WO2024041652A1 - Méthodes de traitement du cancer - Google Patents

Méthodes de traitement du cancer Download PDF

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Publication number
WO2024041652A1
WO2024041652A1 PCT/CN2023/115065 CN2023115065W WO2024041652A1 WO 2024041652 A1 WO2024041652 A1 WO 2024041652A1 CN 2023115065 W CN2023115065 W CN 2023115065W WO 2024041652 A1 WO2024041652 A1 WO 2024041652A1
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antibody
cancer
preceding embodiments
binding fragment
seq
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PCT/CN2023/115065
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English (en)
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Wenjuan ZHENG
Hua-Xin GAO
Xiangyu Liu
Jiyuan ZHANG
Wei Jin
Xiao DING
Hengrui ZHU
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Beigene, Ltd.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • 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
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A61K2039/507—Comprising a combination of two or more separate antibodies
    • 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 that specifically bind human Lag3.
  • Immune checkpoint-inhibitory receptor 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 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-PD1 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) .
  • Tim3 blocking antibodies As demonstrated from the TILs of patient samples or animal models, when expressed on effector T-cells (CD4+ and CD8+) , activation of Tim3 via ligand binding has been shown to reduce cytokine production, T-cell proliferation, and cytotoxicity, all of which could be rescued with Tim3 blocking antibodies (Fourcade et al., 2010; Sakuishi et al., 2010) .
  • Lymphocyte Activation Gene-3 (Lag3 or CD223) is an immune checkpoint protein predominantly expressed on the surface of activated T cells (Huard et al., 1995) , and natural killer (NK) cells (Triebel et al., 1990) .
  • Major histocompatibility complex (MHC) Class II is the main ligand for Lag3 (Huard et al., 1995) , and engagement of Lag3 by MHC II ligand leads to a state of T cell exhaustion, characterized by attenuation of T-cell activation, inability to proliferate in response to antigen and reduced cytokine production (Workman and Vignali 2003, Huang et al., 2004, Workman et al., 2004) .
  • LSECtin (Xu et al., 2014) , galectin 3 (Kouo et al., 2015) , and FGL1 (Wang et al., 2019) are other immune-inhibitory ligands that have been identified to interact with Lag3 and mediate its inhibitory function in T cells. Consistent with its inhibitory function, Lag3 expression is high in chronically exhausted or dysfunctional T cells in cancer, particularly in tumor infiltrated T cells (Matsuzaki et al., 2010) .
  • Lag3 is also expressed on regulatory T (Treg) cells and Lag3 + Treg cells are highly suppressive compared to Lag3-Treg cells (Huang et al., 2004, Camisaschi et al., 2010) .
  • 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.
  • Embodiment 1 A method of cancer treatment or enhancing an immune response, the method comprising administering to a patient an effective amount of an anti-Lag3 antibody or antigen binding fragment thereof alone or in combination with any other one or more therapeutic agents.
  • Embodiment 2 The method of embodiment 1, wherein said therapeutic agent is an anti-PD1 antibody or antigen-binding fragment thereof, an anti-Tim3 antibody or antigen binding fragment thereof, any other checkpoint inhibitor, and/or one or more chemotherapy agents.
  • said therapeutic agent is an anti-PD1 antibody or antigen-binding fragment thereof, an anti-Tim3 antibody or antigen binding fragment thereof, any other checkpoint inhibitor, and/or one or more chemotherapy agents.
  • Embodiment 3 The method of any one of the preceding embodiments, wherein the anti-PD1 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.
  • Embodiment 4 The method of any one of the preceding embodiments, wherein the anti-PD1 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
  • Embodiment 5 The method of any one of the preceding embodiments, wherein 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: 10, (b) HCDR2 of SEQ ID NO: 11, and (c) HCDR3 of SEQ ID NO: 12; and a light chain variable region comprising (d) LCDR1 of SEQ ID NO: 13, (e) LCDR2 of SEQ ID NO: 14, and (f) LCDR3 of SEQ ID NO: 15.
  • Embodiment 6 The method of any one of the preceding embodiments, wherein 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: 16 and a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 17.
  • VH heavy chain variable region
  • VL light chain variable region
  • Embodiment 7 The method of any one of the preceding embodiments, wherein the anti-Tim3 antibody or antigen binding fragment thereof comprises a variant heavy chain constant region of human IgG1 comprising one or more mutations selected from a group consisting of E233P, L234A, L235A, L236 ⁇ and P329A.
  • Embodiment 8 The method of any one of the preceding embodiments, wherein the anti-Tim3 antibody or antigen binding fragment thereof comprises a variant heavy chain constant region of human IgG1 comprising the amino sequence of SEQ ID NO: 18, and a human kappa light chain constant region.
  • Embodiment 9 The method of any one of the preceding embodiments, wherein the anti-Lag3 antibody or antigen binding fragment thereof specifically binds to human Lag3 and comprises a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 21, (b) HCDR2 of SEQ ID NO: 22, and (c) HCDR3 of SEQ ID NO: 23; and a light chain variable region comprising (d) LCDR1 of SEQ ID NO: 24, (e) LCDR2 of SEQ ID NO: 25, and (f) LCDR3 of SEQ ID NO: 26.
  • a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 21, (b) HCDR2 of SEQ ID NO: 22, and (c) HCDR3 of SEQ ID NO: 23; and a light chain variable region comprising (d) LCDR1 of SEQ ID NO: 24, (e) LCDR2 of SEQ ID NO: 25, and (f) LCDR3 of SEQ ID NO: 26.
  • Embodiment 10 The method of any one of the preceding embodiments, wherein the anti-Lag3 antibody or antigen-binding fragment thereof specifically binds to human Lag3 and comprises a heavy chain variable region (VH) comprising an amino acid sequence of SEQ ID NO: 27 and a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 28.
  • VH heavy chain variable region
  • VL light chain variable region
  • Embodiment 11 The method of any one of the preceding embodiments, wherein the antibody or antibodies, 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 antibody or antibodies, 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.
  • Embodiment 12 The method of any one of the preceding embodiments, wherein the administration route of said therapeutic agent or antibody is intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.
  • Embodiment 13 The method of embodiment 12, wherein said administration route is intravenous or subcutaneous administration.
  • Embodiment 14 The method of any one of the preceding embodiments, wherein 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, Non-Small Cell Lung Cancer, Breast Carcinoma, Melanoma, Head And Neck Squamous Cell Cancer, Cholangio Carcinoma, Ovarian cancer, Gastric Or Gastroesophageal Junction Carcinoma, Gastric Or Gastroesophageal Junction Carcinoma, Invasive Ductal Carcinoma Of Breast, Ethmoid SCC, Gastric Or Gastroesophageal Junction Carcinoma, Ovarian/Fallopian Tube cancer, Endometrium, Urothelial Carcinoma, Renal Cell Carcino
  • Embodiment 15 The method of any one of the preceding embodiments, wherein the cancer is small cell lung cancer or non-small cell lung cancer.
  • Embodiment 16 The method of any one of the preceding embodiments, wherein the non-small cell lung cancer is squamous or non-squamous non-small cell lung cancer.
  • Embodiment 17 The method of any one of the preceding embodiments, wherein the cancer is renal cell carcinoma.
  • Embodiment 18 The method of any one of the preceding embodiments, wherein the cancer is head and neck squamous cell carcinoma.
  • Embodiment 19 The method of any one of the preceding embodiments, wherein the cancer is an advanced or metastatic cancer.
  • Embodiment 20 The method of any one of the preceding embodiments, wherein the cancer is a recurrent cancer.
  • Embodiment 21 The method of any one of the preceding embodiments, wherein the cancer is a resistant or refractory cancer.
  • Embodiment 22 The method of any one of the preceding embodiments, wherein the method results in a sustained anti-cancer response in the patient after cessation of the treatment.
  • Embodiment 23 The method of any one of the preceding embodiments, wherein the patient had received 1 or 2 lines of prior therapy.
  • Embodiment 24 The method of any one of the preceding embodiments, wherein the prior therapy includes anti-PD1 antibody or anti-PD-L1 antibody or antigen-binding fragment thereof.
  • Embodiment 25 The method of any one of the preceding embodiments, wherein the method is used as a first-line treatment or front-line treatment.
  • Embodiment 26 The method of any one of the preceding embodiments, wherein the method is used as a first-line treatment in patients with recurrent or metastatic head and neck squamous cell carcinoma.
  • Embodiment 27 The method of any one of the preceding embodiments, wherein the method is used as a first-line treatment in patients with recurrent or metastatic non-small cell lung cancer.
  • Embodiment 28 The method of any one of the preceding embodiments, wherein the method is used as a later-line treatment.
  • Embodiment 29 The method of any one of the preceding embodiments, wherein the therapeutic agents are administered simultaneously or are administered sequentially.
  • Embodiment 30 The method of any one of the preceding embodiments, wherein the anti-PD1 antibody or antigen-binding fragment thereof is administered at a dosage of 200 mg once every 3 weeks.
  • Embodiment 31 The method of any one of the preceding embodiments, wherein the anti-Tim3 antibody or antigen-binding fragment thereof is administered at a dosage of 200 mg-1200 mg once every 3 weeks, preferably 500 mg -700 mg once every 3 weeks, more preferably 550 mg -650 mg once every 3 weeks.
  • Embodiment 32 The method of any one of the preceding embodiments, wherein the anti-Tim3 antibody or antigen-binding fragment thereof is administered at a dosage of 500 mg, 550 mg, 600 mg, 650 mg or 700 mg once every 3 weeks.
  • Embodiment 33 The method of any one of the preceding embodiments, wherein the anti-Tim3 antibody or antigen-binding fragment thereof is administered at a dosage of 600 mg once every 3 weeks.
  • Embodiment 34 The method of any one of the preceding embodiments, wherein the anti-Lag3 antibody or antigen-binding fragment thereof is administered at a dosage of 300 mg –1200 mg once every 3 weeks.
  • Embodiment 35 The method of any one of the preceding embodiments, wherein the anti-Lag3 antibody or antigen-binding fragment thereof is administered at a dosage of 300 mg, 600 mg, 900 mg, or 1200 mg once every 3 weeks.
  • Embodiment 36 The method of any one of the preceding embodiments, wherein the anti-Lag3 antibody or antigen-binding fragment thereof is administered at a dosage of 500 mg -700 mg or 800 mg -1000 mg once every 3 weeks, preferably 550 mg –650 mg or 850 mg –
  • Embodiment 37 The method of any one of the preceding embodiments, wherein the anti-Lag3 antibody or antigen-binding fragment thereof is administered at a dosage of 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, 1150 mg, 1200 mg, or 1250 mg once every 3 weeks.
  • Embodiment 38 The method of any one of the preceding embodiments, wherein the anti-Lag3 antibody or antigen-binding fragment thereof is administered at a dosage of 600 mg or 900mg or 1200mg once every 3 weeks.
  • Embodiment 39 The method of any one of the preceding embodiments, the method comprising administering to a patient 200 mg once every 3 weeks of the anti-PD1 antibody or antigen-binding fragment thereof in combination with 600 mg once every 3 weeks of the anti-Tim3 antibody or antigen binding fragment thereof and 600 mg or 900mg or 1200mg once every 3 weeks of the anti-Lag3 antibody or antigen binding fragment thereof.
  • Embodiment 40 The method of any one of the preceding embodiments, wherein enhancing an immune response is associated with T cells, NK cells and/or macrophages.
  • Embodiment 41 The method of any one of the preceding embodiments, wherein enhancing an immune response is characterized by increased responsiveness to tumor antigen stimulation.
  • Embodiment 42 The method of any one of the preceding embodiments, wherein the T cells have increased cytokine secretion, proliferation, or cytolytic activity.
  • Embodiment 43 The method of embodiment 42, wherein the cytokine is any one or more of IFN-gamma, IL-2, TNF-beta, IL-4, IL-5, IL-13.
  • Embodiment 44 The method of embodiment 42, wherein the cytokine is IFN-gamma or IL-2.
  • Embodiment 45 The method of any one of the preceding embodiments, wherein the T cells are CD4+ T cells and/or CD8+ T cells.
  • Embodiment 46 Use of an effective amount of an anti-Lag3 antibody or antigen binding fragment thereof in the manufacture of a medicament for cancer treatment or enhancing an immune response, wherein the amount is as described herein.
  • Embodiment 47 An effective amount of anti-Lag3 antibody or antigen binding fragment thereof for use in cancer treatment or enhancing an immune response, wherein the amount is as described herein.
  • the use of an effective amount of anti-Lag3 antibody or antigen binding fragment thereof provides an unexpected synergistic efficacy in cancer treatment, such as cytokine release, cancer cell killing, tumor growth inhibition, or ratio of tumor free. Especially, it provides an unexpected synergistic efficacy in tumor growth inhibition and/or ratio of tumor free.
  • the combination of an anti-PD1 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, such as Tislelizumab) 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: 10, (b) HCDR2 of SEQ ID NO: 11, and (c) HCDR3 of SEQ ID NO: 12; and a light chain variable region comprising (d) LCDR1 of SEQ ID NO: 13, (e) LCDR2 of SEQ ID NO:
  • an anti-PD1 antibody or antigen-binding fragment thereof with an anti-Tim3 antibody or antigen binding fragment thereof and an anti-Lag3 antibody or antigen binding fragment thereof as disclosed herein provides an unexpected synergistic efficacy in enhancing an immune response, such as cytokine release.
  • the combination of an anti-PD1 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, such as Tislelizumab) 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: 10, (b) HCDR2 of SEQ ID NO: 11, and (c) HCDR3 of SEQ ID NO: 12; and a light chain variable region comprising (d) LCDR1 of SEQ ID NO: 13, (e) LCDR2 of SEQ ID NO:
  • Figure 1 is a set of graphs showing the increase in surface Lag3 expression in CD3+T cells from two independent donors (Figure 1A &B) after treatment with indicated concentrations of anti-PD1 antibody BGB-A317, or a combination of BGB-A317 and an anti-Tim3 antibody BGB-A425 in a 5-day Staphylococcal enterotoxin B (SEB) stimulation assay.
  • SEB Staphylococcal enterotoxin B
  • Figure 2 is a set of graphs showing the IFN- ⁇ levels produced by PBMCs from two independent donors ( Figure 2A &B) after treatment with indicated concentrations of anti-PD1 antibody BGB-A317, a combination of BGB-A317 and anti-Tim3 antibody BGB-A425, a combination of BGB-A317 and anti-Lag3 antibody BGA-1953 or a combination of antibodies BGB-A317, BGB-A425 and BGA-1953 in a 5-day Staphylococcal enterotoxin B (SEB) stimulation assay.
  • SEB Staphylococcal enterotoxin B
  • FIG. 3 shows MC38 xenograft tumor growth curve in B6-hLag3 mice under different treatments.
  • the mice were randomized into 6 groups according to tumor volume.
  • the mice were treated with vehicle (PBS) , anti-mouse PD1 antibody Ch15mt, the combination of Ch15mt and anti-human Lag3 antibody BGA-1953, the combination of Ch15mt and anti-mouse Tim3 antibody RMT3-23, the combination of BGA-1953 and RMT3-23, or the combination of Ch15mt, BGA-1953 and RMT3-23.
  • the tumor volumes were plotted to Day 26 after tumor implantation. Data were presented as mean tumor volume ⁇ standard error of the mean of 15 animals.
  • One-way ANOVA was used to analyze logarithmic transformed tumor volume data, *p ⁇ 0.05, **p ⁇ 0.01, ***p ⁇ 0.001, ****p ⁇ 0.0001.
  • Figure 4 shows there is no significant impact on animal body weight during treatment. Mouse body weight were measured twice weekly. Data were presented as mean body weight ⁇ standard error of the mean of 15 animals in each group.
  • Figure 5A shows a phase 2 (safety lead-in) study for LBL-007 + Tislelizumab (cohort A) and BGB-A425 + LBL-007 + Tislelizumab (cohort B) .
  • Figure 5B shows a phase 2 (dose expansion) study for LBL-007 + Tislelizumab (cohorts 6 and 7) and BGB-A425 + LBL-007 +Tislelizumab (cohorts 4-5) .
  • Figure 6 shows best change (%) from Baseline in Sum of Diameters per Investigator Assessment (RECIST1.1) for Phase 2 Safety Lead-in Cohorts (BGB-A425 + LBL-007 + BGB-A317) .
  • Best Overall Response observed: 1 partial response in pancreatic ductal adeno carcinoma; 8 stable disease (SD) , and 5 progressive disease (PD) including a PD with target lesions not evaluated (not shown) , and 1 NE (the first and the only response of SD was assessed on Day 23, which is less than the minimum requirement of SD duration (35 days) , hence the BOR is NE as of the data cut) .
  • Figure 7 shows duration of Treatment and Response by Investigator per RECIST 1.1 for Phase 2 Safety Lead-in Cohorts (BGB-A425 + LBL-007 + BGB-A317) .
  • Figure 8 shows best change (%) from Baseline in Sum of Diameters per Investigator Assessment (RECIST1.1) for Phase 2 Safety Lead-in Cohorts (LBL-007 + BGB-A317) .
  • Best Overall Response (BOR) observed: 1 partial response (PR) in NSCLC, 9 stable disease (SD) , and 6 progressive diseases (PD) were observed at the time last data-cut.
  • Figure 9 shows duration of Treatment and Response by Investigator per RECIST 1.1 for Phase 2 Safety Lead-in Cohorts (LBL-007 + BGB-A317) .
  • 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.
  • administering 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) . In another aspect, “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, CH1, 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.
  • the antibodies can be of any isotype/class (e.g., IgG, IgE, IgM, IgD, IgA and IgY) , or subclass (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) .
  • 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 construed 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 IgG1, IgG2, IgG3, IgG4.
  • a hybridoma 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 ⁇ , ⁇ , ⁇ , ⁇ , or ⁇ , and define the antibody's isotypes as IgA, IgD, IgE, IgG, and IgM, respectively.
  • the 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) .
  • 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. (ed.
  • 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., 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 CDR
  • sequences of Proteins of Immunological Interest 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md.
  • 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) .
  • 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 folds 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 variable region amino 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 -l ) . 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 10 - 7 or 10 -8 M, for example, less than about 10 -9 M or 10 -10 M, in some aspects, less than about 10 - 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.
  • combination 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 co-administration 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
  • 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.
  • W word length
  • E expectation
  • B B- 50
  • E expectation
  • 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 system.
  • 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-PD1 antibody, anti-Tim3 antibody or anti-Lag3 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 physiologically 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., 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.
  • terapéuticaally effective amount 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 symptoms 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-PD1 antibody is administered to the subject at the same time as, before, or after administration of an anti-Lag3 antibody and/or anti-Tim3 antibody.
  • the administration of these antibodies could be simultaneously or sequentially.
  • Anti-Lag3 antibodies of the disclosure can be found in US10, 844, 121, WO2019/011306 or Table 3 below.
  • anti-Lag3 antibody comprising an antibody antigen binding domain which specifically binds human Lag3, and comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) : HCDR1 of SEQ ID NO: 21, HCDR2 of SEQ ID NO: 22, and HCDR3 of SEQ ID NO: 23; and a light chain variable region (VL) comprising: LCDR1 of SEQ ID NO: 24, LCDR2 of SEQ ID NO: 25, and LCDR3 of SEQ ID NO: 26.
  • VH heavy chain variable region
  • CDRs complementarity determining regions
  • the anti-Lag3 antibody comprises an antibody antigen binding domain which specifically binds human Lag3, and comprises a heavy chain variable region (VH) comprising an amino acid sequence of SEQ ID NO: 27 and a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 28.
  • VH heavy chain variable region
  • VL light chain variable region
  • the anti-Lag3 antibody or antigen binding fragment thereof comprises a variant heavy chain constant region of human IgG4.
  • the anti-Lag3 antibody comprises a heavy chain having at least 95%, 96%, 97%, 98%, 99%or 100%sequence identity with the amino acid sequence of SEQ ID NO: 29. In some embodiments, the anti-Lag3 antibody comprises a light chain having at least 95%, 96%, 97%, 98%, 99%or 100%sequence identity with the amino acid sequence of SEQ ID NO: 30. In some embodiments, the anti-Lag3 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 29, and a light chain comprising the amino acid sequence of SEQ ID NO: 30.
  • anti-Lag3 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-Lag3 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. 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.
  • PD1 antibodies found, for example, in US Patent No: 8, 735, 553 or Table 1 below.
  • PD1 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-PD1 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-PD1 antibody comprises an IgG4 constant domain comprising SEQ ID NO: 9.
  • anti-PD1 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-PD1 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. 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.
  • T-cell immunoglobulin domain and mucin domain 3 (Tim3, HAVCR2, or CD366) is a 33 KD type I 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.
  • 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: 10, HCDR2 of SEQ ID NO: 11, and HCDR3 of SEQ ID NO: 12; and a light chain variable region (VL) comprising: LCDR1 of SEQ ID NO: 13, LCDR2 of SEQ ID NO: 14, and LCDR3 of SEQ ID NO: 15.
  • 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: 16 and a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 17.
  • 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 IgG1 comprising the amino sequence of SEQ ID NO: 18, and a human kappa light chain constant region.
  • the anti-Tim3 antibody comprises a heavy chain having at least 95%, 96%, 97%, 98%, 99%or 100%sequence identity with the amino acid sequence of SEQ ID NO: 19. In some embodiments, the anti-Tim3 antibody comprises a light chain having at least 95%, 96%, 97%, 98%, 99%or 100%sequence identity with the amino acid sequence of SEQ ID NO: 20. In some embodiments, the anti-Tim3 antibody comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO: 19, and a light chain comprising the amino acid sequence of SEQ ID NO: 20.
  • 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. 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.
  • the present disclosure provides a method of cancer treatment, the method comprising administering to a patient an effective amount of an anti-Lag3 antibody or antigen binding fragment thereof, in combination with any other therapeutical agents, such as an anti-PD1 antibody or antigen-binding fragment thereof, an anti-Tim3 antibody or antigen binding fragment thereof, any other checkpoint inhibitor, and/or one or more chemotherapy agents.
  • any other therapeutical agents such as an anti-PD1 antibody or antigen-binding fragment thereof, an anti-Tim3 antibody or antigen binding fragment thereof, any other checkpoint inhibitor, and/or one or more chemotherapy agents.
  • the amount of said anti-Lag3 antibody or antigen binding fragment thereof is 100 -1200 mg (such as 200 mg, 300 mg, 400 mg, 500mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, or 1200 mg) , preferentially 300-1200mg, 300-900mg, 300-600mg, 600-1200mg, 600-900mg, or 900-1200mg, more preferentially 500-700mg, 700-900mg, 800-1000mg, 1100-1300mg, more preferentially 550-650mg, 850-950mg, 1150-1250mg, or more preferentially 300mg, 600mg, 900mg, or 1200mg.
  • the anti-Lag3 antibody or antigen binding fragment thereof specifically binds to human Lag3 and comprises a heavy chain variable region that comprises (a) HCDR1 of SEQ ID NO: 21, (b) HCDR2 of SEQ ID NO: 22, and (c) HCDR3 of SEQ ID NO: 23; and a light chain variable region that comprises (d) LCDR1 of SEQ ID NO: 24, (e) LCDR2 of SEQ ID NO: 25, and (f) LCDR3 of SEQ ID NO: 26.
  • the anti-Lag3 antibody or antigen-binding fragment thereof specifically binds to human Lag3 and comprises a heavy chain variable region (VH) comprising an amino acid sequence of SEQ ID NO: 27 and a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 28.
  • VH heavy chain variable region
  • VL light chain variable region
  • the anti-PD1 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-PD1 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-PD1 antibody or antigen-binding fragment thereof comprises an IgG4 constant domain comprising any of SEQ ID NO: 9.
  • 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: 10, (b) HCDR2 of SEQ ID NO: 11, and (c) HCDR3 of SEQ ID NO: 12; and a light chain variable region comprising (d) LCDR1 of SEQ ID NO: 13, (e) LCDR2 of SEQ ID NO: 14, and (f) LCDR3 of SEQ ID NO: 15.
  • 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: 16 and a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 17.
  • 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 IgG1 comprising one or more mutations selected from a group consisting of E233P, L234A, L235A, L236 ⁇ and P329A.
  • the anti-Tim3 antibody or antigen binding fragment thereof comprises a variant heavy chain constant region of human IgG1 comprising the amino sequence of SEQ ID NO: 18, and a human kappa light chain constant region.
  • the 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 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 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 triple-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. In another embodiment, the cancer is endometrial cancer. In another embodiment, the cancer is a cancer having microsatellite instability high (MSI-H) .
  • MSI-H microsatellite instability high
  • 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 Scc, 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 is pancreatic adenocarcinoma.
  • the cancer is any of non-small cell lung cancer, breast carcinoma, melanoma, ethmoid SCC, invasive ductal carcinoma of breast, gastric or gastroesophageal junction carcinoma, colorectal cancer, granulosa cell ovarian cancer.
  • the cancer is NSCLC. In another embodiment, the cancer is any of head and neck squamous cell cancer, cholangio carcinoma, ovarian/fallopian tube, head and neck squamous cell cancer, endometrium, renal cell carcinoma, non-small cell lung cancer, urothelial carcinoma, cervical cancer.
  • the cancer treatment is a front-line treatment. In another embodiment, the cancer treatment is a later-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-PD1 antibody or anti-PD-L1 antibody or antigen-binding fragment thereof. In another embodiment, 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-PD1/PD-L1 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 different therapeutical agents including antibodies and chemotherapeutic agents, are administered simultaneously or are administered sequentially.
  • the method comprises administering every 3 weeks to a patient 200 mg of 100 -1200 mg (such as 200 mg, 300 mg, 400 mg, 500mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, or 1200 mg) of the anti-Lag3 antibody or antigen binding fragment thereof in combination with 200 mg-1200 mg (such as 200 mg, 400 mg, 600 mg, 800 mg, 1000 mg, or 1200 mg) of the anti-Tim3 antibody or antigen binding fragment thereof and the anti-PD1 antibody or antigen-binding fragment thereof.
  • 100 -1200 mg such as 200 mg, 300 mg, 400 mg, 500mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, or 1200 mg
  • 200 mg-1200 mg such as 200 mg, 400 mg, 600 mg, 800 mg, 1000 mg, or 1200 mg
  • the anti-PD1 antibody or antigen-binding fragment thereof could be administered at a dose of 200 mg every 3 weeks.
  • the anti-Lag3 antibody or antigen binding fragment thereof could be administered at a dose of 300 mg-1200 mg once every 1 week, 2 weeks, 3 weeks or 1 month. In one embodiment, the anti-Lag3 antibody or antigen binding fragment thereof could be administered at a dose of 300 mg-1200 mg once every 3 weeks.
  • the anti-Lag3 antibody or antigen binding fragment thereof could be administered at a dose of 400 mg -1200 mg or 500 mg -1200 mg once every 1 week, 2 weeks, 3 weeks or 1 month. In one embodiment, the anti-Lag3 antibody or antigen binding fragment thereof could be administered at a dose of 400 mg -1200 mg or 500 mg -1200 mg once every 3 weeks.
  • the anti-Lag3 antibody or antigen binding fragment thereof could be administered at a dose of 500 mg -1200 mg or 600 mg -1200 mg once every 1 week, 2 weeks, 3 weeks or 1 month. In one embodiment, the anti-Lag3 antibody or antigen binding fragment thereof could be administered at a dose of 500 mg -1200 mg or 600 mg -1200 mg once every 3 weeks.
  • the anti-Lag3 antibody or antigen binding fragment thereof could be administered at a dose of 500 mg -700 mg once every 1 week, 2 weeks, 3 weeks or 1 month. In one embodiment, the anti-Lag3 antibody or antigen binding fragment thereof could be administered at a dose of 500 mg -700 mg once every 3 weeks.
  • the anti-Lag3 antibody or antigen binding fragment thereof could be administered at a dose of 550 mg -750 mg, 550 mg -650 mg, 550 mg -700 mg, or 500 mg -650 mg once every 1 week, 2 weeks, 3 weeks or 1 month. In one embodiment, the anti-Lag3 antibody or antigen binding fragment thereof could be administered at a dose of 550 mg -750 mg, 550 mg -650 mg, 550 mg -700 mg, or 500 mg -650 mg once every 3 weeks.
  • the anti-Lag3 antibody or antigen binding fragment thereof could be administered at a dose of 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 or 1200 mg once every 1 week, 2 weeks, 3 weeks or 1 month.
  • the anti-Lag3 antibody or antigen binding fragment thereof could be administered at a dose of 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 or 1200 mg once every 3 weeks.
  • the anti-Lag3 antibody or antigen binding fragment thereof could be 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-Lag3 antibody or antigen binding fragment thereof could be 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-Lag3 antibody or antigen binding fragment thereof is administered at a dose of 300 mg once every 3 weeks. In another embodiment, the anti-Lag3 antibody or antigen binding fragment thereof are administered at a dose of 500 mg once every 3 weeks. In another embodiment, the anti-Lag3 antibody or antigen binding fragment thereof is administered at a dose of 550 mg once every 3 weeks. In another embodiment, the anti-Lag3 antibody or antigen binding fragment thereof are administered at a dose of 600 mg once every 3 weeks. In another embodiment, the anti-Lag3 antibody or antigen binding fragment thereof is administered at a dose of 650 mg once every 3 weeks. In another embodiment, the anti-Lag3 antibody or antigen binding fragment thereof are administered at a dose of 700 mg once every 3 weeks. In another embodiment, the anti-Lag3 antibody or antigen binding fragment thereof is administered at a dose of 750 mg once every 3 weeks.
  • the anti-Lag3 antibody or antigen binding fragment thereof is administered at a dose of 550 mg once every 3 weeks. In another embodiment, the anti-Lag3 antibody or antigen binding fragment thereof is administered at a dose of 560 mg once every 3 weeks. In another embodiment, the anti-Lag3 antibody or antigen binding fragment thereof is administered at a dose of 570 mg once every 3 weeks. In another embodiment, the anti-Lag3 antibody or antigen binding fragment thereof is administered at a dose of 580 mg once every 3 weeks. In another embodiment, the anti-Lag3 antibody or antigen binding fragment thereof is administered at a dose of 590 mg once every 3 weeks. In another embodiment, the anti-Lag3 antibody or antigen binding fragment thereof is administered at a dose of 600 mg once every 3 weeks.
  • the anti-Lag3 antibody or antigen binding fragment thereof is administered at a dose of 610 mg once every 3 weeks. In another embodiment, the anti-Lag3 antibody or antigen binding fragment thereof is administered at a dose of 620 mg once every 3 weeks. In another embodiment, the anti-Lag3 antibody or antigen binding fragment thereof is administered at a dose of 630 mg once every 3 weeks. In another embodiment, the anti-Lag3 antibody or antigen binding fragment thereof is administered at a dose of 640 mg once every 3 weeks. In another embodiment, the anti-Lag3 antibody or antigen binding fragment thereof is administered at a dose of 650 mg once every 3 weeks. In another embodiment, the anti-Lag3 antibody or antigen binding fragment thereof is administered at a dose of 660 mg once every 3 weeks.
  • the anti-Lag3 antibody or antigen binding fragment thereof is administered at a dose of 670 mg once every 3 weeks. In another embodiment, the anti-Lag3 antibody or antigen binding fragment thereof is administered at a dose of 680 mg once every 3 weeks. In another embodiment, the anti-Lag3 antibody or antigen binding fragment thereof is administered at a dose of 690 mg once every 3 weeks. In another embodiment, the anti-Lag3 antibody or antigen binding fragment thereof is administered at a dose of 700 mg once every 3 weeks.
  • the anti-Tim3 antibody or antigen binding fragment thereof could be 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 could be 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 is administered at a dosage of 400 mg, 600 mg, or 800 mg once every 3 weeks. In one embodiment, 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. In one embodiment, 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.
  • the method comprises administering every 3 weeks to a patient 200 mg of the anti-PD1 antibody or antigen-binding fragment thereof in combination with 600 mg of the anti-Tim3 antibody or antigen binding fragment thereof and 600 mg of the anti-Lag3 antibody or antigen binding fragment thereof.
  • 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.
  • Various dosing schedules including but not limited to single or multiple administrations over various time-points, 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 ⁇ g/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 ⁇ g/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-Lag3 antibody or antigen binding fragment thereof, in combination with any other therapeutical agents, such as an anti-PD1 antibody or antigen-binding fragment thereof, an anti-Tim3 antibody or antigen binding fragment thereof, and/or chemotherapy agents.
  • the amount of said anti-Lag3 antibody or antigen binding fragment thereof is 100 -1200 mg (such as 200 mg, 300 mg, 400 mg, 500mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, or 1200 mg) , preferentially 300-1200mg, 300-900mg, 300-600mg, 600-1200mg, 600-900mg, or 900-1200mg, more preferentially 500-700mg, 700-900mg, 800-1000mg, 1100-1300mg, more preferentially 550-650mg, 850-950mg, 1150-1250mg, or more preferentially 300mg, 600mg, 900mg, or 1200mg.
  • 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 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.
  • 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 patients is immune suppressed.
  • the combination therapy of anti-PD1 antibody, anti-Tim3 antibody and anti-Lag3 antibody results in enhancement of anti-cancer immunity or anti-virus infection immunity.
  • section 2.1 for the antibodies and the administration (such as dosing) of the PD1 antibodies or antigen binding fragments thereof in combination with anti-Tim3 antibodies and anti-Lag3 antibodies or antigen binding fragments thereof in the method of enhancing an immune response.
  • the present disclosure provides a use of an effective amount of an anti-PD1 antibody or antigen-binding fragment thereof in combination with an anti-Tim3 antibody or antigen binding fragment thereof and an anti-Lag3 antibody or antigen binding fragment thereof in the manufacture of a medicament for cancer treatment or enhancing an immune response.
  • the present disclosure provides an effective amount of an anti-PD1 antibody or antigen-binding fragment thereof in combination with an anti-Tim3 antibody or antigen binding fragment thereof and an anti-Lag3 antibody or antigen binding fragment thereof for use in cancer treatment or enhancing an immune response.
  • compositions including pharmaceutical formulations, comprising an anti-PD1 antibody or antigen-binding fragment, an anti-Tim3 antibody or antigen binding fragment or an anti-Lag3 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 pharmaceutically acceptable excipients including buffers, which are well known in the art.
  • compositions 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 16 th edition, Osol, A. Ed. (1980) ) , in the form of lyophilized formulations or aqueous solutions.
  • 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 as glycine, glutamine, asparagine, histidine,
  • 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 WO2006/044908, 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:
  • Example 2 Study on anti-PD1, anti-Tim3 and anti-Lag3 triple combination
  • Example 2.1 Increased Lag3 expression on CD3+ T cells induced by anti-PD1 antibody, the combination of anti-PD1 and anti-Tim3 antibodies in SEB stimulation assay
  • the PBMCs from two different donors were pre-stimulated by SEB with a final concentration of 2 ng/ml for 3 days.
  • the pre-stimulated PBMCs were collected and re-stimulated with 2 ng/ml SEB for another 2 days in the presence of BGB-A317, or the dual combination of BGB-A317 and BGB-A425.
  • BGB-A317 group BGB-A317 was added and tested at concentrations of 0.3, 0.1, 0.03, 0.01 ug/ml.
  • BGB-A425 was added and tested at concentrations of 10, 2, 0.4, 0.08 ug/ml on top of 0.3 ug/ml BGB-A317.
  • the cells were harvested, and the surface expression of Lag3 was detected by flow cytometry with an anti-Lag3 antibody.
  • the VH and VL of anti-PD1 antibody BGB-A317 are set forth in Table 1.
  • the VH and VL of anti-Tim3 antibody BGB-A425 are set forth in Table 2.
  • Figure 1A and Figure 1B show the effect of BGB-A317, and the combination of BGB-A317 and BGB-A425 on the surface expression of Lag3 on T cells in the SEB stimulation assay in two different human donors.
  • Anti-PD1 antibody BGB-A317 dose dependently increased surface Lag3 expression on T cells in the SEB stimulation assay.
  • the combination of BGB-A317 and anti-Tim3 antibody BGB-A425 further increased surface Lag3 expression in both donors.
  • anti-PD1 and anti-Tim3 antibodies increased the surface expression of Lag3, the effect of the dual combinations of anti-PD1 and anti-Lag3, the dual combination of anti-PD1 and anti-Tim3, and the triple combination of anti-PD1, anti-Tim3 and anti-Lag3 were further investigated.
  • Example 2.2 Enhanced in-vitro T cells activation by anti-PD1, anti-Tim3 and anti-Lag3 triple combination in Staphylococcal enterotoxin B (SEB) stimulation assay
  • This example demonstrates that administration of PD1, Tim3 and Lag3 using the anti-PD1 antibody BGB-A317, the anti-Tim3 antibody BGB-A425 and the anti-Lag3 antibody BGA-1953 enhances IFN- ⁇ secretion in the SEB stimulation assay.
  • the VH and VL of anti-PD1 antibody BGB-A317 are set forth in Table 1.
  • the VH and VL of anti-Tim3 antibody BGB-A425 are set forth in Table 2.
  • the VH and VL of anti-Lag3 antibody BGA-1953 are set forth in Table 3.
  • PBMCs from two different healthy human donors were stimulated with SEB to induce T-cell activation as measured by increase in IFN- ⁇ production and secretion.
  • the PBMCs from two different donors were pre-stimulated by SEB with a final concentration of 2 ng/ml for 3 days.
  • the pre-stimulated PBMCs were collected and re-stimulated with 2 ng/ml SEB for another 2 days in the presence of BGB-A317, the dual combinations of BGB-A317/BGB-A425 or BGB-A317/BGA-1953, and the triple combination of BGB-A317/BGB-A425/BGA-1953.
  • BGB-A317 group BGB-A317 was added and tested at concentrations of 0.3, 0.1, 0.03, 0.01 ug/ml.
  • BGB-A317/BGB-A425 BGA-1953 were added and tested at concentrations of 10, 2, 0.4, 0.08 ug/ml on top of 0.3 ug/ml BGB-A317.
  • BGA-1953 were added and tested at concentrations of 10, 2, 0.4, 0.08 ug/ml on top of 0.3 ug/ml BGB-A317.
  • BGA-1953 were added and tested at concentrations of 10, 2, 0.4, 0.08 ug/ml on top of 0.3 ug/ml BGB-A317 and 10 ug/ml BGB-A425.
  • Supernatants were harvested and IFN- ⁇ levels were determined by enzyme-linked immunosorbent assay (ELISA) .
  • the triple combination of anti-PD1/anti-Tim3/anti-Lag3 antibodies BGB-A317/BGB-A425/BGA-1953 further significantly enhanced T cell activation by significantly further increasing IFN- ⁇ secretion, much higher in comparison with either dual combination of BGB-A317/BGB-A425 or BGB-A317/BGA-1953.
  • BGB-A425 and BGA-1953 to the triple combination group (e.g., 0.3 ug/ml BGB-A317+10 ug/ml BGB-A425+10 ug/ml BGA-1953) is significantly higher than the contribution of BGB-A425 to the dual combination group (e.g., 0.3 ug/ml BGB-A317+10 ug/ml BGB-A425) or the contribution of BGA-1953 to the dual combination group (e.g., 0.3 ug/ml BGB-A317+10 ug/ml BGA-1953) , which is an unexpected synergistic result.
  • Example 2.3 Synergistic efficacy in the triple combination of anti-PD1, anti-Tim3 and anti-Lag3 on tumor growth in the MC38 syngeneic model in human Lag3 knock-in mice
  • This example demonstrates that triple blockade of PD1, Lag3 and Tim3 using the anti-mouse PD1 antibody ch15mt (BGB-A317 mouse surrogate) , anti-human Lag3 antibody BGA-1953 and anti-mouse Tim3 antibody RMT3-23 showed enhanced antitumor efficacy in MC38 model in human Lag3 knock-in mice.
  • MC38 a mouse colon cancer cell line, was obtained from Kerafast (Cat#ENH204-FP) .
  • Human Lag3 knock-in mice (B6-hLag3 mice) were purchased from Biocytogen Co., Ltd (Cat #110025) .
  • the anti-mouse Tim3 antibody (RMT3-23) was purchased from Bioxcell (New Hampshire Cat #BP0115) .
  • mice Female B6-hLag3 mice were subcutaneously implanted with 1 ⁇ 10 6 MC38 cells in 100 ⁇ L PBS into the right flank of the mouse. On day 8 after cell inoculation, when the average tumor volume reached 80 mm 3 , the mice were randomly assigned into 6 groups, with 15 mice per group. Mice were treated with vehicle (PBS) , anti-mouse PD1 antibody Ch15mt, the combination of Ch15mt and anti-human Lag3 antibody BGA-1953, the combination of Ch15mt and anti-mouse Tim3 antibody RMT3-23, the combination of BGA-1953 and RMT3-23, or the combination of Ch15mt, BGA-1953 and RMT3-23.
  • vehicle PBS
  • anti-mouse PD1 antibody Ch15mt the combination of Ch15mt and anti-human Lag3 antibody BGA-1953
  • the combination of Ch15mt and anti-mouse Tim3 antibody RMT3-23 antibody RMT3-23 the combination of BGA-1953 and RMT3-23, or
  • Ch15mt was administered at 0.5 mg/kg (mpk) once per week (QW) by intraperitoneal (i. p. ) injection.
  • BGA-1953 was administered at 3 mpk twice per week (BIW) by i. p injection.
  • RMT3-23 was administered at 10 mpk BIW by i. p. injection.
  • the treatment duration was 19 days.
  • FIG. 3 and Table 4 shows the tumor growth inhibition and ratio of tumor free by each treatment in the MC38 model.
  • the triple combination of Ch15mt, BGA-1953 and RMT3-23 group showed enhanced tumor growth inhibition compared to either dual combination or monotherapy group.
  • the triple combination treatment resulted in a TGI of 89.67%, which was the highest TGI noted.
  • the TGI using Ch15mt as a single agent was 60.36%.
  • the TGI using the dual combination of Ch15mt/BGA-1953 was 74.08%.
  • the TGI using the dual combination of Ch15mt/RMT3-23 was 67.63%.
  • the dual combination of BGA-1953/RMT3-23 produced the lowest TGI of only 24.16%.
  • the study is an open-label, multicenter, nonrandomized Phase 1 and 2 clinical study evaluating combinations of BGB-A425 (Surzebiclimab) and BGA-1953 (also coded LBL-007) with Tislelizumab. Part of the study design schematic is presented in Figure 5A and Figure 5B.
  • the sequences of anti-PD1 antibody BGB-A317 are set forth in Table 1.
  • the sequences of anti-Tim3 antibody BGB-A425 are set forth in Table 2.
  • the sequences of anti-Lag3 antibody BGA-1953 are set forth in Table 3.
  • Priority enrollment for Phase 2 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 2 (dose expansion) : The combination treatments would be evaluated in patients with various tumor types including HNSCC, NSCLC and RCC, including
  • All patients enrolled in Phase 2 dose expansion must have disease progression that occurred ⁇ 10 weeks from the initiation of anti-PD1/PDL1 treatment for locally advanced or metastatic disease (i.e., prior PD1/PDL1 immune oncology treatment failed) . All eligible patients would receive the combination every 21 days starting on Cycle 1 Day 1. Positive PD L1 expression from either local or central testing would be required in HNSCC and NSCLC patients in all dose expansion cohorts prior to enrollment. For baseline tumor tissue, fresh biopsy will be mandatory in the absence of sufficient archival tissue prior to the patient commencing first drug administration on Cycle 1 Day 1.
  • a 21-day treatment cycle is planned for all of Phase 2 including Phase 2 safety lead-in.
  • the recommend dose (s) for 2 combinations (BGB-A425 + LBL-007 + Tislelizumab and LBL-007 + Tislelizumab) in Phase 2 dose expansion (Cohorts 4 to 7) would be determined based on safety, tolerability, preliminary antitumor activity, pharmacodynamic biomarker, and PK data in Phase 2 safety lead-in.
  • Phase 2 (safety lead-in) data for Cohort B (BGB-A425 + LBL-007 + Tislelizumab) cohorts are shown in Table 5 and Figures 6 and 7.
  • SD stable disease in non-small cell lung cancer, breast carcinoma, melanoma, ethmoid scc, invasive ductal carcinoma of breast, gastric or gastroesophageal junction carcinoma, colorectal cancer, granulosa cell ovarian cancer; and
  • Pancreatic adenocarcinoma (MSI-high) patient is 58 years old female; the patient received 5-FU, oxaliplatin, and irinotecan for 5 months before entering the study. At week 6 imaging, 43.8%tumor reduction was observed. At the time of data cutoff (July 10, 2023) , the pancreatic cancer patient is maintaining the PR and receiving the treatment.
  • Table 5 Summary of patients in safety lead-in Cohort B (BGB-A425 + LBL-007 + Tislelizumab) .
  • Phase 2 (safety lead-in) data for Cohort A (LBL-007 + Tislelizumab) cohorts are shown in Table 6 and Figures 8 and 9.
  • SD stable disease in head and neck squamous cell cancer, cholangio carcinoma, ovarian/fallopian tube, head and neck squamous cell cancer, endometrium, renal cell carcinoma, non-small cell lung cancer, urothelial carcinoma, cervical cancer; and
  • the NSCLC patient is 78 years old male, with positive PD-L1 expression and Patient had received 2 Lines of systemic therapy including anti-PD-1 immunotherapy as one of the prior lines. Following week 12 imaging, 30.8%tumor reduction was observed. At the time of data cutoff (July 10, 2023) , the NSCLC patient is maintaining the PR and receiving the treatment.
  • Table 6 Summary of patients in safety lead-in Cohort A (LBL-007 + Tislelizumab) .
  • the combination treatments include the following cohorts (a21-day treatment cycle) :
  • Example 4 Overall study design of a randomized, Phase 2, open-label, multi-arm study of Tislelizumab in combination with BGB-A425 and BGA-1953 as first-line treatment in Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma
  • the dosing schedule for each arm is shown in Table 7-Table 10.
  • Table 8 Arm 1 Tislelizumab+BGB-A425
  • eligible patients After completing all screening activities, eligible patients would be randomized at a ratio of 1: 1 to each of the experimental arms and the reference arm, respectively.
  • Tumor response will be assessed by investigators using standard RECIST v1.1 criteria.
  • Tumor imaging computed tomography [CT] with or without contrast and/or magnetic resonance imaging [MRI]
  • CT computed tomography
  • MRI magnetic resonance imaging
  • On-study tumor assessments will occur every 6 weeks ( ⁇ 7 days) from randomization for the first 52 weeks and then every 12 weeks ( ⁇ 7 days) thereafter. Tumor assessments should continue until disease progression, as determined by the investigator. Patients who discontinue study treatment early for reasons other than disease progression (e.g., toxicity) will continue to undergo tumor assessments following the original plan until the patient experiences disease progression, dies, withdraws consent, is lost to follow-up, or until the study terminates, whichever occurs first.
  • CT computed tomography
  • MRI magnetic resonance imaging
  • the eligible primary tumor locations are oropharynx, oral cavity, hypopharynx, and larynx.
  • Recurrent or metastatic carcinoma of the nasopharynx (any histology) , squamous cell carcinoma of unknown primary, squamous cell carcinoma that originated from the skin and salivary gland primary tumor or nonsquamous histologies (eg, mucosal melanoma) .
  • curatively eg, resected basal or squamous cell skin cancer, superficial bladder cancer, localized prostate cancer, and carcinoma in situ of the cervix or breast
  • Example 5 A Phase 1b/2, Randomized, Open-Label Study Investigating the Efficacy and Safety of LBL-007 Plus Tislelizumab in Combination With Bevacizumab Plus Capecitabine Versus Bevacizumab Plus Capecitabine as Maintenance Therapy in Patients With Unresectable or Metastatic Microsatellite Stable/Mismatch Repair Proficient Colorectal Cancer (NCT05609370)
  • Phase 1b Number of participants with Adverse events (AE) and Serious AEs (SAE) [Time Frame: First Cycle of treatment (21 days) ] AEs and SAE are characterized by type, frequency, severity (as graded by National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 [NCI-CTCAE v5.0] )
  • PFS Progression Free Survival
  • OS is defined as the time from the date of randomization until the date of death from any cause.
  • Phase 2 PFS 2 as Assessed by The Investigator in PD-L1 Positive Arms A and C and PD-L1 Negative Arms D and E [Time Frame: Approximately 27 months ]
  • PFS2 is defined as the time from the date of randomization to the date of documentation of disease progression in second-line treatment, or death, whichever occurs first
  • ORR Objective Response rate as Assessed by The Investigator in PD-L1 Positive Arms A and C and PD-L1 Negative Arms D and E [Time Frame: Approximately 27 months ] ORR is defined as the proportion of participants with a confirmed complete response (CR) or partial response (PR) from the time of randomization
  • Phase 2 Duration of response (DOR) as Assessed by The Investigator in PD-L1 Positive Arms A and C and PD-L1 Negative arms D and E [Time Frame: Approximately 27 months ]
  • DOR is defined as the time from the first confirmed objective response after randomization until the first documentation of disease progression or death, whichever comes first
  • Phase 2 Progression Free Survival (PFS) as Assessed by The Investigator in PD-L1 Negative Arms D and E [Time Frame: Approximately 27 months ]
  • PFS as assessed by the investigator per RECIST v1.1 is defined as the time from the date of randomization to the date of first documentation of disease progression or death, whichever occurs first
  • Phase 2 Progression Free Survival (PFS) as Assessed by The Investigator in Arms A + D and Arms C + E Regardless of PD-L1 Expression [Time Frame: Approximately 27 months ]
  • PFS as assessed by the investigator per RECIST v1.1 is defined as the time from the date of randomization to the date of first documentation of disease progression or death, whichever occurs first
  • OS is defined as the time from the date of randomization until the date of death from any cause.
  • Phase 2 PFS 2 as Assessed by The Investigator in Arms A + D and Arms C + E Regardless of PD-L1 Expression [Time Frame: Approximately 27 months ]
  • PFS as assessed by the investigator per RECIST v1.1 is defined as the time from the date of randomization to the date of first documentation of disease progression or death, whichever occurs first
  • Phase 2 Objective Response rate (ORR) as Assessed by The Investigator in Arms A + D and Arms C + E Regardless of PD-L1 Expression [Time Frame: Approximately 27 months ]
  • ORR is defined as the proportion of participants with a confirmed complete response (CR) or partial response (PR) from the time of randomization
  • Phase 2 DOR as Assessed by The Investigator in Arms A + D and Arms C + E Regardless of PD-L1 Expression [Time Frame: Approximately 27 months ]
  • DOR is defined as the time from the first confirmed objective response after randomization until the first documentation of disease progression or death, whichever comes first
  • Phase 2 Number of participants with Adverse events (AE) and Serious AEs (SAE) [Time Frame: Up to last dose + 30 days (Approximately 27 months) ]
  • AEs and SAE are characterized by type, frequency, severity as graded by NCI-CTCAE v5.0
  • MSI-H microsatellite instability-high
  • PCR polymerase chain reaction
  • dMMR deficient mismatch repair
  • IHC immunohistochemistry
  • ⁇ Drug Capecitabine (1000 milligrams per square meter (mg/m ⁇ 2) twice daily orally on days 1 to 14 of each 21-day treatment cycle)
  • ⁇ Drug Capecitabine (1000 milligrams per square meter (mg/m ⁇ 2) twice daily orally on days 1 to 14 of each 21-day treatment cycle)
  • ⁇ Drug Capecitabine (1000 milligrams per square meter (mg/m ⁇ 2) twice daily orally on days 1 to 14 of each 21-day treatment cycle)
  • ⁇ Drug Capecitabine (1000 milligrams per square meter (mg/m ⁇ 2) twice daily orally on days 1 to 14 of each 21-day treatment cycle)
  • ⁇ Drug Capecitabine (1000 milligrams per square meter (mg/m ⁇ 2) twice daily orally on days 1 to 14 of each 21-day treatment cycle)
  • ⁇ Drug Capecitabine (1000 milligrams per square meter (mg/m ⁇ 2) twice daily orally on days 1 to 14 of each 21-day treatment cycle)
  • Example 6 A Phase 2, Open-label, Multi-arm Study of Tislelizumab in Combination With Investigational Agents With or Without Chemotherapy in Patients With Previously Untreated, Locally Advanced, Unresectable, or Metastatic Non-Small Cell Lung Cancer (NCT05635708)
  • Sub-study 1 includes participants with non-small cell lung cancer (NSCLC) with high programmed cell death protein ligand-1 (PD-L1) expression ( ⁇ 50%)
  • Sub-study 2 includes participants with NSCLC with low or negative (PD-L1) expression ( ⁇ 50%) .
  • NSCLC non-small cell lung cancer
  • PD-L1 programmed cell death protein ligand-1
  • Phase 1b Number of participants with Adverse events (AE) and Serious AEs (SAE) [Time Frame: First Cycle of treatment (21 days) ] AEs and SAE are characterized by type, frequency, severity (as graded by National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 [NCI-CTCAE v5.0] )
  • Phase 2 Progression Free Survival (PFS) as Assessed by The Investigator in PD-L1 Positive Arms A and C [Time Frame: Approximately 27 months ]
  • PFS as assessed by the investigator per RECIST v1.1 is defined as the time from the date of randomization to the date of first documentation of disease progression or death, whichever occurs first.
  • PFS Progression-free survival
  • PFS is defined as the time from date of randomization, or the first dose for safety lead-in participants, until first documentation of progression or death, whichever comes first, as assessed by the investigator using RECIST v1.
  • DOR is defined as the time from the first determination of a confirmed response per RECIST v1.1 until the first documentation of progression or death, whichever comes first as assessed by the investigator
  • CBR is defined as the percentage of participants with a best overall response of a complete response, partial response, or durable stable disease, as assessed by the investigator using RECIST v1.1
  • DCR is defined as the percentage of participants with a best overall response of complete response, partial response, or stable disease, as assessed by the investigator using RECIST v1.1
  • TEAEs treatment-emergent adverse events
  • SAEs serious adverse events
  • NSCLC nonsquamous or squamous
  • Drug Tislelizumab, 200mg, Administered by intravenous infusion every 3 weeks
  • Drug LBL-007, 600mg, Administered by intravenous infusion every 3 weeks
  • Drug Tislelizumab, 200mg, Administered by intravenous infusion every 3 weeks
  • Drug LBL-007, 600mg, Administered by intravenous infusion every 3 weeks
  • Cisplatin (Investigator's choice; administered by intravenous infusion)
  • Paclitaxel (Investigator's choice; administered by intravenous infusion)
  • Drug Nab paclitaxel (Investigator's choice; administered by intravenous infusion)
  • Sub-study 2 Reference Arm
  • Drug Tislelizumab, 200mg, Administered by intravenous infusion every 3 weeks
  • Cisplatin (Investigator's choice; administered by intravenous infusion)
  • Paclitaxel (Investigator's choice; administered by intravenous infusion)
  • Drug Nab paclitaxel (Investigator's choice; administered by intravenous infusion)
  • Example 7 A Randomized, Open-Label, Multicenter, Phase 2, Umbrella Study to Evaluate the Preliminary Efficacy, Safety, and Pharmacodynamics of Tislelizumab Monotherapy and Multiple Tislelizumab-based Immunotherapy Combinations as Neoadjuvant Treatment in Chinese Patients with Resectable Stage II to IIIA Non-Small Cell Lung Cancer (ClinicalTrials. gov ID NCT05577702)
  • Treatment arms include Arm A (Tislelizumab monotherapy) , Arm B (Tislelizumab in combination with ociperlimab) , and Arm C (Tislelizumab in combination with LBL-007) .
  • MPR pathological response
  • EFS event-free survival
  • OS overall survival
  • DFS disease-free survival
  • Neoadjuvant treatment for resectable Stage II to IIIA non-small cell lung cancer is provided.
  • Study population Patients with resectable, histologically confirmed Stage II to IIIA NSCLC.
  • FFPE block (preferred) or at least 18 freshly cut unstained FFPE slides of the primary tumor for biomarker evaluation during screening. If local results of EGFR mutation status (nonsquamous only) or PD-L1 are not available, 3 additional slides for each testing are required if slides are provided.
  • Any prior antineoplastic therapy (ies) for current lung cancer eg, radiotherapy, targeted therapies, ablation, or other systemic or local antineoplastic treatment
  • Adrenal replacement steroids dose ⁇ 10 mg daily of prednisone or equivalent
  • topical, ocular, intra-articular, intranasal, or inhaled corticosteroid with minimal systemic absorption ⁇ 7 days
  • corticosteroid prescribed prophylactically or for the treatment of a nonautoimmune condition are permitted
  • Severe chronic or active infections requiring systemic antibacterial, antifungal, or antiviral therapy, including tuberculosis infection, etc.
  • Tislelizumab Day 1 of each 3-week cycle, administered as an intravenous infusion
  • Tislelizumab 200mg, Day 1 of each 3-week cycle, administered as an intravenous infusion
  • Ociperlimab 900mg, Day 1 of each 3-week cycle, administered as an intravenous infusion
  • Tislelizumab Day 1 of each 3-week cycle, administered as an intravenous infusion
  • LBL-007 600mg, Day 1 of each 3-week cycle, administered as an intravenous infusion
  • Huard B Prigent P, Tournier M, CD4/major histocompatibility complex class II interaction analyzed with CD4-and lymphocyte activation gene-3 (Lag3) -Ig fusion proteins. Eur J Immunol. 1995; 25 (9) : 2718-21.

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Abstract

La présente invention concerne une méthode de traitement du cancer ou d'amélioration d'une réponse immunitaire, le procédé comprenant l'administration à un patient d'une quantité efficace d'un anticorps anti-Lag3 ou d'un fragment de liaison à l'antigène de celui-ci, seul ou en combinaison avec un ou plusieurs autres agents thérapeutiques.
PCT/CN2023/115065 2022-08-25 2023-08-25 Méthodes de traitement du cancer WO2024041652A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109790218A (zh) * 2016-08-26 2019-05-21 百济神州有限公司 抗tim-3抗体及其用途
CN110621698A (zh) * 2017-04-05 2019-12-27 西福根有限公司 靶向pd-1、tim-3及lag-3的组合疗法
CN110914303A (zh) * 2017-07-13 2020-03-24 南京维立志博生物科技有限公司 结合lag-3的抗体及其用途
CN112457403A (zh) * 2013-09-13 2021-03-09 广州百济神州生物制药有限公司 抗pd1抗体及其作为治疗剂与诊断剂的用途

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CN112457403A (zh) * 2013-09-13 2021-03-09 广州百济神州生物制药有限公司 抗pd1抗体及其作为治疗剂与诊断剂的用途
CN109790218A (zh) * 2016-08-26 2019-05-21 百济神州有限公司 抗tim-3抗体及其用途
CN110621698A (zh) * 2017-04-05 2019-12-27 西福根有限公司 靶向pd-1、tim-3及lag-3的组合疗法
CN110914303A (zh) * 2017-07-13 2020-03-24 南京维立志博生物科技有限公司 结合lag-3的抗体及其用途

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