Combinations and methods of treating solid tumors with anti-BTLA therapy.

Abstract

This disclosure relates to the use of anti-BTLA antagonists (including antibodies and antigen-binding fragments) in combination therapy with other immune checkpoint inhibitor therapies (such as anti-PD-1 or anti-PD-L1), and to a method for selecting patients who require treatment. Preferably, lung cancer is selected from NSCLC and SCLC.

Description

Technical Field

[0001] The present invention relates to combinations and methods for treating solid tumors using anti-BTLA as a combination therapy.

Background Art

[0002] BTLA (B and T lymphocyte attenuator) is a CD28 receptor family member identified in 2003 (Non-Patent Document 1). It is expressed in subpopulations of T lymphocytes, B lymphocytes, and dendritic cells (DCs).

[0003] Herpesvirus entry mediator (HVEM) is a TNF receptor widely expressed in the hematopoietic system and has been identified as a counter-receptor for BTLA (Non-Patent Document 2). HVEM is expressed on T cells, B cells, NK cells, myeloid cells, and dendritic cells, as well as on various tumor cells, including non-small cell lung cancer (NSCLC) (Non-Patent Document 3), melanoma (Non-Patent Document 4), and lymphoma (Non-Patent Documents 5 and 6). Expression of HVEM in tumors is associated with poor prognosis and immune evasion (Non-Patent Documents 7 and 8).

[0004] In several syngeneic mouse models, it has been demonstrated that blockade of the BTLA pathway by mAb can enhance specific T cell responses and inhibit tumor growth. In studies of peripheral blood mononuclear cells (PBMCs) from melanoma patients and NSCLC patients, it has been shown that BTLA is highly expressed in tumor-specific cytotoxic T lymphocytes (CTLs) and inhibits T cell function after binding to HVEM expressed by tumors (Non-Patent Documents 9 and 10).

[0005] From a current immunotherapy perspective, blocking the PD-1 and CTLA-4 pathways with mAbs has demonstrated clinical efficacy against a wide range of human malignancies. However, only a subset of patients benefit from such treatments, and improvements in clinical outcomes with approved PD-1 / PD-L1 and CTLA-4 targeted therapies remain limited (Non-Patent Literature 11). Furthermore, the majority of patients who initially respond eventually develop drug resistance to the treatment, and their disease progresses. Therefore, there is a strong need for superior alternative anti-BTLAmAb immunotherapies aimed at promoting T-cell activation and further enhancing the anti-tumor response in the treatment of human malignancies and solid tumors, including lung cancer. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Watanabe et al., Nat Immunol 4,670-679(2003) [Non-Patent Document 2] Sedy et al., Nat Immunol 6,90-98(2005) [Non-Patent Document 3] Ren et al., Lung Cancer 125, 115-120(2018) [Non-Patent Document 4] Haymaker et al.,Oncoimmunology 4,e1014246(2015) [Non-Patent Document 5] Costello et al., Leukemia 17, 2500-2507(2003) [Non-Patent Document 6] Pasero et al.,Curr Opin Pharmacol 12,478-485(2012) [Non-Patent Document 7] Inoue et al.,Anticancer Res 35,1361-1367(2015) [Non-Patent Document 8] Ren et al., Lung Cancer 125, 115-120(2018) [Non-Patent Document 9] Derre et al., The Journal of clinical investigation 120, 157-167 (2010) [Non-Patent Document 10] Thommen et al., Cancer Immunol Res 3,1344-1355(2015) [Non-Patent Document 11] Chowdhury et al.,J Intern Med 283,110-120(2018) [Overview of the Initiative]

[0007] In one embodiment, the present application discloses a method for treating a solid tumor in a patient in need, the method comprising administering a therapeutically effective amount of an anti-BTLA antibody or its antigen-binding fragment to the patient.

[0008] In another embodiment, the present application discloses a method for treating a solid tumor in a patient in need, the method comprising administering to the patient (i) a therapeutically effective amount of anti-BTLA antibody or its antigen-binding fragment and (ii) a therapeutically effective amount of anti-PD-1 antibody or its antigen-binding fragment, or anti-PD-L1 antibody or its antigen-binding fragment.

[0009] In a further embodiment, the solid tumor treated herein is lung cancer.

[0010] In a further embodiment, the solid tumors treated herein are selected from non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC).

[0011] In another further embodiment, the solid tumor treated herein is extensive-stage small cell lung cancer (ES-SCLC).

[0012] In one embodiment, the present application discloses a method for inhibiting tumor growth in a patient in need, the method comprising co-administering to the patient an effective amount of anti-BTLA antibody or its antigen-binding fragment and an effective amount of anti-PD-1 or its antigen-binding fragment, or anti-PD-L1 antibody or its antigen-binding fragment, wherein the anti-BTLA antibody or its antigen-binding fragment and the anti-PD-1 or anti-PD-L1 or its antigen-binding fragment inhibit tumor growth in the patient.

[0013] In another embodiment, the present application discloses a method for treating lung cancer in a patient in need, the method comprising administering to the patient a therapeutically effective amount of an anti-BTLA antibody or its antigen-binding fragment, optionally, an anti-PD-1 antibody or its antigen-binding fragment, or an anti-PD-L1 antibody or its antigen-binding fragment.

[0014] In another embodiment, the present application discloses a method for treating small cell lung cancer (SCLC) in a patient in need, the method comprising administering to the patient a therapeutically effective dose of an anti-BTLA antibody or its antigen-binding fragment, optionally, an anti-PD-1 antibody or its antigen-binding fragment, or an anti-PD-L1 antibody or its antigen-binding fragment.

[0015] In another embodiment, the present application discloses a method for treating non-small cell lung cancer (NSCLC) in a patient in need, the method comprising administering to the patient a therapeutically effective dose of an anti-BTLA antibody or its antigen-binding fragment, optionally, an anti-PD-1 antibody or its antigen-binding fragment, or an anti-PD-L1 antibody or its antigen-binding fragment.

[0016] In another further embodiment, the present application discloses a method for treating advanced small cell lung cancer (ES-SCLC) in a patient in need, the method comprising administering to the patient a therapeutically effective dose of an anti-BTLA antibody or its antigen-binding fragment, optionally, an anti-PD-1 antibody or its antigen-binding fragment, or an anti-PD-L1 antibody or its antigen-binding fragment.

[0017] In one aspect, the present application discloses a method for treating a solid tumor of a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of an inhibitor that inhibits the interaction between the BTLA receptor and one or more of its ligands.

[0018] In another aspect, the present application discloses a method for inhibiting tumor growth of a patient in need thereof, the method comprising co-administering to the patient an effective amount of an anti-BTLA antibody or an antigen-binding fragment thereof and an effective amount of a chemotherapeutic agent, wherein the anti-BTLA antibody and the chemotherapeutic agent inhibit the tumor growth of the patient, and wherein the anti-BTLA antibody or an antigen-binding fragment thereof inhibits tumor growth by inhibiting the interaction between BTLA and HVEM.

[0019] In one aspect, the present application discloses a method for inhibiting metastatic tumor cells of a patient in need thereof, the method comprising administering to the patient an effective amount of an anti-BTLA antibody or an antigen-binding fragment thereof.

[0020] In another aspect, the present application discloses a method for treating a solid tumor expressing HVEM of a patient in need thereof, the method comprising co-administering to the patient a therapeutically effective amount of an anti-BTLA antibody or an antigen-binding fragment thereof and a therapeutically effective amount of one or more of (i) a chemotherapeutic agent and (ii) an anti-PD-1 or an antigen-binding fragment thereof, or an anti-PD-L1 antibody or an antigen-binding fragment thereof.

[0021] In one aspect, the present application discloses a method for treating a tumor of a subject, the subject being poorly responsive or non-responsive to monotherapy with an anti-PD-1 or an antigen-binding fragment thereof, or an anti-PD-L1 antibody or an antigen-binding fragment thereof, the method comprising administering to the subject an anti-BTLA antibody or an antigen-binding fragment thereof and administering to the subject an anti-PD-1 or an antigen-binding fragment thereof, or an anti-PD-L1 antibody or an antigen-binding fragment thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] [Figure 1] This is a proposed study plan for Phase I / IIb evaluating the combination therapy of TAB004 (also known as icatolimab or tifcemalimab) and tripalimab. [Modes for carrying out the invention]

[0023] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which this disclosure pertains.

[0024] All publications, patents, and patent applications referenced herein are incorporated by reference in the same manner as each individual publication, patent, or patent application is specifically and individually indicated as being incorporated by reference.

[0025] As used herein and in the appended claims, the singular forms “one,” “one kind,” and “the said” include multiple references unless the context otherwise clearly indicates. For example, “one element” means at least one element, and may include two or more elements.

[0026] General definition As used herein, the term “substantially” generally means, when used to change mass, allowing for some degree of change without loss of such mass. For example, in certain embodiments, such degree of change may be less than 0.1%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, 1% to 2%, 2% to 3%, 3% to 4%, 4% to 5%, or more than 5% or 10%.

[0027] When changing the amount (e.g., mg) of a substance or composition or parameter values ​​in a step of a characterization method, the term "about" refers to a change in numerical quantity, which may result from, for example, typical measurement, processing and sampling procedures involved in the preparation, characterization and / or use of the substance or composition, unintentional errors in these procedures, and differences in the manufacture, source and purity of components used to prepare or use the composition or to carry out these procedures. In certain embodiments, "about" may mean a change of ±0.1%, ±0.5%, ±1%, ±2%, ±3%, ±4%, ±5%, ±6%, ±7%, ±8%, ±9%, or ±10%. When referring to a dose of "about 200 mg," the dose may be between 180 mg and 220 mg, 190 mg and 210 mg, 195 mg and 205 mg, 200 mg and 220 mg, or 190 mg and 220 mg. In other embodiments, the dose may be 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, or 220 mg. When "approximately" refers to the amount of time between administrations in a therapeutic treatment regimen (e.g., the amount of time between administrations of an anti-BTLA antibody or its antigen-binding fragment, e.g., "approximately 3 weeks" may be used interchangeably with "approximately every 3 weeks" in this specification), it refers to the specified time ± the patient / clinician schedule and the availability before and after the 3-week target date. For example, "approximately 3 weeks" may mean 3 weeks ± 4 days, 3 weeks ± 3 days, 3 weeks ± 2 days, or 3 weeks ± 1 day, or 2 weeks and 3 days to 3 weeks and 4 days.

[0028] Where a range of values ​​is provided, it should be understood that each intermediate value between the upper and lower limits of that range, and any other specified values ​​or intermediate values ​​within that range, are all included in this disclosure. The upper and lower limits of these smaller ranges may independently be included within the smaller range and are included within this disclosure subject to any specifically excluded limitations within that range. If the range includes one or both of these limits, the range excluding both of the limits that they include is also included in this disclosure.

[0029] As used herein, “anti-BTLA therapy” may mean anti-BTLA monotherapy or anti-BTLA combination therapy. “Anti-BTLA monotherapy” means the use of a BTLA antagonist (e.g., an anti-BTLA antibody or its antigen-binding fragment) alone to treat a patient’s disease or condition without the use of another activating agent or biological component. “Anti-BTLA combination therapy” means the combined administration of a BTLA antagonist (e.g., an anti-BTLA antibody or its antigen-binding fragment) with another activating agent or biological component (e.g., a chemotherapeutic agent or another immune checkpoint inhibitor, e.g., an anti-PD-1 antibody or its antigen-binding fragment) to treat a patient’s disease or condition.

[0030] As used herein, “adjuvant therapy” refers to additional cancer treatment administered after primary treatment to reduce the risk of cancer recurrence. Adjuvant therapy may include chemotherapy, radiotherapy, hormone therapy, targeted therapy, or biological therapy.

[0031] The term “patient” (also referred to herein as “test subject” or “individual”) refers to a mammal (e.g., a rat, mouse, dog, cat, or rabbit), most preferably a human, that can be treated with the methods and compositions relating to this disclosure. In one embodiment, the patient is an adult patient. In another embodiment, the patient is a pediatric patient.

[0032] The terms “cancer,” “tumor,” “malignant,” or “malignant” typically refer to or describe physiological conditions in mammals characterized by unregulated cell growth. Examples of cancer include, but are not limited to, cancer, lymphoma, leukemia, blastoma, and sarcoma. Further specific examples of cancer include, but are not limited to, squamous cell carcinoma, myeloma, small cell lung cancer, non-small cell lung cancer, glioma, Hodgkin lymphoma, non-Hodgkin lymphoma, acute myeloid leukemia (AML), multiple myeloma, gastrointestinal cancer, renal cell carcinoma, ovarian cancer, liver cancer, lymphoblastic leukemia, lymphocytic leukemia, colorectal cancer, endometrial cancer, kidney cancer, prostate cancer, thyroid cancer, melanoma, chondrosarcoma, neuroblastoma, pancreatic cancer, glioblastoma multiforme, cervical cancer, brain cancer, stomach cancer, bladder cancer, hepatocellular carcinoma, breast cancer, colon cancer, and head and neck cancer. Other cancers that can be treated in accordance with this disclosure include cancers characterized by increased expression of one or more of BTLA, HVEM, PD-L1, and PD-L2 in the tested tissue sample.

[0033] As used herein, the term “treatment” means (i) completely or partially inhibiting a disease, illness or symptom, for example, inhibiting its progression; (ii) completely or partially alleviating a disease, illness or symptom, for example, causing the remission of the disease, illness and / or symptom; or (iii) completely or partially preventing the onset of a disease, illness or symptom from a patient who may be susceptible to the disease, illness and / or symptom but has not yet been diagnosed with the disease, illness or symptom. Similarly, “treatment” means therapeutic treatment and preventive or preventive measures.

[0034] As used herein, “treatment” of cancer or tumor means, with or without another agent (e.g., another antibody or antigen-binding fragment or chemotherapeutic agent) administered to a subject who has or has been diagnosed with cancer, achieving at least one positive therapeutic effect, such as a reduction in the number of cancer cells, a reduction in tumor size, a slowing of the rate of cancer cell invasion into peripheral organs, or a slowing of tumor metastasis or tumor growth rate. “Treatment” of cancer or tumor may include inducing / increasing an anti-tumor immune response, reducing the number of one or more tumor markers, stopping or slowing the growth or progression of tumors or hematological malignancies, stabilizing cancerous disease symptoms, inhibiting the growth or survival of tumor cells, eliminating or reducing the size of one or more cancerous lesions or tumors, reducing the level of one or more tumor markers, improving or eliminating the clinical symptoms of cancer, reducing the severity or duration of the clinical symptoms of cancer, extending the patient’s survival compared to the predicted survival of a similar untreated patient, and inducing complete or partial remission of cancerous disease symptoms.

[0035] As used herein, “antibody” refers to any form of antibody, including its full length or fragments, that exhibits desired physiological or binding activity. Therefore, in its broadest sense, and more specifically, it includes, but is not limited to, monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, humanized antibodies, fully human antibodies, chimeric antibodies, fully synthetic antibodies, and single-chain antibodies. Non-human antibodies can be humanized by recombinant methods to reduce their immunogenicity against humans.

[0036] Generally, the basic antibody components consist of a tetramer. Each tetramer contains two pairs of identical polypeptide chains, each pair having one "light" chain (approximately 25 kDa) and one "heavy" chain (approximately 50-70 kDa). The amino-terminal portion of each chain contains a variable region with approximately 100-110 or more amino acids, primarily involved in antigen recognition. The carboxyl-terminal portion of the heavy chain can define a constant region that primarily performs effector functions. Typically, human light chains are divided into κ and λ light chains. Furthermore, human heavy chains are usually divided into μ, δ, γ, α, or ε, and the antibody isotypes are defined as IgM, IgD, IgG, IgA, and IgE, respectively. In the light and heavy chains, the variable and constant regions are linked through a "J" region of approximately 12 or more amino acids, where the heavy chain also contains a "D" region of approximately 10 or more amino acids. The variable region of each light / heavy chain pair forms an antibody binding site. Therefore, generally, a complete antibody has two binding sites. Except for bifunctional or bispecific antibodies, the two binding sites are generally identical.

[0037] Typically, both the heavy and light chain variable domains contain three hypervariable regions located within relatively conserved framework regions (FRs), also known as complementarity-determining regions (CDRs). The CDRs are usually aligned by the framework regions to enable binding to specific epitopes. Generally, from the N-terminus to the C-terminus, both the light and heavy chain variable domains contain FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. Amino acids are typically distributed to each domain according to the definition of an immunologically significant protein sequence. For example, see Kabat Adv. Prot. Chem. 32:1-75 (1978), Kabat et al., J Biol. Chem. 252:6609-6616 (1977), Chothia et al., J. Mol. Biol. 196:901-917 (1987), or Chothia et al., Nature 342:878-883 (1989).

[0038] The term "hypervariable region" refers to the amino acid residues of an antibody involved in antigen binding. The hypervariable region includes amino acid residues from the "complementarity-determining region" or "CDR" (i.e., CDRL1, CDRL2, and CDRL3 in the light chain variable domain, and CDRH1, CDRH2, and CDRH3 in the heavy chain variable domain). See Kabat et al., (1991) "Sequences of Proteins of Immunological Interest," 5th edition, National Institutes of Health, Division of Public Health Services, Bethesda, Maryland (where the CDR region of an antibody is defined by sequence), and also see Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987) (where the CDR region of an antibody is defined by structure). The term "framework" or "FR" residues refer to variable domain residues other than the hypervariable region residues defined as CDR residues in this specification.

[0039] As used herein, “antibody fragment” or “antigen-binding fragment” refers to an antigen-binding fragment of an antibody, i.e., an antibody fragment that retains the ability of a full-length antibody to specifically bind to an antigen, such as a fragment that retains one or more CDR regions. Examples of antigen-binding fragments include, but are not limited to, Fab, Fab', F(ab')2 and Fv fragments, biantibodies, linear antibodies, single-chain antibody molecules, nanoantibodies, and multispecific antibodies consisting of antibody fragments.

[0040] An antibody that "specifically binds" to a particular target protein is an antibody that exhibits preferential binding to that target protein compared to other proteins, but this specificity does not require absolute binding specificity. If the presence of the target protein in a sample is determined by antibody binding, and if, for example, undesirable results (such as false positives) are not produced, then the antibody is considered to have "specificity" for its expected target. Possible antibodies or their binding fragments used in this disclosure bind to the target protein with an affinity at least twice, preferably at least 10 times, more preferably at least 20 times, and most preferably at least 100 times, the affinity of the non-target protein.

[0041] A "chimeric antibody" refers to an antibody in which, insofar as it exhibits the desired physiological activity, a portion of its heavy chain and / or light chain is identical or homologous to the corresponding sequence of an antibody originating from a specific species (such as a human) or belonging to a specific antibody class or subclass, and the rest of the chain is identical or homologous to the corresponding sequence of an antibody originating from another species (such as a mouse) or belonging to another antibody class or subclass, and is a fragment of such an antibody.

[0042] A "human antibody" is an antibody that contains only human immunoglobulin sequences. When produced in mice, mouse cells, or hybridomas derived from mouse cells, human antibodies may contain mouse carbohydrate chains. Similarly, a "mouse antibody" or "rat antibody" is an antibody that contains only mouse or rat immunoglobulin sequences, respectively.

[0043] A "humanized antibody" refers to an antibody form that contains sequences derived from both non-human (e.g., mouse) and human antibodies. Such antibodies contain minimal sequences derived from non-human immunoglobulins. Generally, a humanized antibody contains all of substantially at least one, usually two, variable domains, where all or substantially all hypervariable loops correspond to the hypervariable loops of the non-human immunoglobulin, and all or substantially all FR regions are the FR regions of the human immunoglobulin. Humanized antibodies also optionally contain at least a portion of the immunoglobulin constant region (Fc), usually at least a portion of the human immunoglobulin constant region. When it is necessary to distinguish humanized antibodies from parent rodent antibodies, the prefix "hum," "hu," or "h" is added to the antibody clone name. Certain amino acid substitutions may be included for increased affinity, increased stability of the humanized antibody, or other reasons, but generally, the humanized form of a rodent antibody contains the same CDR sequence as the parent rodent antibody.

[0044] "Isolated antibody" and "isolated antibody fragment" refer to a purified state and, in such context, mean that the molecules are substantially free from other biomolecules such as nucleic acids, proteins, lipids, carbohydrates, or other substances such as cell debris and growth media. Generally, the term "isolated" is not intended to mean the complete absence of such substances, or the absence of water, buffer, or salt, unless they are present in amounts that substantially prevent the experimental or therapeutic use of the conjugated compounds described herein.

[0045] "CDR" generally refers to the complementarity-determining region within an immunoglobulin variable region, as defined using the Kabat numbering system. As used herein, "Kabat" refers to the immunoglobulin alignment and numbering system originally created by Elvin A. Kabat ("Sequences of Proteins of Immunological Interest," 5th edition, National Institutes of Health, Division of Public Health Services, Bethesda, Maryland (1991)).

[0046] As used herein, “monoclonal antibody” or “mAb” or “Mab” refers to a substantially homologous population of antibodies, i.e., the antibody molecules constituting the population have identical amino acid sequences, except for naturally occurring mutations that may exist in small amounts. Conversely, conventional (polyclonal) antibody preparations typically contain many different antibodies, which have different amino acid sequences in their variable domains (particularly CDRs), and these CDRs typically have specificity for different epitopes. The modifier “monoclonal” indicates that the antibody characteristics are obtained from a substantially homologous population of antibodies and should not be interpreted as requiring the antibody to be produced by any particular method. For example, monoclonal antibodies used in accordance with this disclosure may be prepared by the hybridoma method first described by Kohler et al., Nature 256:495 (1975), or by the recombinant DNA method (see, e.g., ET.S. Patent No. 4,816,567). Monoclonal antibodies can be isolated from phage antibody libraries using the techniques described in Clackson et al., Nature 352:624-628 (1991) and Marks et al., J Mol. Biol. 222:581-597 (1991), see, for example, Presta J Allergy Clin. Immunol. 116:731 (2005).

[0047] A “conservatively modified variant” or “conservative substitution” refers to the substitution of an amino acid in a protein with another amino acid having similar properties (e.g., charge, side chain size, hydrophobic / hydrophilicity, backbone conformation, and stiffness) so that the protein can be frequently modified without altering other desired properties such as its physiological activity or antigen affinity and / or specificity. Those skilled in the art recognize that a single amino acid substitution in a non-essential region of a polypeptide generally does not substantially alter its physiological activity (see, for example, Watson et al., “Molecular Biology of the Gene,” The Benjamin / Cummings, p. 224 (4th edition) (1987)). Furthermore, substitutions of structurally or functionally similar amino acids are less likely to disrupt physiological activity.

[0048] The term "intravenous injection" refers to the delivery of a drug into a vein in an animal or human patient over a period of approximately 15 minutes or more, typically between 30 and 90 minutes. This is usually achieved using an intravenous (IV) bag.

[0049] BTLA In this specification, the terms “B and T lymphocyte attenuation factor” and “BTLA” gene / protein are used interchangeably and include variants, isotypes, homologs, orthologs, and paralogs. For example, in one embodiment, a human BTLA-specific antibody may cross-react with BTLA of non-human species. In other embodiments, a human BTLA-specific antibody has complete specificity for human BTLA and does not exhibit species cross-reactivity or other types of cross-reactivity. Unless otherwise specified, the terms “human BTLA” or “hBTLA” refer to a human BTLA sequence. Unless otherwise specified, a human BTLA sequence includes all human isotypes and BTLA variants, for example, the complete amino acid sequence of human BTLA with GenBank registry number AAP44003. At least two human BTLA transcript variants, i.e., transcript variant 1 and transcript variant 2. The former codes for a 289-amino acid protein (GenBank registration number NP_861445) that has nearly 98% identity with the BTLA sequence of registration number AAP44003, while the latter codes for a 241-amino acid protein (GenBank registration number NP_001078826).

[0050] BTLA is a negative regulator of the immune response, possessing a C-terminal inhibitory motif involved in inhibiting IL-2 production and T cell proliferation (Watanabe et al., Nat.Immunol., 4, 670-679, (2003), Chemnitz et al., J.Immunol., 176, 6603-6614, (2006)). In one embodiment, an anti-BTLA antibody disclosed or used herein recognizes an epitope within the extracellular domain of BTLA.

[0051] As used herein, the terms “anti-BTLA antibody” or “anti-BTLA antigen-binding fragment” refer to an antibody that binds to BTLA and partially, substantially, or completely blocks the binding of BTLA to HVEM, and the terms include an antibody fragment or derivative that retains at least a portion of the antibody’s binding specificity, and typically include at least one fragment of the antibody’s antigen-binding region or variable region (e.g., one or more CDRs). Examples of antigen-binding fragments include, but are not limited to, Fab, Fab', F(ab')2, and Fv fragments, biantibodies, linear antibodies, single-chain antibody molecules such as sc-Fv, nanoantibodies formed from antibody fragments, and multispecific antibodies. When BTLA binding activity is expressed in molar concentration, the binding fragment or derivative typically retains at least 10% of its BTLA-binding activity. Preferably, the binding fragment or derivative retains at least 20%, 50%, 70%, 80%, 90%, 95%, or 100% or more of the antibody’s BTLA-binding affinity. Antibody antigen-binding fragments are expected to contain conserved or non-conserved amino acid substitutions (referred to as "conserved variants" or "functionally conserved variants" of the antibody) that do not significantly alter its physiological activity.

[0052] BTLA antagonists In one embodiment, the anti-BTLA therapy disclosed herein uses an anti-BTLA antibody or its antigen-binding fragment and comprises one or more features selected from A) complete blockade of BTLA binding to HVEM, B) cross-reactivity with cynomolgus monkey BTLA, C) binding to human BTLA (wherein KD ≤ 0.28 nM), and D) inability to mediate the ADCC effect. In another embodiment, an anti-BTLA antibody or its antigen-binding fragment from PCT / CN2019 / 098150 is used in anti-BTLA therapy.

[0053] In one embodiment, the anti-BTLA therapy disclosed herein uses an anti-BTLA antibody or its antigen-binding fragment comprising a light chain variable region and a heavy chain variable region, each comprising the heavy chain variable region comprising the HCDR1, HCDR2, and HCDR3, respectively, as indicated by SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, respectively, wherein the heavy chain variable region comprises the HCDR1, HCDR2, and HCDR3, respectively, as indicated by SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, respectively. In another embodiment, the anti-BTLA antibody or its antigen-binding fragment comprises one or more of the aforementioned CDRs, each or any of these CDRs comprising one or more, two or more, or three or more conservative substitutions for SEQ ID NOs. 1 to 6, respectively. In yet another embodiment, the antigen-binding fragment of the anti-BTLA antibody comprises one or more of the aforementioned CDRs, each or any of these CDRs comprising one or more, two or more, or three or more conservative substitutions for SEQ ID NOs. 1 to 6, respectively.

[0054] In one embodiment, the anti-BTLA therapy disclosed herein uses an anti-BTLA antibody or its antigen-binding fragment comprising a light chain variable region sequence having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 7, and a heavy chain variable region sequence having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 8.

[0055] In one embodiment, the anti-BTLA therapy disclosed herein uses an anti-BTLA antibody or its antigen-binding fragment containing the light chain variable region sequence of SEQ ID NO: 7 and the heavy chain variable region sequence of SEQ ID NO: 8. In another embodiment, the anti-BTLA antibody or its antigen-binding fragment contains at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 25, or 30 conservative substitutions for SEQ ID NO: 7 and / or 8. In another embodiment, the anti-BTLA antibody or its antigen-binding fragment contains at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 25, or 30 substitutions for SEQ ID NO: 7 and / or 8. In another embodiment, the anti-BTLA antibody or its antigen-binding fragment contains at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 25, or 30 conservative substitutions relative to SEQ ID NOs. 7 and 8. In another embodiment, the anti-BTLA antibody or its antigen-binding fragment contains at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 25, or 30 substitutions relative to SEQ ID NOs. 7 and 8.

[0056] In one embodiment, the anti-BTLA therapy disclosed herein uses an anti-BTLA antibody or its antigen-binding fragment comprising a light chain sequence having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 9, and a heavy chain sequence having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 10.

[0057] In one embodiment, the anti-BTLA therapy disclosed herein uses an anti-BTLA antibody such as TAB004 (also named or referred to as icatolimab, "JS 004", "JS-004", "JS004", "TAB 004", "TAB-004", or tifcemalimab, or its antigen-binding fragment) containing the light chain sequence of SEQ ID NO: 9 and the heavy chain sequence of SEQ ID NO: 10. In another embodiment, the anti-BTLA antibody or its antigen-binding fragment contains at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 25, or 30 conservative substitutions relative to SEQ ID NO: 9 and / or 10. In another embodiment, the anti-BTLA antibody or its antigen-binding fragment contains at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 25, or 30 substitutions relative to SEQ ID NO: 9 and / or 10. In another embodiment, the anti-BTLA antibody or its antigen-binding fragment contains at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 25, or 30 conservative substitutions relative to SEQ ID NOs. 9 and / or 10.

[0058] Some of the sequences listed above are shown in Table 1 below.

[0059] [Table 1]

[0060] In one embodiment, anti-BTLA therapy includes the use of an anti-BTLA antibody or its antigen-binding fragment containing a Fab fragment identical or substantially identical to the Fab fragment of tifcemalimab. The "Fab fragment" consists of a light chain, a CH1 of the heavy chain, and a variable region. The heavy chain of the Fab molecule cannot form a disulfide bond with the other heavy chain molecule.

[0061] In one embodiment, anti-BTLA therapy involves using a tifcemalimab having one or more, two or more, three or more, or four or more amino acid substitutions in the Fc region. In some embodiments, such amino acid substitutions affect post-translational modifications such as glycosylation. The "Fc" region contains two heavy chain fragments, each containing the CH1 and CH2 domains of the antibody. These two heavy chain fragments are linked by two or more disulfide bonds and the hydrophobicity of the CH3 domain.

[0062] In one embodiment, anti-BTLA therapy comprises using a molecule containing a Fab' fragment of tifcemalimab or a Fab' fragment substantially identical thereto. The “Fab' fragment” includes a portion or fragment of a light chain and a heavy chain, including a VH domain, a CH1 domain, and a region located between the CH1 domain and the CH2 domain, such that an interchain disulfide bond can be formed between the two heavy chains of two Fab' fragments, thereby forming an F(ab')2 molecule.

[0063] In one embodiment, anti-BTLA therapy involves using a molecule containing the F(ab')2 fragment of tifcemalimab or a substantially identical F(ab')2 fragment. The "F(ab')2 fragment" comprises two light chains and two heavy chains containing a portion of a constant region located between the CH1 domain and the CH2 domain, thereby forming an interchain disulfide bond between these two heavy chains. Thus, the F(ab')2 fragment consists of two Fab' fragments linked to each other by a disulfide bond between the two heavy chains.

[0064] In one embodiment, anti-BTLA therapy involves using a molecule containing the Fv region of tifcemalimab. The "Fv region" contains variable regions from both the heavy and light chains but lacks a constant region.

[0065] In one embodiment, anti-BTLA therapy comprises using scFv derived from tifcemalimab. As used herein, the terms “single-chain Fv” or “scFv” antibody refer to an antibody fragment comprising a VH domain and a VL domain of the antibody, where these domains are present on a single polypeptide chain. The scFv polypeptide typically further comprises a polypeptide linker located between the VH domain and the VL domain, enabling the scFv to form a desired structure for antigen binding.

[0066] In one embodiment, anti-BTLA therapy includes the use of a domain antibody derived from tifcemalimab. A “domain antibody” is an immunofunctional immunoglobulin fragment containing only the heavy chain or light chain variable region. In some cases, two or more VH regions covalently bind to a peptide linker to form a bivalent domain antibody. The two VH regions of the bivalent domain antibody can target the same or different antigens.

[0067] In one embodiment, anti-BTLA therapy includes the use of a bivalent antibody derived from tifcemalimab. The "bivalent antibody" contains two antigen-binding sites. In some cases, the two binding sites have the same antigen specificity. However, the bivalent antibody may be bispecific.

[0068] In one embodiment, anti-BTLA therapy comprises the use of a biantibody derived from tifcemalimab. As used herein, the term “biantibody” refers to a small antibody fragment having two antigen-binding sites, contained in a heavy chain variable domain (VH) linked to a light chain variable domain (VL) in a single polypeptide chain (VH-VL or VL-VH). By using a linker that is too short for the pairing between the two domains of one chain, these domains are forced to pair with a complementary domain of the other chain to form two antigen-binding sites.

[0069] In another embodiment, other anti-BTLA antibodies or their antigen-binding fragments that do not necessarily block (or at least not completely block) the binding of BTLA and HVEM may be used for use with TAB004, as disclosed herein. Such additional anti-BTLA antibodies include ANB032 and LY3361237. In another embodiment, the anti-BTLA antibody is HFB200603. In one embodiment, the additional anti-BTLA antibody cross-competes with TAB004 for use in BTLA binding or blocking action compared to BTLA / HVEM binding. In another embodiment, the additional anti-BTLA antibody has substantially similar or the same BTLA affinity as TAB004. In another embodiment, the additional anti-BTLA antibody has a higher affinity for BTLA than TAB004. In one embodiment, the additional anti-BTLA antibody neutralizes the interaction between BTLA and HVEM to the same extent as TAB004. In another embodiment, the additional anti-BTLA antibody recognizes a BTLA epitope sequence or site that overlaps with the BTLA epitope sequence or site of TAB004. In one embodiment, the additional anti-BTLA antibody neutralizes or inhibits the interaction between BTLA and TAB004.

[0070] PD-1 / PD-L1 In one embodiment, the anti-BTLA combination therapies disclosed herein include the use of both an anti-BTLA antibody or its antigen-binding fragment and an anti-PD-1 antibody or its antigen-binding fragment, or a bispecific antibody targeting both BTLA and PD-1. A possible “anti-PD-1 antibody” as used in this disclosure includes a monoclonal antibody (mAb) or its antigen-binding fragment that specifically binds to human PD-1. Alternative names or synonyms for PD-1 and its ligands include PDCD1, PD1, CD279, and SLEB2 for PD-1; PDCD1L1, PDL1, B7H1, B7-4, CD274, and B7-H for PD-L1; and PDCD1L2, PDL2, B7-DC, Btdc, and CD273 for PD-L2.

[0071] In any therapeutic method, composition, or use of the present disclosure in a human subject to treatment, the PD-1 antibody or its antigen-binding fragment is a PD-1 antagonist that blocks the binding of human PD-L1 to human PD-1, or blocks the binding of both human PD-L1 and PD-L2 to human PD-1. The human PD-1 amino acid sequence can be found at NCBI locus number: NP 005009. The human PD-L1 and PD-L2 amino acid sequences can be found at NCBI locus numbers: NP_054862 and NP_079515, respectively. The anti-PD-1 antibody may be a human antibody, a humanized antibody, or a chimeric antibody, and may include a human constant region. In one embodiment, the human constant region is selected from the IgG1, IgG2, IgG3, and IgG4 constant regions, and in a preferred embodiment, the human constant region is the IgG1 or IgG4 constant region. In one embodiment, the antigen-binding fragment is selected from Fab, Fab', F(ab')2, scFv, and Fv fragments.

[0072] In one embodiment, the anti-BTLA combination therapy disclosed herein includes the use of an anti-PD-1 antibody such as nivolumab, pembrolizumab, tripalimab, sintilimab, camrelizumab, tislelizumab, or cemiplimab, or (i) a variant or antigen-binding fragment of any of the aforementioned antibodies, or (ii) a biosimilar molecule. In another embodiment, the anti-BTLA combination therapy disclosed herein includes the use of an anti-PD-L1 antibody such as atezolizumab, durvalumab, or avelumab, or (i) a variant or antigen-binding fragment of any of the aforementioned antibodies, or (ii) a biosimilar molecule.

[0073] In one embodiment, the anti-BTLA combination therapy disclosed herein uses an anti-PD-1 antibody or its antigen-binding fragment comprising a light chain variable region comprising LCDR1, LCDR2, and LCDR3, as indicated by SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: 13, and a heavy chain variable region comprising HCDR1, HCDR2, and HCDR3, as indicated by SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16, respectively. In another embodiment, the anti-PD-1 antibody or its antigen-binding fragment comprises one or more of the aforementioned CDRs, each or any of these CDRs comprising one or more, two or more, or three or more conservative substitutions for SEQ ID NOs. 11-16, respectively. In yet another embodiment, the anti-PD-1 antibody or its antigen-binding fragment comprises one or more of the aforementioned CDRs, each or any of these CDRs comprising one or more, two or more, or three or more substitutions for SEQ ID NOs. 11-16, respectively.

[0074] In one embodiment, the anti-BTLA combination therapy disclosed herein uses an anti-PD-1 antibody or its antigen-binding fragment comprising a light chain variable region sequence having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 17, and a heavy chain variable region sequence having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 18.

[0075] In one embodiment, the anti-BTLA combination therapy disclosed herein uses an anti-PD-1 antibody or its antigen-binding fragment comprising the light chain variable region sequence of SEQ ID NO: 17 and the heavy chain variable region sequence of SEQ ID NO: 18. In another embodiment, the anti-PD-1 antibody or its antigen-binding fragment comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 25, or 30 conservative substitutions relative to SEQ ID NO: 17 and / or 18. In another embodiment, the anti-PD-1 antibody or its antigen-binding fragment comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 25, or 30 substitutions relative to SEQ ID NO: 17 and / or 18. In another embodiment, the anti-PD-1 antibody or its antigen-binding fragment contains at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 25, or 30 conservative substitutions relative to SEQ ID NOs. 17 and / or 18. In another embodiment, the anti-PD-1 antibody or its antigen-binding fragment contains at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 25, or 30 substitutions relative to SEQ ID NOs. 17 and / or 18.

[0076] In one embodiment, the anti-BTLA combination therapy disclosed herein uses an anti-PD-1 antibody or its antigen-binding fragment comprising a light chain sequence having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 19, and a heavy chain sequence having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 20.

[0077] In one embodiment, the anti-BTLA combination therapy disclosed herein uses an anti-PD-1 antibody or its antigen-binding fragment, such as tripalimab (also named or referred to as JS001 or TAB001), comprising the light chain sequence of SEQ ID NO: 19 and the heavy chain sequence of SEQ ID NO: 20. In another embodiment, the anti-PD-1 antibody or its antigen-binding fragment comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 25, or 30 conservative substitutions relative to SEQ ID NO: 19 and / or 20. In another embodiment, the anti-PD-1 antibody or its antigen-binding fragment comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 25, or 30 substitutions relative to SEQ ID NO: 19 and / or 20. In another embodiment, the anti-PD-1 antibody or its antigen-binding fragment contains at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 25, or 30 conservative substitutions relative to SEQ ID NOs. 19 and / or 20. In another embodiment, the anti-PD-1 antibody or its antigen-binding fragment contains at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 25, or 30 substitutions relative to SEQ ID NOs. 19 and / or 20.

[0078] Some of the sequences listed above are shown in Table 2 below.

[0079] [Table 2]

[0080] Combination therapy In one embodiment, anti-BTLA combination therapy comprises using an anti-BLTA antibody or its antigen-binding fragment in combination with another immune checkpoint therapy. As used herein, the term “immune checkpoint therapy” means therapy using one or more agents that can modify immune checkpoint function, including CTLA-4, LAG-3, B7-H3, B7-H4, Tim3, BTLA, KIR, A2aR, CD200, and / or the PD-1 pathway. Exemplary immune checkpoint modulators include anti-CTLA-4 antibodies (e.g., ipilimumab), anti-LAG-3 antibodies, anti-B7-H3 antibodies, anti-B7-H4 antibodies, anti-Tim3 antibodies, anti-KIR antibodies, anti-A2aR antibodies, anti-CD200 antibodies, anti-PD-1 antibodies, anti-PD-LI antibodies, anti-CD28 antibodies, anti-CD80 antibodies or anti-CD86 antibodies, anti-B7RP1 antibodies, anti-B7-H3 antibodies, anti-HVEM antibodies, anti-CD137 antibodies or anti-CD137L antibodies, anti-OX40 antibodies or anti-OX40L antibodies, anti-CD40 antibodies or anti-CD40L antibodies, anti-GAL9 antibodies, anti-IL-10 antibodies, and A2aR drugs.

[0081] In one embodiment, an anti-BTLA antibody or its antigen-binding fragment can be used alone or in combination with other antitumor agents or immunogenic agents (e.g., attenuated cancer cells, tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), antigen-presenting cells such as dendritic cells pulsed with tumor-derived antigens or nucleic acids, immunostimulatory cytokines (e.g., IL-2, IFNa2, GM-CSF), and cells transfected with genes encoding immunostimulatory cytokines, e.g., GM-CSF), standard cancer treatments (e.g., chemotherapy, radiotherapy, or surgery), or other antibodies (including, but not limited to, antibodies against PD-1, PD-L1, VEGF, EGFR, Her2 / neu, VEGF receptor, other growth factor receptors, CD20, CD40, CTLA-4, OX-40, 4-1BB, and ICOS).

[0082] In one embodiment, anti-BTLA therapy is administered concurrently with another immune checkpoint therapy. As used herein, “concurrent administration” of drugs such as BTLA antagonists or PD-1 antagonists means that these drugs are administered in such a way that they have overlapping therapeutic activity, and that these drugs do not need to be administered to the test subject simultaneously. These drugs may or may not be in physical combination prior to administration. Concurrent administration includes, but is not limited to, sequential administration (e.g., injection) and has different intervals between the two administrations (e.g., injections).

[0083] In one embodiment, a BTLA antagonist and a PD-1 or PD-L1 antagonist are co-formulated. As used herein, “co-formulation” or “co-product” means formulating together at least two different antibodies or their antigen-binding fragments, formulating and storing them separately, and storing them as a combined product in separate vials or containers (e.g., injection devices) rather than mixing them before administration or administering them separately. In one embodiment, the co-formulation comprises two different antibodies or their antigen-binding fragments.

[0084] In one embodiment, an anti-BTLA antibody or its antigen-binding fragment is administered concurrently with a chemotherapeutic agent. As used herein, “chemotherapeutic agent” is a compound useful for the treatment of cancer. The class of chemotherapeutic agents includes, but is not limited to, alkylating agents, antimetabolites, kinase inhibitors, spindle poison plant alkaloids, cytotoxic / antitemonic antibiotics, topoisomerase inhibitors, photosensitizers, anti-estrogens and selective estrogen receptor modulators (SERMs), anti-progesterones, estrogen receptor downregulators (ERDs), estrogen receptor antagonists, luteinizing hormone-releasing hormone agonists, anti-androgens, aromatase inhibitors, EGFR inhibitors, VEGF inhibitors, antisense oligonucleotides, or other small RNA molecules that inhibit the expression of genes involved in abnormal cell proliferation or tumor growth. In one embodiment, chemotherapeutic agents useful in the therapeutic methods of the Disclosure include cell inhibitors and / or cytotoxic agents.

[0085] In one embodiment, an anti-BTLA antibody or its antigen-binding fragment is administered concurrently with platinum-containing chemotherapy. As used herein, "platinum-containing chemotherapy" (also called platinum) refers to the treatment of cancer using platinum coordination complexes as chemotherapeutic agents. Platinum-containing chemotherapeutic agents are alkylating agents of cross-linked DNA that result in ineffective DNA mismatch repair and typically lead to cell apoptosis. Examples of platinum include cisplatin, carboplatin, and oxaliplatin.

[0086] In one embodiment, anti-BTLA monotherapy or combination therapy (e.g., in combination with anti-PD-1 or anti-PD-L1) also includes the use of chemotherapeutic agents. Examples of chemotherapy drugs include alkylating agents such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethyleneimines and methylmelamines, including hexamethylmelamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; acetyl (especially bullatacin and bullatacinone); camptothecin (including its synthetic analog topotecan); bryostatin; callystatin; CC-1065 (and its adozelesin) ), including synthetic analogs of carzelesin and bizelesin; cryptophycin (especially cryptophycin-1 and cryptophycin-8); dolastatin; duocalmycin (including synthetic analogs KW-2189 and CBI-TMI); eleutherobin; pancratistatin; sarcodictyin; spongistatin; chlorambucil, chlornafadin, chlorophosphamide, estramustine, ifosfamide, mechloretamine, nitrogen mustard oxide hydrochloride, melphalan, new nitrogen mustard, phenylephrine cholesterol, prednimustine, trophosfamide, uracil mustard and other nitrogen mustard derivatives;Nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics such as engine antibiotics (e.g., calicheamicin, especially calicheamicin gammall and calicheamicin phill, see Agnew, Chem. Intl. Ed. Engl., 33:183-186 (1994)); dynemicins, including dynemicin A; bisphosphonates such as phosphoroclonides; esperamicin;Furthermore, neocarzinostatin chromophore and related chromoprotein enediine antibiotic chromophore, aclasinomycin, actinomycin, autramycin, azaserin, bleomycin, actinomycin C, carabicin, caminomycin, cardinophilin, chromomycin, actinomycin D, daunorubicin (dau Norubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including morpholinodoxorubicin, cyanomorpholinodoxorubicin, 2-pyrrolinodoxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin C, etc. Mitomycin, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidine , ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folate analogs such as denopterin, methotrexate, pteropterin, and trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine;Pyrimidine analogs such as amcitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and phloxuridine; calusterone and dromostanolone propionate. Androgens such as propionate, epithiostanol, mepitiostane, and testolactone; anti-adrenal drugs such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as folinic acid; acegraton; aldofamide glycoside; aminolevulinic acid; eniluracil; amsacrin; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfornithine; elliptinium acetate acetate; epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocin; mitoguazone; mitoxantrone; mopidamol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; razoxane; rhizoxin;Sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2''-trichlorotriethylamine; trichothecene (especially T-2 toxin, verracurin A, roridin A and anguidine); urethane; vindesine; dacarbazine; mannomustine; dibromomannitol; dibromodulcitol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; paclitaxel and doxetaxel Taxoids such as el); chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; vinorelbine; novatron; teniposide; edatrexate; daunomycin; aminopterin; Xeloda; ibandronate; CPT-1; topoisomerase inhibitor RFS2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine;and any pharmaceutically acceptable salt, acid, or derivative thereof. Antihormone agents for modulating or inhibiting the action of hormones on tumors, such as anti-estrogen agents and selective estrogen receptor modulators (SERMs), including tamoxifen, raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene (Fareston); 4(5)-imidazole, aminoglutethimide, megestrol acetate, exemestane (exemes Aromatase inhibitors that inhibit the enzyme aromatase (modulate estrogen production in the adrenal gland), such as tane, formestane, fatrozole, vorozole, letrozole, and anastrozole; and antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and further comprising any pharmaceutically acceptable salts, acids, or derivatives of the above. The chemotherapeutic agents may be administered according to their respective standard dosing regimens.

[0087] Based on standard pharmaceutical practice, each therapeutic agent in the combination therapy of this disclosure may be administered alone or in a drug (also referred to herein as a pharmaceutical composition) comprising the therapeutic agent and one or more pharmaceutically acceptable carriers, excipients, and diluents.

[0088] Each therapeutic agent in the combination therapy of this disclosure may be administered simultaneously (i.e., with the same drug), in parallel (i.e., with individual drugs administered consecutively in any order), or sequentially in any order. Sequential administration is particularly useful when the therapeutic agents in the combination therapy are in different dosage forms (one drug is a tablet or capsule and the other is a sterile liquid) and / or administered in different dosing regimens, for example, when the chemotherapy agent is administered at least daily and the biotherapy agent is administered less frequently, e.g., once a week, once every two weeks, or once every three weeks.

[0089] In one embodiment, the anti-BTLA antibody or its antigen-binding fragment is administered before the administration of the anti-PD-1 antibody or its antigen-binding fragment, or the anti-PD-L1 antibody or its antigen-binding fragment; on the other hand, in another embodiment, the anti-BTLA antibody or its antigen-binding fragment is administered after the administration of the anti-PD-1 antibody or its antigen-binding fragment, or the anti-PD-L1 antibody or its antigen-binding fragment. In yet another embodiment, the anti-BTLA antibody or its antigen-binding fragment is administered simultaneously with the anti-PD-1 antibody or its antigen-binding fragment, or the anti-PD-L1 antibody or its antigen-binding fragment.

[0090] In one embodiment, at least one therapeutic agent in combination therapy is administered in the same dose regimen (dose, frequency, and duration of treatment) as the drug is typically used when treating the same cancer as a monotherapy. In another embodiment, the patient receives the total amount of at least one therapeutic agent in combination therapy at a lower dose than the total amount when the drug is used as monotherapy, for example, at a relatively small dose, a relatively low frequency of administration, and / or a relatively short duration of treatment.

[0091] Each small molecule therapeutic agent in the combination therapies of this disclosure may be administered orally or parenterally, including via intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, topical, and transdermal routes. The combination therapies of this disclosure may be used before or after surgery to remove a tumor, or before, during, or after radiotherapy.

[0092] In one embodiment, the combination therapy of this disclosure is administered to patients who have not previously been treated with a biological agent or chemotherapeutic agent, i.e., untreated patients. In another embodiment, the combination therapy is administered to patients who have not achieved a sustained response after prior treatment with a biological agent or chemotherapeutic agent, i.e., treated patients.

[0093] The combination therapies of this disclosure are generally used to treat tumors that are large enough to be found by palpation or imaging techniques known in the art, such as MRI, ultrasound, or CAT scans. The combination therapies of this disclosure may be administered to human patients with cancer that is positive for one or both of PD-L1 and PD-L2 by testing, and preferably positive for PD-L1 expression by testing. In some preferred embodiments, an IHC assay detects PD-L1 expression in FFPE or frozen tissue sections of tumor samples taken from the patient using a diagnostic anti-human PD-L1 antibody or its antigen-binding fragment. In some preferred embodiments, the combination therapies of this disclosure may be administered to human patients with cancer that is positive for HVEM expression detection.

[0094] In another embodiment, the anti-PD-1 antibody in combination therapy is nivolumab, pembrolizumab, tripalimab, cintilimab, camrelizumab, tislerizumab, or semiprimab, or (i) a variant or antigen-binding fragment of any of the above antibodies, or (ii) a biologically similar molecule, and the antibody is administered in liquid drug at doses of approximately 1 mg / kg Q2W, 2 mg / kg Q2W, 3 mg / kg Q2W, 5 mg / kg Q2W, 10 mg / kg Q2W, 1 mg / kg Q3W, 2 mg / kg Q3W, 3 mg / kg Q3W, 5 mg / kg Q3W, 10 mg / kg Q3W, and any of these doses in a fixed dose equivalent, i.e., doses selected from approximately 200 mg, 240 mg, 280 mg, 300 mg Q3W, etc.

[0095] In another embodiment, the anti-PD-1 antibody or its antigen-binding fragment is administered to the patient every four or six weeks for a duration of 12 weeks or more. In yet another embodiment, the anti-PD-1 antibody or its antigen-binding fragment is administered to the patient once every three or six weeks for a duration of 16 weeks or more, 18 weeks or more, 20 weeks or more, 24 weeks or more, 28 weeks or more, 30 weeks or more, 32 weeks or more, 36 weeks or more, 40 weeks or more, 42 weeks or more, 44 weeks or more, 48 weeks or more, 52 weeks or more, 54 weeks or more, 56 weeks or more, 60 weeks or more, 64 weeks or more, 66 weeks or more, 68 weeks or more, 72 weeks or more, 76 weeks or more, 78 weeks or more, 80 weeks or more, 84 weeks or more, 88 weeks or more, or 90 weeks or more.

[0096] In one embodiment, a selected dose of anti-BTLA or its antigen-binding fragment, or anti-PD-1 / PD-L1 antibody or its antigen-binding fragment, is administered by intravenous injection. In one embodiment, a selected dose of anti-BTLA or its antigen-binding fragment, or anti-PD-1 / PD-L1 antibody or its antigen-binding fragment, is administered by intravenous injection over a period of 25 to 60 minutes or approximately 30 minutes.

[0097] In one embodiment, the patient is treated with combination therapy for at least 24 weeks, for example, in eight 3-week cycles. In one embodiment, treatment with combination therapy is continued until the patient shows signs of progressive disease or complete remission.

[0098] Dosage and regimen The appropriate antibody dose in anti-BTLA monotherapy or combination therapy for the prevention or treatment of disease depends on various factors, including the type of disease being treated, the severity and course of the disease, whether the antibody is administered for preventive or therapeutic purposes, prior treatment, the patient's medical history and response to the antibody, and the attending physician's judgment. The antibody should be administered appropriately to the patient in a single treatment or a series of treatments.

[0099] In one embodiment, the anti-BTLA antibody or its antigen-binding fragment is administered intravenously in a Q3W-based dose of 0.3 mg / kg to 10 mg / kg, or in a fixed Q3W dose of 20 mg to 500 mg. In another embodiment, the anti-BTLA antibody or its antigen-binding fragment is administered intravenously in a Q3W-based dose of approximately 0.3 mg / kg, 0.5 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, or 10 mg / kg. In yet another embodiment, the anti-BTLA antibody or its antigen-binding fragment is administered intravenously in a fixed Q3W dose of approximately 20 mg, 30 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, or 500 mg.

[0100] In one embodiment, an anti-BTLA antibody or its antigen-binding fragment is administered intravenously in a Q3W-based dose of approximately 0.3 mg / kg to 15 mg / kg, approximately 0.3 mg / kg to 12 mg / kg, approximately 0.3 mg / kg to 10 mg / kg, approximately 0.3 mg / kg to 9 mg / kg, approximately 0.3 mg / kg to 8 mg / kg, approximately 0.3 mg / kg to 7 mg / kg, approximately 0.3 mg / kg to 6 mg / kg, approximately 0.3 mg / kg to 5 mg / kg, approximately 0.3 mg / kg to 4 mg / kg, approximately 0.3 mg / kg to 3 mg / kg, approximately 0.3 mg / kg to 2 mg / kg, or approximately 0.3 mg / kg to 1 mg / kg.

[0101] In another embodiment, the anti-BTLA antibody or its antigen-binding fragment is administered intravenously in Q3W body weight-based doses of approximately 0.5 mg / kg to approximately 15 mg / kg, approximately 0.8 mg / kg to approximately 12 mg / kg, approximately 1 mg / kg to approximately 10 mg / kg, approximately 1.2 mg / kg to approximately 8 mg / kg, approximately 1.4 mg / kg to approximately 6 mg / kg, approximately 1.6 mg / kg to approximately 5 mg / kg, approximately 1.8 mg / kg to approximately 4 mg / kg, or approximately 2 mg / kg to approximately 3.5 mg / kg.

[0102] In one embodiment, the anti-BTLA antibody or its antigen-binding fragment is administered intravenously at least once every 1, 2, 3, 4, 5, 6, 7, 8, or 9 weeks. In another embodiment, the anti-BTLA antibody or its antigen-binding fragment is administered intravenously at most once every 1, 2, 3, 4, 5, 6, 7, 8, or 9 weeks.

[0103] In another aspect, an anti-BTLA antibody or its antigen-binding fragment is administered intravenously in a fixed dose of at least about 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, or 450 mg, at a frequency selected from Q1W, Q2W, Q3W, Q4W, Q5W, Q6W, Q7W, Q8W, and Q9W.

[0104] In one embodiment, an anti-BTLA antibody or its antigen-binding fragment is administered intravenously in fixed doses of approximately 20 mg to approximately 500 mg, approximately 30 mg to approximately 450 mg, approximately 50 mg to approximately 400 mg, approximately 75 mg to approximately 350 mg, approximately 100 mg to approximately 300 mg, approximately 125 mg to approximately 275 mg, or approximately 150 mg to approximately 250 mg, or approximately 175 mg to approximately 225 mg, with a frequency selected from Q1W, Q2W, Q3W, Q4W, Q5W, Q6W, Q7W, Q8W, and Q9W.

[0105] In another embodiment, the anti-BTLA antibody or its antigen-binding fragment is administered intravenously in fixed doses of approximately 20 mg to 50 mg, 50 mg to 100 mg, 100 mg to 150 mg, 150 mg to 200 mg, 200 mg to 250 mg, 250 mg to 300 mg, 300 mg to 350 mg, or 350 mg to 400 mg for Q3W.

[0106] In one embodiment, an anti-BTLA antibody or its antigen-binding fragment is administered intravenously in a Q3W-based dose of approximately 0.3 mg / kg, 1 mg / kg, 3 mg / kg, or 10 mg / kg, or in a fixed dose of approximately 20 mg, 70 mg, 200 mg, or 500 mg for Q3W.

[0107] In another embodiment, the anti-BTLA antibody or its antigen-binding fragment is administered intravenously at a Q3W-based dose of approximately 3 mg / kg, or at a fixed dose of approximately 200 mg Q3W.

[0108] In one embodiment, an anti-BTLA antibody or its antigen-binding fragment is administered intravenously once every 1, 2, 3, 4, 5, 6, 7, 8, or 9 weeks at a body weight-based dose of approximately 3 mg / kg, or once every 1, 2, 3, 4, 5, 6, 7, 8, or 9 weeks at a fixed dose of approximately 200 mg.

[0109] In another embodiment, an anti-BTLA antibody or its antigen-binding fragment is administered in a treatment regimen lasting at least 3, 6, 9, 12, 16, 20, 24, 28, 32, 36, 42, 46, 50, 54, 58, 62, or 66 weeks or months.

[0110] In one embodiment, an anti-PD-1 or anti-PD-L1 antibody or its antigen-binding fragment is administered intravenously in a Q3W-based dose of 1 mg / kg to 15 mg / kg, or in a fixed Q3W dose of 120 mg to 500 mg. In another embodiment, an anti-PD-1 or anti-PD-L1 antibody or its antigen-binding fragment is administered intravenously in a Q3W-based dose of approximately 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, or 10 mg / kg. In another embodiment, an anti-PD-1 or anti-PD-L1 antibody or its antigen-binding fragment is administered intravenously in a fixed dose of approximately 100 mg, 120 mg, 150 mg, 200 mg, 240 mg, 250 mg, 300 mg, 350 mg, 360 mg, 400 mg, 450 mg, 480 mg, or 500 mg during Q3W.

[0111] In one embodiment, an anti-PD-1 or anti-PD-L1 antibody or its antigen-binding fragment is administered intravenously in a Q3W-based dose of approximately 1 mg / kg to 15 mg / kg, approximately 1 mg / kg to 12 mg / kg, approximately 1 mg / kg to 10 mg / kg, approximately 1 mg / kg to 9 mg / kg, approximately 1 mg / kg to 8 mg / kg, approximately 1 mg / kg to 7 mg / kg, approximately 1 mg / kg to 6 mg / kg, approximately 1 mg / kg to 5 mg / kg, approximately 1 mg / kg to 4 mg / kg, approximately 1 mg / kg to 3 mg / kg, or approximately 1 mg / kg to 2 mg / kg.

[0112] In another embodiment, an anti-PD-1 or anti-PD-L1 antibody or its antigen-binding fragment is administered intravenously in a Q3W-based dose of approximately 2 mg / kg to 15 mg / kg, approximately 3 mg / kg to 12 mg / kg, approximately 4 mg / kg to 10 mg / kg, approximately 5 mg / kg to 8 mg / kg, approximately 1 mg / kg to 6 mg / kg, approximately 2 mg / kg to 5 mg / kg, approximately 3 mg / kg to 4 mg / kg, or approximately 3 mg / kg to 5 mg / kg.

[0113] In one aspect, an anti-PD-1 antibody or an anti-PD-L1 antibody or its antigen-binding fragment is administered intravenously at least once every 1, 2, 3, 4, 5, 6, 7, 8, or 9 weeks. In another aspect, an anti-PD-1 or anti-PD-L1 antibody or its antigen-binding fragment is administered intravenously at most once every 1, 2, 3, 4, 5, 6, 7, 8, or 9 weeks.

[0114] In another embodiment, an anti-PD-1 antibody, or an anti-PD-L1 antibody or its antigen-binding fragment, is administered intravenously in fixed doses of at least approximately 100 mg, 120 mg, 150 mg, 200 mg, 240 mg, 250 mg, 300 mg, 350 mg, 360 mg, 400 mg, 450 mg, 480 mg, or 500 mg, at frequencies selected from Q1W, Q2W, Q3W, Q4W, Q5W, Q6W, Q7W, Q8W, and Q9W.

[0115] In one embodiment, an anti-PD-1 antibody, an anti-PD-L1 antibody, or its antigen-binding fragment is administered intravenously in fixed doses of approximately 100 mg to approximately 500 mg, approximately 125 mg to approximately 450 mg, approximately 150 mg to approximately 400 mg, approximately 175 mg to approximately 350 mg, approximately 200 mg to approximately 300 mg, approximately 225 mg to approximately 275 mg, or approximately 150 mg to approximately 250 mg, with a frequency selected from Q1W, Q2W, Q3W, Q4W, Q5W, Q6W, Q7W, Q8W, and Q9W.

[0116] In another embodiment, an anti-PD-1 antibody, or an anti-PD-L1 antibody, or its antigen-binding fragment, is administered intravenously in fixed doses of approximately 50 mg to 100 mg, 100 mg to 150 mg, 150 mg to 200 mg, 200 mg to 250 mg, 250 mg to 300 mg, 300 mg to 350 mg, or 350 mg to 400 mg per Q3W.

[0117] In one embodiment, an anti-PD-1 antibody, an anti-PD-L1 antibody, or its antigen-binding fragment is administered intravenously in a body weight-based dose of approximately 2 mg / kg, 3 mg / kg, 4 mg / kg, 6 mg / kg, 8 mg / kg, or 10 mg / kg, or in a fixed dose of approximately 120 mg, 240 mg, 360 mg, or 480 mg for Q3W.

[0118] In another embodiment, an anti-PD-1 antibody, or an anti-PD-L1 antibody or its antigen-binding fragment, is administered intravenously at a body weight-based dose of approximately 3 mg / kg for Q3W, or at a fixed dose of approximately 240 mg for Q3W.

[0119] In one embodiment, an anti-PD-1 antibody, or an anti-PD-L1 antibody or its antigen-binding fragment, is administered intravenously once every 1, 2, 3, 4, 5, 6, 7, 8, or 9 weeks at a body weight-based dose of approximately 3 mg / kg, or once every 1, 2, 3, 4, 5, 6, 7, 8, or 9 weeks at a fixed dose of approximately 240 mg.

[0120] In another embodiment, an anti-PD-1 antibody, or an anti-PD-L1 antibody, or its antigen-binding fragment, is administered in a treatment regimen lasting at least 3, 6, 9, 12, 16, 20, 24, 28, 32, 36, 42, 46, 50, 54, 58, 62, or 66 weeks or months.

[0121] In one embodiment, anti-BTLA monotherapy or combination therapy is administered to the patient until disease progression, disease relapse, or unacceptable toxicity occurs, or for approximately 12, 18, 24, 30, or 36 months.

[0122] Administration The anti-BTLA monotherapy or combination therapy disclosed herein is administered by any preferred means, including parenteral, subcutaneous, intraperitoneal, intrapulmonary, and intranasal, and may be administered intrafocally (including pre-transplant perfusion or contact of the graft with the antibody by other means) if local immunosuppressive therapy is required. In one embodiment, the anti-BTLA antibody or its antigen-binding fragment or agent may be administered, for example, as an injection or as a bolus. Parenteral injection includes intramuscular, intravenous, intra-arterial, intraperitoneal, or subcutaneous administration. In another embodiment, the anti-BTLA antibody or its antigen-binding fragment may be appropriately administered by pulse injection, in particular, the antibody may be administered in tapering doses. In another embodiment, administration is performed by injection, most preferably intravenous or subcutaneous injection, which depends in part on whether the administration is short-term or long-term. In another embodiment, the anti-BTLA antibody or its antigen-binding fragment described herein, or its corresponding pharmaceutical composition, may be administered by non-invasive routes (e.g., oral administration, e.g., as pills, capsules, or tablets), which is also within the scope of the present invention. In another embodiment, an anti-BTLA antibody or its antigen-binding fragment, or a pharmaceutical composition thereof, is administered intramuscularly, intraarterially, intra-articularly (e.g., intra-articularly in arthritis), by inhalation, aerosol delivery, or intratumor administration.

[0123] In one embodiment, a single dose of anti-BTLA antibody or its antigen-binding fragment, anti-PD-1 antibody or its antigen-binding fragment, or anti-PD-L1 antibody or its antigen-binding fragment is administered by intravenous injection over a period of at least approximately 15 minutes, 30 minutes, 60 minutes, 90 minutes, 120 minutes, or 150 minutes.

[0124] In one embodiment, a single dose of anti-BTLA antibody or its antigen-binding fragment, anti-PD-1 antibody or its antigen-binding fragment, or anti-PD-L1 antibody or its antigen-binding fragment is administered by intravenous injection over a period of at most approximately 15 minutes, 30 minutes, 60 minutes, 90 minutes, 120 minutes, or 150 minutes.

[0125] In one embodiment, a single dose of anti-BTLA antibody or its antigen-binding fragment, anti-PD-1 antibody or its antigen-binding fragment, or anti-PD-L1 antibody or its antigen-binding fragment is administered by intravenous injection over a period of 15 to 30 minutes, 30 to 60 minutes, 60 to 90 minutes, 90 to 120 minutes, or 120 to 150 minutes.

[0126] Indications The antibodies or antigen-binding fragments of this disclosure (e.g., anti-BTLA antibodies or their antigen-binding fragments) are useful for the treatment of cancer (i.e., inhibiting the growth or survival of tumor cells). Preferred cancers whose growth can be inhibited using the antibodies of this disclosure include cancers that generally respond to immunotherapy, as well as cancers that have not previously been involved in immunotherapy. Non-limiting examples of cancers preferred for treatment include lung cancer. Preferably, preferred cancers include non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). More preferably, preferred cancers include advanced-stage small cell lung cancer (ES-SCLC). In some embodiments, the cancer is squamous cell NSCLC.

[0127] When applied to a subject diagnosed with or suspected of having cancer, “tumor” refers to a malignant or potentially malignant tumor or tissue mass of any size, and includes primary and secondary tumors. A solid tumor is usually an abnormal growth or mass of tissue that does not contain cysts or fluid areas. Different types of solid tumors are named according to the type of cells that form them. Examples of solid tumors are sarcomas, carcinomas, and lymphomas. Leukemia (blood cancer) does not usually form solid tumors. In one aspect, the lung cancer described above is progressive, unresectable, or metastatic. In one aspect, the patient is drug-resistant to anti-PD-1 or anti-PD-L1 therapy.

[0128] In one embodiment, the cancer treated herein is an advanced cancer. An "advanced" cancer is one that spreads outside of its site of origin or organ by local invasion or metastasis. Accordingly, the term "advanced" cancer includes both locally advanced and metastatic diseases.

[0129] In one aspect, the cancers treated herein are recurrent or locally recurrent cancers. A “recurrent” cancer is a cancer that has grown again at the original site or a distant site after responding to initial treatment such as surgery. A “locally recurrent” cancer is a cancer that has recurred after treatment at the same site as the previously treated cancer.

[0130] In one embodiment, the cancer treated herein is an unresectable cancer. An "unresectable" cancer is one that cannot be removed by surgery (resection).

[0131] In one embodiment, the cancer treated herein is metastatic cancer. "Metastatic" cancer refers to cancer that spreads from one part of the body (for example, the lungs) to another part of the body.

[0132] In one embodiment, the cancer treated herein is locally advanced cancer. "Locally advanced" cancer means cancer that has spread to nearby tissues or lymph nodes but has not metastasized.

[0133] In one embodiment, the cancer treated herein is an advanced, unresectable cancer. An "advanced, unresectable" cancer is one that has spread outside the site or organ of origin due to local invasion or metastasis and cannot be removed (resected) by surgery.

[0134] In one embodiment, the anti-BTLA therapy disclosed herein is used in the treatment of patients with lung cancer, preferably non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), more preferably advanced small cell lung cancer (ES-SCLC) or squamous cell NSCLC. In another embodiment, the anti-BTLA therapy disclosed herein is used in adjuvant therapy for adult and pediatric (12 years of age and older) patients. In one embodiment, lung cancer patients are drug-resistant to anti-PD-1 or anti-PD-L1 therapy. In some embodiments, such patients are pathologically diagnosed with ES-SCLC and are drug-resistant to previous systemic therapies, and preferably these patients are treated in combination with the anti-BTLA therapy described herein and the anti-PD-1 or anti-PD-L1 therapy described herein. In some embodiments, the patient is an ES-SCLC patient who has not previously received systemic antitumor therapy, and preferably these patients are treated with the anti-BTLA therapy described herein in combination with the anti-PD-1 or anti-PD-L1 therapy described herein and standard chemotherapy described herein (particularly etoposide + carboplatin or cisplatin). In some embodiments, the patient is a squamous NSCLC patient whose squamous NSCLC has not progressed after treatment with platinum-containing dual therapy and a PD-1 / PD-L1 inhibitor, and preferably these patients are treated with the anti-PD-1 or anti-PD-L1 therapy described herein and standard chemotherapy described herein (particularly docetaxel).

[0135] Therapeutic effect In one embodiment, the RECIST 1.1 Response Criteria, described in Eisenhauer et al., Eur.J Cancer 45:228-247 (2009), is used to evaluate the effectiveness of cancer treatment on target or non-target lesions, and the specific evaluation is determined based on the background of the measured response.

[0136] In one embodiment, cancer treatment efficacy is evaluated using the "Unidimensional irRC" as described in "Developing a Common Language for Tumor Response to Immunotherapy: Immune-related Response Criteria using Unidimensional measurements" by Nishino et al., Clin Cancer Res. 19(14):3936-3943) (2013). These criteria utilize the longest diameter (cm) of each lesion.

[0137] In one embodiment, the therapies or treatments described herein induce an antitumor response in a patient. “Antitumor response” means, in the case of a cancer patient being treated with a treatment regimen (e.g., the anti-BTLA therapy or anti-BTLA / anti-PD-(L)1 combination therapy described herein), at least one positive therapeutic effect, such as a reduction in the number of cancer cells, a reduction in tumor size, a reduction in the rate of cancer cell invasion into peripheral organs, a reduction in the rate of tumor metastasis or tumor growth, or progression-free survival. Positive therapeutic effects in cancer can be measured in many ways (see Weber, J. Nucl. Med. 50:1S-10S (2009)).

[0138] In one embodiment, the treatment achieved by the therapeutically effective dose is progression-free survival (PFS), disease-free survival (DFS), or overall survival (OS). PFS, also known as "time to tumor progression," represents the length of time during and after treatment when cancer does not grow, and includes the amount of time the patient experiences complete or partial remission, and the amount of time the patient experiences stability. DFS refers to the length of time the patient remains disease-free during and after treatment. OS refers to the extension of life expectancy compared to naive / untreated individuals or patients.

[0139] In one embodiment, the antitumor response to the therapies described herein is evaluated using the RECIST 1.1 standard, two-dimensional irRC, or one-dimensional irRC. In one embodiment, the antitumor response is one of SD, PR, CR, PFS, or DFS. "Two-dimensional irRC" refers to a set of criteria described in "Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria" by Wolchok JD et al., Clin Cancer Res. 15(23):7412-7420 (2009). These criteria are based on the longest diameter and longest vertical diameter (cm) of each lesion. 2 The results of the two-dimensional tumor measurement of the target lesion, obtained by multiplying by ), are used.

[0140] While the therapeutic methods, compositions, and specific modes of use disclosed herein may not effectively achieve positive therapeutic effects in every patient, they should achieve positive therapeutic effects in a statistically significant number of subjects as measured by any statistical test well known in the art (e.g., Student's t-test, Chi-test, Mann and Whitney U-test, Kruskal-Wallis test (H-test), Jonckheere-Terpstra test, and Wilcoxon test).

[0141] In another embodiment, the therapies disclosed herein reduce the tumor burden of a patient. "Tumor burden," also known as "tumor load," refers to the total amount of tumor material distributed throughout the body. Tumor burden refers to the total number of cancer cells throughout the body (including lymph nodes and bone marrow) or the total size of tumors. Tumor burden can be measured by various methods well known in the art, such as measuring the size of the tumor after it has been removed from the patient (e.g., using calipers) or by measuring the size of the tumor in vivo using imaging techniques (e.g., ultrasound, bone scan, computed tomography (CT) or magnetic resonance imaging (MRI) scan).

[0142] In another embodiment, the therapies disclosed herein reduce the size of a patient's tumor. The term “tumor size” means the total size of the tumor, which can be measured as the length and width of the tumor. Tumor size can be measured by measuring the size of the tumor after removal from the patient (e.g., using calipers) or by various methods well known in the art, such as in vivo imaging techniques (e.g., bone scans, ultrasound, CT or MRI scans).

[0143] In one embodiment, the anti-BTLA monotherapy or combination therapy described herein (e.g., in combination with anti-PD-1 or anti-PD-L1) produces a sustained response. “Sustained response” means a sustained therapeutic effect after discontinuation of treatment with the therapeutic agent or combination therapy described herein. In one embodiment, the sustained response has a duration at least the same as the duration of treatment, or at least 1.5, 2.0, 2.5, or 3 times the duration of treatment.

[0144] In one embodiment, the anti-BTLA monotherapy or combination therapy described herein (e.g., in combination with anti-PD-1 or anti-PD-L1) achieves an objective remission rate (ORR) of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 80%, 90%, or 95%. In another embodiment, anti-BTLA monotherapy or combination therapy achieves objective remission rates (ORRs) of 10%–15%, 15%–20%, 20%–25%, 25%–30%, 30%–35%, 35%–40%, 40%–45%, 45%–50%, 50%–55%, 55%–60%, 60%–65%, 65%–70%, 75%–80%, 85%–90%, or 90%–95%. In another embodiment, the above ORR is achieved within 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 months after the first dose. In another embodiment, the ORR described above may be evaluated by one or more of the following standard systems: RECIST, RECIST 1.1, one-dimensional immune-associated response standards (irRCs), and two-dimensional irRCs.

[0145] As used herein, “objective remission rate” refers to the percentage of patients who achieve objective remission. “Objective remission” refers to measurable remission, including complete remission (CR) or partial remission (PR). “Complete response” or “complete remission” refers to the disappearance of all signs of cancer in response to treatment. This does not always mean that the cancer is cured. “Partial remission” refers to a response to treatment, resulting in a reduction in the size of one or more tumors or lesions or a reduction in the extent of cancer in vivo.

[0146] Biomarkers / Patient populations In one embodiment, the cancer being treated is PD-L1 positive. A "PD-L1 positive" cancer is a cancer that includes cells on which PD-L1 is present on the cell surface. Preferably, the cancer according to this disclosure is "PD-L1 positive" if at least 0.1% to at least 10% of the cancer cells have PD-L1 on their cell surface. More preferably, the cancer is "PD-L1 positive" if at least 0.5% to 5% of the cancer cells have PD-L1 on their cell surface. Most preferably, the cancer is "PD-L1 positive" if at least 1%, 2%, 5%, 10%, 20%, 25%, 30%, 40%, 50%, 60%, or 70% of the cancer cells have PD-L1 on their cell surface.

[0147] The term "PD-L1 positive" also refers to cancers that produce sufficient levels of PD-L1 on their cell surface, and in such cases, anti-PD-L1 inhibitors (e.g., antibodies) have a therapeutic effect mediated by the binding of the anti-PD-L1 inhibitor (e.g., antibody) to PD-L1.

[0148] Unless otherwise defined, "PD-L1" or "PD-L2" expression means any detectable level of expression of a specific PD-L protein on the cell surface, or any detectable level of expression of a specific PD-L mRNA within a cell or tissue. PD-L protein expression can be detected in immunohistochemistry (IHC) assays of tumor tissue sections by diagnostic PD-L antibodies or flow cytometry. Alternatively, PD-L protein expression in tumor cells can be detected by PET imaging using a binder (e.g., antibody fragment, affinity, etc.) that specifically binds to a desired PD-L target (e.g., PD-L1 or PD-L2). Techniques for detecting and measuring PD-L mRNA expression include RT-PCR and real-time quantitative RT-PCR.

[0149] Similarly, unless otherwise defined, HVEM expression means any detectable level of HVEM protein expression on the cell surface, or any detectable level of HVEM mRNA expression within a cell or tissue. HVEM protein expression can be detected by diagnostic HVEM antibody or flow cytometry in an IHC assay of tumor tissue sections. Alternatively, HVEM protein expression in tumor cells can be detected by PET imaging using a binder that specifically binds to HVEM (e.g., antibody fragment, affinity, etc.). Techniques for detecting and measuring HVEM mRNA expression include RT-PCR and real-time quantitative RT-PCR.

[0150] Several methods have been described for quantifying PD-L1 protein expression in IHC assays of tumor tissue sections. See, for example, Thompson et al., PNAS 101(49):17174-17179 (2004), Thompson et al., Cancer Res. 66:3381-3385 ​​(2006), Gadiot et al., Cancer 117:2192-2201 (2011), Taube et al., Sci Transl Med 4, l27ra37 (2012), and Toplian et al., New Eng. J Med. 366(26):2443-2454 (2012). Similar methods can be used to quantify HVEM expression in tumor tissue. See also Inoue et al., Anticancer Research 35(3):1361-1367 (2015), Malissen et al., Oncoimmunology 8(12):e1665976 (2019), Fang et al., Journal of BUON 22(1):80-86 (2017), and Ren et al., Lung Cancer 125:115-20 (2018). Similarly, CD8 expression in tumor tissue can be quantified by several methods. See, for example, Si et al., BMC Cancer 22:211 (2022), and Cai et al., Frontiers in Immunology, August 2021, Vol. 12, document 704965.

[0151] In one embodiment, the expression of a protein biomarker is determined by a tumor percentage score (TPS), which refers to the percentage of viable tumor cells that exhibit partial or complete membrane staining at any density. For PD-L1 expression, various immunohistochemical assays (e.g., 28-8, 22C3, SP263, and SP142) can be used. See Prince et al., JCO Precision Oncology no. 5, 953-973 (2021). In one embodiment, if TPS ≥ 1%, the tumor sample is considered to have PD-L1 expression, and if TPS ≥ 50%, the tumor sample is considered to have high PD-L1 expression. Unless otherwise specified, the quantification of biomarker expression disclosed herein (e.g., PD-L1, HVEM, or CD8) is performed according to the assays referenced herein or according to comparable assays applicable to the biomarker expression thresholds disclosed herein.

[0152] formulation In one embodiment, the anti-BTLA antibody or its antigen-binding fragment used herein is found in the formulation described in PCT / CN2021 / 072660.

[0153] In one embodiment, the anti-BTLA antibody or its antigen-binding fragment is a preparation comprising 10 mM to 30 mM histidine buffer, 30 mM to 100 mM sodium chloride, 50 mM to 200 mM trehalose, 0.01% to 0.05% polysorbate 80, and 10 mg / mL to 50 mg / mL of the anti-BTLA antibody or its antigen-binding fragment, wherein the histidine buffer contains histidine to histidine hydrochloride in a molar ratio of 1:2 to 1:5, for example, 1:2, 1:3, 1:4, or 1:5.

[0154] In another embodiment, the anti-BTLA antibody or its antigen-binding fragment is a preparation comprising about 20 mM histidine buffer, about 50 mM sodium chloride, about 140 mM trehalose, about 0.02% polysorbate 80, and about 20 mg / mL of the anti-BTLA antibody or its antigen-binding fragment, wherein the histidine buffer contains histidine to histidine hydrochloride in a molar ratio of 1:3.

[0155] Furthermore, the therapeutic agents disclosed herein may be in various formulations. Examples of pharmaceutically acceptable excipients of this disclosure include solvents, fillers, buffers, tension modifiers, and preservatives (see, for example, Pramanick et al., Pharma Times, 45:65-77 (2013)). In one embodiment, a pharmaceutical composition may include an excipient that functions as one or more of a solvent, filler, buffer, and tension modifier (for example, sodium chloride in saline solution can function as both an aqueous vehicle and a tension modifier). The pharmaceutical compositions of this disclosure are suitable for parenteral administration.

[0156] In one embodiment, the pharmaceutical composition comprises an aqueous vehicle as a solvent. Suitable vehicles include, for example, sterile water, physiological saline, phosphate-buffered saline, and Ringer's solution. In one embodiment, the composition is isotonic.

[0157] Pharmaceutical compositions may contain fillers. Fillers are particularly useful when the pharmaceutical composition is freeze-dried before administration. In one embodiment, the filler is a protective agent that helps stabilize the activator and prevent its degradation during freeze-drying or spray-drying and / or storage. Suitable fillers are sugars (monosaccharides, disaccharides, and polysaccharides) such as sucrose, lactose, trehalose, mannitol, sorbitol, glucose, and raffinose.

[0158] The pharmaceutical composition may contain a buffer. The buffer controls the pH to inhibit the degradation of the activator during processing, storage, and optionally during reconstitution. Suitable buffers include, for example, salts containing acetates, citrates, phosphates, or sulfates. Other suitable buffers include amino acids such as arginine, glycine, histidine, and lysine. The buffer may also contain hydrochloric acid or sodium hydroxide. In one embodiment, the buffer maintains the pH of the composition in the range of 4 to 9. In one embodiment, the pH is greater than (lower limit) 4, 5, 6, 7, or 8. In one embodiment, the pH is less than (upper limit) 9, 8, 7, 6, or 5. That is, the pH is in the range of approximately 4 to 9, where the lower limit is less than the upper limit.

[0159] The pharmaceutical composition may contain a tonicity modifier. Suitable tonicity modifiers include, for example, glucose, glycerin, sodium chloride, glycerol, and mannitol.

[0160] The pharmaceutical composition may contain preservatives. Suitable preservatives include, for example, antioxidants and antimicrobial agents. However, in a preferred embodiment, the pharmaceutical composition does not need to contain preservatives because it is prepared under sterile conditions and contained in disposable containers.

[0161] In one embodiment, a drug containing an anti-BTLA antibody or its antigen-binding fragment, or an anti-PD-1 antibody or its antigen-binding fragment, can be provided as a liquid formulation or a lyophilized formulation.

[0162] In one embodiment, the drug described herein may be provided as a reagent kit comprising a first container, a second container, and a package insert. The first container contains at least one dose of the drug comprising a PD-1 antagonist, the second container contains the drug comprising an anti-BTLA antibody or its antigen-binding fragment, and the package insert or label comprises instructions for treating cancer patients with the drug. The first and second containers may consist of the same or different shapes (e.g., vials, syringes, and cans) and / or materials (e.g., plastic or glass). The reagent kit may further include diluents, filters, intravenous bags and lines, needles, and syringes useful for administering other drugs. In some preferred embodiments of the reagent kit, the PD-1 antagonist is an anti-PD-1 antibody or its antigen-binding fragment, and the instructions state that the drug is for treating cancer patients who are positive for PD-L1 expression as measured by an IHC assay. In some embodiments, the reagent kit may further include one or more of the chemotherapeutic agents described in this disclosure, particularly etoposide, carboplatin, cisplatin, and docetaxel.

[0163] As will be apparent to those skilled in the art, other suitable modifications and adjustments can be made to the methods described herein using appropriate equivalents without departing from the scope of the embodiments disclosed herein. Several aspects have been described in detail so far, and these aspects will be understood more clearly by referring to the following examples, which are included for illustrative purposes only and are not intended to be limiting. All patents, patent applications, and references described herein are incorporated by reference in their entirety for all purposes. [Examples]

[0164] Example 1: Phase I / IIb study evaluating the combination of TAB004 (also known as icatolimab or tifcemalimab) and tripalimab. A phase I / IIb, open-label, two-part study was conducted to evaluate the safety, tolerance, pharmacokinetics, immunogenicity, and antitumor activity of the combination of TAB004 and tripalimab in adult patients with advanced lung cancer. Each cycle was 21 days (3 weeks), and each cycle included the administration of both TAB004 and JS001 by intravenous (IV) injection once every 3 weeks. All subjects received treatment until disease progression occurred according to RECIST v1.1 and iRECIST, or until unacceptable toxicity occurred according to CTCAE 5.0, consent was withdrawn, or the study was terminated (whichever came first). Disease progression should be confirmed at least 4 to 8 weeks after the first record of progression.

[0165] The study in question consists of two parts: Part A (safety induction phase) and Part B (cohort expansion). When 240 mg of tripalimab was administered in combination with intravenous Q3W, TAB004 was evaluated in both Part A and Part B.

[0166] Approximately 6 participants were placed in Part A of this study, and approximately 35 to 78 participants were placed in Part B. Based on the safety and therapeutic efficacy data that emerged from the trial, additional participants were recruited. Participants could not participate in this study unless they met all of the following acceptance criteria.

[0167] 1. The test taker understands and can sign the Informed Consent Form (ICF).

[0168] 2. Applicants must be male or female and 18 years of age or older.

[0169] 3. The test taker's ECOG physical ability score is 0 or 1, and from the researcher's perspective, their life expectancy is ≥3 months.

[0170] 4. The examinee was pathologically diagnosed with partially advanced, metastatic, or recurrent lung cancer, including NSCLC and SCLC.

[0171] In Part A and Cohort I, examinees must have received, failed to receive, or been intolerant to all available approved or standard therapies, or received a therapy lower than third-line, or received no more than one anti-PD-(L)1 inhibitor therapy, but must not have received all standard therapies known to provide clinical benefit.

[0172] In region B, test subjects who do not have known EGFR-sensitive mutations (such as exon 19 deletion or exon 21 L858R, exon 21 L861Q, exon 18 G719X, or exon 20 S768I mutations) and ALK fusions, and test subjects with squamous cell carcinoma, will not be required to undergo gene detection.

[0173] 1. The examinee was pathologically diagnosed with advanced small cell lung cancer (ES-SCLC, staging by the Veterans Administration Lung Study Group (VALG)).

[0174] 2. The test subjects had measurable diseases based on RECIST v1.1 and iRECIST.

[0175] 3. Participants must voluntarily consent to provide cancer tissue samples (participants who are unable to provide some tissue samples will be placed in the cohort with the consent of the researchers and the sponsor).

[0176] 4. The examinee must have organ functions that meet the requirements, as defined below: a) Hematology (no blood transfusions within the last 14 days, and no blood component therapy or granulocyte colony-stimulating factor therapy has been used) b) Liver function: Serum total bilirubin (TBil) ≤ 1.5 × ULN, transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 × ULN, and for liver transplant recipients, AST and ALT ≤ 5 × ULN.

[0177] c) Renal function: Serum creatinine ≤ 1.25 × ULN, or calculated creatinine clearance (CrC1) ≥ 50 mL / min (calculated according to the Cockcroft-Gault formula). d) Coagulation function: International normalized ratio (INR) ≤ 1.5, prothrombin time (PT) or activated partial thromboplastin time (APTT) ≤ 1.5 × ULN.

[0178] e) Thyroid function: Thyroid-stimulating hormone (TSH) levels are normal, or TSH levels are abnormal but FT3 and FT4 levels are normal (individuals with hypothyroidism whose TSH levels are abnormal but FT4 levels are normal).

[0179] 1. Female test subjects who may become pregnant must use effective contraception from the time of screening and must agree to continue using such preventive measures for six months after receiving the last dose of therapy.

[0180] 2. Uncastrated male test subjects who have sexual intercourse with a female partner who may become pregnant must use effective contraception from day 1 and continue it for six months after receiving the last dose of therapy.

[0181] Part A: Safe induction phase, combined intravenous administration of TAB004 and JS001: In the A portion of this Phase I / II study (NCT05000684), a total of six lung cancer patients were enrolled. This portion was conducted to evaluate the safety, tolerance, pharmacokinetics, and preliminary therapeutic effects of combination therapy with TAB004 and JS001. Each participant received a fixed dose of 240 mg of JS001 and a fixed dose of 100 mg or 200 mg of TAB004 every three weeks until disease progression or unbearable toxicity occurred.

[0182] Part B: Cohort expansion, combined intravenous administration of TAB004 and JS001: In Part B, participants were patients with advanced lung cancer who had received all available approved or standard therapies but had failed treatment. The patients were divided into two cohorts to further evaluate the safety and therapeutic efficacy of the combination of TAB004 and JS001.

[0183] Cohort I: Patients with advanced non-small cell lung cancer. Up to 35 patients were enrolled in this cohort. In the first phase, 17 patients were enrolled (patients with the same disease in Part A were included in this phase). The second phase was initiated when more than one patient achieved remission. In the second phase, 18 patients were enrolled.

[0184] Cohort II: Patients with advanced small cell lung cancer. Up to 43 patients were enrolled in the cohort. In the first stage, 18 patients were enrolled (patients with the same disease as in Part A were included in this stage). The second stage was initiated when more than two patients achieved remission. In the second stage, 25 patients were enrolled. In Part B, all patients received a standard 240 mg dose of JS001 and intravenous administration of TAB004 at a Q3W dose of 100 mg or 200 mg. One treatment cycle was 21 days, and administration continued until disease progression, unacceptable toxicity occurred, or treatment was discontinued for other reasons.

[0185] Example 2: Therapeutic effects of combining TAB004 and JS001 in the treatment of ES-SCLC Enrolled patients were those pathologically diagnosed with ES-SCLC and who had drug resistance to previous systemic therapies. Patients participating in the study received intravenous administration of 200 mg tifcemalimab and 240 mg tripalimab every three weeks until disease progression, unacceptable toxicity occurred, or completion of treatment up to two years. Primary endpoints included safety and objective remission rates (ORR), as assessed by the researchers according to RECIST v1.1.

[0186] By December 16, 2023, a total of 43 ES-SCLC patients with drug resistance to previous treatments had been enrolled. Of these, 13 (30.2%) had received previous immunotherapy, 25 (58.1%) had not, and the status of previous immunotherapy was unknown for 5. The median number of previous treatment lines was 1. The median age was 59.0 years (ranging from 38 to 75 years), and 34 (79.1%) were male, with a median number of previous treatment lines of 1. Up to the data cutoff date, 39 (90.7%) of patients experienced adverse events (TEAEs) during treatment, and 17 (39.5%) experienced TEAEs of ≥Grade 3. The most common TEAEs included anemia (23.3%), elevated serum creatine phosphate kinase (23.3%), hyponatremia (20.9%), elevated alanine aminotransferase (20.9%), and hyperglycemia (20.9%). Five patients (11.6%) experienced treatment-related adverse events (TRAEs) leading to discontinuation of the study drug, while no TRAEs leading to withdrawal were reported. Eighteen patients (41.9%) experienced immune-related AEs (irAEs), and five patients (11.6%) experienced irAEs of ≥grade 3. In the 40 evaluable patients, the ORR was 32.6% (14 / 43), the DCR was 51.2% (22 / 43), the median PFS was 3.8 months (95% CI 1.4, 8.3), and the median OS was 12.7 months (95% CI 7.8, NE). Of the 25 patients who had not received immunotherapy, 22 were evaluable, with ORR and DCR rates of 44.0% (11 / 25) and 60.0% (15 / 25), respectively. All patients and those who had not received immunotherapy had a median PFS of 2.8 months (95% CI 1.4, 4.4) and 3.8 months (95% CI 1.4, 8.2), respectively, and a median OS of 12.7 months (95% CI 7.8, NE) in both groups. Evaluation of HVEM and PD-L1 expression in tumors and their association with clinical response revealed that patients with positive PD-L1 or HVEM expression, as demonstrated by preliminary biomarker analysis of available tumor tissue, showed higher ORR and DCR.Further biomarker analysis will be updated.

[0187] Example 3: Therapeutic effect of combining TAB004 and JS001 in first-line treatment for ES-SCLC Patients with ES-SCLC who had not previously received systemic antitumor therapy were eligible to participate in the study. Patients received intravenous administration of tifcemalimab 200 mg and tripalimab 240 mg in combination with standard chemotherapy (etoposide + carboplatin / cisplatin) every three weeks (Q3W) for four cycles, until disease progression, unacceptable toxicity occurred, or completion of two years of treatment. Subsequently, treatment was maintained with tifcemalimab and tripalimab in combination. The primary endpoints included safety and objective remission rates (ORR) as assessed by the researchers according to RECIST v1.1.

[0188] As of December 28, 2023, a total of 44 ES-SCLC patients were enrolled, with a median follow-up time of 8.3 weeks. The median age of the patients was 65.5 years (ranging from 48 to 73 years), and 84.1% (37 / 44) were male. 41 patients (93.2%) experienced treatment-related adverse events (TEAEs), and 26 patients (59.1%) experienced TEAEs of ≥grade 3. The most common TEAEs included leukopenia (65.9%), neutropenia (63.6%), anemia (40.9%), and thrombocytopenia (40.9%). There were no discontinuations of tifcemalimab or tripalimab due to treatment-related adverse events. Four patients (9.1%) experienced immune-related adverse events (irAEs), and one patient experienced an irAE of ≥grade 3. In 37 evaluable patients, 32 partial responses (PR) and 5 stable diseases (SD) were observed. The overall response rate (ORR) was 86.5% (32 / 37), and the disease control rate (DCR) was 100% (37 / 37). 94.6% of responses remained active up to the data cutoff date, and the median response duration had not yet been reached. Evaluation of HVEM and PD-L1 expression in tumors and their association with clinical response revealed that 100% ORR was observed in patients with positive PD-L1 or HVEM expression based on preliminary biomarker analysis of tumor tissue. Further biomarker analysis will be updated.

[0189] Example 4: Therapeutic efficacy of combination therapy with TAB004, JS001, and docetaxel in the second-line treatment of squamous cell NSCLC. Patients who do not experience progression of squamous cell NSCLC after treatment with platinum-containing dual therapy and PD-1 / PD-L1 inhibitors are eligible to participate in the study. Patients will receive tifcemalimab 200 mg and tripalimab 240 mg, and docetaxel 75 mg / m² until disease progression, unacceptable toxicity occurs, or completion of 2 years of treatment. 2 The drug was administered intravenously once every three weeks (Q3W) in combination with another drug. The primary endpoints included safety and objective remission rates (ORR), as assessed by the researchers according to RECIST v1.1.

[0190] As of March 7, 2024, a total of 34 patients with squamous NSCLC were enrolled. No new safety signals were observed. Among the 33 evaluable patients, 8 partial responses (PR) and 20 stable diseases (SD) were observed. The overall response rate (ORR) was 24.2% (8 / 33), and the disease coverage rate (DCR) was 84.8% (28 / 33). To the data cutoff date, the median follow-up time was 5.11 months, the median progression-free survival (PFS) was 6.9 months (95% CI 3.8, NE), and the median overall survival (OS) (95% CI 7.1, NE) was not reached. Further biomarker analyses will be updated to explore the association between HVEM and PD-L1 expression in tumors and clinical response.

Claims

1. A method for treating a solid tumor in a patient in need, the method comprising administering to the patient a therapeutically effective amount of an anti-BTLA antibody or its antigen-binding fragment, wherein the solid tumor is lung cancer. method.

2. The solid tumor is selected from non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). The method according to claim 1.

3. The solid tumor is extensive-stage small cell lung cancer (ES-SCLC). The method according to any one of claims 1 to 2.

4. The aforementioned solid tumor expresses HVEM. The method according to any one of claims 1 to 3.

5. At least approximately 1%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% of tumor cells are positive for HVEM. The method according to claim 4.

6. The solid tumor co-expresses HVEM and CD8. The method according to any one of claims 1 to 5.

7. At least approximately 1%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% of tumor cells are positive for HVEM and CD8. The method according to claim 6.

8. Anti-PD-1 antibodies or their antigen-binding fragments are used as adjuvant therapy. The method according to any one of claims 1 to 7.

9. The aforementioned patient has previously received at least first-line, second-line, or third-line treatment. The method according to any one of claims 1 to 8.

10. The patient has previously received at least one chemotherapy and / or immunotherapy treatment. The method according to any one of claims 1 to 7.

11. The patient has previously received at least one treatment selected from chemotherapy, radiation therapy, surgery, adjuvant therapy, molecular targeted drugs, and immune checkpoint inhibitors. The method according to any one of claims 1 to 7.

12. The patient receives a therapeutically effective dose of the anti-BTLA antibody or its antigen-binding fragment in combination with an anti-PD-1 antibody or its antigen-binding fragment, or the patient receives a therapeutically effective dose of the anti-BTLA antibody or its antigen-binding fragment in combination with an anti-PD-1 antibody or its antigen-binding fragment and one or more chemotherapeutic agents. The method according to any one of claims 1 to 7.

13. The one or more chemotherapeutic agents are selected from alkylating agents, nitrosourea agents, antimetabolites, antitumor antibiotics, plant-derived alkaloids, topoisomerase inhibitors, hormone therapy agents, hormone antagonists, aromatase inhibitors, P-glycoprotein inhibitors, and platinum complex derivatives. The method according to claim 12.

14. The anti-BTLA antibody or its antigen-binding fragment is administered by intravenous injection. The method according to any one of claims 1 to 13.

15. The anti-BTLA antibody or its antigen-binding fragment is administered intravenously in a fixed dose of 20 mg to 500 mg for Q3W, or the anti-BTLA antibody or its antigen-binding fragment is administered intravenously in a fixed dose of approximately 20 mg, 30 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, or 500 mg for Q3W. The method according to any one of claims 1 to 14.

16. The anti-BTLA antibody or its antigen-binding fragment is administered intravenously at least once every 1, 2, 3, 4, 5, 6, 7, 8, or 9 weeks, or, in this case, the anti-BTLA antibody or its antigen-binding fragment is administered intravenously at least once every 1, 2, 3, 4, 5, 6, 7, 8, or 9 weeks. The method according to any one of claims 1 to 15.

17. The anti-BTLA antibody or its antigen-binding fragment is administered intravenously in fixed doses of at least approximately 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, or 450 mg at a frequency selected from Q1W, Q2W, Q3W, Q4W, Q5W, Q6W, Q7W, Q8W, and Q9W, or the anti-BTLA antibody or its antigen-binding fragment is administered in doses of approximately 20 mg to approximately 500 mg, approximately 30 mg to approximately 450 mg, approximately 50 mg to approximately 400 mg, approximately 75 mg to approximately 350 mg, approximately 100 mg to approximately 300 mg, approximately 125 mg to approximately 275 mg, or approximately 150 mg. The anti-BTLA antibody or its antigen-binding fragment is administered intravenously in a fixed dose of approximately 20 mg to approximately 250 mg for Q3W, or the anti-BTLA antibody or its antigen-binding fragment is administered intravenously in a fixed dose of approximately 20 mg to approximately 50 mg, approximately 50 mg to approximately 100 mg, approximately 100 mg to approximately 150 mg, approximately 150 mg to approximately 200 mg, approximately 200 mg to approximately 250 mg, approximately 250 mg to approximately 300 mg, approximately 300 mg to approximately 350 mg, or approximately 350 mg to approximately 400 mg for Q3W, or the anti-BTLA antibody or its antigen-binding fragment is administered intravenously in a fixed dose of approximately 20 mg, 70 mg, 100 mg, 200 mg, or 500 mg for Q3W. The method according to any one of claims 1 to 15.

18. The anti-BTLA antibody or its antigen-binding fragment is administered in a treatment regimen lasting at least 3 weeks, 6 weeks, 9 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 42 weeks, 46 weeks, 50 weeks, 54 weeks, 58 weeks, 62 weeks, or 66 weeks or months. The method according to any one of claims 1 to 17.

19. The anti-BTLA antibody is bound to human BTLA and is a chimeric antibody, a humanized antibody, or a human antibody, or the anti-BTLA antibody is a domain antibody or a bivalent antibody, or it includes a heavy chain constant region of IgG1, IgG2, IgG3, or IgG4 isotype, and optionally includes a substitution of serine 227 to proline in the hinge region of the heavy chain, or the anti-BTLA antibody or its antigen-binding fragment is glycosylated, where the antigen-binding fragment of the anti-BTLA antibody is Fab', F(ab') ２ Selected from Fv, scFv, and sdAb, The method according to any one of claims 1 to 18.

20. The anti-BTLA antibody or its antigen-binding fragment comprises an LCDR1 having the amino acid sequence shown in SEQ ID NO: 1, an LCDR2 having the amino acid sequence shown in SEQ ID NO: 2, an LCDR3 having the amino acid sequence shown in SEQ ID NO: 3, an HCDR1 having the amino acid sequence shown in SEQ ID NO: 4, an HCDR2 having the amino acid sequence shown in SEQ ID NO: 5, and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 6, or the anti-BTLA antibody or its antigen-binding fragment comprises a light chain variable region (LCVR) sequence shown in SEQ ID NO: 7 and a heavy chain variable region (HCVR) sequence shown in SEQ ID NO: 8, or the anti-BTLA antibody or its antigen-binding fragment comprises a light chain sequence shown in SEQ ID NO: 9 and a heavy chain sequence shown in SEQ ID NO:

10. The method according to any one of claims 1 to 19.

21. The anti-BTLA antibody or its antigen-binding fragment is present in a composition containing an effective amount of the anti-BTLA antibody or its antigen-binding fragment, a solubilizer, and a stabilizer in a solution. The method according to any one of claims 1 to 20.

22. The solubilizing agent comprises polysorbate 80. The method according to claim 21.

23. The aforementioned stabilizer includes a combination of sodium chloride and trehalose. The method according to claim 21.

24. The anti-BTLA antibody or its antigen-binding fragment is contained in a formulation comprising 10 mM to 30 mM histidine buffer, 30 mM to 100 mM sodium chloride, 50 mM to 200 mM trehalose, 0.01% to 0.05% polysorbate 80, and 10 mg / mL to 50 mg / mL of the anti-BTLA antibody or its antigen-binding fragment, wherein the histidine buffer contains histidine to histidine hydrochloride in a molar ratio of 1:2 to 1:5, such as 1:2, 1:3, 1:4, or 1:

5. The method according to any one of claims 1 to 23.

25. The formulation comprises approximately 20 mM histidine buffer, approximately 50 mM sodium chloride, approximately 140 mM trehalose, approximately 0.02% polysorbate 80, and approximately 20 mg / mL of the anti-BTLA antibody or its antigen-binding fragment, wherein the histidine buffer comprises histidine to histidine hydrochloride in a molar ratio of 1:

3. The method according to claim 24.

26. Approximately 70%, 60%, 50%, 40%, 30%, 25%, 20%, or less than 10% of patients experience Grade 3 or higher adverse events (TEAEs) during the treatment period in response to the said treatment, or 10% to 70%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 10% to 25%, or 10% to 20% of patients experience Grade 3 or higher adverse events (TEAEs) during the treatment period in response to the said treatment. The method according to any one of claims 1 to 25.

27. The method further comprises administering an effective amount of anti-PD-1 or its antigen-binding fragment, or anti-PD-L1 antibody or its antigen-binding fragment, to the patient. The method according to any one of claims 1 to 26.

28. The anti-PD-1 antibody is selected from nivolumab, pembrolizumab, tripalimab, cintilimab, camrelizumab, tislerizumab, or semiprimab. The method according to claim 27.

29. The anti-PD-1 antibody or the anti-PD-L1 antibody is administered in a dose of approximately 240 mg. The method according to claim 28.

30. The anti-PD-1 antibody or the anti-PD-L1 antibody is administered in a Q3W dose of approximately 240 mg. The method according to claim 29.

31. (i) an anti-BTLA antibody or its antigen-binding fragment and (ii) the anti-PD-1 antibody or its antigen-binding fragment, or the anti-PD-L1 antibody or its antigen-binding fragment, are administered sequentially to the patient, wherein the administration interval does not exceed 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, or 24 hours, or is less than 1 day, 2 days, 3 days, 4 days, 5 days, or 6 days. The method according to any one of claims 27 to 3029.

32. The (i) anti-BTLA antibody or its antigen-binding fragment and (ii) the anti-PD-1 antibody or its antigen-binding fragment, or the anti-PD-L1 antibody or its antigen-binding fragment, are co-formulated. The method according to any one of claims 1 to 31.

33. A method for inhibiting tumor growth in a patient in need, comprising co-administering to the patient an effective amount of anti-BTLA antibody or its antigen-binding fragment and an effective amount of anti-PD-1 antibody or its antigen-binding fragment, or anti-PD-L1 antibody or its antigen-binding fragment, wherein the anti-BTLA antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment, or the anti-PD-L1 antibody or its antigen-binding fragment, inhibit the tumor growth in the patient, wherein the tumor is lung cancer. method.

34. The anti-PD-1 antibody is selected from nivolumab, pembrolizumab, tripalimab, cintilimab, camrelizumab, tislerizumab, or semiprimab. The method according to claim 3233.

35. The patient receives intravenous co-administration of an anti-BTLA antibody or its antigen-binding fragment in a fixed Q3W dose of approximately 20 mg to 500 mg, and an anti-PD-1 antibody or its antigen-binding fragment in a dose of approximately 240 mg, or the anti-PD-L1 antibody or its antigen-binding fragment. The method according to claim 33 or 34.

36. The patient receives intravenous co-administration of a fixed Q3W dose of approximately 20 mg, 70 mg, 100 mg, 200 mg, or 500 mg of anti-BTLA antibody or its antigen-binding fragment, and approximately 240 mg of anti-PD-1 antibody or its antigen-binding fragment, or the anti-PD-L1 antibody or its antigen-binding fragment. The method according to any one of claims 33 to 35.

37. A method for treating non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), or advanced small cell lung cancer (ES-SCLC) in patients in need, the method comprising the patient receiving a therapeutically effective dose of an anti-BTLA antibody or its antigen-binding fragment in combination with an anti-PD-1 antibody or its antigen-binding fragment. method.

38. The aforementioned NSCLC is selected from stages IIIB, IIIC, or IV. The method according to claim 37.

39. The aforementioned NSCLC patient has previously received PD-1 / L1 treatment, and the aforementioned ES-SCLC patient has either previously received PD-1 / L1 treatment or has not received it. The method according to claim 37 or 38.

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