WO2024044675A1 - Méthodes de traitement du cancer à l'aide d'anticorps anti-pd1 en combinaison avec des anticorps anti-tim3 - Google Patents

Méthodes de traitement du cancer à l'aide d'anticorps anti-pd1 en combinaison avec des anticorps anti-tim3 Download PDF

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WO2024044675A1
WO2024044675A1 PCT/US2023/072804 US2023072804W WO2024044675A1 WO 2024044675 A1 WO2024044675 A1 WO 2024044675A1 US 2023072804 W US2023072804 W US 2023072804W WO 2024044675 A1 WO2024044675 A1 WO 2024044675A1
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antibody
weeks
once
binding fragment
cancer
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PCT/US2023/072804
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Song MU
Gilbert Wong
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Beigene, Ltd.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—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 immunoglobulin superfamily
    • C07K16/2818—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 immunoglobulin superfamily against CD28 or CD152
    • 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
    • C07K16/2803—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 immunoglobulin superfamily
    • 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
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • 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

Definitions

  • Disclosed herein is a method treating cancer or enhancing an immune response using antibodies or antigen-binding fragments thereof that specifically bind to human PD1 in combination with antibodies or antigen-binding fragments that specifically bind to human TIM3.
  • Immune checkpoint-inhibitory receptor Programmed Death Receptor 1 (PD1) is mainly expressed in activated T-cells including CD8+ cytotoxic T-lymphocytes and CD4+ T- helper lymphocytes. It is rarely expressed in other human tissues, such as muscle, epithelium, neuronal tissues, etc. It is believed that PD1 plays an important role in immune modulation of tumor progression by regulating the key inhibitory signaling in the T-cells when engaged by its ligands. The PD1 signaling cascade negatively regulates the T-cell receptor and attenuates T-cell proliferation and functional activities, leading to T-cell exhaustion.
  • PD1 Immune checkpoint-inhibitory receptor Programmed Death Receptor 1
  • PD1 expression is markedly upregulated in tumor-infiltrating lymphocytes (TILs), while the expression of PD1 ligand, PD-L1, is significantly increased in tumor cells and tumor-associated immune cells in the presence of stimulating cytokines in the tumor microenvironment. Furthermore, the increased PD1 expression in TILs and/or PD-L1 expression in tumor and tumor-associated stromal cells is observed in many types of solid human tumors.
  • TILs tumor-infiltrating lymphocytes
  • PD-L1 expression in tumor and tumor-associated stromal cells is observed in many types of solid human tumors.
  • anti-PDl agents have been approved for the treatment of several cancers. Thus, PD1 is an established target for cancer immunotherapy.
  • TIM3 also known as hepatitis A virus cellular receptor 2 or CD366
  • CD366 hepatitis A virus cellular receptor 2
  • TIM3 ligands include phosphatidylserine, Galectin-9, carcinoembryonic antigen-related cell adhesion molecule 1, and high mobility group box 1 (Das et al., 2017).
  • the present disclosure provides a method of cancer treatment as a first-line treatment for the patients suffering from cancer, or as a second line (or third line or fourth line) for the patients suffering from recurrent cancer, refractory cancer or resistant cancer.
  • the present disclosure is directed to a combination of an anti-PDl antibody or antigen-binding fragment thereof with an anti-TIM3 antibody or antigen binding fragment thereof and methods of using the combination of these antibodies in cancer treatment or enhancing an immune response.
  • a method of cancer treatment or enhancing an immune response comprising administering to a patient 200 mg once every 3 weeks of an anti-PDl antibody or antigen-binding fragment thereof in combination with an anti-TIM3 antibody or antigen binding fragment thereof at a dose of 20 mg - 1600 mg once every 3 weeks.
  • the anti-PDl antibody or antigen-binding fragment thereof comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 10 and a light chain comprising an amino acid sequence of SEQ ID NO: 11.
  • the anti-TIM3 antibody or antigen binding fragment thereof specifically binds to human TIM3 and comprises a heavy chain variable region comprising: (a) HCDR1 of SEQ ID NO: 12, (b) HCDR2 of SEQ ID NO: 13, and (c) HCDR3 of SEQ ID NO: 14; and a light chain variable region comprising (d) LCDR1 of SEQ ID NO: 15, (e) LCDR2 of SEQ ID NO: 16, and (f) LCDR3 of SEQ ID NO: 17.
  • the anti-TIM3 antibody or antigen binding fragment thereof specifically binds to human TIM3 and comprises a heavy chain variable region (VH) comprising an amino acid sequence of SEQ ID NO: 18 and a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 19.
  • VH heavy chain variable region
  • VL light chain variable region
  • the anti-TIM3 antibody or antigen binding fragment thereof comprises a variant heavy chain constant region of human IgGl comprising one or more mutations selected from a group consisting of E233P, L234A, L235A, L236A and P329A.
  • the anti-TIM3 antibody or antigen binding fragment thereof comprises a variant heavy chain constant region of human IgGl comprising the amino sequence of SEQ ID NO: 20, and a human kappa light chain constant region.
  • the anti-TIM3 antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 21 and a light chain comprising an amino acid sequence of SEQ ID NO: 22.
  • the anti-PDl antibody or antigen binding fragment thereof is a monoclonal antibody, a chimeric antibody, a humanized antibody, a human engineered antibody, a single chain antibody (scFv), a Fab fragment, a Fab’ fragment, or a F(ab’)? fragment.
  • the anti-TIM3 antibody or antigen binding fragment thereof is a monoclonal antibody, a chimeric antibody, a humanized antibody, a human engineered antibody, a single chain antibody (scFv), a Fab fragment, a Fab’ fragment, or a F(ab’)z fragment.
  • cancer head and neck cancer, lung cancer, kidney cancer, gastric cancer, liver cancer, breast cancer, colon cancer, ovarian cancer, cervical cancer, melanoma, skin cancer, colorectal cancer, urothelial carcinoma, nasopharyngeal carcinoma, mesothelioma, lymphoma, leukemia, myeloma, or sarcoma.
  • non-small cell lung cancer is squamous non-small cell lung cancer or non-squamous non-small cell lung cancer.
  • the method comprises administering to the patient 200 mg once every 3 weeks of the anti-PDl antibody or antigenbinding fragment thereof in combination with 200 mg - 1600 mg once every 3 weeks of the anti-TIM3 antibody or antigen binding fragment thereof.
  • the method comprises administering to the patient 200 mg once every 3 weeks of the anti-PDl antibody or antigenbinding fragment thereof in combination with 200 mg - 800 mg once every 3 weeks of the anti-TIM3 antibody or antigen binding fragment thereof.
  • the method comprises administering to the patient 200 mg once every 3 weeks of the anti-PDl antibody or antigenbinding fragment thereof in combination with 300 mg - 900 mg once every 3 weeks of the anti-TIM3 antibody or antigen binding fragment thereof.
  • the method comprises administering to the patient 200 mg once every 3 weeks of the anti-PDl antibody or antigenbinding fragment thereof in combination with 300 mg - 700 mg once every 3 weeks of the anti-TIM3 antibody or antigen binding fragment thereof.
  • the method comprises administering to the patient 200 mg once every 3 weeks of the anti-PDl antibody or antigenbinding fragment thereof in combination with 400 mg - 800 mg once every 3 weeks of the anti-TIM3 antibody or antigen binding fragment thereof.
  • the method comprises administering to the patient 200 mg once every 3 weeks of the anti-PDl antibody or antigen- binding fragment thereof in combination with 500 mg - 700 mg once every 3 weeks of the anti-TIM3 antibody or antigen binding fragment thereof.
  • the method comprises administering to the patient 200 mg once every 3 weeks of the anti-PDl antibody or antigenbinding fragment thereof in combination with 550 mg - 650 mg once every 3 weeks of the anti-TIM3 antibody or antigen binding fragment thereof.
  • the method comprises administering to the patient 200 mg once every 3 weeks of the anti-PDl antibody or antigenbinding fragment thereof in combination with 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1200 mg, 1400 mg, 1600 mg once every 3 weeks of the anti-TIM3 antibody or antigen binding fragment thereof.
  • the method comprises administering to the patient 200 mg once every 3 weeks of the anti-PDl antibody or antigenbinding fragment thereof in combination with 200 mg, 400 mg or 800 mg once every 3 weeks of the anti-TIM3 antibody or antigen binding fragment thereof.
  • the method comprises administering to the patient 200 mg once every 3 weeks of the anti-PDl antibody or antigenbinding fragment thereof in combination with 600 mg once every 3 weeks of the anti-TIM3 antibody or antigen binding fragment thereof.
  • the method comprises administering to the patient 200 mg once every 3 weeks of the anti-PDl antibody or antigenbinding fragment thereof in combination with 300 mg, 500 mg, 700 mg, or 900 mg once every 3 weeks of the anti-TIM3 antibody or antigen binding fragment thereof.
  • the method comprises administering to the patient 200 mg once every 3 weeks of the anti-PDl antibody or antigenbinding fragment thereof in combination with 350 mg, 450 mg, 550 mg, 650 mg, 750 mg, 850 mg, or 950 mg once every 3 weeks of the anti-TIM3 antibody or antigen binding fragment thereof.
  • the method comprises administering to the patient 200 mg once every 3 weeks of the anti-PDl antibody or antigenbinding fragment thereof in combination with 550 mg or 650 mg once every 3 weeks of the anti-TIM3 antibody or antigen binding fragment thereof.
  • the anti-PDl antibody or antigen-binding fragment thereof and the anti-TIM3 antibody or antigen binding fragment thereof are administered simultaneously or are administered sequentially.
  • cytokine is any one or more of IFN-gamma, IL-2, TNF-beta, IL-4, IL-5, IL-13.
  • T cells are CD4+ T cells and/or CD8+ T cells.
  • an effective amount of an anti-PDl antibody or antigen-binding fragment thereof in combination with an anti-TIM3 antibody or antigen binding fragment thereof for use in cancer treatment or enhancing an immune response wherein the anti-PDl antibody or antigen-binding fragment thereof is administered at a dose of 200 mg once every 3 weeks and the anti-TIM3 antibody or antigen binding fragment thereof is administered at a dose of 20 mg - 1600 mg once every 3 weeks.
  • the administration of an anti-PDl antibody or antigen-binding fragment thereof as disclosed herein at a dose of 200 mg once every 3 weeks in combination with an anti-TIM3 antibody or antigen binding fragment thereof as disclosed herein at a dose of 20 mg - 1600 mg once every 3 weeks provides good efficacy in cancer treatment, such as cytokine release, cancer cell killing, or tumor growth inhibition.
  • an anti-PDl antibody or antigen-binding fragment thereof specifically binds to human PD1 and comprises a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: I, (b) HCDR2 of SEQ ID NO: 2, and (c) HCDR3 of SEQ ID NO: 3; and a light chain variable region comprising (d) LCDR1 of SEQ ID NO: 4, (e) LCDR2 of SEQ ID NO: 5, and (f) LCDR3 of SEQ ID NO: 6) at a dose of 200 mg once every 3 weeks in combination with an anti-TIM3 antibody or antigen binding fragment thereof (specifically binds to human TIM3 and comprises a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 15, (b) HCDR2 of SEQ ID NO: 16, and (c) IICDR3 of SEQ ID NO: 17: and a light chain variable region comprising (d) LCDR1 of SEQ ID NO: 18, (
  • the combination of an anti-PDl antibody or antigen-binding fragment thereof as disclosed herein at a dose of 200 mg once every 3 weeks in combination with an anti-TIM3 antibody or antigen binding fragment thereof as disclosed herein at a dose of 20 mg - 1600 mg once every 3 weeks provides good efficacy in enhancing an immune response, such as cytokine release.
  • the combination of an anti-PDl antibody or antigen-binding fragment thereof (specifically binds to human PD1 and comprises a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 1, (b) HCDR2 of SEQ ID NO: 2, and (c) HCDR3 of SEQ ID NO: 3; and a light chain variable region comprising (d) LCDR1 of SEQ ID NO: 4, (e) LCDR2 of SEQ ID NO: 5, and (f) LCDR3 of SEQ ID NO: 6) at a dose of 200 mg once every 3 weeks with an anti-TIM3 antibody or antigen binding fragment thereof (specifically binds to human TIM3 and comprises a heavy chain vari ble region comprising (a) HCDR1 of SEQ ID NO: 15, (b) HCDR2 of SEQ ID NO: 16, and (c) HCDR3 of SEQ ID NO: 17; and a light chain variable region comprising (d) LCDR1 of SEQ ID NO: 18, (e
  • Figure 1 A shows a dose escalation study for BGB-A425 in combination with tislelizumab.
  • Figure IB shows a dose expansion study for BGB-A425 in combination with tislelizumab at the RP2D (600 mg once every 21 days) for BGB-A425.
  • Figure 2A-B shows the concentration-time PK profile of BGB-A425 in semi-log scale for different doses (2 mg, 6 mg, 20 mg, 60 mg, 200 mg, 400 mg, 600 mg, 800 mg, or 1600 mg BGB-A425) in cycle 1 (single dose of BGB-A425, Figure 2A) or in cycle 5 (steady-state of BGB-A425, Figure 2B)
  • Figure 3 shows the duration of treatment and response in dose escalation.
  • Figure 4 shows the effects of treatment with BGB-A425 in combination with tislelizumab.
  • the vertical axis shows the best change (%) from Baseline in Sum of Diameters per Investigator Assessment (RECIST version 1.1).
  • Figure 5 shows the duration of treatment and response in the HNSCC and NSCLC cohorts by Investigator per RECIST version 1.1.
  • anti-cancer agent refers to any agent that can be used to treat a cell proliferative disorder such as cancer, including but not limited to, cytotoxic agents, chemotherapeutic agents, radiotherapy and radiotherapeutic agents, targeted anti-cancer agents, and immunotherapeutic agents.
  • administration when applied to an animal, human, experimental subject, cell, tissue, organ, or biological fluid, means contact of an exogenous pharmaceutical, therapeutic, diagnostic agent, or composition to the animal, human, subject, cell, tissue, organ, or biological fluid.
  • Treatment of a cell encompasses contact of a reagent to the cell, as well as contact of a reagent to a fluid, where the fluid is in contact with the cell.
  • administration and “treatment” also means in vitro and ex vivo treatments, e g., of a cell, by a reagent, diagnostic, binding compound, or by another cell.
  • subject herein includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, rabbit) and most preferably a human.
  • Treating any disease or disorder refer in one aspect, to ameliorating the disease or disorder (i. e. , slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof).
  • “treat,” “treating,” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
  • “treat,” “treating,” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both.
  • “treat,” “treating,” or “treatment” refers to preventing or delaying the onset or development or progression of the disease or disorder.
  • subject in the context of the present disclosure is a mammal, e g., a primate, preferably a higher primate, e.g., a human (e.g., a patient having, or at risk of having, a disorder described herein).
  • affinity refers to the strength of interaction between antibody and antigen. Within the antigen, the variable region of the antibody “arm” interacts through non-covalent forces with the antigen at numerous sites; the more interactions, the stronger the affinity.
  • antibody refers to a polypeptide of the immunoglobulin family that can bind a corresponding antigen non-covalently, reversibly, and in a specific manner.
  • a naturally occurring IgG antibody is a tetramer comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds.
  • Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region.
  • the heavy chain constant region is comprised of three domains, CHI, CH2 and CH3.
  • Each light chain is comprised of a light chain variable region (abbreviated herein as VL) and a light chain constant region.
  • the light chain constant region is comprised of one domain, CL.
  • the VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR).
  • CDRs complementarity determining regions
  • FR framework regions
  • Each VH and VL is composed of three CDRs and four FRs arranged from amino-terminus to carboxyl-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the variable regions of the heavy and light chains contain a binding domain that interacts with an antigen.
  • the constant regions of the antibodies can mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e g., effector cells) and the first component (Clq) of the classical complement system.
  • antibody includes, but is not limited to, monoclonal antibodies, human antibodies, humanized antibodies, chimeric antibodies, and anti-idiotypic (anti-Id) antibodies, a human engineered antibody, a single chain antibody (scFv), a single domain antibody, a Fab fragment, a Fab’ fragment, or a F(ab’)2 fragment or other antibody fragments.
  • the antibodies can be of any isotype/class (e.g., IgG, IgE, IgM, IgD, IgA and IgY), or subclass (e.g., IgGl, IgG2, IgG3, IgG4, IgAl and IgA2).
  • the antibody also includes the derivative agents thereof, such as by linking to another agent (such as other drug) directly or indirectly or forming a complex with another agent.
  • chimeric antibody means molecules made up of domains from different species, i.e., fusing the variable domain of an antibody from one host species (e.g. mouse, rabbit, llama, etc.) with the constant domain of an antibody from a different species (e.g. human).
  • the term “monoclonal antibody” or “mAb” or “Mab” herein means a population of substantially homogeneous antibodies, i.e., the antibody molecules comprised in the population are identical in amino acid sequence except for possible naturally occurring mutations that can be present in minor amounts.
  • conventional (polyclonal) antibody preparations typically include a multitude of different antibodies having different amino acid sequences in their variable domains, particularly their complementarity determining regions (CDRs), which are often specific for different epitopes.
  • CDRs complementarity determining regions
  • the modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies and is not to be constmed as requiring production of the antibody by any particular method.
  • Monoclonal antibodies can be obtained by methods known to those skilled in the art. See, for example Kohler et al., Nature 1975 256:495-497; U.S. Pat. No. 4,376,110; Ausubel et al., CURRENT PROTOCOLS IN MOLECULAR BIOLOGY 1992, Harlow et al., ANTIBODIES: A LABORATORY MANUAL, Cold spring Harbor Laboratory 1988; and Colligan et al., CURRENT PROTOCOLS IN IMMUNOLOGY 1993.
  • the antibodies disclosed herein can be of any immunoglobulin class including IgG, IgM, IgD, IgE, IgA, and any subclass thereof such as IgGl, IgG2, IgG3, IgG4.
  • Ahybridoma producing a monoclonal antibody can be cultivated in vitro or in vivo.
  • High titers of monoclonal antibodies can be obtained in in vivo production where cells from the individual hybridomas are injected intraperitoneally into mice, such as pristine-primed Balb/c mice to produce ascites fluid containing high concentrations of the desired antibodies.
  • Monoclonal antibodies of isotype IgM or IgG can be purified from such ascites fluids, or from culture supernatants, using column chromatography methods well known to those of skill in the art.
  • the basic antibody structural unit comprises a tetramer.
  • Each tetramer includes two identical pairs of polypeptide chains, each pair having one “light chain” (about 25 kDa) and one “heavy chain” (about 50-70 kDa).
  • the amino-terminal portion of each chain includes a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition.
  • the carboxy -terminal portion of the heavy chain can define a constant region primarily responsible for effector function.
  • human light chains are classified as kappa and lambda light chains.
  • human heavy chains are typically classified as a, 5, s, y, or p.
  • variable and constant regions 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.
  • variable regions of each light/heavy chain (VL/VH) pair form the antibody binding site.
  • an intact antibody has two binding sites.
  • the two binding sites are, in general, the same.
  • variable domains of both the heavy and light chains comprise three hypervariable regions, also called “complementarity determining regions (CDRs),” which are located between relatively conserved framework regions (FR).
  • CDRs complementarity determining regions
  • the CDRs are usually aligned by the framework regions, enabling binding to a specific epitope.
  • both light and heavy chain variable domains comprise FR-1 (or FR1), CDR-1 (or CDR1), FR-2 (FR2), CDR-2 (CDR2), FR-3 (or FR3), CDR-3 (CDR3), and FR-4 (or FR4).
  • the positions of the CDRs and framework regions can be determined using various well known definitions in the art, e.g., Kabat, Chothia, and AbM (see, e.g., Johnson et al., Nucleic Acids Res., 29:205-206 (2001); Chothia and Lesk, J. Mol. Biol., 196:901 -917 (1987); Chothia et al., Nature, 342:877-883 (1989); Chothia et al., J. Mol. Biol., 227:799-817 (1992); Al-Lazikani et al., J. Mol. Biol., 273:927-748 (1997)).
  • antigen combining sites are also described in the following: Ruiz et al., Nucleic Acids Res., 28:219-221 (2000); and Lefranc, M. P., Nucleic Acids Res., 29:207-209 (2001); MacCallum et al., J. Mol. Biol., 262:732-745 (1996); and Martin et al., Proc. Natl. Acad. Sci. USA, 86:9268-9272 (1989); Martin et al., Methods Enzymol., 203: 121-153 (1991); and Rees et al., In Sternberg M. J. E.
  • the CDRs correspond to the amino acid residues that are part of a Kabat CDR, a Chothia CDR, or both
  • the CDRs correspond to amino acid residues 26-35 (HC CDR1), 50-65 (HC CDR2), and 95-102 (HC CDR3) in a VH, e.g., a mammalian VH, e.g., a human VH; and amino acid residues 24-34 (LC CDR1), 50-56 (LC CDR2), and 89-97 (LC CDR3) in a VL, e.g., a mammalian VL, e.g., a human VL.
  • hypervariable region means the amino acid residues of an antibody that are responsible for antigen-binding.
  • the hypervariable region comprises amino acid residues from a “CDR” (i.e., VL-CDR1, VL-CDR2 and VL-CDR3 in the light chain variable region and VH-CDR1, VH-CDR2 and VH-CDR3 in the heavy chain variable domain).
  • CDR i.e., Kabat et al. (1991) Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (defining the CDR regions of an antibody by sequence); see also Chothia and Lesk (1987) J. Mol. Biol. 196: 901-917 (defining the CDR regions of an antibody by structure).
  • framework or “FR” residues means those variable domain residues other than the hypervariable region residues defined herein as CDR residues.
  • an “antigen-binding fragment” means antigen-binding fragments of antibodies, i.e., antibody fragments that retain the ability to bind specifically to the antigen bound by the full-length antibody, e.g., fragments that retain one or more CDR regions.
  • antigen-binding fragments include, but not limited to, Fab, Fab', F(ab')2, and Fv fragments; diabodies; linear antibodies; single-chain antibody molecules, e.g., single chain Fv (ScFv); nanobodies and multispecific antibodies formed from antibody fragments.
  • An antibody “specifically binds” to a target protein, meaning the antibody exhibits preferential binding to that target as compared to other proteins, but this specificity does not require absolute binding specificity.
  • An antibody is considered “specific” for its intended target if its binding is determinative of the presence of the target protein in a sample, e.g., without producing undesired results such as false positives.
  • Antibodies or antigen-binding fragments thereof, useful in the current disclosure will bind to the target protein with an affinity that is at least two fold greater, preferably at least 10-times greater, more preferably at least 20-times greater, and most preferably at least 100-times greater than the affinity with non-target proteins.
  • An antibody herein is said to bind specifically to a polypeptide comprising a given amino acid sequence, if it binds to polypeptides comprising that sequence but does not bind to proteins lacking that sequence.
  • human antibody herein means an antibody that comprises human immunoglobulin protein sequences only.
  • mouse antibody or “rat antibody” mean an antibody that comprises only mouse or rat immunoglobulin protein sequences, respectively.
  • humanized antibody means forms of antibodies that contain sequences from non-human (e.g., murine) antibodies as well as human antibodies. Such antibodies contain minimal sequence derived from non-human immunoglobulin.
  • the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin sequence.
  • the humanized antibody optionally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin.
  • Fc immunoglobulin constant region
  • the prefix “hum,” “hu,” “Hu,” or “h” is added to antibody clone designations when necessary to distinguish humanized antibodies from parental rodent antibodies.
  • the humanized forms of rodent antibodies will generally comprise the same CDR sequences of the parental rodent antibodies, although certain amino acid substitutions can be included to increase affinity, increase stability of the humanized antibody, remove a post- translational modification or for other reasons.
  • corresponding human germline sequence refers to the nucleic acid sequence encoding a human variable region amino acid sequence or subsequence that shares the highest determined amino acid sequence identity with a reference variable region amino acid sequence or subsequence in comparison to all other known vanable region ammo acid sequences encoded by human germline immunoglobulin variable region sequences.
  • the corresponding human germline sequence can also refer to the human variable region amino acid sequence or subsequence with the highest amino acid sequence identity with a reference variable region amino acid sequence or subsequence in comparison to all other evaluated variable region amino acid sequences.
  • the corresponding human germline sequence can be framework regions only, complementarity determining regions only, framework and complementary determining regions, a variable segment (as defined above), or other combinations of sequences or subsequences that comprise a variable region. Sequence identity can be determined using the methods described herein, for example, aligning two sequences using BLAST, ALIGN, or another alignment algorithm known in the art.
  • the corresponding human germline nucleic acid or amino acid sequence can have at least about 90%, 91, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the reference variable region nucleic acid or amino acid sequence.
  • Equilibrium dissociation constant refers to the dissociation rate constant (kd, time” 1 ) divided by the association rate constant (ka, time" 1 , M” 1 ). Equilibrium dissociation constants can be measured using any known method in the art.
  • the antibodies of the present disclosure generally will have an equilibrium dissociation constant of less than about IO" 7 or 10" 8 M, for example, less than about 10" 9 M or 10" 10 M, in some aspects, less than about IO" 11 M, 10' 12 M or 10‘ 13 M.
  • cancer or “tumor” herein has the broadest meaning as understood in the art and refers to the physiological condition in mammals that is typically characterized by unregulated cell growth. In the context of the present disclosure, the cancer is not limited to certain type or location.
  • composition therapy refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner. Such administration also encompasses coadministration in multiple, or in separate containers (e.g., capsules, powders, and liquids) for each active ingredient. Powders and/or liquids can be reconstituted or diluted to a desired dose prior to administration. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner, either at approximately the same time or at different times. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.
  • conservative substitution means substitution of the original amino acid by a new amino acid that does not substantially alter the chemical, physical and/or functional properties of the antibody or fragment. Specifically, common conservative substitutions of amino acids are well known in the art.
  • HSPs high scoring sequence pairs
  • initial neighborhood word hits act as values for initiating searches to find longer HSPs containing them.
  • the word hits are extended in both directions along each sequence for as far as the cumulative alignment score can be increased. Cumulative scores are calculated using, for nucleotide sequences, the parameters M (reward score for a pair of matching residues; always > 0) and N (penalty score for mismatching residues; always ⁇ 0). For amino acid sequences, a scoring matrix is used to calculate the cumulative score. Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached.
  • the BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment.
  • the BLAST algorithm also performs a statistical analysis of the similarity between two sequences (see, e.g., Karlin and Altschul, Proc. Natl. Acad. Sci. USA 90:5873-5787, 1993).
  • One measure of similarity provided by the BLAST algorithm is the smallest sum probability (P(N)), which provides an indication of the probability by which a match between two nucleotide or amino acid sequences would occur by chance.
  • P(N) the smallest sum probability
  • a nucleic acid is considered similar to a reference sequence if the smallest sum probability in a comparison of the test nucleic acid to the reference nucleic acid is less than about 0.2, more preferably less than about 0.01, and most preferably less than about 0.001.
  • the percent identity between two amino acid sequences can also be determined using the algorithm of E. Meyers and W. Miller, Comput. Appl. Biosci. 4: 11-17, (1988), which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4.
  • the percent identity between two amino acid sequences can be determined using the Needleman and Wunsch, J. Mol. Biol. 48:444-453, (1970), algorithm which has been incorporated into the GAP program in the GCG software package using either a BLOSUM62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6.
  • nucleic acid is used herein interchangeably with the term “polynucleotide” and refers to deoxyribonucleotides or ribonucleotides and polymers thereof in either single- or double-stranded form.
  • the term encompasses nucleic acids containing known nucleotide analogs or modified backbone residues or linkages, which are synthetic, naturally occurring, and non-naturally occurring, which have similar binding properties as the reference nucleic acid, and which are metabolized in a manner similar to the reference nucleotides.
  • Examples of such analogs include, without limitation, phosphorothioates, phosphoramidates, methyl phosphonates, chiral-methyl phosphonates, 2-O-methyl ribonucleotides, peptide-nucleic acids (PNAs).
  • operably linked in the context of nucleic acids refers to a functional relationship between two or more polynucleotide (e.g., DNA) segments. Typically, it refers to the functional relationship of a transcriptional regulatory sequence to a transcribed sequence.
  • a promoter or enhancer sequence is operably linked to a coding sequence if it stimulates or modulates the transcription of the coding sequence in an appropriate host cell or other expression sy stem.
  • promoter transcriptional regulatory sequences that are operably linked to a transcribed sequence are physically contiguous to the transcribed sequence, i.e., they are cis-acting.
  • some transcriptional regulatory sequences, such as enhancers need not be physically contiguous or located in close proximity to the coding sequences whose transcription they enhance.
  • compositions e.g., pharmaceutically acceptable compositions, which include an anti-PDl antibody or anti-TIM3 antibody described herein, formulated together with at least one pharmaceutically acceptable excipient.
  • pharmaceutically acceptable excipient includes any and all solvents, dispersion media, isotonic and absorption delaying agents, and the like that are phy siologically compatible.
  • the excipient can be suitable for intravenous, intramuscular, subcutaneous, parenteral, rectal, spinal or epidermal administration (e.g., by injection or infusion).
  • compositions disclosed herein can be in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusion solutions), dispersions or suspensions, liposomes, and suppositories.
  • liquid solutions e.g., injectable and infusion solutions
  • dispersions or suspensions e.g., dispersions or suspensions
  • liposomes e.g., liposomes, and suppositories.
  • a suitable form depends on the intended mode of administration and therapeutic application. Typical suitable compositions are in the form of injectable or infusion solutions.
  • One suitable mode of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular).
  • the antibody is administered by intravenous infusion or injection.
  • the antibody is administered by intramuscular or subcutaneous injection.
  • the term “therapeutically effective amount” as herein used refers to the amount of an antibody that, when administered to a subject for treating a disease, or at least one of the clinical symptoms of a disease or disorder, is sufficient to effect such treatment for the disease, disorder, or symptom.
  • the “therapeutically effective amount” can vary with the antibody, the disease, disorder, and/or sy mptoms of the disease or disorder, severity of the disease, disorder, and/or symptoms of the disease or disorder, the age of the subject to be treated, and/or the weight of the subject to be treated. An appropriate amount in any given instance can be apparent to those skilled in the art or can be determined by routine experiments.
  • the “therapeutically effective amount” refers to the total amount of the combination objects for the effective treatment of a disease, a disorder or a condition.
  • the phrase “in combination with” means that an anti-PDl antibody is administered to the subject at the same time as, before, or after administration of an anti- TIM3 antibody.
  • the administration of these antibodies could be simultaneously or sequentially.
  • CR Complete Response
  • PR Partial Response
  • Progressive Disease Al least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of 1 or more new lesions is also considered progression).
  • Stable Disease Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
  • Efficacy endpoints will be based upon investigator derived tumor assessments per RECIST vl. l. The following efficacy endpoints are listed below:
  • Objective response rate is defined as the proportion of patients who had confirmed CR or PR assessed by investigator.
  • Duration of response is defined as the time from the first determination of an objective response, until the first documentation of progression or death, whichever comes first.
  • Best overall response is the best response recorded from the start of the study drug treatment until the end of treatment taking into account any requirement for confirmation.
  • DCR Disease control rate
  • PFS Progression-free survival
  • OS Overall survival
  • Anti-PDl antibodies found, for example, in US Patent No:8,735,553 or Table 1 below.
  • Anti-PDl antibodies are also provided herein and comprise, for example, a heavy chain variable region (VH) comprising the complementarity determining regions (CDRs): HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, and HCDR3 of SEQ ID NO: 3; and a light chain variable region (VL) comprising: LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6.
  • VH heavy chain variable region
  • CDRs complementarity determining regions
  • the anti-PDl antibody or antigen-binding fragment which specifically binds human PD1 and comprises a heavy chain variable region (VH) comprising an amino acid sequence of SEQ ID NO: 7 and a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 8.
  • the anti-PDl antibody comprises an IgG4 constant domain comprising SEQ ID NO: 9.
  • the heavy chain comprises an amino acid sequence having at least 90%, 91, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 10
  • the light chain comprises an amino acid sequence having at least 90%, 91, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO:
  • anti-PDl antibodies or antigen-binding fragments thereof of the present disclosure include amino acids that have been mutated, yet have at least 60%, 70%, 80%, 90%, 95% or 99% percent identity in the CDR regions with the CDR regions depicted in the sequences described herein. In some aspects, it includes mutant amino acid sequences wherein no more than 1, 2, 3, 4 or 5 amino acids have been mutated in the CDR regions when compared with the CDR regions disclosed in the sequences provided.
  • anti-PD l antibodies of the present disclosure include those where the amino acids or nucleic acids encoding the amino acids have been mutated; yet have at least 60%, 70%, 80%, 90%, 95% or 99% percent identity to the sequences described herein, wherein the CDRs do not change. In some aspects, it includes mutant amino acid sequences wherein no more than 1, 2, 3, 4 or 5 amino acids have been mutated in the variable regions when compared with the variable regions depicted in the sequence described herein, while retaining substantially the same therapeutic activity, wherein the CDRs do not change.
  • T-cell immunoglobulin domain and mucin domain 3 (TIM3, HAVCR2, or CD366) is a 33 KD type 1 transmembrane glycoprotein, a member of the T-cell Immunoglobulin- and mucin-domain-containing family that plays an important role in promoting T-cell exhaustion in both chronic viral infections and tumor escape from immune surveillance.
  • Mature human TIM3 contains 280 amino acid residues (NCBI accession number: NP_116171.3). Its extracellular domain consists of amino acid residues 1-181, and the transmembrane domain and cytoplasmic C-terminal tail comprises residues 182-280.
  • inhibitory signaling motifs such as immunoreceptor tyrosine-based inhibitory motif (ITIM) and tyrosine switch motif (ITSM), found in the cytoplasmic domain.
  • Anti-TIM3 antibodies of the disclosure can be found in WO2018/036561or in Table 2 below. Also provided herein are anti-TIM3 antibody comprising an antibody antigen binding domain which specifically binds human TIM3, and comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs): HCDR1 of SEQ ID NO: 12, HCDR2 of SEQ ID NO: 13, and HCDR3 of SEQ ID NO: 14; and a light chain variable region (VL) comprising: LCDR1 of SEQ ID NO: 15, LCDR2 of SEQ ID NO: 16, and LCDR3 of SEQ ID NO: 17.
  • VH heavy chain variable region
  • CDRs complementarity determining regions
  • the anti-TIM3 antibody comprises an antibody antigen binding domain which specifically binds human TIM3, and comprises a heavy chain variable region (VH) comprising an amino acid sequence of SEQ ID NO: 18 and a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 19.
  • VH heavy chain variable region
  • VL light chain variable region
  • the anti-TIM3 antibody or antigen binding fragment thereof comprises a variant heavy chain constant region of human IgGl comprising the amino sequence of SEQ ID NO: 20, and a human kappa light chain constant region.
  • the anti-TIM3 antibody or antigen binding fragment thereof comprises a variant heavy chain constant region of human IgGl comprising one or more mutations selected from a group consisting of E233P, L234A, L235A, L236A and P329A.
  • the anti-TIM3 antibody comprises a heavy chain having at least 90%, 91 , 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO: 21.
  • the anti-TIM3 antibody comprises a light chain having at least 90%, 91 , 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO: 22.
  • the anti-TIM3 antibody comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO: 21, and a light chain comprising the amino acid sequence of SEQ ID NO: 22.
  • anti-TIM3 antibodies or antigen-binding fragments thereof of the present disclosure include amino acids that have been mutated, yet have at least 60%, 70%, 80%, 90%, 95% or 99% percent identity in the CDR regions with the CDR regions depicted in the sequences described herein. In some aspects, it includes mutant amino acid sequences wherein no more than 1, 2, 3, 4 or 5 amino acids have been mutated in the CDR regions when compared with the CDR regions disclosed in the sequences provided.
  • anti-TIM3 antibodies of the present disclosure include those where the amino acids or nucleic acids encoding the amino acids have been mutated; yet have at least 60%, 70%, 80%, 90%, 95% or 99% percent identity to the sequences described herein, wherein the CDRs do not change. In some aspects, it includes mutant amino acid sequences wherein no more than 1, 2, 3, 4 or 5 amino acids have been mutated in the variable regions when compared with the variable regions depicted in the sequence described herein, while retaining substantially the same therapeutic activity, wherein the CDRs do not change.
  • the Fc region is altered by replacing at least one amino acid residue with a different amino acid residue to alter the effector functions of the antibody.
  • one or more amino acids can be replaced with a different amino acid residue such that the antibody has an altered affinity for an effector ligand but retains the antigen-binding ability of the parent antibody.
  • the effector ligand to which affinity is altered can be, for example, an Fc receptor or the C l component of complement. This approach is described in, e.g., U.S. Pat. Nos. 5,624,821 and 5,648,260, both by Winter et al.
  • one or more amino acid residues can be replaced with one or more different amino acid residues such that the antibody has altered Clq binding and/or reduced or abolished complement dependent cytotoxicity (CDC).
  • CDC complement dependent cytotoxicity
  • one or more amino acid residues are altered to thereby alter the ability of the antibody to fix complement. This approach is described in, e.g., the PCT Publication WO 94/29351 by Bodmer et al.
  • one or more amino acids of an antibody or antigen-binding fragment thereof of the present disclosure are replaced by one or more allotypic amino acid residues, for the IgGl subclass and the kappa isotype.
  • Allotypic amino acid residues also include, but are not limited to, the constant region of the heavy chain of the IgGl, IgG2, and IgG3 subclasses as well as the constant region of the light chain of the kappa isotype as described by Jefferis et al., MAbs. 1 :332-338 (2009).
  • the Fc region is modified to increase the ability of the antibody to mediate antibody dependent cellular cytotoxicity (ADCC) and/or to increase the affinity of the antibody for an Fey receptor by modifying one or more amino acids.
  • ADCC antibody dependent cellular cytotoxicity
  • This approach is described in, e.g., the PCT Publication WO 00/42072 by Presta.
  • the binding sites on human IgGl for FcyRI, FcyRII, FcyRIII and FcRn have been mapped and variants with improved binding have been described (see Shields et al., J. Biol. Chem. 276:6591-6604, 2001).
  • the glycosylation of an antibody is modified.
  • an aglycosylated antibody can be made (i.e., the antibody lacks or has reduced glycosylation).
  • Glycosylation can be altered to, for example, increase the affinity of the antibody for “antigen.”
  • Such carbohydrate modifications can be accomplished by, for example, altering one or more sites of glycosylation within the antibody sequence.
  • one or more amino acid substitutions can be made that result in elimination of one or more variable region framework glycosylation sites to thereby eliminate glycosylation at that site.
  • Such aglycosylation can increase the affinity of the antibody for antigen.
  • Such an approach is described in, e.g., U.S. Pat. Nos. 5,714,350 and 6,350,861 by Co et al.
  • an antibody can be made that has an altered type of glycosylation, such as a hypofucosylated antibody having reduced amounts of fucosyl residues or an antibody having increased bisecting GlcNac structures.
  • altered glycosylation patterns have been demonstrated to increase the ADCC ability of antibodies.
  • carbohydrate modifications can be accomplished by, for example, expressing the antibody in a host cell with altered glycosylation machinery. Cells with altered glycosylation machinery have been described in the art and can be used as host cells in which to express recombinant antibodies to thereby produce an antibody with altered glycosylation.
  • EP 1,176,195 by Hang et al. describes a cell line with a functionally disrupted FUT8 gene, which encodes a fucosyl transferase, such that antibodies expressed in such a cell line exhibit hypofucosylation.
  • PCT Publication WO 03/035835 by Presta describes a variant CHO cell line, Lecl3 cells, with reduced ability to attach fucose to Asn (297)-linked carbohydrates, also resulting in hypofucosylation of antibodies expressed in that host cell (see also Shields et al., (2002) J. Biol. Chem. 277:26733-26740).
  • PCT Publication WO 99/54342 by Umana et al. describes cell lines engineered to express gly coprotein-modifying glycosyl transferases (e.g., beta(l,4)-N acetylglucosaminyltransferase III (GnTIII)) such that antibodies expressed in the engineered cell lines exhibit increased bisecting GlcNac structures which results in increased ADCC activity of the antibodies (see also Umana et al., Nat. Biotech. 17:176-180, 1999).
  • gly coprotein-modifying glycosyl transferases e.g., beta(l,4)-N acetylglucosaminyltransferase III (GnTIII)
  • Reduced ADCC can be achieved by operably linking the antibody to IgG4 engineered with combinations of alterations to have reduced or null FcyR binding or Clq binding activities, thereby reducing or eliminating ADCC and CDC effector functions.
  • IgG4 Considering physicochemical properties of antibody as a biological drug, one of the less desirable, intrinsic properties of IgG4 is dynamic separation of its two heavy chains in solution to form half antibody, which lead to bi-specific antibodies generated in vivo via a process called “Fab arm exchange” (Van der Neut Kolfschoten M, et al., 2007 Science, 317: 1554-157). The mutation of serine to proline at position 228 (EU numbering system) appeared inhibitory to the IgG4 heavy chain separation (Angal, S.
  • the modified IgGl Fc molecule includes a variant heavy chain constant region or Fc of human IgGl comprising one or more mutations selected from a group consisting of E233P, L234A, L235A, L236A and P329A.
  • Anti-PDl antibodies and antigen-binding fragments thereof and anti-TIM3 antibodies and antigen-binding fragments thereof can be produced by any means known in the art, including but not limited to, recombinant expression, chemical synthesis, and enzymatic digestion of antibody tetramers, whereas full-length monoclonal antibodies can be obtained by, e g., hybridoma or recombinant production.
  • Recombinant expression can be from any appropriate host cells known in the art, for example, mammalian host cells, bacterial host cells, yeast host cells, insect host cells, etc.
  • the disclosure further provides polynucleotides encoding the antibodies described herein, e.g., polynucleotides encoding heavy' or light chain variable regions or segments comprising the complementarity determining regions as described herein.
  • the polynucleotide encoding the heavy chain variable regions has at least 85%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% nucleic acid sequence identity with a polynucleotide encoding the amino acid sequences disclosed herein.
  • the polynucleotide encoding the light chain variable regions has at least 85%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% nucleic acid sequence identity with a polynucleotide encoding the amino acid sequences described herein.
  • the polynucleotides of the present disclosure can encode the variable region sequence of an anti-PDl antibody or anti-TIM3 antibody. They can also encode both a variable region and a constant region of the antibody. Some of the polynucleotide sequences encode a polypeptide that comprises variable regions of both the heavy chain and the light chain. Some other polynucleotides encode two polypeptide segments that respectively are substantially identical to the variable regions of the heavy chain and the light chain.
  • expression vectors and host cells for producing the anti-PDl antibodies and antigen-binding fragments thereof or anti-TIM3 antibodies and antigen-binding fragments thereof.
  • the choice of expression vector depends on the intended host cells in which the vector is to be expressed.
  • the expression vectors contain a promoter and other regulatory sequences (e.g., enhancers) that are operably linked to the polynucleotides encoding the antibodies or antigen-binding fragments thereof.
  • an inducible promoter is employed to prevent expression of inserted sequences except under the control of inducing conditions.
  • Inducible promoters include, e.g., arabinose, lacZ, metallothionein promoter or a heat shock promoter. Cultures of transformed organisms can be expanded under non-inducing conditions without biasing the population for coding sequences whose expression products are better tolerated by the host cells.
  • promoters other regulatory elements can also be required or desired for efficient expression of an antibody or antigen-binding fragment. These elements typically include an ATG initiation codon and adjacent ribosome binding site or other sequences.
  • the efficiency of expression can be enhanced by the inclusion of enhancers appropriate to the cell system in use (see, e.g., Scharf et al., Results Probl. Cell Differ. 20: 125, 1994; and Bittner et al., Meth Enzymol., 153:516, 1987).
  • the SV40 enhancer or CMV enhancer can be used to increase expression in mammalian host cells.
  • the host cells for harboring and expressing the antibody chains can be either prokary otic or eukaryotic.
  • E. coll is one prokaryotic host useful for cloning and expressing the polynucleotides of the present disclosure.
  • Other microbial hosts suitable for use include bacilli, such as Bacillus subtilis, and other enterobacteriaceae, such as Salmonella, Serratia, and various Pseudomonas species.
  • bacilli such as Bacillus subtilis
  • enterobacteriaceae such as Salmonella, Serratia, and various Pseudomonas species.
  • expression vectors which typically contain expression control sequences compatible with the host cell (e.g., an origin of replication).
  • any number of a variety of well-known promoters will be present, such as the lactose promoter system, a tryptophan (trp) promoter system, a beta-lactamase promoter system, or a promoter system from phage lambda.
  • the promoters ty pically control expression, optionally with an operator sequence, and have ribosome binding site sequences and the like, for initiating and completing transcription and translation.
  • Other microbes such as yeast, can also be employed to express antibody polypeptides.
  • Insect cells in combination with baculovirus vectors can also be used.
  • mammalian host cells are used to express and produce the antibody polypeptides of the present disclosure.
  • they can be either a hybridoma cell line expressing endogenous immunoglobulin genes or a mammalian cell line harboring an exogenous expression vector.
  • These include any normal mortal or normal or abnormal immortal animal or human cell.
  • suitable host cell lines capable of secreting intact immunoglobulins have been developed, including the CHO cell lines, various COS cell lines, HEK 293 cells, myeloma cell lines, transformed B-cells and hybridomas.
  • Expression vectors for mammalian host cells can include expression control sequences, such as an origin of replication, a promoter, and an enhancer (see, e.g., Queen et al., Immunol. Rev. 89:49-68, 1986), and necessary processing information sites, such as ribosome binding sites, RNA splice sites, polyadenylation sites, and transcriptional terminator sequences.
  • expression control sequences such as an origin of replication, a promoter, and an enhancer (see, e.g., Queen et al., Immunol. Rev. 89:49-68, 1986)
  • necessary processing information sites such as ribosome binding sites, RNA splice sites, polyadenylation sites, and transcriptional terminator sequences.
  • These expression vectors usually contain promoters derived from mammalian genes or from mammalian viruses.
  • Suitable promoters can be constitutive, cell type-specific, stage-specific, and/or modulatable or regulatable.
  • Useful promoters include, but are not limited to, the metallothionein promoter, the constitutive adenovirus major late promoter, the dexamethasone-inducible MMTV promoter, the SV40 promoter, the MRP polIII promoter, the constitutive MPSV promoter, the tetracycline-inducible CMV promoter (such as the human immediate-early CMV promoter), the constitutive CMV promoter, and promoterenhancer combinations known in the art.
  • the present disclosure provides a method of cancer treatment, the method comprising administering to a patient an effective amount of an anti-PDl antibody or antigen-binding fragment thereof and/or an anti-TIM3 antibody or antigen binding fragment thereof.
  • the method comprises administering to a patient an effective amount of an anti-PDl antibody or antigen-binding fragment thereof in combination with an anti-TIM3 antibody or antigen binding fragment thereof.
  • the detailed information of antibodies could be found in section I. Antibodies.
  • the present disclosure provides a method of cancer treatment or enhancing an immune response, the method comprising administering to a patient 200 mg once every 3 weeks of an anti-PDl antibody or antigen-binding fragment thereof in combination with an anti-TIM3 antibody or antigen binding fragment thereof at a dose of 20 mg - 1600 mg once every 3 weeks.
  • the anti-PDl antibody or antigen binding fragment thereof specifically binds to human PD1 and comprises: a heavy chain variable region that comprises (a) HCDR1 of SEQ ID NO: 1, (b) HCDR2 of SEQ ID NO: 2, and (c) HCDR3 of SEQ ID NO: 3; and a light chain variable region that comprises (d) LCDR1 of SEQ ID NO: 4, (e) LCDR2 of SEQ ID NO: 5, and (f) LCDR3 of SEQ ID NO: 6.
  • the anti-PDl antibody or antigen-binding fragment thereof specifically binds to human PD1 and comprises a heavy chain variable region (VH) comprising an amino acid sequence of SEQ ID NO: 7 and a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 8.
  • VH heavy chain variable region
  • VL light chain variable region
  • the anti-PDl antibody or antigen-binding fragment thereof comprises an IgG4 constant domain comprising any of SEQ ID NO: 9.
  • the anti-PDl antibody or antigen-binding fragment thereof comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 10 and a light chain comprising an amino acid sequence of SEQ ID NO: 11.
  • the anti-TIM3 antibody or antigen binding fragment thereof specifically binds to human TIM3 and comprises a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 12, (b) HCDR2 of SEQ ID NO: 13, and (c) HCDR3 of SEQ ID NO: 14; and a light chain variable region comprising (d) LCDR1 of SEQ ID NO: 15, (e) LCDR2 of SEQ ID NO: 16, and (f) LCDR3 of SEQ ID NO: 17.
  • the anti-TIM3 antibody or antigen binding fragment thereof specifically binds to human TIM3 and comprises a heavy chain variable region (VH) comprising an amino acid sequence of SEQ ID NO: 18 and a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 19.
  • the anti-TIM3 antibody or antigen binding fragment thereof comprises a variant heavy chain constant region of human IgGl comprising one or more mutations selected from a group consisting of E233P, L234A, L235A, L236A and P329A.
  • the anti-TIM3 antibody or antigen binding fragment thereof comprises a variant heavy chain constant region of human IgGl comprising the amino sequence of SEQ ID NO: 20, and a human kappa light chain constant region.
  • the anti-TIM3 antibody or antigen binding fragment thereof comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 21 and a light chain comprising an amino acid sequence of SEQ ID NO: 22.
  • the anti-PDl antibody or antigen binding fragment thereof is a monoclonal antibody, a chimeric antibody, a humanized antibody, a human engineered antibody, a single chain antibody (scFv), a Fab fragment, a Fab’ fragment, or a F(ab’)2 fragment.
  • the anti-TIM3 antibody or antigen binding fragment thereof is a monoclonal antibody, a chimeric antibody, a humanized antibody, a human engineered antibody, a single chain antibody (scFv), a Fab fragment, a Fab’ fragment, or a F(ab’)2 fragment.
  • the cancer is head and neck cancer, lung cancer, kidney cancer, gastric cancer, liver cancer, breast cancer, colon cancer, ovarian cancer, cervical cancer, melanoma, skin cancer, colorectal cancer, urothelial carcinoma, nasopharyngeal carcinoma, mesothelioma, lymphoma, leukemia, myeloma, or sarcoma.
  • the cancer is small cell lung cancer or non-small cell lung cancer (NSCLC).
  • the non-small cell lung cancer is squamous or non-squamous non-small cell lung cancer.
  • the cancer is renal cell carcinoma (RCC).
  • the cancer is head and neck squamous cell carcinoma (HNSCC).
  • the cancer is tnple-negative breast cancer.
  • the cancer is selected from one or more of NSCLC, HNSCC, hepatocellular carcinoma, gastric or gastroesophageal carcinoma, nasopharyngeal carcinoma, RCC, cervical cancer, triple-negative breast cancer, and urothelial carcinoma.
  • the cancer is esophageal cancer.
  • the cancer is endometrial cancer.
  • the cancer is a cancer having microsatellite instability high (MSI-H).
  • the cancer is any of Breast Cancer, Undifferentiated Pleomorphic Sarcoma, NSCLC, Sarcoma, Uterine Cancer, Colorectal cancer (CRC), Ovarian cancer, Anal Cancer, Endometria, Esophageal, Pancreatic, and Squamous Cell Carcinoma of Vulva.
  • the cancer is any of Peritoneal Cancer, Thymic Carcinoma, Endometrial Carcinoma, Breast Cancer, Undifferentiated Pleomorphic Sarcoma, Non-Small Cell Lung Cancer -Non Squamous, Ampulla of Vater, Merkel Cell Carcinoma of Gall Bladder, Pancreatic Cancer, Sarcoma, Anal Cancer, Uterine Cancer, Ovarian Cancer, Colorectal Cancer, Thymic See, Esophageal Cancer, Endometrial Cancer, Intrahepatic Cholangio Carcinoma, Squamous Cell Carcinoma of Vulva, Non-Small Cell Lung Cancer - Squamous, Haemangiopericytoma, Gastric or Gastroesophageal Junction Cancer.
  • the cancer treatment is a front-line treatment. In another embodiment, the cancer treatment is a late-line treatment. In one embodiment, the cancer treatment is a first line treatment, a second line treatment, a third line treatment or a fourth line treatment.
  • the cancer is an advanced or metastatic cancer. In another embodiment, the cancer is a recurrent cancer. In another embodiment, the cancer is a resistant or refractory cancer. In another embodiment, the cancer treatment results in a sustained anti-cancer response in the patient after cessation of the treatment. In another embodiment, the patient had received 1 or 2 lines of prior therapy. In a further embodiment, the prior therapy includes anti-PDl antibody or anti-PD-Ll antibody or antigen-binding fragment thereof, i.e., the prior PD1/PDL1 immune oncology treatment failed.
  • the patient had received a prior therapy of PD1 or PDL1 immune therapy treatment (e.g., PD1 or PDL1 antibody), and such PD1 or PDL1 immune therapy failed.
  • the prior therapy includes standard systemic therapy, such as chemotherapy.
  • the patients experienced disease progression after receiving checkpoint and require subsequent therapies. In another embodiment, the patients experienced checkpoint inhibition resistance.
  • the patients had disease progression that occurred (such as > 10 weeks) from the initiation of anti-PDl/PD-Ll treatment in the most recent line of therapy for locally advanced or metastatic disease (i.e., prior PD1/PDL1 immune oncology treatment failed).
  • the patients are positive for PD-L1 expression.
  • the method is used as a first-line treatment or front-line treatment. In another embodiment, the method is used as a first-line treatment in patients with recurrent or metastatic head and neck squamous cell carcinoma. In another embodiment, the method is used as a first-line treatment in patients with recurrent or metastatic non-small cell lung cancer.
  • the anti-PDl antibody or antigen-binding fragment thereof and the anti-TIM3 antibody or antigen binding fragment thereof are administered simultaneously or are administered sequentially.
  • the method comprises administering to a patient 200 mg once every 3 weeks of the anti-PDl antibody or antigen-binding fragment thereof in combination with the anti-TIM3 antibody or antigen binding fragment thereof at a dose of 20 mg- 1600 mg once every 1 week, 2 weeks, 3 weeks or 1 month. In one embodiment, the method comprises administering to a patient 200 mg once every 3 weeks of the anti-PDl antibody or antigen-binding fragment thereof in combination with the anti-TIM3 antibody or antigen binding fragment thereof at a dose of 20 mg-1600 mg once every 3 weeks.
  • the method comprises administering to the patient 200 mg once every 3 weeks of the anti-PDl antibody or antigen-binding fragment thereof in combination with of the anti-TIM3 antibody or antigen binding fragment thereof at a dose of 200 mg - 1600 mg once every 1 week, 2 weeks, 3 weeks or 1 month. In one embodiment, the method comprises administering to the patient 200 mg once every 3 weeks of the anti-PDl antibody or antigen-binding fragment thereof in combination with of the anti-TIM3 antibody or antigen binding fragment thereof at a dose of 200 mg - 1600 mg once every 3 weeks.
  • the method comprises administering to the patient 200 mg once every 3 weeks of the anti-PDl antibody or antigen-binding fragment thereof in combination with of the anti-TIM3 antibody or antigen binding fragment thereof at a dose of 200 mg - 800 mg once every 1 week, 2 weeks, 3 w eeks or 1 month. In one embodiment, the method comprises administering to the patient 200 mg once every 3 weeks of the anti-PDl antibody or antigen-binding fragment thereof in combination with of the anti-TIM3 antibody or antigen binding fragment thereof at a dose of 200 mg - 800 mg once every 3 weeks.
  • the method comprises administering to the patient 200 mg once every 3 weeks of the anti-PDl antibody or antigen-binding fragment thereof in combination with of the anti-TIM3 antibody or antigen binding fragment thereof at a dose of 300 mg - 900 mg once every 1 week, 2 weeks, 3 weeks or 1 month. In one embodiment, the method comprises administering to the patient 200 mg once every 3 weeks of the anti-PDl antibody or antigen-binding fragment thereof in combination with of the anti-TIM3 antibody or antigen binding fragment thereof at a dose of 300 mg - 900 mg once every 3 weeks.
  • the method comprises administering to the patient 200 mg once every 3 weeks of the anti-PDl antibody or antigen-binding fragment thereof in combination with of the anti-TIM3 antibody or antigen binding fragment thereof at a dose of 300 mg - 700 mg once every 1 week, 2 weeks, 3 w eeks or 1 month. In one embodiment, the method comprises administering to the patient 200 mg once every 3 weeks of the anti-PD l antibody or antigen-binding fragment thereof in combination with of the anti-TIM3 antibody or antigen binding fragment thereof at a dose of 300 mg - 700 mg once every 3 weeks.
  • the method comprises administering to the patient 200 mg once every 3 weeks of the anti-PDl antibody or antigen-binding fragment thereof in combination with of the anti-TIM3 antibody or antigen binding fragment thereof at a dose of 400 mg - 800 mg once every 1 week, 2 weeks, 3 weeks or 1 month. In one embodiment, the method comprises administering to the patient 200 mg once every 3 weeks of the anti-PDl antibody or antigen-binding fragment thereof in combination with of the anti-TIM3 antibody or antigen binding fragment thereof at a dose of 400 mg - 800 mg once every 3 weeks.
  • the method comprises administering to the patient 200 mg once every 3 weeks of the anti-PDl antibody or antigen-binding fragment thereof in combination with of the anti-TIM3 antibody or antigen binding fragment thereof at a dose of 500 mg - 700 mg once every 1 week, 2 weeks, 3 w eeks or 1 month. In one embodiment, the method comprises administering to the patient 200 mg once every 3 weeks of the anti-PDl antibody or antigen-binding fragment thereof in combination with of the anti-TIM3 antibody or antigen binding fragment thereof at a dose of 500 mg - 700 mg once every 3 weeks.
  • the method comprises administering to the patient 200 mg once every 3 weeks of the anti-PDl antibody or antigen-binding fragment thereof in combination with of the anti-TIM3 antibody or antigen binding fragment thereof at a dose of 550 mg - 750 mg once every 1 week, 2 weeks, 3 w eeks or 1 month. In one embodiment, the method comprises administering to the patient 200 mg once every 3 weeks of the anti-PDl antibody or antigen-binding fragment thereof in combination with of the anti-TIM3 antibody or antigen binding fragment thereof at a dose of 550 mg - 750 mg once every 3 weeks.
  • the method comprises administering to the patient 200 mg once every 3 weeks of the anti-PDl antibody or antigen-binding fragment thereof in combination with of the anti-TIM3 antibody or antigen binding fragment thereof at a dose of 550 mg - 700 mg once every 1 week, 2 weeks, 3 w eeks or 1 month. In one embodiment, the method comprises administering to the patient 200 mg once every 3 weeks of the anti-PDl antibody or antigen-binding fragment thereof in combination with of the anti-TIM3 antibody or antigen binding fragment thereof at a dose of 550 mg - 700 mg once every 3 weeks.
  • the method comprises administering to the patient 200 mg once every 3 weeks of the anti-PDl antibody or antigen-binding fragment thereof in combination with of the anti-TIM3 antibody or antigen binding fragment thereof at a dose of 550 mg - 650 mg once every 1 week, 2 weeks, 3 w eeks or 1 month. In one embodiment, the method comprises administering to the patient 200 mg once every 3 weeks of the anti-PDl antibody or antigen-binding fragment thereof in combination with of the anti-TIM3 antibody or antigen binding fragment thereof at a dose of 550 mg - 650 mg once every 3 weeks.
  • the method comprises administering to the patient 200 mg once every 3 weeks of the anti-PDl antibody or antigen-binding fragment thereof in combination with of the anti-TIM3 antibody or antigen binding fragment thereof at a dose of 500 mg - 600 mg once every 1 week, 2 weeks, 3 weeks or 1 month. In one embodiment, the method comprises administering to the patient 200 mg once every 3 weeks of the anti-PDl antibody or antigen-binding fragment thereof in combination with of the anti-TIM3 antibody or antigen binding fragment thereof at a dose of 500 mg - 600 mg once every 3 weeks.
  • the method comprises administering to the patient 200 mg once every 3 weeks of the anti-PD I antibody or antigen-binding fragment thereof in combination with of the anti-TIM3 antibody or antigen binding fragment thereof at a dose of 550 mg - 600 mg once every 1 week, 2 weeks, 3 w eeks or 1 month. In one embodiment, the method comprises administering to the patient 200 mg once every 3 weeks of the anti-PDl antibody or antigen-binding fragment thereof in combination with of the anti-TIM3 antibody or antigen binding fragment thereof at a dose of 550 mg - 600 mg once every 3 weeks.
  • the method comprises administering to the patient 200 mg once every 3 weeks of the anti-PDl antibody or antigen-binding fragment thereof in combination with of the anti-TIM3 antibody or antigen binding fragment thereof at a dose of 600 mg - 700 mg once every 1 week, 2 weeks, 3 w eeks or 1 month. In one embodiment, the method comprises administering to the patient 200 mg once every 3 weeks of the anti-PDl antibody or antigen-binding fragment thereof in combination with of the anti-TIM3 antibody or antigen binding fragment thereof at a dose of 600 mg - 700 mg once every 3 weeks.
  • the method comprises administering to the patient 200 mg once every 3 weeks of the anti-PDl antibody or antigen-binding fragment thereof in combination with of the anti-TIM3 antibody or antigen binding fragment thereof at a dose of 600 mg - 650 mg once every 1 week, 2 weeks, 3 w eeks or 1 month. In one embodiment, the method comprises administering to the patient 200 mg once every 3 weeks of the anti-PDl antibody or antigen-binding fragment thereof in combination with of the anti-TIM3 antibody or antigen binding fragment thereof at a dose of 600 mg - 650 mg once every 3 weeks.
  • the anti-TIM3 antibody or antigen binding fragment thereof are administered at a dose of 20 mg, 60 mg, 80 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg or 1600 mg once every 1 week, 2 weeks. 3 weeks or 1 month.
  • the anti-TIM3 antibody or antigen binding fragment thereof are administered at a dose of 20 mg, 60 mg, 80 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg or 1600 mg once every 3 weeks.
  • the anti-TIM3 antibody or antigen binding fragment thereof are administered at a dose of 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, or 200 mg once every 1 week, 2 weeks, 3 weeks or 1 month.
  • the anti-TIM3 antibody or antigen binding fragment thereof are administered at a dose of 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, or 200 mg once every 3 weeks.
  • the anti-TIM3 antibody or antigen binding fragment thereof are administered at a dose of 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg or 600 mg once every 1 week, 2 weeks, 3 weeks or 1 month. In another embodiment, the anti-TIM3 antibody or antigen binding fragment thereof are administered at a dose of 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg or 600 mg once every 3 weeks.
  • the anti-TIM3 antibody or antigen binding fragment thereof are administered at a dose of 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, or 900 mg once every 1 week, 2 weeks, 3 weeks or 1 month. In another embodiment, the anti-TIM3 antibody or antigen binding fragment thereof are administered at a dose of 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, or 900 mg once every 3 weeks.
  • the anti-TIM3 antibody or antigen binding fragment thereof are administered at a dose of 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 680 mg, 690 mg or 700 mg once every 1 week, 2 weeks, 3 weeks or 1 month.
  • the anti-TIM3 antibody or antigen binding fragment thereof are administered at a dose of 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 680 mg, 690 mg or 700 mg once every 3 weeks.
  • the anti-TIM3 antibody or antigen binding fragment thereof are administered at a dose of 900 mg, 950 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, or 1600 mg once every 1 week, 2 weeks, 3 weeks or 1 month. In one embodiment, the anti-TIM3 antibody or antigen binding fragment thereof are administered at a dose of 900 mg, 950 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, or 1600 mg once every 3 weeks. [00178] In one embodiment, the anti-TIM3 antibody or antigen binding fragment thereof are administered at a dose of 20 mg once every 3 weeks.
  • the anti-TIM3 antibody or antigen binding fragment thereof are administered at a dose of 200 mg once every 3 weeks. In another embodiment, the anti-TIM3 antibody or antigen binding fragment thereof are administered at a dose of 300 mg once every 3 weeks. In another embodiment, the anti-TIM3 antibody or antigen binding fragment thereof are administered at a dose of 400 mg once every 3 weeks. In another embodiment, the anti-TIM3 antibody or antigen binding fragment thereof are administered at a dose of 500 mg once every 3 weeks. In another embodiment, the anti-TIM3 antibody or antigen binding fragment thereof are administered at a dose of 600 mg once every 3 weeks. In another embodiment, the anti- TIM3 antibody or antigen binding fragment thereof are administered at a dose of 700 mg once every 3 weeks. In another embodiment, the anti-TIM3 antibody or antigen binding fragment thereof are administered at a dose of 800 mg once every 3 weeks. In another embodiment, the anti-TIM3 antibody or antigen binding fragment thereof are administered at a dose of 900 mg once every 3 weeks.
  • the anti-TIM3 antibody or antigen binding fragment thereof are administered at a dose of 250 mg once every' 3 weeks. In another embodiment, the anti- TIM3 antibody or antigen binding fragment thereof are administered at a dose of 350 mg once every 3 weeks. In another embodiment, the anti-TIM3 antibody or antigen binding fragment thereof are administered at a dose of 450 mg once every 3 weeks. In another embodiment, the anti-TIM3 antibody or antigen binding fragment thereof are administered at a dose of 550 mg once every 3 weeks. In another embodiment, the anti-TIM3 antibody or antigen binding fragment thereof are administered at a dose of 650 mg once every 3 weeks. In another embodiment, the anti-TIM3 antibody or antigen binding fragment thereof are administered at a dose of 750 mg once every 3 weeks. In another embodiment, the anti- TIM3 antibody or antigen binding fragment thereof are administered at a dose of 850 mg once every 3 weeks. In another embodiment, the anti-TIM3 antibody or antigen binding fragment thereof are administered at a dose of 950 mg once every 3 weeks.
  • the method comprises administering to a patient an effective amount of an anti-PDl antibody or antigen-binding fragment thereof in combination with an anti-TIM3 antibody or antigen binding fragment thereof.
  • the anti-PDl antibody or antigen binding fragment thereof is administered at a dosage of 200 mg once every 3 weeks.
  • the anti-TIM3 antibody or antigen binding fragment thereof is administered at a dosage of 400 mg, 600 mg, or 800 mg once every 3 weeks.
  • the anti-TIM3 antibody or antigen binding fragment thereof is administered at a dosage of 300 mg, 500 mg, or 700 mg once every 3 weeks.
  • the anti-TIM3 antibody or antigen binding fragment thereof is administered at a dosage of 350 mg, 450 mg, 550 mg, 650 mg, 750 mg or 850 mg once every 3 weeks. In another embodiment, the anti-TIM3 antibody or antigen binding fragment thereof is administered at a dosage of 600 mg once every 3 weeks.
  • the anti-TIM3 antibody or antigen binding fragment thereof is administered at a dosage of 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 680 mg, 690 mg or 700 mg once every 3 weeks.
  • An antibody or antigen-binding fragment of the disclosure can be administered by any suitable means, including parenteral, intrapulmonary, and intranasal, and, if desired for local treatment, intralesional administration.
  • Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.
  • Dosing can be by any suitable route, e.g., by injections, such as intravenous or subcutaneous injections, depending in part on whether the administration is brief or chronic. Vanous dosing schedules including but not limited to single or multiple administrations over various timepoints, bolus administration, and pulse infusion are contemplated herein.
  • Antibodies or antigen-binding fragments of the disclosure would be formulated, dosed, and administered in a fashion consistent with good medical practice.
  • Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners.
  • an antibody or antigen-binding fragment of the disclosure will depend on the type of disease to be treated, the type of antibody, the severity and course of the disease, whether the antibody is administered for preventive or therapeutic purposes, previous therapy, the patient's clinical history and response to the antibody, and the discretion of the attending physician.
  • the antibody is suitably administered to the patient at one time or over a series of treatments.
  • about 1 pg/kg to 100 mg/kg of antibody can be an initial candidate dosage for administration to the patient, whether, for example, by one or more separate administrations, or by continuous infusion.
  • One typical daily dosage might range from about 1 pg/kg to 100 mg/kg or more, depending on the factors mentioned above.
  • the treatment would generally be sustained until a desired suppression of disease symptoms occurs.
  • Such doses can be administered intermittently, e.g., every week or every three weeks (e.g., such that the patient receives from about two to about twenty, or e.g., about six doses of the antibody).
  • An initial higher loading dose, followed by one or more lower doses can be administered.
  • other dosage regimens can be useful. The progress of this therapy is easily monitored by conventional techniques and assays.
  • the present disclosure provides a method of increasing, enhancing, or stimulating an immune response or function, the method comprising administering to a patient an effective amount of an anti-PDl antibody or antigen-binding fragment thereof in combination with an anti-TIM3 antibody or antigen binding fragment thereof.
  • enhancing an immune response has potential therapeutic uses in controlling viral infections and other human diseases that are mechanistically involved in immune tolerance or “exhaustion.”
  • exhaust refers to a process which leads to a depleted ability of immune cells to respond during to a cancer or a chronic viral infection.
  • enhancing an immune response is associated with T cells, NK cells and/or macrophages.
  • the immune response is associated with CD4+ T cells.
  • the immune response is associated with CD8+ T cells.
  • the T cells are CD4+ T cells and/or CD8+ T cells.
  • enhancing an immune response is characterized by increased responsiveness to tumor antigen stimulation.
  • the T cells upon administration of anti-PDl antibodies in combination with anti-TIM3 antibodies, the T cells have increased cytokine secretion, proliferation, or cytolytic activity.
  • the cytokine is any one or more of IFN-gamma, IL-2, TNF- beta, IL-4, IL-5, IL-13.
  • the cytokine is IFN-gamma or IL-2.
  • the cytokine is any one or more of IFN-alpha, IFN-gamma, TNF-alpha, IL-1, IL-6, IL-12, IL-15, IFN-gamma, TNF-beta, IL-2, IL-4, IL-5, IL-13.
  • the cytokine is IFN-gamma. In another embodiment, the cytokine is IFN- alpha. In another embodiment, the cytokine is IL-2. In another embodiment, the cytokine is TNF-beta. In another embodiment, the cytokine is any one of IL-4, IL-5, IL-13.
  • the patient is immune suppressed or is on immune suppressive therapy. The combination therapy of anti-PDl antibody and anti-TIM3 antibody results in enhancement of anti-cancer immunity or anti-virus infection immunity.
  • the present disclosure provides a use of an effective amount of an anti- PDl antibody or antigen-binding fragment thereof in combination with an anti-TIM3 antibody or antigen binding fragment thereof in the manufacture of a medicament for cancer treatment or enhancing an immune response, wherein the anti-PDl antibody or antigenbinding fragment thereof is administered at a dose of 200 mg once every 3 weeks and the anti-TIM3 antibody or antigen binding fragment thereof is administered at a dose of 20 mg - 1600 mg (such as 20 mg, 60 mg, 80 mg, 100 mg, 150 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1200 mg, 1400 mg, or 1600 mg) once every one week, two weeks, three weeks, or one month.
  • 20 mg - 1600 mg such as 20 mg, 60 mg, 80 mg, 100 mg, 150 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1200 mg, 1400 mg, or 1600 mg
  • the present disclosure provides an anti-PDl antibody or antigenbinding fragment thereof in combination with an anti-TIM3 antibody or antigen binding fragment thereof for use in cancer treatment or enhancing an immune response, wherein the anti-PDl antibody or antigen-binding fragment thereof is administered at a dose of 200 mg once every 3 weeks and the anti-TIM3 antibody or antigen binding fragment thereof is administered at a dose of 20 mg - 1600 mg (such as 20 mg, 60 mg, 80 mg, 100 mg, 150 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1200 mg, 1400 mg, or 1600 mg) once every one week, two weeks, three weeks or one month.
  • 20 mg - 1600 mg such as 20 mg, 60 mg, 80 mg, 100 mg, 150 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1200 mg, 1400 mg, or 1600 mg
  • compositions including pharmaceutical formulations, comprising an anti-PD l antibody or antigen-binding fragment or an anti-TIM3 antibody or antigen binding fragment as disclosed herein, or polynucleotides comprising sequences encoding the antibody or antigen-binding fragment as disclosed herein.
  • suitable carriers such as phannaceutically acceptable excipients including buffers, which are well known in the art.
  • Pharmaceutical formulations of the antibody or antigen-binding fragment as described herein are prepared by mixing the antibody or antigen-binding fragment having the desired degree of purity with one or more optional pharmaceutically acceptable carriers (Remington's Pharmaceutical Sciences 16th edition. Osol, A. Ed.
  • Pharmaceutically acceptable carriers are generally nontoxic to recipients at the dosages and concentrations employed, and include, but are not limited to: buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3- pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such
  • Exemplary lyophilized antibody formulations are described in US Patent No. 6,267,958.
  • Aqueous antibody formulations include those described in US Patent No. 6,171,586 and W02006/044908, the latter formulations including a histidine-acetate buffer.
  • Sustained-release preparations can be prepared. Suitable examples of sustained- release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g., films, or microcapsules.
  • the formulations to be used for in vivo administration are generally sterile. Sterility can be readily accomplished, e.g., by filtration through sterile filtration membranes.
  • co-administration As used herein, the terms “co-administration”, “co-administered” and “in combination with,” referring to the combination therapies, is intended to mean, and does refer to and include the following:
  • the study is an open-label, multicenter, nonrandomized Phase 1 and 2 clinical study evaluating combinations of BGB-A425 (Surzebiclimab) with tislelizumab (ClinicalTrials.gov Identifier: NCT03744468).
  • the study design schematic is presented in Figure 1 A and Figure IB.
  • Priority enrollment for Phase 1 includes patients with NSCLC, HNSCC, hepatocellular carcinoma, gastric or gastroesophageal carcinoma, nasopharyngeal carcinoma, RCC, cervical cancer, triple-negative breast cancer, and urothelial carcinoma.
  • Enrollment for Phase 2 includes patients with HNSCC, NSCLC and RCC, and details are described as follows.
  • Phase 1 dose escalation: Sequential cohorts of approximately 8 increasing dose levels of Surzebiclimab were evaluated in combination with tislelizumab 200 mg in patients with advanced solid tumors to determine the RP2D, safety, PK, and other key endpoints for Surzebiclimab in combination with tislelizumab.
  • Phase 2 dose expansion: The combination treatments would be evaluated in patients with various tumor types including HNSCC, NSCLC and RCC, including
  • Phase 1 DLT period a 21 -day treatment cycle is planned for Phase 1 and Phase 2.
  • the Surzebiclimab and Tislelizumab combination RP2D was determined primarily from the Phase 1 safety, tolerability, preliminary antitumor activity, pharmacodynamic biomarker, and PK data.
  • the combination RP2D would be evaluated in the Phase 2 dose expansion.
  • Phase 1 dose level(s) and dosing frequency for surzebiclimab and/or tislelizumab are provided in Table 3.
  • Table 3 Phase 1 Dose Levels for Surzebiclimab and/or Tislelizumab
  • Cycle 1 Only Cycle 1 is 28 days in length. Thereafter starting with Cycle 2, each cycle is 21 days in length (i.e., once every 21 days).
  • surzebiclimab was administered on Day 1
  • tislelizumab was administered on Day 8 (+2 days).
  • patients then received tislelizumab followed by the administration of surzebiclimab on Day 1 of each subsequent 21-day cycle (i.e., once every 21 days).
  • the serum concentration-time profiles of surzebiclimab at various doses are shown in Figure 2.
  • the mean concentration (pg/ml) of surzebiclimab was collected at pre-dose, 6 hours after infusion, pre-dose on Day 1, Day 3, Day 7, Day 14 or Day 21 for various doses (2 mg, 6 mg, 20 mg, 60 mg, 200 mg, 400 mg, 600 mg, 800 mg, or 1600 mg) in cycle 1 (single dose, Figure 2A) or in cycle 5 (steady-state, Figure 2B).
  • surzebiclimab As shown in Figure 2, based on the concentration-time profiles, surzebiclimab exhibits target-mediated drug disposition at 60 mg and below. At 200 mg and above, the terminal elimination phase become linear, suggesting saturation of the target-mediated pathway.
  • Phase 1 dose escalation data are shown in Figure 3, including:
  • Table 4 Summary of patients in dose escalation.
  • the RP2D of Surzebiclimab (600 mg intravenously) is administered in combination with tislelizumab (200 mg intravenously).
  • Surzebiclimab and Tislelizumab are administered once every 21 days starting on Cycle 1 Day 1.
  • HNSCC head neck squamous cell carcinoma
  • NSCLC non-small cell lung cancer
  • HNSCC As show n in Figure 4 and Figure 5, at the time of last data-cut, among 30 evaluable patients, 17 patients were HNSCC (at the left side of Figure 4 and upper side of Figure 5). 1 partial response (PR), 5 stable disease (SD), 11 progressive disease (PD), and 1 non assessable (NA) were observed in 17 HNSCC patients.
  • PR partial response
  • SD stable disease
  • PD progressive disease
  • NA non assessable
  • the HNSCC patient (082037-004) is 46 years old male, with positive PD-L1 expression. Additionally, the patient received cisplatin and anti-PD-Ll immunotherapy Durvalumab as last line of therapy for 6 months w ith demonstrated progression before entering into the study. Following week 6 imaging, 31.2 % tumor reduction was observed. [00221] As show n in Figure 4 and Figure 5, at the time of last data-cut, among 30 evaluable patients, 16 patients were NSCLC (at the right side of Figure 4 and bottom side of Figure 5). 1 partial response (PR), 6 stable disease (SD), and 6 progressive disease (PD) were observed in 13 NSCLC patients.
  • PR partial response
  • SD stable disease
  • PD progressive disease
  • NSCLC patient (082020-004) is 68 years old male, with positive PD-L1.
  • the patients received Vactosertib in combination with anti-PD-Ll immunotherapy, Durvalumab for 10 months with demonstrated progression before entering into the study.
  • Week 6 imaging 46% tumor reduction was observed.
  • the patient was maintaining the PR and receiving the treatment.

Abstract

La présente invention concerne une méthode de traitement du cancer ou d'amélioration d'une réponse immunitaire, cette méthode consistant à administrer à un patient 200 mg une fois toutes les 3 semaines d'un anticorps anti-PDl ou d'un fragment de liaison à l'antigène de celui-ci en combinaison avec un anticorps anti-TIM3 ou un fragment de liaison à l'antigène de celui-ci à une dose de 20 mg à 1600 mg une fois toutes les 3 semaines.
PCT/US2023/072804 2022-08-25 2023-08-24 Méthodes de traitement du cancer à l'aide d'anticorps anti-pd1 en combinaison avec des anticorps anti-tim3 WO2024044675A1 (fr)

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