Method for treating solid tumors

Abstract

Methods for treating solid tumors are provided herein. Specifically, methods for treating solid tumors, such as advanced and / or metastatic solid tumors, using bispecific antibodies are provided.

Description

Technical Field

[0001] The present application relates to a method for treating solid tumors. Specifically, provided is a method for treating solid tumors, such as progressive and / or metastatic solid tumors, using bispecific antibodies.

Background Art

[0002] Claudin is a family of proteins that form important components of tight cell junctions. Claudin-18 splice variant 2 (CLDN18.2) is a stomach-specific membrane protein. In healthy tissues, CLDN18.2 is expressed limitedly in short-lived differentiated cells of the gastric mucosa as a component of tight cell junctions, and access to antibody therapy is limited. However, it is ectopically expressed at significant levels in various primary lesions and metastases of epithelial tumor entities, including gastric, pancreatic, esophageal, and lung adenocarcinoma cells.

[0003] CLDN18.2 is regarded as a therapeutic target with great potential for gastric and other types of solid tumors, providing a new option for cancer treatment.

Summary of the Invention

[0004] The present application addresses the clinical need with bispecific antibodies targeting CLDN18.2.

[0005] In one aspect, a method for treating a solid tumor, comprising administering to a subject in need of treatment of the solid tumor a bispecific antibody comprising (1) an anti-claudin 18.2 (CLDN18.2) unit having binding specificity for the CLDN18.2 protein, and (2) a second antibody unit, wherein the bispecific antibody is administered to the subject at a dosage of about 0.1 to about 30 mg / kg body weight, is provided.

[0006] In some embodiments, the second antibody unit has binding specificity for a target selected from the group consisting of 4-1BB, PD-1, PD-L1, and CD3. In some embodiments, the second antibody comprises an anti-4-1BB unit having binding specificity for the 4-1BB protein.

[0007] In some embodiments, the bispecific antibody is administered to a subject at a dose of about 0.1 to about 15 mg / kg body weight. In some embodiments, the bispecific antibody is administered to a subject at a dose of about 0.3 to about 15 mg / kg body weight. In some embodiments, the bispecific antibody is administered to a subject at a dose of about 1 to about 15 mg / kg body weight. In some embodiments, the bispecific antibody is administered to a subject at a dose of about 3 to about 15 mg / kg body weight. In some embodiments, the bispecific antibody is administered to a subject at a dose of about 5 to about 15 mg / kg body weight. In some embodiments, the bispecific antibody is administered to a subject at a dose of about 8 to about 15 mg / kg body weight. In some embodiments, the bispecific antibody is administered to a subject at a dose of about 12 to about 15 mg / kg body weight. In some embodiments, the bispecific antibody is administered to a subject at a dose of about 8 to about 12 mg / kg body weight. In some embodiments, the bispecific antibody is administered to a subject at a dose of about 0.1, about 0.3, about 1, about 5, about 8, about 12, about 15, or about 30 mg / kg body weight. In some embodiments, the bispecific antibody is administered to a subject at a dose of about 5, about 8, about 12, or about 15 mg / kg body weight.

[0008] In some embodiments, the bispecific antibody is administered to a subject weekly, biweekly, once every three weeks, or monthly. In some embodiments, the bispecific antibody is administered to a subject biweekly.

[0009] In some embodiments, the bispecific antibody is administered to a subject intravenously.

[0010] In some embodiments, the anti-CLDN18.2 unit is selected from the group consisting of a full-length antibody, Fab, Fab’, F(ab’)2, scFv, and sdAb. In some embodiments, the anti-CLDN18.2 unit comprises a Fab.

[0011] In some embodiments, the anti-CLDN18.2 unit comprises HC-CDR1, HC-CDR2, and HC-CDR3, each comprising the amino acid sequences of CDR1, CDR2, and CDR3 within the heavy variable region (VH) set forth in SEQ ID NO: 1. In some embodiments, the anti-CLDN18.2 unit comprises (1) HC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 3 or an amino acid sequence having one or more substitutions as compared to SEQ ID NO: 3, (2) HC-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 4 or an amino acid sequence having one or more substitutions as compared to SEQ ID NO: 4, and (3) HC-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 5 or an amino acid sequence having one or more substitutions as compared to SEQ ID NO: 5. In some embodiments, the anti-CLDN18.2 unit comprises a heavy variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO: 1 or an amino acid sequence having at least 90% identity to SEQ ID NO: 1.

[0012] In some embodiments, the anti-CLDN18.2 unit comprises LC-CDR1, LC-CDR2, and LC-CDR3, each comprising the amino acid sequences of CDR1, CDR2, and CDR3 within the light variable region (VL) set forth in SEQ ID NO: 2. In some embodiments, the anti-CLDN18.2 unit comprises (1) LC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 6 or an amino acid sequence having one or more substitutions as compared to SEQ ID NO: 6, (2) LC-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 7 or an amino acid sequence having one or more substitutions as compared to SEQ ID NO: 7, and (3) LC-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 8 or an amino acid sequence having one or more substitutions as compared to SEQ ID NO: 8. In some embodiments, the anti-CLDN18.2 unit comprises a light variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 2 or an amino acid sequence having at least 90% identity to SEQ ID NO: 2.

[0013] In some embodiments, the anti-CLDN18.2 unit comprises (1) HC-CDR1, HC-CDR2, and HC-CDR3, each comprising the amino acid sequence of CDR1, CDR2, and CDR3 within the heavy variable region (VH) set forth in SEQ ID NO: 1, and (2) LC-CDR1, LC-CDR2, and LC-CDR3, each comprising the amino acid sequence of CDR1, CDR2, and CDR3 within the light variable region (VL) set forth in SEQ ID NO: 2. In some embodiments, the anti-CLDN18.2 unit comprises (1) HC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 3 or an amino acid sequence having one or more substitutions as compared to SEQ ID NO: 3, (2) HC-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 4 or an amino acid sequence having one or more substitutions as compared to SEQ ID NO: 4, (3) HC-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 5 or an amino acid sequence having one or more substitutions as compared to SEQ ID NO: 5, (4) LC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 6 or an amino acid sequence having one or more substitutions as compared to SEQ ID NO: 6, (5) LC-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 7 or an amino acid sequence having one or more substitutions as compared to SEQ ID NO: 7, and (6) LC-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 8 or an amino acid sequence having one or more substitutions as compared to SEQ ID NO: 8.

[0014] In some embodiments, the anti-CLDN18.2 unit comprises (1) a heavy variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO: 1 or an amino acid sequence having at least 90% identity to SEQ ID NO: 1, and (2) a light variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 2 or an amino acid sequence having at least 90% identity to SEQ ID NO: 2.

[0015] In some embodiments, the anti-4-1BB unit is selected from the group consisting of a full-length antibody, Fab, Fab’, F(ab’)2, scFv, and sdAb. In some embodiments, the anti-4-1BB unit comprises an scFv.

[0016] In some embodiments, the anti-4-1BB unit comprises HC-CDR1, HC-CDR2, and HC-CDR3, which respectively include the amino acid sequences of CDR1, CDR2, and CDR3 within the heavy variable region (VH) set forth in SEQ ID NO: 9. In some embodiments, the anti-4-1BB unit comprises (1) HC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11 or an amino acid sequence having one or more substitutions as compared to SEQ ID NO: 11, (2) HC-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 12 or an amino acid sequence having one or more substitutions as compared to SEQ ID NO: 12, and (3) HC-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 13 or an amino acid sequence having one or more substitutions as compared to SEQ ID NO: 13. In some embodiments, the anti-4-1BB unit comprises a heavy variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO: 9, or an amino acid sequence having at least 90% identity to SEQ ID NO: 9.

[0017] In some embodiments, the anti-4-1BB unit comprises LC-CDR1, LC-CDR2, and LC-CDR3, which respectively include the amino acid sequences of CDR1, CDR2, and CDR3 within the light variable region (VL) set forth in SEQ ID NO: 10. In some embodiments, the anti-4-1BB unit comprises (1) LC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 14 or an amino acid sequence having one or more substitutions as compared to SEQ ID NO: 14, (2) LC-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15 or an amino acid sequence having one or more substitutions as compared to SEQ ID NO: 15, and (3) LC-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16 or an amino acid sequence having one or more substitutions as compared to SEQ ID NO: 16. In some embodiments, the anti-4-1BB unit comprises a light variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 10 or an amino acid sequence having at least 90% identity to SEQ ID NO: 10.

[0018] In some embodiments, the anti-4-1BB unit comprises (1) HC-CDR1, HC-CDR2, and HC-CDR3, each comprising the amino acid sequences of CDR1, CDR2, and CDR3 within the heavy variable region (VH) set forth in SEQ ID NO: 9, and (2) LC-CDR1, LC-CDR2, and LC-CDR3, each comprising the amino acid sequences of CDR1, CDR2, and CDR3 within the light variable region (VL) set forth in SEQ ID NO: 10. In some embodiments, the anti-4-1BB unit comprises (1) HC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11 or an amino acid sequence having one or more substitutions as compared to SEQ ID NO: 11, (2) HC-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 12 or an amino acid sequence having one or more substitutions as compared to SEQ ID NO: 12, (3) HC-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 13 or an amino acid sequence having one or more substitutions as compared to SEQ ID NO: 13, (4) LC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 14 or an amino acid sequence having one or more substitutions as compared to SEQ ID NO: 14, (5) LC-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15 or an amino acid sequence having one or more substitutions as compared to SEQ ID NO: 15, and (6) LC-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16 or an amino acid sequence having one or more substitutions as compared to SEQ ID NO: 16.

[0019] In some embodiments, the anti-4-1BB unit comprises (1) a heavy variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO: 9 or an amino acid sequence having at least 90% identity to SEQ ID NO: 9, and (2) a light variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 10 or an amino acid sequence having at least 90% identity to SEQ ID NO: 10.

[0020] In some embodiments, the bispecific antibody comprises a heavy chain component comprising the amino acid sequence set forth in SEQ ID NO: 17 or an amino acid sequence having at least 90% identity with SEQ ID NO: 17. In some embodiments, the bispecific antibody comprises a light chain component comprising the amino acid sequence set forth in SEQ ID NO: 18 or an amino acid sequence having at least 90% identity with SEQ ID NO: 18. In some embodiments, the bispecific antibody comprises (1) a heavy chain component comprising the amino acid sequence set forth in SEQ ID NO: 17 or an amino acid sequence having at least 90% identity with SEQ ID NO: 17, and (2) a light chain component comprising the amino acid sequence set forth in SEQ ID NO: 18 or an amino acid sequence having at least 90% identity with SEQ ID NO: 18.

[0021] In some embodiments, the bispecific antibody is selected from the group consisting of TJ001, IBI389 (Innovent), Q-1802 (QureBio), AMG-910 (Amgen), QLS31905 (Qilu Pharma), PM1032 (Biotheus), and HBM7022 (Harbour, AZ).

[0022] In some embodiments, the solid tumor overexpresses CLDN18.2. In some embodiments, the solid tumor is selected from the group consisting of colorectal cancer, genitourinary cancer, sarcoma, melanoma, hepatocellular carcinoma, gastric cancer, esophageal cancer, gastroesophageal cancer, esophageal cancer, pancreatic cancer, pancreatic ductal adenocarcinoma, lung cancer, non-small cell lung cancer (NSCLC), breast cancer, ovarian cancer, colon cancer, liver cancer, head and neck cancer, gallbladder cancer, Krukenberg tumor, and lymphoma. In some embodiments, the solid tumor is a progressive solid tumor. In some embodiments, the solid tumor is a metastatic solid tumor. In some embodiments, the solid tumor is a progressive and metastatic solid tumor.

[0023] Use of a bispecific antibody in the preparation of a medicament for treating solid tumors in a subject in need of treatment of solid tumors, wherein the bispecific antibody comprises (1) an anti-claudin 18.2 (CLDN18.2) unit having binding specificity for the CLDN18.2 protein, and (2) an anti-4-1BB unit having binding specificity for the 4-1BB protein, and the medicament is administered to the subject at a dosage of about 0.1 to about 30 mg / kg body weight.

[0024] A manufactured product comprising (1) a bispecific antibody comprising an anti-claudin 18.2 (CLDN18.2) unit having binding specificity for the CLDN18.2 protein and an anti-4-1BB unit having binding specificity for the 4-1BB protein, and (2) package insert suggesting administration of the bispecific antibody to a subject in need thereof at a dosage of about 0.1 to about 30 mg / kg body weight.

[0025] It should be understood that one, some, or all of the characteristics of the various embodiments described herein can be combined to form other embodiments of the present invention. These and other aspects of the present invention will be apparent to those skilled in the art. These and other embodiments of the present invention are further described by the following detailed description.

Brief Description of Drawings

[0026]

Figure 1

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Figure 5A

Figure 5B

Figure 5C

Mode for Carrying Out the Invention

[0027] Definitions Before describing the embodiments in detail, it should be understood that the present disclosure is not limited to specific compositions or biological systems, and these can obviously vary. It should also be understood that the terms used in this specification are for the sole purpose of describing specific embodiments and are not intended to be limiting.

[0028] As used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to "a molecule" optionally includes combinations of two or more such molecules.

[0029] The term "about" as used in this specification refers to the customary error range for each value, which is readily understood by those skilled in the art. A reference to an "about" value or parameter in this specification includes (and describes) embodiments directed to that value or parameter itself.

[0030] It should be understood that aspects and embodiments of the present disclosure include aspects and embodiments that "comprise", "consist of", and "consist essentially of".

[0031] As used herein, the term "antibody" is used in the broadest sense and includes intact antibodies (e.g., full-length antibodies), antibody fragments (including, but not limited to, Fab, F(ab’)2, scFv, scFv-Fc, single-domain antibodies, single heavy-chain antibodies, and single light-chain antibodies), monoclonal antibodies, and polyclonal antibodies, so long as they exhibit the desired biological activity (e.g., epitope binding).

[0032] As used herein, the term "isolated" antibody may refer to an antibody substantially free of other cellular material. In one embodiment, an isolated antibody is substantially free of other proteins from the same species. In another embodiment, an isolated antibody is expressed by cells from a different species and is substantially free of other proteins from a different species. In some embodiments, an "isolated" antibody is an antibody that has been identified and separated and / or recovered from components of its natural environment. Contaminating components of its natural environment are materials that would interfere with diagnostic or therapeutic uses for the antibody, and may include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. Antibodies can be rendered substantially free of naturally associated components (or components associated with the cell expression system used to produce the antibody) by isolation using protein purification techniques well known in the art. In some embodiments, the antibody herein is (1) more than 75% by weight antibody, and most preferably more than 80%, 90%, 95%, or 99% by weight antibody, as determined by the Lowry method, or (2) homogeneous and purified by SDS-PAGE under reducing or non-reducing conditions using Coomassie blue or preferably silver staining. Isolated antibodies include antibodies in insitu within recombinant cells because at least one component of the antibody's natural environment is absent. However, isolated antibodies will usually be prepared by at least one purification step.

[0033] As used herein, the terms "natural antibodies and immunoglobulins" generally refer to heterotetrameric glycoproteins of approximately 150,000 daltons composed of two identical light (L) chains and two identical heavy (H) chains. Each light chain is linked to a heavy chain by one covalent disulfide bond (also referred to as a "VH / VL pair"), although the number of disulfide bonds varies between different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide cross-links. Each heavy chain has a variable domain (VH) at one end, followed by several constant domains. Each light chain has a variable domain (VL) at one end and a constant domain at the other end, with the constant domain of the light chain aligned with the first constant domain of the heavy chain and the variable domain of the light chain aligned with the variable domain of the heavy chain. Certain amino acid residues are thought to form the interface between the light chain variable domain and the heavy chain variable domain. See, e.g., Chothia et al., J. Mol. Biol., 186:651 (1985), Novotny and Haber, Proc. Natl. Acad. Sci. U.S.A., 82:4592 (1985).

[0034] As used herein, the term "variable" refers to the fact that specific portions of the variable domains have significantly different sequences among antibodies and are used for the binding and specificity of each particular antibody to its specific antigen. However, the variability is not evenly distributed throughout the entire variable domain of the antibody. It is concentrated in three segments called complementarity determining regions (CDRs) or hypervariable regions in both the light chain variable domain and the heavy chain variable domain. The more highly conserved portions of the variable domain are called frameworks (FRs). The variable domains of the native heavy and light chains each contain four FR regions, predominantly adopt a β-sheet conformation, are connected by three CDRs, which form loops that connect the β-sheet structures and in some cases form part of the β-sheet structure. The CDRs within each chain are held together in close proximity by the FR regions and, together with the CDRs from the other chain, contribute to the formation of the antigen-binding site of the antibody. See, e.g., Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, National Institute of Health, Bethesda, Md. (1991). The constant domains do not directly participate in binding of the antibody to the antigen but exhibit various effector functions such as the participation of the antibody in antibody-dependent cell cytotoxicity. Exemplary variable region sequences include the humanized variable region sequences of the CD47 antibodies described in detail elsewhere herein.

[0035] The terms "hypervariable region (HVR)" or "complementary determining region (CDR)" can refer to subregions of the VH and VL domains that are characterized by enhanced sequence variability and / or defined loop formation. These include three CDRs (H1, H2, and H3) within the VH domain, as well as three CDRs (L1, L2, and L3) within the VL domain. H3 is thought to be important in conferring fine binding specificity, and L3 and H3 exhibit the highest level of diversity. See Johnson and Wu, in Methods in Molecular Biology 248:1-25 (Lo, ed., Human Press, Totowa, N.J., 2003).

[0036] Descriptions of several CDRs / HVRs are known. The Kabat complementary determining regions (CDRs) are based on sequence variability and are the most commonly used (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)). Chothia, on the other hand, refers to the positions of structural loops (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)). The AbM HVRs represent a compromise between the Kabat HVRs and the Chothia structural loops and are used by Oxford Molecular's AbM antibody modeling software. The "contact" HVRs are based on the analysis of available complex crystal structures. The residues from each of these HVR / CDRs are described below. "Framework" or "FR" residues are variable domain residues other than HVR / CDR residues.

[0037] [Table 1]

[0038] The "extended" HVRs are also known in VL as 24 - 36 or 24 - 34 (L1), 46 - 56 or 50 - 56 (L2), and 89 - 97 or 89 - 96 (L3), and in VH as 26 - 35 (H1), 50 - 65 or 49 - 65 (H2), and 93 - 102, 94 - 102, or 95 - 102 (H3).

[0039] "Kabat numbering" can refer to the numbering system used for the heavy - chain variable domain or light - chain variable domain of an antibody compilation in Kabat et al. (supra). The actual linear amino - acid sequence may contain fewer or additional amino acids corresponding to truncations or insertions in the FR or HVR of the variable domain. The Kabat numbering of residues can be determined for a given antibody by alignment in the homologous regions between the sequence of the antibody and the sequence numbered by "standard" Kabat. Typically, Kabat numbering is used when referring to residues within the variable domain (approximately residues 1 - 107 of the light chain and residues 1 - 113 of the heavy chain), while the EU numbering system or indices (e.g., EU indices as in Kabat, numbering by EU IgG1) are generally used when referring to residues within the heavy - chain constant region.

[0040] As used herein, the term "antibody fragment" and all its grammatical variations refer to a part of an intact antibody that contains the antigen - binding site or variable region of the intact antibody, and in some cases, is defined as a part that does not include the constant heavy - chain domains of the Fc region of the intact antibody (i.e., CH2, CH3, and / or CH4 depending on the antibody isotype). Examples of antibody fragments include Fab, Fab’, Fab’ - SH, F(ab’) 2and Fv fragments; diabodies; any antibody fragment that is a polypeptide having a primary structure consisting of a contiguous sequence of amino acid residues, including, but not limited to, (1) single-chain Fv (scFv) molecules, (2) single-chain polypeptides containing only one light chain variable domain, or fragments thereof containing the three CDRs of the light chain variable domain without the associated heavy chain portion, and (3) single-chain polypeptides containing only one heavy chain variable region, or fragments thereof containing the three CDRs of the heavy chain variable region without the associated light chain portion (herein referred to as "single-chain antibody fragments" or "single-chain polypeptides"); and multispecific or multivalent structures formed from antibody fragments. In antibody fragments containing one or more heavy chains, the heavy chain(s) may contain any constant domain sequence found in the non-Fc region of an intact antibody (e.g., CH1 of the IgG isotype), and / or any hinge region sequence found in an intact antibody, and / or may contain a leucine zipper sequence fused to or located within the hinge region sequence or the constant domain sequence of the heavy chain(s).

[0041] The Fab fragment also contains the constant domain of the light chain and the first constant domain (CH 1 ) of the heavy chain. The Fab' fragment differs from the Fab fragment by the addition of several residues to the carboxy terminus of the heavy chain CH 1 domain containing one or more cysteines from the antibody hinge region. Fab'-SH is the designation herein for Fab' in which the cysteine residue(s) of the constant domain carry a free thiol group. F(ab’) 2 antibody fragments were originally produced as pairs of Fab' fragments having hinge cysteines in between. Other chemical couplings of antibody fragments are also known.

[0042] As used herein, the term "monoclonal antibody" (mAb) refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific and target a single antigenic site. Each mAb is directed against a single determinant on the antigen. In addition to their specificity, monoclonal antibodies are advantageous in that they can be synthesized by hybridoma culture and are free of other immunoglobulins. The modifier "monoclonal" indicates the characteristic of the antibody being obtained from a substantially homogeneous population of antibodies and should not be construed to require production of the antibody by any particular method. For example, monoclonal antibodies used in accordance with the present invention can be made in immortalized B cells or their hybridomas, or can be made by recombinant DNA methods.

[0043] Monoclonal antibodies as used herein include hybrid and recombinant antibodies produced by splicing the variable (including hypervariable) domains of a CD47 antibody to a constant domain (e.g., a "humanized" antibody), or by splicing a light chain to a heavy chain, or by splicing a chain from one species to a chain from another species, or by fusion with a heterologous protein (regardless of the species from which it is derived or the species or subclass designation of the immunoglobulin class), and antibody fragments (e.g., Fab, F(ab’) 2 , and Fv) as long as they exhibit the desired biological activity.

[0044] Monoclonal antibodies as used herein specifically include "chimeric" antibodies (immunoglobulins) in which a portion of the heavy and / or light chain is identical or homologous to the corresponding sequence in an antibody derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is derived from another species or is identical or homologous to the corresponding sequence in an antibody belonging to another antibody class or subclass, and fragments of such antibodies as long as they exhibit the desired biological activity.

[0045] As used herein, the term "treatment" refers to a clinical intervention designed to modify the natural course of an individual or cell being treated during the course of a clinical pathology. Desirable effects of treatment include slowing the rate of disease progression, restoring or alleviating the disease state, and improving remission or prognosis. For example, an individual may include, but is not limited to, a reduction (or destruction) of the growth of cancerous cells, a reduction in symptoms resulting from the disease, an improvement in the quality of life of those suffering from the disease, a reduction in the dosage of other agents required for the treatment of the disease, and / or an extension of the individual's survival period. "Treatment" is successful when one or more symptoms associated with cancer, including but not limited to, are reduced or eliminated. In some embodiments, "treating" a disease such as cancer means delaying the progression of the disease, i.e., deferring, hindering, slowing, retarding, stabilizing, and / or postponing the progression of the disease (such as cancer). This delay can be of various lengths depending on the disease being treated and / or the history of the individual. As will be apparent to those skilled in the art, a sufficient or significant delay may in fact encompass prevention in terms of the individual not developing the disease. For example, the onset of metastasis and other terminal cancers can be delayed.

[0046] As used herein, the term "subject" for purposes of treatment refers to any animal classified as a mammal, including humans, domesticated animals and livestock, as well as zoo, sport, or pet animals, such as dogs.

[0047] As used herein, the term "progressive solid tumor" refers to a solid tumor that is either locally progressive or metastatic and cannot be cured or grows beyond the site of its original origin. In some embodiments, progressive solid tumors include, but are not limited to, solid tumors of stage III or stage IV.

[0048] As used herein, the terms "metastatic" or "metastasis" refer to tumors that spread from an initial or primary site within the body of a subject to a different or secondary site. This is generally distinguished from cancer invasion, which is the direct extension and infiltration of adjacent tissues by cancer cells.

[0049] Anti-CLDN18.2 unit Claudin-18 has two isoforms, isoform 1 and isoform 2. Isoform 2 (Claudin 18.2 or CLDN18.2) is a highly selective cell lineage marker. In normal tissues, CLDN18.2 is strictly expressed in differentiated epithelial cells of the gastric mucosa. However, it has been found that CLDN18.2 can be significantly expressed in primary and metastatic gastric cancer tissues, as well as in pancreatic, esophageal, ovarian, and lung cancer tissues, suggesting that CLDN18.2 is an attractive therapeutic target with great potential for gastric cancer and other types of solid tumors.

[0050] Any anti-18.2 known in the art can be used in the bispecific antibodies of the present application. In some embodiments, the anti-CLDN18.2 unit is selected from the group consisting of full-length antibodies, Fab, Fab’, F(ab’)2, scFv, and sdAb. In some embodiments, the anti-CLDN18.2 unit comprises Fab.

[0051] In some embodiments, the anti-CLDN18.2 unit comprises HC-CDR1, HC-CDR2, and HC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the heavy variable region (VH) set forth in SEQ ID NO: 1. In some embodiments, the anti-CLDN18.2 unit comprises (1) HC-CDR1 containing the amino acid sequence set forth in SEQ ID NO: 3 or an amino acid sequence having one or more substitutions as compared to SEQ ID NO: 3, (2) HC-CDR2 containing the amino acid sequence set forth in SEQ ID NO: 4 or an amino acid sequence having one or more substitutions as compared to SEQ ID NO: 4, and (3) HC-CDR3 containing the amino acid sequence set forth in SEQ ID NO: 5 or an amino acid sequence having one or more substitutions as compared to SEQ ID NO: 5.

[0052] In some embodiments, the anti-CLDN18.2 unit comprises a heavy variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO: 1 or an amino acid sequence having at least 80%, 85%, 87%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 1.

[0053] In some embodiments, the anti-CLDN18.2 unit comprises LC-CDR1, LC-CDR2, and LC-CDR3, each comprising the amino acid sequence of CDR1, CDR2, and CDR3 within the light variable region (VL) set forth in SEQ ID NO: 2. In some embodiments, the anti-CLDN18.2 unit comprises (1) LC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 6 or an amino acid sequence having one or more substitutions compared to SEQ ID NO: 6, (2) LC-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 7 or an amino acid sequence having one or more substitutions compared to SEQ ID NO: 7, and (3) LC-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 8 or an amino acid sequence having one or more substitutions compared to SEQ ID NO: 8.

[0054] In some embodiments, the anti-CLDN18.2 unit comprises a light variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 2 or an amino acid sequence having at least 80%, 85%, 87%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2.

[0055] In some embodiments, the anti-CLDN18.2 unit comprises (1) HC-CDR1, HC-CDR2, and HC-CDR3, each comprising the amino acid sequence of CDR1, CDR2, and CDR3 within the heavy variable region (VH) set forth in SEQ ID NO: 1, and (2) LC-CDR1, LC-CDR2, and LC-CDR3, each comprising the amino acid sequence of CDR1, CDR2, and CDR3 within the light variable region (VL) set forth in SEQ ID NO: 2. In some embodiments, the anti-CLDN18.2 unit comprises (1) HC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 3 or an amino acid sequence having one or more substitutions as compared to SEQ ID NO: 3, (2) HC-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 4 or an amino acid sequence having one or more substitutions as compared to SEQ ID NO: 4, (3) HC-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 5 or an amino acid sequence having one or more substitutions as compared to SEQ ID NO: 5, (4) LC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 6 or an amino acid sequence having one or more substitutions as compared to SEQ ID NO: 6, (5) LC-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 7 or an amino acid sequence having one or more substitutions as compared to SEQ ID NO: 7, and (6) LC-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 8 or an amino acid sequence having one or more substitutions as compared to SEQ ID NO: 8.

[0056] In some embodiments, the anti-CLDN18.2 unit comprises (1) a heavy variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO: 1 or an amino acid sequence having at least 80%, 85%, 87%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 1, and (2) a light variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 2 or an amino acid sequence having at least 80%, 85%, 87%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2.

[0057] Anti-4-1BB unit 4-1BB is an inducible costimulatory receptor expressed on activated T cells and natural killer (NK) cells. Trimerization of 4-1BB by the 4-1BB ligand (41BBL) trimer on T cells induces a signaling cascade that results in upregulation of anti-apoptotic molecules, cytokine secretion, and enhanced effector function. In NK cells, 4-1BB signaling can increase antibody-dependent cell-mediated cytotoxicity. Activating monoclonal antibodies targeting 4-1BB have been developed to harness 4-1BB signaling for cancer immunotherapy. Preclinical results in various induced and spontaneous tumor models suggest that targeting 4-1BB with agonist antibodies may result in tumor clearance and durable antitumor immunity.

[0058] Any 4-1BB antibody known in the art can be used in the bispecific antibodies of the present application. In some embodiments, the anti-4-1BB unit is selected from the group consisting of full-length antibodies, Fab, Fab’, F(ab’)2, scFv, and sdAb. In some embodiments, the anti-4-1BB unit comprises an scFv.

[0059] In some embodiments, the anti-4-1BB unit comprises HC-CDR1, HC-CDR2, and HC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the heavy variable region (VH) set forth in SEQ ID NO: 9. In some embodiments, the anti-4-1BB unit comprises (1) HC-CDR1 containing the amino acid sequence set forth in SEQ ID NO: 11 or an amino acid sequence having one or more substitutions as compared to SEQ ID NO: 11, (2) HC-CDR2 containing the amino acid sequence set forth in SEQ ID NO: 12 or an amino acid sequence having one or more substitutions as compared to SEQ ID NO: 12, and (3) HC-CDR3 containing the amino acid sequence set forth in SEQ ID NO: 13 or an amino acid sequence having one or more substitutions as compared to SEQ ID NO: 13.

[0060] In some embodiments, the anti-4-1BB unit comprises a heavy variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO: 9, or an amino acid sequence having at least 80%, 85%, 87%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 9.

[0061] In some embodiments, the anti-4-1BB unit comprises LC-CDR1, LC-CDR2, and LC-CDR3, each comprising the amino acid sequence of CDR1, CDR2, and CDR3 within the light variable region (VL) set forth in SEQ ID NO: 10. In some embodiments, the anti-4-1BB unit comprises (1) LC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 14 or an amino acid sequence having one or more substitutions as compared to SEQ ID NO: 14, (2) LC-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15 or an amino acid sequence having one or more substitutions as compared to SEQ ID NO: 15, and (3) LC-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16 or an amino acid sequence having one or more substitutions as compared to SEQ ID NO: 16.

[0062] In some embodiments, the anti-4-1BB unit comprises a light variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 10 or an amino acid sequence having at least 80%, 85%, 87%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 10.

[0063] In some embodiments, the anti-4-1BB unit comprises (1) HC-CDR1, HC-CDR2, and HC-CDR3, each comprising the amino acid sequence of CDR1, CDR2, and CDR3 within the heavy variable region (VH) set forth in SEQ ID NO: 9, and (2) LC-CDR1, LC-CDR2, and LC-CDR3, each comprising the amino acid sequence of CDR1, CDR2, and CDR3 within the light variable region (VL) set forth in SEQ ID NO: 10. In some embodiments, the anti-4-1BB unit comprises (1) HC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11 or an amino acid sequence having one or more substitutions as compared to SEQ ID NO: 11, (2) HC-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 12 or an amino acid sequence having one or more substitutions as compared to SEQ ID NO: 12, (3) HC-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 13 or an amino acid sequence having one or more substitutions as compared to SEQ ID NO: 13, (4) LC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 14 or an amino acid sequence having one or more substitutions as compared to SEQ ID NO: 14, (5) LC-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15 or an amino acid sequence having one or more substitutions as compared to SEQ ID NO: 15, and (6) LC-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16 or an amino acid sequence having one or more substitutions as compared to SEQ ID NO: 16.

[0064] In some embodiments, the anti-4-1BB unit comprises (1) a heavy variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO: 9 or an amino acid sequence having at least 80%, 85%, 87%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 9, and (2) a light variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 10 or an amino acid sequence having at least 80%, 85%, 87%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 10.

[0065] Bispecific antibody As used herein, the term "bispecific antibody" refers to an antibody having two antigen-binding regions or antibody units with binding specificities for two different antigens or two epitopes.

[0066] In some embodiments, the bispecific antibody of the present application comprises (1) an anti-claudin 18.2 (CLDN18.2) unit having binding specificity for the CLDN18.2 protein, and (2) a second antibody unit. In some embodiments, the anti-CLDN18.2 unit can be any of the anti-CLDN18.2 units described herein. In some embodiments, the second antibody unit has binding specificity for a target selected from the group consisting of 4-1BB, PD-1, PD-L1, and CD3. In some embodiments, the second antibody comprises an anti-4-1BB unit having binding specificity for the 4-1BB protein. In some embodiments, the second antibody comprises an anti-4-1BB unit described herein.

[0067] In some embodiments, the bispecific antibody of the present application comprises (1) an anti-claudin 18.2 (CLDN18.2) unit having binding specificity for the CLDN18.2 protein, and (2) an anti-4-1BB unit having binding specificity for the 4-1BB protein. In some embodiments, the bispecific antibody of the present application comprises (1) an anti-claudin 18.2 (CLDN18.2) unit having binding specificity for the CLDN18.2 protein described herein, and (2) an anti-4-1BB unit having binding specificity for the 4-1BB protein described herein.

[0068] In some embodiments, the anti-4-1BB is an scFv and is fused to the C-terminus of the heavy chain of the anti-CLDN18.2 unit. In some embodiments, the anti-4-1BB is an scFv and is fused to the N-terminus of the heavy chain of the anti-CLDN18.2 unit. In some embodiments, the anti-4-1BB is an scFv and is fused to the C-terminus of the light chain of the anti-CLDN18.2 unit. In some embodiments, the anti-4-1BB is an scFv and is fused to the N-terminus of the light chain of the anti-CLDN18.2 unit.

[0069] In some embodiments, the bispecific antibody comprises a heavy chain component comprising the amino acid sequence set forth in SEQ ID NO: 17, or an amino acid sequence having at least 80%, 85%, 87%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 17. In some embodiments, the bispecific antibody comprises a light chain component comprising the amino acid sequence set forth in SEQ ID NO: 18, or an amino acid sequence having at least 80%, 85%, 87%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 18. In some embodiments, the bispecific antibody comprises (1) a heavy chain component comprising the amino acid sequence set forth in SEQ ID NO: 17, or an amino acid sequence having at least 80%, 85%, 87%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 17, and (2) a light chain component comprising the amino acid sequence set forth in SEQ ID NO: 18, or an amino acid sequence having at least 80%, 85%, 87%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 18.

[0070] In some embodiments, the bispecific antibody is selected from the group consisting of TJ001, IBI389 (Innovent), Q-1802 (QureBio), AMG-910 (Amgen), QLS31905 (Qilu Pharma), PM1032 (Biotheus), and HBM7022 (Harbour, AZ). In some embodiments, the bispecific antibody is TJ001.

[0071] Method In one aspect, a method for treating a solid tumor is provided, which includes administering to a subject in need of treatment of the solid tumor the bispecific antibody described herein. In some embodiments, the bispecific antibody is administered intravenously to the subject. In some embodiments, the bispecific antibody is administered to the subject at a dosage of about 0.1 to about 30 mg / kg body weight. In some embodiments, the bispecific antibody is administered intravenously to the subject at a dosage of about 0.1 to about 30 mg / kg body weight.

[0072] In some embodiments of the method of the present application, the bispecific antibody is administered to the subject at a dosage of about 0.1 to about 15 mg / kg body weight. In some embodiments, the bispecific antibody is administered to the subject at a dosage of about 0.1 to about 12 mg / kg body weight. In some embodiments, the bispecific antibody is administered to the subject at a dosage of about 0.1 to about 8 mg / kg body weight. In some embodiments, the bispecific antibody is administered to the subject at a dosage of about 0.1 to about 5 mg / kg body weight. In some embodiments, the bispecific antibody is administered to the subject at a dosage of about 0.1 to about 5 mg / kg body weight. In some embodiments, the bispecific antibody is administered to the subject at a dosage of about 0.1 to about 3 mg / kg body weight. In some embodiments, the bispecific antibody is administered to the subject at a dosage of about 0.1 to about 1 mg / kg body weight. In some embodiments, the bispecific antibody is administered to the subject at a dosage of about 0.1 to about 0.3 mg / kg body weight.

[0073] In some embodiments of the method of the present application, the bispecific antibody is administered to the subject at a dosage of about 1 to about 15 mg / kg body weight. In some embodiments, the bispecific antibody is administered to the subject at a dosage of about 1 to about 12 mg / kg body weight. In some embodiments, the bispecific antibody is administered to the subject at a dosage of about 1 to about 8 mg / kg body weight. In some embodiments, the bispecific antibody is administered to the subject at a dosage of about 1 to about 5 mg / kg body weight. In some embodiments, the bispecific antibody is administered to the subject at a dosage of about 1 to about 5 mg / kg body weight. In some embodiments, the bispecific antibody is administered to the subject at a dosage of about 1 to about 3 mg / kg body weight.

[0074] In some embodiments of the methods of the present application, the bispecific antibody is administered to a subject at a dose of about 3 to about 15 mg / kg body weight. In some embodiments, the bispecific antibody is administered to a subject at a dose of about 3 to about 12 mg / kg body weight. In some embodiments, the bispecific antibody is administered to a subject at a dose of about 3 to about 8 mg / kg body weight. In some embodiments, the bispecific antibody is administered to a subject at a dose of about 3 to about 5 mg / kg body weight.

[0075] In some embodiments of the methods of the present application, the bispecific antibody is administered to a subject at a dose of about 4 to about 15 mg / kg body weight. In some embodiments, the bispecific antibody is administered to a subject at a dose of about 4 to about 12 mg / kg body weight. In some embodiments, the bispecific antibody is administered to a subject at a dose of about 4 to about 8 mg / kg body weight.

[0076] In some embodiments of the methods of the present application, the bispecific antibody is administered to a subject at a dose of about 5 to about 15 mg / kg body weight. In some embodiments, the bispecific antibody is administered to a subject at a dose of about 5 to about 12 mg / kg body weight. In some embodiments, the bispecific antibody is administered to a subject at a dose of about 5 to about 8 mg / kg body weight.

[0077] In some embodiments of the methods of the present application, the bispecific antibody is administered to a subject at a dose of about 6 to about 15 mg / kg body weight. In some embodiments, the bispecific antibody is administered to a subject at a dose of about 6 to about 12 mg / kg body weight. In some embodiments, the bispecific antibody is administered to a subject at a dose of about 6 to about 8 mg / kg body weight.

[0078] In some embodiments of the methods of the present application, the bispecific antibody is administered to a subject at a dose of about 7 to about 15 mg / kg body weight. In some embodiments, the bispecific antibody is administered to a subject at a dose of about 7 to about 14 mg / kg body weight. In some embodiments, the bispecific antibody is administered to a subject at a dose of about 7 to about 13 mg / kg body weight. In some embodiments, the bispecific antibody is administered to a subject at a dose of about 7 to about 12 mg / kg body weight. In some embodiments, the bispecific antibody is administered to a subject at a dose of about 7 to about 11 mg / kg body weight. In some embodiments, the bispecific antibody is administered to a subject at a dose of about 7 to about 10 mg / kg body weight. In some embodiments, the bispecific antibody is administered to a subject at a dose of about 7 to about 9 mg / kg body weight. In some embodiments, the bispecific antibody is administered to a subject at a dose of about 7 to about 8 mg / kg body weight.

[0079] In some embodiments of the methods of the present application, the bispecific antibody is administered to a subject at a dose of about 8 to about 15 mg / kg body weight. In some embodiments, the bispecific antibody is administered to a subject at a dose of about 8 to about 14 mg / kg body weight. In some embodiments, the bispecific antibody is administered to a subject at a dose of about 8 to about 13 mg / kg body weight. In some embodiments, the bispecific antibody is administered to a subject at a dose of about 8 to about 12 mg / kg body weight. In some embodiments, the bispecific antibody is administered to a subject at a dose of about 8 to about 11 mg / kg body weight. In some embodiments, the bispecific antibody is administered to a subject at a dose of about 8 to about 10 mg / kg body weight. In some embodiments, the bispecific antibody is administered to a subject at a dose of about 8 to about 9 mg / kg body weight.

[0080] In some embodiments of the methods of the present application, the bispecific antibody is administered to a subject at a dose of about 9 to about 15 mg / kg body weight. In some embodiments, the bispecific antibody is administered to a subject at a dose of about 9 to about 14 mg / kg body weight. In some embodiments, the bispecific antibody is administered to a subject at a dose of about 9 to about 13 mg / kg body weight. In some embodiments, the bispecific antibody is administered to a subject at a dose of about 9 to about 12 mg / kg body weight. In some embodiments, the bispecific antibody is administered to a subject at a dose of about 9 to about 11 mg / kg body weight. In some embodiments, the bispecific antibody is administered to a subject at a dose of about 9 to about 10 mg / kg body weight.

[0081] In some embodiments of the methods of the present application, the bispecific antibody is administered to a subject at a dose of about 10 to about 15 mg / kg body weight. In some embodiments, the bispecific antibody is administered to a subject at a dose of about 10 to about 14 mg / kg body weight. In some embodiments, the bispecific antibody is administered to a subject at a dose of about 10 to about 13 mg / kg body weight. In some embodiments, the bispecific antibody is administered to a subject at a dose of about 10 to about 12 mg / kg body weight. In some embodiments, the bispecific antibody is administered to a subject at a dose of about 10 to about 11 mg / kg body weight.

[0082] In some embodiments of the methods of the present application, the bispecific antibody is administered to a subject at a dose of about 11 to about 15 mg / kg body weight. In some embodiments, the bispecific antibody is administered to a subject at a dose of about 11 to about 14 mg / kg body weight. In some embodiments, the bispecific antibody is administered to a subject at a dose of about 11 to about 13 mg / kg body weight. In some embodiments, the bispecific antibody is administered to a subject at a dose of about 11 to about 12 mg / kg body weight.

[0083] In some embodiments of the methods of the present application, the bispecific antibody is administered to the subject at a dose of about 12 to about 15 mg / kg body weight. In some embodiments, the bispecific antibody is administered to the subject at a dose of about 12 to about 14 mg / kg body weight. In some embodiments, the bispecific antibody is administered to the subject at a dose of about 12 to about 13 mg / kg body weight.

[0084] In some embodiments of the methods of the present application, the bispecific antibody is administered to the subject at a dose of about 13 to about 15 mg / kg body weight. In some embodiments, the bispecific antibody is administered to the subject at a dose of about 13 to about 14 mg / kg body weight.

[0085] In some embodiments of the methods of the present application, the bispecific antibody is administered to the subject at a dose of about 14 to about 15 mg / kg body weight.

[0086] In some embodiments, the bispecific antibody is administered to the subject at a dose of about 0.1, about 0.3, about 1, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, about 8.5, about 9, about 9.5, about 10, about 10.5, about 11, about 11.5, about 12, about 12.5, about 13, about 13.5, about 14, about 14.5, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, or about 30 mg / kg body weight. In some embodiments, the bispecific antibody is administered to the subject at a dose of about 0.1, about 0.3, about 1, about 5, about 8, about 12, about 15, or about 30 mg / kg body weight. In some embodiments, the bispecific antibody is administered to the subject at a dose of about 5, about 8, about 12, or about 15 mg / kg body weight.

[0087] In some embodiments, the bispecific antibody is administered to a subject at the dosages described herein once weekly, once every two weeks, once every three weeks, or monthly. In some embodiments, the bispecific antibody is administered to a subject once every two weeks at the dosages described. In some embodiments, the bispecific antibody is administered to a subject at a dosage of about 0.1, about 0.3, about 1, about 5, about 8, about 12, about 15, or about 30 mg / kg body weight once weekly, once every two weeks, once every three weeks, or monthly. In some embodiments, the bispecific antibody is administered to a subject at a dosage of about 0.1, about 0.3, about 1, about 5, about 8, about 12, about 15, or about 30 mg / kg body weight once every two weeks. In some embodiments, the bispecific antibody is administered to a subject at a dosage of about 5, about 8, about 12, or about 15 mg / kg body weight once weekly, once every two weeks, once every three weeks, or monthly. In some embodiments, the bispecific antibody is administered to a subject at a dosage of about 5, about 8, about 12, or about 15 mg / kg body weight once every two weeks. In some embodiments, the bispecific antibody is administered to a subject at a dosage of about 5 mg / kg body weight once every two weeks. In some embodiments, the bispecific antibody is administered to a subject at a dosage of about 6 mg / kg body weight once every two weeks. In some embodiments, the bispecific antibody is administered to a subject at a dosage of about 7 mg / kg body weight once every two weeks. In some embodiments, the bispecific antibody is administered to a subject at a dosage of about 8 mg / kg body weight once every two weeks. In some embodiments, the bispecific antibody is administered to a subject at a dosage of about 9 mg / kg body weight once every two weeks. In some embodiments, the bispecific antibody is administered to a subject at a dosage of about 10 mg / kg body weight once every two weeks. In some embodiments, the bispecific antibody is administered to a subject at a dosage of about 11 mg / kg body weight once every two weeks. In some embodiments, the bispecific antibody is administered to a subject at a dosage of about 12 mg / kg body weight once every two weeks. In some embodiments, the bispecific antibody is administered to a subject at a dosage of about 13 mg / kg body weight once every two weeks. In some embodiments, the bispecific antibody is administered to a subject at a dosage of about 14 mg / kg body weight once every two weeks. In some embodiments, the bispecific antibody is administered to a subject at a dosage of about 15 mg / kg body weight once every two weeks.

[0088] In some embodiments, the solid tumor overexpresses CLDN18.2. In some embodiments, the solid tumor is selected from the group consisting of colorectal cancer, genitourinary cancer, sarcoma, melanoma, hepatocellular carcinoma, gastric cancer, esophageal cancer, gastroesophageal cancer, esophageal cancer, pancreatic cancer, pancreatic ductal adenocarcinoma, lung cancer, non-small cell lung cancer (NSCLC), breast cancer, ovarian cancer, colon cancer, liver cancer, head and neck cancer, gallbladder cancer, Krukenberg tumor, and lymphoma. In some embodiments, the solid tumor is a progressive solid tumor. In some embodiments, the solid tumor is a metastatic solid tumor. In some embodiments, the solid tumor is a progressive and metastatic tumor. In some embodiments, the solid tumor is in stage III or stage IV.

[0089] In another aspect, provided herein is the use of a bispecific antibody described herein in the preparation of a medicament for treating a solid tumor in a subject in need of treatment of the solid tumor, wherein the bispecific antibody comprises (1) an anti-claudin 18.2 (CLDN18.2) unit having binding specificity for the CLDN18.2 protein and (2) an anti-4-1BB unit having binding specificity for the 4-1BB protein, and the medicament is administered to the subject at a dosage of about 0.1 to about 30 mg / kg body weight.

[0090] Manufactured product In another aspect, provided herein is a manufactured product comprising (1) a bispecific antibody comprising an anti-claudin 18.2 (CLDN18.2) unit having binding specificity for the CLDN18.2 protein and an anti-4-1BB unit having binding specificity for the 4-1BB protein, as described herein, and (2) a package insert suggesting administering the bispecific antibody to a subject in need thereof at a dosage of about 0.1 to about 30 mg / kg body weight.

[0091] All publications and patent applications cited herein are hereby incorporated by reference as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

Examples

[0092] The following examples are presented to provide a complete disclosure and description of the manufacturing and use methods of the present invention to those skilled in the art, and are not intended to limit the scope of the invention considered by the inventors, nor are they intended to represent that the following experiments are all or the only experiments conducted. Regarding the numbers used (e.g., amounts, temperatures, etc.), efforts have been made to ensure accuracy, but some experimental errors and deviations should be taken into account. Unless otherwise indicated, parts are parts by weight, molecular weight is weight-average molecular weight, temperature is in degrees Celsius, and pressure is atmospheric pressure or close thereto.

[0093] Example 1. Cytotoxicity of TJ001 against CLDN18.2-expressing tumor cells Three CLDN18.2-expressing MKN45 gastric cancer cell lines, "MKN45 parent", "MKN45 #18", and "MKN45 #14", were provided, and microscopic images of each tumor cell using IHC membrane staining are shown in FIGS. 1A - C. Each tumor cell was characterized for CLDN18.2 positivity using immunohistochemistry (IHC), and detailed CLDN18.2 expression using IHC scores for the three MKN45 cell lines is shown in FIGS. 2A - C. As shown in FIGS. 2A - C, MKN45 #14 mainly showed CLDN18.2 + showing more than 60% of CLDN18.2 ++ showing the highest CLDN18.2 expression level (CLDN 高 ). MKN45 #18 showed more than 50% of CLDN18.2 + but had the minimum CLDN18.2 ++ showing a medium CLDN18.2 expression level (CLDN 中 ). The MKN45 parent showed the lowest CLDN18.2 expression level (CLDN 低 ).

[0094] TJ001 is a CLDN18.2×4-1BB bispecific antibody having two heavy components each having the sequence of SEQ ID NO: 17 and two light components each having the sequence of SEQ ID NO: 18. Such CLDN18.2×4-1BB bispecific antibodies containing TJ001 are also described in WO2021 / 027850, which is incorporated herein by reference. To test the ability of the bispecific antibody TJ001, human PBMCs were used as effector cells and three groups of MKN45 cells were used as target cells. The effector cells were co-cultured with the target cells at two ratios (E:T = 1:10, 1:1). The co-culture with the lower E:T ratio (E:T = 1:10) was designed to mimic the tumor microenvironment of normal tumors, while the co-culture with the higher E:T ratio (E:T = 1:1) was designed to mimic the tumor microenvironment of hot tumors / spots.

[0095] Serial diluted TJ001 was added to the mixed culture at final concentrations starting from 100 nM. The levels of IL-2 and IFN-γ in the culture medium were measured 48 hours after co-culture using the IL-2 (human) LANCE ultra TR-FRET detection kit and the IFN-γ (human) LANCE ultra TR-FRET detection kit (PerkinElmer). As shown in FIGS. 3A - B, for the E:T ratio of 1:1 (hot tumor / spot), more consistent cytotoxicity against tumor cells was observed at concentrations of 1.2 - 33 nM for CLDN18.2 高 tumor cells. For the normal E:T ratio of 1:10 (normal tumor), consistent cytotoxicity against tumor cells was observed at concentrations of 0.4 - 33 nM for both CLDN18.2 高 tumor cells and CLDN18.2 中 tumor cells. This suggests that tumor cells with higher CLDN18.2 expression show a more consistent response to the TJ001 bispecific antibody.

[0096] Example 2. Phase 1 Study Protocol of TJ033721 in Subjects with Progressive or Metastatic Solid Tumors This is an open-label, multi-center, multiple-dose Phase 1 study to evaluate the safety, tolerability, MTD, PK, and PD of TJ033721 in subjects with progressive or metastatic solid tumors. TJ001 is a CLDN18.2×4-1BB bispecific antibody having two heavy components each having the sequence of SEQ ID NO: 17 and two light components each having the sequence of SEQ ID NO: 18. TJ033721 recognizes CLDN18.2 high, medium, and low expression cells and activates 4-1BB signaling to enhance T cell activation.

[0097] Objective The primary objectives of this study are as follows: (1) To evaluate the safety and tolerability of TJ001 in subjects with progressive or metastatic solid tumors, (2) To determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) of TJ001, and (3) To determine the recommended Phase 2 dose (RP2D) of TJ001.

[0098] The secondary objectives of this study are as follows: (1) To characterize the pharmacokinetic (PK) profile of TJ001, (2) To evaluate the pharmacodynamic (PD) profiling of TJ001, (3) To evaluate the immunogenicity of TJ001, and (4) To evaluate the preliminary antitumor activity of TJ001 by assessing the response rate according to RECIST1.1 and iRECIST.

[0099] The exploratory objectives of this study are as follows: (1) To explore the relationship between PD activity and efficacy and safety outcomes in subjects treated with TJ001, (2) To explore the exposure-response relationship for PD activity in subjects treated with TJ001, and (3) To explore the relationship of exploratory biomarkers with PD activity in subjects treated with TJ001.

[0100] Method For the escalating study, a total of 40 - 48 subjects (N = 40 - 48) were administered TJ001 by intravenous infusion for 1 - 2 hours at 0.1 mg / kg (Q2W), 0.3 mg / kg (Q2W), 1 mg / kg (Q2W), 3 mg / kg (Q2W), 5 mg / kg (Q2W), 8 mg / kg (Q2W), 12 mg / kg (Q2W), and 15 mg / kg (Q2W) for each dose.

[0101] PK and / or PD data, efficacy in GI cancer, and safety were reviewed by the Scientific Review Committee (SRC), and the doses for the dose expansion study were determined.

[0102] For the determined dose levels, 30 subjects (N = 30) per cohort were administered TJ001. The first cohort included subjects with pathologically confirmed gastric cancer (GC), gastroesophageal junction adenocarcinoma (GEJ), or esophageal adenocarcinoma (EAC). The second cohort included subjects with pathologically confirmed pancreatic ductal adenocarcinoma (PDAC). Subjects may include those enrolled in the dose expansion study.

[0103] Example 3. Updated Phase 1 Study of TJ001 Based on Escalation Data This is a multi - center dose - escalating Phase 1 study using the Bayesian optimal interval (BOIN) design to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of TJ001.

[0104] Dose Escalation The dose - escalation trial of TJ001 was conducted in subjects with pathologically confirmed progressive or metastatic solid tumors. TJ001 was a CLDN18.2×4 - 1BB bispecific antibody containing two heavy components each having the sequence of SEQ ID NO: 17 and two light components each having the sequence of SEQ ID NO: 18. TJ001 recognized CLDN18.2 high, medium, and low - expressing cells and activated 4 - 1BB signaling to enhance T - cell activation.

[0105] For one subject per cohort (N = 1), TJ001 was administered at 0.1 mg / kg (Q2W) and 0.3 mg / kg (Q2W) for accelerated titration. Additionally, for four or more subjects per cohort (N = 4+), TJ001 was administered at doses of 1 mg / kg (Q2W), 3 mg / kg (Q2W), 5 mg / kg (Q2W), 8 mg / kg (Q2W), 12 mg / kg (Q2W), and 15 mg / kg (Q2W).

[0106] As of April 18, 2023, 50 patients (32 in dose escalation and 18 in parallel expansion) were enrolled, with a median age of 66 years, ECOG 0 / 1 (34% / 66%), and a median of three previous treatment lines. Dose-limiting toxicity up to 15 mg / kg was not observed, and the maximum tolerated dose was not reached. Therefore, TJ001 was confirmed to have good tolerance up to 15 mg / kg Q2W. The most common treatment-related adverse events (TRAEs) were grade 1 / 2 nausea (22%), fatigue (14%), and vomiting (12%), with seven sporadic grade 3 TRAEs and no grade ≥4 TRAEs.

[0107] Figure 4 shows the pharmacokinetic (PK) profile of mean TJ001 serum concentration at each dose level. As shown in Figure 4, TJ001 showed linear PK at dose levels of 5 mg / kg and above, indicating target saturation.

[0108] Among the pharmacodynamic biomarkers, peripheral soluble 4-1BB levels were measured for each cohort at pre-treatment C1D1 (cycle 1 day 1), C1D2, C1D8, C1D15, C2D1, C2D15, C3D1, and C4D1, and the results are shown in Figures 5A - C. Figure 5A shows the peripheral soluble 4-1BB levels (as fold change from baseline) at these time points at different dose levels. Figures 5B - C show the peripheral soluble 4-1BB levels (as fold change from baseline) for each subject at C1D8 and C1D15 at different dose levels, respectively. As shown in FIGS. 5A - C, the induction of soluble 4 - 1BB was dose - dependent, with a plateau of induction observed at 8 - 15 mg / kg and a peak at 12 - 15 mg / kg. CLDN18.2 - dependent s4 - 1BB induction, which reflects localized T - cell activation in tumors, was also observed to be more prominent at 12 mg / kg.

[0109] CLDN18.2 + parallel dose expansion In subjects with pathologically confirmed CLDN18.2 - positive (CLDN18.2 +), gastric cancer (GC), gastroesophageal junction adenocarcinoma (GEJ), esophageal adenocarcinoma (EAC), pancreatic ductal adenocarcinoma (PDAC), or cholangiocarcinoma, a CLDN18.2 + parallel dose expansion of TJ001 was conducted. CLDN18.2 positivity was defined as a membrane intensity score of ≥1 + in ≥1% of tumor cells.

[0110] Six subjects per cohort (N = 6) were administered TJ001 at doses of 5 mg / kg (Q2W), 8 mg / kg (Q2W), 12 mg / kg (Q2W), and 15 mg / kg (Q2W). Among 18 evaluable patients with CLDN18.2 + gastroesophageal cancer (GEC) at 5, 8, 12 mg / kg, partial response (PR) was observed in 1 patient each at 5 and 8 mg / kg, unconfirmed PR in 2 patients at 12 mg / kg, and stable disease in 2 patients. An additional PR was observed in 1 patient with head and neck cancer at 12 mg / kg. The CLDN18.2 expression among responders ranged from 11% to 100%.

[0111] Dose expansion The dose - expansion study of TJ001 was conducted in subjects with pathologically confirmed CLDN18.2 - positive (CLDN18.2 +), gastric cancer (GC), gastroesophageal junction adenocarcinoma (GEJ), esophageal adenocarcinoma (EAC) as third - line or further immunotherapy. CLDN18.2 positivity was defined as a membrane intensity score of ≥1 + in ≥1% of tumor cells. Based on safety, clinical PK / PD, and efficacy, 12 mg / kg was selected as the RP2D.

[0112] TJ001 is administered to 30 subjects (N = 30) at 12 mg / kg (Q2W). * * *

[0113] This disclosure is not limited in scope by the specific embodiments described, which are intended as illustrations of individual aspects of the disclosure, and any compositions or methods functionally equivalent are within the scope of the invention. It will be apparent to those skilled in the art that various modifications and variations can be made to the methods and compositions of the disclosure without departing from the spirit or scope of the disclosure. Accordingly, the disclosure is intended to embrace such modifications and variations as fall within the scope of the appended claims and their equivalents.

[0114] All publications and patent applications mentioned in this specification are incorporated herein by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

[0115] The invention has been described with respect to specific aspects found or proposed by the inventors to include preferred modes for carrying out the invention. It will be understood by those skilled in the art that, in light of the present disclosure, numerous modifications and changes can be made in the exemplified specific embodiments without departing from the intended scope of the invention. For example, due to codon degeneracy, changes can be made in the underlying DNA sequence without affecting the protein sequence. Further, since biological function equivalence is considered, changes can be made in the protein structure without affecting the biological action in kind or amount. All such modifications are intended to be within the scope of the appended claims.

[0116] [Table 2-1] [Table 2-2]

Claims

**Claim 1** A method for treating a solid tumor, comprising administering to a subject in need of treatment of a solid tumor (1) an anti-claudin 18.2 (CLDN18.2) unit having binding specificity for the CLDN18.2 protein, and (2) a second antibody unit, wherein the bispecific antibody is administered to the subject at a dosage of about 0.1 to about 30 mg / kg body weight. The method according to claim 1, wherein the bispecific antibody is administered to the subject at a dosage of about 0.1 to about 30 mg / kg body weight. **Claim 2** The method according to claim 1, wherein the second antibody unit has binding specificity for a target selected from the group consisting of 4-1BB, PD-1, PD-L1, and CD3. **Claim 3** The method according to claim 1 or 2, wherein the second antibody unit has binding specificity for 4-1BB. **Claim 4** The method according to any one of claims 1 to 3, wherein the bispecific antibody is administered to the subject at a dosage of about 0.1 to about 15 mg / kg body weight. **Claim 5** The method according to any one of claims 1 to 3, wherein the bispecific antibody is administered to the subject at a dosage of about 0.3 to about 15 mg / kg body weight. **Claim 6** The method according to any one of claims 1 to 3, wherein the bispecific antibody is administered to the subject at a dosage of about 1 to about 15 mg / kg body weight. **Claim 7** The method according to any one of claims 1 to 3, wherein the bispecific antibody is administered to the subject at a dosage of about 3 to about 15 mg / kg body weight. **Claim 8** The method according to any one of claims 1 to 3, wherein the bispecific antibody is administered to the subject at a dosage of about 5 to about 15 mg / kg body weight. **Claim 9** The method according to any one of claims 1 to 3, wherein the bispecific antibody is administered to the subject at a dosage of about 8 to about 15 mg / kg body weight. **Claim 10** The method according to any one of claims 1 to 3, wherein the bispecific antibody is administered to the subject at a dosage of about 12 to about 15 mg / kg body weight. **Claim 11** The method according to any one of claims 1 to 3, wherein the bispecific antibody is administered to the subject at a dosage of about 8 to about 12 mg / kg body weight. **Claim 12** The method according to any one of claims 1 to 3, wherein the bispecific antibody is administered to the subject at a dosage of about 0.1, about 0.3, about 1, about 5, about 8, about 12, about 15, or about 30 mg / kg body weight. **Claim 13** The method according to any one of claims 1 to 3, wherein the bispecific antibody is administered to the subject at a dose of about 5, about 8, about 12, or about 15 mg / kg body weight.

14. The method according to any one of claims 1 to 13, wherein the bispecific antibody is administered to the subject weekly, bi-weekly, once every three weeks, or monthly.

15. The method according to claim 14, wherein the bispecific antibody is administered to the subject bi-weekly.

16. The method according to any one of claims 1 to 15, wherein the bispecific antibody is administered to the subject intravenously.

17. The method according to any one of claims 1 to 16, wherein the anti-CLDN18.2 unit is selected from the group consisting of a full-length antibody, Fab, Fab’, F(ab’)2, scFv, and sdAb.

18. The method according to claim 17, wherein the anti-CLDN18.2 unit comprises Fab.

19. The anti-CLDN18.2 unit is (1) HC-CDR1, HC-CDR2, and HC-CDR3, each comprising the amino acid sequence of CDR1, CDR2, and CDR3 within the heavy variable region (VH) set forth in SEQ ID NO: 1, and (2) LC-CDR1, LC-CDR2, and LC-CDR3, each comprising the amino acid sequence of CDR1, CDR2, and CDR3 within the light variable region (VL) set forth in SEQ ID NO: 2, and the method according to any one of claims 1 to 18.

20. The anti-CLDN18.2 unit is (1) HC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 3, (2) HC-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 4, (3) HC-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 5, (4) LC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 6, (5) LC-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 7, and (6) LC-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 8, and the method according to any one of claims 1 to 19.

21. The anti-CLDN18.2 unit is (1) a heavy variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO: 1 or an amino acid sequence having at least 90% identity with SEQ ID NO: 1, and (2) a light variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 2 or an amino acid sequence having at least 90% identity with SEQ ID NO: 2, and the method according to any one of claims 1 to 20.

22. The method according to any one of claims 1 to 21, wherein the anti-4-1BB unit is selected from the group consisting of a full-length antibody, Fab, Fab', F(ab')2, scFv, and sdAb.

23. The method according to any one of claims 1 to 22, wherein the anti-4-1BB unit comprises scFv.

24. The anti-4-1BB unit is (1) HC-CDR1, HC-CDR2, and HC-CDR3, each comprising the amino acid sequence of CDR1, CDR2, and CDR3 within the heavy variable region (VH) set forth in SEQ ID NO: 9, and (2) LC-CDR1, LC-CDR2, and LC-CDR3, each comprising the amino acid sequence of CDR1, CDR2, and CDR3 within the light variable region (VL) set forth in SEQ ID NO: 10, the method according to any one of claims 3 to 23.

25. The anti-4-1BB unit is (1) HC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11, (2) HC-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 12, (3) HC-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 13, (4) LC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 14, (5) LC-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and (6) LC-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16, the method according to any one of claims 3 to 24.

26. The anti-4-1BB unit is (1) a heavy variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO: 9 or an amino acid sequence having at least 90% identity with SEQ ID NO: 9, and (2) a light variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 10 or an amino acid sequence having at least 90% identity with SEQ ID NO: 10, the method according to any one of claims 3 to 25.

27. The bispecific antibody is (1) a heavy chain component comprising the amino acid sequence set forth in SEQ ID NO: 17 or an amino acid sequence having at least 90% identity with SEQ ID NO: 17, and (2) a light chain component comprising the amino acid sequence set forth in SEQ ID NO: 18 or an amino acid sequence having at least 90% identity with SEQ ID NO: 18, the method according to any one of claims 1 to 26.

28. The method according to any one of claims 1 to 27, wherein the bispecific antibody is selected from the group consisting of TJ001, IBI389 (Innovent), Q-1802 (QureBio), AMG-910 (Amgen), QLS31905 (Qilu Pharma), PM1032 (Biotheus), and HBM7022 (Harbour, AZ).

29. The method according to any one of claims 1 to 16, wherein the solid tumor overexpresses CLDN18.

2.

30. The method according to any one of claims 1 to 29, wherein the solid tumor is selected from the group consisting of colorectal cancer, genitourinary cancer, sarcoma, melanoma, hepatocellular carcinoma, gastric cancer (GC), esophageal cancer (including esophageal adenocarcinoma (EAC)), gastroesophageal cancer (including gastroesophageal junction adenocarcinoma (GEJ)), esophageal cancer, pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC), lung cancer, non-small cell lung cancer (NSCLC), breast cancer, ovarian cancer, colon cancer, liver cancer, head and neck cancer, gallbladder cancer, Krukenberg tumor, and lymphoma.

31. The method according to any one of claims 1 to 30, wherein the solid tumor is a progressive solid tumor.

32. The method according to any one of claims 1 to 31, wherein the solid tumor is a metastatic solid tumor.

33. The method according to any one of claims 1 to 32, wherein the solid tumor is a progressive and metastatic solid tumor.

34. Use of a bispecific antibody in the preparation of a medicament for treating a solid tumor in a subject in need of treatment of the solid tumor, wherein the bispecific antibody comprises: (1) an anti-Claudin 18.2 (CLDN18.2) unit having binding specificity for the CLDN18.2 protein, and (2) an anti-4-1BB unit having binding specificity for the 4-1BB protein, wherein the medicament is administered to the subject at a dosage of about 0.1 to about 30 mg / kg body weight.

35. A manufactured product comprising: (1) a bispecific antibody comprising an anti-Claudin 18.2 (CLDN18.2) unit having binding specificity for the CLDN18.2 protein and an anti-4-1BB unit having binding specificity for the 4-1BB protein, and (2) package insert suggesting administering the bispecific antibody to a subject in need thereof at a dosage of about 0.1 to about 30 mg / kg body weight.

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