is administered intravenously, and the TLR4 agonist is administered intratumorally, resulting in an abscopal effect in the tumor(s) in the patient.
  • a TLR4 agonist such as CRX-601
  • a humanized monoclonal 0X40 antibody wherein the humanized 0X40 antibody is administered intravenously
  • the TLR4 agonist is administered intratumorally, resulting in an abscopal effect in the tumor(s) in the patient.
  • abscopal effect means a phenomenon in which local treatment causes tumor regression at not only the treated site, but also at distant tumor sites.
  • a further aspect of the invention provides a method of treatment of a disorder wherein engagement of 0X40 and/or TLR4 is beneficial, comprising administering a combination of the invention.
  • a further aspect of the present invention provides the use of a combination of the invention in the manufacture of a medicament for the treatment of a disorder engagement of 0X40 and/or TLR4 is beneficial.
  • the disorder is cancer.
  • the present invention provides the use of the combinations of the present invention for the treatment of cancer.
  • the cancer can comprise a solid cancer, e.g. , solid tumor.
  • 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,
  • lymphoblastic T cell leukemia Chronic myelogenous leukemia, Chronic lymphocytic leukemia, Hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, AML, Chronic neutrophilic leukemia, Acute lymphoblastic T cell leukemia, plasmacytoma, Immunoblastic large cell leukemia, Mantle cell leukemia, Multiple myeloma Megakaryoblastic leukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia, Erythro leukemia, malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma, lymphoblastic T cell lymphoma, Burkit
  • examples of a cancer to be treated include Barret’s adenocarcinoma; biliary tract carcinomas; breast cancer; cervical cancer; cholangiocarcinoma; central nervous system tumors including primary CNS tumors such as glioblastomas, astrocytomas ( e.g ., glioblastoma multiforme) and ependymomas, and secondary CNS tumors (/. ⁇ ?., metastases to the central nervous system of tumors originating outside of the central nervous system); colorectal cancer including large intestinal colon carcinoma; gastric cancer; carcinoma of the head and neck including squamous cell carcinoma of the head and neck; hematologic cancers including leukemias and lymphomas such as acute lymphoblastic leukemia, acute myelogenous leukemia (AML), myelodysplastic syndromes, chronic myelogenous leukemia, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, megakary
  • hepatocellular carcinoma lung cancer including small cell lung cancer and non-small cell lung cancer; ovarian cancer; endometrial cancer; pancreatic cancer; pituitary adenoma; prostate cancer; renal cancer; sarcoma; skin cancers including melanomas; and thyroid cancers.
  • the present invention relates to a method for treating or lessening the severity of a cancer selected from: brain (gliomas), glioblastomas, astrocytomas, glioblastoma multiforme, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate, sarcoma and thyroid.
  • a cancer selected from: brain (gliomas), glioblastomas, astrocytomas, glioblastoma multiforme, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate, sarcoma and thyroid.
  • the present invention relates to a method for treating or lessening the severity of a cancer selected from ovarian, breast, pancreatic and prostate.
  • the present invention relates to a method for treating or lessening the severity of pre-cancerous syndromes in a mammal, including a human, wherein the pre-cancerous syndrome is selected from: cervical intraepithelial neoplasia, monoclonal gammapathy of unknown significance (MGUS), myelodysplastic syndrome, aplastic anemia, cervical lesions, skin nevi (pre-melanoma), prostatic intraepithelial (intraductal) neoplasia (PIN), Ductal Carcinoma in situ (DCIS), colon polyps and severe hepatitis or cirrhosis.
  • MGUS monoclonal gammapathy of unknown significance
  • MUS monoclonal gammapathy of unknown significance
  • myelodysplastic syndrome aplastic anemia
  • cervical lesions aplastic anemia
  • cervical lesions skin nevi (pre-melanoma)
  • PIN prostatic intraepithelial neo
  • the combination of the invention may be used alone, or in combination with, one or more other therapeutic agents.
  • the invention thus provides in a further aspect a further combination comprising a combination of the invention with a further therapeutic agent or agents, compositions and medicaments comprising the combination and use of the further combination, compositions and medicaments in therapy, in particular, in the treatment of diseases susceptible to engagement of 0X40 and/or TLR4.
  • the combination of the invention may be employed with other therapeutic methods of cancer treatment.
  • combination therapy with other chemotherapeutic, hormonal, antibody agents as well as surgical and/or radiation treatments other than those mentioned above are envisaged.
  • Combination therapies according to the present invention thus include the administration of an 0X40 binding protein of the invention and/or a TLR4 modulator as well as optional use of other therapeutic agents including other anti-neoplastic agents.
  • Such combination of agents may be administered together or separately and, when administered separately this may occur simultaneously or sequentially in any order, both close and remote in time.
  • the pharmaceutical combination includes an 0X40 binding protein of the invention and a TLR4 modulator, and optionally at least one additional anti-neoplastic agent.
  • the further anti-cancer therapy is surgical and/or radiotherapy.
  • the further anti-cancer therapy is at least one additional anti neoplastic agent.
  • anti-neoplastic agent that has activity versus a susceptible tumor being treated may be utilized in the combination.
  • Typical anti-neoplastic agents useful include, but are not limited to, anti-microtubule agents such as diterpenoids and vinca alkaloids; platinum coordination complexes; alkylating agents such as nitrogen mustards, oxazaphosphorines, alkylsulfonates, nitrosoureas, and triazenes; antibiotic agents such as anthracyclins, actinomycins and bleomycins; topoisomerase II inhibitors such as epipodophyllotoxins; antimetabolites such as purine and pyrimidine analogues and anti-folate compounds; topoisomerase I inhibitors such as camptothecins; hormones and hormonal analogues; signal transduction pathway inhibitors; non-receptor tyrosine angiogenesis inhibitors; immunotherapeutic agents; proapoptotic agents; and cell cycle signaling inhibitors.
  • Anti-microtubule or anti-mitotic agents are phase specific agents active against the microtubules of tumor cells during M or the mitosis phase of the cell cycle.
  • anti-microtubule agents include, but are not limited to, diterpenoids and vinca alkaloids.
  • Diterpenoids which are derived from natural sources, are phase specific anti -cancer agents that operate at the G 2 /M phases of the cell cycle. It is believed that the
  • diterpenoids stabilize the b-tubulin subunit of the microtubules, by binding with this protein. Disassembly of the protein appears then to be inhibited with mitosis being arrested and cell death following.
  • diterpenoids include, but are not limited to, paclitaxel and its analog, docetaxel.
  • Paclitaxel, 5P,20-epoxy-l,2a,4,7P,l0P,l3a-hexa-hydroxytax-l l-en-9-one 4,10-diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine; is a natural diterpene product isolated from the Pacific yew tree Taxus brevifolia and is commercially available as an injectable solution TAXOL. It is a member of the taxane family of terpenes.
  • Paclitaxel has been approved for clinical use in the treatment of refractory ovarian cancer in the United States (Markman, et ah, Yale Journal of Biology and Medicine , 64:583 (1991); McGuire, et ah, Ann. Intern, Med., 11 1 :273 (989), and for the treatment of breast cancer (Holmes, et al., J. Nat. Cancer Inst., 83: 1797 (1991)). Paclitaxel is a potential candidate for treatment of neoplasms in the skin (Einzig, et. al., Proc. Am. Soc. Clin. Oncol., 20:46 (2001) and head and neck carcinomas (Forastire, et. al., Sem. Oncol.,
  • the compound also shows potential for the treatment of polycystic kidney disease (Woo, et al., Nature, 368:750 (1994)), lung cancer and malaria.
  • Treatment of patients with paclitaxel results in bone marrow suppression (multiple cell lineages,
  • Docetaxel (2R,3S)- N-carboxy-3-phcnylisoscrinc,N-/e/7-butyl ester, 13-ester with 5b-20- epoxy-l,2a,4,7P,lOP,l3a-hexahydroxytax-l l-en-9-one 4-acetate 2-benzoate, trihydrate; is commercially available as an injectable solution as TAXOTERE.
  • Docetaxel is indicated for the treatment of breast cancer.
  • Docetaxel is a semisynthetic derivative of paclitaxel q.v., prepared using a natural precursor, 10-deacetyl-baccatin III, extracted from the needle of the European Yew tree.
  • Vinca alkaloids are phase specific anti-neoplastic agents derived from the periwinkle plant. Vinca alkaloids act at the M phase (mitosis) of the cell cycle by binding specifically to tubulin. Consequently, the bound tubulin molecule is unable to polymerize into microtubules. Mitosis is believed to be arrested in metaphase with cell death following. Examples of vinca alkaloids include, but are not limited to, vinblastine, vincristine, and vinorelbine.
  • Vinblastine vincaleukoblastine sulfate
  • VELBAN an injectable solution.
  • Myelosuppression is the dose-limiting side effect of vinblastine.
  • Vincristine, vincaleukoblastine, 22-oxo-, sulfate is commercially available as ONCOVIN as an injectable solution.
  • Vincristine is indicated for the treatment of acute leukemias and has also found use in treatment regimens for Hodgkin’s and non-Hodgkin’s malignant lymphomas.
  • Alopecia and neurologic effects are the most common side effect of vincristine and to a lesser extent myelosupression and gastrointestinal mucositis effects occur.
  • Liposomally formulated vincristine sulfate is commercially available as MARQUIBO. Liposomally formulated vincristine sulfate is indicated for the treatment of patients with Philadelphia chromosome-negative (Ph-) acute lymphoblastic leukemia (ALL).
  • Ph- Philadelphia chromosome-negative
  • ALL acute lymphoblastic leukemia
  • Liposomally formulated vincristine sulfate is also useful for the treatment of acute leukemias generally and has also found use in treatment regimens for Hodgkin’s and non- Hodgkin’s malignant lymphomas.
  • Vinorelbine 3 ',4'-di dehydro -4'-deoxy-C'-norvincaleukoblastine [R-(R*,R*)-2,3- dihydroxybutanedioate (l :2)(salt)], commercially available as an injectable solution of vinorelbine tartrate (NAVELBINE), is a semi-synthetic vinca alkaloid.
  • Vinorelbine is indicated as a single agent or in combination with other chemotherapeutic agents, such as cisplatin, in the treatment of various solid tumors, such as non-small cell lung, advanced breast, and hormone refractory prostate cancers. Myelosuppression is the most common dose-limiting side effect of vinorelbine.
  • Platinum coordination complexes are non-phase specific anti-cancer agents, which are interactive with DNA. The platinum complexes enter tumor cells, undergo, aquation and form intra- and interstrand cross-links with DNA causing adverse biological effects to the tumor. Examples of platinum coordination complexes include, but are not limited to, oxaliplatin, cisplatin and carboplatin.
  • Cisplatin cis-diamminedichloroplatinum
  • PLATINOL an injectable solution
  • Cisplatin is primarily indicated in the treatment of metastatic testicular and ovarian cancer and advanced bladder cancer.
  • Carboplatin, platinum, diammine [l ,l-cyclobutane-dicarboxylate(2-)-0,0'] is commercially available as PARAP LATIN as an injectable solution.
  • Carboplatin is primarily indicated in the first and second line treatment of advanced ovarian carcinoma.
  • Alkylating agents are non-phase anti-cancer specific agents and strong electrophiles. Typically, alkylating agents form covalent linkages, by alkylation, to DNA through nucleophilic moieties of the DNA molecule such as phosphate, amino, sulfhydryl, hydroxyl, carboxyl, and imidazole groups. Such alkylation disrupts nucleic acid function leading to cell death.
  • alkylating agents include, but are not limited to, nitrogen mustards such as cyclophosphamide, melphalan, and chlorambucil; alkyl sulfonates such as busulfan; nitrosoureas such as carmustine; and triazenes such as dacarbazine.
  • Cyclophosphamide 2-[bis(2-chloroethyl)amino]tetrahydro-2H-l,3,2-oxazaphosphorine 2-oxide monohydrate, is commercially available as an injectable solution or tablets as CYTOXAN. Cyclophosphamide is indicated as a single agent, or in combination with other chemotherapeutic agents, in the treatment of malignant lymphomas, multiple myeloma, and leukemias.
  • Melphalan 4-[bis(2-chloroethyl)amino]-L-phenylalanine, is commercially available as an injectable solution or tablets as ALKERAN. Melphalan is indicated for the palliative treatment of multiple myeloma and non-resectable epithelial carcinoma of the ovary.
  • Bone marrow suppression is the most common dose-limiting side effect of melphalan.
  • Chlorambucil 4-[bis(2-chloroethyl)amino]benzenebutanoic acid, is commercially available as LEUKERAN tablets. Chlorambucil is indicated for the palliative treatment of chronic lymphatic leukemia, and malignant lymphomas such as lymphosarcoma, giant follicular lymphoma, and Hodgkin’s disease.
  • Busulfan 1 ,4-butanediol dimethanesulfonate, is commercially available as MYLERAN TABLETS. Busulfan is indicated for the palliative treatment of chronic myelogenous leukemia.
  • Carmustine, l ,3-[bis(2-chloroethyl)-l -nitrosourea is commercially available as single vials of lyophilized material as BiCNU.
  • Carmustine is indicated for the palliative treatment as a single agent or in combination with other agents for brain tumors, multiple myeloma, Hodgkin’s disease, and non-Hodgkin’s lymphomas.
  • dacarbazine 5-(3,3-dimethyl-l-triazeno)-imidazole-4-carboxamide, is commercially available as single vials of material as DTIC-Dome.
  • dacarbazine is indicated for the treatment of metastatic malignant melanoma and in combination with other agents for the second line treatment of Hodgkin’s Disease.
  • Antibiotic anti-neoplastics are non-phase specific agents, which bind or intercalate with DNA. Typically, such action results in stable DNA complexes or strand breakage, which disrupts ordinary function of the nucleic acids leading to cell death.
  • antibiotic anti-neoplastic agents include, but are not limited to, actinomycins such as dactinomycin, anthrocyclins such as daunorubicin and doxorubicin; and bleomycins.
  • Dactinomycin also known as Actinomycin D
  • Actinomycin D is commercially available in injectable form as COSMEGEN. Dactinomycin is indicated for the treatment of Wilm’s tumor and rhabdomyosarcoma.
  • Daunorubicin (8S-cis-)-8-acetyl-l0-[(3-amino-2,3,6-trideoxy-a-L-lyxo- hcxopyranosyl )oxy] -7,8,9, 10-tetrahydro-6,8 , 11 -trihydroxy- 1 -methoxy-5, 12
  • naphthacenedione hydrochloride is commercially available as a liposomal injectable form as DAUNOXOME or as an injectable as CERUBIDINE. Daunorubicin is indicated for remission induction in the treatment of acute nonlymphocytic leukemia and advanced HIV associated Kaposi’s sarcoma.
  • Doxorubicin is primarily indicated for the treatment of acute lymphoblastic leukemia and acute myeloblastic leukemia, but is also a useful component in the treatment of some solid tumors and lymphomas.
  • Bleomycin a mixture of cytotoxic glycopeptide antibiotics isolated from a strain of Streptomyces verticillus, is commercially available as BLENOXANE. Bleomycin is indicated as a palliative treatment, as a single agent or in combination with other agents, of squamous cell carcinoma, lymphomas, and testicular carcinomas.
  • Topoisomerase II inhibitors include, but are not limited to, epipodophyllotoxins .
  • Epipodophyllotoxins are phase specific anti-neoplastic agents derived from the mandrake plant. Epipodophyllotoxins typically affect cells in the S and G 2 phases of the cell cycle by forming a ternary complex with topoisomerase II and DNA causing DNA strand breaks. The strand breaks accumulate and cell death follows. Examples of
  • epipodophyllotoxins include, but are not limited to, etoposide and teniposide.
  • Etoposide 4'-demethyl-epipodophyllotoxin 9[4,6-0-(R )-ethylidene-P-D- glucopyranoside] is commercially available as an injectable solution or capsules as VePESID and is commonly known as VP- 16. Etoposide is indicated as a single agent, or in combination with, other chemotherapy agents in the treatment of testicular and non small cell lung cancers.
  • Teniposide 4'-demethyl-epipodophyllotoxin 9[4,6-0-(R )-thenylidene-P-D- glucopyranoside], is commercially available as an injectable solution as VUMON and is commonly known as VM-26. Teniposide is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia in children.
  • Antimetabolite neoplastic agents are phase specific anti-neoplastic agents that act at S phase (DNA synthesis) of the cell cycle by inhibiting DNA synthesis or by inhibiting purine or pyrimidine base synthesis and thereby limiting DNA synthesis. Consequently, S phase does not proceed and cell death follows.
  • Examples of antimetabolite anti-neoplastic agents include, but are not limited to, fluorouracil, methotrexate, cytarabine, mecaptopurine, thioguanine, and gemcitabine.
  • 5-fluorouracil 5-fluoro-2,4- (lH,3H) pyrimidinedione
  • fluorouracil is commercially available as fluorouracil.
  • Administration of 5-fluorouracil leads to inhibition of thymidylate synthesis and is also incorporated into both RNA and DNA. The result typically is cell death.
  • 5- fluorouracil is indicated as a single agent or in combination with other chemotherapy agents in the treatment of carcinomas of the breast, colon, rectum, stomach and pancreas.
  • Other fluoropyrimidine analogs include 5-fluoro deoxyuridine (floxuridine) and 5- fluorodeoxyuridine monophosphate.
  • Cytarabine 4-amino- l-P-D-arabinofuranosyl-2 (lH)-pyrimidinone, is commercially available as CYTOSAR-U and is commonly known as Ara-C. It is believed that cytarabine exhibits cell phase specificity at S-phase by inhibiting DNA chain elongation by terminal incorporation of cytarabine into the growing DNA chain. Cytarabine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. Other cytidine analogs include 5-azacytidine and 2', 2'- difluorodeoxycytidine (gemcitabine).
  • Mercaptopurine l,7-dihydro-6H-purine-6-thione monohydrate
  • PURINETHOL is commercially available as PURINETHOL.
  • Mercaptopurine exhibits cell phase specificity at S-phase by inhibiting DNA synthesis by an as of yet unspecified mechanism.
  • Mercaptopurine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia.
  • a useful mercaptopurine analog is azathioprine.
  • Thioguanine 2-amino- l,7-dihydro-6H-purine-6-thione
  • TABLOID Thioguanine exhibits cell phase specificity at S-phase by inhibiting DNA synthesis by an as of yet unspecified mechanism.
  • Thioguanine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia.
  • Other purine analogs include pentostatin, erythrohydroxynonyladenine, fludarabine phosphate, and cladribine.
  • Gemcitabine 2'-deoxy-2', 2'-difluorocytidine monohydrochloride (b-isomer), is commercially available as GEMZAR.
  • Gemcitabine exhibits cell phase specificity at S- phase and by blocking progression of cells through the Gl/S boundary. Gemcitabine is indicated in combination with cisplatin in the treatment of locally advanced non-small cell lung cancer and alone in the treatment of locally advanced pancreatic cancer.
  • Methotrexate N-[4[[(2,4-diamino-6-pteridinyl) methyl] methylamino] benzoyl]-L- glutamic acid, is commercially available as methotrexate sodium. Methotrexate exhibits cell phase effects specifically at S-phase by inhibiting DNA synthesis, repair and/or replication through the inhibition of dyhydrofolic acid reductase which is required for synthesis of purine nucleotides and thymidylate. Methotrexate is indicated as a single agent or in combination with other chemotherapy agents in the treatment of
  • choriocarcinoma meningeal leukemia, non-Hodgkin’s lymphoma, and carcinomas of the breast, head, neck, ovary and bladder.
  • Topoisomerase I inhibitors Camptothecins, including, camptothecin and camptothecin derivatives are available or under development as Topoisomerase I inhibitors.
  • Camptothecins cytotoxic activity is believed to be related to its Topoisomerase I inhibitory activity.
  • camptothecins include, but are not limited to, irinotecan, topotecan, and the various optical forms of 7-(4-methylpiperazino-methylene)-l0,l 1- ethylenedioxy-20-camptothecin described below.
  • Irinotecan is a derivative of camptothecin which binds, along with its active metabolite SN-38, to the topoisomerase I - DNA complex.
  • cytotoxicity occurs as a result of irreparable double strand breaks caused by interaction of the topoisomerase I : DNA : irintecan or SN-38 ternary complex with replication enzymes.
  • Irinotecan is indicated for treatment of metastatic cancer of the colon or rectum.
  • Topotecan HC1 (S)- 10-[(dimethylamino)methyl]-4-ethyl-4, 9-dihydroxy- 1 H- pyrano[3',4',6,7]indolizino[l,2-b]quinoline-3,l4-(4H,l2H)-dione monohydrochloride, is commercially available as the injectable solution HYCAMTIN.
  • Topotecan is a derivative of camptothecin which binds to the topoisomerase I - DNA complex and prevents re ligation of singles strand breaks caused by Topoisomerase I in response to torsional strain of the DNA molecule. Topotecan is indicated for second line treatment of metastatic carcinoma of the ovary and small cell lung cancer.
  • Hormones and hormonal analogues are useful compounds for treating cancers in which there is a relationship between the hormone(s) and growth and/or lack of growth of the cancer.
  • hormones and hormonal analogues useful in cancer treatment include, but are not limited to, adrenocorticosteroids such as prednisone and prednisolone which are useful in the treatment of malignant lymphoma and acute leukemia in children ; aminoglutethimide and other aromatase inhibitors such as anastrozole, letrazole, vorazole, and exemestane useful in the treatment of adrenocortical carcinoma and hormone dependent breast carcinoma containing estrogen receptors; progestrins such as megestrol acetate useful in the treatment of hormone dependent breast cancer and endometrial carcinoma; estrogens, androgens, and anti-androgens such as flutamide, nilutamide, bicalutamide, cyproterone
  • GnRH gonadotropin-releasing hormone
  • LH leutinizing hormone
  • FSH follicle stimulating hormone
  • Signal transduction pathway inhibitors are those inhibitors, which block or inhibit a chemical process which evokes an intracellular change. As used herein this change is cell proliferation or differentiation.
  • Signal transduction inhibitors useful in the present invention include, but are not limited to, inhibitors of receptor tyrosine kinases, non-receptor tyrosine kinases, SH2/SH3 domain blockers, serine/threonine kinases, phosphotidyl inositol-3 kinases, myo-inositol signaling, and Ras oncogenes.
  • protein tyrosine kinases catalyse the phosphorylation of specific tyrosyl residues in various proteins involved in the regulation of cell growth.
  • protein tyrosine kinases can be broadly classified as receptor or non-receptor kinases.
  • Receptor tyrosine kinases are transmembrane proteins having an extracellular ligand binding domain, a transmembrane domain, and a tyrosine kinase domain. Receptor tyrosine kinases are involved in the regulation of cell growth and are generally termed growth factor receptors. Inappropriate or uncontrolled activation of many of these kinases, i.e., aberrant kinase growth factor receptor activity, for example by over expression or mutation, has been shown to result in uncontrolled cell growth.
  • Growth factor receptors include, for example, epidermal growth factor receptor (EGFr), platelet derived growth factor receptor (PDGFr), erbB2, erbB4, ret, vascular endothelial growth factor receptor (VEGFr), tyrosine kinase with immunoglobulin-like and epidermal growth factor identity domains (TIE-2), insulin growth factor -I (IGFI) receptor, macrophage colony stimulating factor (cfms), BTK, ckit, cmet, fibroblast growth factor (FGF) receptors, Trk receptors (TrkA, TrkB, and TrkC), ephrin (eph) receptors, and the RET protooncogene.
  • EGFr epidermal growth factor receptor
  • PDGFr platelet derived growth factor receptor
  • erbB2 erbB2
  • VEGFr vascular endothelial growth factor receptor
  • TIE-2 immunoglobulin-like and epidermal growth factor identity domain
  • inhibitors of growth receptors include ligand antagonists, antibodies, tyrosine kinase inhibitors and anti-sense oligonucleotides.
  • Growth factor receptors and agents that inhibit growth factor receptor function are described, for instance, in Kath, John C., Exp. Opin. Ther. Patents (2000) 10(6): 803-818; Shawver, et al, DDT, Vol 2, No. 2 (February 1997); and Lofts, F. J., et al, “GROWTH FACTOR RECEPTORS AS TARGETS”, NEW MOLECULAR TARGETS FOR CANCER CHEMOTHERAPY (Workman, Paul and Kerr, David, CRC press 1994, London).
  • Non-receptor tyrosine kinases which are not growth factor receptor kinases are termed non-receptor tyrosine kinases.
  • Non-receptor tyrosine kinases useful in the present invention include cSrc, Lck, Fyn, Yes, Jak, cAbl, FAK (Focal adhesion kinase), Brutons tyrosine kinase, and Bcr-Abl.
  • SH2/SH3 domain blockers are agents that disrupt SH2 or SH3 domain binding in a variety of enzymes or adaptor proteins including, PI3-K p85 subunit, Src family kinases, adaptor molecules (She, Crk, Nek, Grb2) and Ras-GAP.
  • SH2/SH3 domains as targets for anti-cancer drugs are discussed in Smithgall, T.E., Journal of Pharmacological and Toxicological Methods, 34(3) 125-32 (1995).
  • Inhibitors of Serine/Threonine Kinases including MAP kinase cascade blockers which include blockers of Raf kinases (rafk), Mitogen or Extracellular Regulated Kinase (MEKs), and Extracellular Regulated Kinases (ERKs); and Protein kinase C family member blockers including blockers of PKCs (alpha, beta, gamma, epsilon, mu, lambda, iota, zeta).
  • IkB kinase family IKKa, IKKb
  • PKB family kinases akt kinase family members
  • TGF beta receptor kinases TGF beta receptor kinases.
  • Serine/Threonine kinases and inhibitors thereof are described in Yamamoto, et al., Journal of Biochemistry , 126 (5) 799-803 (1999) ; Brodt, et al., Biochemical Pharmacology, 60. 1101-1107 (2000); Massague, et al, Cancer Surveys, 27:41-64 (1996); Philip, et al., Cancer Treatment and Research, 78: 3-27 (1995), Lackey, et al., Bioorganic and Medicinal Chemistry Letters, (10) 223-226 (2000); U.S. Patent No. 6,268,391; and Martinez-Iacaci, et al, Int. J. Cancer, 88(1), 44- 52 (2000).
  • Inhibitors of Phosphotidyl inositol-3 Kinase family members including blockers of PI3- kinase, ATM, DNA-PK, and Ku are also useful in the present invention. Such kinases are discussed in Abraham, R.T. (1996), Current Opinion in Immunology. 8 (3) 412-8;
  • myo-inositol signaling inhibitors such as phospholipase C blockers and Myoinositol analogues.
  • signal inhibitors are described in Powis, G., and Kozikowski A., (1994) NEW MOLECULAR TARGETS FOR CANCER CHEMOTHERAPY ED. (Paul Workman and David Kerr, CRC press 1994,
  • Another group of signal transduction pathway inhibitor are inhibitors of Ras Oncogene.
  • Such inhibitors include inhibitors of farnesyltransferase, geranyl-geranyl transferase, and CAAX proteases as well as anti-sense oligonucleotides, ribozymes and immunotherapy.
  • Such inhibitors have been shown to block ras activation in cells containing wild-type mutant ras , thereby acting as antiproliferation agents.
  • Ras oncogene inhibition is discussed in Scharovsky, et al. (2000), Journal of Biomedical Science. 7(4) 292-8;
  • antibody antagonists to receptor kinase ligand binding may also serve as signal transduction inhibitors.
  • This group of signal transduction pathway inhibitors includes the use of humanized antibodies to the extracellular ligand binding domain of receptor tyrosine kinases.
  • Imclone C225 EGFR specific antibody see Green, el al., Monoclonal Antibody Therapy for Solid Tumors, Cancer Treat.
  • Herceptin erbB2 antibody see’’Tyrosine Kinase Signaling in Breast cancenerbB Family Receptor Tyrosine Kinases”, Breast Cancer Res., 2000, 2(3), 176-183
  • 2CB VEGFR2 specific antibody see Brekken, et al.,“Selective Inhibition of VEGFR2 Activity by a monoclonal Anti-VEGF antibody blocks tumor growth in mice”, Cancer Res. (2000) 60, 5117-5124).
  • Anti-angiogenic agents including non-receptorMEKngiogenesis inhibitors may also be useful. Anti-angiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, (for example the anti-vascular endothelial cell growth factor antibody bevacizumab [AVASTIN], and compounds that work by other mechanisms (for example linomide, inhibitors of integrin anb3 function, endostatin and angio statin);
  • vascular endothelial growth factor for example the anti-vascular endothelial cell growth factor antibody bevacizumab [AVASTIN]
  • AVASTIN anti-vascular endothelial cell growth factor antibody bevacizumab
  • compounds that work by other mechanisms for example linomide, inhibitors of integrin anb3 function, endostatin and angio statin
  • Immuno therapeutic agents Agents used in immunotherapeutic regimens may also be useful in combination with the compounds of formula (I).
  • Immunotherapy approaches including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumor cell lines and approaches using anti- idiotypic antibodies
  • Proapoptotic agents Agents used in proapoptotic regimens (e.g ., bcl-2 antisense oligonucleotides) may also be used in the combination of the present invention.
  • Cell cycle signaling inhibitors inhibit molecules involved in the control of the cell cycle.
  • a family of protein kinases called cyclin dependent kinases (CDKs) and their interaction with a family of proteins termed cyclins controls progression through the eukaryotic cell cycle. The coordinate activation and inactivation of different cyclin/CDK complexes is necessary for normal progression through the cell cycle.
  • CDKs cyclin dependent kinases
  • Several inhibitors of cell cycle signaling are under development. For instance, examples of cyclin dependent kinases, including CDK2, CDK4, and CDK6 and inhibitors for the same are described in, for instance, Rosania, el ah, Exp. Opin. Ther. Patents (2000) 10(2):215-230.
  • the combination of the present invention comprises an 0X40 binding protein or antibody and a TLR4 modulator and at least one anti-neoplastic agent selected from anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine MEK angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, and cell cycle signaling inhibitors.
  • anti-neoplastic agent selected from anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine MEK angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, and cell cycle signaling inhibitors.
  • the combination of the present invention comprises an 0X40 binding protein and a TLR4 modulator and at least one anti-neoplastic agent which is an anti microtubule agent selected from diterpenoids and vinca alkaloids.
  • the anti-neoplastic agent is a diterpenoid.
  • the anti-neoplastic agent is a vinca alkaloid.
  • the combination of the present invention comprises an 0X40 binding protein and a TLR4 modulator and at least one anti-neoplastic agent, which is a platinum coordination complex.
  • the anti-neoplastic agent is paclitaxel, carboplatin, or vinorelbine.
  • the combination of the present invention comprises an 0X40 binding protein and a TLR4 modulator and at least one anti-neoplastic agent which is a signal transduction pathway inhibitor.
  • the signal transduction pathway inhibitor is an inhibitor of a growth factor receptor kinase, VEGFR2, TIE2, PDGFR, BTK, erbB2, EGFr, IGFR-l , TrkA, TrkB, TrkC, or c-fms.
  • the signal transduction pathway inhibitor is an inhibitor of a serine/threonine kinase rafk, akt, or PKC-zeta.
  • the signal transduction pathway inhibitor is an inhibitor of a non- receptor tyrosine kinase selected from the src family of kinases.
  • the signal transduction pathway inhibitor is an inhibitor of c-src.
  • the signal transduction pathway inhibitor is an inhibitor of Ras oncogene selected from inhibitors of farnesyl transferase and geranylgeranyl transferase.
  • the signal transduction pathway inhibitor is an inhibitor of a serine/threonine kinase selected from the group consisting of PI3K.
  • the signal transduction pathway inhibitor is a dual EGFr/erbB2 inhibitor, for example N- ⁇ 3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2- (methanesulphonyl) ethyl]amino ⁇ methyl)-2-furyl]-4-quinazolinamine (structure below):
  • the combination of the present invention comprises a compound of formula I or a salt or solvate thereof and at least one anti-neoplastic agent which is a cell cycle signaling inhibitor.
  • cell cycle signaling inhibitor is an inhibitor of CDK2, CDK4, or CDK6.
  • the mammal in the methods and uses of the present invention is a human.
  • therapeutically effective amounts of the combinations of the invention are administered to a human.
  • the therapeutically effective amount of the administered agents of the present invention will depend upon a number of factors including, for example, the age and weight of the subject, the precise condition requiring treatment, the severity of the condition, the nature of the formulation, and the route of administration. Ultimately, the therapeutically effective amount will be at the discretion of the attendant physician.
  • Example 1 Treatment of 0X86 Monotherapy in a CT-26 syngeneic mouse model for colon cancer
  • CT26 mouse colon carcinoma (CT26.WT; ATCC #CRL-2638) cell line was obtained from ATCC. It is an N-nitroso-N-methylurethane-(NNMU) induced, undifferentiated colon carcinoma cell line known in the art. For example, it is described in: Wang M, et al., Active immunotherapy of cancer with a nonreplicating recombinant fowlpox virus encoding a model tumor-associated antigen, J. Immunol. 154: 4685-4692, 1995 (PubMed: 7722321). Rat IgGl was obtained from Bioxcell.
  • 0X86 Hybridoma 134 cells were obtained from the European Cell Culture collection and manufactured by Harlan; 0X86 is the name for a tool anti-OX40 monoclonal antibody used in rodents; it is a rodent antibody that binds rodent 0X40, e.g., mouse 0X40 (receptor).
  • 0X86 and rat IgGl were diluted in diluted DPBS.
  • CT-26 mae colon carcinoma cells
  • ATCC catalog# CRL-2638, lot# 59227052
  • basic RPMI with 10% FBS
  • CT-26 cells (passage 12) were harvested from the flask in complete medium. Cells were centrifuged and resuspended in RPMI (without FBS), this step is repeated 3 times. Cell density and viability were checked via trypan blue exclusion. Cells were then diluted to desired density (5xl0 5 cells per mL) and kept on ice.
  • Escalating doses of 0X40 monoclonal antibody (mAh) 0X86 were evaluated for their efficacy in reducing tumor growth.
  • Animals were weighed and inoculated on the right hind quarter with 0.5x10 5 CT26 tumor cells per mouse on Day 0.
  • tumor growth and total body weight are measured 3 times a week for the duration of the study. Randomization occurred on day 10 or 11 when the average tumor volume was approximately 100 mm 3 .
  • mice were dosed with 0X86 mAh or Rat IgGl isotype i.p. biweekly, for a total of 6 doses. Mice remained on study until tumors reach >2000 cu mm for two consecutive
  • Days 1, 4, 6, 8 Animals were weighed and checked for tumors and if present, tumors measured.
  • Randomization day (approx day 10): Animals were randomized and placed into cages representing appropriate groups
  • TLR4 modulators such as CRX-527 to the above 0X40 monotherapy treatment protocol were used to study TLR4 monotherapy and the combination of anti- mOX40 immunotherapy with TLR4 modulators.
  • Days 1, 4, 6, 8 Animals were weighed and checked for tumors and measured.
  • Randomization day (approx day 10): Animals were randomized and placed into cages representing appropriate groups
  • Example 3 Combination Treatment with 0X40 (Le., OX-86, an antibody raised against rodent 0X40 receptor) and CRX-527
  • Days 1, 4, 6, 8 Animals checked for tumors and if present, tumors measured. Study enrollment day (approx day 10): Animals randomized and received treatment 1.
  • mice received i.p. dose biweekly for a total 6 doses.
  • mice When 0X86 treatment was combined with TLR4 modulator treatment (CRX-527), mice exhibited a higher reduction in tumor burden and survived longer than either treatment alone.
  • Example 4 Monotherapy and Combination Treatment with anti-mOX40R antibody and TLR4 targeting molecules of Formula I Mice were administered 0X40 antibody; a compound of Formula 1 (including a compound of Formula la, CRX-527, CRX-547, and CRX-601 (TLR4 agonists), or a combination of both. Each treatment has significant anti-tumor activity.
  • mice anti-OX40R or combination of anti-OX40 antibody and TLR4 agonist combination each delayed the growth of established CT-26 tumors relative to an untreated control group.
  • mice significant anti-tumor effect was observed in TLR4 agonist and anti-OX40R antibody combinations as compared to monotherapy treatment.
  • Example 5 Combination Treatment with an OX40R ABS (Le., anti-mOX40 receptor antibody clone OX-86, an antibody raised against rodent 0X40 receptor) and CRX-601
  • OX40R ABS Le., anti-mOX40 receptor antibody clone OX-86, an antibody raised against rodent 0X40 receptor
  • the in vivo anti -tumor efficacy of the TLR4 agonist was assessed in the murine CT-26 colon carcinoma syngeneic solid tumor model as a monotherapy and in combination with a rate anti-mouse 0X40 antibody clone 0X86.
  • Seven to eight week old female Balb/c mice (B ALB/c AnNCrl, Charles River) were used in these studies.
  • Murine CT-26 colon carcinoma cells (ATCC catalog number CRL-2638 lot# 59227052) were cultured in RPMI growth medium supplemented with 10% fetal bovine serum (FBS) in a humidified 37°C incubator with 5% CO 2.
  • CT-26 cells cultured in logarithmic growth were harvested from tissue culture flasks and centrifuged for 5 minutes at 450xg at 4°C for ten minutes to pellet cells. The supernatant was discarded, and cells were washed in ice cold phosphate buffered saline (PBS) without calcium and magnesium and centrifuged again for 5 minutes at 450xg at 4°C for ten minutes to pellet cells. The cells were resuspended in sterile RPMI media without FBS and adjusted to a cell concentration of 500,000 cells/mL. 100 m ⁇ of the cell stock was implanted via subcutaneous injection into the right flank of each Balb/c mouse.
  • PBS phosphate buffered saline
  • mice were randomized into study cohorts according to tumor size and the first treatment dose was given.
  • the TLR4 agonist (CRX601) or vehicle was dosed via a systemic intravenous or direct intratumoral injection as indicated.
  • the CRX-601 vehicle used for intravenous and intratumoral dosing was 0.5% where indicated.
  • a DOPC/CHOL liposome prepared by GSK Lot #1783-157-B was used for CRX-601 liposomal intratumoral dosing.
  • the rat anti mouse 0X40 receptor antibody (clone 0X86) (expressed and purified in-house from the rat hybridoma Grits ID 50776, BP232 2013) or Rat IgGl isotype control antibody (BioXCell catalog # BE0088) was dosed via an intraperitoneal injection given twice per week for a total of six doses. Caliper measurements were taken three times per week to assess tumor growth, and mice with tumors ⁇ 2,000 mm 3 were maintained on study from 30 up to approximately 1 15 days. Mice with tumors >2,000 mm 3 for 2 consecutive measurements or mice with tumors which formed open ulcers were removed from the study. Tumor volume was calculated using the formula (0.52) x (Length) x (Width 2 ).
  • mice were re-challenged with CT-26 tumor cells as described above, on the opposite flank from the original inoculation site and tumor growth was monitored, as described above. All studies were conducted in accordance with the GSK Policy on the Care, Welfare and Treatment of Laboratory Animals and were reviewed by the Institutional Animal Care and Use Committee at GSK.
  • Tumors, blood and tissues were harvested from CT-26 mice on day 0, day 1 and day 8 after first CRX-601 dosing.
  • Mouse white blood cells and dissociated tumor single cells were stained freshly with surface or intracellular staining antibodies for multicolor flow cytometry analysis for immune phenotyping.
  • Multiplex cytokine analysis was performed using mouse plasma samples from the same study.
  • tumor volumes at 1 1 (study 1), 15 (studies 2 and 3), or 19 (study 4) days after first dose were compared between the different treatment groups. Prior to the analysis, tumor volumes were natural log transformed due to the inequality of variance in the different treatment groups.
  • the raw p-value, as well as the false discovery rate (FDR) adjusted p-values, from the comparisons of days to events by survival analysis and the comparisons of log transformed tumor volume at indicated days between treatment groups was determined.
  • the ones with FDR adjusted p-values ⁇ 0.05 were declared to be statistically significant.
  • tumor volumes at 12 days after first dose were compared between the different treatment groups.
  • Treatments were compared by standard ANOVA methods followed by FDR adjustment for multiplicity. Response is square root of volume, for homoscedasticity (equal variance) reasons. Kaplan-Meier (KM) method was carried out to estimate the survival probability of different treatment groups at a given time. For these survival analyses, “Death” means crossing the tumor volume cutoff (2000 mm 3 ). “Survival” means proportion of mice not“Dead”, and“Survival time” means days until“Death”. If a mouse crossed the volume cutoff between two measurement days, then the day of“death” was estimated by linear interpolation. If a mouse crossed the volume cutoff more than once, the first crossing was used. Treatments were compared by the standard log-rank test for two treatments. The log-rank p-values were adjusted for multiplicity using the FDR (false discovery rate) method. Significance was defined as FDR ⁇ 0.05. All calculations and graphs were done using R software, version 3.2.3.
  • mice were inoculated with 5xl0 4 CT-26 cells and randomized into groups of 10 listed below when tumor size reached approximately 100 mm 3 as described in Materials and Methods.
  • Group 1 Vehicle dosed intratumoral twice per week for 6 doses total
  • Group 2 CRX-601 0.1 pg/mouse dosed intratumoral twice per week for 6 doses total
  • Group 3 CRX-601 1 pg/mouse dosed intratumoral twice per week for 6 doses total
  • Group 4 CRX-601 10 pg/mouse dosed intratumoral twice per week for 6 doses total
  • Group 5 CRX-601 50 pg/mouse single dose
  • mice treated with the TLR4 agonist CRX-601 in this study also showed a statistically significant increase in survival time.
  • the 50 pg dosed mice showed a statistically significant (*p-values ⁇ 0.05) increase in survival compared to vehicle by day 42 post CT26 tumor cell inoculation when the study was ended.
  • On this day only mice from the 50 pg and 10 pg CRX-601 groups remained on study.
  • Three of the four mice in the 50 pg group were tumor-free, with the fourth mouse showing a tumor volume of 854.19 mm 3 .
  • the single mouse remaining in the 10 pg group was tumor-free (see Figure 19).
  • mice were inoculated with 5x10 4 CT-26 cells and randomized into groups of 10 below when tumor size reached approximately 100 mm 3 as described in Materials and Methods.
  • Group 1 Vehicle dosed intravenous twice per week for 6 doses total
  • Group 2 CRX-601 1 pg/mouse dosed intravenous twice per week for 6 doses total
  • Group 3 CRX-601 10 pg/mouse dosed intravenous twice per week for 6 doses total
  • Group 4 CRX-601 100 pg/mouse single dose
  • mice treated with the TLR4 agonist CRX-601 in this CT-26 syngeneic mouse tumor model also showed statistically significant increase in survival compared with vehicle.
  • the 100 pg dosed mice showed a statistically significant increase (*p-values ⁇ 0.05) in survival compared to vehicle when the study was ended on day 32 post CT-26 tumor cell inoculation.
  • One of the three mice remaining in this group was tumor-free, while the other mice showed tumor volumes of 1500.49 and 962.61 mm 3 .
  • the single mouse remaining in the 10 pg dose group had a tumor volume of 188.0 mm 3 . (See Figure 21)
  • mice were inoculated with 5xl0 4 CT-26 cells and randomized into groups of 10 below when tumor size reached approximately 100 mm 3 as described in Materials and Methods.
  • Group 1 Vehicle dosed intravenous once per week for 3 doses total
  • Group 2 Rat IgGl 10 pg/mouse dosed intraperontoneal twice per week for 6 doses total
  • Group 3 0X86 25 pg/mouse dosed twice per week for 6 doses total
  • Group 4 CRX-601 10 pg/mouse dosed intravenous once per week for 3 doses total
  • Group 5 CRX-601 25 pg/mouse dosed intravenous once per week for 3 doses total
  • Group 6 CRX-601 10 pg/mouse dosed intravenous once per week for 3 doses total + 0X86 25 pg/mouse dosed intraperontoneal twice per week for 6 doses total
  • Group 7 CRX-601 25 pg/mouse dosed intravenous once per week for 3 doses total + 0X86 25 pg/mouse dosed intraperontoneal twice per week for 6 doses total
  • Anti-tumor activity was assessed (as measured by tumor growth inhibition over time) for 25 pg/mouse of a rat anti-mouse 0X40 receptor antibody (clone OX-86), dosed intravenous twice per week for 6 doses total, 10 pg or 25 pg/mouse of TLR4 agonist CRX-601 dosed intravenous lx/week for 3 doses total, and the combination of both in this CT-26 syngeneic mouse model.
  • the sub-optimal monotherapy CRX-601 doses of 10 pg/mouse or 25 pg/mouse dosed once per week did not show statistically significant tumor growth inhibition when dosed alone compared to vehicle, nor did the 0X86 25 pg/mouse dose compared to Rat IgGl .
  • CRX601 dosed intravenous once per week at 10 pg or 25 pg/mouse for 3 doses total in combination with 25 pg/mouse 0X86 dosed twice per week for 6 doses total showed statistically significant (*p- values ⁇ 0.05) tumor growth inhibition 15 days after the initial dose compared to vehicle and Rat IgGl controls, and compared to CRX601 and 0X86 monotherapies (see Figure 22).
  • CRX-601 10 pg and 25 pg/mouse dosed intravenous lx/week for 3 doses total in combination with 25 pg/mouse 0X86 dosed 2x/week for 6 doses total showed a statistically significant ( U p values ⁇ 0.05) increase in survival compared to both vehicle and Rat IgGl controls, and compared to 0X86 and CRX-601 monotherapies.
  • mice in the CRX- 601 25 pg/mouse + 0X86 group were tumor-free, and the one mouse in the CRX-601 10 pg/mouse + 0X86 group was tumor-free (see Figure 23).
  • Study 3 was repeated with 25 pg/mouse of CRX-601 alone and in combination with anti- 0X40. Mice were inoculated with 5xl0 4 CT-26 cells and randomized into groups of 10 below when tumor size reached approximately 100 mm 3 as described in Materials and Methods.
  • Group 1 Vehicle dosed intravenous once per week for 3 doses total + Rat IgGl 25 pg/mouse dosed intraperontoneal twice per week for 6 doses total
  • Group 2 CRX-601 25 pg/mouse dosed intravenous once per week for 3 doses total
  • Group 3 Vehicle dosed intravenous once per week for 3 doses total + 0X86 25 pg/mouse dosed intraperontoneal twice per week for 6 doses total
  • Group 4 CRX-601 25 pg/mouse dosed intravenous once per week for 3 doses total + Rat IgGl 25 pg/mouse dosed intraperontoneal twice per week for 6 doses total
  • Group 5 CRX-601 25 pg/mouse dosed intravenous once per week for 3 doses total + 0X86 25 pg/mouse dosed intraperontoneal twice per week for 6 doses total
  • CRX601 dosed intravenous once per week at 25 pg/mouse for 3 doses total in combination with 25 pg/mouse 0X86 dosed twice per week for 6 doses total showed statistically significant (*p- values ⁇ 0.05) tumor growth inhibition compared to CRX601 and 0X86 monotherapies (see Figure 24).
  • Results are the mean of five animals per cohort.
  • a synergistic increase of expression of T cell activation marker CD25 on circulating CD4 T cells was observed in mice treated with CRX-601 and anti-OX86 in combination.
  • a synergistic increase of T cell activation associated markers CTLA4, PD1 and ICOS on circulating CD4 T cells was observed in mice treated with CRX-601 and anti-OX86 in combination. Results are shown in Figure 26 A-C.
  • mice were inoculated with 5xl0 4 CT-26 cells and randomized into groups of 10 below when tumor size reached approximately 100 mm 3 as described in Materials and Methods.
  • Group 1 Vehicle dosed intravenous once per week for 3 doses total + Rat IgGl 25 pg/mouse dosed intraperontoneal twice per week for 6 doses total
  • Group 2 CRX-601 25 pg/mouse dosed intravenous once per week for 3 doses total + Rat IgGl 25 pg/mouse dosed intraperontoneal twice per week for 6 doses total
  • Group 3 0X86 25 pg/mouse dosed intraperontoneal twice per week for 6 doses total
  • Group 4 CRX-601 25 pg/mouse dosed intravenous once per week for 3 doses total + 0X86 25 pg/mouse dosed intraperontoneal twice per week for 6 doses total
  • Group 5 Vehicle dosed intratumoral once per week for 3 doses total + Rat IgGl 25 pg/mouse dosed intraperontoneal twice per week for 6 doses total
  • Group 6 CRX-601 25 pg/mouse dosed intratumoral once per week for 3 doses total +
  • Group 7 CRX-601 25 pg/mouse dosed intratumoral once per week for 3 doses total + 0X86 25 pg/mouse dosed intraperontoneal (i.p.) twice per week for 6 doses total
  • the sub-optimal monotherapy CRX-601 dose of 25 pg/mouse did not show statistically significant tumor growth inhibition when dosed intravenous (Group 2) or intratumoral (Group 6) compared to corresponding control groups (Group 1 and Group 5 respectively).
  • the monotherapy 0X86 25 pg/mouse dose did not show statistically significant tumor growth inhibition compared to control Groups 1 and 5 either.
  • the CRX601 25 pg/mouse dose given intravenous in combination with the 0X86 25 pg/mouse i.p. dose (Group 4) showed statistically significant (*p- values ⁇ 0.05) tumor growth inhibition 12 days after the initial dose compared to control Group 1 and 0X86 monotherapy Group 3.
  • the monotherapy groups did not show a statistically significant increase in survival compared to control groups (see Figures 30 and 31).
  • Naive control mice and fully regressed tumor- free mice on day 68 were re-challenged with CT26 tumor cells.
  • CT26 tumors grew as expected in naive control mice, but were rejected with no tumor growth in the treatment group mice. This indicates a persistent anti-tumor memory immunity due to CRX-601 or CRX-601 in combination with 0X86 treatment (see Figure 32).
  • the two mice in the 0X86 monotherapy Group 3 on day 68 had tumor volumes of 27.86 and 1576.27 mm 3 , and were not re-challenged.
  • mice were inoculated with 5xl0 4 CT-26 cells and randomized into groups of 10 below when tumor size reached approximately 100 mm 3 as described in Materials and Methods
  • Group 1 Vehicle (0.5% GlyceroP4% dextrose) dosed intravenous once per week for 3 doses total + Rat IgGl 25 pg/mouse dosed intraperontoneal twice per week for 6 doses total
  • Group 2 CRX-601 25 pg/mouse (in 0.5% GlyceroF4% dextrose) dosed intravenous once per week for 3 doses total + Rat IgGl 25 pg/mouse dosed intraperontoneal twice per week for 6 doses total
  • Group 3 Vehicle (0.5% GlyceroF4% dextrose) dosed intravenous once per week for 3 doses total + 0X86 25 pg/mouse dosed intraperontoneal twice per week for 6 doses total
  • Group 4 CRX-601 25 pg/mouse (in 0.5% GlyceroF4% dextrose) dosed intravenous once per week for 3 doses total + 0X86 25 pg/mouse dosed intraperontoneal twice per week for 6 doses total
  • Group 5 Vehicle (DOPC/CHOL Liposome) dosed intratumoral once per week for 3 doses total + Rat IgGl 25 pg/mouse dosed intraperontoneal twice per week for 6 doses total
  • Group 6 Vehicle (DOPC/CHOL Liposome) dosed intratumoral once per week for 3 doses total + 0X86 25 pg/mouse dosed intraperontoneal twice per week for 6 doses total
  • Group 7 CRX-601 25 pg/mouse (in DOPC/CHOL Liposome) dosed intratumoral once per week for 3 doses total + Rat IgGl 25 pg/mouse dosed intraperontoneal twice per week for 6 doses total
  • Group 8 CRX-601 25 pg/mouse (in DOPC/CHOL Liposome) dosed intratumoral once per week for 3 doses total + 0X86 25 pg/mouse dosed intraperontoneal twice per week for 6 doses total
  • Anti-tumor activity was assessed (as measured by tumor growth inhibition over time) for treatment groups 12 days after the initial dose.
  • the sub-optimal monotherapy CRX-601 dose of 25 pg/mouse showed statistically significant (*p- values ⁇ 0.05) tumor growth inhibition when dosed intravenous (Group 2) or intratumoral (Group 7, liposomal formulation) compared to corresponding control groups (Group 1 and Group 5 respectively).
  • the monotherapy 0X86 25 pg/mouse IP dose Group 3 and Group 7 also showed statistically significant (*p- values ⁇ 0.05) tumor growth inhibition compared to control Groups 1 and 5.
  • the CRX601 25 pg/mouse dose given intravenous in combination with the 0X86 25 pg/mouse i.p. dose (Group 4) showed statistically significant (*p-values ⁇ 0.05) tumor growth inhibition compared to control Group 1 and 0X86 monotherapy Group 3.
  • the CRX601 25 pg/mouse dose given intratumoral with the DOPC/CHOL liposomal formulation in combination with the 0X86 25 pg/mouse i.p. dose (Group 8) also showed statistically significant (*p- values ⁇ 0.05) tumor growth inhibition compared to control Group 5.
  • CRX601 dosed as a monotherapy IV (Group 2), or dosed IV in combination with 0X86 i.p. (Group 4) showed a statistically significant (*p-values ⁇ 0.05) increase in survival compared to control Group 1.
  • Groups 2 and 4 had 5 out of 10 mice each showing full tumor regressions (see Figure 35).
  • Both CRX601 dosed as a monotherapy intratumoral with the DOPC/CHOL liposome formulation (Group 7), and the 0X86 monotherapy with the liposomal intratumoral control (Group 6) showed a statistically significant (*p- values ⁇ 0.05) increase in survival compared to control Group 5.
  • the intratumoral CRX601 DOPC/CHOL liposomal formulation dose in combination with 0X86 IP showed a statistically significant (*p-values ⁇ 0.05) increase in survival compared to control Group 5, as well as compared to the CRX601 intratumoral (Group 7) and 0X86 (Group 6) monotherapy control groups.
  • 9 out of 10 mice were fully regressed and tumor- free in the intratumoral CRX601 DOPC/CHOL liposomal dose in combination with 0X86 i.p., compared to 3 and 2 mice in the intratumoral monotherapy control Groups 6 and 7.
  • mice were inoculated with 5x10 4 CT-26 cells on the left flank, and 5xl0 4 CT-26 cells on the right flank as described in Materials and Methods for single tumor inoculation.
  • each mouse possessed two tumors, one on the right flank, and one on the left flank.
  • Mice were randomized into groups of 10 as shown below when tumor size reached approximately 100 mm 3 for the right flank, and left flank tumor size was similar.
  • CRX-601 was dosed intratumoral (IT) in the left flank tumor only using a DOPC/CHOL liposomal formulation or a 0.5% glycerol/4% dextrose formulation. Tumor size was monitored for both the right and left flank tumors.
  • CRX-601 was dosed intravenous (IV) using a 0.5% glycerol/4% dextrose vehicle, alone and in combination with anti-OX40 as a control for systemic activity (Group 7).
  • Group 1 Vehicle (0.5% glycerol/4% dextrose) dosed intravenous once per week for 3 doses total + Rat IgGl 25 pg/mouse dosed intraperontoneal twice per week for 6 doses total
  • Group 2 Vehicle (0.5% glycerol/4% dextrose) dosed intratumoral once per week for 3 doses total + Rat IgGl 25 pg/mouse dosed intraperontoneal twice per week for 6 doses total
  • Group 3 CRX-601 25 pg/mouse (in 0.5% glycerol/4% dextrose) dosed intravenous once per week for 3 doses total + Rat IgGl 25 pg/mouse dosed intraperontoneal twice per week for 6 doses total
  • Group 4 CRX-601 25 pg/mouse (in 0.5% glycerol/4% dextrose) dosed intratumoral once per week for 3 doses total + Rat IgGl 25 pg/mouse dosed intraperontoneal twice per week for 6 doses total
  • Group 5 Vehicle (0.5% glycerol/4% dextrose) dosed intravenous once per week for 3 doses total + 0X86 25 pg/mouse dosed intraperontoneal twice per week for 6 doses total
  • Group 6 Vehicle (0.5% glycerol/4% dextrose) dosed intratumoral once per week for 3 doses total + 0X86 25 pg/mouse dosed intraperontoneal twice per week for 6 doses total
  • Group 7 CRX-601 25 pg/mouse (in 0.5% glycerol/4% dextrose) dosed intravenous once per week for 3 doses total + 0X86 25 pg/mouse dosed intraperontoneal twice per week for 6 doses total
  • Group 8 CRX-601 25 pg/mouse (in 0.5% glycerol/4% dextrose) dosed intratumoral once per week for 3 doses total + 0X86 25 pg/mouse dosed intraperontoneal twice per week for 6 doses total
  • Group 9 Vehicle (DOPC/CHOL Liposome) dosed intratumoral once per week for 3 doses total + Rat IgGl 25 pg/mouse dosed intraperontoneal twice per week for 6 doses total
  • Group 10 Vehicle (DOPC/CHOL Liposome) dosed intratumoral once per week for 3 doses total + 0X86 25 pg/mouse dosed intraperontoneal twice per week for 6 doses total
  • Group 11 CRX-601 25 pg/mouse (in DOPC/CHOL Liposome) dosed intratumoral once per week for 3 doses total + Rat IgGl 25 pg/mouse dosed intraperontoneal twice per week for 6 doses total
  • Group 12 CRX-601 25 pg/mouse (in DOPC/CHOL Liposome) dosed intratumoral once per week for 3 doses total + 0X86 25 pg/mouse dosed intraperontoneal twice per week for 6 doses total
  • Anti-tumor activity was assessed (as measured by tumor growth inhibition over time) for treatment groups. Mice were removed from study if either or both tumors reached 2,000 mm 3 . By study day 60 post first dose, all mice remaining on study were completely tumor free, and abscopal effect and survival advantage was determined.
  • mice showed full tumor regression for both tumors, even though only the left flank tumor received intratumoral injection (Figure 39).
  • CRX-601 formulations dosed intratumoral in combination with 0X86 dosed intraperontoneal demonstrated an abscopal effect (Groups 8 and 12).
  • the local left flank tumor IT injection resulted in distant right flank tumor regression.
  • Group 7 demonstrated a statistically significant increase in survival compared to all vehicle and isotype controls, and also compared to all CRX-601 and 0X86 monotherapy groups (***p-values ⁇
  • Figure 41 shows the survival curves for all groups.
  • Example 6 0X40 expression induced by CRX601 treatment with a range of concentrations (0.01 - 1000 ng/mL) on human CD4+ T cells (A), dendritic cells (B), and monocytes (C) at 24 hours in in vitro cell culture.
  • PBMC peripheral blood mononuclear cell
  • Example 7 A Phase I, Open-Label Study of CRX-601 in Combination with
  • TLR4 agonist targets two complementary steps in the cancer-immunity cycle; TLR engagement results in the production of various inflammatory cytokines/chemokines such as tumor necrosis factor (TNF)a, interleukin (IL) 6, granulocyte colony-stimulating factor (G-CSF), and type I interferons (i.e., IFNa, IFNP) and enhanced uptake, processing, and presentation of antigens.
  • TNF tumor necrosis factor
  • IL interleukin
  • G-CSF granulocyte colony-stimulating factor
  • type I interferons i.e., IFNa, IFNP
  • Part 1 the safety and tolerability of escalating doses of CRX-601 and a single dose level of a monoclonal antibody (mAh) combination partner (ANTIBODY 106-222) will be evaluated in separate cohorts of participants with advanced solid tumor cancers according to an Neuenschwander-Continual Reassessment Method (N-CRM) design to identify doses for evaluation in Part 2 [Neuenschwander, 2008]
  • Part 1 will include a CRX-601 run-in period of 2 weeks (i.e., CRX-601 administration on Days 1 and 8) prior to administration of the combination partner beginning at Day 15. Approximately 5 dose levels of CRX-601 in combination with a single fixed dose level of the combination partner are planned to be evaluated in Part 1. Following protocol amendment, CRX-601 may also be further evaluated by additional routes of administration.
  • expansion cohorts of approximately 6 to 15 participants with squamous cell carcinoma of the head and neck will be enrolled in the combination treatment arm to further evaluate the safety and activity of dose(s) identified in Part 1.
  • the dose(s) of CRX-601 administered in combination with 24 mg ANTIBODY 106-222 will be determined based on data from Part 1 and may differ for the combination treatment.
  • additional expansion cohorts in other tumor types may be enrolled, based on emerging nonclinical and clinical data.
  • PK/Pharmacodynamic cohorts for the combination will be opened to enrollment during Part 1 to obtain additional PK and pharmacodynamic data, with an emphasis to obtain insight on the potential impact of the combination treatment on the immune cells and status of the tumor microenvironment, in conjunction with PK and pharmacodynamic markers obtained from blood.
  • Tumor biopsies are required for enrollment to the PK/Pharmacodynamic cohorts, whereas biopsies are strongly encouraged but not mandatory for Part 1 dose escalation cohorts.
  • participants in the PK/Pharmacodynamic cohorts may be enrolled to any dose level which has already been completed and supported by adequate safety and tolerability from dose escalation for the combination. Up to a maximum of 45 participants may be enrolled into the PK/Pharmacodynamic cohorts with up to approximately 6 per dose level for the combination.
  • CRX-601 Participants will receive the combination of CRX-601 with ANTIBODY 106-222.
  • escalating doses of CRX-601 will be evaluated as guided by the N-CRM approach.
  • participants will receive a single dose level of CRX-601 as identified based on data from Part 1 , in combination with ANTIBODY 106-222.
  • the study includes a screening period, a treatment period, and a follow-up period.
  • Participants will be screened for eligibility beginning 4 weeks before the start of treatment.
  • the duration of study treatment is expected to be up to 2 years.
  • the follow-up period will include disease assessments every 12 weeks until documented PD occurs (PFS Follow Up [FU]).
  • PFS progressive disease
  • participants will be contacted every 12 weeks to assess survival status (Survival FU [SFU]) for up to 2 years from the start of the study treatment.
  • a“cancer-immune cycle” describes a series of feed-forward steps by which the immune system recognizes and kills tumor cells, a cycle which is counterbalanced by tumor and host derived factors which suppress anti-tumor immune activation [Chen,
  • the steps of tumor immune recognition and killing include release of cancer cell antigens, cancer antigen presentation, priming and activation, trafficking of T- cells to tumors, recognition of cancer cells by T-cells, and killing of cancer cells.
  • Immune suppressive factors which may be operative in tumor microenvironment include checkpoint pathways (e.g ., programmed death receptor- 1 [PD-l], cytotoxic T- lymphocyte-associated antigen 4 [CTLA-4]) and a range of immunosuppressive factors (e.g., IDO, TGF-b), as well as immune inhibitory cell populations including T regulatory (Treg) cells, myeloid derived suppressor cells, and immune suppressive macrophages (M2 -macrophages).
  • PD-l programmed death receptor- 1
  • CTLA-4 cytotoxic T- lymphocyte-associated antigen 4
  • IDO immunosuppressive factors
  • TGF-b immune inhibitory cell populations
  • T regulatory (Treg) cells eloid derived suppressor cells
  • engaging novel pathways and combinations may provide therapeutic options for patients wherein the pre-existing host and tumor microenvironment factors do not favor response to PD-l or CTLA-4.
  • TLRs Toll-like receptors
  • PAMPs include molecules such as nucleic acids, flagellar proteins, and lipopolysaccharide (LPS), the prototypical ligand for TLR4.
  • LPS lipopolysaccharide
  • Ligand-driven activation of TLRs results in the production of various inflammatory cytokines and chemokines such as tumor necrosis factor (TNF)a, IL-6, IL-8, IP- 10, G-CSF, interferons (IFNs), and enhanced uptake, processing, and presentation of antigens by antigen presenting cells.
  • TNF tumor necrosis factor
  • IFNs interferons
  • TLR4 agonism results in animal models of cancer include reduction of Treg cells and promotion of macrophage phenotypic switching from an immunosuppressive M2 phenotype to an immune active Ml phenotype.
  • CRX-601 is a synthetic TLR4 agonist that is being developed by GlaxoSmithKline as an immunological adjuvant to be administered in combination with other immune system modulators for the treatment of cancers.
  • CRX-601 is not being developed as a monotherapy given the lack of robust anti-tumor activity that has been reported for the drug class in participants with advanced malignancies [Guha, 2012; Weihrauch, 2015; Pashenkov, 2006] Therefore, the first-time in human (FTIH) study of CRX-601 was performed in healthy participants to evaluate preliminary safety, PK, pharmacodynamics, and to identify a pharmacologically active starting dose to initiate studies in cancer patients.
  • FTIH human
  • the adverse event (AE) profile in the CRX-601 FTIH study was characterized by cytokine-related effects such as flu-like symptoms and changes in temperature and heart rate (see below).
  • Overall, the clinical profile of CRX-601 as evaluated in healthy participants was consistent with that anticipated by the repeat dose GLP toxicology studies in rats and monkeys and with the profiles of other TLR agonists reported in both healthy participants and cancer patients [Kanzler, 2007; Astiz ME, Rackow EC, Still JG, Howell ST, Cato A, Von Eschen KB, et al.
  • Pretreatment of normal humans with monophosphoryl lipid A induces tolerance to endotoxin: a prospective, double -blind, randomized, controlled trial. Crit Care Med. 1995 Jan;23(l):9-l7.
  • 0X40 is one such costimulatory receptor expressed primarily on activated CD4+ and CD8+ T-cells.
  • 0X40 agonists have been shown to increase antitumor immunity and improve tumor- free survival in non-clinical models, and 0X40 agonist monoclonal antibodies (mAbs) are currently being evaluated in Phase I clinical trials.
  • ANTIBODY 106-222 is a humanized wild-type IgGl anti-OX40 agonistic mAh being developed for the treatment of advanced malignancies.
  • ANTIBODY 106-222 is well-suited for combination with CRX-601 based on mechanisms of action targeting complementary nodes of the cancer-immunity cycle and compelling antitumor activity observed in preclinical models. Subsequent combination partners and/or additional routes of administration may be evaluated (following protocol amendment/s) based on biologic rationale, nonclinical data, and/or emerging clinical data.
  • CRX-601 was initially developed in the course of structure-activity studies on LPS (also known as‘endotoxin’), the naturally occurring ligand of TLR4.
  • LPS also known as‘endotoxin’
  • CRX-601 is a monosaccharide from the aminoalkyl glucosaminide 4-phosphate class of compounds intended for use as a vaccine adjuvant or an immune modulator.
  • CRX-601 is an agonist of TLR4 that induces immunologic responses in vitro and in vivo.
  • CRX-601 as a single agent, stimulates cytokine production (in vitro and in vivo), changes in immune cell populations (in vivo) and generates fever response (in vivo).
  • CRX-601 has shown immunomodulatory activity in multiple in vitro and in vivo models. CRX-601 added to whole blood ex vivo induces cytokine production, and when administered to BALB/c mice, induces phenotypic trends in peripheral blood leukocytes including decreased regulatory T-cells (Tregs), increased T-cell activation, and expansion of myeloid cells and monocyte/macrophages. CRX-601 administered to CT-26 tumor bearing BALB/c mice resulted in an increase in survival compared to control groups.
  • Tregs regulatory T-cells
  • CRX-601 administered to CT-26 tumor bearing BALB/c mice resulted in an increase in survival compared to control groups.
  • CRX-601 The in vitro and in vivo pharmacology of CRX-601 is consistent with other TLR agonists [Kanzler, 2007]
  • In vitro cytokine induction (IL-l p, IL-6, IP-10 and TNFa) by CRX-601 is similar to that of LPS.
  • IL-l p, IL-6, IP-10 and TNFa In vitro cytokine induction (IL-l p, IL-6, IP-10 and TNFa) by CRX-601 is similar to that of LPS.
  • rabbits a species used for assessing endotoxin contamination of parenteral formulations due to their high sensitivity, CRX-601 produced a transient increase in body temperature similar to that which occurs following LPS administration.
  • CRX-601 was associated with the expected pro-inflammatory actions of a TLR4 agonist.
  • Adverse findings were only noted in rat and include microscopic changes in the heart valves and lymphocytic inflammatory cell infiltrates in the liver.
  • the no-observed-adverse-effect-level is 15 pg/kg/dosc and 200 pg/kg/dose, in the rat and monkey, respectively.
  • NOAEL no-observed-adverse-effect-level
  • the margin to the NOAEL dose in rat is approximately 2061X for Cmax and 214X for AUC and in monkey is approximately 40,000X for C max and 24,l32X for AUC.
  • CRX-601 Development Plan and Clinical Experience This protocol describes a study evaluating the combination of CRX-601 with other immunotherapies. The study will be the second evaluation of CRX-601 in humans and the first in participants with cancer.
  • CRX-601 is not planned for development as a monotherapy in cancer participants given that the TLR agonist drug class has not produced robust monotherapy antitumor activity in multiple prior clinical trials of participants with advanced malignancies.
  • the safety, PK, and pharmacodynamics results from the FTIH study support the design and conduct of a clinical trial in cancer participants where the benefits of CRX-601 are more likely to be realized as an adjuvant in combination with other immune therapies with complementary modes of action. Should the combination(s) demonstrate robust anti tumor activity and a favorable safety profile, monotherapy study arms could be added by future amendment to explore the relative contributions of the study treatments.
  • TLR agonists including the prototypical TLR4 agonist, LPS, have been evaluated in both healthy participants and cancer patients for experimental and therapeutic purposes.
  • Administration causes dose-dependent increases in cytokines including TNFa, IL-6, and IL-8, which peak within 2 to 4 hours and return to normal within 24 hours.
  • cytokines including TNFa, IL-6, and IL-8, which peak within 2 to 4 hours and return to normal within 24 hours.
  • the PK and pharmacodynamic profiles have been similar for the two populations [Riella, L.V., S. Dada, L. Chabtini, B. Smith,
  • Clinical safety data for the drug class is characterized by a predictable tolerability profile of transient fever and flu-like symptoms (e.g ., chills, nausea, malaise, etc.) attributable to cytokine production [Astiz ME, Rackow EC, Still JG, Howell ST, Cato A, Von Eschen KB, et al. Pretreatment of normal humans with monophosphoryl lipid A induces tolerance to endotoxin: a prospective, double-blind, randomized, controlled trial. Crit Care Med. 1995 Jan;23(l):9-l7.
  • the FTIH study of CRX-601 was a randomized, double-blind (sponsor unblinded), placebo-controlled, ascending dose and parallel group study in healthy participants.
  • Dose escalation was stopped, per protocol, following the 100 ng cohort, in which 3 of 6 participants experienced AEs of moderate intensity.
  • participants were to receive repeat doses of CRX-601. However, Part 2 was not started following an elevation in transaminases on study day 30 for 1 participant in cohort 4 (60 ng) of Part 1 (see details herein).
  • An estimate of the slope with corresponding 90% confidence interval (Cl) was obtained from the power model to assess the degree of dose- proportionality, wherein a slope equal to 1.0 is indicative of dose-proportionality.
  • the 90% confidence interval for the slope was (0.84, 1.20) and (0.96, 1.24) with inclusion and without inclusion, respectively, of a participant from the 100 ng dose cohort who showed an approximately 3-fold lower C max compared to other participants from this cohort.
  • ALT alanine aminotransferase
  • influenza-like symptoms were reported for 5 participants.
  • the participant had multiple elevations in transaminases and total bilirubin before or during other clinical trials at the investigative site, although all were of low grade (maximum ALT ⁇ 4-fold ULN; maximum total bilirubin ⁇ 1.5-fold ULN).
  • the elevation in transaminases and total bilirubin was considered possibly related to CRX-601 by the investigator.
  • the sponsor in consultation with external hepatolo gists, considered an undefined, underlying, low-grade hepatic pathology to possibly have contributed to the elevation in transaminases, given the participant’s history.
  • a potential role for CRX-601 as contributing to the observed increases cannot be ruled out based on the available information.
  • Transaminases were routinely measured in all participants in the study, and no other participant experienced an increase.
  • ANTIBODY 106-222 An overview of ANTIBODY 106-222 is provided below. Detailed information concerning the biology, pharmacology, PK, and safety characteristics can be found in the IB.
  • ANTIBODY 106-222 is a humanized wild-type IgGl anti-OX40 agonistic mAh.
  • ANTIBODY 106-222 demonstrated several mechanisms of action in vitro including promoting effector CD4+ T-cell proliferation, inhibiting the induction of IL- 10-producing CD4+ Type 1 regulatory (Trl) cells and blocking the suppressive function of natural Tregs (nTregs), and binding to the fragment crystallizable region (Fc) receptor (FcR), which is anticipated to augment 0X40 signaling via cross-linking of the antibody via the Fc domain on FcR positive cells.
  • 0X40 activation gives a costimulatory signal to T-cells, dependent on a T-cell receptor (TCR)
  • ANTIBODY 106-222 (and mouse surrogate antibodies) have shown activity in multiple in vitro and in vivo models.
  • ANTIBODY 106-222 demonstrated several mechanisms of action in vitro, including promoting effector CD4+ T-cell proliferation, inhibiting the induction of IL- 10 producing CD4+ Trl cells and blocking the suppressive function of nTregs, and binding to FcR, which is anticipated to augment 0X40 signaling via cross- linking of the antibody via the Fc domain on FcR positive cells.
  • a surrogate mAh to murine 0X40 (0X86) was administered to female BALB/c mice bearing CT26 mouse colon carcinoma tumors, and produced an increase in survival compared to control groups. Together, these data provide rationale for ANTIBODY 106-222 to be used as an immunotherapy for the treatment of cancer.
  • the cynomolgus monkey was demonstrated to be an appropriate toxicology species due to human comparability with 0X40 protein sequence identity, ANTIBODY 106-222 binding and activity.
  • ANTIBODY 106-222 was well tolerated in monkey toxicology studies following weekly IV dosing for up to 4 weeks at doses up to 100 mg/kg/week with no adverse test article-related findings noted.
  • Anti -ANTIBODY 106-222 anti drug antibodies (AD As) were detected in most monkeys given ⁇ 10 mg/kg; however, the ability to determine toxicity in the terminal necropsy animals was not compromised by AD As due to the fact that robust target engagement was observed. No infusion reactions were observed in monkeys, including those with ADA.
  • Eighty-two (82) participants with advanced solid tumors have been treated in the ongoing FTIH study 201212 as of 13 August 2017.
  • 45 were treated with ANTIBODY 106-222 monotherapy across 6 dose levels of (0.003 0.01, 0.3, 1, 3, and 10 mg/kg), and 39 participants were treated with the combination of ANTIBODY 106-222 and pembrolizumab 200 mg, at ANTIBODY 106-222 doses of 0.003 0.01, 0.3, 1 mg/kg.
  • the most common AEs were pleural effusion (9, 23%), fatigue (6, 15%), decreased appetite, (5, 13%), pyrexia (5, 13%), arthralgia (4, 10%), and dyspnoea (4, 10%).
  • the most common treatment related AEs included fatigue (5, 13%) and nausea (3, 8%).
  • ANTIBODY 106-222 and CRX-601 Based on the potentially complementary mechanisms of action of ANTIBODY 106-222 and CRX-601, the combination was evaluated in B ALB/c mice implanted with syngeneic CT-26 tumor xenografts. Four groups of 10 BALB/c mice with intact immune systems were implanted with CT-26 tumors. The mice received one of the following treatments: placebo, CRX-601 (TLR4 agonist), 0X86 agonist (mouse surrogate 0X40 agonist antibody), or the combination of CRX-601 and 0X86 agonist. While the monotherapies had modest effects on tumor growth (Figure 43), the combination treatment of CRX-601 and 0X86 produced greater activity and durable responses.
  • the ratios (combinatiommonotherapy) of median values (from lowest to highest) at 2 hours post dose were 0.59, 0.77, 1.4, 1.6, and 2.5 for MCP-l, IL-8, IP-10, IL-6, and lL-lO, respectively.
  • cytokine values were variable and the distributions were generally overlapping when comparing the monotherapy and combination arms. There were no changes in hematology or clinical pathology parameters.
  • CRX-601 alone and in combination with ANTIBODY 106-222 to induce cytokine release in vitro was evaluated in PBMCs isolated from 10 healthy human donors (5 males and 5 females) under conditions of no anti-CD3 stimulation (resting) and with anti-CD3 stimulation (pre-stimulation), which was previously shown to upregulate 0X40 surface expression on T-cells.
  • Cytokines IL-2, IL-6, IL-10, IFNy, and TNFa
  • CRX-601 10, 100 or 1000 pg/mL
  • ANTIBODY 106-222 (0. 01, 0.1 , 1 or 10 pg/mL).
  • Anti-CD28 and human IgGl were included as positive and negative controls, respectively.
  • Positive cytokine induction by CRX-601 and ANTIBODY 106-222 combination was defined as >3-fold increase above that of CRX-601 alone.
  • No effects on cytokine responses in resting or pre-stimulated PBMCs were detected at 10 pg/mL CRX-601 in combination with any concentration of ANTIBODY 106-222.
  • concentrations >100 pg/mL CRX-601 addition of 1 pg/mL ANTIBODY 106-222 to resting PBMCs produced minimal to mild increases (approx.
  • ANTIBODY 106-222 There was high donor-to-donor variability in cytokine responses, and individual donors had inconsistent concentration-response curves amongst the various incubation conditions. These results suggest that the potential for enhanced cytokine release when these agents are administered in combination in patients appears to be low, but cannot be eliminated due to the high amount of data variability.
  • a target DLT frequency has been set as 16-33%, and a Bayesian adaptive dose escalation design for CRX-601 is employed to efficiently determine the dose(s) associated with this DLT frequency.
  • a Bayesian adaptive dose escalation design for CRX-601 is employed to efficiently determine the dose(s) associated with this DLT frequency.
  • infrequent events unrelated to CRX-601 dose such as increases in hepatic laboratory values, might be observed. This risk will, in part, be mitigated by a run-in period for CRX-601 prior to the initiation of combination study treatment.
  • the run- in provides an evaluation of monotherapy CRX-601 safety and tolerability in participants with cancer and prevents the administration of combination therapy to participants that experience, with CRX-601 alone, a DLT, unacceptable tolerability, or an increase in ALT to 1 5x ULN and 1 5x baseline.
  • risk is typical of a Phase I study of participants with advanced cancer.
  • Part 1 is a treatment arm based on the CRX-601 combination partner.
  • the treatment arm may have up to 5 dose escalation cohorts to investigate the safety and tolerability of escalating doses of CRX-60lwith a single dose level of the combination partner.
  • CRX-601 combination partner is:
  • Part 1 will include a CRX-601 run-in period of 2 weeks (i.e., CRX-601 administration on days 1 and 8) prior to administration of the combinations beginning on day 15 (Week 3). Following protocol amendment, CRX-601 may also be evaluated by additional routes of administration. Safety data will be evaluated according to a Neuenschwander-Continual Reassessment Method (N-CRM) design [Neuenschwander, 2008] to help identify a dose for investigation in Part 2.
  • N-CRM Neuenschwander-Continual Reassessment Method
  • Part 2a is also a treatment arm for the expansion cohorts.
  • PK/Pharmacodynamic cohorts will be opened at cleared dose levels for that combination (i.e. the most recent investigated dose level that supported dose escalation) to explore the potential relationships between dose, biological effects in the tumor microenvironment, and tumor response.
  • a particular emphasis in the PK/Pharmacodynamic cohort is placed on evaluating the possible effects of the
  • the study includes a screening period, a treatment period, and a follow-up period.
  • Participants will be screened for eligibility beginning 4 weeks before the start of treatment.
  • the duration of study treatment will be up to 2 years.
  • the follow-up period includes disease assessments every 12 weeks until documented PD. Following PD or for participants that discontinue study treatment for PD, participants will be contacted every 12 weeks to assess survival status for 2 years from the start of the study.
  • additional participants may be enrolled to evaluate additional routes of study treatment administration (e.g., intratumoral administration), additional agents to be used in combination with CRX-601, or additional indications, based on emerging nonclinical and/or clinical data.
  • routes of study treatment administration e.g., intratumoral administration
  • additional agents to be used in combination with CRX-601 e.g., CRX-601
  • additional indications based on emerging nonclinical and/or clinical data.
  • dose escalation will be performed to identify combination dose levels comprising CRX-601 with 24 mg ANTIBODY 106-222 (Part la.
  • One (1) dose level of ANTIBODY 106-222 with up to 5 dose levels of CRX-601 are planned for evaluation, pending emerging safety and tolerability information as dose escalation proceeds.
  • Part 1 will include a run-in period of 2 weeks in which CRX-601 is administered once- weekly [i.e., administration on day 1 (Week 1) and day 8 (Week 2)] prior to initiation of combination treatment with ANTIBODY 106-222 beginning on day 15 (Week 3).
  • CRX-601 is administered once- weekly [i.e., administration on day 1 (Week 1) and day 8 (Week 2)] prior to initiation of combination treatment with ANTIBODY 106-222 beginning on day 15 (Week 3).
  • participants that experience a DLT, unacceptable toxicity, or an increase in ALT (1 5x ULN and 1 5x baseline) and not attributable to another cause will be discontinued from the study and will not receive CRX-601 in combination (as described herein).
  • the starting schedule for CRX-601 will be at every l-week intervals (Ql W) from Week 1 through Week 12 including the 2-week monotherapy run in period (Week 1 and Week 2) (see SoA Table 1). Subsequently, CRX-601 will be administered at every 3-week intervals (Q3W) to coincide with ANTIBODY 106-222 dosing. Thus, beginning with Week 12 for Part 1 and Week 13 for Part 2, both CRX-601 and combination partners will be
  • Sequential cohorts will be enrolled and dose escalation (or de-escalation) will proceed guided by an N-CRM design. Dose escalation for each cohort will proceed independently of the other cohorts. The first 3 participants at each dose level will receive study treatment at least 3 days apart (e.g., if the first participant in a cohort were dosed on Monday, the earliest the next participant could be dosed is Thursday). Once the 6-week DLT evaluation period has been completed (as described herein), N-CRM analysis will be performed to guide the dose level to which the next 3 participants will be assigned based on DLT frequency (as described herein). The number of participants allocated to any cohort is an estimate; participants may also be allocated to PK/Pharmacodynamic cohorts at a previous dose level that supported dose escalation.
  • Dose levels -1 are available for ANTIBODY 106-222 (8 mg +50 ng CRX-601) if the target toxicity level is exceeded in Cohort 1 and a dose reduction is needed below planned doses.
  • the N-CRM model-based design is a Bayesian adaptive dose escalation scheme that assumes a 2-parameter logistic model for the toxicity rate as a function of dose. It is a modified version of the original Continual Reassessment Method proposed by [O’ Quigley, 1990]
  • the N-CRM method is fully adaptive and makes use of all DLT information, therefore is expected to locate the target dose level efficiently. In this case, the model will be applied to the dose escalation decision for CRX-601, which will be performed independently for each combination.
  • Dose escalation decisions will be held after participants within any given cohort have been observed for at least 6 weeks after starting the study treatment (as described herein).
  • the Fixed and Adaptive Clinical Trial Simulator FACTS [Tessella, Abington, United Kingdom]
  • the N-CRM estimates for each potential dose will provide the posterior probabilities that the DLT rate lies in each of four toxicity ranges:
  • the recommended dose for dose escalation will be the dose with the highest posterior probability of lying in the target toxicity interval with the additional requirement that the sum of the posterior probabilities of the DLT rate lying in the excessive toxicity or unacceptable toxicity range is less than 25%.
  • An updated estimate of the toxicity curve will be provided at the time of each dose escalation meeting. Note that de-escalation as well as escalation is possible using this method. Dose escalation will continue until conditions for either scenario (i) or (ii) are met:
  • the posterior probabilities of the DLT rate lying within the excessive toxicity interval or within the unacceptable toxicity interval sum to less than 25%
  • the posterior probabilities of the DLT rate lying within the excessive toxicity interval or within the unacceptable toxicity interval sum to greater than 25%.
  • No doses are usable (i.e., for all doses, the posterior probabilities of the DLT rate lying within the excessive toxicity interval or within the unacceptable toxicity interval sum to more than 25%)
  • Dose recommendations based on the N-CRM analysis will be used as guidance. To ensure safety of participants, additional participants may be enrolled at a current dose level at the discretion of the study investigators and sponsor, even though a higher dose is
  • a two-parameter logistic model will be used for N-CRM analysis for dose level selection during the dose escalation phase. This model will estimate the probability of observing a DLT at each dose level in the study as DLT information becomes available.
  • the logistic model that used for describing the dose-toxicity relationship is:
  • Characterizing the effects of treatment on the tumor microenvironment is essential to the understanding the mechanism of action of CRX-601 and its combination partners at the site of action.
  • PK/Pharmacodynamic cohorts will be opened to characterize the biological effects in the tumor microenvironment and explore the potential relationships between dose and tumor response.
  • PK/Pharmacodynamic cohorts with up to 6 participants per dose level, will be opened for CRX-601 dose levels previously cleared for dose escalation.
  • PK Pre- and on-treatment tumor biopsies are required for enrollment to this cohort.
  • PK, pharmacodynamic markers, and safety samples will be drawn according to description herein to obtain additional PK and pharmacodynamic data. Participants in the
  • PK/Pharmacodynamic cohort may have the dose escalated to a higher completed dose level (not exceeding the target toxicity level) after Week 9 once the necessary
  • Part 2 of the study will further characterize the safety and tolerability of CRX-601 administered in combination with ANTIBODY 106-222 (Part 2a) in participants with recurrent, locally advanced, or metastatic SCCHN as determined by safety and tolerability results from the respective cohorts in Part 1.
  • Part 2 will also characterize antitumor activity, PK, and pharmacodynamics effects, including effects measured from tumor biopsy.
  • Part 2 may be opened for a given combination before Part 1 has been completed provided a tolerable dose level within or below the target toxicity range has been identified for that combination.
  • the dose of CRX-601 to be administered in the expansion cohort will be based on all available data and may have a DLT frequency within or below the target toxicity range.
  • Interim analysis for futility will be performed on an on-going basis for Part 2a and cohort(s) may be stopped if interim analysis reveals futility. Actual decisions will depend on the totality of the data. Futility criteria are described in greater detail in herein.
  • Intra-Participant Dose Escalation Following the selection of a recommended combination dose for Part 2 (as described herein), participants in respective cohorts in Part 1 may be considered for escalation to the Part 2 dose level. Intra-participant dose escalation will be considered on a case-by-case basis provided the participant has completed at least 6 weeks of study treatment without the occurrence of a SAE or >Grade 2 drug-related toxicity. Approval by the Sponsor is required for intra-participant dose escalation.
  • Eligibility criteria require that participants have progressed after standard therapies or are otherwise unsuitable for standard therapies, and the criteria are intended to minimize the risk of adverse reactions to treatment with immunotherapies.
  • a 2-week run-in period for CRX-601 precedes the administration of the combination therapy.
  • the run-in provides an evaluation of monotherapy CRX-601 safety and tolerability in participants with cancer and prevents the administration of combination therapy to participants that experience, with CRX-601 alone, a DLT, unacceptable tolerability, or an increase in ALT to l.5x ULN and l.5x baseline.
  • TLR agonists are being developed by different routes of administration, including intratumoral injection, SCCHN is a possible indication for future exploration of alternative approaches to dosing.
  • CRX-601 and ANTIBODY 106-222 have been previously administered as monotherapies.
  • the selection of starting combination doses has taken into consideration all available data, including the safety, tolerability, and pharmacology data of monotherapy CRX-601, and monotherapy ANTIBODY 106-222, observed in the respective FTIH studies, together with pharmacology and safety data from animal models and human ex vivo (peripheral blood mononuclear cell [PBMC]) assays, conducted under monotherapy and combination conditions.
  • PBMC peripheral blood mononuclear cell
  • the starting dose of CRX-601 is 50 ng administered once-weekly IV. Previously CRX- 601 was administered at doses up to 100 ng IV to healthy participants in the FTIH Study. Based on data from the FTIH study, the starting dose in the current study (50 ng) is expected to produce low level pharmacological effects consistent with TLR4 agonism based on data from the FTIH study (as described herein).
  • the peak levels of inflammatory cytokines at 2h such as TNFa (median: 12 pg/mL; min: 6 pg/mL; max: 23 pg/mL) and IL-6 (median: 132 pg/mL; min: 81 pg/mL; max: 184 pg/mL pg/mL, respectively), associated with administration of 100 ng CRX-601 are below levels reported in previous studies of TLR agonists in cancer patients (>1000 pg/mL) [Chow, 2017; Engelhardt, 1991] These differences are likely not a function of differences in study populations, given that prior comparisons of TLR agonists in healthy participants and cancer participants have shown similar cytokine responses between populations [Riella, L.V., S.
  • the starting dose of ANTIBODY 106-222 is 24 mg ( ⁇ 0.3 mg/kg) IV administered every 3 weeks (Q3W). No DLTs were observed over a range from 0.003 mg/kg (-0.24 mg) to 10 mg/kg (-800 mg) in cancer patients receiving ANTIBODY 106-222 monotherapy in an earlier study. Thus, the starting dose of 24 mg is 1/33 of the top dose of ANTIBODY 1 Oh- 222 that was evaluated and produced no DLTs in an earlier study.
  • 0X40 receptor occupancy (RO) in the central circulation is expected to be near maximal over the whole 3-week dosing interval with 24 mg ANTIBODY 106-222 based on measured RO in an earlier study (see the 0.3 mg/kg dose level in Figure 45). Efficacy responses to 0X40 agonism have been observed at widely varying dose levels, including 0.3 mg/kg.
  • a 24 mg dose level was selected for ANTIBODY 106-222. Based on emerging safety, exposure and/or pharmacodynamic data, the dose for ANTIBODY 106-222 may be adjusted lower, to 8 mg.
  • CRX-601 is not expected to significantly alter the safety and tolerability profile of ANTIBODY 106-222.
  • ANTIBODY 106-222 did not enhance cytokine induction by CRX-601 in vitro. Based on the nonclinical data, ANTIBODY 106-222 are not expected to
  • ANTIBODY 106-222 did not enhance cytokine induction by CRX-601. Overall, when CRX-601 was evaluated alone or in combination with ANTIBODY 106-222, cytokine values were variable and the distributions were generally overlapping.
  • the tolerability of CRX-601 approximates that of LPS. Therefore, the top dose of CRX-601 for study participants with cancer is expected to be similar to doses of LPS studied in similar populations, namely 2 to 4 ng/kg (i.e., 160 to 320 ng). The top dose of CRX-601 will not exceed approximately 250 ng, which would represent a less than 3-fold escalation beyond the 100 ng dose which has been studied in the FTIH healthy volunteer study.
  • the dose escalation step size of 50 ng increments results in a dose escalation scheme with progressively more conservative relative increases (e.g .,
  • Protocol waivers or exemptions Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as protocol waivers or exemptions, is not permitted.
  • Participant must be >18 years of at the time of signing the informed consent.
  • Archival tumor tissue obtained at any time from the initial diagnosis to study entry is preferred, archival tumor specimen is acceptable if it is not feasible to obtain a fresh biopsy.
  • Participants enrolled in a PK/Pharmacodynamic Cohort must provide a fresh biopsy of a tumour lesion not previously irradiated during the screening period and must agree to provide at least one additional on-treatment biopsy.
  • Measurable disease i.e., presenting with at least 1 measurable lesion per
  • a female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least 1 of the following conditions applies:
  • SCCHN oral cavity, oropharynx, hypopharynx, or larynx
  • CNS central nervous system
  • Replacement therapy e.g ., thyroxine or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.
  • thyroxine or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc. is permitted.
  • asymptomatic gallstones or hepatobiliary involvement of malignancy is acceptable if participant otherwise meets entry criteria.
  • QTcF >450 msec or QTcF >480 msec for participants with bundle branch block
  • the QTcF is the QT interval corrected for heart rate according to Fridericia’s formula, machine-read or manually over-read.
  • CV cardiovascular
  • arrhythmia or clinically significant ECG abnormalities including second degree (Type II) or third degree atrioventricular block.
  • Cardiomyopathy myocardial infarction, acute coronary syndromes (including unstable angina pectoris), coronary angioplasty, stenting, or bypass grafting within the past 6 months before enrollment.
  • Tumor necrosis factor receptor (TNFR) agonists including 0X40, CD27, CD137 (4-1BB), CD357 (glucocorticoid-induced TNFR family-related gene) at any time.
  • Toxicity from previous treatment including:
  • Participants who use products containing caffeine, alcohol, or tobacco are not required to change their habits of using these products during the study treatment.
  • Participants may experience orthostatic dizziness following administration of CRX-601. Precautions should be taken to avoid falls after rising from a lying or seated position for several hours after administration of study treatment. In addition, participants will abstain from strenuous exercise for 8 hours before each blood collection for clinical laboratory tests. Participants may participate in light recreational activities during studies (e.g., watching television, reading). 6.4. Screen Failures
  • Screen failures are defined as participants who consent to participate in the clinical study but are not subsequently entered in the study. A minimal set of screen failure information is required to ensure transparent reporting of screen failure participants to meet the
  • Minimal information includes demography, screen failure details, eligibility criteria, and any SAEs.
  • Screen failure Individuals who do not meet the criteria for participation in this study (screen failure) may be rescreened once. This includes retesting specific vital sign measurements, laboratory assessments, etc. that may not have met eligibility criteria.
  • Study treatment is defined as any investigational treatment(s), marketed product(s), placebo, or medical device(s) intended to be administered to a study participant according to the study protocol.
  • the term‘study treatment’ is used throughout the protocol to describe any combination of products received by the participant as per the protocol design.
  • TLR agonists have rarely been associated with severe bradycardia or asystole in clinical trials, attributed to poor hydration and/or history of syncope
  • Oral hydration should be encouraged in the days prior to study treatment and/or IV fluids ( e.g ., 1 L or as clinically indicated) administered before CRX-601.
  • Participants with a history of syncope and/or uncertain compliance with hydration recommendations should receive additional pre-dose and/or post-dose fluids at the discretion of the investigator.
  • Cytokine-related AEs including changes in vital signs commonly begin within several hours of administration of CRX-601. Participants must be monitored for 6 hours after administration of the first dose of CRX-601 or longer as clinically indicated. Similarly, participants must be monitored for 6 hours after administration of the first 2 study treatments of CRX-601 and combination partners. Participants that tolerate CRX-601 without adverse changes in heart rate or blood pressure may have the duration of observation with subsequent study treatment reduced to 2 hours, provided the dose and schedule has not been changed. Guidelines for monitoring cytokine-related AEs are summarized herein.
  • CRX-601 and mAh combination partner ANTIBODY 106-222 will be administered to participants at each study site under medical supervision of an investigator or designee. ANTIBODY 106-222 will be administered first, and CRX-601 will be administered at least 1 hour after the completion of the mAh infusion. The date and time of administration will be recorded in the source documents and reported in the eCRF.
  • a participant experiences an infusion reaction with the administration of the mAh combination partner associated AEs should resolve before CRX-601 is administered. If AEs associated with the mAh are slow to resolve, it is acceptable to administer CRX-601 on the following day. Should further delay be required, the participant will be discontinued from study treatment. Any participant who experiences an infusion reaction attributable to the mAh may receive CRX-601 on the following day for all subsequent study treatments.
  • the specific time of study treatment administration (e.g., time of the week for first administration; time of the day for each administration) should take into consideration PK sampling time points and study visit procedures. See herein for dosing timepoints and visit windows and section below for additional details regarding dosing delays.
  • the Study Reference Manual contains specific instructions for the preparation of CRX-601 and ANTIBODY 106-222.
  • Infusions may be prolonged in the event of an infusion reaction. If multiple participants experience clinically significant infusion reactions, the infusion rate may be slowed for all future administrations of study treatment(s) for all participants. Should this global change in infusion rate be required, it will be communicated to the sites in writing. 7.2. Dose Modification
  • cytokine-related AEs and infusion reactions include“cytokine-related AEs and infusion reactions” and“immune-related AEs”. Even though both cytokine production and immune activity play roles in both categories of events, the nomenclature is intended to describe distinct classes of AEs, as described below.
  • the dose level of CRX-601 may be changed as determined by the investigator and sponsor. Participants may not discontinue only 1 study treatment. If either study treatment is deemed intolerable and requires discontinuation despite optimal management, as described below, the participant must be discontinued from both study treatments. CRX-601 may be restarted at the next lower dose level, and/or the mAh (ANTIBODY 106-222) at the next lower dose level described above.
  • Disease assessment modalities may include imaging (e.g ., computed tomography [CT] scan, magnetic resonance imaging [MRI], bone scan, plain radiography) and physical examination (as indicated for palpable/superficial lesions). Scans will be collected centrally during the study and may be reviewed or analyzed by an independent central reviewer. Details will be provided in the SRM.
  • the baseline disease assessment will be completed up to 28 days prior to the first dose of study treatment. See the Schedule of Activities Tables (above) for the schedule of assessments of anti-cancer activity subsequent to the baseline disease assessment.
  • irRECIST assessments will be evaluated as well. Treatment decisions according to irRECIST are encouraged, including confirmatory disease assessments at least 4 weeks after the date disease progression was declared. Similarly, new lesions should be measured, as feasible, and may be incorporated into assessments of tumor burden according to irRECIST guidelines.
  • Lymph nodes that have a short axis of ⁇ 10 mm are considered non-patho logical and should not be recorded or followed.
  • Pathological lymph nodes with >15 mm short axis are considered measurable and can be selected as target lesions, however lymph nodes should not be selected as target lesions when other suitable target lesions are available.
  • Measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative of all involved organs, should be identified as target lesions, and recorded and measured at baseline. These lesions should be selected on the basis of their size (lesions with the longest diameter) and their suitability for accurate repeated measurements (either by imaging techniques or clinically).
  • Cystic lesions thought to represent cystic metastases should not be selected as target lesions when other suitable target lesions are available. Note: Measurable lesions that have been previously irradiated and have not been shown to be progressing following irradiation should not be considered as target lesions.
  • Bone scans, fluorodeoxyglucose (FDG)-positron-emission tomography (PET) scans or X-rays are not considered adequate imaging techniques to measure bone lesions.
  • All other lesions should be identified as non-target and should also be recorded at baseline. Non-target lesions will be grouped by organ. Measurements of these lesions are not required, but the presence or absence of each should be noted throughout follow-up.
  • CT scan with contrast of the chest, abdomen, and pelvis is required.
  • SCCHN For participants with SCCHN, a scan of the head and neck area is required. Other areas should be evaluated as indicated by the participant’s underlying disease prior to screening, including clinical disease assessment for palpable/visible lesions.
  • CT scan is preferred, MRI may be used as an alternative method of baseline disease assessment, especially for those participants where a CT scan is contraindicated due to allergy to contrast, provided that the method used to document baseline status is used consistently throughout study treatment to facilitate direct comparison.
  • evaluations of the sites of disease identified by these scans are required.
  • NYHA The Criteria Committee of the New York Heart Association (NYHA).
  • Contrast agents must be used in accordance with the Image Acquisition Guidelines.
  • Fluorodeoxyglucose (FDG)-PET is generally not suitable for ongoing assessments of disease.
  • FDG-PET can be useful in confirming new sites of disease where a positive FDG-PET scans correlates with the new site of disease present on CT/MRI or when a baseline FDG-PET was previously negative for the site of the new lesion.
  • FDG-PET may also be used in lieu of a standard bone scan providing coverage allows interrogation of all likely sites of bone disease and FDG-PET is performed at all assessments.
  • CT component can only be used for standard
  • response assessments if performed to diagnostic quality, which includes the required anatomical coverage and prescribed use of contrast.
  • the method of assessment should be noted as CT on the CRF.
  • Clinical Examination Clinically detected lesions will only be considered measurable when they are superficial (e.g., skin nodules).
  • documentation by color photography including a ruler/calipers to measure the size of the lesion, is required [Dillingh M, van Poelgeest E, Malone K, Kemper E, Stroes E, Moerland M, et al.
  • CT and MRI Contrast enhanced CT with 5mm contiguous slices is recommended.
  • Minimum size of a measurable baseline lesion should be twice the slice thickness, with a minimum lesion size of 10 mm when the slice thickness is 5 mm.
  • MRI is acceptable, but when used, the technical specification of the scanning sequences should be optimized for the evaluation of the type and site of disease and lesions must be measured in the same anatomic plane by use of the same imaging examinations. Whenever possible the same scanner should be used [Dillingh M, van Poelgeest E, Malone K, Kemper E, Stroes E, Moerland M, et al. Characterization of inflammation and immune cell modulation induced by low-dose LPS administration to healthy volunteers. Journal of Inflammation.
  • X-ray In general, X-ray should not be used for target lesion measurements owing to poor lesion definition. Lesions on chest X-ray may be considered measurable if they are clearly defined and surrounded by aerated lung; however, chest CT is preferred over chest X-ray [Dillingh M, van Poelgeest E, Malone K, Kemper E, Stroes E, Moerland M, et al.
  • the minimum size of a measurable lesion must be at least double the slice thickness (e.g ., if the slice thickness is 10 mm, a measurable lesion must be >20 mm).
  • lymph nodes can be considered pathologically enlarged and measurable if
  • All other lesions including lesions too small to be considered measurable (longest diameter ⁇ 10 mm or pathological lymph nodes with > 10 mm and ⁇ 15 mm short axis) as well as truly non-measurable lesions, which include: leptomeningeal disease, ascites, pleural or pericardial effusions, inflammatory breast disease, lymphangitic involvement of the skin or lung, abdominal masses/abdominal organomegaly identified by physical exam that is not measurable by reproducible imaging techniques [Dillingh M, van Poelgeest E, Malone K, Kemper E, Stroes E, Moerland M, et al. Characterization of inflammation and immune cell modulation induced by low-dose LPS administration to healthy volunteers. Journal of Inflammation. 2014; 11(1).
  • Measurable disease The presence of at least 1 measurable lesion. Palpable lesions that are not measurable by radiologic or photographic evaluations may not be utilized as the only measurable lesion.
  • Non-Measurable only disease The presence of only non-measurable lesions. Note: non- measurable only disease is not allowed per protocol.
  • Treatment decisions may be based upon the immune-related RECIST guidelines.

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Abstract

L'invention concerne des combinaisons d'un modulateur d'OX40, tel qu'une protéine de liaison agoniste d'OX40, et un modulateur de TLR4, tel qu'un agoniste de TLR4, des compositions pharmaceutiques de ceux-ci, leurs utilisations, et des méthodes de traitement comprenant l'administration de ladite combinaison, y compris des utilisations dans le cancer.
PCT/EP2019/070978 2018-08-06 2019-08-05 Combinaisons d'un anticorps ox40 et d'un modulateur de tlr4 et leurs utilisations Ceased WO2020030570A1 (fr)

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Cited By (3)

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WO2024235862A1 (fr) 2023-05-12 2024-11-21 Genmab A/S Anticorps capables de se lier à cd27, variants de ceux-ci et leurs utilisations
CN119896729A (zh) * 2023-10-26 2025-04-29 南开大学 靶向髓系细胞进而增强ox40激动剂抗体药效的药物组合物的药物组合物及其应用
WO2025114541A1 (fr) 2023-11-30 2025-06-05 Genmab A/S Anticorps pouvant se lier à ox40 en polythérapie

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