WO2024039670A1

WO2024039670A1 - Antibodies against cldn4 and methods of use thereof

Info

Publication number: WO2024039670A1
Application number: PCT/US2023/030265
Authority: WO
Inventors: Wayne A. Marasco; Matthew Chang
Original assignee: Dana-Farber Cancer Institute, Inc.
Priority date: 2022-08-15
Filing date: 2023-08-15
Publication date: 2024-02-22

Abstract

The present invention comprises human antibodies that bind to Claudin 4 domains (CLDN4) protein. The antibodies can be used to treat cancer.

Description

Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 ANTIBODIES AGAINST CLDN4 AND METHODS OF USE THEREOF [0001] This application is an International Application which claims priority from U.S. provisional patent application no.63/398,075, filed on August 15, 2022, the entire contents of which are incorporated herein by reference. [0002] All patents, patent applications and publications cited herein are hereby incorporated by reference in their entirety. The disclosures of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein. [0003] This patent disclosure contains material that is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction by anyone of the patent document or the patent disclosure as it appears in the U.S. Patent and Trademark Office patent file or records, but otherwise reserves any and all copyright rights. SEQUENCE LISTING [0004] The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on [ ], is named [ ] and is [ ] bytes in size. FIELD OF THE INVENTION [0005] This invention comprises antibodies against Claudin 4 (CLDN4) and methods of use thereof. BACKGROUND [0006] Claudins are tetraspan transmembrane proteins of tight junctions. The claudin 4 protein is encoded by the CLDN4 gene. SUMMARY OF THE INVENTION [0007] Aspects of the invention are drawn towards an isolated monoclonal antibody or antigen-binding fragment thereof that binds to a claudin 4 (CLDN4) protein or fragment thereof, comprising a heavy chain, light chain, or both a heavy chain and a light chain. [0008] In embodiments, the heavy chain comprises a CDR1 comprising GFTFNNYA (SEQ ID NO: 9), GFTFGGYA (SEQ ID NO: 12), GGTFSSYA (SEQ ID NO: 15), or Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 GGTFNNYA (SEQ ID NO: 18), CDR2 comprising IRDSGGST (SEQ ID NO: 10), LSNSGSNA (SEQ ID NO: 13), or IIPIVDIA (SEQ ID NO: 16), CDR3 comprising ARRGYSSSWYGDGYYYGMDV, (SEQ ID NO: 11), ARAVMSSSWYMRRYYYYYMDV (SEQ ID NO: 14), or ARGGSQGAYYMDV (SEQ ID NO: 17), or a combination of CDRs thereof; and wherein the light chain comprises a CDR1 comprising SGSIASSF (SEQ ID NO: 19), RSNIGSNT (SEQ ID NO: 22), SGSIASNY (SEQ ID NO: 25), or QSVSNY (SEQ ID NO: 28), CDR2 comprising ENN (SEQ ID NO: 20), SNN (SEQ ID NO: 23), EDN (SEQ ID NO: 26), or GAS (SEQ ID NO: 29), CDR3 comprising QSYDSTSHV (SEQ ID NO: 21), AAWDDSLNGLYV (SEQ ID NO: 24), QSYDDSNRVV (SEQ ID NO: 27), or HQYGSLPQT (SEQ ID NO: 30), or a combination of CDRs thereof. In embodiments, the antibody sequences have been determined according to IMGT numbering scheme. [0009] In embodiments, the claudin 4 protein is a human claudin 4 protein. [0010] In embodiments, the antibody is fully human or humanized. [0011] In embodiments, the antibody is monospecific, bispecific, or multispecific. [0012] In embodiments, the antibody is an IgG. For example, the antibody is an IgG1, IgG2, IgG3 or IgG4 antibody. [0013] In embodiments, the antibody is a single chain antibody. [0014] In embodiments, the antibody has a binding affinity of at least 1.0 x10^-9 M. [0015] In embodiments, the antibody or fragment comprises a heavy chain constant region, a light chain constant region, an Fc region, and Fc variant, or a combination thereof. [0016] In embodiments, the antibody comprises Gly1-2-F4, Gly1-4-G3, Gly1-1-H9, or Gly1-1-B2. [0017] In embodiments, the antibody competes with binding of Gly1-2-F4, Gly1-4-G3, Gly1-1-H9, or Gly1-1-B2. [0018] In embodiments, the antibody or fragment is linked to a therapeutic agent. [0019] In embodiments, the antibody is a single chain fragment. [0020] Aspects of the invention are also drawn towards an isolated antibody or fragment thereof that binds to a human claudin 4 protein. [0021] In embodiments, the antibody comprises: (a) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 9, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 10, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 11, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 19, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 20, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 21; or (b) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 12, Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 13, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 14, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 22, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 23, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 24; or (c) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 15, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 16, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 17, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 25, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 27; or (d) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 18, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 16, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 17, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 28, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 29, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 30. In embodiments, the antibody sequences have been determined according to IMGT numbering scheme. [0022] Aspects of the invention are also drawn towards an isolated scFv antibody that binds to a human claudin 4 protein comprising: (a) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 9, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 10, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 11, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 19, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 20, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 21; or (b) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 12, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 13, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 14, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 22, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 23, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 24; or (c) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 15, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 16, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 17, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 25, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 27; or (d) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 18, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 16, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 17, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 28, a VL CDR2 Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 comprising the amino acid sequence of SEQ ID NO: 29, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 30. In embodiments, the antibody sequences have been determined according to IMGT numbering scheme. [0023] Aspects of the invention are drawn to an isolated antibody or fragment thereof that binds to a human claudin 4 protein comprising a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 1, 3, 5, and 7, or a sequence at least 90% identical thereto. [0024] Aspects of the invention are drawn to an isolated antibody or fragment thereof that binds to a human claudin 4 protein comprising a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 2, 4, 6, and 8, or a sequence at least 90% identical thereto. [0025] Aspects of the invention are drawn to an isolated antibody or fragment thereof that binds to a human claudin 4 protein comprises a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 1, 3, 5, and 7, or a sequence at least 90% identical thereto, and a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 2, 4, 6, and 8, or a sequence at least 90% identical thereto. [0026] Aspects of the invention are drawn to an isolated scFv that binds to a human claudin 4 protein comprising a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 1, 3, 5, and 7, or a sequence at least 90% identical thereto. [0027] Aspects of the invention are drawn to an isolated scFv that binds to a human claudin 4 protein comprising a light chain variable region comprising a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 2, 4, 6, and 8, or a sequence at least 90% identical thereto. [0028] Aspects of the invention are drawn to an isolated scFv that binds to a human claudin 4 protein comprising a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 1, 3, 5, and 7, or a sequence at least 90% identical thereto, and a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 2, 4, 6, and 8, or a sequence at least 90% identical thereto. [0029] Embodiments of the invention comprise an isolated monoclonal antibody or antigen-binding fragment thereof that binds to a human claudin 4 protein, comprising a heavy chain, a light chain, or a combination thereof, wherein the heavy chain comprises an amino Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 acid sequence about 95% identical to SEQ ID NO: 1, and the light chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 2. [0030] Embodiments of the invention comprise an isolated scFv that binds to a human claudin 4 protein, comprising a heavy chain, a light chain, or a combination thereof, wherein the heavy chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 1, and the light chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 2. [0031] Embodiments of the invention comprise an isolated monoclonal antibody or antigen-binding fragment thereof that binds to a human claudin 4 protein, comprising a heavy chain, a light chain, or a combination thereof, wherein the heavy chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 3, and the light chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 4. [0032] Embodiments of the invention comprise an isolated scFv antibody that binds to a human claudin 4 protein, comprising a heavy chain, a light chain, or a combination thereof, wherein the heavy chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 3, and the light chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 4. [0033] Embodiments of the invention comprise an isolated monoclonal antibody or antigen-binding fragment thereof that binds to a human claudin 4 protein, comprising a heavy chain, a light chain, or a combination thereof, wherein the heavy chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 5, and the light chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 6. [0034] Embodiments of the invention comprise an isolated scFv that binds to a human claudin 4 protein, comprising a heavy chain, a light chain, or a combination thereof, wherein the heavy chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 5, and the light chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 6. [0035] Embodiments of the invention comprise an isolated monoclonal antibody or antigen-binding fragment thereof that binds to a human claudin 4 protein, comprising a heavy chain, a light chain, or a combination thereof, wherein the heavy chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 7, and the light chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 8. [0036] Embodiments of the invention comprise an isolated scFv that binds to a human claudin 4 protein, comprising a heavy chain, a light chain, or a combination thereof, wherein the heavy chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 7, and the light chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 8. Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 [0037] Aspects of the invention are drawn towards an isolated bispecific antibody, comprising an antibody fragment as described herein and a second antigen-binding fragment having specificity to a molecule on an immune cell. In embodiments, the molecule is selected from the group consisting of CCR4, CXCR4, B7H3, B7H4, CD27, CD28, CD40, CD40L, CD47, CD122, CTLA-4, GITR, GITRL, ICOS, ICOSL, LAG-3, LIGHT, OX-40, OX40L, PD-1, TIM3, 4-1BB, TIGIT, VISTA, HEVM, BTLA, and KIR. [0038] In embodiments, the fragment and the second fragment each is independently selected from a Fab fragment, a single-chain variable fragment (scFv), or a single-domain antibody. [0039] Aspects of the invention are further drawn towards a bispecific T cell engager (BiTE) that binds to a human claudin 4 protein. In embodiments, the BiTE comprises: (a) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 9, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 10, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 11, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 19, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 20, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 21; or (b) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 12, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 13, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 14, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 22, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 23, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 24; or (c) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 15, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 16, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 17, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 25, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 27; or (d) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 18, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 16, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 17, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 28, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 29, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 30. In embodiments, the antibody sequences have been determined according to IMGT numbering scheme. [0040] Aspects of the invention further comprise a bispecific T cell engager (BiTE) that binds to a human claudin 4 protein comprising a heavy chain variable region comprising an Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 amino acid sequence selected from the group consisting of SEQ ID NOS: 1, 3, 5, and 7, or a sequence at least 90% identical thereto. [0041] Aspects of the invention further comprise a bispecific T cell engager (BiTE) that binds to a human claudin 4 protein comprising a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 2, 4, 6, and 8, or a sequence at least 90% identical thereto. [0042] Aspects of the invention further comprise a bispecific T cell engager (BiTE) that binds to a human claudin 4 protein comprising a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 1, 3, 5, and 7, or a sequence at least 90% identical thereto, and a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 2, 4, 6, and 8, or a sequence at least 90% identical thereto. [0043] Embodiments as described herein can further comprise an Fc fragment. [0044] Aspects of the invention are further drawn to a nucleic acid encoding the antibody or fragment as described herein. [0045] Still further, aspects of the invention are drawn to a pharmaceutical composition comprising the antibody or fragment thereof as described herein, and a pharmaceutically acceptable carrier or excipient. [0046] In embodiments, the pharmaceutical composition can further comprise at least one additional therapeutic agent. For example, the therapeutic agent can be a toxin, a radiolabel, a siRNA, a small molecule, or a cytokine. [0047] Aspects of the invention are drawn to an isolated cell comprising one or more polynucleotide(s) encoding an antibody or fragment as described herein. [0048] Also, aspects of the invention are drawn to a vector comprising a nucleic acid as described herein. [0049] Still further, aspects of the invention are drawn to a cell comprising a vector as described herein. [0050] Aspects of the invention are drawn to an engineered cell comprising a chimeric antigen receptor. In embodiments, the chimeric antigen receptor comprises an extracellular ligand binding domain that is specific for an antigen on the surface of a cancer cell, wherein the antigen comprises claudin 4, wherein the extracellular ligand binding domain comprises an antibody or fragment thereof, where the antibody or fragment thereof comprises: (a) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 9, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 10, a VH CDR3 comprising the amino acid Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 sequence of SEQ ID NO: 11, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 19, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 20, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 21; or (b) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 12, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 13, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 14, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 22, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 23, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 24; or (c) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 15, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 16, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 17, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 25, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 27; or (d) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 18, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 16, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 17, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 28, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 29, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 30. In embodiments, the antibody sequences have been determined according to IMGT numbering scheme. [0051] In embodiments, the antibody or fragment thereof comprises a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 1, 3, 5, and 7, or a sequence at least 90% identical thereto. [0052] In embodiments, the antibody or fragment thereof comprises a light chain variable region comprising a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 2, 4, 6, and 8, or a sequence at least 90% identical thereto. [0053] In embodiments, the antibody or fragment thereof comprises a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 1, 3, 5, and 7, or a sequence at least 90% identical thereto, and a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 2, 4, 6, and 8, or a sequence at least 90% identical thereto. [0054] In embodiments, the cell comprises a T cell, an NK cell, an NKT cell, an iPS cell, an iPS derived cell, a cell line, or a B cell. For example, the cell comprises a CD4+, CD8+, CD3+ pan T cells, or any combination thereof. Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 [0055] Aspects of the invention are further drawn towards a kit. In embodiments, the kit comprises the at least one pharmaceutical composition of claim 36 or 39; a syringe, needle, or applicator for administration of the at least one antibody to a subject; and instructions for use. [0056] Further, aspects of the invention are drawn towards a method of detecting the presence of claudin 4 in a sample. In embodiments, the method comprises contacting the sample with the isolated monoclonal antibody or fragment thereof as described herein, and detecting the presence or absence of an antibody-antigen complex, thereby detecting the presence of claudin 4 in the sample. In embodiments, contacting comprises immunohistochemistry. For example, immunohistochemistry comprises precipitation, immunofluorescence, western blot, or ELISA. In embodiments, the sample is whole blood, a blood component, a body fluid, a biopsy, a tissue, serum, or one or more cells. [0057] In embodiments, the sample comprises a normal sample or a cancerous sample. For example, the cancer expresses claudin 4. For example, the cancer comprises biliary, breast, cervical, colorectal, esophageal, intestinal, lung, pancreatic, prostate, renal, rectal, stomach, thyroid, or uterine. [0058] In embodiments, the one or more cells comprise an in vitro culture. [0059] In embodiments, the one or more cells comprise claudin 4-expressing cells. [0060] In embodiments, the sample is an in vitro sample. [0061] Embodiments can further comprise the step of obtaining a sample from a subject. [0062] Aspects of the invention are further drawn towards a method for treating cancer in a subject by administering the pharmaceutical composition as described herein to the subject. For example, the cancer expresses claudin 4. For example, the cancer comprises biliary, breast, cervical, colorectal, esophageal, intestinal, lung, pancreatic, prostate, renal, rectal, stomach, thyroid, or uterine. In embodiments, the antibody or fragment as described herein binds to claudin 3 with a binding affinity at least 5-, 10-, 25-, 50-, 100-, or 1000-fold less than the antibody, fragment or bispecific antibody binds to claudin 4. [0063] Other objects and advantages of this invention are readily apparent from the ensuing description. BRIEF DESCRIPTION OF THE FIGURES [0064] FIG. 1 shows non-limiting, exemplary data validating cytopathic effect flow cytometry. [0065] FIG.2 shows a non-limiting, exemplary schematic of panning against claudin-4. Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 [0066] FIG.3 shows a chart of non-limiting, exemplary data of claudin-4 targeting scFv(s) by phage panning using solubilized claudin-4 expressed in insect cells. [0067] FIG. 4 shows a graph of non-limiting, exemplary data of EK01 (see, WO 2019/178359) phage binding specifically soluble claudin-4. [0068] FIG.5 shows a graph of non-limiting, exemplary data of F4 biding claudin-4. [0069] FIG.6 shows histograms of non-limiting, exemplary flow cytometry data. [0070] FIG.7 shows a non-limiting, exemplary Western blot from protein purification. [0071] FIG. 8 shows non-limiting, exemplary data of EK01 (see, WO 2019/178356) minibody binding data. [0072] FIG.9 shows a non-limiting, exemplary schematic of paramagnetic proteoliposomes (PMPL) panning. In embodiments, three rounds panning were performed on soluble claudin-4 and screened with claudin-4. After confirmation ELISAs and dilution series on soluble claudin- 4 one hit was initially identified. Panning initially failed on PMPLs. New PMPLs were then made. [0073] FIG.10 shows non-limiting, exemplary data of PMPL production. [0074] FIG.11 shows non-limiting, exemplary schematic of panning. [0075] FIG. 12 shows non-limiting, exemplary results 6 plates from re-rescue of the panning in Fig.11. [0076] FIG. 13 shows non-limiting, exemplary results of clones and frequencies from rounds 1 and 2 of panning in Fig.11. [0077] FIG. 14 shows non-limiting, exemplary data of next-generation sequencing (NGS) of round 1 and round 2 from Fig.11. [0078] FIG.15 shows non-limiting, exemplary data of phage binding solubilized claudin-4 ELISA. [0079] FIG.16 shows non-limiting, exemplary data of phage binding in Claudin-4 positive cells and cells that are not transfected. [0080] FIG. 17 shows non-limiting, exemplary data on phage binding on cells that are not transduced. [0081] FIG.18 shows a non-limiting, exemplary ELISA data. [0082] FIG.19 shows non-limiting, exemplary minibody binding data. [0083] FIG.20 shows non-limiting, exemplary minibody binding data. [0084] FIG. 21 shows non-limiting, exemplary schematic of claudin-4 whole cell panning path. [0085] FIG.22 shows non-limiting, exemplary purified phage binding curves (CLDN-4). Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 [0086] FIG. 23 shows non-limiting, exemplary CLDN-4 minibody binding of MB231 CLDN-4. In this example, KM is an anti-CLDN4 antibody synthesized from US 8,076,458 and cloned into our scFv-Fc vector as a control. Miltenyi and R&D were purchased and used as is. [0087] FIG. 24 shows a non-limiting, exemplary schematic of CLDN protein structure. In embodiments, structure and expression of CLDN-3 and CLDN-4 can be similar. In embodiments, expression levels can also be similar in cancer tissues. [0088] FIG.25 shows a non-limiting, exemplary schematic of Human CLDN-3 and CLDN- 4 extracellular domains. In some embodiments, homology in extracellular domains can be used to discover CLDN-4 specific antibodies. Homology: ECL198%, ECL279%, Both 93%. [0089] FIG.26 shows examples of commercial antibody stabilities. [0090] FIG.27 shows non-limiting, exemplary quantitation data of cell line staining. [0091] FIG. 28 shows non-limiting, exemplary data of CLDN-3 binding of aCLDN-4 minibodies. [0092] FIG. 29 shows non-limiting, exemplary data of specificity of claudin antibodies. Similar results were seen with 0.1 mg/ml. [0093] FIG.30 shows non-limiting, exemplary data of staining of MB231 with aCXCR4 to KO. [0094] FIG. 31 shows a non-limiting, exemplary graph of CD8+ anti-CLDN-4 CART killing for CLDN-4 expressing MB231 cells. Positive controls KM3900 and CPE killed tumors non-specifically aC4-G3 and aC4-F4 did recognize and kill CLDN+ tumors specifically (9- fold higher). Negative control background killing is low (<10%). Our anti-CLDN-4 CARTs kill tumor cells expressing high levels of CLDN-4 specifically. [0095] FIG. 32 shows graphs of non-limiting, exemplary data of kinetics of CD8+ anti- CLDN-4 CART killing at E:T ratio of 2:1. DETAILED DESCRIPTION [0096] Abbreviations and Definitions [0097] Detailed descriptions of one or more embodiments are provided herein. It is to be understood, however, that the invention can be embodied in various forms. Therefore, specific details disclosed herein are not to be interpreted as limiting, but rather as a basis for the claims and as a representative basis for teaching one skilled in the art to employ the invention in any appropriate manner. Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 [0098] The singular forms “a”, “an” and “the” include plural reference unless the context clearly dictates otherwise. The use of the word “a” or “an” when used in conjunction with the term “comprising” in the claims and/or the specification can mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.” [0099] Wherever any of the phrases “for example,” “such as,” “including” and the like are used herein, the phrase “and without limitation” is understood to follow unless explicitly stated otherwise. Similarly, “an example,” “exemplary” and the like are understood to be nonlimiting. [00100] The term “substantially” allows for deviations from the descriptor that do not negatively impact the intended purpose. Descriptive terms are understood to be modified by the term “substantially” even if the word “substantially” is not explicitly recited. [00101] The terms “comprising” and “including” and “having” and “involving” (and similarly “comprises”, “includes,” “has,” and “involves”) and the like are used interchangeably and have the same meaning. Specifically, each of the terms is defined consistent with the common United States patent law definition of “comprising” and is therefore interpreted to be an open term meaning “at least the following,” and is also interpreted not to exclude additional features, limitations, aspects, etc. Thus, for example, “a process involving steps a, b, and c” means that the process includes at least steps a, b and c. Wherever the terms “a” or “an” are used, “one or more” is understood, unless such interpretation is nonsensical in context. [00102] The term “about” is used herein to mean approximately, roughly, around, or in the region of. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term “about” is used herein to modify a numerical value above and below the stated value by a variance of 20 percent up or down (higher or lower). [00103] Unique recombinant monoclonal claudin 4 (CLDN4) antibodies are described herein. “Recombinant” as it pertains to polypeptides (such as antibodies) or polynucleotides can refer to a form of the polypeptide or polynucleotide that does not exist naturally, a non- limiting example of which can be created by combining polynucleotides or polypeptides that cannot normally occur together. [00104] The amino acid sequence of the monoclonal CLDN4 antibodies are provided herein, in addition to an exemplary wildtype IgG constant region useful in combination with the VH and VL sequences provided herein (see Tables 1-4); the amino acid sequences of the heavy and light chain complementary determining regions CDRs of the CLDN4 antibodies are underlined (CDR1), underlined and bolded (CDR2), or underlined, italicized, and bolded (CDR3) below: Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 Table 1. Gly1-2-F4_PelB-F_2019-12-08_C03 Ab Variable Region amino acid sequences V_H chain of Gly1-2-F4 QVQLVQSGGGLVQPGGSLRLSCAASGFTFNNYAMSWVRQAPGKGLEWVSTIRDSGGSTYYT DSVKGRFTISRDSSKNTLYLQMNSLRADDTAVYYCARRGYSSSWYGDGYYYGMDVWGQGTT PD

V_H chain of Gly1-4-G3 EVQLVESGGGVVQPGRSLRLSCAASGFTFGGYAMHWVRQAPGKGLEWVAELSNSGSNAFYA GT PD

Table 3. Gly1-1-H9_PelB-F_2019-12-08_B03 Ab Variable Region amino acid sequences V_H chain of Gly1-1-H9 YA PD

Table 4. Gly1-1-B2_PelB-F_2019-12-08_A03 Ab Variable Region amino acid sequences YA DR

Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 [00105] The amino acid sequences of the heavy and light chain complementary determining regions of the CLDN4 antibodies are shown in Table 5A-B below: Table 5A. Heavy chain (VH) complementary determining regions (CDRs) of the CLDN4 antibodies Sequence ID V_H CDR1 V_H CDR2 V_H CDR3 GFTFNNYA IRDSGGST V DV Ta

ble 5B. Light chain (VL) complementary determining regions (CDRs) of the CLDN4 antibodies Sequence ID V_L CDR1 V_L CDR2 V_L CDR3

[00106] The amino acid sequences of the heavy and light chain framework regions of the CLDN4 antibodies are shown in Table 6A-B below: Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 Table 6A. Heavy chain (VH) framework regions (FRs) of the CLDN4 antibodies Seq ID VH FR1 VH FR2 VH FR3 VH FR4 Gly1-2- QVQLVQSGGGL MSWVRQAPGK YYTDSVKGRFTI WGQGTTVTVS F4 VQPGGSLRLSC GLEWVST SRDSSKNTLYLQ (SEQ ID NO: AAS (SEQ ID MNSLRADDTAVY 34) S O: S O: S O: Ta

ble 6B. Light chain (VL) framework regions (FRs) of the CLDN4 antibodies Seq ID VL FR1 VL FR2 VL FR3 VL FR4 L O: L O: L O:

Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 Seq ID VL FR1 VL FR2 VL FR3 VL FR4 ETTLTQSPATL TRATGIPDRFSG FGQGTKVEIK SVSPGERATLS LAWYRQKPGQ SGSGTDFTLTIS (SEQ ID NO: CRAS APRLLIY RLEPEDFAVYFC 61) [0 rovided

herein; the nucleic acid sequences of the heavy and light chain complementary determining regions CDRs of the CLDN4 antibodies are underlined (CDR1), underlined and bolded (CDR2), or underlined, italicized, and bolded (CDR3) below: [00108] Table 7A. Heavy chain (VH) complementary determining regions (CDRs) of the CLDN4 antibodies Seq ID VH CDR1 VH CDR2 VH CDR3 GGATTCACCTTTAA ATTCGTGATAGTGGT GCGAGGCGCGGGTATAG TG GT AG GA AC CA GG CA GG

[00109] Table 7B. Heavy chain (VH) complementary determining regions (CDRs) of the CLDN4 antibodies S ID VLCDR1 VLCDR2 VLCDR3 AC AG TG

Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 Seq ID VL CDR1 VL CDR2 VL CDR3 (SEQ ID NO: (SEQ ID NO: 79) 77) AGTGGCAGCATTGC GAGGATAAC CAGTCTTATGATGACAG TT [0 S

eq ID V‐D‐J‐REGION Gly1-2-F4 CAGGTGCAGCTGGTGCAGTCTGGGGGAGGCTTGGTACAGCCTGGGGG (SEQIDNO:86) GTCCCTGAGACTCTCCTGTGCCGCCTCTGGATTCACCTTTAACAACT GG TC GT AT TA CT AG ( CT GG TC GA AT TA CG TC ( CT GG AA AG AT TG TC ( CT GG AG AG AT TG

Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 [00111] Table 8B. V-J-Region of the CLDN4 antibodies Seq ID V‐J‐REGION Gly1-2-F4 AATTTTATGCTGACGCAGCCCCACTCTGTGTCGGAGTCTCCGGGGGA (SEQ ID NO: 90) GACGGTAACCATCTCCTGCGCCCGCAGCAGTGGCAGCATTGCCAGCA GCTTTGTGCAGTGGTACCAGCAGCGCCCGGGCGCTTCCCCCACCACT TT CT AT CT CA ( TA TC TT GC AC GT AA ( CA CT TT CT AT GT GG ( CT TC AG GG TA

[00112] The CLDN4 antibodies described herein bind to CLDN4. In one embodiment, the CLDN4 antibodies have high affinity and high specificity for CLDN4. Some embodiments also feature antibodies that have a specified percentage identity or similarity to the amino acid or nucleotide sequences of the anti-CLDN4 antibodies described herein. For example, “homology” or “identity” or “similarity” refers to sequence similarity between two peptides or between two nucleic acid molecules. Homology can be determined by comparing a position in each sequence, which can be aligned for purposes of comparison. When a position in the compared sequence is occupied by the same base or amino acid, then the molecules are homologous at that position. A degree of homology between sequences is a function of the number of matching or homologous positions shared by the sequences. For example, the Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 antibodies can have 60%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher amino acid sequence identity when compared to a specified region or the full length of any one of the anti-CLDN4 antibodies described herein. For example, the antibodies can have 60%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher nucleic acid identity when compared to a specified region or the full length of any one of the anti-CLDN4 antibodies described herein. Sequence identity or similarity to the nucleic acids and proteins of the invention can be determined by sequence comparison and/or alignment by methods known in the art, for example, using software programs known in the art, such as those described in Ausubel et al. eds. (2007) Current Protocols in Molecular Biology. For example, sequence comparison algorithms (i.e., BLAST or BLAST 2.0), manual alignment or visual inspection can be utilized to determine percent sequence identity or similarity for the nucleic acids and proteins of the invention. [00113] “Polypeptide” as used herein can encompass a singular “polypeptide” as well as plural “polypeptides,” and can refer to a molecule composed of monomers (amino acids) linearly linked by amide bonds (also known as peptide bonds). The term “polypeptide” can refer to any chain or chains of two or more amino acids and does not refer to a specific length of the product. Thus, peptides, dipeptides, tripeptides, oligopeptides, “protein,” “amino acid chain,” or any other term can be used to refer to a chain or chains of two or more amino acids, can refer to “polypeptide” herein, and the term “polypeptide” can be used instead of, or interchangeably with any of these terms. “Polypeptide” can also refer to the products of post- expression modifications of the polypeptide, including without limitation glycosylation, acetylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, or modification by non-naturally occurring amino acids. A polypeptide can be derived from a natural biological source or produced by recombinant technology but is not necessarily translated from a nucleic acid sequence. It can be generated in any manner, including by chemical synthesis. As to amino acid sequences, one of skill in the art will readily recognize that individual substitutions, deletions or additions to a nucleic acid, peptide, polypeptide, or protein sequence which alters, adds, deletes, or substitutes a single amino acid or a small percentage of amino acids in the encoded sequence is collectively referred to herein as a "conservatively modified variant". In some embodiments the alteration results in the substitution of an amino acid with a chemically similar amino acid. Conservative substitution tables providing functionally similar amino acids are well known in the art. Such conservatively modified variants of the anti-CLDN4 antibodies disclosed herein can exhibit increased cross-reactivity to CLDN4 in comparison to an unmodified CLDN4 antibody. Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 [00114] For example, a “conservative amino acid substitution” is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art, including 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). Thus, a nonessential amino acid residue in an immunoglobulin polypeptide is replaced with another amino acid residue from the same side chain family. In another embodiment, a string of amino acids can be replaced with a structurally similar string that differs in order and/or composition of side chain family members. [00115] Antibodies [00116] As used herein, an “antibody” or “antigen-binding polypeptide” can refer to a polypeptide or a polypeptide complex that specifically recognizes and binds to an antigen. An antibody can be a whole antibody and any antigen binding fragment or a single chain thereof. For example, “antibody” can include any protein or peptide containing molecule that comprises at least a portion of an immunoglobulin molecule having biological activity of binding to the antigen. Non-limiting examples a complementarity determining region (CDR) of a heavy or light chain or a ligand binding portion thereof, a heavy chain or light chain variable region, a heavy chain or light chain constant region, a framework (FR) region, or any portion thereof, or at least one portion of a binding protein. As used herein, the term "antibody" can refer to an immunoglobulin molecule and immunologically active portions of an immunoglobulin (Ig) molecule, i.e., a molecule that contains an antigen binding site that specifically binds (immunoreacts with) an antigen. By "specifically binds" or "immunoreacts with" is meant that the antibody reacts with one or more antigenic determinants of the antigen and does not react with other polypeptides. [00117] The terms “antibody fragment” or “antigen-binding fragment”, as used herein, is a portion of an antibody such as F_(ab′)2, F_(ab)2, F_ab′, F_ab, Fv, scFv and the like. Regardless of structure, an antibody fragment binds with the same antigen that is recognized by the intact antibody. The term “antibody fragment” can include aptamers (such as spiegelmers), minibodies, and diabodies. The term “antibody fragment” can also include any synthetic or genetically engineered protein that acts like an antibody by binding to a specific antigen to form a complex. Antibodies, antigen-binding polypeptides, variants, or derivatives described Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 herein include, but are not limited to, polyclonal, monoclonal, multispecific, human, humanized or chimeric antibodies, single chain antibodies, epitope-binding fragments, e.g., Fab, Fab′ and F(ab′)2, Fd, Fvs, single-chain Fvs (scFv), single-chain antibodies, dAb (domain antibody), minibodies, disulfide-linked Fvs (sdFv), fragments comprising a VL or VH domain, fragments produced by a Fab expression library, and anti-idiotypic (anti-Id) antibodies. [00118] A “single-chain variable fragment” or “scFv” refers to a fusion protein of the variable regions of the heavy (VH) and light chains (VL) of immunoglobulins. A single chain Fv ("scFv") polypeptide molecule is a covalently linked VH:VL heterodimer, which can be expressed from a gene fusion including VH- and VL-encoding genes linked by a peptide- encoding linker. (See Huston et al. (1988) Proc Nat Acad Sci USA 85(16):5879-5883). In some aspects the regions are connected with a short linker peptide of ten to about 25 amino acids. The linker can be rich in glycine for flexibility, as well as serine or threonine for solubility, and can connect the N-terminus of the VH with the C-terminus of the VL, or vice versa. This protein retains the specificity of the original immunoglobulin, despite removal of the constant regions and the introduction of the linker. A number of methods have been described to discern chemical structures for converting the naturally aggregated, but chemically separated, light and heavy polypeptide chains from an antibody V region into an scFv molecule, which will fold into a three-dimensional structure substantially similar to the structure of an antigen-binding site. See, e.g., U.S. Patent No. 5,091,513; No. 5,892,019; No. 5,132,405; and No.4,946,778, each of which are incorporated by reference in their entireties. [00119] Very large naive human scFv libraries have been and can be created to offer a large source of rearranged antibody genes against a plethora of target molecules. Smaller libraries can be constructed from individuals with infectious diseases to isolate disease-specific antibodies. (See Barbas et al., Proc. Natl. Acad. Sci. USA 89:9339-43 (1992); Zebedee et al, Proc. Natl. Acad. Sci. USA 89:3175-79 (1992)). [00120] Antibody molecules obtained from humans fall into five classes of immunoglobulins: IgG, IgM, IgA, IgE and IgD, which differ from one another by the nature of the heavy chain present in the molecule. Those skilled in the art will appreciate that heavy chains are classified as gamma, mu, alpha, delta, or epsilon (γ, μ, α, δ, ε) with some subclasses among them (e.g., γ1-γ4). Certain classes have subclasses as well, such as IgG1, IgG2, IgG3 and IgG₄ and others. The immunoglobulin subclasses (isotypes) e.g., IgG₁, IgG₂, IgG₃, IgG₄, IgG₅, etc. are well characterized and are known to confer functional specialization. With regard to IgG, a standard immunoglobulin molecule comprises two identical light chain polypeptides of molecular weight approximately 23,000 Daltons, and two identical heavy chain polypeptides Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 of molecular weight 53,000-70,000. The four chains are joined by disulfide bonds in a “Y” configuration wherein the light chains bracket the heavy chains starting at the mouth of the “Y” and continuing through the variable region. Immunoglobulin or antibody molecules described herein can be of any type (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or subclass of an immunoglobulin molecule. [00121] Light chains are classified as kappa or lambda (κ, λ). Each heavy chain class can be bound with a kappa or lambda light chain. In general, the light and heavy chains are covalently bonded to each other, and the “tail” portions of the two heavy chains are bonded to each other by covalent disulfide linkages or non-covalent linkages when the immunoglobulins are generated by hybridomas, B cells, or genetically engineered host cells. In the heavy chain, the amino acid sequences run from an N-terminus at the forked ends of the Y configuration to the C-terminus at the bottom of each chain. [00122] Both the light and heavy chains are divided into regions of structural and functional homology. The terms “constant” and “variable” are used functionally. The variable domains of both the light (VL) and heavy (VH) chain portions determine antigen recognition and specificity. Conversely, the constant domains of the light chain (CL) and the heavy chain (CH1, CH2 or CH3) confer important biological properties such as secretion, transplacental mobility, Fc receptor binding, complement binding, and the like. The term "antigen-binding site," or "binding portion" can refer to the part of the immunoglobulin molecule that participates in antigen binding. The antigen binding site is formed by amino acid residues of the N-terminal variable ("V") regions of the heavy ("H") and light ("L") chains. Three highly divergent stretches within the V regions of the heavy and light chains, referred to as "hypervariable regions," are interposed between more conserved flanking stretches known as "framework regions," or "FRs". Thus, the term "FR" can refer to amino acid sequences which are naturally found between, and adjacent to, hypervariable regions in immunoglobulins. In an antibody molecule, the three hypervariable regions of a light chain and the three hypervariable regions of a heavy chain are disposed relative to each other in three-dimensional space to form an antigen-binding surface. The antigen-binding surface is complementary to the three- dimensional surface of a bound antigen, and the three hypervariable regions of each of the heavy and light chains are referred to as "complementarity-determining regions," or "CDRs." VH and VL regions, which contain the CDRs, as well as frameworks (FRs) of the CLDN4 antibodies are shown in Table 1-Table 4. [00123] The six CDRs present in each antigen-binding domain are short, non-contiguous sequences of amino acids that are specifically positioned to form the antigen-binding domain Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 as the antibody assumes its three-dimensional configuration in an aqueous environment. The remainder of the amino acids in the antigen-binding domains, the FR regions, show less inter- molecular variability. The framework regions largely adopt a β-sheet conformation and the CDRs form loops which connect, and in some cases form part of, the β-sheet structure. The framework regions act to form a scaffold that provides for positioning the CDRs in correct orientation by inter-chain, non-covalent interactions. The antigen-binding domain formed by the positioned CDRs provides a surface complementary to the epitope on the immunoreactive antigen, which promotes the non-covalent binding of the antibody to its cognate epitope. The amino acids comprising the CDRs and the framework regions, respectively, can be readily identified for a heavy or light chain variable region by one of ordinary skill in the art, since they have been previously defined (See, “Sequences of Proteins of Immunological Interest,” Kabat, E., et al., U.S. Department of Health and Human Services, (1983); and Chothia and Lesk, J. Mol. Biol., 196:901-917 (1987)). [00124] Where there are two or more definitions of a term which is used and/or accepted within the art, the definition of the term as used herein is intended to include such meanings unless explicitly stated to the contrary. A specific example is the use of the term “complementarity determining region” (“CDR”) to describe the non-contiguous antigen combining sites found within the variable region of both heavy and light chain polypeptides. This region has been described by Kabat et al., U.S. Dept. of Health and Human Services, “Sequences of Proteins of Immunological Interest” (1983) and by Chothia et al., J. Mol. Biol.196:901-917 (1987), which are incorporated herein by reference in their entireties. The CDR definitions according to Kabat and Chothia include overlapping or subsets of amino acid residues when compared against each other. Nevertheless, application of definition to refer to a CDR of an antibody or variants thereof is intended to be within the scope of the term as defined and used herein. The appropriate amino acid residues which encompass the CDRs as defined by each of the above cited references are set forth in the table below as a comparison. The exact residue numbers which encompass a CDR will vary depending on the sequence and size of the CDR. Those skilled in the art can routinely determine which residues comprise a CDR given the variable region amino acid sequence of the antibody. DR K i h hi i IM T ing

Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 VL CDR1 24-34 26-32 27-38 VL CDR2 50-56 50-52 56-65 VL CDR3 89-97 91-96 105-117 [00125] nces that is applicab

e o any an o y. e s e ar san can unam guous y ass gn s sys em of “Kabat numbering” to any variable domain sequence, without reliance on any experimental data beyond the sequence itself. As used herein, “Kabat numbering” refers to the numbering system set forth by Kabat et al., U.S. Dept. of Health and Human Services, “Sequence of Proteins of Immunological Interest” (1983). [00126] In addition to table above, the Kabat number system describes the CDR regions as follows: CDR-H1 begins at approximately amino acid 31 (i.e., approximately 9 residues after the first cysteine residue), includes approximately 5-7 amino acids, and ends at the next tryptophan residue. CDR-H2 begins at the fifteenth residue after the end of CDR-H1, includes approximately 16-19 amino acids, and ends at the next arginine or lysine residue. CDR-H3 begins at approximately the thirty third amino acid residue after the end of CDR-H2; includes 3-25 amino acids; and ends at the sequence W-G-X-G, where X is any amino acid. CDR-L1 begins at approximately residue 24 (i.e., following a cysteine residue); includes approximately 10-17 residues; and ends at the next tryptophan residue. CDR-L2 begins at approximately the sixteenth residue after the end of CDR-L1 and includes approximately 7 residues. CDR-L3 begins at approximately the thirty third residue after the end of CDR-L2 (i.e., following a cysteine residue); includes approximately 7-11 residues and ends at the sequence F or W-G-X- G, where X is any amino acid. [00127] In certain aspects, the CDRs of an antibody can be determined according to the IMGT numbering system. The IMGT unique numbering has been defined to compare the variable domains whatever the antigen receptor, the chain type, or the species [Lefranc M.-P., Immunology Today 18, 509 (1997)/Lefranc M.-P., The Immunologist, 7, 132-136 (1999)/Lefranc, M.-P., Pommié, C., Ruiz, M., Giudicelli, V., Foulquier, E., Truong, L., Thouvenin-Contet, V. and Lefranc, Dev. Comp. Immunol., 27, 55-77 (2003)]. In the IMGT unique numbering, the conserved amino acids always have the same position, for instance cysteine 23 (1st-CYS), tryptophan 41 (CONSERVED-TRP), hydrophobic amino acid 89, cysteine 104 (2nd-CYS), phenylalanine or tryptophan 118 (J-PHE or J-TRP). The IMGT unique numbering provides a standardized delimitation of the framework regions (FR1-IMGT: positions 1 to 26, FR2-IMGT: 39 to 55, FR3-IMGT: 66 to 104 and FR4-IMGT: 118 to 128) Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 and of the complementarity determining regions: CDR1-IMGT: 27 to 38, CDR2-IMGT: 56 to 65 and CDR3-IMGT: 105 to 117. As gaps represent unoccupied positions, the CDR-IMGT lengths (shown between brackets and separated by dots, e.g. [8.8.13]) become crucial information. The IMGT unique numbering is used in 2D graphical representations, designated as IMGT Colliers de Perles [Ruiz, M. and Lefranc, M.-P., Immunogenetics, 53, 857-883 (2002)/Kaas, Q. and Lefranc, M.-P., Current Bioinformatics, 2, 21-30 (2007)], and in 3D structures in IMGT/3Dstructure-DB [Kaas, Q., Ruiz, M. and Lefranc, M.-P., T cell receptor and MHC structural data. Nucl. Acids. Res., 32, D208-D210 (2004)]. [00128] As used herein, the term "epitope" can include any protein determinant that can specifically bind to an immunoglobulin, a scFv, or a T-cell receptor. The variable region allows the antibody to selectively recognize and specifically bind epitopes on antigens. For example, the VL domain and VH domain, or subset of the complementarity determining regions (CDRs), of an antibody combine to form the variable region that defines a three-dimensional antigen- binding site. This quaternary antibody structure forms the antigen-binding site present at the end of each arm of the Y. Epitopic determinants can consist of chemically active surface groupings of molecules such as amino acids or sugar side chains and have specific three- dimensional structural characteristics, as well as specific charge characteristics. For example, antibodies can be raised against N- terminal or C-terminal peptides of a polypeptide. More specifically, the antigen-binding site is defined by three CDRs on each of the VH and VL chains (i.e. CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3). In one embodiment, the antibodies can be directed to claudin 4 (CLDN4) having UniProtKB ID: O14493 CLD4_HUMAN. (209 amino acid residues in length), comprising the amino acid sequence of: MASMGLQVMGIALAVLGWLAVMLCCALPMWRVTAFIGSNIVTSQTIWEG LWMNCVVQSTGQMQCKVYDSLLALPQDLQAARALVIISIIVAALGVLLS VVGGKCTNCLEDESAKAKTMIVAGVVFLLAGLMVIVPVSWTAHNIIQDF YNPLVASGQKREMGASLYVGWAASGLLLLGGGLLCCNCPPRTDKPYSAK YSAARSAAASNYV (SEQ ID NO: 94) [00129] As used herein, the terms "immunological binding," and "immunological binding properties" can refer to the non-covalent interactions of the type which occur between an immunoglobulin molecule and an antigen for which the immunoglobulin is specific. The strength, or affinity of immunological binding interactions can be expressed in terms of the dissociation constant (K_d) of the interaction, wherein a smaller K_d represents a greater affinity. Immunological binding properties of selected polypeptides can be quantified using methods Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 well known in the art. One such method entails measuring the rates of antigen- binding site/antigen complex formation and dissociation, wherein those rates depend on the concentrations of the complex partners, the affinity of the interaction, and geometric parameters that equally influence the rate in both directions. Thus, both the "on rate constant" (Kon) and the "off rate constant" (Koff) can be determined by calculation of the concentrations and the actual rates of association and dissociation. (See Nature 361: 186-87 (1993)). The ratio of Koff /Kon allows for the cancellation of parameters not related to affinity, and is equal to the equilibrium binding constant, K_D. (See, Davies et al. (1990) Annual Rev Biochem 59:439- 473). An antibody of the invention can specifically bind to a CLDN4 epitope when the equilibrium binding constant (KD) is ≤1 ^M, ≤10 μΜ, ≤ 10 nM, ≤ 10 pM, or ≤ 100 pM to about 1 pM, as measured by kinetic assays such as radioligand binding assays or similar assays known to those skilled in the art, such as BIAcore or Octet (BLI). For example, in some embodiments, the KD is between about 1E-12 M and a KD about 1E-11 M. In some embodiments, the KD is between about 1E-11 M and a K_D about 1E-10 M. In some embodiments, the K_D is between about 1E-10 M and a KD about 1E-9 M. In some embodiments, the KD is between about 1E-9 M and a K_D about 1E-8 M. In some embodiments, the K_D is between about 1E-8 M and a K_D about 1E-7 M. In some embodiments, the KD is between about 1E-7 M and a KD about 1E-6 M. For example, in some embodiments, the K_D is about 1E-12 M while in other embodiments the KD is about 1E-11 M. In some embodiments, the KD is about 1E-10 M while in other embodiments the K_D is about 1E-9 M. In some embodiments, the K_D is about 1E-8 M while in other embodiments the KD is about 1E-7 M. In some embodiments, the KD is about 1E-6 M while in other embodiments the K_D is about 1E-5 M. In some embodiments, for example, the KD is about 3 E-11 M, while in other embodiments the KD is about 3E-12 M. In some embodiments, the K_D is about 6E-11 M. “Specifically binds” or “has specificity to,” can refer to an antibody that binds to an epitope via its antigen-binding domain, and that the binding entails some complementarity between the antigen-binding domain and the epitope. For example, an antibody is said to “specifically bind” to an epitope when it binds to that epitope, via its antigen-binding domain more readily than it can bind to a random, unrelated epitope. [00130] For example, the CLDN4 antibody can be monovalent or bivalent, and/or can comprise a single or double chain. Functionally, the binding affinity of the CLDN4 antibody is within the range of 10⁻⁵M to 10⁻¹² M. For example, the binding affinity of the CLDN4 antibody is from 10⁻⁶ M to 10⁻¹² M, from 10⁻⁷ M to 10⁻¹² M, from 10⁻⁸ M to 10⁻¹² M, from 10⁻⁹ M to 10⁻¹² M, from 10⁻⁵ M to 10⁻¹¹ M, from 10⁻⁶ M to 10⁻¹¹ M, from 10⁻⁷ M to 10⁻¹¹ M, Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 from 10⁻⁸ M to 10⁻¹¹ M, from 10⁻⁹ M to 10⁻¹¹ M, from 10⁻¹⁰ M to 10⁻¹¹ M, from 10⁻⁵ M to 10⁻¹⁰M, from 10⁻⁶ M to 10⁻¹⁰ M, from 10⁻⁷ M to 10⁻¹⁰ M, from 10⁻⁸ M to 10⁻¹⁰M, from 10⁻⁹ M to 10⁻¹⁰ M, from 10⁻⁵ M to 10⁻⁹ M, from 10⁻⁶ M to 10⁻⁹M, from 10⁻⁷ M to 10⁻⁹ M, from 10⁻⁸ M to 10⁻⁹ M, from 10⁻⁵ M to 10⁻⁸ M, from 10⁻⁶ M to 10⁻⁸ M, from 10⁻⁷ M to 10⁻⁸ M, from 10⁻⁵ M to 10⁻⁷ M, from 10⁻⁶ M to 10⁻⁷ M, or from 10⁻⁵ M to 10⁻⁶ M. [00131] A CLDN4 protein, or a derivative, fragment, analog, homolog or ortholog thereof, can be utilized as an immunogen in the generation of antibodies that immunospecifically bind these protein components. A CLDN4 protein or a derivative, fragment, analog, homolog, or ortholog thereof, coupled to a proteoliposome can be utilized as an immunogen in the generation of antibodies that immunospecifically bind these protein components. [00132] Those skilled in the art will recognize that one can determine, without undue experimentation, if a human monoclonal antibody has the same specificity as a human monoclonal antibody of the invention by ascertaining whether the former prevents the latter from binding to CLDN4. For example, if the human monoclonal antibody being tested competes with the human monoclonal antibody of the invention, as shown by a decrease in binding by the human monoclonal antibody of the invention, then the two monoclonal antibodies bind to the same, or to a closely related, epitope. [00133] Another way to determine whether a human monoclonal antibody has the specificity of a human monoclonal antibody of the invention is to pre-incubate the human monoclonal antibody of the invention with the CLDN4 protein, with which it is normally reactive, and then add the human monoclonal antibody being tested to determine if the human monoclonal antibody being tested is inhibited in its ability to bind CLDN4. If the human monoclonal antibody being tested is inhibited, then it can have the same, or functionally equivalent, epitopic specificity as the monoclonal antibody of the invention. Screening of human monoclonal antibodies of the invention can be also carried out by utilizing CLDN4 and determining whether the test monoclonal antibody is able to neutralize CLDN4. [00134] Various procedures known within the art can be used for the production of polyclonal or monoclonal antibodies directed against a protein of the invention, or against derivatives, fragments, analogs homologs or orthologs thereof. (See, for example, Antibodies: A Laboratory Manual, Harlow E, and Lane D, 1988, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, incorporated herein by reference). [00135] Antibodies can be purified by well-known techniques, such as affinity chromatography using protein A or protein G, which provide primarily the IgG fraction of immune serum. Subsequently, or alternatively, the specific antigen, which is the target of the Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 immunoglobulin sought, or an epitope thereof, can be immobilized on a column to purify the immune specific antibody by immunoaffinity chromatography. Purification of immunoglobulins is discussed, for example, by D. Wilkinson (The Scientist, published by The Scientist, Inc., Philadelphia PA, Vol.14, No.8 (April 17, 2000), pp.25-28). [00136] The term “monoclonal antibody” or “mAb” or “Mab” or “monoclonal antibody composition”, as used herein, can refer to a population of antibody molecules that contain only one molecular species of antibody molecule consisting of a unique light chain gene product and a unique heavy chain gene product. The complementarity determining regions (CDRs) of the monoclonal antibody are identical in the molecules of the population. MAbs contain an antigen binding site that can immunoreact with an epitope of the antigen characterized by a unique binding affinity for it. [00137] Monoclonal antibodies can be prepared using hybridoma methods, such as those described by Kohler and Milstein, Nature, 256:495 (1975). In a hybridoma method, a mouse, hamster, or other appropriate host animal, is immunized with an immunizing agent to elicit lymphocytes that produce or can produce antibodies that will specifically bind to the immunizing agent. Alternatively, the lymphocytes can be immunized in vitro. [00138] The immunizing agent can include the protein antigen, a fragment thereof or a fusion protein thereof. For example, peripheral blood lymphocytes can be used if cells of human origin are preferred, or spleen cells or lymph node cells can be used if non-human mammalian sources are preferred. The lymphocytes are then fused with an immortalized cell line using a suitable fusing agent, such as polyethylene glycol, to form a hybridoma cell (See Goding, Monoclonal Antibodies: Principles and Practice, Academic Press, (1986) pp. 59-103). Immortalized cell lines can be transformed mammalian cells, such as myeloma cells of rodent, bovine and human origin. For example, rat or mouse myeloma cell lines are employed. The hybridoma cells can be cultured in a suitable culture medium that contains one or more substances that inhibit the growth or survival of the unfused, immortalized cells. For example, if the parental cells lack the enzyme hypoxanthine guanine phosphoribosyl transferase (HGPRT or HPRT), the culture medium for the hybridomas will include hypoxanthine, aminopterin, and thymidine ("HAT medium"), which substances prevent the growth of HGPRT-deficient cells. [00139] Immortalized cell lines that are useful are those that fuse efficiently, support stable high-level expression of antibody by the selected antibody-producing cells, and are sensitive to a medium such as HAT medium. For example, immortalized cell lines can be murine myeloma lines, which can be obtained, for instance, from the Salk Institute Cell Distribution Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 Center (San Diego, California) and the American Type Culture Collection (Manassas, Virginia). Human myeloma and mouse-human heteromyeloma cell lines also have been described for the production of human monoclonal antibodies. (See Kozbor, J. Immunol, 133:3001 (1984); Brodeur et al, Monoclonal Antibody Production Techniques and Applications, Marcel Dekker, Inc., New York, (1987) pp.51-63)). [00140] The culture medium in which the hybridoma cells are cultured can then be assayed for the presence of monoclonal antibodies directed against the antigen. For example, the binding specificity of monoclonal antibodies produced by the hybridoma cells is determined by immunoprecipitation or by an in vitro binding assay, such as radioimmunoassay (RIA) or enzyme-linked immunoabsorbent assay (ELISA). Such techniques and assays are known in the art. The binding affinity of the monoclonal antibody can, for example, be determined by the Scatchard analysis of Munson and Pollard, Anal. Biochem., 107:220 (1980). Moreover, in therapeutic applications of monoclonal antibodies, it is important to identify antibodies having a high degree of specificity and a high binding affinity for the target antigen. [00141] After the hybridoma cells are identified, the clones can be subcloned by limiting dilution procedures and grown by standard methods. (See Goding, Monoclonal Antibodies: Principles and Practice, Academic Press, (1986) pp. 59-103). Suitable culture media for this purpose include, for example, Dulbecco's Modified Eagle's Medium and RPMI-1640 medium. Alternatively, the hybridoma cells can be grown in vivo as ascites in a mammal. [00142] The monoclonal antibodies secreted by the subclones can be isolated or purified from the culture medium or ascites fluid by conventional immunoglobulin purification procedures such as, for example, protein A-Sepharose, hydroxylapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography. [00143] Monoclonal antibodies can also be made by recombinant DNA methods, such as those described in U.S. Patent No.4,816,567 (incorporated herein by reference in its entirety). DNA encoding the monoclonal antibodies of the invention can be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that can bind specifically to genes encoding the heavy and light chains of murine antibodies). The hybridoma cells of the invention serve as a source of such DNA. Once isolated, the DNA can be placed into expression vectors, which are then transfected into host cells such as simian COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells that do not otherwise produce immunoglobulin protein, to obtain the synthesis of monoclonal antibodies in the recombinant host cells. The DNA also can be modified, for example, by substituting the coding sequence for human heavy and light chain constant domains in place of the homologous murine Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 sequences (See U.S. Patent No. 4,816,567; Morrison, Nature 368, 812-13 (1994)) or by covalently joining to the immunoglobulin coding sequence all or part of the coding sequence for a non-immunoglobulin polypeptide. Such a non-immunoglobulin polypeptide can be substituted for the constant domains of an antibody of the invention, and/or can be substituted for the variable domains of one antigen-combining site of an antibody of the invention to create a chimeric bivalent antibody. [00144] Fully human antibodies, for example, are antibody molecules in which the entire sequence of both the light chain and the heavy chain, including the CDRs, arise from human genes. Such antibodies are termed "human antibodies" or "fully human antibodies". Human monoclonal antibodies, such as fully human and humanized antibodies, can be prepared by using trioma technique; the human B-cell hybridoma technique (see Kozbor, et al, 1983 Immunol Today 4: 72); and the EBV hybridoma technique to produce human monoclonal antibodies (see Cole, et al, 1985 In: MONOCLONAL ANTIBODIES AND CANCER THERAPY, Alan R. Liss, Inc., pp.77-96). Human monoclonal antibodies can be utilized and can be produced by using human hybridomas (see Cote, et al, 1983. Proc Natl Acad Sci USA 80: 2026-2030) or by transforming human B-cells with Epstein Barr Virus in vitro (see Cole, et al., 1985 In: MONOCLONAL ANTIBODIES AND CANCER THERAPY, Alan R. Liss, Inc., pp.77-96). [00145] “Humanized antibodies” can be antibodies from a non-human species (such as mouse), whose amino acid sequences (for example, in the CDR regions) have been modified to increase their similarity to antibody variants produced in humans. Antibodies can be humanized by methods known in the art, such as CDR-grafting. See also, Safdari et al., (2013) Biotechnol Genet Eng Rev.; 29:175-86. In addition, humanized antibodies can be produced in transgenic plants, as an inexpensive production alternative to existing mammalian systems. For example, the transgenic plant can be a tobacco plant, i.e., Nicotiania benthamiana, and Nicotiana tabaccum. The antibodies are purified from the plant leaves. Stable transformation of the plants can be achieved through the use of Agrobacterium tumefaciens or particle bombardment. For example, nucleic acid expression vectors containing at least the heavy and light chain sequences are expressed in bacterial cultures, i.e., A. tumefaciens strain BLA4404, via transformation. Infiltration of the plants can be accomplished via injection. Soluble leaf extracts can be prepared by grinding leaf tissue in a mortar and by centrifugation. Isolation and purification of the antibodies can be performed by many of the methods known to the skilled artisan in the art. Other methods for antibody production in plants are described in, for example, Fischer et al., Vaccine, 2003, 21:820-5; and Ko et al, Current Topics in Microbiology Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 and Immunology, Vol. 332, 2009, pp. 55-78. As such, the invention further provides any cell or plant comprising a vector that encodes the antibody of the invention or produces the antibody of the invention. [00146] Antibodies can be humanized using a variety of techniques known in the art including, for example, CDR-grafting (EP 239,400; PCT publication WO 91/09967; U.S. Pat. Nos.5,225,539; 5,530,101; and 5,585,089), veneering or resurfacing (EP 592,106; EP 519,596; Padlan, Molecular Immunology 28(4/5):489-498 (1991); Studnicka et al., Protein Engineering 7(6):805-814 (1994); Roguska. et al., Proc. Natl. Sci. USA 91:969-973 (1994)), and chain shuffling (U.S. Pat. No.5,565,332, which is incorporated by reference in its entirety). “Humanization” (also called Reshaping or CDR-grafting) is a well-established technique understood by the skilled artisan for reducing the immunogenicity of monoclonal antibodies (mAbs) from xenogeneic sources (such as rodent) and for improving their activation of the human immune system (See, for example, Hou S, Li B, Wang L, Qian W, Zhang D, Hong X, Wang H, Guo Y (July 2008). "Humanization of an anti-CD34 monoclonal antibody by complementarity-determining region grafting based on computer-assisted molecular modeling". J Biochem.144 (1): 115–20). [00147] In addition, antibodies (such as human antibodies) can also be produced using other techniques, including phage display libraries. (See Hoogenboom and Winter, J. Mol. Biol, 227:381 (1991); Marks et al., J. Mol. Biol, 222:581 (1991)). Similarly, human antibodies can be made by introducing human immunoglobulin loci into transgenic animals, e.g., mice in which the endogenous immunoglobulin genes have been partially or completely inactivated. Upon challenge, human antibody production is observed, which closely resembles that seen in humans in all respects, including gene rearrangement, assembly, and antibody repertoire. This approach is described, for example, in U.S. Patent Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; 5,661,016, and in Marks et al., Bio/Technology 10, 779-783 (1992); Lonberg et al., Nature 368856-859 (1994); Morrison, Nature 368, 812-13 (1994); Fishwild et al, Nature Biotechnology 14, 845-51 (1996); Neuberger, Nature Biotechnology 14, 826 (1996); and Lonberg and Huszar, Intern. Rev. Immunol.13: 65-93 (1995). [00148] Human antibodies can additionally be produced using transgenic nonhuman animals which are modified to produce fully human antibodies rather than the animal's endogenous antibodies in response to challenge by an antigen. (See, PCT publication no. WO94/02602 and U.S. Patent No. 6,673,986). The endogenous genes encoding the heavy and light immunoglobulin chains in the nonhuman host have been incapacitated, and active loci encoding human heavy and light chain immunoglobulins are inserted into the host's genome. Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 The human genes are incorporated, for example, using yeast artificial chromosomes containing the requisite human DNA segments. An animal which provides the preferred modifications is then obtained as progeny by crossbreeding intermediate transgenic animals containing fewer than the full complement of the modifications. A non-limiting example of such a nonhuman animal is a mouse and is termed the Xenomouse™ as disclosed in PCT publication nos. WO96/33735 and WO96/34096. This animal produces B cells which secrete fully human immunoglobulins. The antibodies can be obtained directly from the animal after immunization with an immunogen of interest, as, for example, a preparation of a polyclonal antibody, or alternatively from immortalized B cells derived from the animal, such as hybridomas producing monoclonal antibodies. Additionally, the genes encoding the immunoglobulins with human variable regions can be recovered and expressed to obtain the antibodies directly or can be further modified to obtain analogs of antibodies such as, for example, single chain Fv (scFv) molecules. [00149] Thus, using such a technique, therapeutically useful IgG, IgA, IgM and IgE antibodies can be produced. For an overview of this technology for producing human antibodies, see Lonberg and Huszar Int. Rev. Immunol.73:65-93 (1995). For a detailed discussion of this technology for producing human antibodies and human monoclonal antibodies and protocols for producing such antibodies, see, e.g., PCT publication nos. WO 98/24893; WO 96/34096; WO 96/33735; U.S. Pat. Nos. 5,413,923; 5,625,126; 5,633,425; 5,569,825; 5,661,016; 5,545,806; 5,814,318; and 5,939,598, which are incorporated by reference herein in their entirety. In addition, companies such as Creative BioLabs (Shirley, NY) can be engaged to provide human antibodies directed against a selected antigen using technology similar to that described herein. [00150] An example of a method of producing a nonhuman host, exemplified as a mouse, lacking expression of an endogenous immunoglobulin heavy chain is disclosed in U.S. Patent No. 5,939,598. It can be obtained by a method, which includes deleting the J segment genes from at least one endogenous heavy chain locus in an embryonic stem cell to prevent rearrangement of the locus and to prevent formation of a transcript of a rearranged immunoglobulin heavy chain locus, the deletion being effected by a targeting vector containing a gene encoding a selectable marker; and producing from the embryonic stem cell a transgenic mouse whose somatic and germ cells contain the gene encoding the selectable marker. [00151] One method for producing an antibody of interest, such as a human antibody, is disclosed in U.S. Patent No.5,916,771. This method includes introducing an expression vector that contains a nucleotide sequence encoding a heavy chain into one mammalian host cell in Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 culture, introducing an expression vector containing a nucleotide sequence encoding a light chain into another mammalian host cell, and fusing the two cells to form a hybrid cell. The hybrid cell expresses an antibody containing the heavy chain and the light chain. [00152] In a further improvement on this procedure, a method for identifying a clinically relevant epitope on an immunogen and a correlative method for selecting an antibody that binds immunospecifically to the relevant epitope with high affinity, is disclosed in PCT publication No. WO99/53049. [00153] The antibody of interest can also be expressed by a vector containing a DNA segment encoding the single chain antibody described herein. Vectors include, but are not limited to, chemical conjugates such as described in WO 93/64701, which has targeting moiety (e.g. a ligand to a cellular surface receptor), and a nucleic acid binding moiety (e.g. polylysine), viral vectors (e.g. a DNA or RNA viral vector), fusion proteins such as described in PCT/US 95/02140 (WO 95/22618), which is a fusion protein containing a target moiety (e.g. an antibody specific for a target cell) and a nucleic acid binding moiety (e.g. a protamine), plasmids, phage, viral vectors, etc. The vectors can be chromosomal, non-chromosomal or synthetic. Retroviral vectors can also be used and include moloney murine leukemia viruses. DNA viral vectors can also be used, and include pox vectors such as orthopox or avipox vectors, herpesvirus vectors such as a herpes simplex I virus (HSV) vector (See Geller, A. I. et al, J. Neurochem, 64:487 (1995); Lim, F., et al, in DNA Cloning: Mammalian Systems, D. Glover, Ed. (Oxford Univ. Press, Oxford England) (1995); Geller, A. I. et al, Proc Natl. Acad. Sci.: U.S.A.90:7603 (1993); Geller, A. I., et al, Proc Natl. Acad. Sci USA 87: 1149 (1990), Adenovirus Vectors (see LeGal LaSalle et al, Science, 259:988 (1993); Davidson, et al, Nat. Genet 3 :219 (1993); Yang, et al, J. Virol. 69:2004 (1995) and Adeno-associated Virus Vectors (see Kaplitt, M. G. et al, Nat. Genet.8: 148 (1994). [00154] Pox viral vectors introduce the gene into the cell’s cytoplasm. Avipox virus vectors result in only a short-term expression of the nucleic acid. Adenovirus vectors, adeno- associated virus vectors, and herpes simplex virus (HSV) vectors can be used for introducing the nucleic acid into neural cells. The adenovirus vector results in a shorter-term expression (about 2 months) than adeno-associated virus (about 4 months), which in turn is shorter than HSV vectors. The vector chosen will depend upon the target cell and the condition being treated. The introduction can be by standard techniques, e.g., infection, transfection, transduction or transformation. Examples of modes of gene transfer include e.g., naked DNA, CaP0₄ precipitation, DEAE dextran, electroporation, protoplast fusion, lipofection, cell microinjection, and viral vectors. Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 [00155] The vector can be employed to target essentially any target cell. For example, stereotaxic injection can be used to direct the vectors (e.g., adenovirus, HSV) to a preferred location. Additionally, the particles can be delivered by intracerebroventricular (icv) infusion using a minipump infusion system, such as a SynchroMed Infusion System. A method based on bulk flow, termed convection, has also proven effective at delivering large molecules to extended areas of the brain and can be useful in delivering the vector to the target cell. (See Bobo et al, Proc. Natl. Acad. Sci. USA 91 :2076-2080 (1994); Morrison et al, Am. J. Physiol. 266:292-305 (1994)). Other methods that can be used include catheters, intravenous, parenteral, intraperitoneal and subcutaneous injection, and oral or other known routes of administration. [00156] These vectors can be used to express large quantities of antibodies that can be used in a variety of ways. For example, to detect the presence of CLDN4 in a sample. The antibody can also be used to try to bind to and disrupt a CLDN4 activity. [00157] In an embodiment, the antibodies described herein can be full-length antibodies, including those containing an Fc region similar to wild-type Fc regions that bind to Fc receptors. [00158] Techniques can be adapted for the production of single-chain antibodies specific to an antigenic protein of the invention (See e.g., U.S. Patent No.4,946,778). In addition, methods can be adapted for the construction of F_ab expression libraries (See e.g., Huse, et al, 1989 Science 246: 1275-1281) to allow rapid and effective identification of monoclonal Fab fragments with the preferred specificity for a protein or derivatives, fragments, analogs or homologs thereof. Antibody fragments that contain the idiotypes to a protein antigen can be produced by techniques known in the art including, but not limited to: (i) an F_(ab')2 fragment produced by pepsin digestion of an antibody molecule; (ii) an Fab fragment generated by reducing the disulfide bridges of an F_(ab')2 fragment; (iii) an F_ab fragment generated by the treatment of the antibody molecule with papain and a reducing agent and (iv) Fv fragments. [00159] Heteroconjugate antibodies are also within the scope of the invention. Heteroconjugate antibodies are composed of two covalently joined antibodies. Such antibodies can, for example, target immune system cells to unwanted cells (see U.S. Patent No. 4,676,980), and for treatment of HIV infection (See PCT Publication Nos. WO91/00360; WO92/20373). The antibodies can be prepared in vitro using known methods in synthetic protein chemistry, including those involving crosslinking agents. For example, immunotoxins can be constructed using a disulfide exchange reaction or by forming a thioether bond. Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 Examples of suitable reagents for this purpose include iminothiolate and methyl-4- mercaptobutyrimidate and those disclosed, for example, in U.S. Patent No.4,676,980. [00160] The antibody of the invention can be modified with respect to effector function, so as to enhance, e.g., the effectiveness of the antibody in treating cancer. For example, cysteine residue(s) can be introduced into the Fc region, thereby allowing interchain disulfide bond formation in this region. The homodimeric antibody thus generated can have improved internalization capability and/or increased complement-mediated cell killing and antibody- dependent cellular cytotoxicity (ADCC). (See Caron et al, J. Exp Med., 176: 1191-1195 (1992) and Shopes, J. Immunol., 148: 2918-2922 (1992)). Alternatively, an antibody can be engineered that has dual Fc regions and can thereby have enhanced complement lysis and ADCC capabilities. (See Stevenson et al, Anti-Cancer Drug Design, 3: 219-230 (1989)). In one embodiment, the antibody of the invention has modifications of the Fc region, such that the Fc region does not bind to the Fc receptors. For example, the Fc receptor is Fc ^ receptor. Antibodies with modification of the Fc region such that the Fc region does not bind to Fc ^, but still binds to neonatal Fc receptor are useful as described herein. [00161] In embodiments, an antibody of the invention can comprise an Fc variant. See, for example, WO2018/145075 and WO2019/183362, which provide Fc variant compositions for augmenting antibody mediated receptor signaling. In embodiments, the Fc variant can comprise an amino acid substitution which alters the antigen-independent effector functions of the antibody, such as the circulating half-life of the antibody. Such antibodies exhibit increased or decreased binding to FcRn when compared to antibodies lacking these substitutions, therefore, have an increased or decreased half-life in serum, respectively. Fc variants with improved affinity for FcRn are anticipated to have longer serum half-lives, and such molecules have useful applications in methods of treating mammals where long half-life of the administered antibody is preferred, e.g., to treat a chronic disease or disorder. In contrast, Fc variants with decreased FcRn binding affinity have shorter half-lives, and such molecules are also useful, for example, for administration to a mammal where a shortened circulation time can be advantageous, e.g., for in vivo diagnostic imaging or in situations where the starting antibody has toxic side effects when present in the circulation for prolonged periods. Fc variants with decreased FcRn binding affinity are also less likely to cross the placenta and, thus, are also useful in the treatment of diseases or disorders in pregnant women. In addition, other applications in which reduced FcRn binding affinity can be preferred include those applications in which localization to the brain, kidney, and/or liver is preferred. In one Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 embodiment, the Fc variant-containing antibodies can exhibit reduced transport across the epithelium of kidney glomeruli from the vasculature. In another embodiment, the Fc variant- containing antibodies can exhibit reduced transport across the blood brain barrier (BBB) from the brain, into the vascular space. In one embodiment, an antibody with altered FcRn binding comprises an Fc domain having one or more amino acid substitutions within the "FcRn binding loop" of an Fc domain. The FcRn binding loop is comprised of amino acid residues 280-299 (according to EU numbering). Exemplary amino acid substitutions with altered FcRn binding activity are disclosed in PCT Publication No. WO05/047327 which is incorporated by reference herein. In certain exemplary embodiments, the antibodies, or fragments thereof, of the invention comprise an Fc domain having one or more of the following substitutions: V284E, H285E, N286D, K290E and S304D (EU numbering). [00162] In some embodiments, mutations are introduced to the constant regions of the mAb such that the antibody dependent cell-mediated cytotoxicity (ADCC) activity of the mAb is altered. For example, the mutation is a LALA mutation in the CH2 domain. In one embodiment, the antibody (e.g., a human mAb, or a bispecific Ab) contains mutations on one scFv unit of the heterodimeric mAb, which reduces the ADCC activity. In another embodiment, the mAb contains mutations on both chains of the heterodimeric mAb, which completely ablates the ADCC activity. For example, the mutations introduced into one or both scFv units of the mAb are LALA mutations in the CH2 domain. These mAbs with variable ADCC activity can be optimized such that the mAbs exhibits maximal selective killing towards cells that express one antigen that is recognized by the mAb, however exhibits minimal killing towards the second antigen that is recognized by the mAb. [00163] In other embodiments, antibodies of the invention for use in the diagnostic and treatment methods described herein have a constant region, e.g., an IgG1 or IgG4 heavy chain constant region, which can be altered to reduce or eliminate glycosylation. For example, an antibody of the invention can also comprise an Fc variant comprising an amino acid substitution which alters the glycosylation of the antibody. For example, the Fc variant can have reduced glycosylation (e.g., N- or O-linked glycosylation). In some embodiments, the Fc variant comprises reduced glycosylation of the N-linked glycan normally found at amino acid position 297 (EU numbering). In another embodiment, the antibody has an amino acid substitution near or within a glycosylation motif, for example, an N-linked glycosylation motif that contains the amino acid sequence NXT or NXS. In an embodiment, the antibody comprises an Fc variant with an amino acid substitution at amino acid position 228 or 299 (EU Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 numbering). In another embodiment, the antibody comprises an IgGl or IgG4 constant region comprising an S228P and a T299A mutation (EU numbering). [00164] Exemplary amino acid substitutions which confer reduced or altered glycosylation are described in PCT Publication No, WO05/018572, which is incorporated by reference herein in its entirety. In some embodiments, the antibodies of the invention, or fragments thereof, are modified to eliminate glycosylation. Such antibodies, or fragments thereof, can be referred to as "agly" antibodies, or fragments thereof, (e.g. "agly" antibodies). While not wishing to be bound by theory "agly" antibodies, or fragments thereof, can have an improved safety and stability profile in vivo. Exemplary agly antibodies, or fragments thereof, comprise an aglycosylated Fc region of an IgG₄ antibody which is devoid of Fc-effector function thereby eliminating the potential for Fc mediated toxicity to the normal vital tissues and cells that express CLDN4. In yet other embodiments, antibodies of the invention, or fragments thereof, comprise an altered glycan. For example, the antibody can have a reduced number of fucose residues on an N-glycan at Asn297 of the Fc region, i.e., is afucosylated. In another embodiment, the antibody can have an altered number of sialic acid residues on the N-glycan at Asn297 of the Fc region. [00165] The invention also is directed to immunoconjugates comprising an antibody conjugated to a cytotoxic agent such as a toxin (e.g., an enzymatically active toxin of bacterial, fungal, plant, or animal origin, or fragments thereof), or a radioactive isotope (i.e., a radioconjugate). [00166] Enzymatically active toxins and fragments thereof that can be used include diphtheria A chain, nonbinding active fragments of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, and the tricothecenes. A variety of radionuclides are available for the production of radioconjugated antibodies. Non-limiting examples include ²¹²Bi, ¹³¹I, ¹³¹In, ⁹⁰Y, and ¹⁸⁶Re. [00167] Conjugates of the antibody and cytotoxic agent are made using a variety of bifunctional protein-coupling agents such as N-succinimidyl-3-(2-pyridyldithiol) propionate (SPDP), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCL), active esters (such as disuccinimidyl suberate), aldehydes (such as glutareldehyde), bis-azido compounds (such as bis (p-azidobenzoyl) hexanediamine), bis- diazonium derivatives (such as bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 (such as tolyene 2,6-diisocyanate), and bis-active fluorine compounds (such as l,5-difluoro- 2,4-dinitrobenzene). For example, a ricin immunotoxin can be prepared as described in Vitetta et al, Science 238: 1098 (1987). Carbon- 14-labeled l-isothiocyanatobenzyl-3- methyldiethylene triaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugation of radionucleotide to the antibody. (See PCT Publication No. WO94/11026, and U.S. Patent No.5,736,137). [00168] Those of ordinary skill in the art understand that a large variety of possible moieties can be coupled to the resultant antibodies or to other molecules of the invention. (See, for example, "Conjugate Vaccines", Contributions to Microbiology and Immunology, J. M. Cruse and R. E. Lewis, Jr (eds), Carger Press, New York, (1989), the entire contents of which are incorporated herein by reference). [00169] Coupling can be accomplished by any chemical reaction that will bind the two molecules so long as the antibody and the other moiety retain their respective activities. This linkage can include many chemical mechanisms, for instance covalent binding, affinity binding, intercalation, coordinate binding, and complexation. In one embodiment, binding is, covalent binding. Covalent binding can be achieved by direct condensation of existing side chains or by the incorporation of external bridging molecules. Many bivalent or polyvalent linking agents are useful in coupling protein molecules, such as the antibodies of the invention, to other molecules. For example, representative coupling agents can include organic compounds such as thioesters, carbodiimides, succinimide esters, diisocyanates, glutaraldehyde, diazobenzenes and hexamethylene diamines. This listing is not intended to be exhaustive of the various classes of coupling agents known in the art but, rather, is exemplary of the more common coupling agents. (See Killen and Lindstrom, Jour. Immun. 133: 1335- 2549 (1984); Jansen et al., Immunological Reviews 62: 185-216 (1982); and Vitetta et al, Science 238: 1098 (1987)). Non-limiting examples of linkers are described in the literature. (See, for example, Ramakrishnan, S. et al., Cancer Res. 44:201-208 (1984) describing use of MBS (M-maleimidobenzoyl-N-hydroxysuccinimide ester). See also, U.S. Patent No. 5,030,719, describing use of halogenated acetyl hydrazide derivative coupled to an antibody by way of an oligopeptide linker. Non-limiting examples of useful linkers that can be used with the antibodies of the invention include: (i) EDC (l-ethyl-3- (3-dimethylamino-propyl) carbodiimide hydrochloride; (ii) SMPT (4- succinimidyloxycarbonyl-alpha-methyl-alpha-(2- pridyl-dithio)-toluene (Pierce Chem. Co., Cat. (21558G); (iii) SPDP (succinimidyl-6 [3-(2- pyridyldithio) propionamido]hexanoate (Pierce Chem. Co., Cat #21651G); (iv) Sulfo-LC- SPDP (sulfosuccinimidyl 6 [3-(2- pyridyldithio)-propianamide] hexanoate (Pierce Chem. Co. Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 Cat. #2165-G); and (v) sulfo- NHS (-hydroxysulfo-succinimide: Pierce Chem. Co., Cat. #24510) conjugated to EDC. [00170] The linkers described herein contain components that have different attributes, thus leading to conjugates with differing physio-chemical properties. For example, sulfo- NHS esters of alkyl carboxylates are more stable than sulfo-NHS esters of aromatic carboxylates. NHS-ester containing linkers are less soluble than sulfo-NHS esters. Further, the linker SMPT contains a sterically hindered disulfide bond, and can form conjugates with increased stability. Disulfide linkages, are in general, less stable than other linkages because the disulfide linkage is cleaved in vitro, resulting in less conjugate available. Sulfo-NHS can enhance the stability of carbodimide couplings. Carbodimide couplings (such as EDC) when used in conjunction with sulfo-NHS, forms esters that are more resistant to hydrolysis than the carbodimide coupling reaction alone. [00171] The antibodies disclosed herein can also be formulated as immunoliposomes. Liposomes containing the antibody are prepared by methods known in the art, such as described in Epstein et al, Proc. Natl. Acad. Sci. USA, 82: 3688 (1985); Hwang et al, Proc. Natl Acad. Sci. USA, 77: 4030 (1980); and U.S. Pat. Nos. 4,485,045 and 4,544,545. Liposomes with enhanced circulation time are disclosed in U.S. Patent No.5,013,556. [00172] Non-limiting examples of useful liposomes can be generated by the reverse-phase evaporation method with a lipid composition comprising phosphatidylcholine, cholesterol, and PEG-derivatized phosphatidylethanolamine (PEG-PE). Liposomes are extruded through filters of defined pore size to yield liposomes with the preferred diameter. Fab' fragments of the antibody of the invention can be conjugated to the liposomes as described in Martin et al, J. Biol. Chem., 257: 286-288 (1982) via a disulfide-interchange reaction. [00173] Multispecific Antibodies (Bispecific and Trispecific) [00174] Embodiments as described herein can be comprise a monospecific antibody or a multispecific antibody. [00175] Monospecific antibodies are antibodies with one or more binding sites that specifically binds to a single antigen. [00176] Multispecific antibodies are antibodies that can recognize two or more different antigens. For example, a bi-specific antibody (bsAb) is an antibody comprising two variable domains or scFv units such that the resulting antibody recognizes two different antigens. For example, a trispecific antibody (tsAb) is an antibody comprising two variable domains or scFv units such that the resulting antibody recognizes three different antigens. This invention provides for multispecific antibodies, such as bi-specific and trispecific antibodies, that Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 recognize CLDN4 and a second antigen and/or a third antigen. In one embodiment, multispecific antibodies (e.g., bi-specific antibodies and trispecific antibodies) can comprise CLDN4 specific fusion proteins encompassing the antibodies described herein. Exemplary second and or third antigens include tumor associated antigens (e.g., LINGO1), cytokines (e.g., IL-12 (IL-12A (p35 subunit) protein sequence having NCBI Reference No. NP_000873.2; IL- 12B (p40 subunit) protein sequence having NCBI Reference No. NP_002178.2); IL-18 (protein sequence having NCBI Reference no. NP_001553.1); IL-15 (protein sequence having NCBI Reference No. NP_000576.1); IL-7 (protein sequence having NCBI Reference No. NP_000871.1); IL-2 (protein sequence having NCBI Reference No. NP_000577.2); and IL-21 (protein sequence having NCBI Reference No. NP_068575.1)), cytokine cognate receptors (eg., IL-12R), and cell surface receptors. Non-limiting examples of second and/or third antigens include CTLA-4, CXCR4, LAG-3, CD28, CD122, 4-1BB, TIM3, OX-40, OX40L, CD40, CD40L, LIGHT, ICOS, ICOSL, GITR, GITRL, TIGIT, CD27, VISTA, B7H3, B7H4, HEVM (or BTLA), CD47 and CD73. In one embodiment, the bispecific and trispecific antibodies comprise CLDN4 fusion proteins. For example, the fusion protein comprises an antibody comprising a variable domain or scFv unit and a ligand or antigen and/or a third ligand or antigen as described herein such that the resulting antibody recognizes an antigen and binds to the ligand-specific receptor. Exemplary antibody compositions (e.g., VH and/or VL sequences or fragments thereof) that are useful for the design of CLDN4 fusion proteins as described herein include, but are not limited to, anti-CAIX antibodies described in PCT/US2006/046350 and PCT/US2015/067178; anti-CXCR4 antibodies described in PCT/US20006/005691 and PCT/US2019/022272; anti-CCR4 antibodies described in PCT/US2008/088435, PCT/US2013/039744, and PCT/US2015/054202; anti-PD-L1 antibodies described in PCT/US2008/088435 and PCT/US2020/062815; anti-PD-1 antibodies described in PCT/US2020/037791 and PCT/US2020/037781; anti-GITR antibodies described in PCT/US2017/043504; anti-claudin-4 antibodies described in PCT/US2019/022272; and anti-MUC1 antibodies described in PCT/US2020/037783 (each of the applications which are incorporated by reference in their entireties). In one embodiment, the fusion protein further comprises a constant region, and/or a linker as described herein. Different formats of multispecific antibodies (e.g., bispecific antibodies and trispecific antibodies such as a fusion protein comprises an antibody that recognizes CLDN4 and a ligand) are described herein. Ligands can be tumor associated antigens (e.g., LINGO1, ErbB2 (HER2/neu), carcinoembryonic antigen (CEA), epithelial cell adhesion molecule (EpCAM), epidermal growth factor receptor (EGFR), MUC1, MSLN, CD19, CD20, CD30, CD40, CD22, RAGE-l, Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 MN-CA IX, RET1, RET2 (AS), prostate specific antigen (PSA), TAG-72, PAP, p53, Ras, prostein, PSMA, survivin, 9D7, prostate-carcinoma tumor antigen-l (PCTA-1), GAGE, MAGE, mesothelin, β-catenin, TGF-βRII, BRCA1/2, SAP-1, HPV-E6, HPV-E7 (see also, PCT/US2015/067225 and PCT/US2019/022272 for additional tumor-associated surface antigens, which are incorporated by reference in their entireties)); cytokines (e.g., IL-12 (IL- 12A (p35 subunit) protein sequence having NCBI Reference No. NP_000873.2; IL-12B (p40 subunit) protein sequence having NCBI Reference No. NP_002178.2); IL-18 (protein sequence having NCBI Reference no. NP_001553.1); IL-15 (protein sequence having NCBI Reference No. NP_000576.1); IL-7 (protein sequence having NCBI Reference No. NP_000871.1); IL-2 (protein sequence having NCBI Reference No. NP_000577.2); and IL-21 (protein sequence having NCBI Reference No. NP_068575.1)); CTLA-4, LAG-3, CD28, CD122, 4-1BB, TIM3, OX-40, OX40L, CD40, CD40L, LIGHT, ICOS, ICOSL, GITR, GITRL, TIGIT, CD27, VISTA, B7H3, B7H4, HEVM (or BTLA), CD47 and CD73. Different formats of bispecific or trispecific antibodies are also provided herein. In some embodiments, each of the anti- CLDN4 fragment and the second antigen-specific fragment and/or the third antigen-specific fragment is each independently selected from a Fab fragment, a single-chain variable fragment (scFv), or a single-domain antibody. In some embodiments, the bispecific or trispecific antibody further includes a Fc fragment (e.g., as described in PCT/US2015/021529 and PCT/US2019/023382, each of which are incorporated by reference in their entireties). A bispecific or trispecific antibody of the invention can comprise a heavy chain and a light chain combination or scFv of the CLDN4 antibodies described herein. [00177] Multispecific antibodies (e.g., bispecific antibodies and trispecific antibodies) of the invention (for example, an anti-CLDN4-scFv fusion protein) can be constructed using methods known art. In some embodiments, the bi-specific antibody is a single polypeptide wherein the two scFv fragments are joined by a long linker polypeptide, of sufficient length to allow intramolecular association between the two scFv units to form an antibody. In other embodiments, the bi-specific antibody is more than one polypeptide linked by covalent or non- covalent bonds. In some embodiments, the amino acid linker depicted herein (GGGGSGGGGS; “(G4S)2”) can be generated with a longer G4S linker to improve flexibility. For example, the linker can also be: “(G₄S)₃” (e.g., GGGGSGGGGSGGGGS); “(G4S)4” (e.g., GGGGSGGGGSGGGGSGGGGS); “(G₄S)₅” (e.g., GGGGSGGGGSGGGGSGGGGSGGGGS); “(G4S)6” (e.g., GGGGSGGGGSGGGGSGGGGSGGGGSGGGGS); Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 “(G4S)7” (e.g., GGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGS); and the like. For example, use of the (G4S)₅ linker can provide more flexibility to a ligand described herein and can improve expression. In some embodiments, the linker can also be (GS)n, (GGS)n, (GGGS)n, (GGSG)_n, (GGSGG)_n, or (GGGGS)_n, wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. Non-limiting examples of linkers known to those skilled in the art that can be used to construct the fusions described herein can be found in U.S. Patent No. 9,708,412; U.S. Patent Application Publication Nos. US 20180134789 and US 20200148771; and PCT Publication No. WO2019051122 (each of which are incorporated by reference in their entireties). [00178] In another embodiment, the multispecific antibodies (e.g., bispecific antibodies and trispecific antibodies such as anti-CLDN4-scFv fusions) can be constructed using the "knob into hole" method (Ridgway et al, Protein Eng 7:617-621 (1996)). In this method, the Ig heavy chains of the two different variable domains are reduced to selectively break the heavy chain pairing while retaining the heavy-light chain pairing. The two heavy-light chain heterodimers that recognize two different antigens/ligands or three different antigens/ligands are mixed to promote heteroligation pairing, which is mediated through the engineered "knob into holes" of the CH3 domains. [00179] In another embodiment the multispecific antibodies (e.g., bispecific antibodies and trispecific antibodies such as anti-CLDN4-scFv fusions) can be constructed through exchange of heavy-light chain dimers from two or more different antibodies to generate a hybrid antibody where the first heavy-light chain dimer recognizes CLDN4 and the second heavy-light chain dimer recognizes a second antigen and/or third antigen. The mechanism for heavy-light chain dimer is similar to the formation of human IgG4, which also functions as a bispecific molecule. Dimerization of IgG heavy chains is driven by intramolecular force, such as the pairing the CH3 domain of each heavy chain and disulfide bridges. Presence of a specific amino acid in the CH3 domain (R409) has been shown to promote dimer exchange and construction of the IgG4 molecules. Heavy chain pairing is also stabilized further by interheavy chain disulfide bridges in the hinge region of the antibody. Specifically, in IgG₄, the hinge region contains the amino acid sequence Cys-Pro-Ser-Cys (in comparison to the stable IgGl hinge region which contains the sequence Cys-Pro-Pro-Cys) at amino acids 226- 230. This sequence difference of Serine at position 229 has been linked to the tendency of IgG4 to form intrachain disulfides in the hinge region (Van der Neut Kolfschoten, M. et al, 2007, Science 317: 1554-1557 and Labrijn, A.F. et al, 2011, Journal of Immunol 187:3238-3246). [00180] The multispecific antibodies (e.g., bispecific antibodies and trispecific antibodies such as anti-CLDN4-scFv fusions) of the invention can be created through introduction of the Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 R409 residue in the CH3 domain and the Cys-Pro-Ser-Cys sequence in the hinge region of antibodies that recognize CLDN4 or a second and/or third antigen, so that the heavy-light chain dimers exchange to produce an antibody molecule with one heavy-light chain dimer recognizing CLDN4 and the second heavy-light chain dimer recognizing a second and/or third antigen, wherein the second and/or third antigen (or ligand) is any antigen (or ligand) disclosed herein. Known IgG₄ molecules can also be altered such that the heavy and light chains recognize CLDN4 or a second and/or third antigen, as disclosed herein. Use of this method for constructing the multispecific antibodies (e.g., bispecific antibodies and trispecific antibodies such as anti-CLDN4-scFv fusions) of the invention can be beneficial due to the intrinsic characteristic of IgG₄ molecules wherein the Fc region differs from other IgG subtypes in that it interacts poorly with effector systems of the immune response, such as complement and Fc receptors expressed by certain white blood cells. This specific property makes these IgG₄-based multispecific antibodies (e.g., bispecific antibodies and trispecific antibodies such as anti- CLDN4-scFv fusions) attractive for therapeutic applications, in which the antibody is required to bind the target(s) and functionally alter the signaling pathways associated with the target(s), however not trigger effector activities. [00181] The multispecific antibodies (e.g., bispecific antibodies and trispecific antibodies such as anti-CLDN4-scFv fusions) described herein can be engineered with a non-depleting heavy chain isotype, such as IgG1-LALA or stabilized IgG4 or one of the other non-depleting variants. In some embodiments, mutations are introduced to the constant regions of the bsAb such that the antibody dependent cell-mediated cytotoxicity (ADCC) activity of the bsAb is altered. For example, the mutation is a LALA mutation in the CH2 domain. In one aspect, the multispecific antibody (e.g., bispecific antibodies and trispecific antibodies such as anti- CLDN4-scFv fusions) contains mutations on one scFv unit of the heterodimeric multispecific antibody, which reduces the ADCC activity. In another aspect, the multispecific antibody (e.g., bispecific antibodies and trispecific antibodies such as anti-CLDN4-scFv fusions) contains mutations on both chains of the heterodimeric multispecific antibody, which completely ablates the ADCC activity. For example, the mutations introduced in one or both scFv units of the multispecific antibody (e.g., bispecific antibodies and trispecific antibodies such as anti- CLDN4-scFv fusions) are LALA mutations in the CH2 domain. These multispecific antibodies (e.g., bispecific antibodies and trispecific antibodies such as anti-CLDN4-scFv fusions) with variable ADCC activity can be optimized such that the multi-specific antibodies exhibit maximal selective killing towards cells that express one antigen that is recognized by the Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 multispecific antibody; however, exhibits minimal killing towards the second antigen that is recognized by the multispecific antibody. [00182] The multispecific antibodies (e.g., bispecific antibodies) described herein can be engineered as modular tetrameric bispecific antibodies (tBsAb). See, for example, WO 2018/071913, which is incorporated by reference herein in its entirety. For example, the tetravalent antibody can be a dimer of a bispecific scFv fragment including a first binding site for a first antigen, and a second binding site for a second antigen. In embodiments, the anti- CLDN4 antibody can be the first binding site for a first antigen. In embodiments, the anti- CLDN4 antibody can be the second binding site for a second antigen. The two binding sites can be joined together via a linker domain. In embodiments, the scFv fragment is a tandem scFv, the linker domain includes an immunoglobulin hinge region (e.g., an IgGl, an IgG2, an IgG3, or an IgG4 hinge region) amino acid sequence. In embodiments, the immunoglobulin hinge region amino acid sequence can be flanked by a flexible linker amino acid sequence, e.g., having the linker amino acid sequence (GGGS)_x1-6, (GGGGS)_x1-6, or GSAGSAAGSGEF. In embodiments, the linker domain includes at least a portion of an immunoglobulin Fc domain, e.g., an IgGl, an IgG2, an IgG3, or an IgG4 Fc domain. In embodiments, the at least a portion of the immunoglobulin Fc domain does not include a CH2 domain. In embodiments, the at least a portion of the immunoglobulin Fc domain can be a CH2 domain. An exemplary CH2 domain amino acid sequence includes APELLGGPDVFLF (SEQ ID NO: 95). The Fc domain can be linked to the C-terminus of an immunoglobulin hinge region (e.g., an IgGl, an IgG2, an IgG3, or an IgG4 hinge region) amino acid sequence. The linker domain can include a flexible linker amino acid sequence (e.g., (GGGS)x1-6, (GGGGS)x1-6, or GSAGSAAGSGEF) at one terminus or at both termini. [00183] In embodiments, the tBsAb can be specific for CLDN4, and also a target selected from the group consisting of B7H3, B7H4, CD27, CD28, CD40, CD40L, CD47, CD122, CCR4, CXCR4, CTLA-4, GITR, GITRL, ICOS, ICOSL, LAG-3, LIGHT, OX-40, OX40L, PD-L1, PD-1, TIM3, 4-1BB, TIGIT, VISTA, HEVM, BTLA, and KIR. [00184] In embodiments, the multispecific antibody can be a bi-specific T-cell engager (BiTE). The term "BiTEs " (a bispecific T-cell engager) refers to a single polypeptide chain molecule with two antigen binding domains, one of which binds to a T-cell antigen. For example, the BiTE can comprise a CLDN4 antibody disclosed herein, or a functional fragment thereof, and an antibody or fragment thereof that binds to a T-cell antigen. For example, the antibody or fragment thereof that binds to a T-cell antigen can be specific for CD3. Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 [00185] In embodiments, the multispecific antibody can be a tri-specific T-cell engager (TriTE). The term "TriTEs " (a trispecific T-cell engager) can refer to a single polypeptide chain molecule with three antigen binding domains, one or more of which binds to a T-cell antigen. For example, the TriTE can comprise a CLDN4 antibody disclosed herein, or a functional fragment thereof, and an antibody or fragment thereof that binds to a T-cell antigen. For example, the antibody or fragment thereof that binds to a T-cell antigen can be specific for CD3, CD28, or both. [00186] The multispecific antibodies (e.g., bispecific antibodies and trispecific antibodies such as anti-CLDN4-scFv fusions) disclosed herein can be useful in treatment of chronic infections, diseases, or medical conditions, for example, cancer. [00187] Fusion Proteins [00188] The invention provides a fusion protein containing a CLDN4 antibody disclosed herein, or a functional fragment thereof, operably linked to a second protein. The second protein can be, for example, a cytokine or a growth factor. In embodiments, the cytokine is IL-2 or TGF-beta and variants thereof. In some other embodiments, the second protein can be a therapeutic agent, such as a toxin, a detectable moiety, such as a fluorescent protein for detection, or a biological agent, such as an agent that stimulates T cells (i.e., CD3). In some embodiments, the CLDN4 antibodies of the invention can be operably linked to more than one additional protein or peptide, for example 2, 3, 4, 5, 6, 7, 8, 9, or 10 additional proteins or peptide sequences. [00189] In some embodiments, the CLDN4 antibody disclosed herein, or functional fragment thereof, is joined directly to the second protein. In other embodiments, the CLDN4 antibody, or functional fragment thereof, is joined to the second protein via a linker, such as a flexible polypeptide chain. The linker can be any suitable linker of any length, but can be at least 1, 2, 3, 4, 5, 10, 15, 20, 25, or 30 amino acids in length. In one embodiment, the linker is an amino acid sequence that is naturally present in immunoglobulin molecules of the host, such that the presence of the linker cannot result in an immune response against the linker sequence by the mammal. Fusion proteins of the invention that include more than one additional protein to the CLDN4 antibody can have multiple linker sequences that join each additional protein or peptide sequence. [00190] The fusion proteins of the invention can be constructed by recombinant methods known to the skilled artisan. For example, an expression vector containing the nucleic acid sequence encoding a CLDN4 antibody of the invention can be operably linked to the nucleic acid sequence encoding the second protein and can be introduced to an expression Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 system to translate and produce the fusion protein. Alternatively, one skilled in the art can readily utilize de nova protein synthesis techniques to produce the fusion proteins described herein. [00191] Use of Antibodies Against CLDN4 [00192] Antibodies of the invention specifically binding a CLDN4 protein, or a fragment thereof, can be administered for the treatment of a CLDN4 associated disease or disorder. A"CLDN4-associated disease or disorder" includes disease states and/or symptoms associated with a disease state, where increased levels of CLDN4 and/or activation of cellular signaling pathways involving CLDN4 are found. Exemplary CLDN4-associated diseases or disorders include, but are not limited to, diseases where T cells are suppressed, such as in cancer and infectious diseases. In some embodiments, the cancer can be lung cancer, kidney cancer, ovarian cancer, prostate cancer, colon cancer, breast cancer, cervical cancer, uterine cancer, brain cancer, skin cancer, liver cancer, pancreatic cancer, or stomach cancer. In embodiments, the cancer can be a CLDN4-associated cancer. In embodiments, the CLDN-4 associated cancer can be triple negative breast cancer. [00193] Antibodies of the invention, including bi-specific, polyclonal, monoclonal, humanized and fully human antibodies, can be used as therapeutic agents. Such agents can be employed to treat cancer in a subject, increase vaccine efficiency or augment a natural immune response. An antibody preparation, for example, one having high specificity and high affinity for its target antigen, is administered to the subject and will have an effect due to its binding with the target. Administration of the antibody can abrogate or inhibit or interfere with an activity of the CLDN4 protein. [00194] Pharmaceutical Compositions [00195] Antibodies of the invention specifically binding a CLDN4 protein or fragment thereof can be administered for the treatment of a cancer in the form of pharmaceutical compositions. Principles and considerations involved in preparing therapeutic pharmaceutical compositions comprising the antibody, as well as guidance in the choice of components are provided, for example, in: Remington: The Science And Practice Of Pharmacy 20th ed. (Alfonso R. Gennaro, et al, editors) Mack Pub. Co., Easton, Pa., 2000; Drug Absorption Enhancement: Concepts, Possibilities, Limitations, And Trends, Harwood Academic Publishers, Langhorne, Pa., 1994; and Peptide And Protein Drug Delivery (Advances In Parenteral Sciences, Vol.4), 1991, M. Dekker, New York. [00196] A specific dosage and treatment regimen for any patient will depend upon a variety of factors, including the specific antibodies, variant or derivative thereof used, the patient's age, Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 body weight, general health, sex, and diet, and the time of administration, rate of excretion, drug combination, and the severity of the disease being treated. Judgment of such factors by medical caregivers is within the ordinary skill in the art. The amount will also depend on the individual patient to be treated, the route of administration, the type of formulation, the characteristics of the compound used, the severity of the disease, and the preferred effect. The amount used can be determined by pharmacological and pharmacokinetic principles well known in the art. [00197] A therapeutically effective amount of an antibody of the invention can be the amount needed to achieve a therapeutic objective. As noted herein, this can be a binding interaction between the antibody and its target antigen that, in certain cases, interferes with the functioning of the target. The amount required to be administered will furthermore depend on the binding affinity of the antibody for its specific antigen and will also depend on the rate at which an administered antibody is depleted from the free volume other subject to which it is administered. The dosage administered to a subject (e.g., a patient) of the antigen-binding polypeptides described herein is about 0.1 mg/kg to 100 mg/kg of the patient's body weight, between 0.1 mg/kg and 20 mg/kg of the patient's body weight, or 1 mg/kg to 10 mg/kg of the patient's body weight. Human antibodies have a longer half-life within the human body than antibodies from other species due to the immune response to the foreign polypeptides. Thus, lower dosages of human antibodies and less frequent administration is often possible. Further, the dosage and frequency of administration of antibodies of the disclosure can be reduced by enhancing uptake and tissue penetration (e.g., into the brain) of the antibodies by modifications such as, for example, lipidation. Common ranges for therapeutically effective dosing of an antibody or antibody fragment of the invention can be, by way of nonlimiting example, from about 0.1 mg/kg body weight to about 50 mg/kg body weight. Common dosing frequencies can range, for example, from twice daily to once a week. [00198] Where antibody fragments are used, the smallest inhibitory fragment that specifically binds to the binding domain of the target protein is preferred. For example, based upon the variable-region sequences of an antibody, peptide molecules can be designed that retain the ability to bind the target protein sequence. Such peptides can be synthesized chemically and/or produced by recombinant DNA technology. (See, e.g., Marasco et al, Proc. Natl. Acad. Sci. USA, 90: 7889-7893 (1993)). The formulation can also contain more than one active compound as necessary for the indication being treated, for example, those with complementary activities that do not adversely affect each other. Alternatively, or in addition, the composition can comprise an agent that enhances its function, such as, for example, a Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 cytotoxic agent, cytokine (e.g., IL-15), chemotherapeutic agent, or growth-inhibitory agent. Such molecules are suitably present in combination in amounts that are effective for the purpose intended. [00199] The active ingredients can also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) or in macroemulsions. [00200] The formulations to be used for in vivo administration must be sterile. This is readily accomplished by filtration through sterile filtration membranes. [00201] Sustained-release preparations can be prepared. Suitable examples of sustained- release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2- hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and γ ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid. While polymers such as ethylene-vinyl acetate and lactic acid-glycolic acid allow for release of molecules for over 100 days, certain hydrogels release proteins for shorter time periods. [00202] The antibodies or agents of the invention (also referred to herein as "active compounds"), and derivatives, fragments, analogs and homologs thereof, can be incorporated into pharmaceutical compositions suitable for administration. Such pharmaceutical compositions can comprise the antibody or agent and a pharmaceutically acceptable carrier. As used herein, the term "pharmaceutically acceptable carrier" can include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Suitable carriers are described in the most recent edition of Remington's Pharmaceutical Sciences, a standard reference text in the field, which is incorporated herein by reference. Non-limiting examples of such carriers or diluents include water, saline, ringer's solutions, dextrose solution, and 5% human serum albumin. Liposomes and non-aqueous vehicles such as fixed oils can also be used. The use of such media and agents for pharmaceutically active substances is well known Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is intended. Supplementary active compounds can also be incorporated into the compositions. [00203] A pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (i.e., topical), transmucosal, and rectal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. [00204] Pharmaceutical compositions suitable for injectable use can include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL^™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In embodiments, the composition is sterile and is fluid to the extent that easy syringeability exists. It can be stable under the conditions of manufacture and storage and can be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, isotonic agents can be included, for example, sugars, polyalcohols such as manitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin. Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 [00205] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. For example, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional ingredient from a previously sterile-filtered solution thereof. [00206] Oral compositions can include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. [00207] For administration by inhalation, the compounds can be delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer. [00208] Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as known in the art. [00209] The compounds can also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery. Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 [00210] In one embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations are apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811. [00211] Oral or parenteral compositions can be formulated in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the preferred therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention can be dictated by and directly dependent on the unique characteristics of the active compound and the therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals. [00212] The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration. [00213] Diagnostics [00214] An antibody according to the invention can be used as an agent for detecting the presence of CLDN4 (or a protein fragment thereof) in a sample. For example, the sample can be a cancer sample or a sample from a subject at risk of having cancer. For example, the cancer can be lung cancer, kidney cancer, ovarian cancer, prostate cancer, colon cancer, breast cancer, cervical cancer, uterine cancer, brain cancer, skin cancer, liver cancer, pancreatic cancer, or stomach cancer. For example, the antibody can contain a detectable label. Antibodies can be polyclonal or monoclonal. An intact antibody, or a fragment thereof (e.g., Fab, scFv, or F(ab)2) can be used. The term "labeled", with regard to the probe or antibody, can encompass direct labeling of the probe or antibody by coupling (i.e., physically linking) a detectable substance to the probe or antibody, as well as indirect labeling of the probe or antibody by reactivity with another reagent that is directly labeled. Examples of indirect labeling include detection of a Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 primary antibody using a fluorescently-labeled secondary antibody and end-labeling of a DNA probe with biotin such that it can be detected with fluorescently-labeled streptavidin. The term "biological sample" can include tissues, cells and biological fluids isolated from a subject, as well as tissues, cells and fluids present within a subject. Included within the usage of the term "biological sample", therefore, is blood and a fraction or component of blood including blood serum, blood plasma, or lymph. That is, the detection method of the invention can be used to detect an analyte mRNA, protein, or genomic DNA in a biological sample in vitro as well as in vivo. For example, in vitro techniques for detection of an analyte mRNA includes Northern hybridizations and in situ hybridizations. In vitro techniques for detection of an analyte protein include enzyme linked immunosorbent assays (ELISAs), Western blots, immunoprecipitations, and immunofluorescence. In vitro techniques for detection of an analyte genomic DNA include Southern hybridizations. [00215] Procedures for conducting immunoassays are described, for example in "ELISA: Theory and Practice: Methods in Molecular Biology", Vol. 42, J. R. Crowther (Ed.) Human Press, Totowa, NJ, 1995; "Immunoassay", E. Diamandis and T. Christopoulus, Academic Press, Inc., San Diego, CA, 1996; and "Practice and Theory of Enzyme Immunoassays", P. Tijssen, Elsevier Science Publishers, Amsterdam, 1985. Furthermore, in vivo techniques for detection of an analyte protein include introducing into a subject a labeled anti-analyte protein antibody. For example, the antibody can be labeled with a radioactive marker whose presence and location in a subject can be detected by standard imaging techniques. [00216] Antibodies directed against a CLDN4 protein (or a fragment thereof) can be used in methods known within the art relating to the localization and/or quantitation of a CLDN4 protein (e.g., for use in measuring levels of the CLDN4 protein within appropriate physiological samples, for use in diagnostic methods, for use in imaging the protein, and the like). In a given embodiment, antibodies specific to a CLDN4 protein, or derivative, fragment, analog or homolog thereof, that contain the antibody derived antigen binding domain, are utilized as pharmacologically active compounds (referred to herein as "therapeutics"). [00217] An antibody of the invention specific for a CLDN4 protein can be used to isolate a CLDN4 polypeptide by standard techniques, such as immunoaffinity, chromatography or immunoprecipitation. Antibodies directed against a CLDN4 protein (or a fragment thereof) can be used diagnostically to monitor protein levels in tissue as part of a clinical testing procedure, e.g., to, for example, determine the efficacy of a given treatment regimen. [00218] Detection can be facilitated by coupling (i.e., physically linking) the antibody to a detectable substance. Examples of detectable substances include, but are not limited to, various Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, and radioactive materials. Non-limiting examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, β-galactosidase, or acetylcholinesterase; examples of suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; an example of a luminescent material includes luminol; examples of bioluminescent materials include luciferase, luciferin, and aequorin, and examples of suitable radioactive material include ¹²⁵I, ¹³¹I, ³⁵S, ³²P or ³H. [00219] Screening Methods [00220] The invention provides methods (also referred to herein as "screening assays") for identifying modulators, i.e., candidate or test compounds or agents (e.g., peptides, peptidomimetics, small molecules or other drugs) that modulate or otherwise interfere with a CLDN4 activity. Also provided are methods of identifying compounds useful to treat cancer. The invention also encompasses compounds identified using the screening assays described herein. [00221] For example, the invention provides assays for screening candidate or test compounds which modulate CLDN4 expression and/or activity. The test compounds of the invention can be obtained using any of the numerous approaches in combinatorial library methods known in the art, including but not limited to: biological libraries; spatially addressable parallel solid phase or solution phase libraries; synthetic library methods requiring deconvolution; the "one-bead one-compound" library method; and synthetic library methods using affinity chromatography selection. The biological library approach is limited to peptide libraries, while the other four approaches are applicable to peptide, non-peptide oligomer or small molecule libraries of compounds. (See, e.g., Lam, 1997. Anticancer Drug Design 12: 145). [00222] A "small molecule" as used herein, can refer to a composition that has a molecular weight of less than about 5 kD and most preferably less than about 4 kD. Small molecules can be, e.g., nucleic acids, peptides, polypeptides, peptidomimetics, carbohydrates, lipids or other organic or inorganic molecules. Libraries of chemical and/or biological mixtures, such as fungal, bacterial, or algal extracts, are known in the art and can be screened with any of the assays of the invention. [00223] Examples of methods for the synthesis of molecular libraries can be found in the art, for example in: DeWitt, et al., 1993. Proc. Natl. Acad. Sci. U.S.A.90: 6909; Erb, et al., 1994. Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 Proc. Natl. Acad. Sci. U.S.A. 91: 11422; Zuckermann, et al., 1994. J. Med. Chem. 37: 2678; Cho, et al., 1993. Science 261: 1303; Carrell, et al., 1994. Angew. Chem. Int. Ed. Engl. 33: 2059; Carell, et al., 1994. Angew. Chem. Int. Ed. Engl. 33: 2061; and Gallop, et al., 1994. J. Med. Chem.37: 1233. [00224] Libraries of compounds can be presented in solution (see e.g., Houghten, 1992. Biotechniques 13: 412-421), or on beads (see Lam, 1991. Nature 354: 82-84), on chips (see Fodor, 1993. Nature 364: 555-556), bacteria (see U.S. Patent No.5,223,409), spores (see U.S. Patent 5,233,409), plasmids (see Cull, et al., 1992. Proc. Natl. Acad. Sci. USA 89: 1865-1869) or on phage (see Scott and Smith, 1990. Science 249: 386-390; Devlin, 1990. Science 249: 404-406; Cwirla, et al., 1990. Proc. Natl. Acad. Sci. U.S.A. 87: 6378-6382; Felici, 1991. J. Mol. Biol.222: 301-310; and U.S. Patent No.5,233,409.). [00225] In one embodiment, a candidate compound is introduced to an antibody-antigen complex and determining whether the candidate compound disrupts the antibody-antigen complex, wherein a disruption of this complex indicates that the candidate compound modulates an CLDN4 activity. [00226] In another embodiment, at least one CLDN4 protein is provided, which is exposed to at least one monoclonal antibody. Formation of an antibody-antigen complex is detected, and one or more candidate compounds are introduced to the complex. If the antibody-antigen complex is disrupted following introduction of the one or more candidate compounds, the candidate compound is useful to treat cancer or a proliferative disease or disorder. [00227] Determining the ability of the test compound to interfere with or disrupt the antibody-antigen complex can be accomplished, for example, by coupling the test compound with a radioisotope or enzymatic label such that binding of the test compound to the antigen or biologically active portion thereof can be determined by detecting the labeled compound in a complex. For example, test compounds can be labeled with 125r, 35 S, 14C, or 3H, directly or indirectly, and the radioisotope detected by direct counting of radioemission or by scintillation counting. Alternatively, test compounds can be enzymatically labeled with, for example, horseradish peroxidase, alkaline phosphatase, or luciferase, and the enzymatic label detected by determination of conversion of an appropriate substrate to product. [00228] In one embodiment, the assay comprises contacting an antibody-antigen complex with a test compound and determining the ability of the test compound to interact with the antigen or otherwise disrupt the existing antibody-antigen complex. In this embodiment, determining the ability of the test compound to interact with the antigen and/or disrupt the antibody-antigen complex comprises determining the ability of the test compound to Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 preferentially bind to the antigen or a biologically active portion thereof, as compared to the antibody. [00229] In another embodiment, the assay comprises contacting an antibody-antigen complex with a test compound and determining the ability of the test compound to modulate the antibody-antigen complex. Determining the ability of the test compound to modulate the antibody-antigen complex can be accomplished, for example, by determining the ability of the antigen to bind to or interact with the antibody, in the presence of the test compound. [00230] Those skilled in the art will recognize that, in any of the screening methods disclosed herein, the antibody can be a CLDN4 antibody. Additionally, the antigen can be a CLDN4 protein or a portion thereof. [00231] The screening methods disclosed herein can be performed as a cell-based assay or as a cell-free assay. In the case of cell-free assays comprising the membrane-bound forms of the CLDN4 proteins, it can be desirable to utilize a solubilizing agent such that the membrane- bound form of the proteins is maintained in solution. Examples of such solubilizing agents include non-ionic detergents such as n-octylglucoside, n-dodecy lglucoside, n-dodecy lmaltoside, octanoy 1-N-methy lglucamide, decanoyl-N-methylglucamide, Triton® X-100, Triton® X-114, Thesit®, Isotridecypoly( ethylene glycol ether )n, N-dodecy 1--N ,N-dimethy 1-3-ammonio-1-propane sulfonate, 3-(3-cholamidopropyl) dimethylamminiol-1-propane sulfonate (CHAPS), or 3-(3-cholamidopropyl)dimethylamminiol-2-hydroxy-1-propane sulfonate (CHAPSO). [00232] In more than one embodiment, it can be desirable to immobilize the antibody or the antigen to facilitate separation of complexed from uncomplexed forms of one or both following introduction of the candidate compound, as well as to accommodate automation of the assay. Observation of the antibody-antigen complex in the presence and absence of a candidate compound can be accomplished in any vessel suitable for containing the reactants. Examples of such vessels include microtiter plates, test tubes, and micro-centrifuge tubes. In one embodiment, a fusion protein can be provided that adds a domain that allows one or both of the proteins to be bound to a matrix. For example, GST-antibody fusion proteins or GST- antigen fusion proteins can be adsorbed onto glutathione sepharose beads (Sigma Chemical, St. Louis, MO) or glutathione derivatized microtiter plates, that are then combined with the test compound, and the mixture is incubated under conditions conducive to complex formation (e.g., at physiological conditions for salt and pH). Following incubation, the beads or microtiter plate wells are washed to remove any unbound components, the matrix immobilized in the case of beads, complex determined directly or indirectly. Alternatively, the complexes can be Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 dissociated from the matrix, and the level of antibody-antigen complex formation can be determined using standard techniques. [00233] Other techniques for immobilizing proteins on matrices can also be used in the screening assays of the invention. For example, the antibody or the antigen (e.g. the CLDN4 protein) can be immobilized utilizing conjugation of biotin and streptavidin. Biotinylated antibody or antigen molecules can be prepared from biotin-NHS (N-hydroxy-succinimide) using techniques well-known within the art (e.g., biotinylation kit, Pierce Chemicals, Rockford, Ill.), and immobilized in the wells of streptavidin-coated 96 well plates (Pierce Chemical). Alternatively, other antibodies reactive with the antibody or antigen of interest, but which do not interfere with the formation of the antibody-antigen complex of interest, can be derivatized to the wells of the plate, and unbound antibody or antigen trapped in the wells by antibody conjugation. Methods for detecting such complexes, in addition to those described herein for the GST-immobilized complexes, include immunodetection of complexes using such other antibodies reactive with the antibody or antigen. [00234] The invention further pertains to new agents identified by any of the screening assays described herein and uses thereof for treatments as described herein. [00235] Chimeric antigen receptor (CAR) cell therapies [00236] Cellular therapies, such as chimeric antigen receptor (CAR) cell therapies, are also provided herein. For example, the cell can be a CAR T-cell or a CAR NK-cell. [00237] CAR cell therapies redirect a patient’s T-cells and/or NK-cells to kill tumor cells by the exogenous expression of a CAR on a T-cell or NK-cell, for example. A CAR can be a membrane spanning fusion protein that links the antigen recognition domain of an antibody to the intracellular signaling domains of the T-cell receptor and co-receptor or NK-cell receptor. [00238] In one embodiment, monospecific CAR cells are provided. For example, the anti- CLDN4 antibodies described herein can be used as the targeting moiety for the CAR cell. For example, the CLDN4 antibody can have low affinity but high avidity for its antigen. In another example, the CLDN4 antibody can have high affinity but low avidity for its antigen. Antibodies with fewer binding sites can have high affinity and low avidity, while those with greater binding sites can have low affinity and high avidity. [00239] In another embodiment, bispecific (or dual-targeted) CAR cells are provided. In another embodiment, the CAR cell is an engineered cell comprising a chimeric antigen receptor, wherein the chimeric antigen receptor comprises an extracellular ligand binding domain that is specific for a first antigen and a second antigen on the surface of a cancer cell, Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 wherein the first antigen comprises an antigen that is not CLDN4 and the second antigen comprises CLDN4. [00240] In embodiments, the anti-CLDN4 antibodies or the CLDN4 fusion proteins described herein can be used as a payload for armored CAR-cell therapies. A suitable cell can be used, for example, that can secrete an anti-CLDN4 antibody of the invention (or alternatively engineered to express an anti-CLDN4 antibody as described herein to be secreted). The anti- CLDN4 “payloads” to be secreted, can be, for example, minibodies, scFvs, IgG molecules, bispecific fusion molecules, and other antibody fragments as described herein. Upon contact or engineering, the cell described herein can then be introduced to a patient in need of a treatment by infusion therapies known to one of skill in the art. [00241] In embodiments, the patient can have a CLDN4-associated disease or disorder as described herein, such as cancer. The cell (e.g., a T cell) can be, for instance, T lymphocyte, a CD4+ T cell, a CD8+ T cell, or the combination thereof, without limitation. Exemplary CARs and CAR factories useful in aspects of the invention include those disclosed in, for example, PCT/US2015/067225 and PCT/US2019/022272, each of which are hereby incorporated by reference in their entireties. In one embodiment, the CLDN4 antibodies discussed herein can be used in the construction of multi-specific antibodies or as the payload for a CAR-T cell or CAR NK-cell. For example, in one embodiment, the anti-CLDN4 antibodies discussed herein can be used for the targeting of the CARs (i.e., as the targeting moiety). In another embodiment, the anti-CLDN4 antibodies discussed herein can be used as the targeting moiety, and a different CLDN4 antibody that targets a different epitope can be used as the payload. In another embodiment, the payload can be an immunomodulatory antibody payload. [00242] Solid tumors offer unique challenges for CAR-T therapies. Some barriers to CAR-T effectiveness in solid tumors include heterogeneous antigen expression, insufficient tissue homing, activation, persistence, and the immunosuppressive tumor microenvironment. Unlike blood cancers, tumor-associated target proteins are overexpressed between the tumor and healthy tissue resulting in on-target/off-tumor T-cell killing of healthy tissues. Furthermore, immune repression in the tumor microenvironment (TME) limits the activation of CAR-T cells towards killing the tumor. Upon such contact or engineering, the cell can then be introduced to a cancer patient in need of a treatment by infusion therapies known to one of skill in the art. The cancer patient can have a cancer of any of the types as disclosed herein. The cell (e.g., a T cell) can be, for instance, a tumor-infiltrating T lymphocyte, a CD4+ T cell, a CD8+ T cell, or the combination thereof, without limitation. Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 [00243] In embodiments, CAR cells (i.e., CAR T cells or CAR NK cells) can be generated according to methods known in the art using lentivirus systems (via transduction), retrovirus systems (via transfection (electroporation)), and transposon systems (via PiggyBac). Useful for promoters for payloads that can be used in the generating of CAR-Ts include, for example, constitutive promoters (where the promoter is the same as for CAR-T, such as EF1a then IRES or 2A); inducible promoters (where the promoter is different from the promoter for CAR-T, such as NFAT, IL-2 prom); and genetically engineered promoters (such as a CLDN4 locus “knock in” of cytokine and/or a promoter that is under the control of an endogenous promoter). In one embodiment, the CLDN4 antibodies or the CLDN4 fusion proteins discussed herein can be used in the construction of multi-specific antibodies or as the payload for a CAR cell. For example, in one embodiment, the anti-CLDN4 antibodies or the CLDN4 fusion proteins discussed herein can be used for the targeting of the CARS (i.e., as the targeting moiety). In one embodiment, the anti-CLDN4 antibodies or the CLDN4 fusion proteins discussed herein can be used as a payload to be secreted by a CAR cell. In another embodiment, the anti-CLDN4 antibodies or the CLDN4 fusion proteins discussed herein can be used as the targeting moiety, and a different CLDN4 antibody that targets a different epitope can be used as the payload. In another embodiment, the payload can be an immunomodulatory antibody payload. In some embodiments, the CLDN4 antibodies or the CLDN4 fusion proteins as described herein for use in CAR-T compositions are not high-affinity CLDN4 antibodies (for example, so that the antibody does not bind strongly to its CLDN4 target). For example, the CLDN4 antibodies or the CLDN4 fusion proteins described herein can be used as a payload secreted by the CAR cell, with the two targeting moieties (for example, tumor-associated surface antigens) selected for a specific cancer. Non-limiting examples of a tumor-associated surface antigen include ErbB2 (HER2/neu), carcinoembryonic antigen (CEA), epithelial cell adhesion molecule (EpCAM), epidermal growth factor receptor (EGFR), MUC1, MSLN, CD19, CD20, CD30, CD40, CD22, RAGE-l, MN-CAIX, RET1, RET2 (AS), prostate specific antigen (PSA), TAG- 72, PAP, p53, Ras, prostein, PSMA, survivin, 9D7, prostate-carcinoma tumor antigen-l (PCTA-1), GAGE, MAGE, mesothelin, β-catenin, TGF-βRII, BRCA1/2, SAP-1, HPV-E6, HPV-E7 (see also, PCT/US2015/067225 and PCT/US2019/022272 for additional tumor- associated surface antigens, which are incorporated by reference in their entireties). Exemplary armored CAR-T cells are listed in the table below. CART Payload Format Promoter Publication Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 ^{PSMA DN-TGFb Molecular Therapy 26: 1855 (2018)} ^{GD2 cJun cDNA Nature 576: 293(2019 )} ^{Fibronectin CD47 VHH Cancer Immunol Res. 8:518-529 (2020)} ^{PD-L1 PD-L1} ^CTLA-4 ^{GPC3 IL-12 J Immunol 2019; 203:198} ^{CD20 PD-1 Cancer Science. 2019;110:3079} ^{CD19 PD-1 nature biotechnology 36:847 (2018)} ^Muc16 ^{CD19 IL-18 Cell Reports 23:2130 (2018)} ^Muc16 CD19 IL-12 fusion IRES Scientific REPOrTS 7: 10541 (2017) ^Muc16 CD19 PD-1 scFv P2A Clin Cancer Res 23:6982 (2017) CAE IL-18 NFAT Cell Reports 21:3205 (2017)

can sources known to the skilled artisan. Non-limiting examples include T cells, NK cells, iPSC- derived cells (e.g., iPSC-derived T-cells and/or iPSC-derived NK cells), peripheral blood cells (e.g., peripheral blood mononuclear cells), cord blood cells, cell lines (e.g., NK92 cell line), human embryonic stem cells (hESCs) and CD34+ hematopoietic progenitor cells (HPCs). See, for example, Lu, Hui, et al. "From CAR-T cells to CAR-NK cells: a developing immunotherapy method for hematological malignancies." Frontiers in Oncology (2021): 3151. [00245] Chimeric B-cell Receptor [00246] A modified B cell receptor called chimeric B cell receptor, such as a B cell receptor containing an antibody or antibody fragment previously selected by high affinity against a specific disease associated antigen, is a powerful new approach against diseases. As B cells serve as professional antigen presenting cells, they can process and present antigens on MHC class II molecules, enhancing immune cell recognition of the tumor and assisting in neoantigen spreading. A key component of immunologic memory, chimeric antibody signaling and Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 secreting (CASS) B cells will simultaneously recruit a wide range of immune cells and reverse tumor infiltrating lymphocyte exhaustion, providing a robust and lifelong surveillance program protecting against tumor metastasis and recurrence. In embodiments, the B cell can include a receptor that is chimeric, non-natural and engineered at least in part by the hand of man. In certain cases, the engineered chimeric B cell receptor has one, two, three, four, or more components, and in some embodiments the one or more components facilitate targeting or binding of the B cell to one or more antigen-comprising cells. [00247] Aspects of the invention include genetically engineered B cells that are modified to express and bear on its surface a chimeric B cell receptor. In embodiments, the genetically modified B cell can comprise a single chimeric B cell receptor targeting one antigen, such as CLDN4, or a single chimeric B cell receptor targeting two or more antigens (e.g., a bi-specific chimeric B cell receptor, or a multispecific chimeric B cell receptor). In some embodiments, the cells comprise a split chimeric B cell receptor, such as two different scFvs expressed on the B cell surface with different co-stimulation domains. Further, some embodiments comprise a fine-tuned chimeric B cell receptor. [00248] In embodiments, the chimeric B cell receptor comprises an extracellular domain, a transmembrane domain, and an intracellular signaling domain; such that the polypeptides assemble together to form a chimeric B cell receptor. [00249] For example, the extracellular ligand-binding domain can be chosen to recognize a ligand, such as CLDN4, that acts as a cell surface marker on target cells associated with a disease state. For example, the disease state can be cancer, and the target ligand can be a cancer associated antigen, such as CLDN4. [00250] In embodiments, the extracellular ligand-binding domain can comprise an antigen binding domain or antigen recognition domain derived from an antibody against an antigen of the target, such as an anti-CLDN4 antibody described herein. In embodiments, the extracellular ligand-binding domain can comprise an antibody or fragment thereof described herein. [00251] In an embodiment, the transmembrane domain comprises a stalk region. The stalk region can be derived from all or part of naturally occurring molecules, such as from all or part of the extracellular region of CD8, CD4 or CD28, or from all or part of an antibody constant region (such as CH1, CH2, CH3, or both CH2 and CH3 for an IgG antibody, or CH1, CH2, CH3, CH4, or any combination thereof for an IgM antibody). In other embodiments, the stalk region can be a synthetic sequence that corresponds to a naturally occurring stalk sequence or can be an entirely synthetic stalk sequence. In an embodiment said stalk region is a part of human CD8 alpha chain. Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 [00252] The signal transducing domain or intracellular signaling domain of the chimeric B cell receptor of the invention is responsible for intracellular signaling following the binding of extracellular ligand binding domain to the target resulting in the activation of the immune cell and immune response. In other words, the signal transducing domain is responsible for the activation of at least one of the normal functions of the B cell in which the chimeric B cell receptor is expressed. Thus, the term "signal transducing domain" can refer to the portion of a protein which directs the cell to perform a specialized function, such as early activation of Lyn and Syk and late activation of NFAT and NFĸB as examples. [00253] The chimeric B cell receptor can comprise native transmembrane and intracellular domains. In native B cells, engagement of the B cell receptor leads to rapid tyrosine phosphorylation of the intracellular domains and calcium ion polarization, resulting in downstream activation of NFAT and NF-kB. Using the NFAT/NF-kB response elements to drive expression of our secreted proteins, we have designed an inducible expression system that will be activated by antigens associated with disease states, such as cancer. [00254] The distinguishing features of appropriate transmembrane polypeptides comprise the ability to be expressed at the surface of an immune cell, such as B cells, and to interact together for directing cellular response of immune cell against a predefined target cell. The different transmembrane polypeptides of the chimeric B cell receptor comprising an extracellular ligand- binding domain and/or a signal transducing domain interact together to take part in signal transduction following the binding with a target ligand and induce an immune response. The transmembrane domain can be derived from a natural or from a synthetic source. The transmembrane domain can be derived from any membrane-bound or transmembrane protein. [00255] Methods of Treatment [00256] As used herein, the terms “treat” or “treatment” refer to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an unsought physiological change or disorder, such as the progression of cancer. Beneficial or preferred clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can refer to prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented. Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 [00257] The invention provides for both prophylactic and therapeutic methods of treating a subject at risk of (or susceptible to) a cancer (for example, if an early detection cancer biomarker is identified in such a subject), or other cell proliferation-related diseases or disorders. Such diseases or disorders include but are not limited to, e.g., those diseases or disorders associated with aberrant expression of CLDN4 and/or aberrant activation of cellular signaling pathways involving CLDN4. Such diseases or disorders are included in CLDN- associated disease or disorders. For example, the methods are used to treat, prevent, or alleviate a symptom of cancer. In an embodiment, the methods are used to treat, prevent, or alleviate a symptom of a solid tumor. Non-limiting examples of other tumors that can be treated by compositions described herein comprise lung cancer, kidney cancer, ovarian cancer, prostate cancer, colon cancer, cervical cancer, uterine cancer, brain cancer, skin cancer, liver cancer, pancreatic cancer, or stomach cancer. Additionally, the methods of the invention can be used to treat hematologic cancers such as leukemia and lymphoma. Alternatively, the methods can be used to treat, prevent, or alleviate a symptom of a cancer that has metastasized. For example, cancers that can be treated or prevented or for which symptoms can be alleviated include B- cell chronic lymphocytic leukemia (CLL), non-small-cell lung cancer, melanoma, ovarian cancer, lymphoma, or renal-cell cancer. Cancers that can also be treated or prevented or for which symptoms can be alleviated include those solid tumors with a high mutation burden and WBC in filtrate. [00258] Accordingly, in one aspect, the invention provides methods for preventing, treating, or alleviating a symptom cancer or a cell proliferative disease or disorder in a subject by administering to the subject a monoclonal antibody, scFv antibody or bi- specific antibody of the invention. For example, an anti-CLDN4 antibody can be administered in therapeutically effective amounts. [00259] Subjects at risk for cancer or cell proliferation-related diseases or disorders can include patients who have a family history of cancer or a subject exposed to a known or suspected cancer-causing agent. Administration of a prophylactic agent can occur prior to the manifestation of cancer such that the disease is prevented or, alternatively, delayed in its progression. [00260] In another aspect, tumor cell growth is inhibited by contacting a cell with an anti- CLDN4 antibody of the invention. The cell can be any cell that expresses CLDN4. [00261] The invention further provides for both prophylactic and therapeutic methods of treating a subject at risk of (or susceptible to) a chronic or acute viral, bacterial, or parasitic infection. The invention also provides for therapeutic methods for both prophylactic and Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 therapeutic methods of treating a subject at risk of a disease or disorder or condition associated with T-cell exhaustion or a risk of developing T-cell exhaustion. The invention also provides for therapeutic methods for both prophylactic and therapeutic methods of treating a subject at risk of a disease or disorder or condition associated with T-cell exhaustion or a risk of developing T-cell exhaustion. Such diseases or disorder include, but are not limited to HIV, AIDS, and chronic or acute bacterial, viral or parasitic infections. Other such chronic infections include those caused by, for example, hepatitis B virus (HBV), hepatitis C virus (HCV), herpes simplex virus 1 (HSV-1), H. pylori, or Toxoplasma gondii. Other acute infections included are those caused by, for example, microorganisms, such as a Gram-positive bacterium, a Gram-negative bacterium, a protozoan, or a fungus, as described herein. [00262] Also included in the invention are methods of increasing or enhancing an immune response to an antigen. An immune response is increased or enhanced by administering to the subject a monoclonal antibody, scFv antibody, or bi-specific antibody of the invention. The immune response is augmented for example by augmenting antigen specific T effector function. The antigen is a viral (e.g., HIV), bacterial, parasitic or tumor antigen. The immune response is a natural immune response. By natural immune response is meant an immune response that is a result of an infection. The infection is a chronic infection. Increasing or enhancing an immune response to an antigen can be measured by a number of methods known in the art. For example, an immune response can be measured by measuring any one of the following: T cell activity, T cell proliferation, T cell activation, production of effector cytokines, and T cell transcriptional profile. Alternatively, the immune response is a response induced due to a vaccination. [00263] Accordingly, in another aspect the invention provides a method of increasing vaccine efficiency by administering to the subject a monoclonal antibody or scFv antibody of the invention and a vaccine. The antibody and the vaccine are administered sequentially or concurrently. The vaccine is a tumor vaccine a bacterial vaccine or a viral vaccine. [00264] Combinatory Methods [00265] Compositions of the invention as described herein can be administered in combination with a chemotherapeutic agent. Chemotherapeutic agents that can be administered with the compositions of the disclosure include, but are not limited to, antibiotic derivatives (e.g., doxorubicin, bleomycin, daunorubicin, and dactinomycin); antiestrogens (e.g., tamoxifen); antimetabolites (e.g., fluorouracil, 5-FU, methotrexate, floxuridine, interferon alpha-2b, glutamic acid, plicamycin, mercaptopurine, and 6-thioguanine); cytotoxic agents (e.g., carmustine, BCNU, lomustine, CCNU, cytosine arabinoside, cyclophosphamide, Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 estramustine, hydroxyurea, procarbazine, mitomycin, busulfan, cis-platin, and vincristine sulfate); hormones (e.g., medroxyprogesterone, estramustine phosphate sodium, ethinyl estradiol, estradiol, megestrol acetate, methyltestosterone, diethylstilbestrol diphosphate, chlorotrianisene, and testolactone); nitrogen mustard derivatives (e.g., mephalen, chorambucil, mechlorethamine (nitrogen mustard) and thiotepa); steroids and combinations (e.g., bethamethasone sodium phosphate); and others (e.g., dicarbazine, asparaginase, mitotane, vincristine sulfate, vinblastine sulfate, and etoposide). [00266] In additional embodiments, the compositions of the invention as described herein can be administered in combination with cytokines. Cytokines that can be administered with the compositions include, but are not limited to, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-10, IL- 12, IL-13, IL-15, anti-CD40, CD40L, and TNF-α. [00267] In additional embodiments, the compositions described herein can be administered in combination with other therapeutic or prophylactic regimens, such as, for example, radiation therapy. [00268] In some embodiments, the compositions described herein can be administered in combination with other immunotherapeutic agents. Non-limiting examples of immunotherapeutic agents include simtuzumab, abagovomab, adecatumumab, afutuzumab, alemtuzumab, altumomab, amatuximab, anatumomab, arcitumomab, bavituximab, bectumomab, bevacizumab, bivatuzumab, blinatumomab, brentuximab, cantuzumab, catumaxomab, cetuximab, citatuzumab, cixutumumab, clivatuzumab, conatumumab, daratumumab, drozitumab, duligotumab, dusigitumab, detumomab, dacetuzumab, dalotuzumab, ecromeximab, elotuzumab, ensituximab, ertumaxomab, etaracizumab, farletuzumab, ficlatuzumab, figitumumab, flanvotumab, futuximab, ganitumab, gemtuzumab, girentuximab, glembatumumab, ibritumomab, igovomab, imgatuzumab, indatuximab, inotuzumab, intetumumab, ipilimumab, iratumumab, labetuzumab, lexatumumab, lintuzumab, lorvotuzumab, lucatumumab, mapatumumab, matuzumab, milatuzumab, minretumomab, mitumomab, moxetumomab, narnatumab, naptumomab, necitumumab, nimotuzumab, nofetumomab, ocaratuzumab, ofatumumab, olaratumab, onartuzumab, oportuzumab, oregovomab, panitumumab, parsatuzumab, patritumab, pemtumomab, pertuzumab, pintumomab, pritumumab, racotumomab, radretumab, rilotumumab, rituximab, robatumumab, satumomab, sibrotuzumab, siltuximab, solitomab, tacatuzumab, taplitumomab, tenatumomab, teprotumumab, tigatuzumab, tositumomab, trastuzumab, tucotuzumab, ublituximab, veltuzumab, vorsetuzumab, votumumab, zalutumumab, CC49, and 3F8. Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 [00269] The invention provides for methods of treating cancer in a patient by administering two antibodies that bind to the same epitope of the CLDN4 protein or, alternatively, two different epitopes of the CLDN4 protein. Alternatively, the cancer can be treated by administering a first antibody that binds to CLDN4 and a second antibody that binds to a protein other than CLDN4. In other embodiments, the cancer can be treated by administering a bispecific antibody that binds to CLDN4 and that binds to a protein other than CLDN4. For example, the other protein other than CLDN4 can include, but is not limited to, IL-12, IL-12R, IL-2, IL-2R, IL-15, IL-15R, IL-7, IL-7R, IL-21, or IL-21R. For example, the other protein other than CLDN4 is a tumor-associated antigen; the other protein other than CLDN4 can also be a cytokine. Non-limiting examples of the other protein other than CLDN4 includes CTLA- 4, CXCR4, LAG-3, CD28, CD122, 4-1BB, TIM3, OX-40, OX40L, CD40, CD40L, LIGHT, ICOS, ICOSL, GITR, GITRL, TIGIT, CD27, VISTA, B7H3, B7H4, HEVM (or BTLA), CD47 and CD73. [00270] In some embodiments, the invention provides for the administration of an anti-PD- 1 antibody alone or in combination with an additional antibody that recognizes another protein other than CLDN4, with cells that can effect or augment an immune response. For example, these cells can be peripheral blood mononuclear cells (PBMC), or any cell type that is found in PBMC, e.g., cytotoxic T cells, macrophages, and natural killer (NK) cells. [00271] Additionally, the invention provides administration of an antibody that binds to the CLDN4 protein and an anti-neoplastic agent, such as a small molecule, a growth factor, a cytokine or other therapeutic including biomolecules such as peptides, peptidomimetics, peptoids, polynucleotides, lipid-derived mediators, small biogenic amines, hormones, neuropeptides, and proteases. Small molecules include, but are not limited to, inorganic molecules and small organic molecules. Suitable growth factors or cytokines include an IL-2, GM-CSF, IL-12, and TNF-alpha. Small molecule libraries are known in the art. (See, Lam, Anticancer Drug Des., 12: 145, 1997.) [00272] Diagnostic Assays [00273] The anti-CLDN4 antibodies can be used diagnostically to, for example, monitor the development or progression of cancer as part of a clinical testing procedure to, e.g., determine the efficacy of a given treatment and/or prevention regimen. [00274] In some embodiments, for diagnostic purposes, the anti-CLDN4 antibody of the invention is linked to a detectable moiety, for example, so as to provide a method for detecting a cancer cell in a subject at risk of or suffering from a cancer. Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 [00275] The detectable moieties can be conjugated directly to the antibodies or fragments, or indirectly by using, for example, a fluorescent secondary antibody. Direct conjugation can be accomplished by standard chemical coupling of, for example, a fluorophore to the antibody or antibody fragment, or through genetic engineering. Chimeras, or fusion proteins can be constructed which contain an antibody or antibody fragment coupled to a fluorescent or bioluminescent protein. For example, Casadei, et al, (Proc Natl Acad Sci U S A. 1990 Mar;87(6):2047-51) describe a method of making a vector construct that can express a fusion protein of aequorin and an antibody gene in mammalian cells. [00276] As used herein, the term "labeled", with regard to the probe or antibody, can encompass direct labeling of the probe or antibody by coupling (i.e., physically linking) a detectable substance to the probe or antibody, as well as indirect labeling of the probe or antibody by reactivity with another reagent that is directly labeled. Examples of indirect labeling include detection of a primary antibody using a fluorescently-labeled secondary antibody and end-labeling of a DNA probe with biotin such that it can be detected with fluorescently-labeled streptavidin. The term "biological sample" is intended to include tissues, cells and biological fluids isolated from a subject (such as a biopsy), as well as tissues, cells and fluids present within a subject. That is, the detection method of the invention can be used to detect cells that express CLDN4 in a biological sample in vitro as well as in vivo. For example, in vitro techniques for detection of CLDN4 include enzyme linked immunosorbent assays (ELISAs), Western blots, immunoprecipitations, and immunofluorescence. Furthermore, in vivo techniques for detection of CLDN4 include introducing into a subject a labeled anti-CLDN4 antibody. For example, the antibody can be labeled with a radioactive marker whose presence and location in a subject can be detected by standard imaging techniques. [00277] In the case of "targeted" conjugates, that is, conjugates which contain a targeting moiety— a molecule or feature designed to localize the conjugate within a subject or animal at a specific site or sites, localization can refer to a state when an equilibrium between bound, "localized", and unbound, "free" entities within a subject has been essentially achieved. The rate at which such equilibrium is achieved depends upon the route of administration. For example, a conjugate administered by intravenous injection can achieve localization within minutes of injection. On the other hand, a conjugate administered orally can take hours to achieve localization. Alternatively, localization can simply refer to the location of the entity within the subject or animal at selected time periods after the entity is administered. By way Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 of another example, localization is achieved when an moiety becomes distributed following administration. [00278] A reasonable estimate of the time to achieve localization can be made by one skilled in the art. Furthermore, the state of localization as a function of time can be followed by imaging the detectable moiety (e.g., a light-emitting conjugate) according to the methods of the invention, such as with a photodetector device. The "photodetector device" used can have a high enough sensitivity to allow for the imaging of faint light from within a mammal in a reasonable amount of time, and to use the signal from such a device to construct an image. [00279] In cases where it is possible to use light-generating moieties which are extremely bright, and/or to detect light-generating fusion proteins localized near the surface of the subject or animal being imaged, a pair of "night- vision" goggles or a standard high- sensitivity video camera, such as a Silicon Intensified Tube (SIT) camera (e.g., from Hammamatsu Photonic Systems, Bridgewater, N.J.), can be used. However, a more sensitive method of light detection is required. [00280] In extremely low light levels, the photon flux per unit area becomes so low that the scene being imaged no longer appears continuous. Instead, it is represented by individual photons which are both temporally and spatially distinct form one another. Viewed on a monitor, such an image appears as scintillating points of light, each representing a single detected photon. By accumulating these detected photons in a digital image processor over time, an image can be acquired and constructed. In contrast to conventional cameras where the signal at each image point is assigned an intensity value, in photon counting imaging the amplitude of the signal carries no significance. The objective is to simply detect the presence of a signal (photon) and to count the occurrence of the signal with respect to its position over time. [00281] At least two types of photodetector devices, described herein, can detect individual photons and generate a signal which can be analyzed by an image processor. Reduced-Noise Photodetection devices achieve sensitivity by reducing the background noise in the photon detector, as opposed to amplifying the photon signal. Noise is reduced primarily by cooling the detector array. The devices include charge coupled device (CCD) cameras referred to as "backthinned", cooled CCD cameras. In the more sensitive instruments, the cooling is achieved using, for example, liquid nitrogen, which brings the temperature of the CCD array to approximately -120°C. "Backthinned" refers to an ultra- thin backplate that reduces the path length that a photon follows to be detected, thereby increasing the quantum efficiency. A Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 sensitive backthinned cryogenic CCD camera is the "TECH 512", a series 200 camera available from Photometries, Ltd. (Tucson, Ariz.). [00282] "Photon amplification devices" amplify photons before they hit the detection screen. This class includes CCD cameras with intensifiers, such as microchannel intensifiers. A microchannel intensifier contains a metal array of channels perpendicular to and co-extensive with the detection screen of the camera. The microchannel array is placed between the sample, subject, or animal to be imaged, and the camera. Most of the photons entering the channels of the array contact a side of a channel before exiting. A voltage applied across the array results in the release of many electrons from each photon collision. The electrons from such a collision exit their channel of origin in a "shotgun" pattern and are detected by the camera. [00283] Even greater sensitivity can be achieved by placing intensifying microchannel arrays in series, so that electrons generated in the first stage in turn result in an amplified signal of electrons at the second stage. Increases in sensitivity, however, are achieved at the expense of spatial resolution, which decreases with each additional stage of amplification. An exemplary microchannel intensifier-based single-photon detection device is the C2400 series, available from Hamamatsu. [00284] Image processors process signals generated by photodetector devices which count photons to construct an image which can be, for example, displayed on a monitor or printed on a video printer. Such image processors are sold as part of systems which include the sensitive photon-counting cameras described herein, and accordingly, are available from the same sources. The image processors are connected to a personal computer, such as an IBM- compatible PC or an Apple Macintosh (Apple Computer, Cupertino, Calif), which can or cannot be included as part of a purchased imaging system. Once the images are in the form of digital files, they can be manipulated by a variety of image processing programs (such as "ADOBE PHOTOSHOP", Adobe Systems, Adobe Systems, Mt. View, Calif.) and printed. [00285] In an embodiment, the biological sample contains protein molecules from the test subject. One exemplary biological sample is a peripheral blood leukocyte sample isolated by conventional means from a subject. [00286] The invention also encompasses kits for detecting the presence of CLDN4 or a TIGIT-expressing cell in a biological sample. For example, the kit can comprise: a labeled compound or agent that can of detect a cancer or tumor cell (e.g., an anti-CLDN4 scFv or monoclonal antibody) in a biological sample; means for determining the amount of CLDN4 in the sample; and means for comparing the amount of CLDN4 in the sample with a standard. The standard is, in some embodiments, a non-cancer cell or cell extract thereof. The compound Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 or agent can be packaged in a suitable container. The kit can further comprise instructions for using the kit to detect cancer in a sample. [00287] Other Embodiments [00288] While the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims. [00289] The invention is further described in the following examples, which do not limit the scope of the invention described in the claims. EXAMPLES [00290] Examples are provided below to facilitate a more complete understanding of the invention. The following examples illustrate the exemplary modes of making and practicing the invention. However, the scope of the invention is not limited to specific embodiments disclosed in these Examples, which are for purposes of illustration only, since alternative methods can be utilized to obtain similar results. EXAMPLE 1 – Claudin 4 as a therapeutic target [00291] We have identified two anti-claudin4 scFvs (Gly1-4-G3 and Gly1-2-F4) via whole cell panning. We performed 3 rounds of panning, alternating between 293T and Cf2Th cells transduced to stably express CLDN4. Our scfvs display minimal cross reactivity with the structurally related protein claudin3. [00292] Claudin 4 is a therapeutic target for numerous cancers, including triple negative breast cancer, pancreatic cancer, and biliary tract cancers. Our scFv is able to specifically target CLDN4 and can be used for targeting of CAR T cells. [00293] These scFvs can be developed as monoclonal antibodies for therapeutic or diagnostic purposes. Additionally, they can be used as a targeting moiety for CAR T cells against cancers that overexpress CLND4. EXAMPLE 2 [00294] – We have transiently transfected 293T cells with CLDN-3 plasmid Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 [00295] - Low to no background binding of antibodies to 293T without CLDN-3 or CLDN- 4 [00296] – a CLDN-3 antibody specifically recognized only CLDN-3 cell line [00297] – a CDLN-4 antibodies bound CLDN-3 cell line weakly [00298] - Some 293T CLDN-4 cells can have lost CLDN-4 expression [00299] - We can perform assay of binding of a CLDN-4 minibodies to CLDN-3 expressing cell line ***** EQUIVALENTS [00300] Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific substances and procedures described herein. Such equivalents are considered to be within the scope of this invention and are covered by the following claims.

Claims

Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 What is claimed: 1. An antibody or antigen-binding fragment thereof that binds to a claudin 4 (CLDN4) protein or fragment thereof, comprising a heavy chain, light chain, or both a heavy chain and a light chain, wherein the heavy chain comprises a HCDR1 comprising GFTFNNYA (SEQ ID NO: 9), GFTFGGYA (SEQ ID NO: 12), GGTFSSYA (SEQ ID NO: 15), or GGTFNNYA (SEQ ID NO: 18), HCDR2 comprising IRDSGGST (SEQ ID NO: 10), LSNSGSNA (SEQ ID NO: 13), or IIPIVDIA (SEQ ID NO: 16), HCDR3 comprising ARRGYSSSWYGDGYYYGMDV, (SEQ ID NO: 11), ARAVMSSSWYMRRYYYYYMDV (SEQ ID NO: 14), or ARGGSQGAYYMDV (SEQ ID NO: 17), or a combination of CDRs thereof; and wherein the light chain comprises a LCDR1 comprising SGSIASSF (SEQ ID NO: 19), RSNIGSNT (SEQ ID NO: 22), SGSIASNY (SEQ ID NO: 25), or QSVSNY (SEQ ID NO: 28), LCDR2 comprising ENN (SEQ ID NO: 20), SNN (SEQ ID NO: 23), EDN (SEQ ID NO: 26), or GAS (SEQ ID NO: 29), LCDR3 comprising QSYDSTSHV (SEQ ID NO: 21), AAWDDSLNGLYV (SEQ ID NO: 24), QSYDDSNRVV (SEQ ID NO: 27), or HQYGSLPQT (SEQ ID NO: 30), or a combination of CDRs thereof. 2. The antibody of claim 1, comprising a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 1, 3, 5, and 7, or a sequence at least 90% identical thereto, and a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 2, 4, 6, and 8, or a sequence at least 90% identical thereto. 3. An antibody as described herein. 4. A therapeutic antibody that binds claudin 4 (CLDN4) comprising a variable domain and a constant domain, wherein the constant domain is IgG and the variable domain comprises a framework region and a complementary determining means for binding claudin 4. 5. The antibody of claim 4, wherein the constant region is IgG1 or IgG4. Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 6. An isolated antibody or fragment thereof that binds to a human claudin 4 protein comprising: (a) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 9, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 10, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 11, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 19, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 20, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 21; or (b) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 12, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 13, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 14, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 22, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 23, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 24; or (c) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 15, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 16, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 17, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 25, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 27; or (d) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 18, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 16, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 17, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 28, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 29, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 30. 7. An isolated scFv antibody that binds to a human claudin 4 protein comprising: (a) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 9, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 10, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 11, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 19, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 20, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 21; or (b) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 12, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 13, a VH CDR3 comprising Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 the amino acid sequence of SEQ ID NO: 14, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 22, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 23, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 24; or (c) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 15, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 16, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 17, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 25, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 27; or (d) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 18, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 16, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 17, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 28, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 29, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 30. 8. An isolated antibody or fragment thereof that binds to a human claudin 4 protein, comprising a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 1, 3, 5, and 7, or a sequence at least 90% identical thereto, and a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 2, 4, 6, and 8, or a sequence at least 90% identical thereto. 9. An isolated scFv that binds to a human claudin 4 protein, comprising a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 1, 3, 5, and 7, or a sequence at least 90% identical thereto, and a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 2, 4, 6, and 8, or a sequence at least 90% identical thereto. 10. A F(ab) that binds claudin 4, comprising: (a) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 9, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 10, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 11, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 19, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 20, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 21; or Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 (b) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 12, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 13, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 14, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 22, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 23, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 24; or (c) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 15, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 16, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 17, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 25, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 27; or (d) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 18, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 16, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 17, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 28, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 29, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 30. 11. A VhH that binds claudin 4, comprising: (a) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 9, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 10, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 11; or (b) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 12, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 13, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 14; or (c) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 15, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 16, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 17; or (d) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 18, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 16, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 17. 12. An isolated bispecific antibody, comprising the fragment of any one of claims 1-11 and a second antigen-binding fragment having specificity to a molecule on an immune cell. Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 13. The bispecific antibody of claim 12, wherein the molecule is selected from the group consisting of CCR4, B7H3, B7H4, CD27, CD28, CD40, CD40L, CD47, CD122, CTLA-4, GITR, GITRL, ICOS, ICOSL, LAG-3, LIGHT, OX-40, OX40L, PD-1, TIM3, 4-1BB, TIGIT, VISTA, HEVM, BTLA, and KIR. 14. The bispecific antibody of claim 12, wherein the fragment and the second fragment each is independently selected from a Fab fragment, a single-chain variable fragment (scFv), or a single-domain antibody. 15. The bispecific antibody of claim 12, further comprising a Fc fragment. 16. A bispecific T cell engager (BiTE) that binds to a human claudin 4 protein comprising: (a) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 9, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 10, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 11, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 19, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 20, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 21; or (b) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 12, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 13, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 14, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 22, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 23, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 24; or (c) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 15, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 16, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 17, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 25, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 27; or (d) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 18, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 16, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 17, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 28, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 29, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 30. Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 17. A bispecific T cell engager (BiTE) that binds to a human claudin 4 protein, comprising a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 1, 3, 5, and 7, or a sequence at least 90% identical thereto, and a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 2, 4, 6, and 8, or a sequence at least 90% identical thereto. 18. The antibody of any one of claims 1-11 having at least 90% sequence identity. 19. A nucleic acid encoding an antibody of any one of claims 1-11, wherein: the nucleic acid sequence encoding HCDR1 is SEQ ID NO: 62, SEQ ID NO: 65, SEQ ID NO: 68, or SEQ ID NO: 71, or a degenerate variant thereof; the nucleic acid sequence encoding HCDR2 is SEQ ID NO: 63, SEQ ID NO: 66, SEQ ID NO: 69, or SEQ ID NO: 72, or a degenerate variant thereof; the nucleic acid sequence encoding HCDR3 is SEQ ID NO: 64, SEQ ID NO: 67, SEQ ID NO: 70, or SEQ ID NO: 73, or a degenerate variant thereof; the nucleic acid sequence encoding LCDR1 is SEQ ID NO: 74, SEQ ID NO: 77, SEQ ID NO: 80, or SEQ ID NO: 83, or a degenerate variant thereof; the nucleic acid sequence encoding LCDR2 is SEQ ID NO: 75, SEQ ID NO: 78, SEQ ID NO: 81, or SEQ ID NO: 84, or a degenerate variant thereof; and the nucleic acid sequence encoding LCDR3 is SEQ ID NO: 76, SEQ ID NO: 79, SEQ ID NO: 82, or SEQ ID NO: 85, or a degenerate variant thereof. 20. A nucleic acid encoding an antibody of any one of claims 1-11, wherein: the nucleic acid sequence encoding HCVR is SEQ ID NO: 86, SEQ ID NO: 87, SEQ ID NO: 88, or SEQ ID NO: 89,or a degenerate variant thereof; and the nucleic acid sequence encoding LCVR is SEQ ID NO: 90, , SEQ ID NO: 91, SEQ ID NO: 92, or SEQ ID NO: 93, or a degenerate variant thereof. 21. A pharmaceutical composition, comprising: the antibody of any one of claims 1-11, and one or more pharmaceutically acceptable carriers, diluents, or excipients. 22. The pharmaceutical composition of claim 21, comprising: (a) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 9, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 10, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 11, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 19, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 20, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 21; or Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 (b) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 12, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 13, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 14, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 22, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 23, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 24; or (c) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 15, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 16, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 17, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 25, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 27; or (d) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 18, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 16, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 17, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 28, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 29, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 30. 23. The pharmaceutical composition of claim 21, comprising a heavy chain variable region (HCVR) and a light chain variable region (LCVR), wherein the amino acid sequence of the HCVR is SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 5, or SEQ ID NO: 7, and the amino acid sequence of the LCVR is SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6, or SEQ ID NO: 8. 24. A nucleic acid encoding the antibody or fragment according to any one of claims 1- 11. 25. A nucleic acid encoding the bispecific antibody according to any one of claims 12-15. 26. A nucleic acid encoding the BiTE according to any one of claims 16-17. 27. The antibody or fragment according to any one of claims 1-11, the bispecific antibody according to any one of claims 12-15, or the BiTE according to any one of claims 16- 17, wherein the antibody, fragment or bispecific antibody binds to claudin 3 with a binding affinity at least 5-, 10-, 25-, 50-, 100-, or 1000-fold less than the antibody, fragment or bispecific antibody binds to claudin 4. 28. An engineered cell comprising a chimeric antigen receptor, wherein the chimeric antigen receptor comprises an extracellular ligand binding domain that is specific for Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 an antigen on the surface of a cancer cell, wherein the antigen comprises claudin 4, wherein the extracellular ligand binding domain comprises an antibody or fragment thereof, where the antibody or fragment thereof comprises: (a) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 9, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 10, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 11, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 19, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 20, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 21; or (b) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 12, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 13, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 14, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 22, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 23, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 24; or (c) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 15, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 16, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 17, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 25, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 27; or (d) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 18, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 16, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 17, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 28, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 29, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 30. 29. The engineered cell of claim 28, wherein the antibody or fragment thereof comprises a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 1, 3, 5, and 7, or a sequence at least 90% identical thereto, and a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 2, 4, 6, and 8, or a sequence at least 90% identical thereto. 30. The engineered cell of claim 28, wherein the cell comprises a T cell, an NK cell, an NKT cell, an iPS cell, an iPS-derived cell, a cell line, or a B cell. Docket No.: 5031461-133-WO1 Date of Filing: August 15, 2023 31. The engineered cell of claim 28, wherein the cell comprises a CD4+, CD8+, CD3+ pan T cells, or any combination thereof. 32. A method of treating cancer comprising administering to a subject in need thereof an effective amount of (a) the antibody of any one of claims 1-11, or (b) the pharmaceutical composition of claim 21. 33. A method of inhibiting claudin 4 in a subject, comprising administering to the subject an effective amount of (a) the antibody of any one of claims 1-11, or (b) the pharmaceutical composition of claim 21. 34. The method of claim 33, comprising a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 1, 3, 5, and 7, or a sequence at least 90% identical thereto, and a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 2, 4, 6, and 8, or a sequence at least 90% identical thereto. 35. Use of (a) the antibody of any one of claims 1-11, or (b) the pharmaceutical composition of claim 21 for treating cancer. 36. The antibody of any one of claims 1-11, or (b) the pharmaceutical composition of claim 21 for use in therapy. 37. The antibody of any one of claims 1-11, or (b) the pharmaceutical composition of claim 21 for use in treating cancer.