WO2020081783A2 - Anticorps anti-ox40, anti-pd-l1 et anti-ctla-4 pour le traitement de tumeurs - Google Patents

Anticorps anti-ox40, anti-pd-l1 et anti-ctla-4 pour le traitement de tumeurs Download PDF

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WO2020081783A2
WO2020081783A2 PCT/US2019/056691 US2019056691W WO2020081783A2 WO 2020081783 A2 WO2020081783 A2 WO 2020081783A2 US 2019056691 W US2019056691 W US 2019056691W WO 2020081783 A2 WO2020081783 A2 WO 2020081783A2
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medi0562
administered
dose
tumor
antigen
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WO2020081783A3 (fr
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Scott Hammond
Victoria CHIOU
Katie Streicher
Ngocdiep LE
Danielle TOWNSLEY
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MedImmune LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2878—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39541—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against normal tissues, cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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 [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2827—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against B7 molecules, e.g. CD80, CD86
    • 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
    • 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
    • A61K2039/507—Comprising a combination of two or more separate antibodies
    • 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
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • 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
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto

Definitions

  • This disclosure relates to a monoclonal antibody directed against 0X40 or an antigen-binding fragment thereof, and the use of such antibody or antigen-binding fragment thereof in the treatment of tumors.
  • the disclosure also relates to methods for the treatment of tumors comprising administering to a patient in need thereof an anti-OX40 antibody or antigen-binding fragment thereof in combination with a monoclonal antibody directed against programmed death-ligand l(PD-Ll) also known as B7 homolog 1 (B7-H1), or an antigen binding fragment thereof or in combination with a monoclonal antibody directed against Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) or an antigen-binding fragment thereof.
  • PD-Ll programmed death-ligand l
  • B7-H1 B7 homolog 1
  • CTLA-4 Cytotoxic T-lymphocyte-associated protein 4
  • Cancer continues to be a major global health burden. Despite progress in the treatment of cancer, there continues to be an unmet medical need for more effective and less toxic therapies, especially for those patients with advanced disease or cancers that are resistant to existing therapeutics.
  • T cell-mediated cytotoxicity The role of the immune system, in particular T cell-mediated cytotoxicity, in tumor control is well recognized. There is mounting evidence that T cells control tumor growth and survival in cancer patients, both in early and late stages of the disease. However, tumor-specific T-cell responses are difficult to mount and sustain in cancer patients.
  • 0X40 (CD 134; TNFRSF4) is a tumor necrosis factor receptor found primarily on activated CD4 + and CD8 + T cells, regulatory T (Treg) cells and natural killer (NK) cells (Croft et al., 2009, Immunol. Rev. 229: 173-91).
  • 0X40 has one known endogenous ligand, 0X40 ligand (OX40L; CD 152; TNFSF4), which exists in atrimeric form and can cluster 0X40, resulting in potent cell signaling events within T cells. Id.
  • MEDI0562 is a humanized monoclonal antibody directed against 0X40, which selectively binds to and activates the 0X40 receptor, inducing proliferation of memory and effector T-lymphocytes.
  • Treg- cell inhibition and co-stimulation of effector T cells were shown to be necessary for tumor growth inhibition of 0X40 agonists (Piconese et al., 2008, J. Exp. Med. 205: 825-39). Many strategies and technologies have been explored to enhance the anti tumor effect of 0X40 agonist therapy through combinations with vaccines, chemotherapy, radiotherapy, and immunotherapy (Jensen et al., 2010, Semin. Oncol. 37: 524-32; Melero et al, 2013, Clin. Cancer Res. 19: 997-1008).
  • PD-L1 Programmed death-ligand 1
  • T cells normal tissue
  • B cells dendritic cells
  • macrophages mesenchymal stem cells
  • bone marrow-derived mast cells as well as various nonhematopoietic cells. Its normal function is to regulate the balance between T-cell activation and tolerance through interaction with its two receptors: programmed death 1 (also known as PD-l or CD279) and CD80 (also known as B7-1 or B7.1).
  • PD-L1 is also expressed by tumors and acts at multiple sites to help tumors evade detection and elimination by the host immune system.
  • PD-L1 is expressed in a broad range of cancers with a high frequency. In some cancers, expression of PD-L 1 has been associated with reduced survival and unfavorable prognosis.
  • Antibodies that block the interaction between PD-L1 and its receptors are able to relieve PD-L 1 -dependent immunosuppressive effects and enhance the cytotoxic activity of antitumor T cells in vitro.
  • Durvalumab is a human monoclonal antibody directed against human PD-L1 that is capable of blocking the binding of PD-L1 to both the PD-l and CD80 receptors.
  • CTLA-4 Cytotoxic T-lymphocyte-associated protein 4
  • Antagonistic anti-CTLA-4 antibodies that block the CTLA-4 signaling pathway have been reported to enhance T cell activation.
  • One such antibody, ipilimumab was approved by the FDA in 2011 for the treatment of metastatic melanoma.
  • Another anti-CTLA-4 antibody, tremelimumab is currently being investigated for the treatment of various cancer types.
  • the disclosure provides a method of treating a tumor in a human patient, comprising administering MEDI0562 to the patient.
  • MEDI0562 is administered at a dose of 3 mg/kg. In other embodiments, MEDI0562 is administered at a dose of 10 mg/kg.
  • MEDI0562 is administered every 14 to 28 days. In other embodiments, MEDI0562 is administered every 14 days. In other embodiments, MEDI0562 is administered every 28 days.
  • the administration of MEDI0562 results in a partial response or a complete response. In other embodiments the administration of MEDI0562 results in disease stabilization.
  • the disclosure further provides a method of treating a tumor in a human patient, comprising administering MEDI0562 and an immune therapeutic agent to the patient.
  • the immune therapeutic agent is durvalumab or tremelimumab.
  • MEDI0562 is administered at a dose of 2.25 mg, 7.5 mg, 22.5 mg, 75 mg, 225 mg, or 750 mg.
  • durvalumab is administered at a dose of 750 mg or 1500 mg.
  • tremelimumab is administered at a dose of 75 mg, 225 mg, or 750 mg.
  • MEDI0562 is administered every 14 days.
  • durvalumab is administered every 28 days.
  • tremelimumab is administered every 28 days.
  • tremelimumab is administered four times. In certain embodiments, this treatment with tremelimumab (four times every 28 days) can be reinduced, i.e., repeated upon disease progression.
  • the methods disclosed herein can be used to treat a solid tumor such as squamous cell carcinoma of the head and neck, cervical cancer, colorectal cancer, non-small cell lung cancer, pancreatic cancer, prostate cancer, or urothelial bladder cancer.
  • a solid tumor such as squamous cell carcinoma of the head and neck, cervical cancer, colorectal cancer, non-small cell lung cancer, pancreatic cancer, prostate cancer, or urothelial bladder cancer.
  • the patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
  • EOG Eastern Cooperative Oncology Group
  • any of the foregoing treatment methods can be combined with chemotherapy.
  • Figures 1A-1I show that concurrent checkpoint blockade and 0X40 costimulation enhances antitumor activity as compared to monotherapy, i.e., these protocols were utilized for both combination and monotherapy studies.
  • Ten BALB/c mice in each group were inoculated subcutaneously (SC) on day 1 with CT26 cells.
  • Tumor-bearing mice were randomized on day 17 and administered intraperitoneally an isotype control, 0.1 mg/kg anti- 0X40 mAh 0X86 mouse IgG2a, 20 mg/kg anti-CTLA-4 mAh 9D9 mouse IgG2b, 20 mg/kg anti-PD-l mAh RMP1-14 rat IgG2a, and/or 30 mg/kg anti-PD-Ll mAh 10F.9G2 rat IgG2b. All antibodies were administered as indicated twice a week for 2 weeks, except 0X86 which was administered twice a week for only the first week. Individual values of tumor volumes overtime are shown for untreated mice (Fig 1A), isotype control mice (Fig.
  • Individual values of tumor volumes over time are shown for dual immunotherapy for CTLA-4 + 0X40 (Fig. 1G), PD-l + 0X40 (Fig. 1H) and PD-L1 + 0X40 (Fig. II). The number of complete responses (CR; no measurable tumor) are listed for each group.
  • Figures 2A and 2B show that concurrent checkpoint blockade and 0X40 costimulation enhances survival as compared to monotherapy or dual immunotherapy.
  • Figures 3A-3I show that triple combination of immunotherapy agents improves antitumor activity in mice bearing MCA205 sarcoma as compared to monotherapy or dual immunotherapy. Twelve C57BL/6 mice in each group were inoculated SC on day 1 with MCA205 cells.
  • Tumor-bearing mice were randomized on day 14 and control article (isotype control) and test articles (20 mg/kg mouse 0X40 ligand mouse IgGl fusion protein, 20 mg/kg anti-CTLA-4 mAh 9D9 mouse IgG2b and/or 20 mg/kg anti-PD-Ll mAh 10F.9G2 rat IgG2b) were administered as indicated by arrows twice a week for 2 weeks, except for the 0X40 ligand fusion protein which was administered twice a week for only the first week. Individual values of tumor volumes over time are shown for untreated mice (Fig 3A), isotype control mice (Fig.
  • mice administered a monotherapy of anti-CTLA-4 mAh 9D9 mouse IgG2b Fig. 3C
  • anti-PD-Ll mAh 10F.9G2 rat IgG2b Fig. 3D
  • mouse 0X40 ligand mouse IgGl fusion protein Fig. 3E
  • Individual values of tumor volumes over time are shown for dual immunotherapy for CTLA-4 + PD-L1 (Fig. 3F), PD-L1 + 0X40 (Fig.
  • FIGS 4A-4F show that concurrent checkpoint blockade and 0X40 costimulation enhances antitumor activity as compared to monotherapy.
  • Twelve BALB/c mice in each group were inoculated SC on day 1 with CT26 cells.
  • Tumor-bearing mice were randomized on day 14 and on study days 15 and 19 administered intraperitoneally isotype control, 0.1 mg/kg anti-OX40 mAh 0X86 mouse IgG2a, 30 mg/kg anti-PD-Ll mAh clone 80 mouse IgGl, and/or 30 mg/kg anti-PD-Ll mAh 10F.9G2 rat IgG2b.
  • FIG. 5 shows that concurrent checkpoint blockade and 0X40 costimulation inhibits tumor growth as compared to monotherapy. Twelve BALB/c mice in each group were inoculated SC on day 1 with CT26 cells. Tumor-bearing mice were randomized on day 14 and on study days 15 and 19 were administered intraperitoneally isotype control, 0.1 mg/kg anti-OX40 mAh 0X86 mouse IgG2a, 30 mg/kg anti-PD-Ll mAh clone 80 mouse IgGl, and/or 30 mg/kg anti-PD-Ll mAh 10F.9G2 rat IgG2b. Mean values of tumor volumes over time are shown. Error bars represent standard error of the mean.
  • FIGS 6A-6F show that concurrent checkpoint blockade and 0X40 costimulation enhances antitumor activity as compared to monotherapy.
  • Twelve BALB/c mice in each group were inoculated SC on day 1 with CT26 cells.
  • Tumor-bearing mice were randomized on day 14 and on study days 15, 19, 22, and 25 were administered intraperitoneally isotype control, 0.1 mg/kg anti-OX40 mAh 0X86 mouse IgG2a, 30 mg/kg anti-PD-Ll mAh clone 80 mouse IgGl, and/or 30 mg/kg anti-PD-Ll mAh 10F.9G2 rat IgG2b.
  • FIG. 7 shows that concurrent checkpoint blockade and 0X40 costimulation inhibits tumor growth as compared to monotherapy. Twelve BALB/c mice in each group were inoculated SC on day 1 with CT26 cells. Tumor-bearing mice were randomized on day 14 and on study days 15, 19, 22, and 25 were administered intraperitoneally isotype control, 0.1 mg/kg anti-OX40 mAh 0X86 mouse IgG2a, 30 mg/kg anti-PD-Ll mAh clone 80 mouse IgGl, and/or 30 mg/kg anti-PD-Ll mAh 10F.9G2 rat IgG2b. Mean values of tumor volumes over time are shown. Error bars represent standard error of the mean.
  • Figures 8A-8F show that sequential 0X40 costimulation followed by checkpoint blockade enhances antitumor activity as compared to monotherapy.
  • Twelve BALB/c mice in each group were inoculated SC on day 1 with CT26 cells. Tumor-bearing mice were randomized on day 14 and were administered intraperitoneally isotype control, 0.1 mg/kg anti-OX40 mAh 0X86 mouse IgG2a, 30 mg/kg anti-PD-Ll mAh clone 80 mouse IgGl, and/or 30 mg/kg anti-PD-Ll mAh 10F.9G2 rat IgG2b. Control and test articles were administered on the indicated study days for each group.
  • Figure 9 shows that sequential 0X40 costimulation followed by checkpoint blockade inhibits tumor growth as compared to monotherapy. Twelve BALB/c mice in each group were inoculated SC on day 1 with CT26 cells. Tumor-bearing mice were randomized on day 14 and were administered intraperitoneally isotype control, 0.1 mg/kg anti-OX40 mAb 0X86 mouse IgG2a, 30 mg/kg anti-PD-Ll mAb clone 80 mouse IgGl, and/or 30 mg/kg anti-PD-Ll mAb 10F.9G2 rat IgG2b. Control and test articles were administered on the indicated study days for each group. Mean values of tumor volumes over time are shown. Error bars represent standard error of the mean.
  • Figures 10A-10F show that sequential checkpoint blockade followed by 0X40 costimulation enhances antitumor activity as compared to monotherapy.
  • Twelve BALB/c mice in each group were inoculated SC on day 1 with CT26 cells. Tumor-bearing mice were randomized on day 14 and were administered intraperitoneally isotype control, 0.1 mg/kg anti-OX40 mAb 0X86 mouse IgG2a, 30 mg/kg anti-PD-Ll mAb clone 80 mouse IgGl, and/or 30 mg/kg anti-PD-Ll mAb 10F.9G2 rat IgG2b. Control and test articles were administered on the indicated study days for each group.
  • FIG. 11 shows that sequential 0X40 costimulation followed by checkpoint blockade does not inhibit tumor growth as compared to monotherapy.
  • Twelve BALB/c mice in each group were inoculated SC on day 1 with CT26 cells.
  • Tumor-bearing mice were randomized on day 14 and were administered intraperitoneally isotype control, 0.1 mg/kg anti-OX40 mAb 0X86 mouse IgG2a, 30 mg/kg anti-PD-Ll mAb clone 80 mouse IgGl, and/or 30 mg/kg anti-PD-Ll mAb 10F.9G2 rat IgG2b.
  • Control and test articles were administered on the indicated study days for each group. Mean values of tumor volumes over time are shown. Error bars represent standard error of the mean.
  • Figures 12A and 12B show that 0X40 agonist antibody 0X86 mIgG2a induces transient upregulation of Ki67 and cell surface CD25 on live peripheral blood
  • CD45+CD4+FoxP3- and CD45+CD4+FoxP3+ cells in C57BL/6 mice were administered 30 mg/kg isotype control antibody or 2.5 mg/kg 0X86 mIgG2a intraperitoneally on study day 0 and/or day 21. At the indicated intervals, peripheral blood cells were tested for cell surface expression of CD45, CD4, and CD25, and intracellular FoxP3 and Ki67.
  • Figure 12A represents the percentage of CD45+CD4+FoxP3- cells that were Ki67 positive over time.
  • Figure 12B represents the percentage of CD45+CD4+FoxP3+ cells that also expressed CD25 over time.
  • Figures 13A and 13B show that 0X40 agonist mAh 0X86 mIgG2a alters the levels of free and total 0X40 on live peripheral blood CD45+CD4+FoxP3+ cells in C57BL/6 mice.
  • peripheral blood cells were tested for cell surface expression of free 0X40 (as determined by staining with 0X86 mAh) and total 0X40 (as determined by staining with mouse 0X40 ligand mouse IgGl fusion protein; non-competitive to 0X86 binding to mouse 0X40) on CD45+CD4+FoxP3+ cells.
  • Figure 13A represents the percentage of free 0X40 positive CD45+CD4+FoxP3- cells over time.
  • Figure 13B represents the percentage of total 0X40 positive CD45+CD4+FoxP3+ cells over time.
  • Figure 14 shows the study flow diagram for a dose-escalation study administering MEDI0562 as a monotherapy to human patients with advanced solid tumors.
  • Figure 15 shows the dosing schema for the screening, treatment, and follow-up periods of the study administering MEDI0562 as a monotherapy to human patients with advanced solid tumors.
  • Figure 16 illustrates tumor burden change in human patients with solid tumors measured by irRECIST at varying doses of MEDI0562 monotherapy administered Q2W.
  • Figure 17A shows mean (standard deviation) percentage Ki67+CD4+ memory T cells in subjects with advanced solid tumors following multiple IV doses of MEDI0562 (as- treated population).
  • Figure 17B shows mean (standard deviation) percentage Ki67+CD8+ memory T cells in subjects with advanced solid tumors following multiple IV doses of MEDI0562 (as-treated population).
  • Figure 18A shows programmed death ligand 1 positive (PD-L1+) cell densities in tumor biopsy samples.
  • Figure 18B shows CD8+ tumor infiltrating lymphocyte (TIL) densities in tumor biopsy samples.
  • TIL tumor infiltrating lymphocyte
  • Figure 19A shows mean (standard deviation) concentration-time profiles of MEDI0562 in subjects with advanced solid tumors following the first IV doses of MEDI0562 (as-treated population).
  • Figure 19B shows mean (standard deviation) concentration-time profiles of MEDI0562 in subjects with advanced solid tumors following multiple IV doses of MEDI0562 Q2W (as-treated population).
  • IV intravenous;
  • LLOQ lower limit of quantification;
  • Q2W every 2 weeks.
  • Data below the LLOQ (0.025 qg/mL: as shown by the dotted horizontal line) are plotted at 1/2 LLOQ for illustrative purposes.
  • Figure 20 shows individual concentration-time profiles of MEDI0562 by ADA status for each dose cohort in subjects with advanced solid tumors following multiple IV doses of MEDI0562 Q2W (as-treated population).
  • ADA anti-drug antibody
  • IV intravenous
  • LLOQ lower limit of quantification
  • Q2W every 2 weeks.
  • Data below the LLOQ (0.025 pg/mL; as shown by the dotted horizontal line) are plotted at 1/2 LLOQ for illustrative purposes.
  • ADA status is positive if any post-baseline sample is positive, negative if all post-baseline samples are negative, unknown if there is no post-baseline ADA sample.
  • Figures 21A-21B are graphs illustrating that OX40+FOXP3+ T cells measured by immunohistochemistry (IHC) decreased in tumors administered MEDI0562 in a dose dependent manner indicating a decrease in Tregs.
  • Figure 101C is an image of a tumor sample showing OX40+FOXP3+ T cells pre- (day 0 or DO) and post-treatment (day 29 or D29) with MEDI0562.
  • Figures 22A-22C illustrate that T effector: T regulatory cell gene signature ratio increased in tumors at high doses of MEDI0562 monotherapy.
  • Figure 22A is a graph showing T effector cell gene signature in tumors following MEDI0562 treatment.
  • Figure 22B is a graph showing T regulatory cell gene signature in tumors following MEDI0562 treatment.
  • Figure 22C is a graph showing the T effectorT regulatory cell gene signature ratio in tumors following MEDI0562 treatment.
  • Figures 23A-23C illustrate that human patients with high exposure to MEDI0562 and/or high baseline of 0X40 levels exhibit dual mechanisms of action on T cells.
  • Figure 23A is a graph showing T effector cell gene signature in tumors following MEDI0562 treatment.
  • Figure 23B is a graph showing 0X40 gene signature in tumors following MEDI0562 treatment.
  • Figure 23C is a graph showing T regulatory cell gene signature reduction in tumors following MEDI0562 treatment.
  • Figures 24A-24F illustrate changes in peripheral gene expression following administration of varying doses of MEDI0562 monotherapy.
  • Figure 24A is a graph showing the change in T effector / T regulatory cell gene signature ratio.
  • Figure 24B is graph showing the change in IFNy gene signature.
  • Figure 24C is a graph showing the change in CXCL9 gene expression.
  • Figure 24D is a graph showing the change in T effector cell gene signature.
  • Figure 24E is a graph showing the change in PD-L1 gene expression.
  • Figure 104F is a graph showing the change in 0X40 gene expression.
  • Figures 25A-25B are graphs illustrating the exposure relationship of peak %OX40+ response in the peripheral blood following varying doses of MEDI0562.
  • Figure 25A shows a box plot of the maximum % decrease in % OX40+CD4+ memory T cells in peripheral blood from baseline during the first dosing cycle (0-14 days post first dose) by dose level. Circles represent individual data.
  • Figure 25B shows a scatter plot of individual maximum % decrease in %OX40+CD4+ memory T cells in peripheral blood from baseline during the first dosing cycle vs. AUCo-i4 d stratified by ADA status at day 15. The peak 0X40+ response saturated at 0.3 mg/kg of MEDI0562 with a trend of greater peak 0X40+ response with increased exposure. Solid line represents the loess smooth line, and the grey area represents the standard error of the smooth line.
  • Figure 26 shows the study flow diagram for the dose-expansion and dose- escalation portions of the study administering MEDI0562 as a combination therapy with durvalumab to human patients with advanced solid tumors.
  • Figure 27 shows the study flow diagram for the dose-expansion and dose- escalation portions of the study administering MEDI0562 as a combination therapy with tremelimumab to human patients with advanced solid tumors.
  • Figure 28 shows the dosing schema for the screening, treatment, and follow-up periods of the study administering MEDI0562 as a combination therapy with durvalumab or tremelimumab to human patients with advanced solid tumors.
  • PD progressive disease;
  • Q2W every 2 weeks;
  • Q4W every 4 weeks;
  • Figure 29 is a graph that shows the mean (SD) MEDI0562 concentration-time profiles in serum following intravenous infusion of 2.25-22.5 mg MEDI0562 Q2W in combination with Durvalumab/Tremelimumab Q4W in subjects with solid tumors.
  • Figure 30A is a graph that shows the mean (SD) %Ki67+ CD4+ memory T cell time profiles following intravenous infusion of 2.25-22.5 mg MEDI0562 Q2W in combination with Durvalumab/Tremelimumab Q4W in subjects with solid tumors.
  • Figure 30 B is a graph that shows the mean (SD) %Ki67+ CD8+ memory T cell-time profiles following intravenous infusion of 2.25-22.5 mg MEDI0562 Q2W in combination with
  • FIG. 30C is a graph that shows the mean (SD) %OX40+ CD4+ memory T Cell-time profiles following intravenous infusion of 2.25-22.5 mg MEDI0562 Q2W in combination with Durvalumab/Tremelimumab Q4W in subjects with solid tumors.
  • This disclosure relates to a monoclonal antibody directed against 0X40, such as MEDI0562, or an antigen-binding fragment thereof, and the use of such antibody or antigen binding fragment thereof in the treatment of tumors.
  • the disclosure also relates to methods for the treatment of a tumor comprising administering to a patient in need thereof an anti- 0X40 antibody, such as MEDI0562, or antigen-binding fragment thereof in combination with a monoclonal antibody directed against programmed death-ligand l(PD-Ll), also known as B7 homolog 1 (B7-H1), such as durvalumab, or an antigen-binding fragment thereof or in combination with a monoclonal antibody directed against Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), such as tremelimumab, or an antigen-binding fragment thereof.
  • PD-Ll programmed death-ligand l
  • B7-H1 B7 homolog 1
  • CTL-4 Cytotoxic T-ly
  • antibody refers to a protein that is capable of recognizing and specifically binding to an antigen.
  • Ordinary or conventional mammalian antibodies comprise a tetramer, which is typically composed of two identical pairs of polypeptide chains, each pair consisting of one "light” chain (typically having a molecular weight of about 25 kDa) and one "heavy” chain (typically having a molecular weight of about 50-70 kDa).
  • each light and heavy chain typically includes a variable domain of about 100 to 110 or more amino acids that typically is responsible for antigen recognition.
  • the carboxy -terminal portion of each chain typically defines a constant domain responsible for effector function.
  • a full-length heavy chain immunoglobulin polypeptide includes a variable domain (V H ) and three constant domains (C HI , Cm, and Cm) and a hinge region between C HI and Cm, wherein the V H domain is at the amino-terminus of the polypeptide and the C domain is at the carboxyl-terminus
  • a full-length light chain immunoglobulin polypeptide includes a variable domain (V L ) and a constant domain (C L ), wherein the V L domain is at the amino-terminus of the polypeptide and the C L domain is at the carboxyl -terminus.
  • variable and constant domains typically are joined by a "J" region of about 12 or more amino acids, with the heavy chain also including a "D" region of about 10 more amino acids.
  • the variable regions of each light/heavy chain pair typically form an antigen-binding site.
  • the variable domains of naturally occurring antibodies typically exhibit the same general structure of relatively conserved framework regions (FR) joined by three hypervariable regions, also called complementarity determining regions or CDRs.
  • the CDRs from the two chains of each pair typically are aligned by the framework regions, which may enable binding to a specific epitope.
  • both light and heavy chain variable domains typically comprise the domains FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • antigen-binding fragment refers to a portion of an intact antibody and/or refers to the antigenic determining variable domains of an intact antibody. It is known that the antigen-binding function of an antibody can be performed by fragments of a full- length antibody. Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab')2, and Fv fragments, linear antibodies, single chain antibodies, diabodies, and multispecific antibodies formed from antibody fragments.
  • patient as used herein includes human subjects.
  • a “ disorder” is any condition that would benefit from treatment using the antibodies of the disclosure.
  • “Disorder” and “condition” are used interchangeably herein and include chronic and acute disorders or diseases, including those pathological conditions that predispose a patient to the disorder in question.
  • solid tumor refers to an abnormal mass of tissue that normally does not contain cysts or liquid areas.
  • solid tumors include squamous cell carcinoma of the head and neck, cervical cancer, colorectal cancer, non-small cell lung cancer, pancreatic cancer, prostate cancer, and urothelial bladder cancer.
  • treatment refers to both therapeutic treatment and prophylactic or preventative measures.
  • Those in need of treatment include patients having a tumor as well as those prone to have a tumor or those in which a tumor is to be prevented.
  • the antibodies disclosed herein can be used to treat tumors such as solid tumors.
  • treatment of a tumor includes inhibiting tumor growth, promoting tumor reduction, or both.
  • composition or “therapeutic composition” as used herein refer to a compound or composition capable of inducing a desired therapeutic effect when properly administered to a patient.
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one antibody of the disclosure.
  • pharmaceutically acceptable carrier or “physiologically acceptable carrier” as used herein refers to one or more formulation materials suitable for accomplishing or enhancing the delivery of one or more antibodies of the disclosure.
  • the term "MEDI0562” as used herein refers to a humanized immunoglobulin Gl kappa (IgGlK) monoclonal antibody that specifically binds to and triggers signaling by human 0X40 (CD 134; TNFRSF4), a member of the tumor necrosis factor receptor superfamily, as disclosed in U.S. Patent No. 9,738,723 (referred to as“OX40mAb24”), which is incorporated by reference herein in its entirety.
  • IgGlK immunoglobulin Gl kappa
  • MEDI0562 or an antigen binding fragment thereof comprises a heavy chain variable domain and a light chain variable domain.
  • MEDI0562 comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 1 and a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 2.
  • MEDI0562 or an antigen-binding fragment thereof comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 3-5, and wherein the light chain variable domain comprises CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 6-8.
  • a tumor in a human patient is treated by administering MEDI0562 or an antigen-binding fragment thereof to the patient.
  • the monotherapy dose of MEDI0562 or an antigen-binding fragment thereof to be administered to the patient will vary depending, in part, upon the size (body weight, body surface, or organ size) and condition (the age and general health) of the patient.
  • the patient is administered one or more doses of MEDI0562 or an antigen-binding fragment thereof as a monotherapy, wherein the dose is 0.03 mg/kg, 0.1 mg/kg, 0.3 mg/kg, 1.0 mg/kg, 3.0 mg/kg, or 10 mg/kg.
  • the dose is 0.03 mg/kg, 0.1 mg/kg, 0.3 mg/kg, 1.0 mg/kg, 3.0 mg/kg, or 10 mg/kg.
  • the patient is administered one or more doses of MEDI0562 or an antigen binding fragment thereof as a monotherapy wherein the dose is 0.1 mg/kg. In other embodiments, the patient is administered one or more doses of MEDI0562 or an antigen binding fragment thereof as a monotherapy wherein the dose is 0.3 mg/kg. In still other embodiments, the patient is administered one or more doses of MEDI0562 or an antigen binding fragment thereof as a monotherapy wherein the dose is 1.0 mg/kg. In other embodiments, the patient is administered one or more doses of MEDI0562 or an antigen binding fragment thereof as a monotherapy wherein the dose is 3.0 mg/kg. In other embodiments, the patient is administered one or more doses of MEDI0562 or an antigen binding fragment thereof as a monotherapy wherein the dose is 10 mg/kg.
  • a patient presenting with a tumor is administered MEDI0562 or an antigen-binding fragment thereof only once or infrequently while still providing benefit to the patient.
  • the patient is administered additional follow-on doses.
  • follow-on doses can be administered at various time intervals depending on the patient's age, weight, clinical assessment, tumor burden, and/or other factors, including the judgment of the attending physician.
  • MEDI0562 or an antigen-binding fragment thereof is administered over a two-week treatment period, over a four-week treatment period, over a six-week treatment period, over an eight-week treatment period, over a twelve-week treatment period, over a twenty -four-week treatment period, or over a one-year or more treatment period.
  • MEDI0562 or an antigen-binding fragment thereof is administered over a three-week treatment period, over a six-week treatment period, over a nine-week treatment period, over a twelve-week treatment period, over a twenty-four- week treatment period, or over a one-year or more treatment period.
  • MEDI0562 or an antigen-binding fragment thereof is administered over a two- month treatment period, over a four-month treatment period, or over a six-month or more treatment period (e.g., during a maintenance phase).
  • MEDI0562 or an antigen-binding fragment thereof is administered every two weeks, every four weeks, every six weeks, every eight weeks, every ten weeks, or every twelve weeks.
  • the administration of MEDI0562 is repeated every 14 to 28 days. In other embodiments, the administration is repeated every 14 days. In further embodiments, the administration is repeated every 28 days.
  • the patient receiving treatment using the antibodies disclosed herein has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
  • ECOG Eastern Cooperative Oncology Group
  • the patient receiving treatment has a solid tumor such as squamous cell carcinoma of the head and neck, cervical cancer, colorectal cancer, non small cell lung cancer, pancreatic cancer, prostate cancer, or urothelial bladder cancer.
  • MEDI0562 or an antigen-binding fragment thereof can be administered in a combination therapy with an immune therapeutic agent for treatment of a tumor.
  • durvalumab refers to an antibody that selectively binds PD-L1 and blocks the binding of PD-L1 to the PD-l and CD80 receptors, as disclosed in U.S. Patent No. 9,493,565 (referred to as“2.14H90PT”), which is incorporated by reference herein in its entirety.
  • the fragment crystallizable (Fc) domain of durvalumab contains a triple mutation in the constant domain of the IgGl heavy chain that reduces binding to the complement component Clq and the Fey receptors responsible for mediating antibody- dependent cell-mediated cytotoxicity (ADCC).
  • Durvalumab can relieve PD-F1 -mediated suppression of human T-cell activation in vitro and inhibits tumor growth in a xenograft model via a T-cell dependent mechanism.
  • the immune therapeutic agent is durvalumab or an antigen-binding fragment thereof.
  • durvalumab or an antigen binding fragment thereof comprises a heavy chain variable domain and a light chain variable domain.
  • durvalumab comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 9 and a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 10.
  • durvalumab or an antigen-binding fragment thereof comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 11-13, and wherein the light chain variable domain comprises CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 14-16.
  • Tremelimumab refers to an antibody that selectively binds a CTLA-4 polypeptide, as disclosed in U.S. Patent No. 8,491,895 (referred to as clone 11.2.1), which is incorporated by reference herein in its entirety.
  • Tremelimumab is specific for human CTLA-4, with no cross-reactivity to related human proteins. Tremelimumab blocks the inhibitory effect of CTLA-4, and therefore enhances T-cell activation.
  • Tremelimumab shows minimal specific binding to Fc receptors, does not induce natural killer (NK) antibody-dependent cell-mediated cytotoxicity (ADCC) activity, and does not deliver inhibitory signals following plate-bound aggregation.
  • NK natural killer
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • the immune therapeutic agent is tremelimumab or an antigen-binding fragment thereof.
  • tremelimumab or an antigen binding fragment thereof comprises a heavy chain variable domain and a light chain variable domain.
  • tremelimumab comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 17 and a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 18.
  • tremelimumab or an antigen-binding fragment thereof comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 19-21, and wherein the light chain variable domain comprises CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 22- 24.
  • a patient presenting with a tumor is administered MEDI0562 or an antigen-binding fragment thereof in combination with durvalumab or tremelimumab only once or infrequently while still providing benefit to the patient.
  • the patient is administered additional follow-on doses.
  • follow-on doses can be administered at various time intervals depending on the patient's age, weight, clinical assessment, tumor burden, and/or other factors, including the judgment of the attending physician.
  • MEDI0562 or an antigen-binding fragment thereof administered in a combination therapy is administered over a two-week treatment period, over a four-week treatment period, over a six-week treatment period, over an eight-week treatment period, over a twelve-week treatment period, over a twenty-four-week treatment period, or over a one-year or more treatment period.
  • MEDI0562 or an antigen-binding fragment thereof is administered in a combination therapy over a three- week treatment period, over a six-week treatment period, over a nine-week treatment period, over a twelve-week treatment period, over a twenty-four-week treatment period, or over a one-year or more treatment period.
  • MEDI0562 or an antigen binding fragment thereof is administered in a combination therapy over a two-month treatment period, over a four-month treatment period, or over a six-month or more treatment period (e.g., during a maintenance phase).
  • MEDI0562 or an antigen-binding fragment thereof is administered in a combination therapy every two weeks, every four weeks, every six weeks, every eight weeks, every 10 weeks, or every twelve weeks.
  • the administration of MEDI0562 in a combination therapy is repeated every 14 to 28 days. In other embodiments, the administration is repeated about every 14 days. In further embodiments, the administration is repeated every 28 days. [0079] In particular embodiments, durvalumab or tremelimumab is administered about as frequently as MEDI0562. In certain embodiments, MEDI0562 is administered about two times as frequently as durvalumab or tremelimumab.
  • the administration of durvalumab or tremelimumab is repeated every 14 to 28 days. In other embodiments the administration of durvalumab or tremelimumab is repeated every 14 days. In further embodiments, the administration of durvalumab or tremelimumab is repeated every 28 days.
  • the combination therapy dose of MEDI0562 with durvalumab will vary depending, in part, upon the size (body weight, body surface, or organ size) and condition (the age and general health) of the patient.
  • the patient is administered one or more doses of MEDI0562 or an antigen-binding fragment thereof as a combination therapy wherein the dose is 2.25 mg, 7.5 mg, 22.5 mg, 75 mg, 225 mg, or 750 mg.
  • the combination therapy dose of durvalumab with MEDI0562 will vary depending, in part, upon the size (body weight, body surface, or organ size) and condition (the age and general health) of the patient.
  • the patient is administered one or more doses of durvalumab or an antigen-binding fragment thereof as a combination therapy wherein the dose is 750 mg or 1500 mg.
  • the patient is administered 2.25 mg of MEDI0562 or an antigen-binding fragment thereof every two weeks and 1500 mg of durvalumab or an antigen-binding fragment thereof every 4 weeks.
  • the patient is administered 7.5 mg of MEDI0562 or an antigen-binding fragment thereof every two weeks and 1500 mg of durvalumab or an antigen-binding fragment thereof every 4 weeks.
  • the patient is administered 22.5 mg of MEDI0562 or an antigen-binding fragment thereof every two weeks and 1500 mg of durvalumab or an antigen-binding fragment thereof every 4 weeks.
  • the patient is administered 75 mg of MEDI0562 or an antigen-binding fragment thereof every two weeks and 1500 mg of durvalumab or an antigen-binding fragment thereof every 4 weeks. In other embodiments, the patient is administered 225 mg of MEDI0562 or an antigen-binding fragment thereof every two weeks and 1500 mg of durvalumab or an antigen-binding fragment thereof every 4 weeks. In some embodiments, the patient is administered 750 mg of MEDI0562 or an antigen-binding fragment thereof every two weeks and 1500 mg of durvalumab or an antigen-binding fragment thereof every 4 weeks.
  • the patient is administered 2.25 mg of MEDI0562 or an antigen-binding fragment thereof every two weeks and 750 mg of durvalumab or an antigen-binding fragment thereof every 4 weeks. In some embodiments, the patient is administered 7.5 mg of MEDI0562 or an antigen-binding fragment thereof every two weeks and 750 mg of durvalumab or an antigen-binding fragment thereof every 4 weeks. In other embodiments, the patient is administered 22.5 mg of MEDI0562 or an antigen-binding fragment thereof every two weeks and 750 mg of durvalumab or an antigen-binding fragment thereof every 4 weeks. In some embodiments, the patient is administered 75 mg of
  • the patient is administered 225 mg of MEDI0562 or an antigen-binding fragment thereof every two weeks and 750 mg of durvalumab or an antigen-binding fragment thereof every 4 weeks.
  • the patient is administered 750 mg of MEDI0562 or an antigen-binding fragment thereof every two weeks and 750 mg of durvalumab or an antigen binding fragment thereof every 4 weeks.
  • the combination can be administered in either order or simultaneously.
  • the MEDI0562 or an antigen binding fragment thereof is administered first followed by administration of the durvalumab or an antigen-binding fragment.
  • the durvalumab or an antigen binding fragment is administered first followed by administration of the administration of MEDI0562 or an antigen-binding fragment thereof.
  • the MEDI0562 or an antigen-binding fragment thereof and the durvalumab or an antigen-binding fragment are administered simultaneously.
  • the combination therapy dose of tremelimumab with MEDI0562 will vary depending, in part, upon the size (body weight, body surface, or organ size) and condition (the age and general health) of the patient.
  • the patient is administered one or more doses of tremelimumab or an antigen-binding fragment thereof as a combination therapy wherein the dose is 75 mg, 225 mg, or 750 mg.
  • a patient is administered four doses of tremelimumab.
  • this combination treatment can be repeated upon disease progression.
  • the patient is administered 2.25 mg of MEDI0562 or an antigen-binding fragment thereof every two weeks and 75 mg of tremelimumab or an antigen-binding fragment thereof every 4 weeks for four doses.
  • the patient is administered 7.5 mg of MEDI0562 or an antigen-binding fragment thereof every two weeks and 75 mg of tremelimumab or an antigen-binding fragment thereof every 4 weeks for four doses.
  • the patient is administered 22.5 mg of MEDI0562 or an antigen-binding fragment thereof every two weeks and 75 mg of tremelimumab or an antigen-binding fragment thereof every 4 weeks for four doses.
  • the patient is administered 75 mg of MEDI0562 or an antigen-binding fragment thereof every two weeks and 75 mg of tremelimumab or an antigen-binding fragment thereof every 4 weeks for four doses. In other embodiments, the patient is administered 225 mg of MEDI0562 or an antigen-binding fragment thereof every two weeks and 75 mg of tremelimumab or an antigen-binding fragment thereof every 4 weeks for four doses. In some embodiments, the patient is administered 750 mg of MEDI0562 or an antigen-binding fragment thereof every two weeks and 75 mg of tremelimumab or an antigen-binding fragment thereof every 4 weeks for four doses.
  • the patient is administered 2.25 mg of MEDI0562 or an antigen-binding fragment thereof every two weeks and 225 mg of tremelimumab or an antigen-binding fragment thereof every 4 weeks for four doses.
  • the patient is administered 7.5 mg of MEDI0562 or an antigen-binding fragment thereof every two weeks and 225 mg of tremelimumab or an antigen-binding fragment thereof every 4 weeks for four doses.
  • the patient is administered 22.5 mg of MEDI0562 or an antigen-binding fragment thereof every two weeks and 225 mg of tremelimumab or an antigen-binding fragment thereof every 4 weeks for four doses.
  • the patient is administered 75 mg of MEDI0562 or an antigen-binding fragment thereof every two weeks and 225 mg of tremelimumab or an antigen-binding fragment thereof every 4 weeks for four doses. In other embodiments, the patient is administered 225 mg of MEDI0562 or an antigen-binding fragment thereof every two weeks and 225 mg of tremelimumab or an antigen-binding fragment thereof every 4 weeks for four doses. In some embodiments, the patient is administered 750 mg of MEDI0562 or an antigen-binding fragment thereof every two weeks and 225 mg of tremelimumab or an antigen-binding fragment thereof every 4 weeks for four doses.
  • the patient is administered 2.25 mg of MEDI0562 or an antigen-binding fragment thereof every two weeks and 750 mg of tremelimumab or an antigen-binding fragment thereof every 4 weeks for four doses.
  • the patient is administered 7.5 mg of MEDI0562 or an antigen-binding fragment thereof every two weeks and 750 mg of tremelimumab or an antigen-binding fragment thereof every 4 weeks for four doses.
  • the patient is administered 22.5 mg of
  • MEDI0562 or an antigen-binding fragment thereof every two weeks and 750 mg of tremelimumab or an antigen-binding fragment thereof every 4 weeks for four doses In some embodiments, the patient is administered 75 mg of MEDI0562 or an antigen-binding fragment thereof every two weeks and 750 mg of tremelimumab or an antigen-binding fragment thereof every 4 weeks for four doses. In other embodiments, the patient is administered 225 mg of MEDI0562 or an antigen-binding fragment thereof every two weeks and 750 mg of tremelimumab or an antigen-binding fragment thereof every 4 weeks for four doses. In some embodiments, the patient is administered 750 mg of MEDI0562 or an antigen-binding fragment thereof every two weeks and 750 mg of tremelimumab or an antigen-binding fragment thereof every 4 weeks for four doses.
  • the MEDI0562 or an antigen-binding fragment thereof is administered first followed by administration of the tremelimumab or an antigen-binding fragment thereof.
  • the tremelimumab or an antigen-binding fragment thereof is administered first followed by administration of the administration of MEDI0562 or an antigen-binding fragment thereof.
  • the MEDI0562 or an antigen binding fragment thereof and the tremelimumab or an antigen-binding fragment thereof are administered simultaneously.
  • the antibodies of the disclosure can be selected for parenteral administration.
  • the antibodies of the disclosure can be administered by intravenous infusion or by subcutaneous injection.
  • the administration is by intravenous infusion.
  • RECIST Response Evaluation Criteria In Solid Tumors
  • CR complete response
  • PR partial response
  • PD progressive disease
  • SD stable disease
  • the methods provided herein can be used for disease control (DC) of a tumor.
  • Disease control can be a complete response (CR), partial response (PR), or stable disease (SD).
  • a "complete response” refers to the disappearance of all lesions, whether measurable or not, and no new lesions. Confirmation of a complete response can be obtained using a repeat, consecutive assessment no less than four weeks from the date of first documentation. New, non-measurable lesions preclude CR.
  • a "partial response” refers to a decrease in tumor burden of > 50% relative to baseline. Confirmation can be obtained using a consecutive repeat assessment at least 4 weeks from the date of first documentation.
  • PD Progressive disease
  • SD stable disease
  • AUC area under the curve
  • tau refers to AUC until the end of the dosing period
  • AUC (inf) refers to the AUC until infinite time.
  • RNA quality was assessed on an Agilent 2100 Bioanalyzer using the RNA 6000 Nano FabChip ® .
  • cDNA was generated using Superscript ® III First-Strand Synthesis SuperMix kit (Fife Technologies, Carlsbad, CA) and random primers. Samples were prepared using the TaqMan Pre-Amp Master Mix Kit and analyzed with the BioMark Real-Time PCR System. Cycle threshold (Ct) values above 28 were excluded from calculations. Delta-delta Ct values (AACt) were calculated using the mean of two reference genes (b-actin and GAPDH) and each patient’s baseline expression level as controls. Fold change values were determined by calculating 2 DDa .
  • MEDI0562 was measured in serum samples using a colorimetric EFISA method that was developed and validated by Medlmmune. Samples were diluted 1 :40 in assay buffer and incubated on microtiter plate coated with anti-idiotype antibody (clone 2E3.1.1) for capture of MEDI0562. Plates were washed and biotin-labeled anti-idiotype antibody (clone 1A4.1) added for binding MEDI0562 at a separate site. Streptavidin horseradish peroxidase conjugate and tetramethylbenzidine enzyme substrate were sequentially added for generation of a colorimetric reaction measured at a wavelength of 450 nm.
  • MEDI0562 concentrations in samples were determined by interpolation from a standard curve using a four-parameter curve fit with l/Y 2 weight value relating color intensity to concentrations of MEDI0562.
  • the quantitative range of the assay was 25 to 1600 ng/mF in 100% serum.
  • Anti -drug -antibodies (ADA) to MEDI0562 were measured using a solution-phase,
  • MSD Meso Scale Discovery
  • Samples that measured above the screening assay cut point were retested for confirmation in both the absence and presence of excess MEDI0562.
  • Samples with inhibition levels at or above the confirmatory cut point (19.2%) were classified as positive and titered for determination of relative amounts of ADA.
  • the assay could detect 13.0 ng/mL of positive control in the absence of MEDI0562 and 250 ng/mL positive control in the presence of 50 pg/mL MEDI0562.
  • Example 1 Combination checkpoint blockade and 0X40 costimulation enhanced antitumor activity as compared to monotherapy
  • 0X86 is a rat anti-mOX40 IgGl antibody that specifically binds to and triggers signaling of mOX40 and has anti-tumor activity in immunocompetent mouse models of cancer.
  • a rat/mouse anti-mOX40 IgG2a chimera antibody (0X86 mIgG2a; rat anti-OX40 light and heavy chain variable regions with mouse IgG2a constant regions) was generated from 0X86. This example was designed to determine if 0X40 mAb 0X86 mouse IgG2a is effective in a combination therapy for the treatment of tumors.
  • CT26 cell line (mouse colon carcinoma) was obtained from ATCC,
  • Manassas, VA, and the cell line MCA 205 (chemically-induced mouse soft tissue sarcoma) was obtained from the Buffalo Cancer Center, Portland, OR. Both cell lines were maintained in RPMI 1640 medium +10% FBS at 37°C, 5% CO2.
  • Allografts were established by subcutaneous (SC) injection of 5.0 x 10 5 CT26 cells, resuspended in 0.1 mL of PBS, into BALB/c mice. Allografts were also established by SC injection of 2.5 x 10 5 MCA205 cells, resuspended in 0.1 mL of PBS, into C57BL/6 mice.
  • SC subcutaneous
  • Tumors were measured by caliper twice weekly and tumor volumes were calculated using the following formula:
  • tumor volume [length (mm) x width (mm) 2 ] /2 where length was defined as the larger side, and width as the smaller side perpendicular to the length.
  • TGI tumor growth inhibition
  • the first dosing protocol included tumor-bearing mice inoculated SC on day 1 with CT26 cells that were randomized on day 17 and administered intraperitoneally an isotype control, the 0.1 mg/kg anti-OX40 mAb 0X86 mouse IgG2a, 20 mg/kg anti-CTLA-4 mAb 9D9 mouse IgG2b, 20 mg/kg anti-PD-l mAb RMP1-14 rat IgG2a, and 30 mg/kg anti-PD-Ll mAb 10F.9G2 rat IgG2b. All antibodies were administered twice a week for 2 weeks, except 0X86, which was administered twice a week for only the first week.
  • the second dosing protocol included tumor-bearing mice inoculated SC on day 1 with MCA205 cells that were randomized on day 14 and control article (isotype control) and test articles (20 mg/kg mouse 0X40 ligand mouse IgGl fusion protein, 20 mg/kg anti-CTLA- 4 mAb 9D9 mouse IgG2b, and 20 mg/kg anti-PD-Ll mAb 10F.9G2 rat IgG2b) were administered twice a week for 2 weeks, except for the 0X40 ligand fusion protein, which was administered twice a week for only the first week.
  • the third dosing protocol included concurrent 0X40 agonist and PD-L1 blockade on study days 15 and 18 as illustrated in Table 1.
  • Tumor-bearing mice inoculated SC on day 1 with CT26 cells were randomized on day 14 and on study days 15 and 18 administered intraperitoneally isotype control, the 0.1 mg/kg anti-OX40 mAb 0X86 mouse IgG2a, 30 mg/kg anti-PD-Ll mAb clone 80 mouse IgGl and 30 mg/kg anti-PD-Ll mAb 10F.9G2 rat IgG2b.
  • the fourth dosing protocol included concurrent 0X40 agonist and PD-L1 blockade on study days 15, 18, 22, and 25 as illustrated in Table 2.
  • Tumor-bearing mice inoculated SC on day 1 with CT26 cells were randomized on day 14 and on study days 15, 18, 22, and 25 administered intraperitoneally isotype control, the 0.1 mg/kg anti-OX40 mAb 0X86 mouse IgG2a, 30 mg/kg anti-PD-Ll mAb clone 80 mouse IgGl, and 30 mg/kg anti- PD-L1 mAb 10F.9G2 rat !gG2b.
  • the fifth dosing protocol included sequential administration of 0X40 agonist followed by PD-L1 blockade as illustrated in Table 3.
  • Tumor-bearing mice inoculated SC on day 1 with CT26 cells were randomized on day 14 and were administered intraperitoneally isotype control, the 0.1 mg/kg anti-OX40 mAb 0X86 mouse IgG2a, 30 mg/kg anti-PD-Ll mAb clone 80 mouse IgGl, and 30 mg/kg anti-PD-Ll mAb 10F.9G2 rat IgG2b.
  • Table 3 Table 3
  • the sixth dosing protocol included sequential administration of PD-L1 blockade followed by 0X40 agonist as illustrated in Table 4.
  • Tumor-bearing mice inoculated SC on day 1 with CT26 cells were randomized on day 14 and were administered intraperitoneally isotype control, the 0.1 mg/kg anti-OX40 mAb 0X86 mouse IgG2a, 30 mg/kg anti-PD-Ll mAb clone 80 mouse IgGl, and 30 mg/kg anti-PD-Ll mAb 10F.9G2 rat IgG2b.
  • Example 2 Cell surface expression on peripheral blood cells following 0X86 administration
  • Peripheral blood cells were tested for cell surface expression of CD45, CD4, and CD25, intracellular FoxP3, Ki67, free 0X40 (as determined by staining with 0X86 mAb), and total 0X40 (as determined by staining with mouse 0X40 ligand mouse IgGl fusion protein; non-competitive to 0X86 binding to mouse 0X40) .
  • Red blood cell lysis (RBCL) buffer (2 mL) was added to blood (50 pL) and incubated for 5 min. Volumes obtained from in-life bleeds ranged from 20 pL to 50 pL. Terminal bleeds were 50 pL.
  • RPMI +10% fetal bovine serum (FBS) 8 mL was added to each sample. Cells in each sample were pelleted (300 x g, 5 min) and then resuspended in 0.3 mL Flow Buffer. Cell suspensions (200 pL) were added to each well of a 96-well round- bottomed plate for staining with fluorescent antibodies. Pooled group samples were used for unstained, the single antibody control staining, isotype control staining and the fluorescence- minus-one (FMO) antibody staining controls.
  • FMO fluorescence- minus-one
  • Treated cells were washed twice in IX Permeabilization Buffer (diluted in water). Intracellular labelling antibodies were diluted into Permeabilization Buffer (100 pL per well) and added to the cells, which were then incubated at room temperature in the dark for 30 minutes. Antibodies for single marker staining (intracellular) were added to cells at 1 pL per well into 100 pL Permeabilization Buffer and incubated for 30 min on ice in the dark. Cells were washed once in Permeabilization Buffer and resuspended in 3.7% formaldehyde solution (100 pL) before being analyzed on a LSRII flow cytometer (BD Biosciences, San Jose, CA). 3. Results
  • 0X40 agonist antibody 0X86 altered the levels of free and total 0X40 on live peripheral blood CD45+CD4+FoxP3+ cells in C57BL/6 mice.
  • the study was a first-time-in-human Phase 1, multicenter, open-label, single-arm, dose-escalation, and dose-expansion study of MEDI0562 to evaluate the safety, tolerability, PK, immunogenicity, pharmacodynamics, and preliminary antitumor activity in adult subjects with selected advanced solid tumors.
  • Subjects in this study included adult subjects, > 18 years of age with advanced solid tumors that have received and have progressed, were refractory, or were intolerant to standard therapy appropriate for the specific tumor type and had not received more than 3 prior lines of therapy for recurrent or metastatic disease including both standards of care and investigational therapies.
  • subjects had histologic or cytologic documentation of advanced solid tumors, excluding primary CNS tumors and advanced solid tumors with CNS- only disease.
  • subjects had histologic or cytologic diagnosis of Squamous Cell Carcinoma of the Head and Neck (SCCHN) that was incurable by local therapy, cervical cancer (CC), microsatellite stable (MSS) colorectal cancer (CRC), PD-L1+ non-small cell lung cancer, pancreatic cancer, prostate cancer, urothelial bladder cancer (UBC), or immunotherapy-relapsed or -refractory select solid tumors.
  • SCCHN Squamous Cell Carcinoma of the Head and Neck
  • MSS microsatellite stable
  • CRC colorectal cancer
  • PD-L1+ non-small cell lung cancer pancreatic cancer
  • prostate cancer urothelial bladder cancer
  • UBC urothelial bladder cancer
  • Subjects were excluded from participation in the study if administered prior treatment with a TNLRSP agonist, prior treatment with CTLA-4, PD-L1, or PD-l antagonists, a history of severe allergic reactions to any unknown allergens or any components of the study drug formulations, active or prior documented autoimmune disease within the past two years, untreated CNS metastatic disease, unresolved toxicities from prior anticancer therapy, had a medical condition requiring current systemic anticoagulation or a history of congenital hypercoagulable condition, had current or prior use of
  • immunosuppressive medication within 14 days prior to the first dose of MEDI0562, a history of primary immunodeficiency, solid organ transplantation, tuberculosis or active infection with human immunodeficiency virus (HIV) or hepatitis B or C, receipt of live, attenuated vaccine within 28 days prior to the first dose of investigational product, had major surgery within 28 days prior to first dose of MEDI0562 or still recovering from prior surgery, prior malignancy active within the previous 2 years, or uncontrolled intercurrent illness.
  • HIV human immunodeficiency virus
  • Dose-escalation was conducted in subjects with advanced solid tumors, excluding primary CNS tumors and advanced solid tumors with CNS-only disease.
  • Ligure 15 demonstrates the dosing schema. Sequential cohorts of 3 to 6 subjects each received 1 of 6 dose levels of MEDI0562 (0.03, 0.1, 0.3, 1.0, 3.0, or 10 mg/kg) via intravenous (IV) infusion every 2 weeks (Q2W), unless the maximum tolerated dose (MTD) was reached before all dose-escalation cohorts were completed.
  • the MTD was determined based on the assessment of dose limiting toxicities (DLT) during the DLT-evaluation period, which was defined as the time from the first dose of investigational product through 28 days post Dose 1 (i.e., until the planned administration of the third dose). Subjects remained on treatment until unacceptable toxicity, documentation of confirmed disease progression, or other reason for treatment discontinuation developed. Ongoing surveillance of pharmacodynamic, PK, clinical, safety, and antitumor activity data was performed throughout dose-escalation.
  • DLT dose limiting toxicities
  • MEDI0562 Alternate treatment schedules of MEDI0562 (e.g., every 4 weeks (Q4W)) were explored based on PK, pharmacodynamic, safety, and response data.
  • the first cohort of 3 to 6 subjects on a Q4W schedule received MEDI0562 at the highest Q2W dose level that had not exceeded the MTD. If the MTD was not exceeded at that dose level on a Q4W schedule and provided this was not the highest protocol-defined dose, MEDI0562 Q4W dose escalation proceeded with additional sequential cohorts of 3 to 6 subjects according to the aforementioned dose levels.
  • PK of MEDI0562 was assessed using individual subject MEDI0562 concentrations in serum at different time points after MEDI0562 administration measured utilizing a validated immunoassay method.
  • Pharmacokinetic parameters included but were not limited to maximum observed concentration, area under the concentration-time curve from day 1 to day 15, clearance, and terminal half-life.
  • Immunogenicity of MEDI0562 was assessed by the number and percentage of subjects who develop detectable anti-drug antibodies.
  • the endpoints for assessment of pharmacodynamic activity included induction of Ki67 on peripheral cluster of differentiation (CD)4+ and CD8+ memory T-cell populations and assessment of programmed death ligand 1 (PD-L1) and tumor-infiltrating lymphocytes (TILs) in tumor biopsy specimens.
  • PD-L1 programmed death ligand 1
  • TILs tumor-infiltrating lymphocytes
  • samples were stained with a panel of fluorochrome conjugated antibodies that included antibodies to CD4/CD8/CD3/GITR/CD279/CD73/CD278/CD45/CD45RA and CD134.
  • the anti-CDl34 stain utilized clone ACT35, which is not competitive with
  • MEDI0562 in its binding for 0X40, to generate a percent 0X40+ positive (against a negative control) as well as 0X40 expression levels on positive cells as measured by the instruments median fluorescence intensity. Conversions from percent positive to absolute cell counts, where performed, multiplied the available percentage of CD4 and CD8 cell measures against CD4 and/or CD8 T cells counts per volume of whole blood generated from a separate fit for purposed validated test that quantifies these populations in whole blood. For Ki67 cell proliferation evaluations, samples were first surface stained with fluorochorme conjugated mAb that included CD4/CD8/CD3/CD45RA/CCR7/CD19/CD56 followed by
  • %Ki67+ for cell subsets was determined by comparison to a staining of an identical sample that lacked the Ki67 mAb.
  • the safety evaluation was based on the presence of adverse event (AE), serious adverse event (SAE), DLT, abnormal laboratory parameter, vital sign, and electrocardiogram results.
  • AE adverse event
  • SAE serious adverse event
  • DLT abnormal laboratory parameter
  • vital sign vital sign
  • Q2W every 2 weeks.
  • the denominator for all percentages is the number of subjects enrolled and treated in each group. a Subjects completed the protocol-defined end of study if they were on study at the time of study termination.
  • Table 7 related adverse events for treatment of human patients administered varying MEDI0562 doses Q2W
  • Figure 16 illustrates the best percent change from baseline in tumor burden based on irRECIST. Two subjects had a significant reduction in tumor burden, one subject receiving 0.03 mg/kg MEDI0562 and one subject receiving 3.0 mg/kg MEDI0562.
  • DCR Disease control rate
  • DCR > 8 weeks was 41.8% (23/55 subjects; 95% Cl: 28.7%, 55.9%) (Table 11).
  • DCR > 8 weeks was achieved by 2 subjects in the 1.0 mg/kg MEDI0562 cohort, 3 subjects in the 0.03 mg/kg MEDI0562 cohort, 4 subjects in each of the 0.1 and 0.3 mg/kg MEDI0562 cohorts, and 5 subjects in each of the 3.0 and 10.0 mg/kg MEDI0562 cohorts.
  • DCR > 8 weeks was 46.0% (23/50 subjects; 95% Cl: 31.8%, 60.7%).
  • PFS Progression-free Survival
  • OS Overall Survival
  • the median OS for the As-treated Population was 10.4 months (95% Cl: 7.4, not applicable months; Table 10). OS rates at 3, 6, 9, and 12 months were 89.2% (95% Cl: 76.0%, 95.4%), 70.2% (95% Cl: 54.1%, 81.5%), 57.2% (95% Cl: 40.8%, 70.7%), and 46.6% (95% Cl: 30.7%, 61.0%), respectively.
  • Table 10 Overall Survival (As-treated Population)
  • PD-L1+ cell and CD8+ TIL densities were reported pre- and post-MEDI0562.
  • Samples collected at screening demonstrated a range of PD-L1+ cell and CD8+ TIL densities, from 0 to 1400 cells/mm 2 and 0 to 2000 cells/mm 2 , respectively. This type of variability is consistent with that reported for both immune markers (see Steele et al., 2018, J. Immunother. Cancer. 6:20; Rebelatto et al., 2016, Diagn. Pathol. 11:95).
  • T cell effects MEDI0562 at varying doses was shown to reduce the number of OX40+FOXP3+ T cells indicating a reduction in Tregs in tumors in a dose dependent manner ( Figures 21A-101C). Treatment with varying doses of MEDI0562 also demonstrated increased T effector cell function across all doses of MEDI0562 in tumors and the T effectorT regulatory cell ratio increased in tumors at higher doses of MEDI0562
  • Pharmacogenomics Pharmacogenomics analysis of patterns of gene expression consistent with immune activation was conducted and the results are illustrated in Figure 24.
  • MEDI0562 at varying doses was shown to increase expression of PD-L1, T effector cell signature, T effector cell/ T regulatory cell ratio, CXCL9, and interferon-gamma signature in whole blood within one week of treatment. Increased expression of these genes and signatures indicate increased immune function and increased effector capabilities of circulating T cells, as seen for tumor T cells.
  • a dose -dependent decrease in 0X40 gene expression in circulating blood cells was also observed within one week of MEDI0562 treatment. This was similarly shown by flow cytometry analysis. Although not explicitly tested, this decrease may reflect 0X40+ cells moving from peripheral blood to the tumor.
  • PK Pharmacokinetics
  • C maX increased from 0.957 to 193 pg/mF, and the area under the concentration-time curve from time 0 to the time of last quantifiable concentration (AUCi ast ) during the first dosing interval increased from 3.11 to 823 pg*day/mF at 0.03 to 10 mg/kg, after the first dose (Table 11).
  • the increases in C maX and AUCi ast were proportional to dose.
  • the serum clearance was 0.483 to 0.808 F/day and terminal half-life was 3.81 to 5.92 days.
  • Adverse events A total of 53 (96.4%) subjects had at least one treatment- emergent adverse event (TEAE), and 37 (67.3%) subjects had at least one TEAE considered to be related to MEDI0562 (Table 12). TEAEs > Grade 3 were experienced by 33 (60.0%) subjects; 8 (14.5%) subjects had > Grade 3 events that were considered to be related to MEDI0562. A total of 24 (43.6%) subjects experienced a serious adverse event (SAE); 2 (3.61%) subjects experienced SAEs considered to be related to MEDI0562. Four (7.3%) subjects had TEAEs that led to discontinuation of MEDI0562. There was one death with a contributing AE in the study, which was not considered to be related to MEDI0562. Eight (14.5%) subjects had at least one infusion-related reaction, all of which were considered to be related to MEDI0562. All infusion-related reactions were non-serious, low grade, and did not result in discontinuation of MEDI0562.
  • TEAEs were most frequently reported (> 40% subjects overall) in the SOCs of General Disorders and Administration Site Conditions (32 [58.2%] subjects) and Gastrointestinal Disorders, and Metabolism and Nutrition Disorders (23 [41.8%] subjects each). The most frequently reported TEAEs regardless of causality (occurring in > 20% of subjects overall) were fatigue, nausea, and hyponatremia.
  • the sensitivity analysis was supportive of the main analysis and the irRECIST data was comparable with the RECIST vl.1 analysis.
  • the lack of efficacy with MEDI0562 contributed to the sponsor’s decision to discontinue the study and to focus further MEDI0562 development as part of a combination therapy.
  • MEDI0562 exhibited linear PK with a mean serum clearance of 0.483 to 0.808 L/day and terminal half-life of 3.81 to 5.92 days. Treatment with MEDI0562 increased percentages of Ki67+CD4+ and Ki67+CD8+ memory T cells in the peripheral blood.
  • Treatment with MEDI0562 also increased CD8+ T cell and PD-L1 densities in the tumors of a subset of patients.
  • the small number of evaluable pre/post-treatment biopsies coupled with patient heterogeneity limited the ability to observe a dose-dependent change in these immune markers post-MEDI0562.
  • ADAs against MEDI0562 were detected in 51.0% of subjects post-baseline, and the impact of ADAs on MEDI0562 PK was observed at all doses less than 3 mg/kg.
  • MEDI0562 was reasonably well tolerated, considering the patient population. At least one Grade 3 or 4 TEAE was reported in 33 (60.0%) of 55 subjects; 1 [1.8 %] subject had a Grade 5 TEAE; 4 (7.3%) subjects had TEAEs that led to permanent discontinuation of MEDI0562. Twenty-four of the 25 deaths that occurred during the study were due to the disease under study. The MAD was identified as 10 mg/kg; this dose as monotherapy was considered safe and tolerable.
  • MEDI0562 was reasonably well tolerated in the study population.
  • the MAD was 10 mg/kg.
  • No dose-response relationship was observed between MEDI0562 and the emergence of AEs.
  • Two subjects one in each of the 0.03 mg/kg and 3.0 mg/kg
  • MEDI0562 cohorts had a BoR of irPR; all other subjects who were evaluable for efficacy had a BoR of either irSD or irPD.
  • Peak serum MEDI0562 concentrations were reached immediately following IV infusion and declined thereafter in a biexponential manner. Serum MEDI0562 concentrations increased in a dose-proportional manner. The serum clearance was 0.483 to 0.808 L/day and terminal half-life was 3.81 to 5.92 days.
  • ADAs against MEDI0562 were detected in approximately half of subjects with ADA results post-baseline. The impact of ADA on MEDI0562 PK was observed at all doses less than 3 mg/kg.
  • Example 4 Dosing of MEDI0562 and Durvalumab or Tremelimumab Combination Therapy [00160]
  • the mouse studies described above demonstrated that combination treatment of tumor-bearing mice with 0X86 mIgG2 and anti-CTLA-4, anti-PD-l, and/or anti-PD-Ll resulted in anti-tumor activity that reduced growth of multiple tumors.
  • the positive mouse data were used as the rationale for conducting a human clinical trial using
  • MEDI0562/durvalumab combination therapy and MEDI0562/tremelimumab combination therapy for the treatment of tumors.
  • the study was a Phase 1, multicenter, open-label study of MEDI0562 in combination with immune therapeutic agents to evaluate the safety, tolerability, PK, pharmacodynamics, immunogenicity, and antitumor activity in adult subjects with advanced solid tumors, excluding primary CNS tumors and hematologic malignancies.
  • the study flow diagrams for Arms A and B are illustrated in Figures 26 and 27.
  • MEDI0562 was administered first as an IV infusion over approximately 60 to 90 minutes, followed by durvalumab or tremelimumab approximately 50 minutes after the end of MEDI0562 infusion.
  • Durvalumab and tremelimumab was administered over approximately 1 hour.
  • the dosing schedule is illustrated in Figure 23.
  • Subjects in this study included adult subjects, > 18 years of age, with advanced solid tumors relapsed following or refractory to standard therapy and have not received more than 3 prior lines of systemic therapy for recurrent or metastatic disease (including both standard of care and investigational therapies).
  • Subjects in the dose-escalation phase had histologic documentation of advanced solid tumors, excluding primary CNS tumors and hematologic malignancies.
  • Subjects in the dose-expansion phase had recurrent or metastatic disease for the following tumor types based on treatment arm as described below: (i) Arm A: UC, MSS, CRC, NSCLC, or SCCHN; (ii) Arm B: HCC or MEL.
  • Subjects were excluded from participation in the study if administered prior treatment with a TNFRSF agonist, prior treatment with IMT for subjects with UC, a history of severe allergic reactions to any unknown allergens or any components of the study drug formulations, active or prior documented autoimmune disease within the past 2 years, unresolved toxicities from prior anticancer therapy, use of a systemic therapeutic
  • Subjects were not permitted to have any conventional or investigational anticancer therapy within 28 days prior to the first dose of MEDI0562 and durvalumab or tremelimumab combination treatment, concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for cancer treatment, but concurrent use of hormones for non-cancer related conditions and local palliative treatment of lesions was allowed.
  • the dose-escalation phase enrolled subjects with previously treated advanced solid tumors, excluding those with primary CNS tumors or hematologic malignancies.
  • Enrollment began with the first dose-level cohort in Arm A, followed immediately with enrollment in the first dose-level cohort of Arm B. Enrollment into both Arm A and Arm B proceeded such that the dose level of MEDI0562 administered did not exceed the MEDI0562 monotherapy dose. Arm A and Arm B dose escalation proceeded independently.
  • tremelimumab 75, 225, or 750 mg
  • the first cohort of subjects received 2.25 mg MEDI0562 and 75 mg tremelimumab.
  • Dose escalation proceeded initially with 2.25 mg MEDI0562 and increasing dose levels of tremelimumab.
  • Tremelimumab was administered Q4W for 4 doses only in combination with MEDI0562 Q2W followed by monotherapy MEDI0562 Q2W thereafter.
  • Arm A of the dose-expansion phase began with enrollment in the urothelial carcinoma (UC) cohort, and proceeded with enrollment in up to 5 additional tumor-type cohorts.
  • the UC cohort included approximately 40 immunotherapy (IMT)-naive first-line cisplatin-ineligible UC subjects.
  • IMT immunotherapy
  • Following initiation of the UC cohort in Arm A up to 5 additional expansion cohorts, with up to 40 subjects each, IMT-naive/PD-Ll high non-small- cell lung cancer (NSCLC), IMT-refractory NSCLC, IMT-relapsed NSCLC, or IMT- pretreated squamous cell carcinoma of the head and neck (SCCHN) was initiated.
  • NSCLC non-small- cell lung cancer
  • SCCHN IMT-pretreated squamous cell carcinoma of the head and neck
  • Arm B of the dose-expansion phase included up to 2 tumor-type cohorts, with up to 40 subjects each. Enrollment began in the cohort of IMT-pretreated, unresectable hepatocellular carcinoma (HCC) subjects. Following initiation of the HCC cohort in Arm B, an additional expansion cohort of IMT-pretreated melanoma (MEL) subjects was initiated.
  • HCC unresectable hepatocellular carcinoma
  • Assessment of antitumor activity will include best overall response, objective response (OR), disease control (DC), time to response (TTR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and the percent change from baseline in target lesion sum of diameters.
  • RECIST Version 1.1 will be used for assessment of tumor response.
  • PK of MEDI0562 and durvalumab or tremelimumab will be assessed by individual MEDI0562, durvalumab, and tremelimumab concentrations at different time points after administration.
  • PK parameters that may be modeled on these data include but are not limited to Cmax, area under the concentration-time curve (AUC), CL, and t 1 ⁇ 2.
  • the endpoints for assessment of immunogenicity of MEDI0562, durvalumab, and tremelimumab include the number and percentage of subjects who develop detectable antidrug antibodies.
  • the endpoints for assessment of pharmacodynamic activity include induction of Ki67 on peripheral cluster of differentiation (CD)4+ and CD8+ memory T-cell populations.
  • the safety evaluation was based on the presence of adverse event (AE), serious adverse event (SAE), DLT, abnormal laboratory parameter, vital sign, and electrocardiogram results.
  • Arm A included 3 subjects in Cohort A-l (2.25 mg MEDI0562 + 1500 mg durvalumab), 5 subjects in Cohort A- 2 (7.5 mg MEDI0562 + 1500 mg durvalumab), and 5 subjects in Cohort A-3 (22.5 mg MEDI0562 + 1500 mg durvalumab).
  • Arm B included 5 subjects in Cohort B-al (2.25 mg MEDI0562 + 75 mg tremelimumab) and 4 subjects in Cohort B-a2 (2.25 mg MEDI0562 + 225 mg tremelimumab).
  • SAEs serious adverse events
  • PK and immunogenicity, and PD data are available from 19 subjects from 5 dose cohorts (2.25 mg MEDI0562 Q2W + 1500 mg durvalumab/75 mg tremelimumab/225 mg tremelimumab Q4W, 7.5 mg MEDI0562 Q2W+ 1500 mg durvalumab Q4W, and 22.5 mg MEDI0562 Q2W + 1500 mg durvalumab Q4W).
  • the mean MEDI0562 concentration-time profiles are presented in Figure 29.
  • ADA was not detected at pre-dose day 1 in any subject. After treatment with MEDI0562 in combination with durvalumab or tremelimumab, 13 of 19 subjects tested positive for ADA against MEDI0562. Some of the ADA-positive subjects showed reduced exposure compared to ADA-negative subjects at the time ADA was detected, indicating impact of ADA on MEDI0562 PK.
  • the mean %Ki67+ CD4+ memory T cell, %Ki67+ CD8+ memory T cell and %OX40+ CD4+ memory T cells over time are shown in Figures 30A-30C.

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Abstract

La présente invention concerne un anticorps monoclonal dirigé contre OX40 ou un fragment de celui-ci de liaison à l'antigène, et l'utilisation d'un tel anticorps ou d'un tel fragment de celui-ci de liaison à l'antigène dans le traitement de tumeurs. L'invention concerne également des méthodes de traitement de tumeurs comprenant l'administration à un patient qui en a besoin d'un anticorps anti-OX40 ou d'un fragment de celui-ci de liaison à l'antigène en association avec un anticorps monoclonal dirigé contre le ligand de mort programmée l (PD-Ll), également appelé homologue 1 de B7 (B7-H1), ou un fragment de celui-ci de liaison à l'antigène ou en association avec un anticorps monoclonal dirigé contre la protéine 4 associée aux lymphocytes T cytotoxiques (CTLA-4) ou un fragment de celui-ci de liaison à l'antigène.
PCT/US2019/056691 2018-10-18 2019-10-17 Anticorps anti-ox40, anti-pd-l1 et anti-ctla-4 pour le traitement de tumeurs Ceased WO2020081783A2 (fr)

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