Methods of treating solid tumors using BI-specific antibodies

Abstract

Provided herein are methods of treating cancer in a subject, comprising administering a bi-specific antibody at the dose of between about 0.1 mg / kg and about 20 mg / kg of the subject's body weight at the frequency of once every two weeks or once every three weeks, wherein the bi-specific antibody comprises a Claudin 18.2 binding domain and a 4-1BB binding domain, wherein the 4-1BB binding domain is incapable of activating 4-1BB signaling upon binding to 4-1BB in the absence of the Claudin 18.2 binding domain binding to Claudin 18.2.

Description

Attorney Docket No. IMAB-002 / 02WO 328834-2191METHODS OF TREATING SOLID TUMORS USING BI-SPECIFIC ANTIBODIESCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority from U.S. Provisional Application No. 63 / 693,641, filed September 11, 2024, and U.S. Provisional Application No. 63 / 827,766, filed June 20, 2025, the disclosure of each of which is incorporated by reference in its entirety.FIELD OF THE DISCLOSURE

[0002] The present disclosure generally relates to methods of treating solid tumors using bi- specific antibodies targeting claudin 18.2 and 4- IBB.REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0003] The contents of the electronic sequence listing (IMAB_002_02WO_SeqList_ST26.xml; Size: 34,014 bytes; and Date of Creation: September 11, 2025) are herein incorporated by reference in its entirety.BACKGROUND

[0004] Claudins are a family of proteins that form the important components of the tight cell junctions. Claudin-18 splice variant 2 (Claudin 18.2 or CLDN18.2) is a gastric-specific membrane protein. In healthy tissues, Claudin 18.2 is restrictively expressed in the short-lived differentiated cells of gastric mucosa as a component of tight junction with limited accessibility of antibody treatment. However, Claudin 18.2 is ectopically expressed in a variety of primary and metastasis epithelial tumors, including gastric, pancreatic, esophageal, and lung adenocarcinoma cells.

[0005] 4-1BB (CD137) is a member of TNF-receptor superfamily (TNFRSF) and is a costimulatory molecule expressed following the activation of both innate and adaptive immune cells. 4- IBB plays an important role in modulating the activity of various immune cells. Activation of 4- IBB can enhance immune response to eliminate tumors.SUMMARY

[0006] The present disclosure provides a method of treating cancer in a subject, comprising administering a bi-specific antibody at a dose of between about 0.1 mg / kg and about 20 mg / kg of the subject’s body weight at a frequency of once every two weeks or once every three weeks, wherein the bi-specific antibody comprises a Claudin 18.2 binding domain and a 4-1BBAttorney Docket No. IMAB-002 / 02WO 328834-2191 binding domain, wherein the Claudin 18.2 binding domain comprises a heavy chain CDR1(HCDR1) comprising an amino acid sequence of SEQ ID NO: 1, a heavy chain CDR2 (HCDR2) comprising an amino acid sequence of SEQ ID NO: 2, a heavy chain CDR3 (HCDR3) comprising an amino acid sequence of SEQ ID NO: 3, a light chain CDR1 (LCDR1) comprising an amino acid sequence of SEQ ID NO: 4, a light chain CDR2 (LCDR2) comprising an amino acid sequence of SEQ ID NO: 5, and a light chain CDR3 (LCDR3) comprising an amino acid sequence of SEQ ID NO: 6, and wherein the 4-1BB binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 9, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 10, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 11, an LCDR1 comprising an amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 13, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 14.

[0007] In some embodiments, the Claudin 18.2 binding domain comprises an immunoglobulin heavy chain variable (VH) region and an immunoglobulin light chain variable (VL) region, wherein the VH region comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to SEQ ID NO: 7, and wherein the VL region comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to SEQ ID NO: 8. In some embodiments, the Claudin 18.2 binding domain is a Fab fragment.

[0008] In some embodiments, the 4- IBB binding domain comprises a VH region and a VL region, wherein the VH region comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to SEQ ID NO: 15, and wherein the VL region comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to SEQ ID NO: 16. In some embodiments, the 4-1BB binding domain is an scFv.

[0009] In some embodiments, the bi-specific antibody further comprises an Fc fragment. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to SEQ ID NO: 19.

[0010] In some embodiments, the Claudin 18.2 binding domain is a Fab fragment, wherein the 4- IBB binding domain is an scFv, wherein the bi-specific antibody comprises two firstAttorney Docket No. IMAB-002 / 02WO 328834-2191 polypeptides and two second polypeptides, wherein each of the first polypeptides comprise, from N-terminus to C-terminus, the heavy chain of the Fab fragment, the Fc fragment, and the scFv, and wherein each of the second polypeptides comprise the light chain of the Fab fragment.

[0011] In some embodiments, the bi-specific antibody comprises two first polypeptides and two second polypeptides, wherein each of the first polypeptides comprise an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to SEQ ID NO: 20, and wherein each of the second polypeptides comprise an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to SEQ ID NO: 21.

[0012] In some embodiments, the 4- IBB binding domain is incapable of activating 4- IBB signaling upon binding to 4-1BB in the absence of the Claudin 18.2 binding domain binding to Claudin 18.2.

[0013] In some embodiments, the bi-specific antibody is administered at a dose of between about 5 mg / kg and about 18 mg / kg of the subject’s body weight. In some embodiments, the bi- specific antibody is administered at a dose of between about 8 mg / kg and about 12 mg / kg of the subject’s body weight. In some embodiments, the bi-specific antibody is administered at a dose of about 5 mg / kg, about 8 mg / kg, about 12 mg / kg, about 15 mg / kg, or about 18 mg / kg of the subject’s body weight. In some embodiments, the bi-specific antibody is administered at a dose of about 8 mg / kg of the subject’s body weight. In some embodiments, the bi-specific antibody is administered at a dose of about 12 mg / kg of the subject’s body weight. In some embodiments, the bi-specific antibody is administered at a dose of about 18 mg / kg of the subject’s body weight.

[0014] In some embodiments, the bi-specific antibody is administered intravenously.

[0015] In some embodiments, the method further comprises administering to the subject a chemotherapy and a check point inhibitor. In some embodiments, the method further comprises administering to the subject a chemotherapy or a check point inhibitor.

[0016] In some embodiments, the chemotherapy comprises 5 -fluorouracil (5-FU) and platinum. In some embodiments, the chemotherapy comprises a combination of 5-FU, leucovorin, oxaliplatin, and capecitabine. In some embodiments, the chemotherapy comprises capecitabine and oxaliplatin. In some embodiments, the 5-FU is administered intravenously at a dose between about 200 mg / m2to about 800 mg / m2. In some embodiments, the leucovorin is administered intravenously at a dose between about 100 mg / m2to about 300 mg / m2. In some embodiments, the oxaliplatin is administered intravenously at a dose between about 50 mg / m2Attorney Docket No. IMAB-002 / 02WO 328834-2191 to about 200 mg / m2. In some embodiments, oxaliplatin is administered intravenously at a dose of about 130 mg / m2. In some embodiments, the chemotherapy is administered once every two weeks or once every three weeks. In some embodiments, capecitabine is administered orally at a dose of about 1000 mg / m2. In some embodiments, capecitabine is administered orally twice daily.

[0017] In some embodiments, the check point inhibitor is a PD-1 inhibitor. In some embodiments, the checkpoint inhibitor is nivolumab. In some embodiments, the nivolumab is administered intravenously at a dose of about 240 mg. In some embodiments, the checkpoint inhibitor is administered once every three weeks.

[0018] In some embodiments, the cancer is primary. In some embodiments, the cancer is metastatic. In some embodiments, the cancer is relapsed. In some embodiments, the cancer is refractory. In some embodiments, the cancer is refractory to a PD-1 inhibitor or a PD-L1 inhibitor. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is gastric adenocarcinoma (GC), gastro-esophageal junction adenocarcinoma (GEJ), esophageal adenocarcinoma (EAC), pancreatic ductal adenocarcinoma (PDAC), or cholangiocarcinoma. In some embodiments, the cancer is Claudin 18.2-positive. In some embodiments, the cancer is HER2-negative. In some embodiments, the cancer is unresectable. In some embodiments, the cancer is metastatic.

[0019] In some embodiments, the serum concentration of the bi-specific antibody is at least about 12 pg / mL throughout the treatment. In some embodiments, the serum half-life of the bispecific antibody is between about 5 days and about 7 days.

[0020] In some embodiments, the treatment results in increased serum concentration of soluble 4-1BB. In some embodiments, the serum concentration of soluble 4-1BB is between about 2 and about 130 times as high as that prior to the treatment. In some embodiments, the serum concentration of soluble 4- IBB is between about 5 and about 50 times as high as that prior to the treatment.

[0021] In some embodiments, the treatment results in a partial response. In some embodiments, the treatment results in a stable disease.

[0022] In some embodiments, the cancer is a solid tumor, and wherein the treatment results in a decrease in size of the solid tumor. In some embodiments, the size of the solid tumor is decreased by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, or at least about 80%, compared to the size of the solid tumor prior to the treatment.Attorney Docket No. IMAB-002 / 02WO 328834-2191

[0023] In some embodiments, the duration of response is at least about 3 months, at least about 6 months, at least about 9 months, at least about 12 months, at least about 15 months, at least about 18 months, or at least about 24 months. In some embodiments, the duration of response is at least about 9 months.

[0024] In some embodiments, the progression free survival is at least about 0.5 months, at least about 1 month, at least about 1.5 months, at least about 2 months, at least about 2.5 months, at least about 3 months, at least about 3.5 months, at least about 4 months, at least about 4.5 months, at least about 5 months, at least about 5.5 months, or at least about 6 months. In some embodiments, the progression free survival is about 1.7 months, about 3 months, or about 3.9 months.

[0025] In some embodiments, the objective response rate is at least about 5%, at least about 10%, at least about 15%, at least about 20%, or at least about 25%. In some embodiments, the objective response rate is about 11%, about 17%, or about 19%.

[0026] In some embodiments, the disease control rate is at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, or at least about 65%. In some embodiments, the disease control rate is about 37%, about 42%, or about 57%.

[0027] In some embodiments, the treatment results in a treatment related adverse event (TRAE) in the subject. In some embodiments, the TRAE is selected from any one of: neutropenia, peripheral neuropathy, nausea, vomiting, infusion related reaction, diarrhea, abdominal pain, gastritis, increased alanine aminotransferase (ALT), or increased aspartate aminotransferase (AST). In some embodiments, the TRAE is neutropenia, peripheral neuropathy, nausea, vomiting, or infusion related reaction. In some embodiments, the TRAE is Grade < 2. In some embodiments, the treatment does not result in any > Grade 3 nausea or vomiting. In some embodiments, the treatment results in a Grade >3 TRAE in less than about 50%, less than about 55%, less than about 60%, or less than about 65% of treated subjects. In some embodiments, the treatment does not result in any Grade 4 or Grade 5 TRAEs.BRIEF DESCRIPTION OF THE FIGURES

[0028] Fig. 1 shows the study design of the monotherapy of the phase 1 clinical study of Givastomig in subjects with solid tumors.

[0029] Fig. 2 shows the baseline characteristics of 55 subjects enrolled in the dose escalation and the parallel dose expansion of the phase 1 clinical study.Attorney Docket No. IMAB-002 / 02WO 328834-2191

[0030] Fig. 3 shows the treatment-related adverse events occurred among 55 subjects enrolled in the dose escalation and the parallel dose expansion of the phase 1 clinical study.

[0031] Fig. 4 shows the mean serum concentration of Givastomig at the designated time points after Givastomig was intravenously administered to the subjects at the dosage of 0.1 mg / kg, 0.3 mg / kg, 1 mg / kg, 3 mg / kg, 5 mg / kg, 8 mg / kg, 12 mg / kg, or 15 mg / kg, every 2 weeks (Q2W), during the dose escalation and the parallel dose expansion of the phase 1 clinical study.

[0032] Fig. 5 shows the fold change of soluble 4- IBB from baseline at the designated time points after Givastomig was intravenously administered to the subjects at the dosage of 0.1 mg / kg, 0.3 mg / kg, 1 mg / kg, 3 mg / kg, 5 mg / kg, 8 mg / kg, 12 mg / kg, or 15 mg / kg, every 2 weeks (Q2W), during the dose escalation and the parallel dose expansion of the phase 1 clinical study.

[0033] Fig. 6 shows the efficacy of Givastomig in subjects that were efficacy evaluable during the dose escalation and the parallel dose expansion of the phase 1 clinical study.

[0034] Fig. 7 shows the duration of treatment during the dose escalation and the parallel dose expansion of the phase 1 clinical study.

[0035] Fig. 8 shows the change of the tumor size in a subject with metastatic esophageal adenocarcinoma who had a partial response to Givastomig at the dosage of 5 mg / kg, Q2W.

[0036] Fig. 9 shows the baseline characteristics of 43 subjects with Claudin 18.2+ GEC enrolled in the parallel dose expansion and the dose expansion of the phase 1 clinical study.

[0037] Fig. 10 shows the treatment-related adverse events occurred among 43 subjects enrolled in the parallel dose expansion and the dose expansion of the phase 1 clinical study.

[0038] Fig. 11 shows the mean serum concentration of Givastomig at the designated time points after Givastomig was intravenously administered to the subjects at the dosage of 5 mg / kg, 8 mg / kg, 12 mg / kg, or 15 mg / kg, every 2 weeks (Q2W), during the parallel dose expansion and the dose expansion of the phase 1 clinical study.

[0039] Fig. 12 shows the fold change of soluble 4-1BB from baseline at the designated time points after Givastomig was intravenously administered to the subjects at the dosage of 5 mg / kg, 8 mg / kg, 12 mg / kg, or 15 mg / kg, every 2 weeks (Q2W), and 18 mg / kg, every 3 weeks (Q3W), during the parallel dose expansion and the dose expansion of the phase 1 clinical study.

[0040] Fig. 13 shows the efficacy of Givastomig in subjects that were efficacy evaluable during the parallel dose expansion and the dose expansion of the phase 1 clinical study.

[0041] Fig. 14 shows the duration of treatment during the parallel dose expansion and the dose expansion of the phase 1 clinical study.

[0042] Fig. 15 shows the percentage change of the tumor size from baseline at the designated time points after Givastomig was intravenously administered to the subjects at the dosage of 5Attorney Docket No. IMAB-002 / 02WO 328834-2191 mg / kg, 8 mg / kg, 12 mg / kg, or 15 mg / kg, every 2 weeks (Q2W), and 18 mg / kg, every 3 weeks (Q3W), during the parallel dose expansion and the dose expansion of the phase 1 clinical study.

[0043] Figs. 16A-16B show the maximum extent of tumor shrinkage (Fig. 16A) and the duration of Givastomig treatment (Fig. 16B).

[0044] Figs. 17A-17B show pharmacokinetic data for Givastomig administered to subjects in the dose escalation study.

[0045] Figs. 18A-18D show the pharmacodynamic effect of Givastomig on peripheral s4- 1BB in subjects in the dose escalation study (Fig. 18A-18B) and in patients with GEC from both dose escalation and expansion cohorts receiving 8 to 15 mg / kg Givastomig (Figs. 18C- 18D).

[0046] Fig. 19A-19B show the study design (Fig. 19A) and the baseline characteristics of 17 subjects enrolled (Fig. 19B) in the combined therapy arm of the phase lb clinical study of Givastomig in subjects with solid tumors. ECOG = Eastern Cooperative Oncology Group Eastern Cooperative Oncology Group performance status 0 or 1.

[0047] Fig. 20 shows the treatment-related adverse events occurred among 17 subjects enrolled in the combined therapy arm of the phase lb clinical study. TEAE = treatment- emergent adverse event; TRAE = treatment-related adverse event; SAE = serious adverse event; DC = discontinued; ALT = alanine aminotransferase; AST aspartate aminotransferase.

[0048] Fig. 21 shows the fold change of soluble 4- IBB from baseline in subjects treated with 5 mg / kg, 8 mg / kg, or 12 mg / kg Givastomig in the combined therapy arm of the phase lb study.

[0049] Figs. 22A-22B shows the efficacy of combined therapy in subjects that were efficacy evaluable (Fig. 22A) and the duration of treatment (Fig. 22B) during the combined therapy arm of the phase lb clinical study. CPS = combined positive score; CLDN = positive for claudin- 18.2 expression; SD = stable disease; PR = partial response; PD = progressive disease.

[0050] Fig. 23 shows the percentage change of the tumor size from baseline at the designated time points during the combined therapy arm of the phase lb clinical study.DETAILED DESCRIPTION

[0051] The present disclosure provides methods of treating cancer in a subject, comprising administering a bi-specific antibody at specified dosages, wherein the bi-specific antibody comprises a Claudin 18.2 binding domain and a 4-1BB binding domain, wherein the 4-1BB binding domain is incapable of activating 4- IBB signaling upon binding to 4- IBB in the absence of the Claudin 18.2 binding domain binding to Claudin 18.2. In some embodiments, the cancer is a Claudin 18.2-positive cancer.Attorney Docket No. IMAB-002 / 02WO 328834-2191

[0052] In some embodiments, the bi-specific antibody is Givastomig. Givastomig is a first- in-class bi-specific antibody targeting Claudin 18.2 and 4- IBB. Givastomig binds to tumors with a wide range of Claudin 18.2 expression levels, allowing for stronger Claudin 18.2 binding even in low Claudin 18.2 expressing tumor cells. This makes Givastomig unique among the Claudin 18.2-targeted agents whose anti-tumor activity is limited by higher Claudin 18.2 expression in tumor. In addition, Givastomig stimulates 4-1BB pathway in a Claudin 18.2- dependent way (i.e., upon local tumor engagement). This makes Givastomig a unique T cell activator only localized at the tumor cite, resulting in minimized systemic toxicity.Definitions

[0053] Unless otherwise defined herein, technical and scientific terms used in the present description have the meanings that are commonly understood by those of ordinary skill in the art. For purposes of interpreting this specification, the following description of terms will apply and whenever appropriate, terms used in the singular will also include the plural and vice versa unless the content clearly dictates otherwise. In the event that any description of a term set forth conflicts with any document incorporated herein by reference, the description of the term set forth below shall control.

[0054] The terms “a”, “an”, and “the”, as used herein, include plural references unless the context clearly dictates otherwise.

[0055] The term “about” or “approximately”, as used herein, in reference to a number or range of numbers, is understood to mean the stated number and numbers + / - 10% thereof, or 10% below the lower listed limit and 10% above the higher listed limit for the values listed for a range (except where such number would exceed 100% of a possible value or go below 0%). It is used to indicate that a value includes the inherent variation of error for the device or the method being employed to determine the value, or the variation that exists among the samples being measured.

[0056] The term “between”, as used in a phrase as such “between A and B” or “between A- B” refers to a range including both A and B.

[0057] The terms “comprise” and its grammatical equivalents, as used herein, specify the presence of stated features, integers, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof.

[0058] The terms “including”, “includes”, “included”, and other forms, as used herein, are not limiting.Attorney Docket No. IMAB-002 / 02WO 328834-2191

[0059] The terms “or” and “and / or”, as used herein, include any, and all, combinations of one or more of the associated listed items.

[0060] In the present description, any concentration range, percentage range, ratio range, or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated.

[0061] The term “administer”, “administration”, or “administering”, as used herein refers to the act of injecting or otherwise physically delivering a substance (e.g., a pharmaceutical composition provided herein) to a subject (e.g., human), such as by oral, mucosal, topical, intradermal, parenteral, intravenous, intravitreal, intraarticular, subretinal, intramuscular, intrathecal delivery and / or any other method of physical delivery described herein or known in the art. The delivery can be systemic or to a specific tissue.

[0062] The terms “amino-terminal” and “carboxyl-terminal” are used herein to denote positions within polypeptides. Where the context allows, these terms are used with reference to a particular sequence or portion of a polypeptide to denote proximity or relative position.

[0063] The term “antibody,” “immunoglobulin,” or “Ig” is used interchangeably herein, and is used in the broadest sense and specifically covers, for example, monoclonal antibodies (including agonist, antagonist, neutralizing antibodies, full length or intact monoclonal antibodies), antibody compositions with polyepitopic or monoepitopic specificity, polyclonal or monovalent antibodies, multivalent antibodies, and multi-specific antibodies (e.g., bispecific antibodies so long as they exhibit the desired biological activity). A conventional antibody is composed of two identical pairs of polypeptide chains, wherein each pair has one heavy chain (about 50-70 kDa) and one light chain (about 25 kDa), each amino-terminal portion of each chain includes a variable region of about 100 to about 130 or more amino acids, and each carboxy-terminal portion of each chain includes a constant region. See, e.g., Antibody Engineering (Borrebaeck, ed., 2d ed. 1995); and Kuby, Immunology (3d ed. 1997). An antibody can be human, humanized, chimeric and / or affinity matured, as well as an antibody from other species, for example, mouse and rabbit, etc. Antibodies also include, but are not limited to, synthetic antibodies, recombinantly produced antibodies, camelized antibodies or their humanized variants, and intrabodies. An antibody can be selected from any class of immunoglobulins, including IgM, IgG, IgD, IgA and IgE, and any isotype, including IgGl, IgG2, IgG3 and IgG4 (e.g., variants of IgG4 and IgG4 nullbody). An antibody can comprise kappa or lambda light chain constant sequences.Attorney Docket No. IMAB-002 / 02WO 328834-2191

[0064] The term “antigen”, as used herein, refers to a structure to which an antibody or an antibody fragment can specifically bind. An antigen may be a polypeptide, carbohydrate, nucleic acid, lipid, hapten, or other naturally occurring or synthetic compound.

[0065] The term “antigen-binding domain”, as used herein, refers to a portion of a binding molecule that specifically binds a target antigen or target epitope. Antigen-binding domains may comprise antibodies or antigen-binding fragments thereof.

[0066] The term “antigen-binding fragment”, as used herein, refers to a portion of an antibody heavy and / or light chain polypeptide that retains some or all of the binding activity of the antibody from which the fragment was derived. An antigen-binding fragment may comprise 1, 2, 3, 4, 5, or all 6 CDRs of a variable heavy chain (VH) and / or variable light chain (VL) sequence. Non-limiting examples of functional fragments include single-chain Fvs (scFv), Fab fragments, F(ab’) fragments, F(ab)2 fragments, F(ab’)2 fragments, disulfide-linked Fvs (dsFv), Fd fragments, Fv fragments, diabody, triabody, tetrabody, and minibody. Such functional antigen-binding fragment can be found in, for example, Harlow and Lane, Antibodies: A Laboratory Manual (1989); Mol. Biology and Biotechnology: A Comprehensive Desk Reference (Myers, ed., 1995); Huston, et al, 1993, Cell Biophysics 22: 189-224; Pliickthun and Skerra, 1989, Meth. Enzymol. 178:497-515; and Day, Advanced Immunochemistrv (2d ed. 1990).

[0067] The term “binds” or “binding”, as used herein, refers to a covalent or non-covalent interaction between molecules (e.g., forming a complex by interactions). Exemplary non- covalent interactions include hydrogen bonds, ionic bonds, hydrophobic interactions, and / or van der Waals interactions. Terms such as “specific binding,” “specifically binds to,” or “is specific for” means that a binding domain or a binding molecule comprising a binding domain binds the target with an affinity or Ka(z.e., an equilibrium association constant of a particular binding interaction with units of 1 / M) equal to or greater than 105M’1, while not significantly binding other components present in a test sample.

[0068] The term “binding affinity”, as used herein, refers to the strength of the sum total of noncovalent interactions between a binding domain X and its binding partner Y. Unless indicated otherwise, as used herein, “binding affinity” refers to intrinsic binding affinity which reflects a 1 : 1 interaction between members of a binding pair (e.g., antibody and antigen). Binding domains can be classified as “high affinity” binding domains and “low affinity” binding domains. “High affinity” binding domains refer to those binding domains with a Kaof at least 107M’1, at least 108M’1, at least 109M’1, at least 1010M’1, at least 1011M’1, at least 1012M’1, or at least 1013M’1. “Low affinity” binding domains refer to those binding domainsAttorney Docket No. IMAB-002 / 02WO 328834-2191 with a Kaof up to 107M’1, up to 106M-1, up to 105M-1. High-affinity binding domains generally bind the binding partners faster and tend to remain bound longer, whereas low- affinity binding domains generally bind the binding partners slowly and tend to dissociate readily. Affinity can also be defined as an equilibrium dissociation constant (Ka) of a particular binding interaction with units of M e.g., 10'5M to 10'13, or about 1000 nM, about 900 nM, about 800 nM, about 700 nM, about 600 nM, about 500 nM, about 300 nM, about 250 nM, about 200 nM, about 150 nM, about 100 nM, about 50 nM, about 25 nM, about 10 nM, or about 5 nM). Affinities of binding domains according to the present disclosure can be readily determined using conventional techniques (see, e.g., Scatchard et al. (1949) Ann. N.Y. Acad. Sci. 51 :660; and U.S. Patent Nos. 5,283,173, 5,468,614, or the equivalent).

[0069] The term “binding molecule”, as used herein, refers to a polypeptide or complex of polypeptides comprising at least one binding domain that specifically binds to a target.

[0070] The term “constant region” or “constant domain”, as used herein, refers to a carboxy terminal portion of the light and heavy chain which is not directly involved in binding of the antibody to antigen but exhibits various effector function, such as interaction with the Fc receptor. This portion has a more conserved amino acid sequence relative to the variable region. The constant region may contain the CHI, CH2, and CH3 regions of the heavy chain and the CL region of the light chain.

[0071] The term “contact”, as used in the context of contacting a target cell with a compound or another cell, is intended to include incubating the target cell and the compound or the other cell together.

[0072] The term “effective amount”, as used herein, refers to an amount of a therapeutic (e.g., a pharmaceutical composition provided herein) which is sufficient to prevent, diagnose, treat, delay the onset of, reduce and / or ameliorate the severity, duration, advancement, and / or recurrence of a given condition, disorder or disease and / or a symptom related thereto. The term also encompasses an amount necessary to improve or enhance the prophylactic or therapeutic effect (s) of another therapy or to serve as a bridge to another therapy.

[0073] The term “epitope”, as used herein, refers to a localized region of an antigen to which an antibody can bind. In the case of a polypeptide antigen, for example, an epitope can be contiguous amino acids of the polypeptide (a “linear” epitope) or an epitope can comprise amino acids from two or more non-contiguous regions of the polypeptide (a “conformational,” “non-linear” or “discontinuous” epitope). It will be appreciated by one of skill in the art that, in general, a linear epitope may or may not be dependent on secondary, tertiary, or quaternary structure. In some embodiments, an antibody binds to a group of amino acids regardless ofAttorney Docket No. IMAB-002 / 02WO 328834-2191 whether they are folded in a natural three dimensional protein structure. In some embodiments, an antibody requires amino acid residues making up the epitope to exhibit a particular conformation (e.g., bend, twist, turn or fold) in order to recognize and bind the epitope.

[0074] The term “Fab” or “Fab region”, as used herein, refers to an antibody region that binds to antigens. A conventional IgG usually comprises two Fab regions, each residing on one of the two arms of the Y-shaped IgG structure. Each Fab region is typically composed of one variable region and one constant region of each of the heavy and the light chain. More specifically, the variable region and the constant region of the heavy chain in a Fab region are VH and CHI regions, and the variable region and the constant region of the light chain in a Fab region are VL and CL regions. The VH, CHI, VL, and CL in a Fab region can be arranged in various ways to confer an antigen binding capability. For example, VH and CHI regions can be on one polypeptide, and VL and CL regions can be on a separate polypeptide, similarly to a Fab region of a conventional IgG. Alternatively, VH, CHI, VL and CL regions can all be on the same polypeptide and oriented in different orders.

[0075] The term “Fc region”, as used herein, refers to a C-terminal region of an immunoglobulin heavy chain, including, for example, native sequence Fc regions, recombinant Fc regions, and variant Fc regions. Although the boundaries of the Fc region of an immunoglobulin heavy chain might vary, the human IgG heavy chain Fc region is often defined to stretch from an amino acid residue at position Cys226, or from Pro230, to the C-terminus thereof. The C-terminal lysine (residue 447 according to the EU numbering system) of the Fc region may be removed, for example, during production or purification of the antibody, or by recombinantly engineering the nucleic acid encoding a heavy chain of the antibody. Accordingly, a composition of intact antibodies may comprise antibody populations with all K447 residues removed, antibody populations with no K447 residues removed, and antibody populations having a mixture of antibodies with and without the K447 residue. A “functional Fc region” possesses an “effector function” of a native sequence Fc region. Exemplary “effector functions” include Clq binding; CDC; Fc receptor binding; ADCC; phagocytosis; downregulation of cell surface receptors (e.g., B cell receptor), etc. Such effector functions generally require the Fc region to be combined with a binding region or binding domain (e.g., an antibody variable region or domain) and can be assessed using various assays known to those skilled in the art.

[0076] The term “fragment”, as used herein, refers to a portion of a polypeptide or polynucleotide molecule containing less than the entire polypeptide or polynucleotide sequence. In some embodiments, a fragment of a polypeptide or polynucleotide comprises at least aboutAttorney Docket No. IMAB-002 / 02WO 328834-219110%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99% of the entire length of the reference polypeptide or polynucleotide. In some embodiments, a fragment of a polypeptide or polynucleotide comprises about 10%-99%, about 20%-99%, about 30%-99%, about 40%-99%, about 50%-99%, about 60%-99%, about 70%-99%, about 80%-99%, about 90%-99%, about 95%-99%, about 96%-99%, about 97%-99%, or about 98%-99%, of the entire length of the reference polypeptide or polynucleotide. In some embodiments, a polypeptide or polynucleotide fragment may contain about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 60, about 70, about 80, about 90, about 100, about 200, about 300, about 400, about 500, about 600, about 700, about 800, about 900, about 1000, or more nucleotides or amino acids.

[0077] The term “heavy chain”, when used in reference to an antibody, refers to a polypeptide chain of about 50-70 kDa, wherein the amino-terminal portion includes a variable region of about 120 to 130 or more amino acids, and a carboxy -terminal portion includes a constant region. The constant region can be one of five distinct types, (e.g, isotypes) referred to as alpha, delta, epsilon, gamma, and mu, based on the amino acid sequence of the heavy chain constant region. The distinct heavy chains differ in size: alpha, delta, and gamma contain approximately 450 amino acids, while epsilon and mu contain approximately 550 amino acids. When combined with a light chain, these distinct types of heavy chains give rise to five well known classes (e.g., isotypes) of antibodies, IgA, IgD, IgE, IgG, and IgM, respectively, including four subclasses of IgG, namely IgGl, IgG2, IgG3, and IgG4.

[0078] The term “light chain”, when used in reference to an antibody, refers to a polypeptide chain of about 25 kDa, wherein the amino-terminal portion includes a variable region of about 100 to about 110 or more amino acids, and a carboxy -terminal portion includes a constant region. The approximate length of a light chain is 211 to 217 amino acids. There are two distinct types, referred to as kappa or lambda based on the amino acid sequence of the constant domains.

[0079] The term “monoclonal antibody,” as used herein, refers to an antibody obtained from a population of substantially homogeneous antibodies, e.g., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts, and each monoclonal antibody will typically recognize a single epitope on the antigen.

[0080] The term “pharmaceutically acceptable excipient, carrier or diluent”, as used herein, refers to any substance formulated alongside the active ingredient of a pharmaceutical composition that allows the active ingredient to retain biological activity and is non-reactiveAttorney Docket No. IMAB-002 / 02WO 328834-2191 with the subject’s immune system. Such a substance can be included for the purpose of longterm stabilization, bulking up solid formulations that contain potent active ingredients in small amounts, or to confer a therapeutic enhancement on the active ingredient in the final dosage form, such as facilitating absorption, reducing viscosity, or enhancing solubility. The selection of appropriate substance can depend upon the route of administration and the dosage form, as well as the active ingredient and other factors. Compositions having such substances can be formulated by well-known conventional methods (see, e.g., Remington, The Science and Practice of Pharmacy, 23rd edition, A. Adejare, ed., Academic Press, 2020).

[0081] The term “pharmaceutical composition” or “therapeutic composition”, as used herein, refers to a composition capable of being administered to a subject for the treatment of a particular disease or disorder.

[0082] The terms “polypeptide” and “peptide” and “protein”, as used herein, refer to polymers of amino acids of any length. The polymer may be linear or branched, it may comprise modified amino acids, and it may be interrupted by non-amino acids. The terms also encompass an amino acid polymer that has been modified naturally or by intervention; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification. Also included within the definition are, for example, polypeptides containing one or more analogs of an amino acid, including but not limited to, unnatural amino acids, as well as other modifications known in the art.

[0083] The term “single-chain variable fragment (scFv)”, as used herein, refers to a fusion protein of the variable heavy chain (VH) and the variable light chain (VL) of an antibody, connected with a short scFv linker peptide. In some embodiments, the scFv linker is about 5 amino acids to about 30 amino acids in length. In some embodiments, the scFv linker is rich in glycine for flexibility, as well as serine or threonine for solubility, and can either connect the N-terminus of the VH region with the C-terminus of the VL region, or vice versa. scFvs retain the specificity of the original antibody, despite removal of the constant regions and the introduction of the scFv linker. scFvs are, described in e.g., Houston, J. S., Methods in Enzymol. 203 (1991) 46-96).

[0084] The term “sequence identity”, as used herein, refers to the percentage of bases or amino acids between two polynucleotide or polypeptide sequences that are the same, when compared and aligned for maximum correspondence over a comparison window or designated region. As such one polynucleotide or polypeptide sequence has a certain percentage of sequence identity compared to another polynucleotide or polypeptide sequence. For sequence comparison, typically one sequence acts as a reference sequence, to which test sequences areAttorney Docket No. IMAB-002 / 02WO 328834-2191 compared. The term “reference sequence” refers to a molecule to which a test sequence is compared. Methods of sequence alignment for comparison and determination of percent sequence identity and percent complementarity are well known in the art. Optimal alignment of sequences for comparison can be conducted, e.g., by the homology alignment algorithm of Needleman and Wunsch, (1970) J. Mol. Biol. 48:443, by the search for similarity method of Pearson and Lipman, (1988) Proc. Nat’l. Acad. Sci. USA 85:2444, by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, WI), by manual alignment and visual inspection (see, e.g., Brent et al., (2003) Current Protocols in Molecular Biology), by use of algorithms know in the art including the BLAST and BLAST 2.0 algorithms, which are described in Altschul et al., (1977) Nuc. Acids Res. 25:3389-3402; and Altschul et al., (1990) J. Mol. Biol. 215:403-410, respectively. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information. BLAST nucleotide searches can be performed with the NBLAST nucleotide program parameters set, e.g., for score 100, word length-2 to obtain nucleotide sequences homologous to a nucleic acid molecule described herein. BLAST protein searches can be performed with the XBLAST program parameters set, e.g., to score 50, word length-3 to obtain amino acid sequences homologous to a protein molecule described herein. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al., Nucleic Acids Res., 1997, 25:3389-402. Alternatively, PSI BLAST can be used to perform an iterated search which detects distant relationships between molecules (Id.). When utilizing BLAST, Gapped BLAST, and PSI BLAST programs, the default parameters of the respective programs (e.g., of XBLAST and NBLAST) can be used (see, e.g., National Center for Biotechnology Information (NCBI) on the worldwide web, ncbi.nlm.nih.gov). Another non-limiting example of a mathematical algorithm utilized for the comparison of sequences is the algorithm of Myers and Miller, 1988, CABIOS 4: 11 17. Such an algorithm is incorporated in the ALIGN program (version 2.0) which is part of the GCG sequence alignment software package. When utilizing the ALIGN program for comparing amino acid sequences, a PAM 120 weight residue table, a gap length penalty of 12, and a gap penalty of 4 can be used.

[0085] The term “subject”, as used herein, refers to an “animal” and in particular a “mammal” such as a non-primate (e.g., mice, rats, bovines, horses, household cats, tigers and other large cats, dogs, pigs, rabbits, goats, deer, sheep, ferrets, gerbils, guinea pigs, hamsters, bats, and birds e.g., chickens, turkeys, and ducks)) or a primate (e.g., monkeys, baboons, chimpanzees, and human). The term may be used interchangeably with the term “patient” or “individual”. InAttorney Docket No. IMAB-002 / 02WO 328834-2191 some embodiments, the subject is a mammal, e.g., a human, diagnosed with a disease or disorder provided herein. In some embodiments, the subject is a mammal, e.g., a human, at risk of developing a disease or disorder provided herein. In some embodiments, the subject is human. The term does not denote a particular age or sex. Thus, individuals of all ages, from newborn to adult, whether male or female, are intended to be covered.

[0086] The terms “treatment” and “treating”, as used herein, refer to a pharmaceutical or other intervention regimen for obtaining beneficial or desired results in the recipient. Beneficial or desired results include but are not limited to a therapeutic benefit and / or a prophylactic benefit. A therapeutic benefit may refer to eradication or amelioration of symptoms or of an underlying disorder being treated. Also, a therapeutic benefit can be achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. A prophylactic effect includes delaying, preventing, or eliminating the appearance of a disease or condition, delaying, or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof. For prophylactic benefit, a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease may undergo treatment, even though a diagnosis of this disease may not have been made.

[0087] The term “variable region”, “variable domain”, “V region”, or “V domain”, as used herein, refers to a portion of the light or heavy chains of an antibody that is generally located at the amino-terminal of the light or heavy chain and has a length of about 120 to 130 amino acids in the heavy chain and about 100 to 110 amino acids in the light chain, and are used in the binding and specificity of each particular antibody for its particular antigen. The variable region of the heavy chain may be referred to as “VH.” The variable region of the light chain may be referred to as “VL.” The term “variable” refers to the fact that certain segments of the variable regions differ extensively in sequence among antibodies. The V region mediates antigen binding and defines specificity of a particular antibody for its particular antigen. However, the variability is not evenly distributed across the 110-amino acid span of the variable regions. Instead, the V regions consist of less variable (e.g., relatively invariant) stretches called framework regions (FRs) of about 15-30 amino acids separated by shorter regions of greater variability (e.g., extreme variability) called “hypervariable regions” or “complementarity determining regions” that are each about 9-12 amino acids long. The variable regions of heavy and light chains each comprise four FRs, largely adopting a P sheet configuration, connectedAttorney Docket No. IMAB-002 / 02WO 328834-2191 by three hypervariable regions, which form loops connecting, and in some cases form part of, the P sheet structure. The hypervariable regions in each chain are held together in close proximity by the FRs and, with the hypervariable regions from the other chain, contribute to the formation of the antigen-binding site of antibodies (see, e.g., Kabat et al, Sequences of Proteins of Immunological Interest (5th ed. 1991)).

[0088] The complementarity determining regions (CDRs) have been defined by well-known numbering systems. For example, the Kabat Complementarity Determining Regions (CDRs) are based on sequence variability and are the most commonly used (see, e.g., Kabat, et al., supra). Chothia refers instead to the location of the structural loops (see, e.g., Chothia and Lesk, J. Mol. Biol., 1987, 196:901-17). The end of the Chothia CDR-H1 loop when numbered using the Kabat numbering convention varies between H32 and H34 depending on the length of the loop (this is because the Kabat numbering scheme places insertions at H35A and H35B; if neither 35A nor 35B is present, the loop ends at 32; if only 35A is present, the loop ends at 33; if both 35 A and 35B are present, the loop ends at 34). The AbM hypervariable regions represent a compromise between the Kabat CDRs and Chothia structural loops, and are used by Oxford Molecular’s AbM antibody modeling software (see, e.g., Antibody Engineering Vol. 2 (Rontermann and Diibel, eds., 2d ed. 2010)). The “contact” CDRs are based on an analysis of the available complex crystal structures. Another universal numbering system that has been developed and widely adopted is ImMunoGeneTics (IMGT) Information System® (Lafranc, et al, Dev. Comp. Immunol., 2003, 27(l):55-77). IMGT is an integrated information system specializing in immunoglobulins (IG), T-cell receptors (TCR), and major histocompatibility complex (MHC) of human and other vertebrates. An additional numbering system (AHon) has been developed by Honegger and Pluckthun, J. Mol. Biol., 2001, 309: 657-70. Correspondence between the numbering system, including, for example, the Kabat numbering and the IMGT unique numbering system, is well known to one skilled in the art (see, e.g., Kabat, supra, Chothia and Lesk, supra; Martin, supra, Lefranc, et al., supra).

[0089] The boundaries of a given CDR may vary depending on the scheme used for identification. Thus, unless otherwise specified, the CDRs of a given antibody or region thereof, such as a variable region, should be understood to encompass the complementary determining region as defined by any of the known schemes described herein. In some instances, the scheme for identification of a particular CDR or CDRs is specified, such as the CDR as defined by the Kabat, Chothia, or Contact method. In other cases, the particular amino acid sequence of a CDR is given. In some embodiments, a combination of CDR numbering systems may be used. In such embodiments, CDR sequences of a given binding molecule as determined by multipleAttorney Docket No. IMAB-002 / 02WO 328834-2191 numbering systems (e.g., a CDR1 sequence as determined by the Kabat, IMGT, and Chothia numbering systems) are compiled into a single sequence that encompasses the entirety of each of the CDR amino acid ranges in the variable region.

[0090] As the “location” of the CDRs within the structure of the immunoglobulin variable domain is conserved between species and present in structures called loops, by using numbering systems that align variable domain sequences according to structural features, CDR and framework residues are readily identified. This information can be used in grafting and replacement of CDR residues from immunoglobulins of one species into an acceptor framework from, typically, a human antibody.

[0091] The term “variant”, when used in relation to polypeptide, refers to a polypeptide comprising one or more (such as, for example, about 1 to about 25, about 1 to about 20, about 1 to about 15, about 1 to about 10, or about 1 to about 5) amino acid sequence substitutions, deletions, and / or additions as compared to a native or unmodified sequence. Variants may be naturally occurring, such as allelic or splice variants, or may be artificially constructed. Polypeptide variants may be prepared from the corresponding nucleic acid molecules encoding the variants.

[0092] General methods in molecular and cellular biochemistry can be found in such standard textbooks as Molecular Cloning: A Laboratory Manual, 3rd Ed. (Sambrook et cd.. HaRBor Laboratory Press 2001 ); Short Protocols in Molecular Biology, 4th Ed. (Ausubel et al. eds., John Wiley & Sons 1999); Protein Methods (Bollag etal., John Wiley & Sons 1996); Nonviral Vectors for Gene Therapy (Wagner et al. eds., Academic Press 1999); Viral Vectors (Kaplift & Loewy eds., Academic Press 1995); Immunology Methods Manual (I. Lefkovits ed., Academic Press 1997); and Cell and Tissue Culture: Laboratory Procedures in Biotechnology (Doyle & Griffiths, John Wiley & Sons 1998), the disclosures of which are incorporated herein by reference.Methods of Treatment

[0093] Provided herein are methods of treating cancer in a subject, comprising administering a bi-specific antibody at a dose of between about 0.1 mg / kg and about 20 mg / kg of the subj ect’ s body weight at a frequency of once every two weeks or once every three weeks. In some embodiments, the bi-specific antibody comprises a Claudin 18.2 binding domain that specifically binds to Claudin 18.2 and a 4-1BB binding domain that specifically binds to 4- 1BB. In some embodiments, the cancer is a Claudin 18.2-positive cancer.Attorney Docket No. IMAB-002 / 02WO 328834-2191Bi-specific Antibodies Used in the Methods of Treatment

[0094] In some embodiments, the bi-specific antibody comprises a Claudin 18.2 binding domain and a 4- IBB binding domain. In some embodiments, the 4- IBB binding domain is incapable of activating 4- IBB signaling upon binding to 4- IBB in the absence of the Claudin 18.2 binding domain binding to Claudin 18.2. In some embodiments, the binding of the 4-1BB binding domain to 4- IBB on a cell does not result in clustering of 4- IBB in the absence of the Claudin 18.2 binding domain binding to Claudin 18.2.

[0095] The exemplary amino acid sequences of the Claudin 18.2 binding domain(anti- Claudin 18.2) and the 4-1BB binding domain (anti-4-lBB), as well as other exemplary sequences related to bi-specific antibodies comprising these domains, are listed in Table 1 below.Table 1.Attorney Docket No. IMAB-002 / 02WO 328834-2191Attorney Docket No. IMAB-002 / 02WO 328834-2191

[0096] In some embodiments, the Claudin 18.2 binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 1 or an amino acid sequence having one or two amino acid substitutions in reference to SEQ ID NO: 1.

[0097] In some embodiments, the Claudin 18.2 binding domain comprises an HCDR2 comprising an amino acid sequence of SEQ ID NO: 2 or an amino acid sequence having one or two amino acid substitutions in reference to SEQ ID NO: 2.

[0098] In some embodiments, the Claudin 18.2 binding domain comprises an HCDR3 comprising an amino acid sequence of SEQ ID NO: 3 or an amino acid sequence having one or two amino acid substitutions in reference to SEQ ID NO: 3.

[0099] In some embodiments, the Claudin 18.2 binding domain comprises an LCDR1 comprising an amino acid sequence of SEQ ID NO: 4 or an amino acid sequence having one or two amino acid substitutions in reference to SEQ ID NO: 4.

[0100] In some embodiments, the Claudin 18.2 binding domain comprises an LCDR2 comprising an amino acid sequence of SEQ ID NO: 5 or an amino acid sequence having one or two amino acid substitutions in reference to SEQ ID NO: 5.

[0101] In some embodiments, the Claudin 18.2 binding domain comprises an LCDR3 comprising an amino acid sequence of SEQ ID NO: 6 or an amino acid sequence having one or two amino acid substitutions in reference to SEQ ID NO: 6.

[0102] In some embodiments, the Claudin 18.2 binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising an amino acid sequence of SEQ ID NO: 4, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 5, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 6.

[0103] In some embodiments, the 4- IBB binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 9 or an amino acid sequence having one or two amino acid substitutions in reference to SEQ ID NO: 9.

[0104] In some embodiments, the 4- IBB binding domain comprises an HCDR2 comprising an amino acid sequence of SEQ ID NO: 10 or an amino acid sequence having one or two amino acid substitutions in reference to SEQ ID NO: 10.

[0105] In some embodiments, the 4- IBB binding domain comprises an HCDR3 comprising an amino acid sequence of SEQ ID NO: 11 or an amino acid sequence having one or two amino acid substitutions in reference to SEQ ID NO: 11.Attorney Docket No. IMAB-002 / 02WO 328834-2191

[0106] In some embodiments, the 4- IBB binding domain comprises an LCDR1 comprising an amino acid sequence of SEQ ID NO: 12 or an amino acid sequence having one or two amino acid substitutions in reference to SEQ ID NO: 12.

[0107] In some embodiments, the 4- IBB binding domain comprises an LCDR2 comprising an amino acid sequence of SEQ ID NO: 13 or an amino acid sequence having one or two amino acid substitutions in reference to SEQ ID NO: 13.

[0108] In some embodiments, the 4- IBB binding domain comprises an LCDR3 comprising an amino acid sequence of SEQ ID NO: 14 or an amino acid sequence having one or two amino acid substitutions in reference to SEQ ID NO: 14.

[0109] In some embodiments, the 4- IBB binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 9, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 10, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 11, an LCDR1 comprising an amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 13, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 14.

[0110] In some embodiments, the Claudin 18.2 binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising an amino acid sequence of SEQ ID NO: 4, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 5, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 6, and the 4-1BB binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 9, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 10, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 11, an LCDR1 comprising an amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 13, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 14.

[0111] In some embodiments, the Claudin 18.2 binding domain comprises an immunoglobulin heavy chain variable (VH) region and an immunoglobulin light chain variable (VL) region. In some embodiments, the VH region comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to SEQ ID NO: 7. In some embodiments, the VL region comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to SEQ ID NO: 8.Attorney Docket No. IMAB-002 / 02WO 328834-2191In some embodiments, the VH region comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to SEQ ID NO: 7, and the VL region comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to SEQ ID NO: 8.

[0112] In some embodiments, the 4-1BB binding domain comprises an immunoglobulin heavy chain variable (VH) region and an immunoglobulin light chain variable (VL) region. In some embodiments, the VH region comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to SEQ ID NO: 15. In some embodiments, the VL region comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to SEQ ID NO: 16. In some embodiments, the VH region comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to SEQ ID NO: 15, and the VL region comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to SEQ ID NO: 16.

[0113] In some embodiments, the VH region of the Claudin 18.2 binding domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to SEQ ID NO: 7, the VL region of the Claudin 18.2 binding domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to SEQ ID NO: 8, the VH region of the 4-1BB binding domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to SEQ ID NO: 15, and the VL region of the 4-1BB binding domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to SEQ ID NO: 16.Attorney Docket No. IMAB-002 / 02WO 328834-2191

[0114] In some embodiments, the Claudin 18.2 binding domain is a single chain variable fragment (scFv), Fab, Fab’, or F(ab’)2. In some embodiments, the Claudin 18.2 binding domain is a Fab fragment. In some embodiments, the 4- IBB binding domain is a single chain variable fragment (scFv), Fab, Fab’, or F(ab’)2. In some embodiments, the 4-1BB binding domain is an scFv.

[0115] In some embodiments, the 4- IBB binding domain is an scFv, and the C-terminus of the VH region is linked to the N-terminus of the VL region. In some embodiments, the 4- IBB binding domain is an scFv, and the C-terminus of the VL region is linked to the N-terminus of the VH region. In some embodiments, the VH region and the VL region is linked via a linker. Suitable linkers are generally those which allow both the VH region and the VL region to fold with a three-dimensional structure very similar to the VH region and the VL region produced individually without any linker or other component. Linkers include single amino acids, peptides, polypeptides, non-proteinaceous polymers such as polyethylene glycol (PEG), polypropylene glycol, polyoxyalkylenes, or copolymers of polyethylene glycol and polypropylene glycol, and chemical linkers.

[0116] In some embodiments, the VH region and the VL region are linked by a peptide linker. In some embodiments, the peptide linker can predominantly include the following amino acid residues: Gly, Ser, Ala, Pro, or Thr. Exemplary linkers include, but are not limited to, glycine-serine linkers, glycine-alanine linkers, proline-threonine, and alanine-serine linkers.

[0117] The linker peptide should have a length that is adequate to link the VH region and the VL region in such a way that they assume the correct conformation relative to one another so that they retain the desired activity. In some embodiments, the linker is between about 5 amino acids to about 10 amino acids in length. In some embodiments, the linker is between about 5 amino acids to about 15 amino acids in length. In some embodiments, the linker is between about 5 amino acids to about 20 amino acids in length. In some embodiments, the linker is between about 5 amino acids to about 30 amino acids in length. In some embodiments, the linker is between about 10 amino acids to about 15 amino acids in length. In some embodiments, the linker is between about 10 amino acids to about 20 amino acids in length. In some embodiments, the linker is between about 10 amino acids to about 30 amino acids in length. In some embodiments, the linker is between about 15 amino acids to about 30 amino acids in length. In some embodiments, the linker is between about 15 amino acids to about 45 amino acids in length. In some embodiments, the linker is 5 amino acids in length. In some embodiments, the linker is 10 amino acids in length. In some embodiments, the linker is 15 amino acids in length. In some embodiments, the linker is 20 amino acids in length. In someAttorney Docket No. IMAB-002 / 02WO 328834-2191 embodiments, the linker is 25 amino acids in length. In some embodiments, the linker is 30 amino acids in length. In some embodiments, the linker is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 amino acids in length.

[0118] In some embodiments, the linker is (G)n, n can be an integer between 2 and 20 (SEQ ID NO: 24). In some embodiments, the linker is (GxS)n, x = 1-5, n can be an integer between 2 and 20 (SEQ ID NO: 25). In some embodiments, the linker is (SxG)n, x = 1-5 (SEQ ID NO: 26), n can be an integer between 2 and 20. In some embodiments, the linker is (GSGGS)n, n can be an integer between 2 and 20 (SEQ ID NO: 27). In some embodiments, the linker is (GGGGS)n, n can be an integer between 2 and 20 (SEQ ID NO: 28). In some embodiments, the peptide linker is (GGGGS)4 (SEQ ID NO: 29).

[0119] In some embodiments, the 4- IBB binding domain is an scFv comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to SEQ ID NO: 17.

[0120] In some embodiments, the bi-specific antibody further comprises an Fc fragment. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to wildtype human IgGl Fc.

[0121] Wild-type human IgGl Fc (SEQ ID NO: 23):EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEV KFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNG QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SLSPGK

[0122] In some embodiments, the Fc fragment has reduced effector function. In some embodiments, the effector function is antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), or antibody-dependent cellular phagocytosis (ADCP).

[0123] In some embodiments, the Fc fragment has reduced binding or no binding to FcyR or Clq. In some embodiments, the Fc fragment has one or more mutations to reduce or eliminate FcyR or Clq binding. In some embodiments, the Fc fragment is an IgGl Fc fragment with a L235E mutation. In some embodiments, the Fc fragment is an IgGl Fc fragment with aAttorney Docket No. IMAB-002 / 02WO 328834-2191L234A and / or L235A mutation. In some embodiments, the Fc fragment is an IgGl Fc fragment with a P329G or P329A mutation. In some embodiments, the Fc fragment is an IgG4 Fc fragment with a F234A and / or L235A or L235E mutation. In some embodiments, the Fc fragment is an IgG2 Fc fragment with a H268Q, V309L, A330S, and / or P331S mutation. In some embodiments, the Fc fragment is an IgG2 Fc fragment with a V234A, G237A, P238S, H268A, V309L, A330S, and / or P331S mutation. In some embodiments, the mutations are based on EU numbering.

[0124] In some embodiments, the Fc fragment is aglycosylated. In some embodiments, the Fc fragment comprises a mutation that eliminates glycosylation. In some embodiments, the mutation is at N297. In some embodiments, the mutation is N297A, N297G, or N297Q. In some embodiments, the mutation is N297A.

[0125] In some embodiments, the Fc fragment comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to SEQ ID NO: 19.

[0126] In some embodiments, the Claudin 18.2 binding domain is a Fab fragment, and the 4- IBB binding domain is an scFv. In some embodiments, the bi-specific antibody comprises two first polypeptides and two second polypeptides, wherein each of the first polypeptides comprise, from N-terminus to C-terminus, the heavy chain of the Fab fragment, the Fc fragment, and the scFv, and wherein each of the second polypeptides comprise the light chain of the Fab fragment. In some embodiments, the C-terminus of the heavy chain of the Fab fragment is directly linked to the N-terminus of the Fc fragment. In some embodiments, the C-terminus of the heavy chain of the Fab fragment is linked to the N-terminus of the Fc fragment via a linker. In some embodiments, the C-terminus of the Fc fragment is directly linked to the N-terminus of the scFv. In some embodiments, the C-terminus of the Fc fragment is linked to the N- terminus of the scFv via a linker.

[0127] Suitable linkers are generally those which allow the Fab fragment, the Fc fragment, and / or the scFv to fold with a three-dimensional structure very similar to the Fab fragment, the Fc fragment, and / or the scFv produced individually without any linker or other component. Linkers include single amino acids, peptides, polypeptides, non-proteinaceous polymers such as polyethylene glycol (PEG), polypropylene glycol, polyoxyalkylenes, or copolymers of polyethylene glycol and polypropylene glycol, and chemical linkers.

[0128] In some embodiments, the Fab fragment and the Fc fragment, and / or the Fc fragment and the scFv are linked by a peptide linker. In some embodiments, the peptide linker canAttorney Docket No. IMAB-002 / 02WO 328834-2191 predominantly include the following amino acid residues: Gly, Ser, Ala, Pro, or Thr. Exemplary linkers include, but are not limited to, glycine-serine linkers, glycine-alanine linkers, proline-threonine, and alanine-serine linkers.

[0129] The linker peptide should have a length that is adequate to link the Fab fragment, the Fc fragment, and / or the scFv in such a way that they assume the correct conformation relative to one another so that they retain the desired activity. In some embodiments, the linker is between about 5 amino acids to about 10 amino acids in length. In some embodiments, the linker is between about 5 amino acids to about 15 amino acids in length. In some embodiments, the linker is between about 5 amino acids to about 20 amino acids in length. In some embodiments, the linker is between about 5 amino acids to about 30 amino acids in length. In some embodiments, the linker is between about 10 amino acids to about 15 amino acids in length. In some embodiments, the linker is between about 10 amino acids to about 20 amino acids in length. In some embodiments, the linker is between about 10 amino acids to about 30 amino acids in length. In some embodiments, the linker is between about 15 amino acids to about 30 amino acids in length. In some embodiments, the linker is between about 15 amino acids to about 45 amino acids in length. In some embodiments, the linker is 5 amino acids in length. In some embodiments, the linker is 10 amino acids in length. In some embodiments, the linker is 15 amino acids in length. In some embodiments, the linker is 20 amino acids in length. In some embodiments, the linker is 25 amino acids in length. In some embodiments, the linker is 30 amino acids in length. In some embodiments, the linker is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 amino acids in length.

[0130] In some embodiments, the linker is (G)n, n can be an integer between 2 and 20 (SEQ ID NO: 24). In some embodiments, the linker is (GxS)n, x = 1-5, n can be an integer between 2 and 20 (SEQ ID NO: 25). In some embodiments, the linker is (SxG)n, x = 1-5, n can be an integer between 2 and 20 (SEQ ID NO: 26). In some embodiments, the linker is (GSGGS)n, n can be an integer between 2 and 20 (SEQ ID NO: 27). In some embodiments, the linker is (GGGGS)n, n can be an integer between 2 and 20 (SEQ ID NO: 28). In some embodiments, the peptide linker is (GGGGS)3 (SEQ ID NO: 30).

[0131] In some embodiments, the bi-specific antibody comprises two first polypeptides and two second polypeptides, the first polypeptide comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to SEQ ID NO: 20, and the second polypeptide comprises an amino acid sequence that is at least about 80%, atAttorney Docket No. IMAB-002 / 02WO 328834-2191 least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to SEQ ID NO: 21.

[0132] In some embodiments, the bi-specific antibody comprises two first polypeptides and two second polypeptides, each of the first polypeptides comprise an amino acid sequence of SEQ ID NO: 20, and each of the second polypeptides comprise an amino acid sequence of SEQ ID NO: 21.

[0133] Amino acid sequence modification(s) of the bi-specific antibodies provided herein are contemplated. These modifications can provide for some additional property, such as to remove / add amino acids capable of disulfide bonding, to increase its bio-longevity, to alter its secretory characteristics, etc. In addition, it may be desirable to improve the binding affinity between the bi-specific antibodies and Claudin 18.2 and / or 4-1BB; it may also be desirable to improve other biological properties of the bi-specific antibodies, including but not limited to specificity, thermostability, expression level, or solubility. Thus, in addition to the bi-specific antibodies described herein, it is contemplated that variants can be prepared.

[0134] In some embodiments, the bi-specific antibodies provided herein are chemically modified, for example, by the covalent attachment of any type of molecule to the bi-specific antibodies. Exemplary non-limiting modifications include glycosylation, acetylation, pegylation, phosphorylation, amidation, derivatization by known protecting / blocking groups, proteolytic cleavage, linkage to a cellular ligand or other protein, etc. Additionally, the bi- specific antibodies may contain one or more non-classical amino acids.

[0135] In some embodiments, variations may be a substitution, deletion, or insertion of one or more codons encoding the bi-specific antibodies that results in a change in the amino acid sequence as compared with the original sequence. The variation allowed may be determined by systematically making insertions, deletions, or substitutions of amino acids in the sequence and testing the resulting variants for activity exhibited by the full-length or mature native sequence.

[0136] Amino acid substitutions can be the result of replacing one amino acid with another amino acid having similar structural and / or chemical properties, such as the replacement of a leucine with a serine, e.g., conservative amino acid replacements. Standard techniques known to those of skill in the art can be used to introduce mutations in the nucleotide sequence encoding a molecule provided herein, including, for example, site-directed mutagenesis and PCR-mediated mutagenesis which results in amino acid substitutions.

[0137] A “conservative amino acid substitution” is one in which the amino acid residue is replaced with an amino acid residue having a side chain with a similar charge. Families ofAttorney Docket No. IMAB-002 / 02WO 328834-2191 amino acid residues having side chains with similar charges have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g, tyrosine, phenylalanine, tryptophan, histidine). Table 2 below list exemplary conservative amino acid substitutions. Alternatively, mutations can be introduced randomly along all or part of the coding sequence, such as by saturation mutagenesis, and the resultant mutants can be screened for biological activity to identify mutants that retain activity. Following mutagenesis, the encoded protein can be expressed and the activity of the protein can be determined.Table 2. Amino Acid Substitutions

[0138] Substantial modifications in the biological properties of the antibody are accomplished by selecting substitutions that differ significantly in their effect on maintaining (a) the structure of the polypeptide backbone in the area of the substitution, for example, as a sheet or helical conformation, (b) the charge or hydrophobicity of the molecule at the target site, or (c) the bulk of the side chain. The substitutions which in general are expected to produce the greatest changes in the protein properties will be those in which (a) a hydrophilic residue, e.g. seryl or threonyl, is substituted for (or by) a hydrophobic residue, e.g. leucyl, isoleucyl,Attorney Docket No. IMAB-002 / 02WO 328834-2191 phenylalanyl, valyl or alanyl; (b) a cysteine or proline is substituted for (or by) any other residue; (c) a residue having an electropositive side chain, e.g., lysyl, arginyl, or histidyl, is substituted for (or by) an electronegative residue, e.g., glutamyl or aspartyl; or (d) a residue having a bulky side chain, e.g., phenylalanine, is substituted for (or by) one not having a side chain, e.g., glycine, in this case, (e) by increasing the number of sites for sulfation and / or glycosylation.

[0139] Substitution of one or more CDR residues or omission of one or more CDRs is also contemplated. Antibodies have been described in the scientific literature in which one or two CDRs can be dispensed with for binding. Padlan et al. (1995 FASEB J. 9: 133-139) analyzed the contact regions between antibodies and their antigens, based on published crystal structures, and concluded that only about one fifth to one third of CDR residues actually contact the antigen. Padlan also found many antibodies in which one or two CDRs had no amino acids in contact with an antigen (see also, Vajdos et al. 2002 J Mol Biol 320:415-428).

[0140] CDR residues not contacting antigen can be identified based on previous studies (for example residues H60-H65 in CDRH2 are often not required), from regions of Kabat CDRs lying outside Chothia CDRs, by molecular modeling and / or empirically. If a CDR or residue(s) thereof is omitted, it is usually substituted with an amino acid occupying the corresponding position in another human antibody sequence or a consensus of such sequences. Positions for substitution within CDRs and amino acids to substitute can also be selected empirically.

[0141] Amino acid sequence insertions include amino- and / or carboxyl-terminal fusions ranging in length from 1 residue to polypeptides containing 100 or more residues, as well as intrasequence insertions of single or multiple amino acid residues. Examples of terminal insertions include an antibody with an N-terminal methionyl residue. Other insertional variants of the antibody molecule include the fusion to the N-terminus or C-terminus of the bi-specific antibody to a polypeptide which increases the serum half-life of the antibody.

[0142] Amino acid sequence deletions include amino- and / or carboxyl-terminal deletions ranging in length from 1 residue to polypeptides containing 100 or more residues, as well as intrasequence deletions of single or multiple amino acid residues.Pharmaceutical Compositions Used in the Methods of Treatment

[0143] In some embodiments, the bi-specific antibodies used in the methods of treatment are in the form of pharmaceutical compositions. In some embodiments, the pharmaceutical composition further comprises a pharmaceutical acceptable carrier.

[0144] Pharmaceutically acceptable carrier, diluent or excipient includes, without limitation, any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant,Attorney Docket No. IMAB-002 / 02WO 328834-2191 flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, surfactant, and / or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans and / or domestic animals. Exemplary pharmaceutically acceptable carriers include, but are not limited to, sugars, such as lactose, glucose and sucrose; starches, such as com starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; tragacanth; malt; gelatin; talc; cocoa butter; waxes; animal and vegetable fats; paraffins; silicones; bentonites; silicic acid; zinc oxide; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen- free water; isotonic saline; Ringer’s solution; ethyl alcohol; phosphate buffer solutions; and any other compatible substances employed in pharmaceutical formulations. Except insofar as any conventional media and / or agent is incompatible with the agents of the present disclosure, its use in therapeutic compositions is contemplated. Supplementary active ingredients also can be incorporated into the compositions.

[0145] Pharmaceutically acceptable salt includes both acid and base addition salts. Pharmaceutically-acceptable salts include the acid addition salts (formed with the free amino groups of the protein) and which are formed with inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4- acetamidobenzoic acid, camphoric acid, camphor- 10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-l,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-l,5-disulfonic acid, naphthal ene-2-sulfonic acid, l-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, ptoluenesulfonic acid, trifluoroacetic acid, undecylenic acid, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, forAttorney Docket No. IMAB-002 / 02WO 328834-2191 example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N- ethylpiperidine, polyamine resins and the like. In some embodiments, organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.

[0146] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[0147] Examples of pharmaceutically-acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0148] The pharmaceutical compositions provided herein can be provided as a controlled release or sustained release system. In some embodiments, a pump may be used to achieve controlled or sustained release (see, e.g., Sefton, Crit. Ref. Biomed. Eng. 14: 201-40 (1987); Buchwald et al., Surgery 88: 507-16 (1980); and Saudek et al., N. Engl. J. Med. 321: 569-74 (1989)). In some embodiments, polymeric materials can be used to achieve controlled or sustained release of a prophylactic or therapeutic agent or a composition provided herein (see, e.g., Medical Applications of Controlled Release (Langer and Wise eds., 1974); Controlled Drug Bioavailability, Drug Product Design and Performance (Smolen and Ball eds., 1984); Ranger and Peppas, J. Macromol. Sci. Rev. Macromol. Chem. 23: 61-126 (1983); Levy et al., Science 228: 190-92 (1985); During et al., Ann. Neurol. 25: 351-56 (1989); Howard et al., J. Neurosurg. 71 : 105-12 (1989); U.S. Pat. Nos. 5,679,377; 5,916,597; 5,912,015; 5,989,463; and 5,128,326; PCT Publication Nos. WO 99 / 15154 and WO 99 / 20253). Examples of polymersAttorney Docket No. IMAB-002 / 02WO 328834-2191 used in sustained release formulations include, but are not limited to, poly (2-hydroxy ethyl methacrylate) , poly (methyl methacrylate) , poly (acrylic acid) , poly (ethylene-co-vinyl acetate) , poly (methacrylic acid) , polyglycolides (PLG) , poly anhydrides, poly (N-vinyl pyrrolidone) , poly (vinyl alcohol) , polyacrylamide, poly (ethylene glycol) , polylactides (PLA) , poly (lactide-co-glycolides) (PLGA) , and polyorthoesters. In some embodiments, the polymer used in a sustained release formulation is inert, free of leachable impurities, stable on storage, sterile, and biodegradable. In some embodiments, a controlled or sustained release system can be placed in proximity of a particular target tissue, for example, the kidney, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, Medical Applications of Controlled Release Vol. 2, 115-38 (1984)). Controlled release systems are discussed, for example, by Langer, Science 249: 1527-33 (1990). Any technique known to one of skill in the art can be used to produce sustained release formulations comprising one or more agents as described herein (see, e.g., U.S. Pat. No. 4,526,938, PCT publication Nos. WO 91 / 05548 and WO 96 / 20698, Ning et al., Radiotherapy &Oncology 39: 179-89 (1996); Song et al., PDA J. of Pharma. Sci. &Tech. 50: 372-97 (1995); Cleek et al., Pro. IntT. Symp. Control. Rel. Bioact. Mater. 24: 853-54 (1997); and Lam et al., Proc. IntT. Symp. Control Rel. Bioact. Mater. 24: 759-60 (1997)).

[0149] The active ingredients may also be entrapped in microcapsules prepared, for example, by coascervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly- (methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington’s Pharmaceutical Sciences 18th edition.

[0150] Further guidance regarding formulations that are suitable for various types of administration can be found in Remington’s Pharmaceutical Sciences, Mace Publishing Company, Philadelphia, Pa., 17th ed. (1985). For a brief review of methods for drug delivery, see, Langer, Science 249: 1527-1533 (1990).

[0151] In order for the pharmaceutical compositions to be used for in vivo administration, they are preferably sterile. The pharmaceutical composition may be rendered sterile by filtration through sterile filtration membranes. The pharmaceutical compositions provided herein generally can be placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.Attorney Docket No. IMAB-002 / 02WO 328834-2191Details of the Methods of Treatment

[0152] In some embodiments, the subject is human. In some embodiments, the subject is non-human primates (e.g., monkeys, baboons, and chimpanzees), mice, rats, bovines, horses, household cats, tigers and other large cats, dogs, pigs, rabbits, goats, deer, sheep, ferrets, gerbils, guinea pigs, hamsters, bats, and birds (e.g., chickens, turkeys, and ducks). In some embodiments, the subject may be a neonate, a juvenile, or an adult.

[0153] The effective amount of the bi-specific antibody or the pharmaceutical composition comprising the same administered to a particular subject will depend on a variety of factors, several of which will differ from patient to patient including the disorder being treated and the severity of the disorder; activity of the specific agent(s) employed; the age, body weight, general health, sex and diet of the patient; the timing of administration, route of administration; the duration of the treatment; drugs used in combination; the judgment of the prescribing physician; and like factors known in the medical arts. Dosage amount and interval can be adjusted individually to provide plasma levels of the bi-specific antibody or the pharmaceutical composition comprising the same which are sufficient to maintain therapeutic or prophylactic effect. In cases of local administration or selective uptake, such as local topical administration, the effective local concentration of active compound(s) cannot be related to plasma concentration.

[0154] In some embodiments, the bi-specific antibody or the pharmaceutical composition comprising the same is administered at the dose of about 0.1 mg / kg and about 20 mg / kg of the subject’s body weight. In some embodiments, the bi-specific antibody or the pharmaceutical composition comprising the same is administered at the dose of at least about 0.1 mg / kg. In some embodiments, the bi-specific antibody or the pharmaceutical composition comprising the same is administered at the dose of at most about 20 mg / kg. In some embodiments, the bi- specific antibody or the pharmaceutical composition comprising the same is administered at the dose of about 0.1 mg / kg to about 1 mg / kg, about 0.1 mg / kg to about 3 mg / kg, about 0.1 mg / kg to about 5 mg / kg, about 0.1 mg / kg to about 8 mg / kg, about 0.1 mg / kg to about 9 mg / kg, about 0.1 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 11 mg / kg, about 0.1 mg / kg to about 12 mg / kg, about 0.1 mg / kg to about 15 mg / kg, about 0.1 mg / kg to about 18 mg / kg, about 0.1 mg / kg to about 20 mg / kg, about 1 mg / kg to about 3 mg / kg, about 1 mg / kg to about 5 mg / kg, about 1 mg / kg to about 8 mg / kg, about 1 mg / kg to about 9 mg / kg, about 1 mg / kg to about 10 mg / kg, about 1 mg / kg to about 11 mg / kg, about 1 mg / kg to about 12 mg / kg, about 1 mg / kg to about 15 mg / kg, about 1 mg / kg to about 18 mg / kg, about 1 mg / kg to about 20 mg / kg, about 3 mg / kg to about 5 mg / kg, about 3 mg / kg to about 8 mg / kg, about 3 mg / kg to about 9 mg / kg,Attorney Docket No. IMAB-002 / 02WO 328834-2191 about 3 mg / kg to about 10 mg / kg, about 3 mg / kg to about 11 mg / kg, about 3 mg / kg to about 12 mg / kg, about 3 mg / kg to about 15 mg / kg, about 3 mg / kg to about 18 mg / kg, about 3 mg / kg to about 20 mg / kg, about 5 mg / kg to about 8 mg / kg, about 5 mg / kg to about 9 mg / kg, about 5 mg / kg to about 10 mg / kg, about 5 mg / kg to about 11 mg / kg, about 5 mg / kg to about 12 mg / kg, about 5 mg / kg to about 15 mg / kg, about 5 mg / kg to about 18 mg / kg, about 5 mg / kg to about 20 mg / kg, about 8 mg / kg to about 9 mg / kg, about 8 mg / kg to about 10 mg / kg, about 8 mg / kg to about 11 mg / kg, about 8 mg / kg to about 12 mg / kg, about 8 mg / kg to about 15 mg / kg, about 8 mg / kg to about 18 mg / kg, about 8 mg / kg to about 20 mg / kg, about 9 mg / kg to about 10 mg / kg, about 9 mg / kg to about 11 mg / kg, about 9 mg / kg to about 12 mg / kg, about 9 mg / kg to about 15 mg / kg, about 9 mg / kg to about 18 mg / kg, about 9 mg / kg to about 20 mg / kg, about 10 mg / kg to about 11 mg / kg, about 10 mg / kg to about 12 mg / kg, about 10 mg / kg to about 15 mg / kg, about 10 mg / kg to about 18 mg / kg, about 10 mg / kg to about 20 mg / kg, about 11 mg / kg to about 12 mg / kg, about 11 mg / kg to about 15 mg / kg, about 11 mg / kg to about 18 mg / kg, about 11 mg / kg to about 20 mg / kg, about 12 mg / kg to about 15 mg / kg, about 12 mg / kg to about 18 mg / kg, about 12 mg / kg to about 20 mg / kg, about 15 mg / kg to about 18 mg / kg, about 15 mg / kg to about 20 mg / kg, or about 18 mg / kg to about 20 mg / kg. In some embodiments, the bi-specific antibody or the pharmaceutical composition comprising the same is administered at the dose of about 0.1 mg / kg, about 0.3 mg / kg, about 1 mg / kg, about 3 mg / kg, about 5 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 15 mg / kg, about 18 mg / kg, or about 20 mg / kg. In some embodiments, the bi-specific antibody or the pharmaceutical composition comprising the same is administered at the dose of between about 5 mg / kg and about 18 mg / kg. In some embodiments, the bi-specific antibody or the pharmaceutical composition comprising the same is administered at the dose of between about 8 mg / kg and about 12 mg / kg. In some embodiments, the bi-specific antibody or the pharmaceutical composition comprising the same is administered at the dose of about 5 mg / kg. In some embodiments, the bi-specific antibody or the pharmaceutical composition comprising the same is administered at the dose of about 8 mg / kg. In some embodiments, the bi-specific antibody or the pharmaceutical composition comprising the same is administered at the dose of about 9 mg / kg. In some embodiments, the bi-specific antibody or the pharmaceutical composition comprising the same is administered at the dose of about 10 mg / kg. In some embodiments, the bi-specific antibody or the pharmaceutical composition comprising the same is administered at the dose of about 11 mg / kg. In some embodiments, the bi-specific antibody or the pharmaceutical composition comprising the same is administered at the dose of about 12 mg / kg. In some embodiments, the bi-specific antibody or the pharmaceutical compositionAttorney Docket No. IMAB-002 / 02WO 328834-2191 comprising the same is administered at the dose of about 15 mg / kg. In some embodiments, the bi-specific antibody or the pharmaceutical composition comprising the same is administered at the dose of about 18 mg / kg.

[0155] The number of administrations of the bi-specific antibody or the pharmaceutical composition comprising the same to a subject may vary. In some embodiments, such treatment may require an on-going series of repeated treatments. In some embodiments, multiple administrations of the pharmaceutical compositions may be required before an effect is observed. In some embodiments, the bi-specific antibody or the pharmaceutical composition comprising the same is administered at the frequence of once every week. In some embodiments, the bi-specific antibody or the pharmaceutical composition comprising the same is administered at the frequence of once every two weeks. In some embodiments, the bi-specific antibody or the pharmaceutical composition comprising the same is administered at the frequence of once every three weeks. In some embodiments, the bi-specific antibody or the pharmaceutical composition comprising the same is administered at the frequence of once every four weeks.

[0156] Administration of the bi-specific antibody or the pharmaceutical composition comprising the same can occur by infusion (e.g., continuous or bolus), injection, irrigation, inhalation, consumption, electro-osmosis, hemodialysis, iontophoresis, and other methods known in the art.

[0157] In some embodiments, administration route is intraarterial, intracranial, intradermal, intraduodenal, intrammamary, intrameningeal, intraperitoneal, intrathecal, intratumoral, intravenous, intravitreal, ophthalmic, parenteral, spinal, subcutaneous, ureteral, urethral, vaginal, or intrauterine. In some embodiments, administration route is direct, local, or systemic. In some embodiments, the bi-specific antibody or the pharmaceutical composition comprising the same is administered intravenously.

[0158] In some embodiments, provided herein is a method of treating cancer in a subject, comprising intravenously administering a bi-specific antibody at the dose of about 8 mg / kg of the subject’s body weight at the frequency of once every two weeks, wherein the bi-specific antibody comprises a Claudin 18.2 binding domain and a 4-1BB binding domain, wherein the 4- IBB binding domain is incapable of activating 4- IBB signaling upon binding to 4- IBB in the absence of the Claudin 18.2 binding domain binding to Claudin 18.2, wherein the Claudin 18.2 binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising an amino acid sequence ofAttorney Docket No. IMAB-002 / 02WO 328834-2191SEQ ID NO: 4, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 5, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 6, and wherein the 4-1BB binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 9, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 10, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 11, an LCDR1 comprising an amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 13, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 14. In some embodiments, the cancer is a Claudin 18.2-positive cancer.

[0159] In some embodiments, provided herein is a method of treating cancer in a subject, comprising intravenously administering a bi-specific antibody at the dose of about 9 mg / kg of the subject’s body weight at the frequency of once every two weeks, wherein the bi-specific antibody comprises a Claudin 18.2 binding domain and a 4-1BB binding, wherein the 4-1BB binding domain is incapable of activating 4- IBB signaling upon binding to 4- IBB in the absence of the Claudin 18.2 binding domain binding to Claudin 18.2, wherein the Claudin 18.2 binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising an amino acid sequence of SEQ ID NO: 4, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 5, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 6, and wherein the 4-1BB binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 9, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 10, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 11, an LCDR1 comprising an amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 13, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 14. In some embodiments, the cancer is a Claudin 18.2-positive cancer.

[0160] In some embodiments, provided herein is a method of treating cancer in a subject, comprising intravenously administering a bi-specific antibody at the dose of about 10 mg / kg of the subject’s body weight at the frequency of once every two weeks, wherein the bi-specific antibody comprises a Claudin 18.2 binding domain and a 4-1BB binding domain, wherein the 4- IBB binding domain is incapable of activating 4- IBB signaling upon binding to 4- IBB in the absence of the Claudin 18.2 binding domain binding to Claudin 18.2, wherein the Claudin 18.2 binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising an amino acid sequence ofAttorney Docket No. IMAB-002 / 02WO 328834-2191SEQ ID NO: 4, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 5, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 6, and wherein the 4-1BB binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 9, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 10, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 11, an LCDR1 comprising an amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 13, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 14. In some embodiments, the cancer is a Claudin 18.2-positive cancer.

[0161] In some embodiments, provided herein is a method of treating cancer in a subject, comprising intravenously administering a bi-specific antibody at the dose of about 11 mg / kg of the subject’s body weight at the frequency of once every two weeks, wherein the bi-specific antibody comprises a Claudin 18.2 binding domain and a 4-1BB binding domain, wherein the 4- IBB binding domain is incapable of activating 4- IBB signaling upon binding to 4- IBB in the absence of the Claudin 18.2 binding domain binding to Claudin 18.2, wherein the Claudin 18.2 binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising an amino acid sequence of SEQ ID NO: 4, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 5, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 6, and wherein the 4-1BB binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 9, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 10, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 11, an LCDR1 comprising an amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 13, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 14. In some embodiments, the cancer is a Claudin 18.2-positive cancer.

[0162] In some embodiments, provided herein is a method of treating cancer in a subject, comprising intravenously administering a bi-specific antibody at the dose of about 12 mg / kg of the subject’s body weight at the frequency of once every two weeks, wherein the bi-specific antibody comprises a Claudin 18.2 binding domain and a 4-1BB binding domain, wherein the 4- IBB binding domain is incapable of activating 4- IBB signaling upon binding to 4- IBB in the absence of the Claudin 18.2 binding domain binding to Claudin 18.2, wherein the Claudin 18.2 binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising an amino acid sequence ofAttorney Docket No. IMAB-002 / 02WO 328834-2191SEQ ID NO: 4, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 5, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 6, and wherein the 4-1BB binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 9, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 10, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 11, an LCDR1 comprising an amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 13, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 14. In some embodiments, the cancer is a Claudin 18.2-positive cancer.

[0163] In some embodiments, provided herein is a method of treating cancer in a subject, comprising intravenously administering a bi-specific antibody at the dose of about 15 mg / kg of the subject’s body weight at the frequency of once every two weeks, wherein the bi-specific antibody comprises a Claudin 18.2 binding domain and a 4-1BB binding domain, wherein the 4- IBB binding domain is incapable of activating 4- IBB signaling upon binding to 4- IBB in the absence of the Claudin 18.2 binding domain binding to Claudin 18.2, wherein the Claudin 18.2 binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising an amino acid sequence of SEQ ID NO: 4, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 5, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 6, and wherein the 4-1BB binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 9, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 10, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 11, an LCDR1 comprising an amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 13, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 14. In some embodiments, the cancer is a Claudin 18.2-positive cancer.

[0164] In some embodiments, provided herein is a method of treating cancer in a subject, comprising intravenously administering a bi-specific antibody at the dose of about 18 mg / kg of the subject’s body weight at the frequency of once every two weeks, wherein the bi-specific antibody comprises a Claudin 18.2 binding domain and a 4-1BB binding domain, wherein the 4- IBB binding domain is incapable of activating 4- IBB signaling upon binding to 4- IBB in the absence of the Claudin 18.2 binding domain binding to Claudin 18.2, wherein the Claudin 18.2 binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising an amino acid sequence ofAttorney Docket No. IMAB-002 / 02WO 328834-2191SEQ ID NO: 4, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 5, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 6, and wherein the 4-1BB binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 9, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 10, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 11, an LCDR1 comprising an amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 13, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 14. In some embodiments, the cancer is a Claudin 18.2-positive cancer.

[0165] In some embodiments, provided herein is a method of treating cancer in a subject, comprising intravenously administering a bi-specific antibody at the dose of about 8 mg / kg of the subject’s body weight at the frequency of once every three weeks, wherein the bi-specific antibody comprises a Claudin 18.2 binding domain and a 4-1BB binding domain, wherein the 4- IBB binding domain is incapable of activating 4- IBB signaling upon binding to 4- IBB in the absence of the Claudin 18.2 binding domain binding to Claudin 18.2, wherein the Claudin 18.2 binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising an amino acid sequence of SEQ ID NO: 4, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 5, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 6, and wherein the 4-1BB binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 9, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 10, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 11, an LCDR1 comprising an amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 13, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 14. In some embodiments, the cancer is a Claudin 18.2-positive cancer.

[0166] In some embodiments, provided herein is a method of treating cancer in a subject, comprising intravenously administering a bi-specific antibody at the dose of about 9 mg / kg of the subject’s body weight at the frequency of once every three weeks, wherein the bi-specific antibody comprises a Claudin 18.2 binding domain and a 4-1BB binding domain, wherein the 4- IBB binding domain is incapable of activating 4- IBB signaling upon binding to 4- IBB in the absence of the Claudin 18.2 binding domain binding to Claudin 18.2, wherein the Claudin 18.2 binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising an amino acid sequence ofAttorney Docket No. IMAB-002 / 02WO 328834-2191SEQ ID NO: 4, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 5, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 6, and wherein the 4-1BB binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 9, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 10, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 11, an LCDR1 comprising an amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 13, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 14. In some embodiments, the cancer is a Claudin 18.2-positive cancer.

[0167] In some embodiments, provided herein is a method of treating cancer in a subject, comprising intravenously administering a bi-specific antibody at the dose of about 10 mg / kg of the subj ect’ s body weight at the frequency of once every three weeks, wherein the bi-specific antibody comprises a Claudin 18.2 binding domain and a 4-1BB binding domain, wherein the 4- IBB binding domain is incapable of activating 4- IBB signaling upon binding to 4- IBB in the absence of the Claudin 18.2 binding domain binding to Claudin 18.2, wherein the Claudin 18.2 binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising an amino acid sequence of SEQ ID NO: 4, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 5, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 6, and wherein the 4-1BB binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 9, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 10, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 11, an LCDR1 comprising an amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 13, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 14. In some embodiments, the cancer is a Claudin 18.2-positive cancer.

[0168] In some embodiments, provided herein is a method of treating cancer in a subject, comprising intravenously administering a bi-specific antibody at the dose of about 11 mg / kg of the subj ect’ s body weight at the frequency of once every three weeks, wherein the bi-specific antibody comprises a Claudin 18.2 binding domain and a 4-1BB binding domain, wherein the 4- IBB binding domain is incapable of activating 4- IBB signaling upon binding to 4- IBB in the absence of the Claudin 18.2 binding domain binding to Claudin 18.2, wherein the Claudin 18.2 binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising an amino acid sequence ofAttorney Docket No. IMAB-002 / 02WO 328834-2191SEQ ID NO: 4, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 5, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 6, and wherein the 4-1BB binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 9, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 10, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 11, an LCDR1 comprising an amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 13, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 14. In some embodiments, the cancer is a Claudin 18.2-positive cancer.

[0169] In some embodiments, provided herein is a method of treating cancer in a subject, comprising intravenously administering a bi-specific antibody at the dose of about 12 mg / kg of the subj ect’ s body weight at the frequency of once every three weeks, wherein the bi-specific antibody comprises a Claudin 18.2 binding domain and a 4-1BB binding domain, wherein the 4- IBB binding domain is incapable of activating 4- IBB signaling upon binding to 4- IBB in the absence of the Claudin 18.2 binding domain binding to Claudin 18.2, wherein the Claudin 18.2 binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising an amino acid sequence of SEQ ID NO: 4, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 5, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 6, and wherein the 4-1BB binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 9, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 10, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 11, an LCDR1 comprising an amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 13, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 14. In some embodiments, the cancer is a Claudin 18.2-positive cancer.

[0170] In some embodiments, provided herein is a method of treating cancer in a subject, comprising intravenously administering a bi-specific antibody at the dose of about 15 mg / kg of the subj ect’ s body weight at the frequency of once every three weeks, wherein the bi-specific antibody comprises a Claudin 18.2 binding domain and a 4-1BB binding domain, wherein the 4- IBB binding domain is incapable of activating 4- IBB signaling upon binding to 4- IBB in the absence of the Claudin 18.2 binding domain binding to Claudin 18.2, wherein the Claudin 18.2 binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising an amino acid sequence ofAttorney Docket No. IMAB-002 / 02WO 328834-2191SEQ ID NO: 4, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 5, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 6, and wherein the 4-1BB binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 9, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 10, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 11, an LCDR1 comprising an amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 13, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 14. In some embodiments, the cancer is a Claudin 18.2-positive cancer.

[0171] In some embodiments, provided herein is a method of treating cancer in a subject, comprising intravenously administering a bi-specific antibody at the dose of about 18 mg / kg of the subj ect’ s body weight at the frequency of once every three weeks, wherein the bi-specific antibody comprises a Claudin 18.2 binding domain and a 4-1BB binding domain, wherein the 4- IBB binding domain is incapable of activating 4- IBB signaling upon binding to 4- IBB in the absence of the Claudin 18.2 binding domain binding to Claudin 18.2, wherein the Claudin 18.2 binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising an amino acid sequence of SEQ ID NO: 4, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 5, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 6, and wherein the 4-1BB binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 9, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 10, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 11, an LCDR1 comprising an amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 13, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 14. In some embodiments, the cancer is a Claudin 18.2-positive cancer.

[0172] In some embodiments, provided herein is a method of treating cancer in a subject, comprising intravenously administering a bi-specific antibody at the dose of about 8 mg / kg of the subject’s body weight at the frequency of once every two weeks, wherein the bi-specific antibody comprises a Claudin 18.2 binding domain and a 4-1BB binding domain, wherein the 4- IBB binding domain is incapable of activating 4- IBB signaling upon binding to 4- IBB in the absence of the Claudin 18.2 binding domain binding to Claudin 18.2, wherein the bi- specific antibody comprises two first polypeptides and two second polypeptides, wherein each of the first polypeptides comprises an amino acid sequence of SEQ ID NO: 20, and whereinAttorney Docket No. IMAB-002 / 02WO 328834-2191 each of the second polypeptides comprises an amino acid sequence of SEQ ID NO: 21. In some embodiments, the cancer is a Claudin 18.2-positive cancer.

[0173] In some embodiments, provided herein is a method of treating cancer in a subject, comprising intravenously administering a bi-specific antibody at the dose of about 9 mg / kg of the subject’s body weight at the frequency of once every two weeks, wherein the bi-specific antibody comprises a Claudin 18.2 binding domain and a 4-1BB binding domain, wherein the 4- IBB binding domain is incapable of activating 4- IBB signaling upon binding to 4- IBB in the absence of the Claudin 18.2 binding domain binding to Claudin 18.2, wherein the bi- specific antibody comprises two first polypeptides and two second polypeptides, wherein each of the first polypeptides comprises an amino acid sequence of SEQ ID NO: 20, and wherein each of the second polypeptides comprises an amino acid sequence of SEQ ID NO: 21. In some embodiments, the cancer is a Claudin 18.2-positive cancer.

[0174] In some embodiments, provided herein is a method of treating cancer in a subject, comprising intravenously administering a bi-specific antibody at the dose of about 10 mg / kg of the subject’s body weight at the frequency of once every two weeks, wherein the bi-specific antibody comprises a Claudin 18.2 binding domain and a 4-1BB binding domain, wherein the 4- IBB binding domain is incapable of activating 4- IBB signaling upon binding to 4- IBB in the absence of the Claudin 18.2 binding domain binding to Claudin 18.2, wherein the bi- specific antibody comprises two first polypeptides and two second polypeptides, wherein each of the first polypeptides comprises an amino acid sequence of SEQ ID NO: 20, and wherein each of the second polypeptides comprises an amino acid sequence of SEQ ID NO: 21. In some embodiments, the cancer is a Claudin 18.2-positive cancer.

[0175] In some embodiments, provided herein is a method of treating cancer in a subject, comprising intravenously administering a bi-specific antibody at the dose of about 11 mg / kg of the subject’s body weight at the frequency of once every two weeks, wherein the bi-specific antibody comprises a Claudin 18.2 binding domain and a 4-1BB binding domain, wherein the 4- IBB binding domain is incapable of activating 4- IBB signaling upon binding to 4- IBB in the absence of the Claudin 18.2 binding domain binding to Claudin 18.2, wherein the bi- specific antibody comprises two first polypeptides and two second polypeptides, wherein each of the first polypeptides comprises an amino acid sequence of SEQ ID NO: 20, and wherein each of the second polypeptides comprises an amino acid sequence of SEQ ID NO: 21. In some embodiments, the cancer is a Claudin 18.2-positive cancer. In some embodiments, the cancer is a Claudin 18.2-positive cancer.Attorney Docket No. IMAB-002 / 02WO 328834-2191

[0176] In some embodiments, provided herein is a method of treating cancer in a subject, comprising intravenously administering a bi-specific antibody at the dose of about 12 mg / kg of the subject’s body weight at the frequency of once every two weeks, wherein the bi-specific antibody comprises a Claudin 18.2 binding domain and a 4-1BB binding domain, wherein the 4- IBB binding domain is incapable of activating 4- IBB signaling upon binding to 4- IBB in the absence of the Claudin 18.2 binding domain binding to Claudin 18.2, wherein the bi- specific antibody comprises two first polypeptides and two second polypeptides, wherein each of the first polypeptides comprises an amino acid sequence of SEQ ID NO: 20, and wherein each of the second polypeptides comprises an amino acid sequence of SEQ ID NO: 21. In some embodiments, the cancer is a Claudin 18.2-positive cancer.

[0177] In some embodiments, provided herein is a method of treating cancer in a subject, comprising intravenously administering a bi-specific antibody at the dose of about 15 mg / kg of the subject’s body weight at the frequency of once every two weeks, wherein the bi-specific antibody comprises a Claudin 18.2 binding domain and a 4-1BB binding domain, wherein the 4- IBB binding domain is incapable of activating 4- IBB signaling upon binding to 4- IBB in the absence of the Claudin 18.2 binding domain binding to Claudin 18.2, wherein the bi- specific antibody comprises two first polypeptides and two second polypeptides, wherein each of the first polypeptides comprises an amino acid sequence of SEQ ID NO: 20, and wherein each of the second polypeptides comprises an amino acid sequence of SEQ ID NO: 21. In some embodiments, the cancer is a Claudin 18.2-positive cancer.

[0178] In some embodiments, provided herein is a method of treating cancer in a subject, comprising intravenously administering a bi-specific antibody at the dose of about 18 mg / kg of the subject’s body weight at the frequency of once every two weeks, wherein the bi-specific antibody comprises a Claudin 18.2 binding domain and a 4-1BB binding domain, wherein the 4- IBB binding domain is incapable of activating 4- IBB signaling upon binding to 4- IBB in the absence of the Claudin 18.2 binding domain binding to Claudin 18.2, wherein the bi- specific antibody comprises two first polypeptides and two second polypeptides, wherein each of the first polypeptides comprises an amino acid sequence of SEQ ID NO: 20, and wherein each of the second polypeptides comprises an amino acid sequence of SEQ ID NO: 21. In some embodiments, the cancer is a Claudin 18.2-positive cancer.

[0179] In some embodiments, provided herein is a method of treating cancer in a subject, comprising intravenously administering a bi-specific antibody at the dose of about 8 mg / kg of the subject’s body weight at the frequency of once every three weeks, wherein the bi-specific antibody comprises a Claudin 18.2 binding domain and a 4-1BB binding domain, wherein theAttorney Docket No. IMAB-002 / 02WO 328834-21914- IBB binding domain is incapable of activating 4- IBB signaling upon binding to 4- IBB in the absence of the Claudin 18.2 binding domain binding to Claudin 18.2, wherein the bispecific antibody comprises two first polypeptides and two second polypeptides, wherein each of the first polypeptide comprises an amino acid sequence of SEQ ID NO: 20, and wherein each of the second polypeptide comprises an amino acid sequence of SEQ ID NO: 21. In some embodiments, the cancer is a Claudin 18.2-positive cancer.

[0180] In some embodiments, provided herein is a method of treating cancer in a subject, comprising intravenously administering a bi-specific antibody at the dose of about 9 mg / kg of the subject’s body weight at the frequency of once every three weeks, wherein the bi-specific antibody comprises a Claudin 18.2 binding domain and a 4-1BB binding domain, wherein the 4- IBB binding domain is incapable of activating 4- IBB signaling upon binding to 4- IBB in the absence of the Claudin 18.2 binding domain binding to Claudin 18.2, wherein the bi- specific antibody comprises two first polypeptides and two second polypeptides, wherein each of the first polypeptide comprises an amino acid sequence of SEQ ID NO: 20, and wherein each of the second polypeptide comprises an amino acid sequence of SEQ ID NO: 21. In some embodiments, the cancer is a Claudin 18.2-positive cancer.

[0181] In some embodiments, provided herein is a method of treating cancer in a subject, comprising intravenously administering a bi-specific antibody at the dose of about 10 mg / kg of the subj ect’ s body weight at the frequency of once every three weeks, wherein the bi-specific antibody comprises a Claudin 18.2 binding domain and a 4-1BB binding domain, wherein the 4- IBB binding domain is incapable of activating 4- IBB signaling upon binding to 4- IBB in the absence of the Claudin 18.2 binding domain binding to Claudin 18.2, wherein the bi- specific antibody comprises two first polypeptides and two second polypeptides, wherein each of the first polypeptide comprises an amino acid sequence of SEQ ID NO: 20, and wherein each of the second polypeptide comprises an amino acid sequence of SEQ ID NO: 21. In some embodiments, the cancer is a Claudin 18.2-positive cancer.

[0182] In some embodiments, provided herein is a method of treating cancer in a subject, comprising intravenously administering a bi-specific antibody at the dose of about 11 mg / kg of the subj ect’ s body weight at the frequency of once every three weeks, wherein the bi-specific antibody comprises a Claudin 18.2 binding domain and a 4-1BB binding domain, wherein the 4- IBB binding domain is incapable of activating 4- IBB signaling upon binding to 4- IBB in the absence of the Claudin 18.2 binding domain binding to Claudin 18.2, wherein the bi- specific antibody comprises two first polypeptides and two second polypeptides, wherein each of the first polypeptide comprises an amino acid sequence of SEQ ID NO: 20, and whereinAttorney Docket No. IMAB-002 / 02WO 328834-2191 each of the second polypeptide comprises an amino acid sequence of SEQ ID NO: 21. In some embodiments, the cancer is a Claudin 18.2-positive cancer.

[0183] In some embodiments, provided herein is a method of treating cancer in a subject, comprising intravenously administering a bi-specific antibody at the dose of about 12 mg / kg of the subj ect’ s body weight at the frequency of once every three weeks, wherein the bi-specific antibody comprises a Claudin 18.2 binding domain and a 4-1BB binding domain, wherein the 4- IBB binding domain is incapable of activating 4- IBB signaling upon binding to 4- IBB in the absence of the Claudin 18.2 binding domain binding to Claudin 18.2, wherein the bi- specific antibody comprises two first polypeptides and two second polypeptides, wherein each of the first polypeptide comprises an amino acid sequence of SEQ ID NO: 20, and wherein each of the second polypeptide comprises an amino acid sequence of SEQ ID NO: 21. In some embodiments, the cancer is a Claudin 18.2-positive cancer.

[0184] In some embodiments, provided herein is a method of treating cancer in a subject, comprising intravenously administering a bi-specific antibody at the dose of about 15 mg / kg of the subj ect’ s body weight at the frequency of once every three weeks, wherein the bi-specific antibody comprises a Claudin 18.2 binding domain and a 4-1BB binding domain, wherein the 4- IBB binding domain is incapable of activating 4- IBB signaling upon binding to 4- IBB in the absence of the Claudin 18.2 binding domain binding to Claudin 18.2, wherein the bi- specific antibody comprises two first polypeptides and two second polypeptides, wherein each of the first polypeptide comprises an amino acid sequence of SEQ ID NO: 20, and wherein each of the second polypeptide comprises an amino acid sequence of SEQ ID NO: 21. In some embodiments, the cancer is a Claudin 18.2-positive cancer.

[0185] In some embodiments, provided herein is a method of treating cancer in a subject, comprising intravenously administering a bi-specific antibody at the dose of about 18 mg / kg of the subj ect’ s body weight at the frequency of once every three weeks, wherein the bi-specific antibody comprises a Claudin 18.2 binding domain and a 4-1BB binding domain, wherein the 4- IBB binding domain is incapable of activating 4- IBB signaling upon binding to 4- IBB in the absence of the Claudin 18.2 binding domain binding to Claudin 18.2, wherein the bi- specific antibody comprises two first polypeptides and two second polypeptides, wherein each of the first polypeptide comprises an amino acid sequence of SEQ ID NO: 20, and wherein each of the second polypeptide comprises an amino acid sequence of SEQ ID NO: 21. In some embodiments, the cancer is a Claudin 18.2-positive cancer.

[0186] In some embodiments, the cancer is primary. In some embodiments, the cancer is metastatic. In some embodiments, the cancer is relapsed. In some embodiments, the cancer isAttorney Docket No. IMAB-002 / 02WO 328834-2191 unresectable. In some embodiments, the cancer is refractory. In some embodiments, the cancer is refractory to a PD-1 inhibitor or a PD-L1 inhibitor. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is gastric adenocarcinoma (GC). In some embodiments, the cancer is gastro-esophageal junction adenocarcinoma (GEJ). In some embodiments, the cancer is esophageal adenocarcinoma (EAC). In some embodiments, the cancer is pancreatic ductal adenocarcinoma (PDAC). In some embodiments, the cancer is cholangiocarcinoma. In some embodiments, the cancer is HER2 -negative. In some embodiments, the cancer is Claudin 18.2-positive.

[0187] In some embodiments, treating refers to the treatment of a disease in a mammal, e.g., in a human, including (a) inhibiting the disease, z.e., arresting disease development or preventing disease progression; (b) relieving the disease, z.e., causing regression of the disease state or relieving one or more symptoms of the disease; and (c) curing the disease, z.e., remission of one or more disease symptoms. In some embodiments, treatment results in an improvement or remediation of the symptoms of the disease. In some embodiments, treatment may refer to a short-term (e.g., temporary and / or acute) and / or a long-term (e.g., sustained) improvement or remediation in one or more disease symptoms. In some embodiments, the improvement is an observable or measurable improvement. In some embodiments, the improvement is an improvement in the general feeling of well-being of the subject.

[0188] In some embodiments, the serum concentration of the bi-specific antibody is at least about 8 pg / mL throughout the treatment. In some embodiments, the serum concentration of the bi-specific antibody is at least about 10 pg / mL throughout the treatment. In some embodiments, the serum concentration of the bi-specific antibody is at least about 12 pg / mL throughout the treatment. In some embodiments, the serum concentration of the bi-specific antibody is at least about 14 pg / mL throughout the treatment.

[0189] In some embodiments, the serum half-life of the bi-specific antibody is between about 3 days and about 9 days. In some embodiments, the serum half-life of the bi-specific antibody is between about 4 days and about 9 days. In some embodiments, the serum half-life of the bi-specific antibody is between about 5 days and about 9 days. In some embodiments, the serum half-life of the bi-specific antibody is between about 3 days and about 8 days. In some embodiments, the serum half-life of the bi-specific antibody is between about 4 days and about 8 days. In some embodiments, the serum half-life of the bi-specific antibody is between about 5 days and about 8 days. In some embodiments, the serum half-life of the bi-specific antibody is between about 3 days and about 7 days. In some embodiments, the serum half-lifeAttorney Docket No. IMAB-002 / 02WO 328834-2191 of the bi-specific antibody is between about 4 days and about 7 days. In some embodiments, the serum half-life of the bi-specific antibody is between about 5 days and about 7 days.

[0190] In some embodiments, the treatment results in increased serum concentration of soluble 4-1BB. In some embodiments, the serum concentration of soluble 4-1BB is between about 2 and about 200 times as high as that prior to the treatment. In some embodiments, the serum concentration of soluble 4- IBB is between about 2 and about 180 times as high as that prior to the treatment. In some embodiments, the serum concentration of soluble 4- IBB is between about 2 and about 160 times as high as that prior to the treatment. In some embodiments, the serum concentration of soluble 4-1BB is between about 2 and about 140 times as high as that prior to the treatment. In some embodiments, the serum concentration of soluble 4-1BB is between about 2 and about 130 times as high as that prior to the treatment. In some embodiments, the serum concentration of soluble 4- IBB is between about 2 and about 120 times as high as that prior to the treatment. In some embodiments, the serum concentration of soluble 4-1BB is between about 2 and about 100 times as high as that prior to the treatment. In some embodiments, the serum concentration of soluble 4-1BB is between about 2 and about 80 times as high as that prior to the treatment. In some embodiments, the serum concentration of soluble 4-1BB is between about 2 and about 60 times as high as that prior to the treatment. In some embodiments, the increased serum concentration of soluble 4- IBB is not accompanied by systemic changes in peripheral T cell activation. In some embodiments, the increased serum concentration of soluble 4- IBB is not accompanied by systemic changes in circulating cytokines.

[0191] In some embodiments, the treatment results in partial response. In some embodiments, the treatment results in stable disease.

[0192] In some embodiments, the cancer is a solid tumor, and the treatment results in a decrease in size of the solid tumor. In some embodiments, the size of the solid tumor is decreased by at least about 10%, compared to the size of the solid tumor prior to the treatment. In some embodiments, the size of the solid tumor is decreased by at least about 20%, compared to the size of the solid tumor prior to the treatment. In some embodiments, the size of the solid tumor is decreased by at least about 30%, compared to the size of the solid tumor prior to the treatment. In some embodiments, the size of the solid tumor is decreased by at least about 40%, compared to the size of the solid tumor prior to the treatment. In some embodiments, the size of the solid tumor is decreased by at least about 50%, compared to the size of the solid tumor prior to the treatment. In some embodiments, the size of the solid tumor is decreased by at least about 60%, compared to the size of the solid tumor prior to the treatment. In some embodiments,Attorney Docket No. IMAB-002 / 02WO 328834-2191 the size of the solid tumor is decreased by at least about 70%, compared to the size of the solid tumor prior to the treatment. In some embodiments, the size of the solid tumor is decreased by at least about 80%, compared to the size of the solid tumor prior to the treatment. In some embodiments, the size of the solid tumor is decreased by at least about 90%, compared to the size of the solid tumor prior to the treatment. In some embodiments, the cancer is a Claudin 18.2-positive cancer.

[0193] In some embodiments, the duration of response is at least about 3 months, at least about 6 months, at least about 9 months, at least about 12 months, at least about 15 months, at least about 18 months, or at least about 24 months in treated subjects. In some embodiments, the duration of response is at least about 9 months in treated subjects.

[0194] In some embodiments, the progression free survival is at least about 0.5 months, at least about 1 month, at least about 1.5 months, at least about 2 months, at least about 2.5 months, at least about 3 months, at least about 3.5 months, at least about 4 months, at least about 4.5 months, at least about 5 months, at least about 5.5 months, at least about 6 months, at least about 6.5 months, at least about 7 months, at least about 7.5 months, at least about 8 months, at least about 8.5 months, at least about 9 months, at least about 9.5 months, at least about 10 months, at least about 10.5 months, at least about 11.5 months, or at least about 12 months in treated subjects. In some embodiments, the progression free survival is about 1.7 months in treated subjects. In some embodiments, the progression free survival is about 3 months in treated subjects. In some embodiments, the progression free survival is about 3.9 months in treated subjects.

[0195] In some embodiments, the overall survival is at least about 0.5 months, at least about 1 month, at least about 1.5 months, at least about 2 months, at least about 2.5 months, at least about 3 months, at least about 3.5 months, at least about 4 months, at least about 4.5 months, at least about 5 months, at least about 5.5 months, at least about 6 months, at least about 6.5 months, at least about 7 months, at least about 7.5 months, at least about 8 months, at least about 8.5 months, at least about 9 months, at least about 9.5 months, at least about 10 months, at least about 10.5 months, at least about 11.5 months, or at least about 12 months in treated subjects. In some embodiments, the overall survival is about 7.5 months in treated subjects.

[0196] In some embodiments, the objective response rate is at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24% at least about 25%,Attorney Docket No. IMAB-002 / 02WO 328834-2191 at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50% in treated subjects. In some embodiments, the objective response rate is about 11% in treated subjects. In some embodiments, the objective response rate is about 17% in treated subjects. In some embodiments, the objective response rate is about 19% in treated subjects.

[0197] In some embodiments, the disease control rate is at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, or at least about 75% in treated subjects. In some embodiments, the disease control rate is about 37% in treated subjects. In some embodiments, the disease control rate is about 42% in treated subjects. In some embodiments, the disease control rate is about 57% in treated subjects.

[0198] In some embodiments, the bi-specific antibody or the pharmaceutical composition comprising the same is administered in combination with additional therapeutic composition(s).

[0199] In some embodiments, the bi-specific antibody or pharmaceutical composition comprising the same is administered in combination with a chemotherapy and a checkpoint inhibitor. In some embodiments, the checkpoint inhibitor is a PD-1 inhibitor. In some embodiments, the PD-1 inhibitor is nivolumab.

[0200] In some embodiments, the bi-specific antibody or pharmaceutical composition comprising the same is administered in combination with a chemotherapy. In some embodiments, the chemotherapy is CAPOX, wherein CAPOX comprises oxaliplatin and capecitabine.

[0201] In some embodiments, the chemotherapy comprises 5 -fluorouracil (5-FU) and platinum. In some embodiments, the chemotherapy is mFOLFOX6, wherein mFOLFOX6 comprises folinic acid (leucovorin), 5-FU, and oxaliplatin. In some embodiments, the chemotherapy is CAPOX, wherein CAPOX comprises oxaliplatin and capecitabine. In some embodiments, the chemotherapy is mFOLFOX6 and CAPOX.

[0202] In some embodiments, the leucovorin in mFOLFOX6 is administered intravenously at a dose of about 50 mg / m2, about 75 mg / m2, about 85 mg / m2, about 90 mg / m2, about 95 mg / m2, about 100 mg / m2, about 105 mg / m2, about 110 mg / m2, about 115 mg / m2, about 120 mg / m2, about 125 mg / m2, about 130mg / m2, about 135mg / m2, about 140mg / m2, about 145mg / m2, about 150mg / m2, about 155mg / m2, about 160mg / m2, about 175 mg / m2, about 200 mg / m2, about 225 mg / m2, about 300 mg / m2, about 325 mg / m2, about 350 mg / m2, about 375 mg / m2, or about 400 mg / m2. In some embodiments, the mFOLFOX6 is administered intravenously once every two weeks to the subject.Attorney Docket No. IMAB-002 / 02WO 328834-2191

[0203] In some embodiments, the 5’FU in mFOLFOX6 is administered intravenously at a dose of about 50 mg / m2, about 75 mg / m2, about 85 mg / m2, about 90 mg / m2, about 95 mg / m2, about 100 mg / m2, about 105 mg / m2, about 110 mg / m2, about 115 mg / m2, about 120 mg / m2, about 125 mg / m2, about 130 mg / m2, about 135 mg / m2, about 140 mg / m2, about 145 mg / m2, about 150 mg / m2, about 155 mg / m2, about 160 mg / m2, about 175 mg / m2, about 200 mg / m2, about 225 mg / m2, about 300 mg / m2, about 325 mg / m2, about 350 mg / m2, about 375 mg / m2, about 400 mg / m2, about 425 mg / m2, about 450 mg / m2, about 475 mg / m2, about 500 mg / m2, about 525 mg / m2, about 550 mg / m2, about 575 mg / m2, about 600 mg / m2, about 625 mg / m2, about 650 mg / m2, about 675 mg / m2, about 700 mg / m2, about 725 mg / m2, about 750 mg / m2, about 775 mg / m2, or about 800 mg / m2. In some embodiments, the mFOLFOX6 is administered intravenously once every two weeks to the subject.

[0204] In some embodiments, the oxaliplatin in mFOLFOX6 is administered intravenously at a dose of about 25 mg / m2, about 30 mg / m2, about 35 mg / m2, about 45 mg / m2, about 55 mg / m2, about 65 mg / m2, about 75 mg / m2, about 80 mg / m2, about 85 mg / m2, about 90 mg / m2, about 95 mg / m2, about 100 mg / m2, about 105 mg / m2, about 110 mg / m2, about 115 mg / m2, about 120 mg / m2, about 125 mg / m2, about 130 mg / m2, about 135 mg / m2, about 140 mg / m2, about 145 mg / m2, about 150 mg / m2, about 155 mg / m2, or about 160 mg / m2. In some embodiments, the mFOLFOX6 is administered intravenously once every two weeks to the subject.

[0205] In some embodiments, the oxaliplatin is administered intravenously at a dose of about 85 mg / m2, about 90 mg / m2, about 95 mg / m2, about 100 mg / m2, about 105 mg / m2, about 110 mg / m2, about 115 mg / m2, about 120 mg / m2, about 125 mg / m2, about 130 mg / m2, about 135 mg / m2, about 140 mg / m2, about 145 mg / m2, about 150 mg / m2, about 155 mg / m2, or about 160 mg / m2. In some embodiments, the oxaliplatin is administered intravenously at a dose between about 80 mg / m2and about 140 mg / m2. In some embodiments, the oxaliplatin is administered intravenously at a dose of about 130 mg / m2. In some embodiments, the oxaliplatin is administered intravenously once every three weeks to the subject.

[0206] In some embodiments, the capecitabine is administered orally at a dose of about 750 mg / m2, about 800 mg / m2, about 850 mg / m2, about 950 mg / m2, 1000 mg / m2, about 1050 mg / m2, about 1100 mg / m2, about 1150 mg / m2, about 1200 mg / m2, or about 1250 mg / m2. In some embodiments, the capecitabine is administered orally at a dose between about 900 mg / m2and about 1300 mg / m2. In some embodiments, the capecitabine is administered orally at a dose of about 1000 mg / m2. In some embodiments, the capecitabine is administered orally at a frequency of twice daily to the subject.Attorney Docket No. IMAB-002 / 02WO 328834-2191

[0207] In some embodiments, the check point inhibitor in a PD-1 inhibitor. In some embodiments, the check point inhibitor is nivolumab. In some embodiments, the nivolumab is administered intravenously at a dose of about 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, or 5 mg / kg. In some embodiments, the nivolumab is administered intravenously at a dose of about 3 mg / kg. In some embodiments, the nivolumab is administered intravenously at a dose of about 60 mg, about 120 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280mg, about 300 mg, about 320 mg, about 340 mg, about 360 mg, about 380 mg, about 400 mg, about 420 mg, about 440 mg, about 460 mg, about 480 mg, about 500 mg, about 520 mg, about 540 mg, about 560 mg, about 580 mg, about 600 mg, about 660 mg, about 720 mg, or about 800 mg. In some embodiments, the nivolumab is administered intravenously at a dose of about 240 mg or about 480 mg. In some embodiments, the nivolumab is administered intravenously at a dose of about 240 mg every 2 weeks or about 480 mg every 4 weeks. In some embodiments, the nivolumab is administered intravenously at a dose of about 240 mg every 3 weeks to the subject.

[0208] In some embodiments, the bi-specific antibody or the pharmaceutical composition comprising the same and the additional therapeutic composition(s) are administered simultaneously. In some embodiments, bi-specific antibody or the pharmaceutical composition comprising the same is administered before the additional therapeutic composition(s). In some embodiments bi-specific antibody or the pharmaceutical composition comprising the same is administered after the additional therapeutic composition(s).

[0209] In some embodiments, the additional therapeutic composition comprises a chemotherapy. In some embodiments, the additional therapeutic composition comprises a checkpoint inhibitor. In some embodiments, the additional therapeutic composition comprises a chemotherapy and a check point inhibitor. In some embodiments, the chemotherapy and / or the check point inhibitor are administered to the subject at a frequency of once every two weeks or once every three weeks. In some embodiments, the chemotherapy and / or the check point inhibitor are administered to the subject at a frequency of once every two weeks.

[0210] In some embodiments, the nivolumab is administered to the subject once every three weeks. In some embodiments, the oxaliplatin is administered to the subject once every three weeks. In some embodiments, the capecitabine is administered at a frequency of twice daily (BID) to the subject. In some embodiments, the oxaliplatin is administered at a frequency of once every two weeks or once every three weeks, the capecitabine is administered at a frequency of twice daily (BID), and the nivolumab is administered at a frequency of once every two weeks or once every three weeks. In some embodiments, the nivolumab and oxaliplatinAttorney Docket No. IMAB-002 / 02WO 328834-2191 are intravenously administered once every three weeks and the capeci tabine is administered orally at a frequency of twice daily to the subject.

[0211] In some embodiments, the serum concentration of the bi-specific antibody is at least about 8 pg / mL throughout the treatment with the additional therapeutic compositions. In some embodiments, the serum concentration of the bi-specific antibody is at least about 10 pg / mL throughout the treatment with the additional therapeutic compositions. In some embodiments, the serum concentration of the bi-specific antibody is at least about 12 pg / mL throughout the treatment with the additional therapeutic compositions. In some embodiments, the serum concentration of the bi-specific antibody is at least about 14 pg / mL throughout the treatment with the additional therapeutic compositions. In some embodiments, the additional therapeutic compositions are nivolumab and mFOLFOX.

[0212] In some embodiments, the serum half-life of the bi-specific antibody is between about 3 days and about 9 days with the additional therapeutic compositions. In some embodiments, the serum half-life of the bi-specific antibody is between about 4 days and about 9 days with the additional therapeutic compositions. In some embodiments, the serum half-life of the bi-specific antibody is between about 5 days and about 9 days with the additional therapeutic compositions. In some embodiments, the serum half-life of the bi-specific antibody is between about 3 days and about 8 days with the additional therapeutic compositions. In some embodiments, the serum half-life of the bi-specific antibody is between about 4 days and about 8 days with the additional therapeutic compositions. In some embodiments, the serum half-life of the bi-specific antibody is between about 5 days and about 8 days with the additional therapeutic compositions. In some embodiments, the serum half-life of the bi-specific antibody is between about 3 days and about 7 days with the additional therapeutic compositions. In some embodiments, the serum half-life of the bi-specific antibody is between about 4 days and about 7 days with the additional therapeutic compositions. In some embodiments, the serum half-life of the bi-specific antibody is between about 5 days and about 7 days with the additional therapeutic compositions. In some embodiments, the serum half-life of the bi-specific antibody is about 6 days (or about 140 hours) with the additional therapeutic compositions. In some embodiments, the additional therapeutic compositions are nivolumab and mFOLFOX.

[0213] In some embodiments, the treatment results in increased serum concentration of soluble 4-1BB. In some embodiments, the serum concentration of soluble 4-1BB is between about 5 and about 200 times as high as that prior to the treatment. In some embodiments, the serum concentration of soluble 4-1BB is between about 5 and about 180 times as high as that prior to the treatment. In some embodiments, the serum concentration of soluble 4-1BB isAttorney Docket No. IMAB-002 / 02WO 328834-2191 between about 5 and about 160 times as high as that prior to the treatment. In some embodiments, the serum concentration of soluble 4-1BB is between about 5 and about 140 times as high as that prior to the treatment. In some embodiments, the serum concentration of soluble 4-1BB is between about 5 and about 130 times as high as that prior to the treatment. In some embodiments, the serum concentration of soluble 4- IBB is between about 5 and about 120 times as high as that prior to the treatment. In some embodiments, the serum concentration of soluble 4-1BB is between about 5 and about 100 times as high as that prior to the treatment. In some embodiments, the serum concentration of soluble 4-1BB is between about 5 and about 80 times as high as that prior to the treatment. In some embodiments, the serum concentration of soluble 4-1BB is between about 5 and about 60 times as high as that prior to the treatment. In some embodiments, the serum concentration of soluble 4-1BB is between about 5 and about 50 times as high as that prior to the treatment. In some embodiments, the increased serum concentration of soluble 4- IBB is not accompanied by systemic changes in peripheral T cell activation. In some embodiments, the increased serum concentration of soluble 4- IBB is not accompanied by systemic changes in circulating cytokines. In some embodiments, the treatment comprises additional therapeutic compositions. In some embodiments, the additional therapeutic compositions are nivolumab and mFOLFOX.

[0214] In some embodiments, the treatment results in partial response. In some embodiments, the treatment results in stable disease.

[0215] In some embodiments, the cancer is a solid tumor, and the treatment results in decreased size of the solid tumor. In some embodiments, the size of the solid tumor is decreased by at least about 10%, compared to that prior to the treatment. In some embodiments, the size of the solid tumor is decreased by at least about 20%, compared to that prior to the treatment. In some embodiments, the size of the solid tumor is decreased by at least about 30%, compared to that prior to the treatment. In some embodiments, the size of the solid tumor is decreased by at least about 40%, compared to that prior to the treatment. In some embodiments, the size of the solid tumor is decreased by at least about 50%, compared to that prior to the treatment. In some embodiments, the size of the solid tumor is decreased by at least about 60%, compared to that prior to the treatment. In some embodiments, the size of the solid tumor is decreased by at least about 70%, compared to that prior to the treatment. In some embodiments, the size of the solid tumor is decreased by at least about 80%, compared to that prior to the treatment. In some embodiments, the size of the solid tumor is decreased by at least about 90%, compared to that prior to the treatment. In some embodiments, the cancer is a Claudin 18.2-positive cancer.Attorney Docket No. IMAB-002 / 02WO 328834-2191

[0216] In some embodiments, administration of the bi-specific antibody or the pharmaceutical composition comprising the same in combination with the additional therapeutic composition(s) results in an enhanced therapeutic effect in treating cancer than is observed by treatment with either the bi-specific antibody or the pharmaceutical composition comprising the same or the additional therapeutic composition alone. In some embodiments, administration of the bi-specific antibody in combination with the additional therapeutic composition(s) results in an objective response rate of at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95%. In some embodiments, administration of the bi-specific antibody in combination with the additional therapeutic composition(s) results in an objective response rate of about 71%. In some embodiments, administration of the bi-specific antibody in combination with the additional therapeutic composition(s) results in an objective response rate of about 83%. In some embodiments, the cancer is a Claudin 18.2-positive cancer.

[0217] In some embodiments, administration of the bi-specific antibody in combination with the additional therapeutic composition(s) results in a treatment related adverse event (TRAE) in the subject. Non-limiting examples of TRAEs include neutropenia, peripheral neuropathy, nausea, vomiting, infusion-related reaction, diarrhea, abdominal pain, gastritis, increased alanine aminotransferase (ALT), or increased aspartate aminotransferase (AST). In some embodiments, the TRAE is neutropenia, peripheral neuropathy, nausea, vomiting, or infusion related reaction. In some embodiments, the TRAE is Grade < 2. In some embodiments, administration of the bi-specific antibody in combination with the additional therapeutic composition(s) does not result in any > Grade 3 nausea or vomiting.

[0218] In some embodiments, administration of the bi-specific antibody in combination with the additional therapeutic composition(s) is well-tolerated. In some embodiments, administration of the bi-specific antibody in combination with the additional therapeutic composition(s) results in a Grade >3 TRAE in less than about 50%, less than about 55%, less than about 60%, less than about 65%, or less than about 70% of treated subjects. In some embodiments, administration of the bi-specific antibody in combination with the additional therapeutic composition(s) does not result in any Grade 4 or Grade 5 TRAEs.

[0219] In some embodiments, administration of the bi-specific antibody in combination with the additional therapeutic composition(s) results in a Grade >3 Givastomig-related adverse event in less than about 20%, less than about 25%, less than about 30%, less than about 35%, or less than about 40% of treated subjects. In some embodiments, administration of the bi-Attorney Docket No. IMAB-002 / 02WO 328834-2191 specific antibody in combination with the additional therapeutic composition(s) results in a Grade 4 TRAE in less than about 10%, less than about 15%, or less than about 20% of treated subjects. In some embodiments, administration of the bi-specific antibody in combination with the additional therapeutic composition(s) results in a TRAE leading to treatment interruption in less than about 15%, less than about 20%, less than about 25%, less than about 30%, less than about 35%, less than about 40%, less than about 50%, or less than about 55% of treated subjects. In some embodiments, administration of the bi-specific antibody in combination with the additional therapeutic composition(s) results in a TRAE leading to treatment discontinuation in less than about 10%, less than about 12%, less than about 14%, less than about 16%, less than about 18%, less than about 20%, less than about 22%, or less than about 24% of treated subjects.

[0220] In some embodiments, the present disclosure relates to a method of treating cancer in a subject, comprising administering: a) a bi-specific antibody at the dose of about 5 mg / kg, about 8 mg / kg, or about 12 mg / kg, of the subject’s body weight at the frequency of once every two weeks; b) a chemotherapy; and c) a check point inhibitor, wherein the bi-specific antibody comprises a Claudin 18.2 binding domain and a 4-1BB binding domain, wherein the 4-1BB binding domain is incapable of activating 4- IBB signaling upon binding to 4- IBB in the absence of the Claudin 18.2 binding domain binding to Claudin 18.2, wherein the Claudin 18.2 binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising an amino acid sequence of SEQ ID NO: 4, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 5, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 6, wherein the 4-1BB binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 9, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 10, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 11, an LCDR1 comprising an amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 13, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 14, wherein the chemotherapy comprises oxaliplatin and capecitabine, and wherein the checkpoint inhibitor is nivolumab. In some embodiments, the cancer is a Claudin 18.2-positive cancer.Attorney Docket No. IMAB-002 / 02WO 328834-2191NUMBERED EMBODIMENTS

[0221] Embodiment 1. A method of treating cancer in a subject, comprising administering a bi-specific antibody at a dose of between about 0.1 mg / kg and about 20 mg / kg of the subj ect’ s body weight at a frequency of once every two weeks or once every three weeks, wherein the bi-specific antibody comprises a Claudin 18.2 binding domain and a 4-1BB binding domain, wherein the Claudin 18.2 binding domain comprises a heavy chain CDR1 (HCDR1) comprising an amino acid sequence of SEQ ID NO: 1, a heavy chain CDR2 (HCDR2) comprising an amino acid sequence of SEQ ID NO: 2, a heavy chain CDR3 (HCDR3) comprising an amino acid sequence of SEQ ID NO: 3, a light chain CDR1 (LCDR1) comprising an amino acid sequence of SEQ ID NO: 4, a light chain CDR2 (LCDR2) comprising an amino acid sequence of SEQ ID NO: 5, and a light chain CDR3 (LCDR3) comprising an amino acid sequence of SEQ ID NO: 6, and wherein the 4- IBB binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 9, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 10, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 11, an LCDR1 comprising an amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 13, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 14.

[0222] Embodiment 2. The method of embodiment 1, wherein the Claudin 18.2 binding domain comprises an immunoglobulin heavy chain variable (VH) region and an immunoglobulin light chain variable (VL) region, wherein the VH region comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to SEQ ID NO: 7, and wherein the VL region comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to SEQ ID NO: 8.

[0223] Embodiment 3. The method of embodiment 1 or 2, wherein the Claudin 18.2 binding domain is a Fab fragment.

[0224] Embodiment 4. The method of any one of embodiments 1-3, wherein the 4-1BB binding domain comprises a VH region and a VL region, wherein the VH region comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to SEQ ID NO: 15, and wherein the VL region comprises an amino acid sequence that is at leastAttorney Docket No. IMAB-002 / 02WO 328834-2191 about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to SEQ ID NO: 16.

[0225] Embodiment 5. The method of any one of embodiments 1-4, wherein the 4- IBB binding domain is an scFv.

[0226] Embodiment 6. The method of any one of embodiments 1-5, wherein the bi-specific antibody further comprises an Fc fragment.

[0227] Embodiment 7. The method of embodiment 6, wherein the Fc fragment comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to SEQ ID NO: 19.

[0228] Embodiment 8. The method of embodiment 6 or 7, wherein the Claudin 18.2 binding domain is a Fab fragment, wherein the 4-1BB binding domain is an scFv, wherein the bispecific antibody comprises two first polypeptides and two second polypeptides, wherein each of the first polypeptides comprise, from N-terminus to C-terminus, the heavy chain of the Fab fragment, the Fc fragment, and the scFv, and wherein each of the second polypeptides comprise the light chain of the Fab fragment.

[0229] Embodiment 9. The method of any one of embodiments 1-8, wherein the bi-specific antibody comprises two first polypeptides and two second polypeptides, wherein each of the first polypeptides comprise an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to SEQ ID NO: 20, and wherein each of the second polypeptides comprise an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to SEQ ID NO: 21.

[0230] Embodiment 10. The method of any one of embodiments 1-9, wherein the bi-specific antibody is administered at a dose of between about 5 mg / kg and about 18 mg / kg of the subject’s body weight.

[0231] Embodiment 11. The method of any one of embodiments 1-10, wherein the bi- specific antibody is administered at a dose of between about 8 mg / kg and about 12 mg / kg of the subject’s body weight.

[0232] Embodiment 12. The method of any one of embodiments 1-11, wherein the bi- specific antibody is administered at a dose of about 5 mg / kg, about 8 mg / kg, about 12 mg / kg, about 15 mg / kg, or about 18 mg / kg of the subject’s body weight.Attorney Docket No. IMAB-002 / 02WO 328834-2191

[0233] Embodiment 13. The method of any one of embodiments 1-12, wherein the bispecific antibody is administered at a dose of about 8 mg / kg of the subject’s body weight.

[0234] Embodiment 14. The method of any one of embodiments 1-12, wherein the bispecific antibody is administered at a dose of about 12 mg / kg of the subject’s body weight.

[0235] Embodiment 15. The method of any one of embodiments 1-14, wherein the bispecific antibody is administered intravenously.

[0236] Embodiment 16. A method of treating cancer in a subject, comprising intravenously administering a bi-specific antibody at a dose of about 8 mg / kg, about 12 mg / kg, about 15 mg / kg, or about 18 mg / kg of the subject’s body weight at a frequency of once every two weeks, wherein the bi-specific antibody comprises a Claudin 18.2 binding domain and a 4-1BB binding domain, wherein the Claudin 18.2 binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising an amino acid sequence of SEQ ID NO: 4, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 5, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 6, and wherein the 4-1BB binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 9, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 10, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 11, an LCDR1 comprising an amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 13, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 14.

[0237] Embodiment 17. A method of treating cancer in a subject, comprising intravenously administering a bi-specific antibody at a dose of about 8 mg / kg, about 12 mg / kg, about 15 mg / kg, or about 18 mg / kg of the subject’s body weight at a frequency of once every three weeks, wherein the bi-specific antibody comprises a Claudin 18.2 binding domain and a 4-1BB binding domain, wherein the Claudin 18.2 binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising an amino acid sequence of SEQ ID NO: 4, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 5, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 6, and wherein the 4-1BB binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 9, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 10, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 11, an LCDR1 comprising an amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising an amino acidAttorney Docket No. IMAB-002 / 02WO 328834-2191 sequence of SEQ ID NO: 13, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 14.

[0238] Embodiment 18. A method of treating cancer in a subject, comprising intravenously administering a bi-specific antibody at a dose of about 8 mg / kg, about 12 mg / kg, about 15 mg / kg, or about 18 mg / kg of the subject’s body weight at a frequency of once every two weeks, wherein the bi-specific antibody comprises a Claudin 18.2 binding domain and a 4-1BB binding domain, wherein the bi-specific antibody comprises two first polypeptides and two second polypeptides, wherein each of the first polypeptides comprise an amino acid sequence of SEQ ID NO: 20, and wherein each of the second polypeptides comprise an amino acid sequence of SEQ ID NO: 21.

[0239] Embodiment 19. A method of treating cancer in a subject, comprising intravenously administering a bi-specific antibody at a dose of about 8 mg / kg, about 12 mg / kg, about 15 mg / kg, or about 18 mg / kg of the subject’s body weight at a frequency of once every three weeks, wherein the bi-specific antibody comprises a Claudin 18.2 binding domain and a 4-1BB binding domain, wherein the bi-specific antibody comprises two first polypeptides and two second polypeptides, wherein each of the first polypeptides comprise an amino acid sequence of SEQ ID NO: 20, and wherein each of the second polypeptides comprise an amino acid sequence of SEQ ID NO: 21.

[0240] Embodiment 20. The method of any one of embodiments 1-19, wherein the 4-1BB binding domain is incapable of activating 4- IBB signaling upon binding to 4- IBB in the absence of the Claudin 18.2 binding domain binding to Claudin 18.2.

[0241] Embodiment 21. The method of any one of embodiments 1-20, wherein the cancer is primary.

[0242] Embodiment 22. The method of any one of embodiments 1-21, wherein the cancer is metastatic.

[0243] Embodiment 23. The method of any one of embodiments 1-22, wherein the cancer is relapsed.

[0244] Embodiment 24. The method of any one of embodiments 1-23, wherein the cancer is refractory.

[0245] Embodiment 25. The method of embodiment 24, wherein the cancer is refractory to a PD-1 inhibitor or a PD-L1 inhibitor.

[0246] Embodiment 26. The method of any one of embodiments 1-25, wherein the cancer is a solid tumor.Attorney Docket No. IMAB-002 / 02WO 328834-2191

[0247] Embodiment 27. The method of any one of embodiments 1-26, wherein the cancer is gastric adenocarcinoma (GC), gastro-esophageal junction adenocarcinoma (GEJ), esophageal adenocarcinoma (EAC), pancreatic ductal adenocarcinoma (PDAC), or cholangiocarcinoma.

[0248] Embodiment 28. The method of any one of embodiments 1-27, wherein the cancer is Claudin 18.2-positive.

[0249] Embodiment 29. The method of any one of embodiments 1-28, wherein the serum concentration of the bi-specific antibody is at least about 12 pg / mL throughout the treatment.

[0250] Embodiment 30. The method of any one of embodiments 1-29, wherein the serum half-life of the bi-specific antibody is between about 5 days and about 7 days.

[0251] Embodiment 31. The method of any one of embodiments 1-30, wherein the treatment results in increased serum concentration of soluble 4-1BB.

[0252] Embodiment 32. The method of embodiment 31, wherein the serum concentration of soluble 4-1BB is between about 2 and about 130 times as high as that prior to the treatment.

[0253] Embodiment 33. The method of any one of embodiments 1-32, wherein the treatment results in a partial response.

[0254] Embodiment 34. The method of any one of embodiments 1-32, wherein the treatment results in a stable disease.

[0255] Embodiment 35. The method of any one of embodiments 1-34, wherein the cancer is a solid tumor, and wherein the treatment results in a decrease in size of the solid tumor.

[0256] Embodiment 36. The method of embodiment 35, wherein the size of the solid tumor is decreased by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, or at least about 80%, compared to the size of the solid tumor prior to the treatment.

[0257] Embodiment 37. The method of any one of embodiments 1-36, wherein the duration of response is at least about 3 months, at least about 6 months, at least about 9 months, at least about 12 months, at least about 15 months, at least about 18 months, or at least about 24 months.

[0258] Embodiment 38. The method of embodiment 37, wherein the duration of response is at least about 9 months.

[0259] Embodiment 39. The method of any one of embodiments 1-38, wherein the progression free survival is at least about 0.5 months, at least about 1 month, at least about 1.5 months, at least about 2 months, at least about 2.5 months, at least about 3 months, at least about 3.5 months, at least about 4 months, at least about 4.5 months, at least about 5 months, at least about 5.5 months, or at least about 6 months.Attorney Docket No. IMAB-002 / 02WO 328834-2191

[0260] Embodiment 40. The method of embodiment 39, wherein the progression free survival is about 1.7 months, about 3 months, or about 3.9 months.

[0261] Embodiment 41. The method of any one of embodiments 1-40, wherein the objective response rate is at least about 5%, at least about 10%, at least about 15%, at least about 20%, or at least about 25%.

[0262] Embodiment 42. The method of embodiment 41, wherein the objective response rate is about 11%, about 17%, or about 19%.

[0263] Embodiment 43. The method of any one of embodiments 1-42, wherein the disease control rate is at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, or at least about 65%.

[0264] Embodiment 44. The method of embodiment 43, wherein the disease control rate is about 37%, about 42%, or about 57%.

[0265] Embodiment 45. The method of any one of embodiments 1-44, wherein the method further comprises administering to the subject a chemotherapy and a check point inhibitor.

[0266] Embodiment 46. The method of any one of embodiments 1-44, wherein the method further comprises administering to the subject a chemotherapy or a check point inhibitor.

[0267] Embodiment 47. The method of embodiment 45 or 46, wherein the chemotherapy comprises 5 -fluorouracil (5-FU) and platinum.

[0268] Embodiment 48. The method of embodiment 45 or 46, wherein the chemotherapy comprises a combination of 5-FU, leucovorin, oxaliplatin, and capecitabine.

[0269] Embodiment 49. The method of embodiment 45 or 46, wherein the chemotherapy comprises a combination of oxaliplatin and capecitabine.

[0270] Embodiment 50. The method of embodiment 47 or 48, wherein the 5-FU is administered intravenously at a dose between about 200 mg / m2to about 800 mg / m2'

[0271] Embodiment 51. The method of embodiment 48 or 50, wherein the leucovorin is administered intravenously at a dose between about 100 mg / m2to about 300 mg / m2'

[0272] Embodiment 52. The method of any one of embodiments 48-51, wherein the oxaliplatin is administered intravenously at a dose between about 50 mg / m2to about 200 mg / m2

[0273] Embodiment 53. The method of embodiment 52, wherein oxaliplatin is administered intravenously at a dose of about 130 mg / m2.

[0274] Embodiment 54. The method of any one of embodiments 45-53, wherein the chemotherapy is administered once every two weeks or once every three weeks.Attorney Docket No. IMAB-002 / 02WO 328834-2191

[0275] Embodiment 55. The method of any one of embodiments 48-54, wherein capecitabine is administered orally at a dose of about 1000 mg / m2.

[0276] Embodiment 56. The method of any one of embodiments 48-55, wherein capecitabine is administered orally twice daily.

[0277] Embodiment 57. The method of any one of embodiments 45-56, wherein the check point inhibitor is a PD-1 inhibitor

[0278] Embodiment 58. The method of any one of embodiments 45-56, wherein the checkpoint inhibitor is nivolumab.

[0279] Embodiment 59. The method of embodiment 58, wherein the nivolumab is administered intravenously at a dose of about 240 mg.

[0280] Embodiment 60. The method of any one of embodiments 45-59, wherein the checkpoint inhibitor is administered once every three weeks.

[0281] Embodiment 61. The method of any one of embodiments 45-60, wherein the serum concentration of the bi-specific antibody is at least about 12 pg / mL throughout the treatment.

[0282] Embodiment 62. The method of any one of embodiments 45-61, wherein the serum half-life of the bi-specific antibody is between about 5 days and about 7 days.

[0283] Embodiment 63. The method of any one of embodiments 45-62, wherein the treatment results in increased serum concentration of soluble 4- IBB.

[0284] Embodiment 64. The method of embodiment 63, wherein the serum concentration of soluble 4- IBB is between about 5 and about 50 times as high as that prior to the treatment.

[0285] Embodiment 65. The method of any one of embodiments 45-64, wherein the treatment results in partial response or stable disease.

[0286] Embodiment 66. The method of any one of embodiments 45-65, wherein the cancer is a solid tumor, and wherein the treatment results in a decrease in size of the solid tumor.

[0287] Embodiment 67. The method of embodiment 66, wherein the size of the solid tumor is decreased by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, or at least about 80%, compared to the size of the solid tumor prior to the treatment.

[0288] Embodiment 68. The method of any one of embodiments 45-67, wherein the treatment results in an objective response rate of at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90%.

[0289] Embodiment 69. The method of any one of embodiments 45-68, wherein the treatment results in an objective response rate of about 71%.Attorney Docket No. IMAB-002 / 02WO 328834-2191

[0290] Embodiment 70. The method of any one of embodiments 45-68, wherein the treatment results in an objective response rate of about 83%.

[0291] Embodiment 71. The method of any one of embodiments 45-70, wherein the treatment results in a treatment related adverse event (TRAE) in the subject.

[0292] Embodiment 72. The method of embodiment 71, wherein the TRAE is selected from any one of: neutropenia, peripheral neuropathy, nausea, vomiting, infusion related reaction, diarrhea, abdominal pain, gastritis, increased alanine aminotransferase (ALT), or increased aspartate aminotransferase (AST).

[0293] Embodiment 73. The method of embodiment 72, wherein the TRAE is neutropenia, peripheral neuropathy, nausea, vomiting, or infusion related reaction.

[0294] Embodiment 74. The method of any one of embodiments 71-73, wherein the TRAE is Grade < 2.

[0295] Embodiment 75. The method of any one of embodiments 45-74, wherein the treatment does not result in any > Grade 3 nausea or vomiting.

[0296] Embodiment 76. The method of any one of embodiments 45-75, wherein the treatment results in a Grade >3 TRAE in less than about 50%, less than about 55%, less than about 60%, or less than about 65% of treated subjects.

[0297] Embodiment 77. The method of any one of embodiments 45-76, wherein the treatment does not result in any Grade 4 or Grade 5 TRAEs.

[0298] Embodiment 78. A method of treating cancer in a subject, comprising administering: a bi-specific antibody at the dose of about 5 mg / kg, about 8 mg / kg, or about 12 mg / kg, of the subject’s body weight at a frequency of once every two weeks; a chemotherapy; and a check point inhibitor; wherein the bi-specific antibody comprises a Claudin 18.2 binding domain and a 4-1BB binding domain, wherein the Claudin 18.2 binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising an amino acid sequence of SEQ ID NO: 4, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 5, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 6, wherein the 4-1BB binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 9, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 10, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 11, an light chain CDR1 (LCDR1) comprising an amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 13, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 14, wherein the chemotherapy comprises a combination of 5’Attorney Docket No. IMAB-002 / 02WO 328834-2191FU, leucovorin, oxaliplatin and capecitabine, and wherein the checkpoint inhibitor is nivolumab.

[0299] Embodiment 79. A method of treating cancer in a subject, comprising administering: a bi-specific antibody at the dose of about 18 mg / kg of the subj ect’ s body weight at a frequency of once every two weeks; a chemotherapy; and a check point inhibitor, wherein the bi-specific antibody comprises a Claudin 18.2 binding domain and a 4-1BB binding domain, wherein the Claudin 18.2 binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising an amino acid sequence of SEQ ID NO: 4, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 5, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 6, wherein the 4-1BB binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 9, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 10, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 11, an light chain CDR1 (LCDR1) comprising an amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 13, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 14, wherein the chemotherapy comprises a combination of oxaliplatin and capecitabine, and wherein the checkpoint inhibitor is nivolumab.

[0300] Embodiment 80. A method of treating cancer in a subject, comprising administering: a bi-specific antibody at the dose of about 18 mg / kg of the subj ect’ s body weight at a frequency of once every two weeks; and a chemotherapy; wherein the bi-specific antibody comprises a Claudin 18.2 binding domain and a 4-1BB binding domain, wherein the Claudin 18.2 binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising an amino acid sequence of SEQ ID NO: 4, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 5, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 6, wherein the 4-1BB binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 9, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 10, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 11, an light chain CDR1 (LCDR1) comprising an amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 13, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 14, wherein the chemotherapy comprises a combination of oxaliplatin and capecitabine.Attorney Docket No. IMAB-002 / 02WO 328834-2191

[0301] Embodiment 81. The method of any one of embodiments 78-80, wherein capecitabine is administered orally twice daily at a dose of about 1000 mg / m2.

[0302] Embodiment 82. The method of embodiment 78 or 81, wherein the 5-FU is administered intravenously at a dose between about 200 mg / m2to about 800 mg / m2once every two weeks.

[0303] Embodiment 83. The method of embodiment 78, 81, or 82, wherein the leucovorin is administered intravenously at a dose between about 100 mg / m2to about 300 mg / m2once every two weeks.

[0304] Embodiment 84. The method of any one of embodiments 78-83, wherein the oxaliplatin is administered intravenously at a dose between about 50 mg / m2to about 200 mg / m2once every two weeks.

[0305] Embodiment 85. The method of any one of embodiments 78-84, wherein oxaliplatin is administered intravenously at a dose of about 130 mg / m2once every three weeks.

[0306] Embodiment 86. The method of any one of embodiments 78, 79, and 81-85, wherein the nivolumab is administered intravenously at a dose of about 240 mg once every three weeks.

[0307] Embodiment 87. The method of any one of embodiments 78-86, wherein the treatment results in partial response or stable disease.

[0308] Embodiment 88. The method of any one of embodiments 78-87, wherein the cancer is a solid tumor, and wherein the treatment results in decreased size of the solid tumor.

[0309] Embodiment 89. The method of embodiment 88, wherein the size of the solid tumor is decreased by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, or at least about 80%, compared to the size of the solid tumor prior to the treatment.

[0310] Embodiment 90. The method of any one of embodiments 78-89, wherein the treatment results in an objective response rate of at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90%.

[0311] Embodiment 91. The method of any one of embodiments 78-90, wherein the treatment results in an objective response rate of about 71%.

[0312] Embodiment 92. The method of any one of embodiments 78-91, wherein the treatment results in an objective response rate of about 83%.

[0313] Embodiment 93. The method of any one of embodiments 1-92, wherein the cancer is HER2-negative.Attorney Docket No. IMAB-002 / 02WO 328834-2191

[0314] Embodiment 94. The method of any one of embodiments 1-93, wherein the cancer is unresectable.

[0315] Embodiment 95. The method of any one of embodiments 1-94, wherein the cancer is metastatic.

[0316] Embodiment 96. The method of any one of embodiments 78-95, wherein the cancer is Claudin 18.2 positive.

[0317] Embodiment 97. The method of any one of embodiments 78-96, wherein the cancer is gastric adenocarcinoma (GC), gastro-esophageal junction adenocarcinoma (GEJ), esophageal adenocarcinoma (EAC), pancreatic ductal adenocarcinoma (PDAC), or cholangiocarcinoma.EXAMPLES

[0318] The following is a description of various methods and materials used in the studies. They are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as their invention, nor are they intended to represent that the experiments below were performed and are all of the experiments that may be performed. It is to be understood that exemplary descriptions written in the present tense were not necessarily performed, but rather that the descriptions can be performed to generate the data and the like associated with the teachings of the present invention. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, percentages, etc.), but some experimental errors and deviations should be accounted for.EXAMPLE 1 — Clinical Protocol of a Phase 1 Study of Givastomig in Subjects with Advanced or Metastatic Solid Tumors

[0319] This Example section provides a brief summary of the clinical protocol of an open label, first-in-human, multi-center, multiple dose Phase 1 study. The study utilized the Bayesian Optimal Interval (BOIN) design to evaluate the safety, tolerability, maximal tolerable dose (MTD), pharmacokinetics (PK), and pharmacodynamics (PD), recommended phase 2 dose (RP2D), and preliminary efficacy of Givastomig in subjects with advanced or metastatic solid tumors.Participation Criteria

[0320] Below is the Inclusion CriteriaAttorney Docket No. IMAB-002 / 02WO 328834-2191• For Part 1 and Part 2, eligible subjects were 18 years or older, with at least 1 histologically confirmed, unresectable, measurable lesion as assessed by RECIST vl. l; Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 with adequate organ function and estimated life expectancy > 12 weeks;• Part 1 (Monotherapy): Subjects with advanced or metastatic solid tumor whose disease had progressed despite standard therapy, or who had no further standard therapy, or who was unsuitable for available standard treatment options.• Part 2 (Combination Therapy with nivolumab and chemotherapy): Subjects with treatment naive locally advanced, unresectable or metastatic gastric, GEJ, esophageal adenocarcinoma; Had known PD-L1 status with prior testing by immunohistochemistry and a corresponding combined positive score (CPS).• For dose expansion and Part 2 Combination: subjects must have Claudin 18.2-positive tumor expression. Claudin 18.2-positive is defined as >1% of tumor cells with > 1+ membrane intensity by immunohistochemistry; Had known PD-L1 status with prior testing by immunohistochemistry and a corresponding combined positive score (CPS).

[0321] Below is the Exclusion Criteria• Prior exposure to CLDN 18.2 -targeted therapy• Prior exposure to 4- IBB agonists• Second malignancy within the last 3 years with the exception of cutaneous squamous cell carcinoma or cutaneous basal cell carcinoma or cervical carcinoma in situ• Known active or chronic Hepatitis B or Hepatitis C, other hepatitides• Unstable / active ulcer or digestive tract bleeding within 6 weeks• Active autoimmune disease requiring systemic treatment within the past 2 years• Active interstitial lung disease (ILD) or pneumonitis or a history of ILD or pneumonitis requiring treatment• Known active CNS metastases and / or carcinomatous meningitis. Subjects with previously treated brain metastases might participate provided they were clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment;• New York Heart Association (NYHA) Class 3 or 4 congestive heart failure, severe / unstable angina, myocardial infarction (MI), symptomatic congestive heart failure, cerebrovascular accident, transient ischemic attack (TIA), arterial embolism, pulmonaryAttorney Docket No. IMAB-002 / 02WO 328834-2191 embolism, percutaneous transluminal coronary angioplasty (PTCA), deep vein thrombosis, or coronary artery bypass grafting (CABG) in the previous 6 months• Diagnosis of immunodeficiency such as known active HIV• Any active infection requiring parenteral treatment Study Plan

[0322] Table 3 shows the arms and interventions of the monotherapy and the combination therapy. Fig. 1 shows the study design of the monotherapy. Fig. 19A shows the study design of the combined therapy arm.Table 3.

[0323] Table 4 shows the primary outcome measures.Table 4.Attorney Docket No. IMAB-002 / 02WO 328834-2191

[0324] Table 5 shows the secondary outcome measures.Table 5.Attorney Docket No. IMAB-002 / 02WO 328834-2191Clinical Data from Dose Escalation and the Parallel Dose Expansion Study

[0325] This Example section provides clinical data for subjects enrolled in the dose escalation and the parallel dose expansion.

[0326] 55 subjects with advanced relapsed / refractory solid tumors have been enrolled (32 in dose escalation and 23 in parallel dose expansion): 21 GC (20 Claudin 18.2+), 2 GEJ (2 Claudin 18.2+), 5 EAC (4 Claudin 18.2+), 14 PDAC (8 Claudin 18.2+), and 13 other various types of cancers (2 Claudin 18.2+). Claudin 18.2 expression was evaluable in 87.3% of subjects and 65.5% of all enrolled subjects were Claudin 18.2 positive. Subjects enrolled had a median age of 66 years old, ECOG 0 / 1 (30.9% / 69.1%), and 3 median prior lines of systemic therapy (range 1-10). Fig. 2 shows the baseline characteristics of these 55 subjects.

[0327] During the dose escalation, Givastomig was intravenously administered to the subjects at the dosage of 0.1 mg / kg, 0.3 mg / kg, 1 mg / kg, 3 mg / kg, 5 mg / kg, 8 mg / kg, 12 mg / kg, or 15 mg / kg, every 2 weeks (Q2W), irrespective of Claudin 18.2 expression. During the parallel dose expansion, Givastomig was intravenously administered to the subjects at the dosage of 5 mg / kg, 8 mg / kg, 12 mg / kg, or 15 mg / kg, every 2 weeks (Q2W). Fig. 3 shows the treatment- related adverse events occurred among these 55 subjects. Givastomig monotherapy was safe and well tolerated up to 15 mg / kg Q2W in subjects with advanced solid tumors. No doselimiting-toxicity (DLT) was observed and maximum-tolerated-dose (MTD) was not reached. The most common reported treatment-related adverse events (TRAEs) (reported from >10% of subjects) were Graede 1 or 2 nausea (23.6%), vomiting (16.4%), fatigue (14.5%), and anemia (10.9%). 10 subjects (18.2%) experienced at least one Grade 3 TRAE. No Grade 3 TRAEs occurred in more than 1 subject. Event onset of gastrointestinal TRAEs were generally after 14 days of treatment and recovered within 1 week. No TRAE led to drug withdrawal.

[0328] At designated time points, subjects’ serum samples were collected. Givastomig concentrations were measured by a validated ELISA method, soluble 4- IBB in serum was measured using an electrochemiluminescence immunoassay, serum cytokines andAttorney Docket No. IMAB-002 / 02WO 328834-2191 immunophenotypes in peripheral blood mononuclear cells were also measured. As shown in Fig. 4, linear PK of Givastomig were observed in all subjects with an apparent effective halflife of 5.5-6.7 days at > 5 mg / kg Q2W; at > 8 mg / kg Q2W, all individual Ctrough after one cycle reached the target concentration of 12 pg / mL. As shown in Fig. 5, soluble 4-1BB showed sustained and dose-dependent increase, with the highest level of induction seen at 8 mg / kg and 12 mg / kg. Systemic changes in peripheral T cell activation or circulating cytokines were not observed.

[0329] Anti-tumor activity was evaluated based on Response Evaluation Criteria in Solid Tumors (RECIST vl. l) and iRECIST. Of the 26 subjects with GC / GEJZEAC whose tumors were Claudin 18.2+, 20 subjects were efficacy evaluable and dosed at 5 mg / kg, 8 mg / kg, 12 mg / kg, or 15 mg / kg, every 2 weeks (Q2W). Fig. 6 and Fig. 7 show the efficacy of Givastomig and the duration of treatment, respectively. Encouraging monotherapy activity was observed in heavily pre-treated GC, GEJ, andEAC subjects with a wide range ofClaudin 18.2 expression, including low Claudin 18.2 expression tumors.

[0330] Partial response (PR) was observed in 3 out of the 20 subjects that included 1 at 5 mg / kg (Claudin 18.2 IHC 1+, 10%; 2+, 1%), 1 at 8 mg / kg (Claudin 18.2 IHC 1+, 20%; 2+, 30%), and 1 at 12 mg / kg (Claudin 18.2 IHC 2+, 10%; 3+, 90%). All three responders occurred at the time of first tumor assessment (8 weeks). Two responders had received prior anti-PDl or anti-PD-Ll therapy, both concluding approximately 4 months before starting Givastomig. Stable disease (SD) was also observed in 4 out of the 20 efficacy evaluable subjects. One subject had a PR on the first scan and subsequently withdrew from the study, meeting criteria for SD. An additional responder was observed in one subject with head and neck squamous cell carcinoma receiving 12 mg / kg, who remained on study at 280 days.

[0331] Fig. 8 shows the change of the tumor size in a subject with metastatic esophageal adenocarcinoma who had a partial response to Givastomig at the dosage of 5 mg / kg, Q2W. The subject’s treatment history included: IL: FOLFOX + nivolumab; 2L: FOLFIRI + nivolumab; 3L: Paclitaxel + ramucirumab (last nivolumab dose was administered 4 months prior to the study). The subject’s biomarker included: Claudin 18.2 11% (IHC 1+, 10%; 2+, 1%); PD-L1 CPS: 5, HER2: IHC 0. The treatment lasted for 169 days. As shown in Fig. 8, the tumor size decreased significantly by week 16.Attorney Docket No. IMAB-002 / 02WO 328834-2191Clinical Data from Parallel Dose Expansion and Dose Expansion Study

[0332] This Example section provides clinical data for subjects enrolled in the parallel dose expansion and dose expansion. The measuring methods here are the same as those provided in Example 8.2.

[0333] 43 subjects with Claudin 18.2+ Gastroesophageal Carcinoma (GEC) were enrolled in expansion and received intravenous Givastomig at the dosage of 5 mg / kg (n=7), 8 mg / kg (n=5), 12 mg / kg (n=21), and 15mg / kg (n=6) Q2W, and 18mg / kg Q3W (n=4). Subjects had a median age of 59 years old, ECOG 0 / 1 (27.9% / 72.1%), and a median of 3 prior lines of systemic therapy (range 1-6). Fig. 9 shows the baseline characteristics of these 43 subjects.

[0334] Fig. 10 shows the treatment-related adverse events occurred among these 43 subj ects. No DLT was reported up to 15 mg / kg Q2W and 18 mg / kg Q3W. MTD was not reached. The most commonly reported TRAEs (>20%) were nausea (25.6%), anemia (23.3%), and white blood cell count decreased (23.3%). Grade > 3 TRAE were reported in 15 subjects (34.9%) which included one Grade 4 event of platelet count decreased. There was no Grade 5 TRAE. Most gastrointestinal TRAEs were Grade 1 or 2 and did not appear to be dose-related.

[0335] As shown in Fig. 11, at dosages > 5 mg / kg Q2W, a linear PK was observed and the average Ctrough reached the target threshold of 12 pg / mL; at dosages > 8 mg / kg Q2W, all subjects would be predicted to achieve the target threshold. As shown in Fig. 12, dosedependent induction in soluble 4- IBB reached a plateau for Givastomig at 8 mg / kg to 18 mg / kg.

[0336] Fig. 13 and Fig. 14 show the efficacy of Givastomig and the duration of treatment, respectively. Fig. 15 shows the percentage change of the tumor size from baseline at the designated time points. Of the 43 subjects with Claudin 18.2+ GEC who received Givastomig monotherapy at doses ranging from 5 to 18 mg / kg, a partial response was observed in 7 subjects (1 at 5mg / kg, 1 at 8mg / kg, 4 at 12mg / kg, and 1 at 18mg / kg) with an objective response rate (ORR) of 16.3% for single agent Givastomig. Stable disease was reported in 14 subjects (disease control rate = 48.8%). Claudin 18.2 expression in responders ranged from 11% to 100%. Additionally, five responders had received prior treatment with Programmed Cell Death Protein 1 (PD-1) or Programmed Cell Death Ligand 1 (PD-L1) inhibitors. Response to therapy was generally observed at the first scan with a median time to response of 1.7 months. Median duration of response was 9.4 months and median progression-free survival was 3.0 months. As of the cutoff date, 4 PR subjects remained on the study.Attorney Docket No. IMAB-002 / 02WO 328834-2191Clinical Update on Dose Escalation and Parallel Dose Expansion Study

[0337] This Example section provides updated clinical data for subjects enrolled in the dose escalation and the parallel dose expansion described in Example 8.1.1 and 8.1.2.

[0338] Study population

[0339] A total of 75 patients had received Givastomig across 9 sequential dose levels between 0.1 and 18 mg / kg (0.1 [n = 1], 0.3 [n = 1], 1 [n = 4], 3 [n = 4], 5 [n = 12], 8 [n = 10], 12 [n = 27], 15 [n = 12], and 18 mg / kg [n = 4]) at sites in the United States and China. The median age was 63 years (range, 27-82). Most patients were white (57%), male (56%), and had ECOG PS 1 (69%) (Table 6).

[0340] The study population was heavily pretreated, with a median of 3 prior lines of therapy. 53% had received prior PD-(L)1 therapy. Approximately half of the patients (56%) had gastric / GEJ cancers, 19% had pancreatic cancer and 9% had esophageal cancer. Across all dose levels, 36% had liver metastases, and 25% had peritoneal metastases; 75% of patients were CLDN18.2 positive by the trial definition (Table 6).

[0341] Reasons for not meeting eligibility criteria reported in at least 2 subjects included inadequate organ function (n=7), CLDN negative (expansion only, n=6), other acute / chronic medical issue (n=5), ECOG >1 (n=4), CHF, unstable angina, or recent CVA / TIA (n=3), unable to comply with study procedures (n=3), and no measurable disease (n=2).Table 6. Patient demographics and baseline characteristics.Patients (all comers) (N =Characteristic 75)Median age (range), years 63 (27-82)Male / female, n (%) 42 (56) / 33 (44)Race, n (%)Asian 26 (35)Black or African American 2 (3)White 43 (57)Not reported 4 (5)ECOG performance status, n (%)0 23 (31)1 52 (69)CLDN 18.2-positive expression, n (%) 56 (75)Prior lines of therapy, median (range) 3 ( 1-9)Prior PD-1 / PD-L1 therapy, n (%) 40 (53)Attorney Docket No. IMAB-002 / 02WO 328834-2191Liver metastases, n (%) 27 (36)Peritoneal metastases, n (%) 19 (25)Tumor types, n (%)Gastric / GEJ 42 (56)Pancreatic 14 (19)Esophageal 7 (9)CRC 4 (5)NSCLC 2 (3)Ovarian 2 (3)Other34 (5)Abbreviations: CRC, colorectal cancer; CLDN18.2, claudin-18 isoform 2; ECOG, Eastern Cooperative Oncology Group; GEJ, gastroesophageal junction; HNSCC, head and neck squamous cell carcinoma; NSCLC, non-small cell lung cancer; PD-1, programmed cell death protein; PD-L1, programmed cell death ligand 1. including one each of cholangiocarcinoma, HNSCC, synovial sarcoma, and uterine carcinosarcoma.

[0342] Safety

[0343] During cycle 1, adverse events meeting the dose-limiting toxicity (DLT) criteria (Table 4) were considered DLTs unless clearly unrelated to Givastomig. No DLTs were observed up to 15 mg / kg IV Q2W and 18 mg / kg IV Q3W, and the MTD was not reached. The most common all-grade treatment-related adverse events (>10%) (TRAEs) were nausea (21%), anemia (15%), fatigue (13%), white blood cell count decreased (13%), vomiting (12%), and ALT increased (11%) (Table 7). Grade 3 nausea or vomiting was seen in 1% of patients.Table 7. TRAEs in >2 of patients by preferred term and grade (safety set; N = 75).Grade 1 n Grade 2 n Grade 3 n Grade 4 n Grade 5 n All Grades nAdverse Event (%) (%) (%) (%) (%) (%)Nausea 12 (16) 3 (4) 1 (1) 0 0 16 (21)Anaemia 2 (3) 5 (7) 4 (5) 0 0 11 (15)Fatigue 8 (11) 2 (3) 0 0 0 10 (13)WBC count decreased 4 (5) 3 (4) 3 (4) 0 0 10 (13)Vomiting 7 (9) 1 (1) 1 (1) 0 0 9 (12)ALT increased 4 (5) 3 (4) 1 (1) 0 0 8 (11)AST increased 3 (4) 1 (1) 2 (3) 0 0 6 (8)Decreased appetite 3 (4) 2 (3) 1 (1) 0 0 6 (8)Neutropenia 1 (1) 3 (4) 2 (3) 0 0 6 (8)GGT increased 1 (1) 3 (4) 1 (1) 0 0 5 (7)Infusion related reaction 1 (1) 3 (4) 1 (1) 0 0 5 (7)Lymphocytes decreased 0 1 (1) 4 (5) 0 0 5 (7)Abdominal pain 3 (4) 0 0 0 0 3 (4)Arthralgia 3 (4) 0 0 0 0 3 (4)Blood AlkPhos increased 2 (3) 1 (1) 0 0 0 3 (4)Attorney Docket No. IMAB-002 / 02WO 328834-2191Diarrhea 3 (4) 0 0 0 0 3 (4)Headache 2 (3) 1 (1) 0 0 0 3 (4)Hypoalbuminemia 2 (3) 1 (1) 0 0 0 3 (4)Insomnia 3 (4) 0 0 0 0 3 (4)Lipase increased 1 (1) 1 (1) 1 (1) 0 0 3 (4)Platelets decreased 1 (1) 1 (1) 0 1 (1) 0 3 (4)Pyrexia 3 (4) 0 0 0 0 3 (4)Urinary tract infection 2 (3) 1 (1) 0 0 0 3 (4)Weight decreased 2 (3) 1 (1) 0 0 0 3 (4)Constipation 2 (3) 0 0 0 0 2 (3)Dyspepsia 2 (3) 0 0 0 0 2 (3)Hypophosphatemia 2 (3) 0 0 0 0 2 (3)Pruritus 1 (1) 0 1 (1) 0 0 2 (3)Tumor pain 2 (3) 0 0 0 0 2 (3)Upper GI hemorrhage 0 0 2 (3) 0 0 2 (3)Abbreviations: AlkPhos alkaline phosphatase; ALT alanine aminotransferase; AST aspartate aminotransferase GGT gamma-glutamyltransferase; WBC white blood cell; n, number of subjects. Percentages are based on the number of subjects enrolled and computed only when the numerator does not equal zero.

[0344] Grade >3 TRAEs were reported in 21% of patients; those that occurred in at least 2 subjects were anemia (5%), lymphocyte count decreased (5%), white blood cell count decreased (4%), AST increased (3%), neutropenia (3%), and upper gastrointestinal (GI) hemorrhage (3%). Treatment-related nausea and vomiting was grade 1 or 2 in most patients. Grade 3 nausea and vomiting leading to withdrawal of study drug was seen in 1 patient treated at Givastomig 18 mg / kg.

[0345] Overall, TRAEs resulting in study drug withdrawal occurred in 5% of patients, including 1 grade 3 ALT increase (5 mg / kg), 1 grade 3 nausea (18 mg / kg), 1 grade 3 infusion- related reaction (5 mg / kg), and 1 grade 2 pulmonary embolism (12 mg / kg). In addition, 20 patients (27%) experienced treatment emergent adverse events (TEAEs) resulting in death. Of the fatal TEAEs, 18 (90%) were related to disease progression, and two patients (10%) experienced fatal sepsis (ANC nadirs 3.2 and 3.0 for each of these patients); neither of which were attributed to study drug. SAEs were reported in 53% of patients, and treatment-related SAEs were reported in 17% of patients (Table 8). The protocol does not permit dose reductions of Givastomig. Nine subjects experienced dose interruptions due to events attributed to Givastomig. There were no interruptions or withdrawals of Givastomig due to nausea and vomiting.Attorney Docket No. IMAB-002 / 02WO 328834-2191Table 8. Overview of Treatment Emergent Adverse Events (TEAEs)Givastomig (all doses) (N = 75), n (%)TEAEsAny 73 (97)Serious 40 (53)Grade >3 50 (67)Leading to Givastomig interruption 9 (12)Leading to Givastomig withdrawal 9 (12)Resulted in death 20 (27)Progressive disease 17 (23)Related to Givastomig 50 (67)Serious 13 (17)Grade >3 16 (21)Leading to Givastomig withdrawal 4 (5)Resulted in death 0

[0346] Pharmacokinetics

[0347] Preliminary PK data were obtained from patients treated with Givastomig 0.1 to 15 mg / kg Q2W and 18 mg / kg Q3W. The exposure of Givastomig (both Cmax and AUC) in the blood of these patients increased with the doses. At dose levels >5 mg / kg, the exposure increased in an approximately dose-proportional manner, as evidenced by the mean concentration-time profiles (Fig. 17A). In patients receiving Givastomig doses higher than 5 mg / kg, the mean half-life ranged from 108 to 160 hours. The mean PK parameters are shown in Fig. 17B.

[0348] Among the 48 patients who received Givastomig doses ranging from 0.1 to 18 mg / kg during dose escalation in the US, a dose- and time-dependent increase in s4-lBB was observed. Induction in s4-lBB approached a plateau above 5 mg / kg, with a sustained increase after cycle 1 day 8 in patients dosed at >3 mg / kg (Figs. 18A and 18B).

[0349] Among the 29 patients with GEC from both dose escalation and expansion cohorts dosed at 8 to 15 mg / kg Q2W, induction in s4-lBB at Cycle 1 Day 15 (after the first dose) was numerically higher in patients with partial response (PR) and stable disease (SD) (fold change of 63; n = 15), compared with patients with progressive disease (fold change of 40; n = 14; P = 0.143; (Fig. 18C) Induction was also statistically higher in the CLDN18.2-high group (defined as CLDN18.2 at least 1+ in >50% of tumor cells; fold change of 72; n = 18), compared with the CLDN18.2-low group (CLDN18.2-positive <50%; fold change of 28; n = 11; P = 0.0005) (Fig. 18D).

[0350] Pro-inflammatory cytokines were quantified in serum samples from 31 patients in dose cohorts 0.1 to 12 mg / kg. In addition, immunophenotyping of T-cell subsets was performed on whole blood samples from 33 patients in dose cohorts 0.1 to 15 mg / kg. No discernible dose-Attorney Docket No. IMAB-002 / 02WO 328834-2191 related peripheral PD relationship was observed for any of the inflammatory cytokines and T - cell subsets tested, suggesting no systemic immune activation by Givastomig.

[0351] Antitumor activity

[0352] Of 73 efficacy evaluable patients (defined as all subjects who received at least 1 dose of study drug), the confirmed ORR was 11% with 8 PRs (95% CI, 4.9-20.5), and the disease control rate (DCR) was 37% with 19 SDs (95% CI, 26.0-49.1) (Table 9). Stable disease must be documented on at least one on-treatment scan occurring at least 8 weeks from the start of treatment or a prior on-treatment scan. Figure 16A depicts the maximum extent of tumor shrinkage. Figure 16B shows the duration of Givastomig treatment. C1D1, cycle 1 day 1. Table 9. Best Overall Response (BOR) and Overall Response Rate (ORR)Givastomig (all doses, all- Givastomig (5-18 mg / kg) in comers) CLDN18.2-positive GECParameter (N = 73) (N = 43)BOR, n (%)PR 8 (11) 7 (16)SD 19 (26) 14 (33)PD 36 (49) 15 (35)Other310 (14) 7 (16)Confirmed ORR« (%) 8 (11) 7 (16)95% CI 4.9-20.5 6.8-30.7CLDN 18.2+ tumor cells<50% 1 (4) 1 (109)>50% 6 (14) 6 (18)<75% 2 (6) 2 (13)>75% 5 (15) 5 (18)DCR (PR + SD)« (%) 27 (37) 21 (49)95% CI 26.0-49.1 33.3-64.5CLDN 18.2+ tumor cells<50%6 (23) 3 (30)<>0%20 (48) 18 (55)<75%9 (27) 5 (33)>75% 17 (50) 16 (57)Abbreviations: BOR, best overall response; CI, confidence interval; DCR, disease control rate; ORR, objective response rate; PR, partial response; SD, stable disease; PD, progressive disease.aClinical progressive disease or death before first post-treatment scan.

[0353] 56 patients had CLDN18.2-positive tumors that exhibited at least 1+ staining in 1% to 100% of tumor cells. 7 PRs were observed in patients with CLDN18.2 -positive GEC, andAttorney Docket No. IMAB-002 / 02WO 328834-21911 PR was observed in a patient with squamous cell head and neck carcinoma with unknown CLDN18.2 expression. Of 43 efficacy-evaluable patients with CLDN18.2+ GEC who received Givastomig ranging from 5 to 18 mg / kg, 7 PRs were observed (1 at 5 mg / kg, 1 at 8 mg / kg, 4 at 12 mg / kg, and 1 at 18 mg / kg), with an ORR of 16%. The median time to response was 1.7 months (95% CI, 0.9-1.84), and the median duration of response was 9.4 months (95% CI, 3.2-NA). The DCR rate was 49%. The median PFS was 1.7 months (95% CI, 1.71-2.83). Responses were observed across a broad range of CLDN18.2 tumor cell expression (11%- 100%). Locally determined PD-L1 combined positive score (CPS) data were available for 5 of the 7 patients with GEC who achieved a PR. A CPS of 5 was observed in 2 of the 5 patients, and a CPS <5 was observed in the remaining 3 patients, including 1 patient with a CPS of 0.

[0354] Overall, the results from the monotherapy arm of the ongoing clinical study show that Givastomig was well tolerated in patients with advanced solid tumors up to 18 mg / kg.Clinical Update on Dose Escalation and Parallel Dose Expansion Study

[0355] This Example section provides updated clinical data for subjects enrolled in the dose escalation and the parallel dose expansion described in Example 8.1.1 and 8.1.2. During escalation, subjects with solid tumors irrespective of CLDN18.2 expression received Givastomig intravenously every 2 weeks (Q2W) across 8 dose levels (0.1 mg / kg to 15 mg / kg), and at 18 mg / kg Q3W. During expansion, subjects with CLDN18.2 positive (CLDN18.2+, >1% of tumor cells with >1+ intensity by immunohistochemistry) GEC were included. Differences in objective response rate (ORR) and disease control rate (DCR) between CLDN18.2-high subjects (> 75% tumor cells of IHC 2+ / 3+) and CLDN18.2-low subjects were evaluated by Chi-square test. Progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan -Meier method and Cox proportional hazards. Outcomes for CLDN18.2+ GEC subjects at doses > 5 mg / kg are reported here.

[0356] 45 subjects with GEC received Givastomig intravenously at a dose of 5 mg / kg (n = 7), 8 mg / kg (n = 5), 12 mg / kg (n = 21), and 15 mg / kg (n= 6) once every two weeks (Q2W), and 18 mg / kg (n = 6) once every three weeks. Subjects had received a median of 3 prior therapies, including 74% with prior PD-L1 inhibitor.

[0357] No new safety signal was identified with longer follow up. No dose limiting toxi cities were observed. Common treatment-related adverse events (>15%, any grade / grade 3) included anemia (27% / 9%), decreased white blood cells (22% / 7%), nausea (20% / 2%), increased ALT (16% / 2%), and increased AST (16% / 4%).Attorney Docket No. IMAB-002 / 02WO 328834-2191

[0358] A partial response (PR) was observed in 8 subjects (1 PR at 5 mg / kg, 1 PR at 8 mg / kg, 4 PRs at 12mg / kg, and 2 PRs at 18 mg / kg) with an objective response rate (ORR) of 18%. CLDN18.2 expression in responders ranged from 11% (1+, 10%; 2+, 1%) to 100% (2+, 10%; 3+, 90%). Stable disease was observed in 14 subjects (DCR 48.9%). Two subjects were ongoing (4%), with one PR at 8 mg / kg at 33 months and one PR at 18 mg / kg at 10 months. The median PFS (mPFS) and median OS (mOS) are 2.96 (95% CI 1.71-3.91) and 7.49 mo (95% CI 4.96-12.5), respectively. There was no statistically significant difference in ORR, DCR, PFS, or OS between CLDN18.2-high subjects (n=21) and CLDN18.2-low subjects (n=24): ORR 19% vs. 17% (p=l .00), DCR 57% vs. 42% (p=0.46), mPFS 3.68 vs. 1.84 mo, PFS hazard ratio (HR) 0.87 (p=0.67), and mOS 7.49 vs. 7.49 mo, OS HR 0.88 (p=0.74), respectively.

[0359] Givastomig was well-tolerated up to 15 mg / kg Q2W and 18 mg / kg Q3W and continues to show encouraging monotherapy activity in heavily pre-treated GEC subjects with a wide range of CLDN 18.2 expression. Givastomig may have the ability to target subj ects with lower CLDN18.2 expression compared with other CLDN18.2 agents.Clinical Data from Combination Therapy Study

[0360] This Example section provides clinical data for subjects enrolled in the Combination Therapy arm, for which Fig. 19A shows the study design.

[0361] 17 subjects with IL unresectable or metastatic, HER2-negative, CLDN18.2+ gastric, esophageal, or gastroesophageal adenocarcinomas (GEC) have been enrolled: 14 gastric cancer (GC), 2 gastroesophageal (GEJ), and 1 esophageal. CLDN18.2+ is defined as >1+ intensity in >1% of tumor cells. Claudin 18.2 was expressed on >75% of cells in 71% of subjects and was expressed on >40% of cells in 82% of subjects. Subjects enrolled had a median age of 56 years old, Eastern Cooperative Oncology Group Eastern Cooperative Oncology Group (ECOG) performance status ECOG 0 / 1 (53% / 47%), and PD-L1 combined positive score (CPS) >1 in 88% of subjects. Fig. 19B shows the baseline characteristics of these 17 subjects. Abbreviations: ECOG PS = Eastern Cooperative Oncology Group performance status; GEJ = gastroesophageal junction; CPS = combined positive score; MSI = microsatellite instability; MSLH = microsatellite instability-high; MSS = microsatellite stable; NR = not reported. During the dose escalation, Givastomig was intravenously administered to the subjects at the dosage of 5 mg / kg, 8 mg / kg, or 12 mg / kg, every 2 weeks (Q2W). In parallel, nivolumab (240mg) was intravenously administered to subjects Q2W and mFOLFOX6 was administered to subjects Q2W. As used herein, mFOLFOX6 refers to 130mg / m2oxaliplatin administered intravenously and 1000mg / m2capecitabine administered orally. During the dose expansion,Attorney Docket No. IMAB-002 / 02WO 328834-2191Givastomig was intravenously administered to the subjects at the dosage of 8 mg / kg or 12 mg / kg Q2W, and nivolumab and mFOLFOX6 were administered as during the dose escalation.

[0362] Fig. 20 shows adverse events that occurred among these 17 subjects. Combined therapy was safe and well tolerated up to a Givastomig dose of 12 mg / kg Q2W. No dose limiting toxicities were observed; a maximum tolerated dose was not reached. Common TRAEs (>10% of pts) included neutropenia (71%), peripheral neuropathy (59%), nausea (53%), vomiting (35%), infusion related reaction (41%), diarrhea (29%), abdominal pain (18%), gastritis (12%, ALT increased (12%), and AST increased (12%). Grade 3 TRAEs attributed to Givastomig were rare, with single cases of abdominal pain, ALT / AST increase, gastritis, and infusion related reaction. No grade 4 or 5 TRAE were reported. Abbreviations: TEAE = treatment-emergent adverse event; TRAE = treatment-related adverse event; SAE = serious adverse event; DC = discontinued; ALT = alanine aminotransferase; AST aspartate aminotransferase.

[0363] At designated time points, subjects’ serum samples were collected. Givastomig concentrations were measured by a validated ELISA method, soluble 4- IBB in serum was measured using an electrochemiluminescence immunoassay, serum cytokines and immunophenotypes in peripheral blood mononuclear cells were also measured. Dosedependent PK was observed, similar to monotherapy (data not shown). As shown in Fig. 21 induction of soluble 4-1BB was dose-dependent .

[0364] Anti-tumor activity was evaluated based on Response Evaluation Criteria in Solid Tumors (RECIST vl. l) and iRECIST. Fig. 22A and Fig. 22B show the efficacy of combined therapy and the duration of treatment, respectively. Abbreviations: CPS = combined positive score; CLDN = positive for Claudin-18.2 expression; SD = stable disease; PR = partial response; PD = progressive disease. Partial responses were observed in 12 of 17 pts (ORR 71%), including 2 at 5 mg / kg, 5 at 8 mg / kg, and 5 partial responses plus at 12 mg / kg.

[0365] Fig. 23 shows the percentage change of tumor size from baseline at the designated time points. Table 10 below summarizes objective response rates (ORR%) in subjects receiving 8 or 12 mg / kg Givastomig, according to PD-L1 combined positive score (CPS) and Claudin-18.2 expression (CLDN). Abbreviations: SD = stable disease; ORR = objective response rate.

[0366] In doses selected for expansion (8 mg / kg and 12 mg / kg), ORR was 83%. PRs were observed in all subgroups. Disease control rate was 100%. Mean follow-up time and progression-free survival (PFS) are shown in Table 11 below. 8 patients are receiving ongoing treatment; the longest treatment duration is 11.3 months.Attorney Docket No. IMAB-002 / 02WO 328834-2191Table 10. Objective Response Rates in Subjects Receiving Combined TherapyCohorts for expansion(8, 12 mg / kg) AllORR: % (n) (n=12) (n=17)PD-L1Any 83 (10 / 12) 71 (12 / 17)>5 89 (8 / 9) 82 (9 / 11)<5 67 (2 / 3) 50 (3 / 6)>1 82 (9 / 11) 73 (11 / 15)<1 100 (1 / 1) 50 (1 / 2)CLDN>75 78 (7 / 9) 67 (8 / 12)<75 100 (3 / 3) 80 (4 / 5)Table 11. Follow-up and Progression-Free Survival in Subjects Receiving Combined Therapy8 and 12 mg / kg All(n=12) (n=17)Median follow up (months) (95% CI) 7.8 (5.7, 10.2) 9.0 (6.1, 11.5)Median duration of response (months)N ir,z. ,N ir,.N ir,z. „(95% CI) NE (4.5, NE) NE (4.8, NE)PFS median (months) (95% CI) NE (4.5, NE) NE (4.8, NE)PFS 6 months (%) (95% CI) 81.5 (43.5, 95.1) 72.9 (42.6, 89.0)PFS = progression free survival; CI = confidence interval; PD = progressive disease; PR = partial response; SD = stable disease; NE = not evaluable

[0367] It will be appreciated by those skilled in the art that changes could be made to the embodiments described above without departing from the broad inventive concept thereof. It is understood, therefore, that this invention is not limited to the particular embodiments disclosed, but it is intended to cover modifications within the spirit and scope of the present invention as defined by the present description.Attorney Docket No. IMAB-002 / 02WO 328834-2191INCORPORATION BY REFERENCE

[0368] All references, articles, publications, patents, patent publications, and patent applications cited herein are incorporated by reference in their entireties for all purposes, International Application No. PCT / CN2020 / 108707; International Application No. PCT / CN2023 / 095544; and International Application No. PCT / CN2023 / 122092. However, mention of any reference, article, publication, patent, patent publication, and patent application cited herein is not, and should not be taken as an acknowledgment or any form of suggestion that they constitute valid prior art or form part of the common general knowledge in any country in the world.

Claims

Attorney Docket No. IMAB-002 / 02WO 328834-2191WHAT IS CLAIMED:

1. A method of treating cancer in a subject, comprising administering a bi-specific antibody at a dose of between about 0.1 mg / kg and about 20 mg / kg of the subject’s body weight at a frequency of once every two weeks or once every three weeks, wherein the bi-specific antibody comprises a Claudin 18.2 binding domain and a 4-1BB binding domain, wherein the Claudin 18.2 binding domain comprises a heavy chain CDR1 (HCDR1) comprising an amino acid sequence of SEQ ID NO: 1, a heavy chain CDR2 (HCDR2) comprising an amino acid sequence of SEQ ID NO: 2, a heavy chain CDR3 (HCDR3) comprising an amino acid sequence of SEQ ID NO: 3, a light chain CDR1 (LCDR1) comprising an amino acid sequence of SEQ ID NO: 4, a light chain CDR2 (LCDR2) comprising an amino acid sequence of SEQ ID NO: 5, and a light chain CDR3 (LCDR3) comprising an amino acid sequence of SEQ ID NO: 6, and wherein the 4-1BB binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 9, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 10, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 11, an LCDR1 comprising an amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 13, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 14.

2. The method of claim 1, wherein the Claudin 18.2 binding domain comprises an immunoglobulin heavy chain variable (VH) region and an immunoglobulin light chain variable (VL) region, wherein the VH region comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to SEQ ID NO: 7, and wherein the VL region comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to SEQ ID NO: 8.

3. The method of claim 1 or 2, wherein the Claudin 18.2 binding domain is a Fab fragment.

4. The method of any one of claims 1-3, wherein the 4-1BB binding domain comprises a VH region and a VL region, wherein the VH region comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to SEQ ID NO: 15, and wherein the VL region comprises an amino acid sequence that is at least about 80%, at least about 85%,Attorney Docket No. IMAB-002 / 02WO 328834-2191 at least about 90%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to SEQ ID NO: 16.

5. The method of any one of claims 1-4, wherein the 4- IBB binding domain is an scFv.

6. The method of any one of claims 1-5, wherein the bi-specific antibody further comprises an Fc fragment.

7. The method of claim 6, wherein the Fc fragment comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to SEQ ID NO: 19.

8. The method of claim 6 or 7, wherein the Claudin 18.2 binding domain is a Fab fragment, wherein the 4- IBB binding domain is an scFv, wherein the bi-specific antibody comprises two first polypeptides and two second polypeptides, wherein each of the first polypeptides comprise, from N-terminus to C-terminus, the heavy chain of the Fab fragment, the Fc fragment, and the scFv, and wherein each of the second polypeptides comprise the light chain of the Fab fragment.

9. The method of any one of claims 1-8, wherein the bi-specific antibody comprises two first polypeptides and two second polypeptides, wherein each of the first polypeptides comprise an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to SEQ ID NO: 20, and wherein each of the second polypeptides comprise an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to SEQ ID NO: 21.

10. The method of any one of claims 1-9, wherein the bi-specific antibody is administered at a dose of between about 5 mg / kg and about 18 mg / kg of the subject’s body weight.

11. The method of any one of claims 1-10, wherein the bi-specific antibody is administered at a dose of between about 8 mg / kg and about 12 mg / kg of the subject’s body weight.Attorney Docket No. IMAB-002 / 02WO 328834-219112. The method of any one of claims 1-11, wherein the bi-specific antibody is administered at a dose of about 5 mg / kg, about 8 mg / kg, about 12 mg / kg, about 15 mg / kg, or about 18 mg / kg of the subject’s body weight.

13. The method of any one of claims 1-12, wherein the bi-specific antibody is administered at a dose of about 8 mg / kg of the subject’s body weight.

14. The method of any one of claims 1-12, wherein the bi-specific antibody is administered at a dose of about 12 mg / kg of the subject’s body weight.

15. The method of any one of claims 1-14, wherein the bi-specific antibody is administered intravenously.

16. A method of treating cancer in a subject, comprising intravenously administering a bi- specific antibody at a dose of about 8 mg / kg, about 12 mg / kg, about 15 mg / kg, or about 18 mg / kg of the subject’s body weight at a frequency of once every two weeks, wherein the bi-specific antibody comprises a Claudin 18.2 binding domain and a 4-1BB binding domain, wherein the Claudin 18.2 binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising an amino acid sequence of SEQ ID NO: 4, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 5, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 6, and wherein the 4- IBB binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 9, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 10, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 11, an LCDR1 comprising an amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 13, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 14.

17. A method of treating cancer in a subject, comprising intravenously administering a bi- specific antibody at a dose of about 8 mg / kg, about 12 mg / kg, about 15 mg / kg, or about 18 mg / kg of the subject’s body weight at a frequency of once every three weeks, wherein the bi-specific antibody comprises a Claudin 18.2 binding domain and a 4-1BB binding domain,Attorney Docket No. IMAB-002 / 02WO 328834-2191 wherein the Claudin 18.2 binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising an amino acid sequence of SEQ ID NO: 4, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 5, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 6, and wherein the 4- IBB binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 9, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 10, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 11, an LCDR1 comprising an amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 13, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 14.

18. A method of treating cancer in a subject, comprising intravenously administering a bispecific antibody at a dose of about 8 mg / kg, about 12 mg / kg, about 15 mg / kg, or about 18 mg / kg of the subject’s body weight at a frequency of once every two weeks, wherein the bi-specific antibody comprises a Claudin 18.2 binding domain and a 4-1BB binding domain, wherein the bi-specific antibody comprises two first polypeptides and two second polypeptides, wherein each of the first polypeptides comprise an amino acid sequence of SEQ ID NO: 20, and wherein each of the second polypeptides comprise an amino acid sequence of SEQ ID NO: 21.

19. A method of treating cancer in a subject, comprising intravenously administering a bi- specific antibody at a dose of about 8 mg / kg, about 12 mg / kg, about 15 mg / kg, or about 18 mg / kg of the subject’s body weight at a frequency of once every three weeks, wherein the bi-specific antibody comprises a Claudin 18.2 binding domain and a 4-1BB binding domain, wherein the bi-specific antibody comprises two first polypeptides and two second polypeptides, wherein each of the first polypeptides comprise an amino acid sequence of SEQ ID NO: 20, and wherein each of the second polypeptides comprise an amino acid sequence of SEQ ID NO: 21.

20. The method of any one of claims 1-19, wherein the 4-1BB binding domain is incapable of activating 4-1BB signaling upon binding to 4-1BB in the absence of the Claudin 18.2 binding domain binding to Claudin 18.2.Attorney Docket No. IMAB-002 / 02WO 328834-219121. The method of any one of claims 1-20, wherein the cancer is primary.

22. The method of any one of claims 1-21, wherein the cancer is metastatic.

23. The method of any one of claims 1-22, wherein the cancer is relapsed.

24. The method of any one of claims 1-23, wherein the cancer is refractory.

25. The method of claim 24, wherein the cancer is refractory to a PD-1 inhibitor or a PD- L1 inhibitor.

26. The method of any one of claims 1-25, wherein the cancer is a solid tumor.

27. The method of any one of claims 1-26, wherein the cancer is gastric adenocarcinoma (GC), gastro-esophageal junction adenocarcinoma (GEJ), esophageal adenocarcinoma (EAC), pancreatic ductal adenocarcinoma (PDAC), or cholangiocarcinoma.

28. The method of any one of claims 1-27, wherein the cancer is Claudin 18.2-positive.

29. The method of any one of claims 1-28, wherein the serum concentration of the bispecific antibody is at least about 12 pg / mL throughout the treatment.

30. The method of any one of claims 1-29, wherein the serum half-life of the bi-specific antibody is between about 5 days and about 7 days.

31. The method of any one of claims 1-30, wherein the treatment results in increased serum concentration of soluble 4- IBB.

32. The method of claim 31, wherein the serum concentration of soluble 4- IBB is between about 2 and about 130 times as high as that prior to the treatment.

33. The method of any one of claims 1-32, wherein the treatment results in a partial response.

34. The method of any one of claims 1-32, wherein the treatment results in a stable disease.

35. The method of any one of claims 1-34, wherein the cancer is a solid tumor, and wherein the treatment results in a decrease in size of the solid tumor.Attorney Docket No. IMAB-002 / 02WO 328834-219136. The method of claim 35, wherein the size of the solid tumor is decreased by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, or at least about 80%, compared to the size of the solid tumor prior to the treatment.

37. The method of any one of claims 1-36, wherein the duration of response is at least about 3 months, at least about 6 months, at least about 9 months, at least about 12 months, at least about 15 months, at least about 18 months, or at least about 24 months.

38. The method of claim 37, wherein the duration of response is at least about 9 months.

39. The method of any one of claims 1-38, wherein the progression free survival is at least about 0.5 months, at least about 1 month, at least about 1.5 months, at least about 2 months, at least about 2.5 months, at least about 3 months, at least about 3.5 months, at least about 4 months, at least about 4.5 months, at least about 5 months, at least about 5.5 months, or at least about 6 months.

40. The method of claim 39, wherein the progression free survival is about 1.7 months, about 3 months, or about 3.9 months.

41. The method of any one of claims 1-40, wherein the objective response rate is at least about 5%, at least about 10%, at least about 15%, at least about 20%, or at least about 25%.

42. The method of claim 41, wherein the objective response rate is about 11%, about 17%, or about 19%.

43. The method of any one of claims 1-42, wherein the disease control rate is at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, or at least about 65%.

44. The method of claim 43, wherein the disease control rate is about 37%, about 42%, or about 57%.

45. The method of any one of claims 1-44, wherein the method further comprises administering to the subject a chemotherapy and a check point inhibitor.

46. The method of any one of claims 1-44, wherein the method further comprises administering to the subject a chemotherapy or a check point inhibitor.Attorney Docket No. IMAB-002 / 02WO 328834-219147. The method of claim 45 or 46, wherein the chemotherapy comprises 5 -fluorouracil (5- FU) and platinum.

48. The method of claim 45 or 46, wherein the chemotherapy comprises a combination of 5-FU, leucovorin, oxaliplatin, and capecitabine.

49. The method of claim 45 or 46, wherein the chemotherapy comprises a combination of oxaliplatin and capecitabine.

50. The method of claim 47 or 48, wherein the 5-FU is administered intravenously at a dose between about 200 mg / m2to about 800 mg / m2'51. The method of claim 48 or 50, wherein the leucovorin is administered intravenously at a dose between about 100 mg / m2to about 300 mg / m2'52. The method of any one of claims 48-51, wherein the oxaliplatin is administered intravenously at a dose between about 50 mg / m2to about 200 mg / m2'53. The method of claim 52, wherein oxaliplatin is administered intravenously at a dose of about 130 mg / m2.

54. The method of any one of claims 45-53, wherein the chemotherapy is administered once every two weeks or once every three weeks.

55. The method of any one of claims 48-54, wherein capecitabine is administered orally at a dose of about 1000 mg / m2.

56. The method of any one of claims 48-55, wherein capecitabine is administered orally twice daily.

57. The method of any one of claims 45-56, wherein the check point inhibitor is a PD-1 inhibitor58. The method of any one of claims 45-56, wherein the checkpoint inhibitor is nivolumab.

59. The method of claim 58, wherein the nivolumab is administered intravenously at a dose of about 240 mg.Attorney Docket No. IMAB-002 / 02WO 328834-219160. The method of any one of claims 45-59, wherein the checkpoint inhibitor is administered once every three weeks.

61. The method of any one of claims 45-60, wherein the serum concentration of the bispecific antibody is at least about 12 pg / mL throughout the treatment.

62. The method of any one of claims 45-61, wherein the serum half-life of the bi-specific antibody is between about 5 days and about 7 days.

63. The method of any one of claims 45-62, wherein the treatment results in increased serum concentration of soluble 4- IBB.

64. The method of claim 63, wherein the serum concentration of soluble 4-1BB is between about 5 and about 50 times as high as that prior to the treatment.

65. The method of any one of claims 45-64, wherein the treatment results in partial response or stable disease.

66. The method of any one of claim 45-65, wherein the cancer is a solid tumor, and wherein the treatment results in a decrease in size of the solid tumor.

67. The method of claim 66, wherein the size of the solid tumor is decreased by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, or at least about 80%, compared to the size of the solid tumor prior to the treatment.

68. The method of any one of claims 45-67, wherein the treatment results in an objective response rate of at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90%.

69. The method of any one of claims 45-68, wherein the treatment results in an objective response rate of about 71%.

70. The method of any one of claims 45-68, wherein the treatment results in an objective response rate of about 83%.Attorney Docket No. IMAB-002 / 02WO 328834-219171. The method of any one of claims 45-70, wherein the treatment results in a treatment related adverse event (TRAE) in the subject.

72. The method of claim 71, wherein the TRAE is selected from any one of: neutropenia, peripheral neuropathy, nausea, vomiting, infusion related reaction, diarrhea, abdominal pain, gastritis, increased alanine aminotransferase (ALT), or increased aspartate aminotransferase (AST).

73. The method of claim 72, wherein the TRAE is neutropenia, peripheral neuropathy, nausea, vomiting, or infusion related reaction.

74. The method of any one of claims 71-73, wherein the TRAE is Grade < 2.

75. The method of any one of claims 45-74, wherein the treatment does not result in any > Grade 3 nausea or vomiting.

76. The method of any one of claims 45-75, wherein the treatment results in a Grade >3 TRAE in less than about 50%, less than about 55%, less than about 60%, or less than about 65% of treated subjects.

77. The method of any one of claims 45-76, wherein the treatment does not result in any Grade 4 or Grade 5 TRAEs.

78. A method of treating cancer in a subject, comprising administering: a. a bi-specific antibody at the dose of about 5 mg / kg, about 8 mg / kg, or about 12 mg / kg, of the subject’s body weight at a frequency of once every two weeks; b. a chemotherapy; and c. a check point inhibitor, wherein the bi-specific antibody comprises a Claudin 18.2 binding domain and a 4-1BB binding domain, wherein the Claudin 18.2 binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising an amino acid sequence of SEQ ID NO: 4, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 5, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 6,Attorney Docket No. IMAB-002 / 02WO 328834-2191 wherein the 4- IBB binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 9, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 10, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 11, an light chain CDR1 (LCDR1) comprising an amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 13, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 14, wherein the chemotherapy comprises a combination of 5’ FU, leucovorin, oxaliplatin and capecitabine, and wherein the checkpoint inhibitor is nivolumab.

79. A method of treating cancer in a subject, comprising administering: a. a bi-specific antibody at the dose of about 18 mg / kg of the subj ect’ s body weight at a frequency of once every two weeks; b. a chemotherapy; and c. a check point inhibitor, wherein the bi-specific antibody comprises a Claudin 18.2 binding domain and a 4-1BB binding domain, wherein the Claudin 18.2 binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising an amino acid sequence of SEQ ID NO: 4, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 5, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 6, wherein the 4- IBB binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 9, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 10, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 11, an light chain CDR1 (LCDR1) comprising an amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 13, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 14, wherein the chemotherapy comprises a combination of oxaliplatin and capecitabine, and wherein the checkpoint inhibitor is nivolumab.

80. A method of treating cancer in a subject, comprising administering:Attorney Docket No. IMAB-002 / 02WO 328834-2191 a. a bi-specific antibody at the dose of about 18 mg / kg of the subj ect’ s body weight at a frequency of once every two weeks; and b. a chemotherapy; wherein the bi-specific antibody comprises a Claudin 18.2 binding domain and a 4-1BB binding domain, wherein the Claudin 18.2 binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising an amino acid sequence of SEQ ID NO: 4, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 5, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 6, wherein the 4- IBB binding domain comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 9, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 10, an HCDR3 comprising an amino acid sequence of SEQ ID NO: 11, an light chain CDR1 (LCDR1) comprising an amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 13, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 14, wherein the chemotherapy comprises a combination of oxaliplatin and capecitabine.

81. The method of any one of claims 78-80, wherein capecitabine is administered orally twice daily at a dose of about 1000 mg / m2.

82. The method of claim 78 or 81, wherein the 5-FU is administered intravenously at a dose between about 200 mg / m2to about 800 mg / m2once every two weeks.

83. The method of claim 78, 81, or 82, wherein the leucovorin is administered intravenously at a dose between about 100 mg / m2to about 300 mg / m2once every two weeks.

84. The method of any one of claims 78-83, wherein the oxaliplatin is administered intravenously at a dose between about 50 mg / m2to about 200 mg / m2once every two weeks.

85. The method of any one of claims 78-84, wherein oxaliplatin is administered intravenously at a dose of about 130 mg / m2once every three weeks.

86. The method of any one of claims 78, 79, and 81-85, wherein the nivolumab is administered intravenously at a dose of about 240 mg once every three weeks.Attorney Docket No. IMAB-002 / 02WO 328834-219187. The method of any one of claims 78-86, wherein the treatment results in partial response or stable disease.

88. The method of any one of claims 78-87, wherein the cancer is a solid tumor, and wherein the treatment results in decreased size of the solid tumor.

89. The method of claim 88, wherein the size of the solid tumor is decreased by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, or at least about 80%, compared to the size of the solid tumor prior to the treatment.

90. The method of any one of claims 78-89, wherein the treatment results in an objective response rate of at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90%.

91. The method of any one of claims 78-90, wherein the treatment results in an objective response rate of about 71%.

92. The method of any one of claims 78-91, wherein the treatment results in an objective response rate of about 83%.

93. The method of any one of claims 1-92, wherein the cancer is HER2-negative.

94. The method of any one of claims 1-93, wherein the cancer is unresectable.

95. The method of any one of claims 1-94, wherein the cancer is metastatic.

96. The method of any one of claims 78-95, wherein the cancer is Claudin 18.2 positive.

97. The method of any one of claims 78-96, wherein the cancer is gastric adenocarcinoma (GC), gastro-esophageal junction adenocarcinoma (GEJ), esophageal adenocarcinoma (EAC), pancreatic ductal adenocarcinoma (PDAC), or cholangiocarcinoma.

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