TRP-1 binding antibodies and chimeric antigen receptors for targeting melanoma

Abstract

Disclosed are compositions and methods for targeted treatment of TRP1-expressing cancers. In particular, recombinant antibodies and chimeric antigen receptors capable of targeting TRP1-expressing malignant cells.

Description

ATTORNEY DOCKET NO. MOE 24MB020 PCTTRP-1 BINDING ANTIBODIES AND CHIMERIC ANTIGEN RECEPTORS FOR TARGETING MELANOMA CROSS-REFERENCE TO RELATED APPLICATIONSThis application claims benefit of U.S. Provisional Application No. 63 / 684,054, filed August 16, 2024 and U.S Provisional Application No. 63 / 691,541, filed September 06, 2024, is hereby incorporated herein by reference in its entirety.SEQUENCE LISTINGThis application contains a sequence listing filed in ST.26 format entitled “MOF 24MB020 PCT Sequence Listing” created on August 14, 2025 and having 230,026 bytes. The content of the sequence listing is incorporated herein in its entirety.BACKGROUND OF THE INVENTIONSurgery, radiation therapy, and chemotherapy have been the standard accepted approaches for treatment of cancers including leukemia, solid tumors, and metastases. Immunotherapy (sometimes called biological therapy, biotherapy, or biological response modifier therapy), which uses the body’s immune system, either directly or indirectly, to shrink or eradicate cancer has been studied for many years as an adjunct to conventional cancer therapy. It is believed that the human immune system is an untapped resource for cancer therapy and that effective treatment can be developed once the components of the immune system are properly harnessed.A major advance for anti-cancer T cell therapy is the chimeric antigen receptor (CAR), which is a single chain variable fragment (scFv) derived from an antibody fused to the signaling domains of a T cell receptor (TCR) (Davila, M.L., et al., Oncoimmunology, 2012. 1(9): 1577- 1583). The intracellular domain of a first- generation CAR includes only CD3ij, while second-generation CARs also include co-stimulatory domains such as CD28 or 4 IBB. These second-generation CAR domains support highly-efficacious tumor killing in mice and led to the clinical evaluation of CAR T cell therapies in patients. The potential of CD19-targeted CAR T cells was confirmed by reports of complete remission rates of 90% for patients with B cell acute lymphoblastic leukemia (B-ALL) (Davila, M.L., et al., Sci Transl Med, 2014. 6(224) :224ra25; Maude, S.L., et al., N Engl J Med, 2014. 371 (16) : 1507- 17). However, poor CAR T cell persistence and excessive T cell activation contribute to relapses and severe toxicities, respectively, and suggest a critical need to understand CAR T cell biology (Gangadhar, T.C. and R.H. Vonderheide, Nat Rev Clin Oncol, 2014. 11(2):91- 9). Furthermore, relapses and toxicities have been seen with all second-generation CARs suggesting that the addition of co-stimulatory domains to CARs improved efficacy, but at the cost of biologic complications.45753670.1 1ATTORNEY DOCKET NO. MOE 24MB020 PCTAny discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present disclosure as it existed before the priority date of each claim of this application.BRIEF SUMMARY OF THE INVENTIONDisclosed herein are anti-tyrosinase-related protein 1 (TRP1) antibodies and chimeric antigen receptor (CAR) polypeptides that can be used to target and kill cancers. The disclosed CAR polypeptides contain an ectodomain that contains an anti-TRPl binding domain, a hinge domain, a transmembrane (TM) domain, and an endodomain that contains a signaling region. In some embodiments, the endodomain of the disclosed CAR polypeptides contains an intracellular domain of an NK cell receptor and does not require the signaling domain from CD3 zeta (CD3Q.The disclosed CAR polypeptides therefore utilize a completely different signaling route (NKG2D / DAP10) than current CAR-T cells (CD3, 0X40, ICOS, etc.). Because the signaling route does not rely on CD3^ or ZAP70 signaling, it may be insensitive to PD-1 -mediated inhibition. Moreover, studies have shown that in T cells, NKG2D / DAP10 results in target killing, memory formation (Perez C, et al. J Immunother Cancer 2019), can substitute the need for CD4 help help’ (Zloza A, et al. Nat Med 2012 18:422-8), mediate resistance to immune suppression by TGF-P, and enhanced migratory properties.Therefore, disclosed herein is a CAR polypeptide having an anti-TRPl binding domain, a hinge domain, a transmembrane domain, and an endodomain that contains an NK cell receptor intracellular domain, or fragment thereof capable of activating NK cell killing. In some embodiments, the CAR polypeptide further contains the NK cell receptor extracellular domain, or a fragment thereof.The disclosed polypeptides can in some embodiments further contain in the endodomain additional motifs, such as one or more DAP10 or other signaling motifs, e.g. 0X40, ICOS, CD3, etc. However, in some embodiments, the CAR polypeptides lack any other intracellular signaling or co-stimulatory domains, such as a CD3 , 41BB, and / or CD28 domains.Also disclosed are isolated nucleic acid sequences encoding the disclosed CAR polypeptides, vectors comprising these isolated nucleic acids, and cells containing these vectors. For example, the cell can be an immune effector cell selected from the group consisting of an alphabeta T cells, a gamma-delta T cell, a Natural Killer (NK) cells, a Natural Killer T (NKT) cell, a B cell, an innate lymphoid cell (ILC), a cytokine induced killer (CIK) cell, a cytotoxic T lymphocyte (CTL), a lymphokine activated killer (LAK) cell, and a regulatory T cell.45753670.1 2ATTORNEY DOCKET NO. MOE 24MB020 PCTIn some embodiments, the cell exhibits an anti-tumor immunity when the antigen binding domain of the CAR binds to a TRP 1 on a tumor.In some embodiments, the cell exhibits an anti-tumor immunity when the antigen binding domain of the CAR binds to a TAA on a tumor.Also disclosed is a method of providing an anti-tumor immunity in a subject with a TAA- expressing cancer that involves administering to the subject an effective amount of an immune effector cell genetically modified with a disclosed TRP 1 -specific CAR.Also disclosed are isolated nucleic acid sequences encoding the disclosed polypeptides, vectors comprising these isolated nucleic acids, and cells containing these vectors. For example, the cell can be an immune effector cell selected from the group consisting of an alpha-beta T cells, a gamma-delta T cell, a Natural Killer (NK) cells, a Natural Killer T (NKT) cell, a B cell, an innate lymphoid cell (ILC), a cytokine induced killer (CIK) cell, a cytotoxic T lymphocyte (CTL), a lymphokine activated killer (LAK) cell, and a regulatory T cell.In some embodiments, the cell exhibits an anti-tumor immunity when the antibody binds to TRP1.In some embodiments, the cell exhibits an anti-tumor immunity when the antigen binding domain of the CAR binds to a TAA on a tumor.Also disclosed is a method of providing an anti-tumor immunity in a subject with a TRP1- expressing cancer that involves administering to the subject an effective amount of an immune effector cell genetically modified with a disclosed TRP 1 -specific CAR.Also disclosed is a method of providing an anti-tumor immunity in a subject with a TAA- expressing cancer that involves administering to the subject an effective amount of an immune effector cell genetically modified with a disclosed TAA-specific CAR.Additional advantages of the disclosed method and compositions will be set forth in part in the description which follows, and in part will be understood from the description, or can be learned by practice of the disclosed method and compositions. The advantages of the disclosed method and compositions will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention as claimed.45753670.1 3ATTORNEY DOCKET NO. MOE 24MB020 PCTBRIEF DESCRIPTION OF THE DRAWINGSThe accompanying drawings illustrate several embodiments of the disclosed method and compositions and together with the description, serve to explain the principles of the disclosed method and compositions.FIGs. 1A and IB show cytotoxicity of a 2nd generation CAR construct with an scFv derived from TA99 and a 41BB-CD3z cytoplasmic domain with B 16 and CHO-CD33 used as target cells at 10: 1 (FIG. 1A) and 5: 1 (FIG. IB) E:T ratios.FIG. 2 illustrates CAR constructs used in examples.FIG. 3 shows RTCA cytotoxicity of humLCl-TA99BBz. Arrow indicates addition of T cells. humTA99 is specific for B 16 target cells. humTA99BBz shows effective killing.FIG. 4 shows RTCA cytotoxicity hTA99LClBBz.FIG. 5 shows RTCA cytotoxicity hTA99LC2BBz.FIG. 6 shows RTCA cytotoxicity humTA99NKG2D. The effector:target ratio is 1:5, this implies that one CAR has to kill more than once. This indicates that the CARs have the ability to conduct repetitive killing.FIG. 7 shows that while CTL killing was comparable, cytokine production (IL6) was reduced with humTA99BBz. This feature may help reduce the development of irAEs, like cytokine storm.FIG. 8 shows flank tumor growth in NSG mice challenged with B16 melanoma, no preconditioning (CTX or TBI), and then treatment with 200K untransduced or LCl-BBz human ab- T cells.FIG. 9 illustrates CAR constructs used in examples with (x) standing in for one of 10 different scFvs labeled a-j.FIG. 10 shows RTCA cytotoxicity scFv (variants against TRPl)-BBz melanoma targets. Cells are plated at a 5: 1 ET ratio.FIG. 11 shows RTCA cytotoxicity where cells are plated at a 5:1 ET ratio. Cells are cultured in hypoxic conditions (0.5% 02).FIG. 12 illustrates the functional activity of CD28-CD3C, CAR-T cells expressing a panel of affinity-optimized human anti-TRPl scFvs, following co-culture with melanoma target cells.FIG. 13 shows quantitative correlation plot between binding strength and killing effectiveness for selected scFvs used in functional CAR-T constructs.FIG. 14 shows aggregate analysis of IFNy production across all tumor lines and donors.45753670.1 4ATTORNEY DOCKET NO. MOE 24MB020 PCTFIG. 15 reveals reproducibility of cytokine responses and donor-to-donor variation in magnitude.FIG. 16 shows real-time cell adhesion index of B16 melanoma cells treated with murine CAR-T cells expressing the TRPld scFv (mTRPld-CD28z), measured using xCELLigence platform. CAR-T cells were added at different effector-to-target (E:T) ratios (1:1, 1:5, 1: 10, 1:20).FIG. 17 shows Kaplan-Meier survival analysis of mice bearing leptomeningeal melanoma treated with murine CAR-T cells expressing TRPld-CD28z (mTRPld-CARs).FIG. 18 shows real-time killing of TRP 1+canine melanoma cell lines by canine T cells expressing LCl-derived scFv CARs with CD28 signaling domains.FIG. 19 reveals both caninized LC1 and humanized LC1 scFvs test to assess cross-species reactivity and performance of donor 7.FIG. 20 reveals both caninized LC1 and humanized LC1 scFvs test to assess cross-species reactivity and performance of donor 9.FIG. 21 shows IFNy levels measured from CAR-T cells co-cultured with B16 (mouse), CMGD2 (canine), and TLM (canine) melanoma cell lines.FIG. 22 shows Kaplan-Meier survival analysis of tumor-bearing mice treated with CD3^- based or CD3^-less CAR-T cells, with isotype or anti-PD-l / PD-Ll ICI.FIG. 23 displays tumor growth curves.DETAILED DESCRIPTION OF THE INVENTIONThe disclosed method and compositions can be understood more readily by reference to the following detailed description of particular embodiments and the Example included therein and to the Figures and their previous and following description.Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the disclosure. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference and are incorporated herein by reference to disclose and describe the45753670.1 5ATTORNEY DOCKET NO. MOE 24MB020 PCT methods and / or materials in connection with which the publications are cited. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present disclosure is not entitled to antedate such publication by virtue of prior disclosure. Further, the dates of publication provided could be different from the actual publication dates that may need to be independently confirmed.As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present disclosure. Any recited method can be carried out in the order of events recited or in any other order that is logically possible.Embodiments of the present disclosure will employ, unless otherwise indicated, techniques of chemistry, biology, and the like, which are within the skill of the art.It is to be understood that the disclosed method and compositions are not limited to specific synthetic methods, specific analytical techniques, or to particular reagents unless otherwise specified, and, as such, can vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to perform the methods and use the probes disclosed and claimed herein. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C, and pressure is at or near atmospheric. Standard temperature and pressure are defined as 20 °C and 1 atmosphere.It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise.I. DefinitionsThe term “amino acid sequence” refers to a list of abbreviations, letters, characters or words representing amino acid residues. The amino acid abbreviations used herein are conventional one letter codes for the amino acids and are expressed as follows: A, alanine; B, asparagine or aspartic acid; C, cysteine; D aspartic acid; E, glutamate, glutamic acid; F, phenylalanine; G, glycine; H histidine; I isoleucine; K, lysine; L, leucine; M, methionine; N, asparagine; P, proline; Q, glutamine; R, arginine; S, serine; T, threonine; V, valine; W, tryptophan; Y, tyrosine; Z, glutamine or glutamic acid.45753670.1 6ATTORNEY DOCKET NO. MOE 24MB020 PCTThe term “antibody” refers to an immunoglobulin, derivatives thereof which maintain specific binding ability, and proteins having a binding domain which is homologous or largely homologous to an immunoglobulin binding domain. These proteins may be derived from natural sources, or partly or wholly synthetically produced. An antibody may be monoclonal or polyclonal. The antibody may be a member of any immunoglobulin class from any species, including any of the human classes: IgG, IgM, IgA, IgD, and IgE. In exemplary embodiments, antibodies used with the methods and compositions described herein are derivatives of the IgG class. In addition to intact immunoglobulin molecules, also included in the term “antibodies” are fragments or polymers of those immunoglobulin molecules, and human or humanized versions of immunoglobulin molecules that selectively bind the target antigen.The term “aptamer” refers to oligonucleic acid or peptide molecules that bind to a specific target molecule. These molecules are generally selected from a random sequence pool. The selected aptamers are capable of adapting unique tertiary structures and recognizing target molecules with high affinity and specificity. A “nucleic acid aptamer” is a DNA or RNA oligonucleic acid that binds to a target molecule via its conformation, and thereby inhibits or suppresses functions of such molecule. A nucleic acid aptamer may be constituted by DNA, RNA, or a combination thereof. A “peptide aptamer” is a combinatorial protein molecule with a variable peptide sequence inserted within a constant scaffold protein. Identification of peptide aptamers is typically performed under stringent yeast dihybrid conditions, which enhances the probability for the selected peptide aptamers to be stably expressed and correctly folded in an intracellular context.The term “carrier” means a compound, composition, substance, or structure that, when in combination with a compound or composition, aids or facilitates preparation, storage, administration, delivery, effectiveness, selectivity, or any other feature of the compound or composition for its intended use or purpose. For example, a carrier can be selected to minimize any degradation of the active ingredient and to minimize any adverse side effects in the subject.The term “chimeric molecule” refers to a single molecule created by joining two or more molecules that exist separately in their native state. The single, chimeric molecule has the desired functionality of all of its constituent molecules. One type of chimeric molecules is a fusion protein.The term “fusion protein” refers to a polypeptide formed by the joining of two or more polypeptides through a peptide bond formed between the amino terminus of one polypeptide and the carboxyl terminus of another polypeptide. The fusion protein can be formed by the chemical coupling of the constituent polypeptides or it can be expressed as a single polypeptide from nucleic acid sequence encoding the single contiguous fusion protein. A single chain fusion protein is a45753670.1 7ATTORNEY DOCKET NO. MOE 24MB020 PCT fusion protein having a single contiguous polypeptide backbone. Fusion proteins can be prepared using conventional techniques in molecular biology to join the two genes in frame into a single nucleic acid, and then expressing the nucleic acid in an appropriate host cell under conditions in which the fusion protein is produced.The term “identity” refers to sequence identity between two nucleic acid molecules or polypeptides. Identity can be determined by comparing a position in each sequence which may be aligned for purposes of comparison. When a position in the compared sequence is occupied by the same base, then the molecules are identical at that position. A degree of similarity or identity between nucleic acid or amino acid sequences is a function of the number of identical or matching nucleotides at positions shared by the nucleic acid sequences. Various alignment algorithms and / or programs may be used to calculate the identity between two sequences, including FASTA, or BLAST which are available as a part of the GCG sequence analysis package (University of Wisconsin, Madison, Wis.), and can be used with, e.g., default setting. For example, polypeptides having at least 70%, 85%, 90%, 95%, 98% or 99% identity to specific polypeptides described herein and preferably exhibiting substantially the same functions, as well as polynucleotide encoding such polypeptides, are contemplated. Unless otherwise indicated a similarity score will be based on use of BLOSUM62. When BLASTP is used, the percent similarity is based on the BLASTP positives score and the percent sequence identity is based on the BLASTP identities score. BLASTP “Identities” shows the number and fraction of total residues in the high scoring sequence pairs which are identical; and BLASTP “Positives” shows the number and fraction of residues for which the alignment scores have positive values and which are similar to each other. Amino acid sequences having these degrees of identity or similarity or any intermediate degree of identity of similarity to the amino acid sequences disclosed herein are contemplated and encompassed by this disclosure. The polynucleotide sequences of similar polypeptides are deduced using the genetic code and may be obtained by conventional means, in particular by reverse translating its amino acid sequence using the genetic code.The term “nucleic acid” refers to a natural or synthetic molecule comprising a single nucleotide or two or more nucleotides linked by a phosphate group at the 3 ’ position of one nucleotide to the 5’ end of another nucleotide. The nucleic acid is not limited by length, and thus the nucleic acid can include deoxyribonucleic acid (DNA) or ribonucleic acid (RNA).The term “operably linked to” refers to the functional relationship of a nucleic acid with another nucleic acid sequence. Promoters, enhancers, transcriptional and translational stop sites, and other signal sequences are examples of nucleic acid sequences operably linked to other45753670.1 8ATTORNEY DOCKET NO. MOE 24MB020 PCT sequences. For example, operable linkage of DNA to a transcriptional control element refers to the physical and functional relationship between the DNA and promoter such that the transcription of such DNA is initiated from the promoter by an RNA polymerase that specifically recognizes, binds to and transcribes the DNA.The terms “peptide,” “protein,” and “polypeptide” are used interchangeably to refer to a natural or synthetic molecule comprising two or more amino acids linked by the carboxyl group of one amino acid to the alpha amino group of another.The term “pharmaceutically acceptable” refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit / risk ratio.The term “protein domain” refers to a portion of a protein, portions of a protein, or an entire protein showing structural integrity; this determination may be based on amino acid composition of a portion of a protein, portions of a protein, or the entire protein.A “spacer” as used herein refers to a peptide that joins the proteins comprising a fusion protein. Generally a spacer has no specific biological activity other than to join the proteins or to preserve some minimum distance or other spatial relationship between them. However, the constituent amino acids of a spacer may be selected to influence some property of the molecule such as the folding, net charge, or hydrophobicity of the molecule.The term “specifically binds”, as used herein, when referring to a polypeptide (including antibodies) or receptor, refers to a binding reaction which is determinative of the presence of the protein or polypeptide or receptor in a heterogeneous population of proteins and other biologies. Thus, under designated conditions (e.g. immunoassay conditions in the case of an antibody), a specified ligand or antibody “specifically binds” to its particular “target” (e.g. an antibody specifically binds to an endothelial antigen) when it does not bind in a significant amount to other proteins present in the sample or to other proteins to which the ligand or antibody may come in contact in an organism. Generally, a first molecule that “specifically binds” a second molecule has an affinity constant (Ka) greater than about 105M-1(e.g., 106M-1, 107M-1, 108M-1, 109M-1, IO10M-1, 1011M-1, and 1012M-1or more) with that second molecule.The term “specifically deliver” as used herein refers to the preferential association of a molecule with a cell or tissue bearing a particular target molecule or marker and not to cells or tissues lacking that target molecule. It is, of course, recognized that a certain degree of non-specific45753670.1 9ATTORNEY DOCKET NO. MOE 24MB020 PCT interaction may occur between a molecule and a non- target cell or tissue. Nevertheless, specific delivery, may be distinguished as mediated through specific recognition of the target molecule. Typically specific delivery results in a much stronger association between the delivered molecule and cells bearing the target molecule than between the delivered molecule and cells lacking the target molecule.The term “subject” refers to any individual who is the target of administration or treatment. The subject can be a vertebrate, for example, a mammal. Thus, the subject can be a human or veterinary patient. The term “patient” refers to a subject under the treatment of a clinician, e.g., physician.The term “therapeutically effective” refers to the amount of the composition used is of sufficient quantity to ameliorate one or more causes or symptoms of a disease or disorder. Such amelioration only requires a reduction or alteration, not necessarily elimination.The terms “transformation” and “transfection” mean the introduction of a nucleic acid, e.g., an expression vector, into a recipient cell including introduction of a nucleic acid to the chromosomal DNA of said cell.The term “treatment” refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder.The term “variant” refers to an amino acid or peptide sequence having conservative amino acid substitutions, non-conservative amino acid subsitutions (i.e. a degenerate variant), substitutions within the wobble position of each codon (i.e. DNA and RNA) encoding an amino acid, amino acids added to the C-terminus of a peptide, or a peptide having 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% sequence identity to a reference sequence.The term “vector” refers to a nucleic acid sequence capable of transporting into a cell another nucleic acid to which the vector sequence has been linked. The term “expression vector” includes45753670.1 10ATTORNEY DOCKET NO. MOE 24MB020 PCT any vector, (e.g., a plasmid, cosmid or phage chromosome) containing a gene construct in a form suitable for expression by a cell (e.g., linked to a transcriptional control element).Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein.Use of the term “about” is intended to describe values either above or below the stated value in a range of approx. + / - 10%; in other embodiments the values may range in value either above or below the stated value in a range of approx. 4- / - 5%; in other embodiments the values may range in value either above or below the stated value in a range of approx. + / - 2%; in other embodiments the values may range in value either above or below the stated value in a range of approx. + / - 1%. The preceding ranges are intended to be made clear by context, and no further limitation is implied. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.Disclosed are materials, compositions, and components that can be used for, can be used in conjunction with, can be used in preparation for, or are products of the disclosed method and compositions. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds may not be explicitly disclosed, each is specifically contemplated and described herein. For example, if a ligand is disclosed and discussed and a number of modifications that can be made to a number of molecules including the ligand are discussed, each and every combination and permutation of ligand and the modifications that are possible are specifically contemplated unless specifically indicated to the contrary. Thus, if a class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited, each is individually and collectively contemplated. Thus, in this example, each of the combinations A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are specifically contemplated and should be considered disclosed from disclosure of A, B, and C; D, E, and F; and the example combination A-D. Likewise, any subset or combination of these is also45753670.1 11ATTORNEY DOCKET NO. MOE 24MB020 PCT specifically contemplated and disclosed. Thus, for example, the sub-group of A-E, B-F, and C-E are specifically contemplated and should be considered disclosed from disclosure of A, B, and C; D, E, and F; and the example combination A-D. Further, each of the materials, compositions, components, etc. contemplated and disclosed as above can also be specifically and independently included or excluded from any group, subgroup, list, set, etc. of such materials.These concepts apply to all aspects of this application including, but not limited to, steps in methods of making and using the disclosed compositions. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the disclosed methods, and that each such combination is specifically contemplated and should be considered disclosed.Unless otherwise indicated, the disclosure encompasses conventional techniques of molecular biology, microbiology, cell biology and recombinant DNA, which are within the skill of the art. Unless otherwise noted, technical terms are used according to conventional usage, and in the art, such as in the references cited herein, each of which is specifically incorporated by reference herein in its entirety.IL CompositionsA. AntibodiesAntibodies that can be used in the disclosed compositions and methods include whole immunoglobulin (i.e., an intact antibody) of any class, fragments thereof, and synthetic proteins containing at least the antigen binding variable domain of an antibody. The variable domains differ in sequence among antibodies and are used in the binding and specificity of each particular antibody for its particular antigen. However, the variability is not usually evenly distributed through the variable domains of antibodies. It is typically concentrated in three segments called complementarity determining regions (CDRs) or hypervariable regions both in the light chain and the heavy chain variable domains. The more highly conserved portions of the variable domains are called the framework (FR). The variable domains of native heavy and light chains each comprise four FR regions, largely adopting a beta-sheet configuration, connected by three CDRs, which form loops connecting, and in some cases forming part of, the beta-sheet structure. The CDRs in each chain are held together in close proximity by the FR regions and, with the CDRs from the other chain, contribute to the formation of the antigen binding site of antibodies.Transgenic animals (e.g., mice) that are capable, upon immunization, of producing a full repertoire of human antibodies in the absence of endogenous immunoglobulin production can be employed. For example, it has been described that the homozygous deletion of the antibody heavy45753670.1 12ATTORNEY DOCKET NO. MOE 24MB020 PCT chain joining region (J(H)) gene in chimeric and germ-line mutant mice results in complete inhibition of endogenous antibody production. Transfer of the human germ-line immunoglobulin gene array in such germ-line mutant mice will result in the production of human antibodies upon antigen challenge (see, e.g., Jakobovits et al., Proc. Natl. Acad. Sci. USA, 90:2551-255 (1993); Jakobovits et al., Nature, 362:255-258 (1993); Bruggemann et al., Year in Immuno., 7:33 (1993)). Human antibodies can also be produced in phage display libraries (Hoogenboom et al., J. Mol. Biol., 227:381 (1991); Marks et al., J. Mol. Biol., 222:581 (1991)). The techniques of Cote et al. and Boemer et al. are also available for the preparation of human monoclonal antibodies (Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985); Boerner et al., J. Immunol., 147(l):86-95 (1991)).Optionally, the antibodies are generated in other species and “humanized” for administration in humans. Humanized forms of non-human (e.g., murine) antibodies are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab', F(ab’)2, or other antigen-binding subsequences of antibodies) which contain minimal sequence derived from non-human immunoglobulin. Humanized antibodies include human immunoglobulins (recipient antibody) in which residues from a complementarity determining region (CDR) of the recipient antibody are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat or rabbit having the desired specificity, affinity and capacity. In some instances, Fv framework residues of the human immunoglobulin are replaced by corresponding non-human residues. Humanized antibodies may also comprise residues that are found neither in the recipient antibody nor in the imported CDR or framework sequences. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin consensus sequence. The humanized antibody optimally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin (lones et al., Nature, 321:522-525 (1986); Riechmann et al., Nature, 332:323-327 (1988); and Presta, Curr. Op. Struct. Biol., 2:593-596 (1992))Methods for humanizing non-human antibodies are well known in the art. Generally, a humanized antibody has one or more amino acid residues introduced into it from a source that is non-human. These non-human amino acid residues are often referred to as “import” residues, which are typically taken from an “import” variable domain. Antibody humanization techniques generally involve the use of recombinant DNA technology to manipulate the DNA sequence encoding one or45753670.1 13ATTORNEY DOCKET NO. MOE 24MB020 PCT more polypeptide chains of an antibody molecule. Humanization can be essentially performed following the method of Winter and co-workers (Jones et al., Nature, 321:522-525 (1986); Riechmann et al., Nature, 332:323-327 (1988); Verhoeyen et al., Science, 239:1534-1536 (1988)), by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. Accordingly, a humanized form of a non human antibody (or a fragment thereof) is a chimeric antibody or fragment (U.S. Pat. No. 4,816,567), wherein substantially less than an intact human variable domain has been substituted by the corresponding sequence from a non-human species. In practice, humanized antibodies are typically human antibodies in which some CDR residues and possibly some FR residues are substituted by residues from analogous sites in rodent antibodies.Also disclosed are fragments of antibodies which have bioactivity. The fragments, whether attached to other sequences or not, include insertions, deletions, substitutions, or other selected modifications of particular regions or specific amino acids residues, provided the activity of the fragment is not significantly altered or impaired compared to the non-modified antibody or antibody fragment.Techniques can also be adapted for the production of single-chain antibodies specific to an antigenic protein of the present disclosure. Methods for the production of single-chain antibodies are well known to those of skill in the art. A single chain antibody can be created by fusing together the variable domains of the heavy and light chains using a short peptide linker, thereby reconstituting an antigen binding site on a single molecule. Single-chain antibody variable fragments (scFvs) in which the C-terminus of one variable domain is tethered to the N-terminus of the other variable domain via a 15 to 25 amino acid peptide or linker have been developed without significantly disrupting antigen binding or specificity of the binding. The linker is chosen to permit the heavy chain and light chain to bind together in their proper conformational orientation.Divalent single-chain variable fragments (di-scFvs) can be engineered by linking two scFvs. This can be done by producing a single peptide chain with two VH and two VL regions, yielding tandem scFvs. ScFvs can also be designed with linker peptides that are too short for the two variable regions to fold together (about five amino acids), forcing scFvs to dimerize. This type is known as diabodies. Diabodies have been shown to have dissociation constants up to 40-fold lower than corresponding scFvs, meaning that they have a much higher affinity to their target. Still shorter linkers (one or two amino acids) lead to the formation of trimers (triabodies or tribodies). Tetrabodies have also been produced. They exhibit an even higher affinity to their targets than diabodies.45753670.1 14ATTORNEY DOCKET NO. MOE 24MB020 PCTA bi-specific antibody designed to selectively bind CD3 and TRP1 would trigger nonspecific T-cell activation & cytokine storm. A bi-specific diabody designed to selectively bind CD3 and TRP1 would have a molecular weight (55-60 kD) less than the renal clearance threshold, which would result in rapid elimination. As such, diabodies must be administered by a continuous infusion. The disclosed tetravalent, bi-specific antibody can have a molecular weight (e.g., 105-110 kD) greater than the renal filtration threshold with markedly extended PK.Provided are fusion polypeptides capable of forming a multivalent engineered antibody that is able to engage T-cells to destroy TRP1 -expressing malignant cells. The engineered antibody may comprise for example, at least one scFv, at least one Fab fragment, at least one Fv fragment, etc. It may be bivalent, trivalent, tetravalent, etc. The multivalent antibodies is multispecific, e.g., bispecific, trispecific, tetraspecific, etc. The multivalent antibodies may be in any form, such as a diabody, triabody, tetrabody, etc.

[0057] Bivalent and bispecific antibodies can be constructed using only antibody variable domains. A fairly efficient and relatively simple method is to make the linker sequence between the VH and VL domains so short that they cannot fold over and bind one another. Reduction of the linker length to 3-12 residues prevents the monomeric configuration of the scFv molecule and favors intermolecular VH-VL pairings with formation of a 60 kDa non-covalent scFv dimer “diabody”. The diabody format can also be used for generation of recombinant bis-pecific antibodies, which are obtained by the noncovalent association of two single-chain fusion products, consisting of the VH domain from one antibody connected by a short linker to the VL domain of another antibody. Reducing the linker length still further below three residues can result in the formation of trimers (“triabody”, about 90 kDa) or tetramers (“tetrabody”, about 120 kDa). For a review of engineered antibodies, particularly single domain fragments, see Holliger and Hudson, 2005, Nature Biotechnology, 23: 1126-1136. All of such engineered antibodies may be used in the fusion polypeptides provided herein. Tetravalent Tandab® may be prepared substantially as described in WO 1999057150 A3 or US20060233787, which are incorporated by reference for the teaching of methods of making Tandab® molecules.The antigen recognition sites or entire variable regions of the engineered antibodies may be derived from one or more parental antibodies directed against any antigen of interest (e.g., TRP1). The parental antibodies can include naturally occurring antibodies or antibody fragments, antibodies or antibody fragments adapted from naturally occurring antibodies, antibodies constructed de novo using sequences of antibodies or antibody fragments known to be specific for45753670.1 15ATTORNEY DOCKET NO. MOE 24MB020 PCT an antigen of interest. Sequences that may be derived from parental antibodies include heavy and / or light chain variable regions and / or CDRs, framework regions or other portions thereof.Multivalent, multispecific antibodies may contain a heavy chain comprising two or more variable regions and / or a light chain comprising one or more variable regions wherein at least two of the variable regions recognize different epitopes on the same antigen.Candidate engineered antibodies for inclusion in the fusion polypeptides, or the fusion polypeptides themselves, may be screened for activity using a variety of known assays. For example, screening assays to determine binding specificity are well known and routinely practiced in the art. For a comprehensive discussion of such assays, see Harlow et al. (Eds.), ANTIBODIES: A LABORATORY MANUAL; Cold Spring Harbor Laboratory; Cold Spring Harbor, N.Y., 1988, Chapter 6.In some embodiments, the anti-TRPl binding agent is single chain variable fragment (scFv) antibody. The affinity / specificity of an anti-TRPl scFv is driven in large part by specific sequences within complementarity determining regions (CDRs) in the heavy (VH) and light (VL) chain. Each VH and VL sequence will have three CDRs (CDR1, CDR2, CDR3).In some embodiments, the anti-TRPl binding agent is derived from natural antibodies, such as monoclonal antibodies. In some cases, the antibody is human. In some cases, the antibody has undergone an alteration to render it less immunogenic when administered to humans. For example, the alteration comprises one or more techniques selected from the group consisting of chimerization, humanization, CDR-grafting, deimmunization, and mutation of framework amino acids to correspond to the closest human germline sequence.Tumor antigens are proteins that are produced by tumor cells that elicit an immune response, particularly T-cell mediated immune responses. The additional antigen binding domain can be an antibody or a natural ligand of the tumor antigen. The selection of the additional antigen binding domain will depend on the particular type of cancer to be treated. Tumor antigens are well known in the art and include, for example, a glioma-associated antigen, carcinoembryonic antigen (CEA), EGFRvIII, IL-llRa, IL-13Ra, EGFR, FAP, B7H3, Kit, CA LX, CS-1, MUC1, BCMA, bcr-abl, HER2, P-human chorionic gonadotropin, alphafetoprotein (AFP), ALK, CD19, CD123, cyclin Bl, lectin-reactive AFP, Fos-related antigen 1, ADRB3, thyroglobulin, EphA2, RAGE-1, RU1, RU2, SSX2, AKAP-4, LCK, OY-TES1, PAX5, SART3, CLL-1, fucosyl GM1, GloboH, MN-CA IX, EPCAM, EVT6-AML, TGS5, human telomerase reverse transcriptase, plysialic acid, PLAC1, RU1, RU2 (AS), intestinal carboxyl esterase, lewisY, sLe, LY6K, mut hsp70-2, M-CSF, MYCN, RhoC, TRP-2, CYPIBI, BORIS, prostase, prostate-specific antigen (PSA), PAX3, PAP, NY-ESO-1,45753670.1 16ATTORNEY DOCKET NO. MOE 24MB020 PCTLAGE-la, LMP2, NCAM, p53, p53 mutant, Ras mutant, gplOO, prostein, OR51E2, PANX3, PSMA, PSCA, Her2 / neu, hTERT, HMWMAA, HAVCR1, VEGFR2, PDGFR-beta, survivin and telomerase, legumain, HPV E6,E7, sperm protein 17, SSEA-4, tyrosinase, TARP, WT1, prostatecarcinoma tumor antigen- 1 (PCTA-1), ML-IAP, MAGE, MAGE-A1,MAD-CT-1, MAD-CT-2, MelanA / MART 1, XAGE1 , ELF2M, ERG (TMPRSS2 ETS fusion gene), NAU, neutrophil elastase, sarcoma translocation breakpoints, NY-BR-1, ephnnB2, CD20, CD22, CD24, CD30, CD123, CD38, CD44v6, CD97, CD171, CD179a, androgen receptor, FAP, insulin growth factor (IGF)-I, IGFII, IGF-I receptor, GD2, o-acetyl-GD2, GD3, GM3, GPRC5D, GPR20, CXORF61, folate receptor (FRa), folate receptor beta, ROR1, Flt3, TAG72, TN Ag, Tie 2, TEM1, TEM7R, CLDN6, TSHR, UPK2, and mesothelin. In a preferred embodiment, the tumor antigen is selected from the group consisting of folate receptor (FRa), mesothelin, EGFRvIII, IL-13Ra, CD19, CD123, BCMA, GD2, CLL-1, CA-IX, MUC1, HER2, and any combination thereof.Non-limiting examples of tumor antigens include the following: Differentiation antigens such as tyrosinase, TRP-1, TRP-2 and tumor-specific multilineage antigens such as MAGE-1, MAGE-3, BAGE, GAGE-1, GAGE-2, pi 5; overexpressed embryonic antigens such as CEA; overexpressed oncogenes and mutated tumor-suppressor genes such as p53, Ras, HER-2 / neu; unique tumor antigens resulting from chromosomal translocations; such as BCR-ABL, E2A-PRL, H4-RET, IGH-IGK, MYL-RAR; and viral antigens, such as the Epstein Barr virus antigens EBVA and the human papillomavirus (HPV) antigens E6 and E7. Other large, protein-based antigens include TSP- 180, MAGE-4, MAGE-5, MAGE-6, RAGE, NY-ESO, pl85erbB2, pl80erbB-3, c-met, nm- 23H1, PSA, CA 19-9, CA 72-4, CAM 17.1, NuMa, K-ras, beta-Catenin, CDK4, Mum-1, p 15, p 16, 43-9F, 5T4, 791Tgp72, alpha-fetoprotein, beta-HCG, BCA225, BTAA, CA 125, CA 15-3\CA 27.29\BCAA, CA 195, CA 242, CA-50, CAM43, CD68\P1, CO-029, FGF-5, G250, Ga733\EpCAM, HTgp-175, M344, MA-50, MG7-Ag, M0V18, NB / 70K, NY-CO-1, RCAS1, SDCCAG1 6, TA-90\Mac-2 binding protein\cyclophilm C-associated protein, TAAL6, TAG72, TLP, TPS, GPC3, MUC16, LMP1, EBMA-1, BARF-1, CS1, CD319, HER1, B7H6, L1CAM, IL6, and MET.B. TRPl-specific chimeric antigen receptorsCARs generally incorporate an antigen recognition domain from the single-chain variable fragments (scFv) of a monoclonal antibody (mAb) with transmembrane signaling motifs involved in lymphocyte activation (Sadelain M, et al. Nat Rev Cancer 2003 3:35-45). Disclosed herein is a TRPl-specific chimeric antigen receptor (CAR) that can be expressed in immune effector cells to enhance antitumor activity against TRPl-specific CARs.45753670.1 17ATTORNEY DOCKET NO. MOE 24MB020 PCTThe disclosed CAR is generally made up of three domains: an ectodomain, a transmembrane domain, and an endodomain. The ectodomain comprises the TRP1 -binding region and is responsible for antigen recognition. It also optionally contains a signal peptide (SP) so that the CAR can be glycosylated and anchored in the cell membrane of the immune effector cell. The transmembrane domain (TD), is as its name suggests, connects the ectodomain to the endodomain and resides within the cell membrane when expressed by a cell. The endodomain is the business end of the CAR that transmits an activation signal to the immune effector cell after antigen recognition. For example, the endodomain can contain an intracellular signaling domain (ISD) and optionally a co-stimulatory signaling region (CSR). In some embodimenst the disclosed CARs contain in the endodomain the intracellular domain of NKG2D.A “signaling domain (SD)” generally contains immunoreceptor tyrosine-based activation motifs (IT AMs) that activate a signaling cascade when the ITAM is phosphorylated. The term “costimulatory signaling region (CSR)” refers to intracellular signaling domains from costimulatory protein receptors, such as CD28, 41BB, and ICOS, that are able to enhance T-cell activation by T- cell receptors.In some embodiments, the endodomain contains an SD or a CSR, but not both. In these embodiments, an immune effector cell containing the disclosed CAR is only activated if another CAR (or a T-cell receptor) containing the missing domain also binds its respective antigen.In some embodiments, the disclosed CAR is defined by the formula:SP- BD -HG-i-TM-CSR-SD; orSP- BD -HG-i-TM-SD-CSR; wherein “SP” represents an optional signal peptide, wherein “BD” represents a TRPl-binding region, wherein “HG” represents an optional hinge domain, wherein “TM” represents a transmembrane domain, wherein “CSR” represents one or more co-stimulatory signaling regions, wherein “SD” represents a signaling domain, and whereinrepresents a peptide bond or linker.In some embodiments, the disclosed CAR is defined by the formula:SP-BD-HG-i-TM-NKRIC; wherein “SP” represents an optional signal peptide, wherein “BD” represents a TRP1 target binding domain, wherein “HG” represents an optional hinge domain,45753670.1 18ATTORNEY DOCKET NO. MOE 24MB020 PCT wherein “TM” represents a transmembrane domain, wherein “NKRIC” represents an NK cell receptor intracellular domain, and wherein represents a peptide bond or linker.Additional CAR constructs are described, for example, in Fresnak AD, et al. Engineered T cells: the promise and challenges of cancer immunotherapy. Nat Rev Cancer. 2016 Aug 23;16(9):566-81, which is incorporated by reference in its entirety for the teaching of these CAR models.For example, the CAR can be a TRUCK, Universal CAR, Self-driving CAR, Armored CAR, Self-destruct CAR, Conditional CAR, Marked CAR, TenCAR, Dual CAR, or sCAR.TRUCKs (T cells redirected for universal cytokine killing) co-express a chimeric antigen receptor (CAR) and an antitumor cytokine. Cytokine expression may be constitutive or induced by T cell activation. Targeted by CAR specificity, localized production of pro-inflammatory cytokines recruits endogenous immune cells to tumor sites and may potentiate an antitumor response.Universal, allogeneic CAR T cells are engineered to no longer express endogenous T cell receptor (TCR) and / or major histocompatibility complex (MHC) molecules, thereby preventing graft-versus-host disease (GVHD) or rejection, respectively.Self-driving CARs co-express a CAR and a chemokine receptor, which binds to a tumor ligand, thereby enhancing tumor homing.CAR T cells engineered to be resistant to immunosuppression (Armored CARs) may be genetically modified to no longer express various immune checkpoint molecules (for example, cytotoxic T lymphocyte-associated antigen 4 (CTLA4) or programmed cell death protein 1 (PD1)), with an immune checkpoint switch receptor, or may be administered with a monoclonal antibody that blocks immune checkpoint signaling.A self-destruct CAR may be designed using RNA delivered by electroporation to encode the CAR. Alternatively, inducible apoptosis of the T cell may be achieved based on ganciclovir binding to thymidine kinase in gene-modified lymphocytes or the more recently described system of activation of human caspase 9 by a small-molecule dimerizer.A conditional CAR T cell is by default unresponsive, or switched ‘off’ , until the addition of a small molecule to complete the circuit, enabling full transduction of both signal 1 and signal 2, thereby activating the CAR T cell. Alternatively, T cells may be engineered to express an adaptorspecific receptor with affinity for subsequently administered secondary antibodies directed at target antigen.45753670.1 19ATTORNEY DOCKET NO. MOE 24MB020 PCTMarked CAR T cells express a CAR plus a tumor epitope to which an existing monoclonal antibody agent binds. In the setting of intolerable adverse effects, administration of the monoclonal antibody clears the CAR T cells and alleviates symptoms with no additional off-tumor effects.A tandem CAR (TanCAR) T cell expresses a single CAR consisting of two linked singlechain variable fragments (scFvs) that have different affinities fused to intracellular co-stimulatory domain(s) and a CD3^ domain. TanCAR T cell activation is achieved only when target cells coexpress both targets.A dual CAR T cell expresses two separate CARs with different ligand binding targets; one CAR includes only the CD3^ domain and the other CAR includes only the co-stimulatory domain(s). Dual CAR T cell activation requires co-expression of both targets on the tumor.A safety CAR (sCAR) consists of an extracellular scFv fused to an intracellular inhibitory domain. sCAR T cells co-expressing a standard CAR become activated only when encountering target cells that possess the standard CAR target but lack the sCAR target.The antigen recognition domain of the disclosed CAR is usually an scFv. There are however many alternatives. An antigen recognition domain from native T-cell receptor (TCR) alpha and beta single chains have been described, as have simple ectodomains (e.g. CD4 ectodomain to recognize HIV infected cells) and more exotic recognition components such as a linked cytokine (which leads to recognition of cells bearing the cytokine receptor). In fact almost anything that binds a given target with high affinity can be used as an antigen recognition region.The endodomain is the business end of the CAR that after antigen recognition transmits a signal to the immune effector cell, activating at least one of the normal effector functions of the immune effector cell. Effector function of a T cell, for example, may be cytolytic activity or helper activity including the secretion of cytokines. Therefore, the endodomain may comprise the “intracellular signaling domain” of a T cell receptor (TCR) and optional co-receptors. While usually the entire intracellular signaling domain can be employed, in many cases it is not necessary to use the entire chain. To the extent that a truncated portion of the intracellular signaling domain is used, such truncated portion may be used in place of the intact chain as long as it transduces the effector function signal.Cytoplasmic signaling sequences that regulate primary activation of the TCR complex that act in a stimulatory manner may contain signaling motifs which are known as immunoreceptor tyrosine-based activation motifs (IT AMs). Examples of IT AM containing cytoplasmic signaling sequences include those derived from CD8, CD3 , CD35, CD3y, CD3a, CD32 (Fc gamma Rlla), DAP10, DAP12, CD79a, CD79b, FcyRIy, FcyRIIIy, FcsRip (FCERIB), and FcsRIy (FCERIG).45753670.1 20ATTORNEY DOCKET NO. MOE 24MB020 PCTIn particular embodiments, the intracellular signaling domain is derived from CD3 zeta (CD3Q (TCR zeta, GenBank aceno. BAG36664.1). T-cell surface glycoprotein CD3 zeta (CD3Q chain, also known as T-cell receptor T3 zeta chain or CD247 (Cluster of Differentiation 247), is a protein that in humans is encoded by the CD247 gene.First-generation CARs typically had the intracellular domain from the CD3^ chain, which is the primary transmitter of signals from endogenous TCRs. Second-generation CARs add intracellular signaling domains from various costimulatory protein receptors (e.g., CD28, 41BB, ICOS) to the endodomain of the CAR to provide additional signals to the T cell. Preclinical studies have indicated that the second generation of CAR designs improves the antitumor activity of T cells. More recent, third-generation CARs combine multiple signaling domains to further augment potency. T cells grafted with these CARs have demonstrated improved expansion, activation, persistence, and tumor-eradicating efficiency independent of costimulatory receptor / ligand interaction (Imai C, et al. Leukemia 2004 18:676-84; Maher J, et al. Nat Biotechnol 2002 20:70-5).For example, the endodomain of the CAR can be designed to comprise the CD3 signaling domain by itself or combined with any other desired cytoplasmic domain(s) useful in the context of the CAR of the invention. For example, the cytoplasmic domain of the CAR can comprise a CD3 chain portion and a costimulatory signaling region. The costimulatory signaling region refers to a portion of the CAR comprising the intracellular domain of a costimulatory molecule. A costimulatory molecule is a cell surface molecule other than an antigen receptor or their ligands that is required for an efficient response of lymphocytes to an antigen. Examples of such molecules include CD27, CD28, 4-1BB (CD137), 0X40, CD30, CD40, ICOS, lymphocyte function- associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, and a ligand that specifically binds with CD83, CD8, CD4, b2c, CD80, CD86, DAP10, DAP12, MyD88, BTNL3, and NKG2D. Thus, while the CAR is exemplified primarily with CD28 as the co-stimulatory signaling element, other costimulatory elements can be used alone or in combination with other co-stimulatory signaling elements.In some embodiments, the CAR comprises a hinge sequence. A hinge sequence is a short sequence of amino acids that facilitates antibody flexibility (see, e.g., Woof et al., Nat. Rev. Immunol., 4(2): 89-99 (2004)). The hinge sequence may be positioned between the antigen recognition moiety (e.g., anti-TRPl scFv) and the transmembrane domain. The hinge sequence can be any suitable sequence derived or obtained from any suitable molecule. In some embodiments, for example, the hinge sequence is derived from a CD8a molecule or a CD28 molecule.45753670.1 21ATTORNEY DOCKET NO. MOE 24MB020 PCTThe transmembrane domain may be derived either from a natural or from a synthetic source. Where the source is natural, the domain may be derived from any membrane-bound or transmembrane protein. For example, the transmembrane region may be derived from (i.e. comprise at least the transmembrane region(s) of) the alpha, beta or zeta chain of the T-cell receptor, CD28, CD3 epsilon, CD45, CD4, CD5, CD8 (e.g., CD8 alpha, CD8 beta), CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, or CD154, KIRDS2, 0X40, CD2, CD27, LFA-1 (CDl la, CD18) , ICOS (CD278) , 4-1BB (CD137) , GITR, CD40, BAFFR, HVEM (LIGHTR) , SLAMF7, NKp80 (KLRF1) , CD160, CD19, IL2R beta, IL2R gamma, IL7R a, ITGA1, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CDl ld, ITGAE, CD103, ITGAL, CDlla, LFA-1, ITGAM, CDl lb, ITGAX, CDl lc, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, TNFR2, DNAM1 (CD226) , SLAMF4 (CD244, 2B4) , CD84, CD96 (Tactile) , CEACAM1, CRTAM, Ly9 (CD229) , CD160 (BY55) , PSGL1, CD100 (SEMA4D) , SLAMF6 (NTB-A, Lyl08) , SLAM (SLAMF1, CD150, IPO-3) , BLAME (SLAMF8) , SELPLG (CD162) , LTBR, and PAG / Cbp. Alternatively the transmembrane domain may be synthetic, in which case it will comprise predominantly hydrophobic residues such as leucine and valine. In some cases, a triplet of phenylalanine, tryptophan and valine will be found at each end of a synthetic transmembrane domain. A short oligo- or polypeptide linker, such as between 2 and 10 amino acids in length, may form the linkage between the transmembrane domain and the endoplasmic domain of the CAR.In some embodiments, the CAR has more than one transmembrane domain, which can be a repeat of the same transmembrane domain, or can be different transmembrane domains.In some embodiments, the CAR is a multi-chain CAR, as described in WO2015 / 039523, which is incorporated by reference for this teaching. A multi-chain CAR can comprise separate extracellular ligand binding and signaling domains in different transmembrane polypeptides. The signaling domains can be designed to assemble in juxtamembrane position, which forms flexible architecture closer to natural receptors, that confers optimal signal transduction. For example, the multi-chain CAR can comprise a part of an FCERI alpha chain and a part of an FCERI beta chain such that the FCERI chains spontaneously dimerize together to form a CAR.In some embodiments, the anti-TRPl binding agent is single chain variable fragment (scFv) antibody. The affinity / specificity of an anti-TRPl scFv is driven in large part by specific sequences within complementarity determining regions (CDRs) in the heavy (VH) and light (VL) chain. Each VH and VL sequence will have three CDRs (CDR1, CDR2, CDR3).45753670.1 22ATTORNEY DOCKET NO. MOE 24MB020 PCTIn some cases, the binding domain is an affinity maturated scFv. In some cases, the binding domain has a dissociation constant (KD) for the TAA that is less than 50 nM, 40 nM, 30 nM, 25 nM, 20 nM, 15 nM, or 10 nM.In some embodiments, the anti-TRPl binding agent is derived from natural antibodies, such as monoclonal antibodies. In some cases, the antibody is human. In some cases, the antibody has undergone an alteration to render it less immunogenic when administered to humans. For example, the alteration comprises one or more techniques selected from the group consisting of chimerization, humanization, CDR-grafting, deimmunization, and mutation of framework amino acids to correspond to the closest human germline sequence.Also disclosed are bi-specific CARs that target TRP1 and at least one additional tumor antigen. Also disclosed are CARs designed to work only in conjunction with another CAR that binds a different antigen, such as a tumor antigen. For example, in these embodiments, the endodomain of the disclosed CAR can contain only an signaling domain (SD) or a co-stimulatory signaling region (CSR), but not both. The second CAR (or endogenous T-cell) provides the missing signal if it is activated. For example, if the disclosed CAR contains an SD but not a CSR, then the immune effector cell containing this CAR is only activated if another CAR (or T-cell) containing a CSR binds its respective antigen. Likewise, if the disclosed CAR contains a CSR but not a SD, then the immune effector cell containing this CAR is only activated if another CAR (or T-cell) containing an SD binds its respective antigen.Tumor antigens are proteins that are produced by tumor cells that elicit an immune response, particularly T-cell mediated immune responses. The additional antigen binding domain can be an antibody or a natural ligand of the tumor antigen. The selection of the additional antigen binding domain will depend on the particular type of cancer to be treated. Tumor antigens are well known in the art and include, for example, a glioma-associated antigen, carcinoembryonic antigen (CEA), EGFRvIII, IL-llRa, IL-13Ra, EGFR, FAP, B7H3, Kit, CA LX, CS-1, MUC1, BCMA, bcr-abl, HER2, P-human chorionic gonadotropin, alphafetoprotein (AFP), ALK, CD19, TIM3, cyclin Bl, lectin-reactive AFP, Fos-related antigen 1, ADRB3, thyroglobulin, EphA2, RAGE-1, RU1, RU2, SSX2, AKAP-4, LCK, OY-TES1, PAX5, SART3, CLL-1, fucosyl GM1, GloboH, MN-CA IX, EPCAM, EVT6-AML, TGS5, human telomerase reverse transcriptase, plysialic acid, PLAC1, RU1, RU2 (AS), intestinal carboxyl esterase, lewisY, sLe, LY6K, mut hsp70-2, M-CSF, MYCN, RhoC, TRP-2, CYPIBI, BORIS, prostase, prostate-specific antigen (PSA), PAX3, PAP, NY-ESO-1, LAGE-la, LMP2, NCAM, p53, p53 mutant, Ras mutant, gplOO, prostein, OR51E2, PANX3, PSMA, PSCA, Her2 / neu, hTERT, HMWMAA, HAVCR1, VEGFR2, PDGFR-beta, survivin and45753670.1 23ATTORNEY DOCKET NO. MOE 24MB020 PCT telomerase, legumain, HPV E6,E7, sperm protein 17, SSEA-4, tyrosinase, TARP, WT1, prostatecarcinoma tumor antigen- 1 (PCTA-1), ML-IAP, MAGE, MAGE-A1,MAD-CT-1, MAD-CT-2, MelanA / MART 1, XAGE1 , ELF2M, ERG (TMPRSS2 ETS fusion gene), NA17, neutrophil elastase, sarcoma translocation breakpoints, NY-BR-1, ephnnB2, CD20, CD22, CD24, CD30, TIM3, CD38, CD44v6, CD97, CD171, CD179a, androgen receptor, FAP, insulin growth factor (IGF)-I, IGFII, IGF-I receptor, GD2, o-acetyl-GD2, GD3, GM3, GPRC5D, GPR20, CXORF61, folate receptor (FRa), folate receptor beta, ROR1, Flt3, TAG72, TN Ag, Tie 2, TEM1, TEM7R, CLDN6, TSHR, UPK2, and mesothelin. In a preferred embodiment, the tumor antigen is selected from the group consisting of folate receptor (FRa), mesothelin, EGFRvIII, IL-13Ra, CD123, CD19, TIM3, BCMA, GD2, CLL-1, CA-IX, MUC1, HER2, and any combination thereof.Non-limiting examples of tumor antigens include the following: Differentiation antigens such as tyrosinase, TRP- 1 , TRP-2 and tumor-specific multilineage antigens such as MAGE- 1 , MAGE-3, BAGE, GAGE-1, GAGE-2, pi 5; overexpressed embryonic antigens such as CEA; overexpressed oncogenes and mutated tumor-suppressor genes such as p53, Ras, HER-2 / neu; unique tumor antigens resulting from chromosomal translocations; such as BCR-ABL, E2A-PRL, H4-RET, 1GH-1GK, MYL-RAR; and viral antigens, such as the Epstein Barr virus antigens EBVA and the human papillomavirus (HPV) antigens E6 and E7. Other large, protein-based antigens include TSP- 180, MAGE-4, MAGE-5, MAGE-6, RAGE, NY-ESO, pl85erbB2, pl80erbB-3, c-met, nm- 23H1, PSA, CA 19-9, CA 72-4, CAM 17.1, NuMa, K-ras, beta-Catenin, CDK4, Mum-1, p 15, p 16, 43-9F, 5T4, 791Tgp72, alpha-fetoprotein, beta-HCG, BCA225, BTAA, CA 125, CA 15-3\CA 27.29\BCAA, CA 195, CA 242, CA-50, CAM43, CD68\P1, CO-029, FGF-5, G250, Ga733\EpCAM, HTgp-175, M344, MA-50, MG7-Ag, M0V18, NB / 70K, NY-CO-1, RCAS1, SDCCAG1 6, TA-90\Mac-2 binding protein\cyclophilm C-associated protein, TAAL6, TAG72, TLP, TPS, GPC3, MUC16, LMP1, EBMA-1, BARF-1, CS1, CD319, HER1, B7H6, L1CAM, IL6, and MET.C. NK Receptors1. NKG2DIn some embodiments, the NK cell receptor is hNKG2D. In some embodiments, the NK cell receptor intracellular (IC) domain comprises the amino acid sequence MGWIRGRRSRHSWEMSEFHNYNLDLKKSDFSTRWQKQRCPVVKSKCRENAS (SEQ ID NO:182), or a variant / fragment thereof having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 182. In some embodiments, the TM has the amino acid sequence PFFFCCFIAVAMGIRFIIMVTIW (SEQ ID NO: 183), or a variant / fragment thereof having at least45753670.1 24ATTORNEY DOCKET NO. MOE 24MB020 PCT70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 183. Therefore, in some embodiments, the CAR comprises the hNKG2D TM / IC domains having the amino acid sequence PFFFCCF1AVAMG1RF11MVT1WMGW1RGRRSRHSWEMSEFHNYNLDLKKSDFSTRWQKQR CPVVKSKCRENAS (SEQ ID NO:184), or a variant / fragment thereof 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, or 74 amino acids in length and having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 184 that is capable of integrating into a plasma membrane and binding DAP 10 when crosslinked. In some embodiments, the extracellular domain has the amino acid sequence MGWIRGRRSRHSWEMSEFHNYNLDLKKSDFSTRWQKQRCPVVKSKCRENAS (SEQ ID NO:218), or a variant / fragment thereof having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:218. In some embodiments, hNKG2D has the amino acid sequence MGWIRGRRSRHSWEMSEFHNYNLDLKKSDFSTRWQKQRCPVVKSKCRENASPFFFCCFIA VAMGIRFIIMVTIWSAVFLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWY ESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGSILSPNLLTII EMQKGDCALYASSFKGYIENCSTPNTYICMQRTV (SEQ ID NO:219), or a variant / fragment thereof having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:219.2. CD16In some embodiments, the NK cell receptor is hCD16 (FCGR3A). Therefore, in some embodiments, the NK cell receptor intracellular domain comprises the amino acid sequence KTNIRSSTRDWKDHKFKWRKDPQDK (SEQ ID NO:185), or a variant / fragment thereof having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 185. In some embodiments, the TM has the amino acid sequence VSFCLVMVLLFAVDTGLYFSV (SEQ ID NO: 186), or a variant / fragment thereof having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:186. Therefore, in some embodiments, the CAR comprises the hCD16 TM / IC domains having the amino acid sequence VSFCLVMVLLFAVDTGLYFSVKTNIRSSTRDWKDHKFKWRKDPQDK (SEQ ID NO: 187), or a variant / fragment thereof 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, or 46 amino acids in length and having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 187 that is capable of integrating into a plasma membrane and binding FceRly when crosslinked. In some embodiments, the extracellular domain has the amino acid sequenceMWQLLLPTALLLLVSAGMRTEDLPKAVVFLEPQWYRVLEKDSVTLKCQGAYSPEDNSTQ WFHNESLISSQASSYFIDAATVDDSGEYRCQTNLSTLSDPVQLEVHIGWLLLQAPRWVFKE EDPIHLRCHSWKNTALHKVTYLQNGKGRKYFHHNSDFYIPKATLKDSGSYFCRGLFGSKN VSSETVNITITQGLAVSTISSFFPPGYQ (SEQ ID NO:220), or a variant / fragment thereof having45753670.1 25ATTORNEY DOCKET NO. MOE 24MB020 PCT at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:220. In some embodiments, hNKG2D has the amino acid sequence MWQLLLPTALLLLVSAGMRTEDLPKAVVFLEPQWYRVLEKDSVTLKCQGAYSPEDNSTQ WFHNESLISSQASSYFIDAATVDDSGEYRCQTNLSTLSDPVQLEVHIGWLLLQAPRWVFKE EDPIHLRCHSWKNTALHKVTYLQNGKGRKYFHHNSDFYIPKATLKDSGSYFCRGLFGSKN VSSETVNITITQGLAVSTISSFFPPGYQVSFCLVMVLLFAVDTGLYFSVKTNIRSSTRDWKDH KFKWRKDPQDK (SEQ ID NO:221), or a variant / fragment thereof having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:221.3. NKp30In some embodiments, the NK cell receptor is hNKp30 (NCR3). Therefore, in some embodiments, the NK cell receptor intracellular domain comprises the amino acid sequence GSTVYYQGKCLTWKGPRRQLPAVVPAPLPPPCGSSAHLLPPVPG (SEQ ID NO: 188), or a variant / fragment thereof having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 188. In some embodiments, the TM has the amino acid sequence AGTVLLLRAGFYAVSFLSVAV (SEQ ID NO:189), or a variant / fragment thereof having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:189. Therefore, in some embodiments, the CAR comprises the hNKp30TM / IC domains having the amino acid sequence AGTVLLLRAGFYAVSFLSVAVGSTVYYQGKCLTWKGPRRQLPAVVPAPLPPPCGSSAHLL PPVPG (SEQ ID NO: 190), or a variant / fragment thereof 55, 56, 57, 58, 59, 60, 61, 61, 62, 64, or 65 amino acids in length and having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 190 that is capable of integrating into a plasma membrane and binding FcsRly when crosslinked. In some embodiments, the extracellular domain has the amino acid sequence MAWMLLLILIMVHPGSCALWVSQPPEIRTLEGSSAFLPCSFNASQGRLAIGSVTWFRDEVV PGKEVRNGTPEFRGRLAPLASSRFLHDHQAELHIRDVRGHDASIYVCRVEVLGLGVGTGN GTRLVVEKEHPQLG (SEQ ID NO:222), or a variant / fragment thereof having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:222. In some embodiments, hNKG2D has the amino acid sequence MAWMLLLILIMVHPGSCALWVSQPPEIRTLEGSSAFLPCSFNASQGRLAIGSVTWFRDEVV PGKEVRNGTPEFRGRLAPLASSRFLHDHQAELHIRDVRGHDASIYVCRVEVLGLGVGTGN GTRLVVEKEHPQLGAGTVLLLRAGFYAVSFLSVAVGSTVYYQGKCLTWKGPRRQLPAVV PAPLPPPCGSSAHLLPPVPGG (SEQ ID NO:223), or a variant / fragment thereof having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:223.45753670.1 26ATTORNEY DOCKET NO. MOE 24MB020 PCT4. NKG2CIn some embodiments, the NK cell receptor is hNKG2C. Therefore, in some embodiments, the NK cell receptor intracellular domain comprises the amino acid sequenceIPFLEQNNSSPNTRTQKARHCGHCPEEWITYSNSCYYIGKERRTWEESLLACTSKNSSLLSID NEEEMKFLASILPSSWIGVFRNSSHHPWVTINGLAFKHKIKDSDNAELNCAVLQVNRLKSA QCGSSMIYHCKHKL (SEQ ID NO: 191), or a variant / fragment thereof having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 191. In some embodiments, the TM has the amino acid sequence LTAEVLGIICIVLMATVLKTIVL (SEQ ID NO: 192), or a variant / fragment thereof having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 192. Therefore, in some embodiments, the CAR comprises the hNKG2C TM / IC domains having the amino acid sequence LTAEVLGIICIVLMATVLKTIVLIPFLEQNNSSPNTRTQKARHCGHCPEEWITYSNSCYYIGK ERRTWEESLLACTSKNSSLLSIDNEEEMKFLASILPSSWIGVFRNSSHHPWVTINGLAFKHKI KDSDNAELNCAVLQVNRLKSAQCGSSMIYHCKHKL (SEQ ID NO: 193), or a variant / fragment thereof 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, or 161 amino acids in length and having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 193 that is capable of integrating into a plasma membrane and binding DAP12 when crosslinked. In some embodiments, the extracellular domain has the amino acid sequenceMSKQRGTFSEVSLAQDPKRQQRKPKGNKSSISGTEQEIFQVELNLQNPSLNHQGIDKIYDCQ GLLPPPEK (SEQ ID NO:224), or a variant / fragment thereof having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:224. In some embodiments, hNKG2D has the amino acid sequenceMSKQRGTFSEVSLAQDPKRQQRKPKGNKSSISGTEQEIFQVELNLQNPSLNHQGIDKIYDCQ GLLPPPEKLTAEVLGIICIVLMATVLKTIVLIPFLEQNNSSPNTRTQKARHCGHCPEEWITYS NSCYYIGKERRTWEESLLACTSKNSSLLSIDNEEEMKFLASILPSSWIGVFRNSSHHPWVTIN GLAFKHKIKDSDNAELNCAVLQVNRLKSAQCGSSMIYHCKHKL (SEQ ID NO:225), or a variant / fragment thereof having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:225.5. 2B4In some embodiments, the NK cell receptor is h2B4. Therefore, in some embodiments, the NK cell receptor intracellular domain comprises the amino acid sequenceWRRKRKEKQSETSPKEFLTIYEDVKDLKTRRNHEQEQTFPGGGSTIYSMIQSQSSAPTSQEP AYTLYSLIPSRKSGSRKRNHSPSFNSTIYEVIGKSQPKAQNPARLSRKELENFDVYS (SEQ ID NO: 194), or a variant / fragment thereof having at least 70%, 85%, 90%, 95%, 98% or 99% identity45753670.1 27ATTORNEY DOCKET NO. MOE 24MB020 PCT to SEQ ID NO: 194. In some embodiments, the TM has the amino acid sequence FLVIIVILSALFLGTLACFCV (SEQ ID NO: 195), or a variant / fragment thereof having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 195. Therefore, in some embodiments, the CAR comprises the h2B4TM / IC domains having the amino acid sequenceFLVIIVILSALFLGTLACFCVWRRKRKEKQSETSPKEFLTIYEDVKDLKTRRNHEQEQTFPGG GSTIYSMIQSQSSAPTSQEPAYTLYSLIPSRKSGSRKRNHSPSFNSTIYEVIGKSQPKAQNPAR LSRKELENFDVYS (SEQ ID NO: 196), or a variant / fragment thereof 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, or 140 amino acids in length and having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 196 that is capable of signaling when crosslinked. In some embodiments, the extracellular domain has the amino acid sequenceMLGQVVTLILLLLLKVYQGKGCQGSADHVVSISGVPLQLQPNSIQTKVDSIAWKKLLPSQN GFHHILKWENGSLPSNTSNDRFSFIVKNLSLLIKAAQQQDSGLYCLEVTSISGKVQTATFQV FVFESLLPDKVEKPRLQGQGKILDRGRCQVALSCLVSRDGNVSYAWYRGSKLIQTAGNLT YLDEEVDINGTHTYTCNVSNPVSWESHTLNLTQDCQNAHQEFRFWP (SEQ ID NO:226), or a variant / fragment thereof having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:226. In some embodiments, hNKG2D has the amino acid sequenceMLGQVVTLILLLLLKVYQGKGCQGSADHVVSISGVPLQLQPNSIQTKVDSIAWKKLLPSQN GFHHILKWENGSLPSNTSNDRFSFIVKNLSLLIKAAQQQDSGLYCLEVTSISGKVQTATFQV FVFESLLPDKVEKPRLQGQGKILDRGRCQVALSCLVSRDGNVSYAWYRGSKLIQTAGNLT YLDEEVDINGTHTYTCNVSNPVSWESHTLNLTQDCQNAHQEFRFWPFLVIIVILSALFLGTL ACFCVWRRKRKEKQSETSPKEFLTIYEDVKDLKTRRNHEQEQTFPGGGSTIYSMIQSQSSAP TSQEPAYTLYSLIQPSRKSGSRKRNHSPSFNSTIYEVIGKSQPKAQNPARLSRKELENFDVYS (SEQ ID NO:227), or a variant / fragment thereof having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:227.6. DNAM-1In some embodiments, the NK cell receptor is hDNAM-1. Therefore, in some embodiments, the NK cell receptor intracellular domain comprises the amino acid sequenceNRRRRRERRDLFTESWDTQKAPNNYRSPISTSQPTNQSMDDTREDIYVNYPTFSRRPKTRV (SEQ ID NO: 197), or a variant / fragment thereof having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 197. In some embodiments, the TM has the amino acid sequence GGTVLLLLFVISITTIIVIFL (SEQ ID NO: 198), or a variant / fragment thereof having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 198. Therefore, in some embodiments, the CAR comprises the hDNAM TM / IC domains having the amino acid sequence45753670.1 28ATTORNEY DOCKET NO. MOE 24MB020 PCTGGTVLLLLFVISITTIIVIFLNRRRRRERRDLFTESWDTQKAPNNYRSPISTSQPTNQSMDDTR EDIYVNYPTFSRRPKTRV (SEQ ID NO: 199), or a variant / fragment thereof 30, 31, 72, 73, 74, 75, 76, 77. 78, 79, 80, 81, or 82, amino acids in length and having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 199 that is capable of signaling when crosslinked. In some embodiments, the extracellular domain has the amino acid sequence MTWPVQAVRWEKIQPRQIDLLTYCNLVHGRNFTSKFPRQIVSNCSHGRWSVIVIPDVTVSD SGLYRCYLQASAGENETFVMRLTVAEGKTDNQYTLFVA (SEQ ID NO:228), or a variant / fragment thereof having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:228. In some embodiments, hNKG2D has the amino acid sequence MTWPVQAVRWEKIQPRQIDLLTYCNLVHGRNFTSKFPRQIVSNCSHGRWSVIVIPDVTVSD SGLYRCYLQASAGENETFVMRLTVAEGKTDNQYTLFVAGGTVLLLLFVISITTIIVIFLNRRR RRERRDLFTESWDTQKAPNNYRSPISTSQPTNQSMDDTREDIYVNYPTFSRRPKTRV (SEQ ID NO:229), or a variant / fragment thereof having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:229.7. CD137In some embodiments, the NK cell receptor is hCD137 (TNFRSF9). Therefore, in some embodiments, the NK cell receptor intracellular domain comprises the amino acid sequence KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL (SEQ ID NG:200), or a variant / fragment thereof having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:200. In some embodiments, the TM has the amino acid sequence IISFFLALTSTALLFLLFFLTLRFSVV (SEQ ID NO:201), or a variant / fragment thereof having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:201. Therefore, in some embodiments, the CAR comprises the hCD137 TM / IC domains having the amino acid sequence IISFFLALTSTALLFLLFFLTLRFSVVKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEE GGCEL (SEQ ID NO:202), or a variant / fragment thereof 59, 60, 61, 61, 62, 64, 65, 66, 67, 68, or 69 amino acids in length and having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:202 that is capable of signaling when crosslinked. In some embodiments, the extracellular domain has the amino acid sequenceMGNSCYNIVATLLLVLNFERTRSLQDPCSNCPAGTFCDNNRNQICSPCPPNSFSSAGGQRTC DICRQCKGVFRTRKECSSTSNAECDCTPGFHCLGAGCSMCEQDCKQGQELTKKGCKDCCF GTFNDQKRGICRPWTNCSLDGKSVLVNGTKERDVVCGPSPADLSPGASSVTPPAPAREPGH SPQ (SEQ ID NO:230), or a variant / fragment thereof having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:230. In some embodiments, hNKG2D has the amino acid sequence45753670.1 29ATTORNEY DOCKET NO. MOE 24MB020 PCTMGNSCYNIVATLLLVLNFERTRSLQDPCSNCPAGTFCDNNRNQICSPCPPNSFSSAGGQRTC DICRQCKGVFRTRKECSSTSNAECDCTPGFHCLGAGCSMCEQDCKQGQELTKKGCKDCCF GTFNDQKRG1CRPWTNCSLDGKSVLVNGTKERDVVCGPSPADLSPGASSVTPPAPAREPGH SPQIISFFLALTSTALLFLLFFLTLRFSVVKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPE EEEGGCEL (SEQ ID NO:231), or a variant / fragment thereof having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:231.8. OX-40In some embodiments, the NK cell receptor is hOX-40. Therefore, in some embodiments, the NK cell receptor intracellular domain comprises the amino acid sequence VSHRYPRIQSIKVQFTEYKKEKGFILTSQKEDEIMKVQNNSVIINCDGFYLISLKGYFSQEVN ISLHYQKDEEPLFQLKKVRSVNSLMVASLTYKDKVYLNVTTDNTSLDDFHVNGGELILIHQ NPGEFCVL (SEQ ID NQ:203), or a variant / fragment thereof having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:203. In some embodiments, the TM has the amino acid sequence LLLVASVIQGLGLLLCFTYICLHFSAL (SEQ ID NO:204), or a variant / fragment thereof having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:204. Therefore, in some embodiments, the CAR comprises the hOX-40TM / lC domains having the amino acid sequence LLLVASVIQGLGLLLCFTYICLHFSALVSHRYPRIQSIKVQFTEYKKEKGFILTSQKEDEIMK VQNNSVIINCDGFYLISLKGYFSQEVNISLHYQKDEEPLFQLKKVRSVNSLMVASLTYKDK VYLNVTTDNTSLDDFHVNGGELILIHQNPGEFCVL (SEQ ID NO:205), or a variant / fragment thereof 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159 amino acids in length and having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:205 that is capable of signaling when crosslinked. In some embodiments, the extracellular domain has the amino acid sequence MERVQPLEENVGNAARPRFERNK (SEQ ID NO:232), or a variant / fragment thereof having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:232. In some embodiments, hNKG2D has the amino acid sequenceMERVQPLEENVGNAARPRFERNKLLLVASVIQGLGLLLCFTYICLHFSALQVSHRYPRIQSI KVQFTEYKKEKGFILTSQKEDEIMKVQNNSVIINCDGFYLISLKGYFSQEVNISLHYQKDEE PLFQLKKVRSVNSLMVASLTYKDKVYLNVTTDNTSLDDFHVNGGELILIHQNPGEFCVL (SEQ ID NO:233), or a variant / fragment thereof having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:233.45753670.1 30ATTORNEY DOCKET NO. MOE 24MB020 PCT9. CD27In some embodiments, the NK cell receptor is hCD27. Therefore, in some embodiments, the NK cell receptor intracellular domain comprises the amino acid sequence QRRKYRSNKGESPVEPAEPCHYSCPREEEGSTIPIQEDYRKPEPACSP (SEQ ID NO:206), or a variant / fragment thereof having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:206. In some embodiments, the TM has the amino acid sequence ILVIFSGMFLVFTLAGALFLH (SEQ ID NO:207), or a variant / fragment thereof having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:207. Therefore, in some embodiments, the CAR comprises the hCD27TM / IC domains having the amino acid sequence ILVIFSGMFLVFTLAGALFLHQRRKYRSNKGESPVEPAEPCHYSCPREEEGSTIPIQEDYRKP EPACSP (SEQ ID NO:208), or a variant / fragment 59, 60, 61, 61, 62, 64, 65, 66, 67, 68, or 69 amino acids in length and having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:208 that is capable of integrating into a plasma membrane and binding TRAF when crosslinked. In some embodiments, the extracellular domain has the amino acid sequence MNAVIISPSSLQFQKLRPVYTRIAGFKVAPLNKCSLARHFLEPGLLVRNCTITANAECACRN GWQCRDKECTECDPLPNPSLTARSSQALSPHPQPTHLPYVSEMLEARTAGHMQTLADFRQ LPARTLSTHWPPQRSLCSSDFIR (SEQ ID NO:234), or a variant / fragment thereof having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:234. In some embodiments, hNKG2D has the amino acid sequence MNAVIISPSSLQFQKLRPVYTRIAGFKVAPLNKCSLARHFLEPGLLVRNCTITANAECACRN GWQCRDKECTECDPLPNPSLTARSSQALSPHPQPTHLPYVSEMLEARTAGHMQTLADFRQ LPARTLSTHWPPQRSLCSSDFIRILVIFSGMFLVFTLAGALFLHQRRKYRSNKGESPVEPAEP CHYSCPREEEGSTIPIQEDYRKPEPACSP (SEQ ID NO:235), or a variant / fragment thereof having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:235.10. 2DS5In some embodiments, the NK cell receptor is Killer cell immunoglobulin-like receptor 2DS5 (KIR2DS5). In some embodiments, the NK cell receptor intracellular (IC) domain comprises the amino acid sequence LLHRWCSNKKNASVMDQGPAGNRTVNREDSDEQDHQEVSYA (SEQ ID NO:209), or a variant / fragment thereof having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:209. In some embodiments, the TM has the amino acid sequence VLIGTSVVKLPFTILLFFL (SEQ ID NO:210), or or a variant / fragment thereof having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:210. Therefore, in some embodiments, the CAR comprises the hNKG2D TM / IC domains having the amino acid sequence45753670.1 31ATTORNEY DOCKET NO. MOE 24MB020 PCTVLIGTSVVKLPFTILLFFLLLHRWCSNKKNASVMDQGPAGNRTVNREDSDEQDHQEVSYA (SEQ ID NO:211), or a variant / fragment thereof 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60 amino acids in length and having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:211 that is capable of integrating into a plasma membrane and binding DAP 12 when crosslinked. In some embodiments, the extracellular domain has the amino acid sequence MSLMVISMACVAFFLLQGAWPHEGFRRKPSLLAHPGPLVKSEETVILQCWSDVMFEHFLL HREGTFNHTLRLIGEHIDGVSKGNFSIGRMTQDLAGTYRCYGSVTHSPYQLSAPSDPLDIVI TGLYEKPSLSAQPGPTVLAGESVTLSCSSRSSYDMYHLSREGEAHERRLPAGPKVNRTFQA DFPLDPATHGGTYRCFGSFRDSPYEWSKSSDPLLVSVTGNSSNSWPSPTEPSSETGNPRHLH (SEQ ID NO:236), or a variant / fragment thereof having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:236. In some embodiments, hNKG2D has the amino acid sequence MSLMVISMACVAFFLLQGAWPHEGFRRKPSLLAHPGPLVKSEETVILQCWSDVMFEHFLL HREGTFNHTLRLIGEHIDGVSKGNFSIGRMTQDLAGTYRCYGSVTHSPYQLSAPSDPLDIVI TGLYEKPSLSAQPGPTVLAGESVTLSCSSRSSYDMYHLSREGEAHERRLPAGPKVNRTFQA DFPLDPATHGGTYRCFGSFRDSPYEWSKSSDPLLVSVTGNSSNSWPSPTEPSSETGNPRHLH VL1GTSVVKLPFTILLFFLLHRWCSNKKNASVMDQGPAGNRTVNREDSDEQDHQEVSYA (SEQ ID NO:237), or a variant / fragment thereof having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:237.11. KIR3DS1In some embodiments, the NK cell receptor is KIR3DS1. In some embodiments, the NK cell receptor intracellular (IC) domain comprises the amino acid sequence HRWCSNKKKCCCNGPRACREQK (SEQ ID NO:212), or a variant / fragment thereof having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:212. In some embodiments, the TM has the amino acid sequence ILIGTSVVKIPFTILLFFLL (SEQ ID NO:213), or a variant / fragment thereof having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:213. Therefore, in some embodiments, the CAR comprises the hNKG2D TM / IC domains having the amino acid sequence ILIGTSVVKIPFTILLFFLLHRWCSNKKKCCCNGPRACREQK (SEQ ID NO:214), or a variant / fragment thereof 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42 amino acids in length and having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:214 that is capable of integrating into a plasma membrane and binding DAP 12 when crosslinked. In some embodiments, the extracellular domain has the amino acid sequenceMLLMVVSMACVGLFLVQRAGPHMGGQDKPFLSAWPSAVVPRGGHVTLRCHYRHRFNNF MLYKEDRIHVPIFHGRIFQEGFNMSPVTTAHAGNYTCRGSHPHSPTGWSAPSNPMVIMVTG45753670.1 32ATTORNEY DOCKET NO. MOE 24MB020 PCTNHRKPSLLAHPGPLVKSGERVILQCWSDIMFEHFFLHREWISKDPSRLVGQIHDGVSKANFS IGSMMRALAGTYRCYGSVTHTPYQLSAPSDPLDIVVTGLYEKPSLSAQPGPKVQAGESVTL SCSSRSSYDMYHLSREGGAHERRLPAVRKVNRTFQADFPLGPATHGGTYRCFGSFRHSPYE WSDPSDPLLVSVTGNPSSSWPSPTEPSSKSGNLRHLH (SEQ ID NO:238), or a variant / fragment thereof having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:238. In some embodiments, hNKG2D has the amino acid sequenceMLLMVVSMACVGLFLVQRAGPHMGGQDKPFLSAWPSAVVPRGGHVTLRCHYRHRFNNF MLYKEDRIHVPIFHGRIFQEGFNMSPVTTAHAGNYTCRGSHPHSPTGWSAPSNPMVIMVTG NHRKPSLLAHPGPLVKSGERVILQCWSDIMFEHFFLHREWISKDPSRLVGQIHDGVSKANFS IGSMMRALAGTYRCYGSVTHTPYQLSAPSDPLDIVVTGLYEKPSLSAQPGPKVQAGESVTL SCSSRSSYDMYHLSREGGAHERRLPAVRKVNRTFQADFPLGPATHGGTYRCFGSFRHSPYE WSDPSDPLLVSVTGNPSSSWPSPTEPSSKSGNLRHLHILIGTSVVKIPFTILLFFLLHRWCSNK KKCCCNGPRACREQK (SEQ ID NO:239), or a variant / fragment thereof having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:239.12. NKp80 / KLRFlIn some embodiments, the NK cell receptor is NKp80 / KLRFl. In some embodiments, the NK cell receptor intracellular (IC) domain comprises the amino acid sequence MQDEERYMTLNVQSKKRSSAQTSQLTFKDYSVTLHWYK (SEQ ID NO:215), or a variant / fragment thereof having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:215. In some embodiments, the TM has the amino acid sequence ILLGISGTVNGILTLTLISLI (SEQ ID NO:216), or a variant / fragment thereof having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:216. Therefore, in some embodiments, the CAR comprises the hNKG2D TM / IC domains having the amino acid sequenceMQDEERYMTLNVQSKKRSSAQTSQLTFKDYSVTLHWYKILLGISGTVNGILTLTLISLI (SEQ ID NO:217), or a variant / fragment thereof 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 acids in length and having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:217 that is capable of integrating signaling when crosslinked. In some embodiments, the extracellular domain has the amino acid sequenceLLVSQGVLLKCQKGSCSNATQYEDTGDLKVNNGTRRNISNKDLCASRSADQTVLCQSEWL KYQGKCYWFSNEMKSWSDSYVYCLERKSHLLIIHDQLEMAFIQKNLRQLNYVWIGLNFTS LKMTWTWVDGSPIDSKIFFIKGPAKENSCAAIKESKIFSETCSSVFKWICQY (SEQ ID NO:240), or a variant / fragment thereof having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:240. In some embodiments, hNKG2D has the amino acid sequence45753670.1 33ATTORNEY DOCKET NO. MOE 24MB020 PCTMQDEERYMTLNVQSKKRSSAQTSQLTFKDYSVTLHWYKILLGISGTVNGILTLTLISLILLV SQGVLLKCQKGSCSNATQYEDTGDLKVNNGTRRNISNKDLCASRSADQTVLCQSEWLKY QGKCYWFSNEMKSWSDSYVYCLERKSHLLI1HDQLEMAF1QKNLRQLNYVW1GLNFTSLK MTWTWVDGSPIDSKIFFIKGPAKENSCAAIKESKIFSETCSSVFKWICQY (SEQ ID NO:241), or a variant / fragment thereof having at least 70%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO:241.D. Anti-TRPl Binding DomainThe binding domain is in some embodiments an antibody fragment that specifically binds TRP1 on a cell. For example, the antigen binding domain can be a Fab or a single-chain variable fragment (scFv) of an antibody that specifically binds the target molecule. The binding domain is in some embodiments an aptamer that specifically binds the tar target molecule. For example, the binding domain can be a peptide aptamer selected from a random sequence pool based on its ability to bind the target molecule. The binding domain can also be a natural ligand of the target molecule, or a variant and / or fragment thereof capable of binding the target molecule.In some embodiments, the anti-TRPl scFv can comprise a variable heavy (VH) domain having CDR1, CDR2 and CDR3 sequences and a variable light (VL) domain having CDR1, CDR2 and CDR3 sequences.For example, in some embodiments, the CDR1 sequence of the VH domain comprises the amino acid sequence GFTFSYYW (SEQ ID NO: 1), CDR2 sequence of the VH domain comprises the amino acid sequence IKQDGNEK (SEQ ID NO:2), CDR3 sequence of the VH domain comprises the amino acid sequence ARGRRGRPPPDY (SEQ ID NO:3), CDR1 sequence of the VL comprises the amino acid sequence QGISNY (SEQ ID NO:4), CDR2 sequence of the VL domain comprises the amino acid sequence AAS, and CDR3 sequence of the VL domain comprises the amino acid sequence QKYNSAPRT (SEQ ID NO:5).In some embodiments, the CDR1 sequence of the VH domain comprises the amino acid sequence GYTFTGYY (SEQ ID NO:6), CDR2 sequence of the VH domain comprises the amino acid sequence INPNRGGT (SEQ ID NO:7), CDR3 sequence of the VH domain comprises the amino acid sequence ARDGGAAADGFDY (SEQ ID NO:8), CDR1 sequence of the VL comprises the amino acid sequence QSIGNW (SEQ ID NO:9), CDR2 sequence of the VL domain comprises the amino acid sequence KAS, and CDR3 sequence of the VL domain comprises the amino acid sequence QQYDRYPQT (SEQ ID NO: 10).In some embodiments, the CDR1 sequence of the VH domain comprises the amino acid sequence GFTFSDYY (SEQ ID NO: 11), CDR2 sequence of the VH domain comprises the amino45753670.1 34ATTORNEY DOCKET NO. MOE 24MB020 PCT acid sequence SRSRPNNYST (SEQ ID NO: 12), CDR3 sequence of the VH domain comprises the amino acid sequence TRGRSGTSFPFYYYGMDL (SEQ ID NO: 13), CDR1 sequence of the VL comprises the amino acid sequence QS1SSN (SEQ ID NO: 14), CDR2 sequence of the VL domain comprises the amino acid sequence GAS, and CDR3 sequence of the VL domain comprises the amino acid sequence QQKYNTPPVT (SEQ ID NO: 15).In some embodiments, the CDR1 sequence of the VH domain comprises the amino acid sequence GDSVSTNSAS (SEQ ID NO: 16), CDR2 sequence of the VH domain comprises the amino acid sequence TYYRSKWYN (SEQ ID NO: 17), CDR3 sequence of the VH domain comprises the amino acid sequence VRGSSGLNAFDI (SEQ ID NO: 18), CDR1 sequence of the VL comprises the amino acid sequence NSNIGGNT (SEQ ID NO: 19), CDR2 sequence of the VL domain comprises the amino acid sequence GRN, and CDR3 sequence of the VL domain comprises the amino acid sequence SAWDDSLKGPV (SEQ ID NO:20).In some embodiments, the CDR1 sequence of the VH domain comprises the amino acid sequence GFTFSSYG (SEQ ID NO:21), CDR2 sequence of the VH domain comprises the amino acid sequence ITTAGDT (SEQ ID NO:22), CDR3 sequence of the VH domain comprises the amino acid sequence ARKFSSSWYDWYFDL (SEQ ID NO:23), CDR1 sequence of the VL comprises the amino acid sequence QDISNF (SEQ ID NO:24), CDR2 sequence of the VL domain comprises the amino acid sequence DAS, and CDR3 sequence of the VL domain comprises the amino acid sequence LQYHTYPYT (SEQ ID NO:25).In some embodiments, the CDR1 sequence of the VH domain comprises the amino acid sequence GYTFTTTW (SEQ ID NO:26), CDR2 sequence of the VH domain comprises the amino acid sequence IYPDDSDT (SEQ ID NO:27), CDR3 sequence of the VH domain comprises the amino acid sequence ATAPGDY (SEQ ID NO:28), CDR1 sequence of the VL comprises the amino acid sequence GSNIGTNS (SEQ ID NO:29), CDR2 sequence of the VL domain comprises the amino acid sequence RGD, and CDR3 sequence of the VL domain comprises the amino acid sequence SSWDDRLSSWA (SEQ ID NO:30).In some embodiments, the CDR1 sequence of the VH domain comprises the amino acid sequence GDSVSSNNVA (SEQ ID NO:31), CDR2 sequence of the VH domain comprises the amino acid sequence TYYRSKWYN (SEQ ID NO:32), CDR3 sequence of the VH domain comprises the amino acid sequence AREEATVADAFDI (SEQ ID NO:33), CDR1 sequence of the VL comprises the amino acid sequence NIG ATS (SEQ ID NO: 34), CDR2 sequence of the VL domain comprises the amino acid sequence DYG, and CDR3 sequence of the VL domain comprises the amino acid sequence QMWDIGSDEQL (SEQ ID NO:35).45753670.1 35ATTORNEY DOCKET NO. MOE 24MB020 PCTIn some embodiments, the CDR1 sequence of the VH domain comprises the amino acid sequence GYNFGTYH (SEQ ID NO:36), CDR2 sequence of the VH domain comprises the amino acid sequence IYPGDSET (SEQ ID NO:37), CDR3 sequence of the VH domain comprises the amino acid sequence ARQFPGYARQGMDV (SEQ ID NO:38), CDR1 sequence of the VL comprises the amino acid sequence NIGSKS (SEQ ID NO:39), CDR2 sequence of the VL domain comprises the amino acid sequence DDS, and CDR3 sequence of the VL domain comprises the amino acid sequence QVWDSYVV (SEQ ID NO:40).In some embodiments, the CDR1 sequence of the VH domain comprises the amino acid sequence GYTLTELS (SEQ ID NO:41), CDR2 sequence of the VH domain comprises the amino acid sequence FDPEDGET (SEQ ID NO:42), CDR3 sequence of the VH domain comprises the amino acid sequence ATDNSAVGYPHYYYYGMDV (SEQ ID NO:43), CDR1 sequence of the VL comprises the amino acid sequence GSNVGDQG (SEQ ID NO:44), CDR2 sequence of the VL domain comprises the amino acid sequence RYN, and CDR3 sequence of the VL domain comprises the amino acid sequence SAWDNNLSAWV (SEQ ID NO:45).In some embodiments, the CDR1 sequence of the VH domain comprises the amino acid sequence GGS1SSGGYY (SEQ ID NO:46), CDR2 sequence of the VH domain comprises the amino acid sequence IYYSGST (SEQ ID NO:47), CDR3 sequence of the VH domain comprises the amino acid sequence ARMGYGGNFDY (SEQ ID NO:48), CDR1 sequence of the VL comprises the amino acid sequence NSNIGSNS (SEQ ID NO:49), CDR2 sequence of the VL domain comprises the amino acid sequence DNN, and CDR3 sequence of the VL domain comprises the amino acid sequence GTWDTSLSAEV (SEQ ID NO: 50).In some embodiments, the CDR1 sequence of the VH domain comprises the amino acid sequence GGTFSSYA (SEQ ID NO: 132), CDR2 sequence of the VH domain comprises the amino acid sequence IIPIFGTA (SEQ ID NO: 133), CDR3 sequence of the VH domain comprises the amino acid sequence ASGVVIMPYDAFDI (SEQ ID NO: 134), CDR1 sequence of the VL comprises the amino acid sequence NIGATS (SEQ ID NO: 135), CDR2 sequence of the VL domain comprises the amino acid sequence DYG, and CDR3 sequence of the VL domain comprises the amino acid sequence QAWDIGSDEQM (SEQ ID NO: 136).In some embodiments, the CDR1 sequence of the VH domain comprises the amino acid sequence GGASSSNA (SEQ ID NO: 137), CDR2 sequence of the VH domain comprises the amino acid sequence ITPIFDTT (SEQ ID NO:138), CDR3 sequence of the VH domain comprises the amino acid sequence ARDGRRGLGGFFDS (SEQ ID NO: 139), CDR1 sequence of the VL comprises the amino acid sequence KLGEKY (SEQ ID NO: 140), CDR2 sequence of the VL45753670.1 36ATTORNEY DOCKET NO. MOE 24MB020 PCT domain comprises the amino acid sequence QDN, and CDR3 sequence of the VL domain comprises the amino acid sequence QAWDSSTYV (SEQ ID NO: 141).In some embodiments, the CDR1 sequence of the VH domain comprises the amino acid sequence GDSVSSNIAS (SEQ ID NO: 142), CDR2 sequence of the VH domain comprises the amino acid sequence TYYRSKWYN (SEQ ID NO: 143), CDR3 sequence of the VH domain comprises the amino acid sequence ARGDGSTFDY (SEQ ID NO: 144), CDR1 sequence of the VL comprises the amino acid sequence SSNIGSNS (SEQ ID NO: 145), CDR2 sequence of the VL domain comprises the amino acid sequence GNN, and CDR3 sequence of the VL domain comprises the amino acid sequence AAWDDSLNGWV (SEQ ID NO: 146).In some embodiments, the CDR1 sequence of the VH domain comprises the amino acid sequence GGSISSGGYY (SEQ ID NO: 147), CDR2 sequence of the VH domain comprises the amino acid sequence IYYSGST (SEQ ID NO: 148), CDR3 sequence of the VH domain comprises the amino acid sequence ARMGYGGNFDY (SEQ ID NO:149), CDR1 sequence of the VL comprises the amino acid sequence NSNIGSNS (SEQ ID NO: 150), CDR2 sequence of the VL domain comprises the amino acid sequence DNN, and CDR3 sequence of the VL domain comprises the amino acid sequence GTWDTSLSAEV (SEQ ID NO: 151).In some embodiments, the CDR1 sequence of the VH domain comprises the amino acid sequence GGTFSSYA (SEQ ID NO: 152), CDR2 sequence of the VH domain comprises the amino acid sequence IIPIFGTA (SEQ ID NO: 153), CDR3 sequence of the VH domain comprises the amino acid sequence ARDKMGFGVRSPYYYGMDV (SEQ ID NO: 154), CDR1 sequence of the VL comprises the amino acid sequence QTVSNY (SEQ ID NO: 155), CDR2 sequence of the VL domain comprises the amino acid sequence AAA, and CDR3 sequence of the VL domain comprises the amino acid sequence QQSYSGPLT (SEQ ID NO: 156).In some embodiments, the CDR1 sequence of the VH domain comprises the amino acid sequence GFVFPNYA (SEQ ID NO: 157), CDR2 sequence of the VH domain comprises the amino acid sequence IRGQSYNGTT (SEQ ID NO: 158), CDR3 sequence of the VH domain comprises the amino acid sequence YTRPLTSLQI (SEQ ID NO: 159), CDR1 sequence of the VL comprises the amino acid sequence QSILYSPSNKNY (SEQ ID NO: 160), CDR2 sequence of the VL domain comprises the amino acid sequence WAS, and CDR3 sequence of the VL domain comprises the amino acid sequence QQYYTTYPT (SEQ ID NO: 161).In some embodiments, the CDR1 sequence of the VH domain comprises the amino acid sequence GFTFSSYW (SEQ ID NO: 162), CDR2 sequence of the VH domain comprises the amino acid sequence INGDGSQT (SEQ ID NO: 163), CDR3 sequence of the VH domain comprises the45753670.1 37ATTORNEY DOCKET NO. MOE 24MB020 PCT amino acid sequence ARMASYDRSGYYGFFQH (SEQ ID NO: 164), CDR1 sequence of the VL comprises the amino acid sequence QYINTY (SEQ ID NO: 165), CDR2 sequence of the VL domain comprises the amino acid sequence GAS, and CDR3 sequence of the VL domain comprises the amino acid sequence QQSFSTPRT (SEQ ID NO: 166).In some embodiments, the CDR1 sequence of the VH domain comprises the amino acid sequence GFTFSSYW (SEQ ID NO: 162), CDR2 sequence of the VH domain comprises the amino acid sequence INGDGSQT (SEQ ID NO: 163), CDR3 sequence of the VH domain comprises the amino acid sequence ARMASYDRSGYYGFFQH (SEQ ID NO: 164), CDR1 sequence of the VL comprises the amino acid sequence QYINTY (SEQ ID NO: 165), CDR2 sequence of the VL domain comprises the amino acid sequence GAS, and CDR3 sequence of the VL domain comprises the amino acid sequence QQSFSTPRT (SEQ ID NO: 166).In some embodiments, the CDR1 sequence of the VH domain comprises the amino acid sequence GYSFSDRY (SEQ ID NO: 167), CDR2 sequence of the VH domain comprises the amino acid sequence IDPEDGET (SEQ ID NO: 168), CDR3 sequence of the VH domain comprises the amino acid sequence GRDIQTYGGSPRNWIDP (SEQ ID NO: 169), CDR1 sequence of the VL comprises the amino acid sequence SSN1GSNT (SEQ ID NO: 170), CDR2 sequence of the VL domain comprises the amino acid sequence SNN, and CDR3 sequence of the VL domain comprises the amino acid sequence AAWDDSLNGYV (SEQ ID NO: 171).In some embodiments, the CDR1 sequence of the VH domain comprises the amino acid sequence GYTFTSYD (SEQ ID NO: 172), CDR2 sequence of the VH domain comprises the amino acid sequence MNPNSGNT (SEQ ID NO: 173), CDR3 sequence of the VH domain comprises the amino acid sequence ARANGRSLGSGWNSLYYYYYGMDV (SEQ ID NO: 174), CDR1 sequence of the VL comprises the amino acid sequence QTISPY (SEQ ID NO: 175), CDR2 sequence of the VL domain comprises the amino acid sequence SAS, and CDR3 sequence of the VL domain comprises the amino acid sequence QQSSSSWT (SEQ ID NO: 176).In some embodiments, the CDR1 sequence of the VH domain comprises the amino acid sequence GYDFTASS (SEQ ID NO: 177), CDR2 sequence of the VH domain comprises the amino acid sequence IFPDDSDV (SEQ ID NO: 178), CDR3 sequence of the VH domain comprises the amino acid sequence ARLRDYGNGHWYFDL (SEQ ID NO: 179), CDR1 sequence of the VL comprises the amino acid sequence SSDVGGYKY (SEQ ID NO: 180), CDR2 sequence of the VL domain comprises the amino acid sequence EVS, and CDR3 sequence of the VL domain comprises the amino acid sequence SSYTSTTTYI (SEQ ID NO:181).45753670.1 38ATTORNEY DOCKET NO. MOE 24MB020 PCTIn some embodiments, the VH domain comprises the amino acid sequence: EVQLVESGGGLVQPGGSLRLSCAASGFTFSYYWMTWVRQAPGKGLEWVANIKQDGNEK YYVDSVKGRFTISRDNAKNSVYLHMKNLRAEDTAVFYCARGRRGRPPPDYWGQGTLVTV SS (SEQ ID NO:51, R3P1-A5), and the VL domain comprises the amino acid sequence: DIVMTQPPSSLSASVGDRVTITCRASQGISNYLAWYQQKPGKVPKLLIYAASTLQSGVPSRF SGSGSGTDFTLTISSLQPEDVATYYCQKYNSAPRTFGQGTRLEIK (SEQ ID NO:52, R3P1- A5).In some embodiments, the VH domain comprises the amino acid sequence: EVQLVESGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWINPNRGGT NYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARDGGAAADGFDYWGQGTLV TVSS (SEQ ID NO:53, R3P1-C3), and the VL domain comprises the amino acid sequence: AIRMTQSPSTLSASVGDRVTITCRASQSIGNWLAWYQQKAGKAPKLLIYKASTLESGVPSR FSGSGSGTQFTLTVSSLQPDDFASYYCQQYDRYPQTFGQGTKVEIK (SEQ ID NO:54, R3P1- C3).In some embodiments, the VH domain comprises the amino acid sequence: QVQLVQSGGGLVQPGGSLRLTCVVSGFTFSDYYMDWVRQAPGKGLEWLARSRSRPNNYS TEYAASVKGRFTVSRDDSKNSLYLQMNSLRAEDTALYYCTRGRSGTSFPFYYYGMDLWG LGTLVTVSS (SEQ ID NO:55, R3P1-E11), and the VL domain comprises the amino acid sequence: EIVLTQSPSSVSASVGDRVTITCRASQSISSNLNWYQQKSGKAPKLLIYGASILQSGVPPRFS GSGSGTDFTLTISSLQPEDYATYYCQQKYNTPPVTFGGGTKVEIK (SEQ ID NO:56, R3P1- Ell).In some embodiments, the VH domain comprises the amino acid sequence: QVQLQQSGPELVKPSQTLSLTCVISGDSVSTNSASWNWIRQSPSRGLEWLGRTYYRSKWY NDYAASVKSRITINPDTSKNQFSLQLNFVTPEDTALYYCVRGSSGLNAFDIWGQGTLVTVS S (SEQ ID NO:57, R4P1-A6), and the VL domain comprises the amino acid sequence: QPVLTQPPSASGAPGQRVTISCSGSNSNIGGNTVNWYQQLPGTAPKLLIFGRNQRPSGVPDR FSGSKSGTSASLAISGLQSEDEADYYCSAWDDSLKGPVFGGGTKLTVL (SEQ ID NO:58, R4P1-A6).In some embodiments, the VH domain comprises the amino acid sequence: EVQLVETGGGLVQPGGSLRLSCAASGFTFSSYGMHWVRQATGKGLEWVSGITTAGDTYY PGSVKGRFTISREDAKNSLYLQMNSLRPGDTAIYYCARKFSSSWYDWYFDLWGRGTLVTV SS (SEQ ID NO:59, R4P1-D1), and the VL domain comprises the amino acid sequence:45753670.1 39ATTORNEY DOCKET NO. MOE 24MB020 PCTAIRMTQSPSSLSASAGDKITITCRASQDISNFLAWFQQRPGGAPKSLIYDASTLQGGVPSKFS GRGSGTDFTLTISSLQAEDFATYYCLQYHTYPYTFGQGTKLEIK (SEQ ID NO:60, R4P1-D1).In some embodiments, the VH domain comprises the amino acid sequence:QVQLVQSGAEVKKPGESLKISCEASGYTFTTTWIGWVRQLPGKGLEWMGIIYPDDSDTRYS PSFQGQVTISADKSINTAYLQWSSLKASDTAIYYCATAPGDYWGQGTLVTVSS (SEQ ID NO:61, R4P1-D5), and the VL domain comprises the amino acid sequence:QPVLTQPPSASGTPGQRISISCSGGGSNIGTNSAHWHRQVPGAAPKLLFYRGDQRYAAVPE RFSASRSGSSASLVINGLQSEDEATYYCSSWDDRLSSWAFGGGTKVTVL (SEQ ID NO:62, R4P1-D5).In some embodiments, the VH domain comprises the amino acid sequence:QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNNVAWNWIRQSPSRGLEWLGRTYYRSKWY NDYAESVKSRIIINPDTSNNQFSLQLNSVTPEDTAVYYCAREEATVADAFDIWGQGTMVTV SS (SEQ ID NO:63, R4P1-E12), and the VL domain comprises the amino acid sequence:QPVLTQPPSVSVAPGETATIACEGDNIGATSVHWYQQKPGQPPVLFVYDYGDRASGIPERF SASSSGNTATLTISSVEAGDEADYYCQMWDIGSDEQLFGGGTQLIIL (SEQ ID NO:64, R4P1- E12).In some embodiments, the VH domain comprises the amino acid sequence:QVQLVQSGAEVKKPGESLKISCKVSGYNFGTYHIAWVRQMPGKGLEWMGIIYPGDSETRY SPSFQGHVTISADKSNSTAFLQWSSLKASDSAMYYCARQFPGYARQGMDVWGQGTLVTV SS (SEQ ID NO:65, R4P2-D11), and the VL domain comprises the amino acid sequence:QPVLTQPPSVSVAPGKTARITCGGNNIGSKSVHWYQQKPGQAPVLVVYDDSDRPSGIPERF SGSNSGNTATLTISRVEAGDEADYYCQVWDSYVVIGGGTQLTVL (SEQ ID NO:66, R4P2- Dll).In some embodiments, the VH domain comprises the amino acid sequence:QVQLVQSGAEVKKPGASVKVSCKVSGYTLTELSMHWVRQAPGKGLEWMGGFDPEDGETI YAQKFQGRVTMTEDTSTDTAYMELSSLRSEDTAVYYCATDNSAVGYPHYYYYGMDVWG QGTMVTVSS (SEQ ID NO:67, R4P2-H4), and the VL domain comprises the amino acid sequence:QPVLTQPPSMSKGLRQTATLTCTGTGSNVGDQGALWLQLRRGLPPKLLSDRNYQRPSEISE RFSASRSANTASLTITGLQPEDEADYYCSAWDNNLSAWVFGGGTKVTVL (SEQ ID NO:68, R4P2-H4).In some embodiments, the VH domain comprises the amino acid sequence: QLQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHPGKGLEWIGYIYYSGSTYY45753670.1 40ATTORNEY DOCKET NO. MOE 24MB020 PCTNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARMGYGGNFDYWGQGTLVTVSS (SEQ ID NO:69, R4P4-B11), and the VL domain comprises the amino acid sequence:QSVLTQPPSVSAAPGQRVT1SCSGSNSN1GSNSVSWYQHLPGTAPKLL1YDNNKRPSG1PDRF SASKSGTSATLGITGLQTGDEADYYCGTWDTSLSAEVFGGGTELTVL (SEQ ID NO:70,R4P4-B11).In some embodiments, the VH domain comprises the amino acid sequence:EVQLVQS GAEVKKPGS S VKVSCKAS GGTFS S Y AS WVRQAPGQGLEWMGGIIPIFGTAN Y A QKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCASGVVIMPYDAFDIWGQGTTVTVSS (SEQ ID NO:71, R4P1-C4), and the VL domain comprises the amino acid sequence:QPVLTQPPSVSVAPGETARIACEGDNIGATSVHWYQQKPGQPPILFVYDYGDRASGIPERFS ASSSGSTATLTISSVEAGDEADYYCQAWDIGSDEQMFGGGTQLIIL (SEQ ID NO:72, R4P1-C4).In some embodiments, the VH domain comprises the amino acid sequence: QVQLVQSGAEVKKPGSSVKVSCKASGGASSSNAFSWVRQAPGQGLEWMGGITPIFDTTNY AQRFQGRVTITADDSTSTSYMELSSLRSDDTAVYYCARDGRRGLGGFFDSWGQGTLVTVS S (SEQ ID NO:73, R4P1-H4), and the VL domain comprises the amino acid sequence:QPVLTQPPSVSVSPGQTASVTCSGDKLGEKYVSWYQQRPGQSPLMVIYQDNKRPSGIPERF SGSNSGNTATLTISGTQAMDEADYYCQAWDSSTYVFGAGTKLTVL (SEQ ID NO:74, R4P1- H4).In some embodiments, the VH domain comprises the amino acid sequence: QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNIASWNWIRQSPSRGLEWLGRTYYRSKWYN DYAVSVKSRITINPDTSKNQFSLQLNSMTPEDSAVYYCARGDGSTFDYWGQGTLVTVSS (SEQ ID NO:75, R4P2-D8), and the VL domain comprises the amino acid sequence:QPVLTQPPSASGTPGQRVTISCSGISSNIGSNSVHWYQQVPGTAPKLLIYGNNHRPSGLPDRF SGSKSGTSASLAISGLQSEDEADYYCAAWDDSLNGWVFGGGTQLTVL (SEQ ID NO:76, R4P2-D8).In some embodiments, the VH domain comprises the amino acid sequence: QLQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHPGKGLEWIGYIYYSGSTYY NPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARMGYGGNFDYWGQGTLVTVSS (SEQ ID NO:77, R4P3-H9), and the VL domain comprises the amino acid sequence:QSVLTQPPSVSAAPGQRVTISCSGSNSNIGSNSVSWYQHLPGTAPKLLIYDNNKRPSGIPDRF SASKSGTSATLGITGLQTGDEADYYCGTWDTSLSAEVFGGGTELTVL (SEQ ID NO:78, R4P3-H9).45753670.1 41ATTORNEY DOCKET NO. MOE 24MB020 PCTIn some embodiments, the VH domain comprises the amino acid sequence: QVQLQES GAEVKKPGS S VKVSCKAS GGTFS S Y AIS WVRQ APGQGLEWMGGIIPIFGTANYA QKFQGRVT1TADESTSTAYMELSSLRSEDTAVYYCARDKMGFGVRSPYYYGMDVWGQGT LVTVSS (SEQ ID NO:79, R3P1-A10), and the VL domain comprises the amino acid sequence: DIVMTQSPSSLSAFVGDRVSITCRASQTVSNYLNWYQQKPGKAPKVLIYAAATLQSGVPSR FSGSGSGTEFTLTISSLQPEDVASYFCQQSYSGPLTFGGGTKVEIK (SEQ ID NO: 80, R3P1- A10).In some embodiments, the VH domain comprises the amino acid sequence: QVQLVQSGGALVRPGRSLRLSCTGSGFVFPNYAFNWVRQAPGKGLEWVGFIRGQSYNGTT DYAASVNGRFTISRDDSKRVVYLQMNSLKSEDTATYYCYTRPLTSLQIWGPGTL VTVSS (SEQ ID NO:81, R3P1-C8), and the VL domain comprises the amino acid sequence: EIVLTQSPDSLAVSLGERATINCKSSQSILYSPSNKNYLAWYQQKPGQPPQVLITWASTRES GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYTTYPTFGQGTKVEIK (SEQ ID NO:82, R3P1-C8).In some embodiments, the VH domain comprises the amino acid sequence: EVQLLESGGGLIQPGGSLRLSCAASGFTFSSYWINWVRQVPGKGLVWVSRINGDGSQTDY ADSVKGRFTISRDNAKNTVDLQMNSLRAEDTALYYCARMASYDRSGYYGFFQHWGQATP VTVSS (SEQ ID NO:83, R3P1-D7), and the VL domain comprises the amino acid sequence: DIVMTQPPSSLSASVGDRLTITCRASQYINTYLNWFQQKPGKAPNLLIYGASTLQSGVPSRF SGSGSGTEFTLTISSLQPEDFATYYCQQSFSTPRTFGPGTKVDIK (SEQ ID NO:84, R3P1-D7).In some embodiments, the VH domain comprises the amino acid sequence: QVQLVQSGPEVKKPGTTVKVSCKASGYSFSDRYMHWLRQAPGKGPEWMGLIDPEDGETR YAEKFLGRLTISADTSSDTAYMELNGLRSDDTAVYYCGRDIQTYGGSPRNWIDPWGQGTL VTVSS (SEQ ID NO:85, R3P1-E2), and the VL domain comprises the amino acid sequence: QAVLTQPPSASGTPGQRVTISCSGSSSNIGSNTVNWYQQLPGTAPKLLIYSNNQRPSGVPDR FSGSKSGTSASLAISGLQSEDEADYYCAAWDDSLNGYVFGTGTKVTVL (SEQ ID NO:86, R3P1-E2).In some embodiments, the VH domain comprises the amino acid sequence: EVQLVESGAEVKKPGASVKVSCKASGYTFTSYDINWVRQATGQGLEWMGWMNPNSGNT GYAQKFQGRVTMTRNTSISTAYMELSSLRSEDTAVYYCARANGRSLGSGWNSLYYYYYG MDVWGQGTTVTVSS (SEQ ID NO:87, R3P1-H1), and the VL domain comprises the amino acid sequence:45753670.1 42ATTORNEY DOCKET NO. MOE 24MB020 PCTAIRMTQSPSSLSASVGDRVTITCRASQTISPYLNWYQQKPGKAPKLLISSASTLQSGVPSRFT GSGSGTVFTLTISRLEPEDSATYYCQQSSSSWTFGQGTKLEIK (SEQ ID NO:88, R3P1-H1).In some embodiments, the VH domain comprises the amino acid sequence: EVQLVESGAEVRKPGESLKISCKASGYDFTASSIAWVRQMPDEGLEWMGIIFPDDSDVRYS PSFQGQVTISADKSINTAYLHWTRLKAADTAIYSCARLRDYGNGHWYFDLWGRGTLVTVS S (SEQ ID NO:89, R3P1-H5), and the VL domain comprises the amino acid sequence: SYELTQPASVSGSPGQSITISCTGTSSDVGGYKYVSWYQQHPGKAPKLLIYEVSNRPSGVSN RFSGSKSGNTASLTISGLQAEDEADYYCSSYTSTTTYIFGTGTELTVL (SEQ ID NO:90, R3P1-H5).The heavy and light chains are preferably separated by a linker. Suitable linkers for scFv antibodies are known in the art. In some embodiments, the linker comprises the amino acid sequence GGGGSGGGGSGGGGS (SEQ ID NO:91).In some embodiments, the anti-TRPl scFv comprises an amino acid sequence: EVQLVESGGGLVQPGGSLRLSCAASGFTFSYYWMTWVRQAPGKGLEWVANIKQDGNEK YYVDSVKGRFTISRDNAKNSVYLHMKNLRAEDTAVFYCARGRRGRPPPDYWGQGTLVTV SSGGGGSGGGGSGGGGSD1VMTQPPSSLSASVGDRVT1TCRASQG1SNYLAWYQQKPGKVP KLLIYAASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQKYNSAPRTFGQGTRLEIK (SEQ ID NO:92, R3P1-A5), and in some embodiments, the anti-TRPl scFv comprises an amino acid sequence: DIVMTQPPSSLSASVGDRVTITCRASQGISNYLAWYQQKPGKVPKLLIYAASTLQSGVPSRF SGSGSGTDFTLTISSLQPEDVATYYCQKYNSAPRTFGQGTRLEIKGGGGSGGGGSGGGGSE VQLVESGGGLVQPGGSLRLSCAASGFTFSYYWMTWVRQAPGKGLEWVANIKQDGNEKY YVDSVKGRFTISRDNAKNSVYLHMKNLRAEDTAVFYCARGRRGRPPPDYWGQGTLVTVS S (SEQ ID NO:93, R3P1-A5).In some embodiments, the anti-TRPl scFv comprises an amino acid sequence: EVQLVESGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWINPNRGGT NYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARDGGAAADGFDYWGQGTLV TVSSGGGGSGGGGSGGGGSAIRMTQSPSTLSASVGDRVTITCRASQSIGNWLAWYQQKAG KAPKLLIYKASTLESGVPSRFSGSGSGTQFTLTVSSLQPDDFASYYCQQYDRYPQTFGQGTK VEIK (SEQ ID NO:94, R3P1-C3), and in some embodiments, the anti-TRPl scFv comprises an amino acid sequence: AIRMTQSPSTLSASVGDRVTITCRASQSIGNWLAWYQQKAGKAPKLLIYKASTLESGVPSR FSGSGSGTQFTLTVSSLQPDDFASYYCQQYDRYPQTFGQGTKVEIKGGGGSGGGGSGGGG45753670.1 43ATTORNEY DOCKET NO. MOE 24MB020 PCTSEVQLVESGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWINPNRGGTNYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARDGGAAADGFDYWGQGTLVTVSS (SEQ ID NO:95, R3P1-C3).In some embodiments, the anti-TRPl scFv comprises an amino acid sequence: QVQLVQSGGGLVQPGGSLRLTCVVSGFTFSDYYMDWVRQAPGKGLEWLARSRSRPNNYS TEYAASVKGRFTVSRDDSKNSLYLQMNSLRAEDTALYYCTRGRSGTSFPFYYYGMDLWG LGTLVTVSSGGGGSGGGGSGGGGSEIVLTQSPSSVSASVGDRVTITCRASQSISSNLNWYQQ KSGKAPKLLIYGAS ILQSGVPPRFS GS GSGTDFTLTIS SLQPED YATYYCQQKYNTPP VTFGG GTKVEIK (SEQ ID NO:96, R3P1-E11), and in some embodiments, the anti-TRPl scFv comprises an amino acid sequence:EIVLTQSPSSVSASVGDRVTITCRASQSISSNLNWYQQKSGKAPKLLIYGASILQSGVPPRFS GSGSGTDFTLTISSLQPEDYATYYCQQKYNTPPVTFGGGTKVEIKGGGGSGGGGSGGGGSQ VQLVQSGGGLVQPGGSLRLTCVVSGFTFSDYYMDWVRQAPGKGLEWLARSRSRPNNYST EYAASVKGRFTVSRDDSKNSLYLQMNSLRAEDTALYYCTRGRSGTSFPFYYYGMDLWGL GTL VTVSS (SEQ ID NO:97, R3P1-E11).In some embodiments, the anti-TRPl scFv comprises an amino acid sequence: QVQLQQSGPELVKPSQTLSLTCVISGDSVSTNSASWNWIRQSPSRGLEWLGRTYYRSKWY NDYAASVKSRITINPDTSKNQFSLQLNFVTPEDTALYYCVRGSSGLNAFDIWGQGTLVTVS SGGGGSGGGGSGGGGSQPVLTQPPSASGAPGQRVTISCSGSNSNIGGNTVNWYQQLPGTAP KLLIFGRNQRPSGVPDRFSGSKSGTSASLAISGLQSEDEADYYCSAWDDSLKGPVFGGGTK LTVL (SEQ ID NO:98, R4P1-A6), and in some embodiments, the anti-TRPl scFv comprises an amino acid sequence:QPVLTQPPSASGAPGQRVTISCSGSNSNIGGNTVNWYQQLPGTAPKLLIFGRNQRPSGVPDR FSGSKSGTSASLAISGLQSEDEADYYCSAWDDSLKGPVFGGGTKLTVLGGGGSGGGGSGG GGSQVQLQQSGPELVKPSQTLSLTCVISGDSVSTNSASWNWIRQSPSRGLEWLGRTYYRSK WYNDYAASVKSRITINPDTSKNQFSLQLNFVTPEDTALYYCVRGSSGLNAFDIWGQGTLVT VSS (SEQ ID NO:99, R4P1-A6).In some embodiments, the anti-TRPl scFv comprises an amino acid sequence: EVQLVETGGGLVQPGGSLRLSCAASGFTFSSYGMHWVRQATGKGLEWVSGITTAGDTYY PGSVKGRFTISREDAKNSLYLQMNSLRPGDTAIYYCARKFSSSWYDWYFDLWGRGTLVTV SSGGGGSGGGGSGGGGSAIRMTQSPSSLSASAGDKITITCRASQDISNFLAWFQQRPGGAPK SLIYDASTLQGGVPSKFSGRGSGTDFTLTISSLQAEDFATYYCLQYHTYPYTFGQGTKLEIK (SEQ ID NO: 100, R4P1-D1), and in some embodiments, the anti-TRPl scFv comprises an amino45753670.1 44ATTORNEY DOCKET NO. MOE 24MB020 PCT acid sequence: AIRMTQSPSSLSASAGDKITITCRASQDISNFLAWFQQRPGGAPKSLIYDASTLQGGVPSKFS GRGSGTDFTLTISSLQAEDFATYYCLQYHTYPYTFGQGTKLEIKGGGGSGGGGSGGGGSEV QLVETGGGLVQPGGSLRLSCAASGFTFSSYGMHWVRQATGKGLEWVSGITTAGDTYYPGS VKGRFTISREDAKNSLYLQMNSLRPGDTAIYYCARKFSSSWYDWYFDLWGRGTLVTVSS (SEQ ID NO: 101, R4P1-D1).In some embodiments, the anti-TRPl scFv comprises an amino acid sequence: QVQLVQSGAEVKKPGESLKISCEASGYTFTTTWIGWVRQLPGKGLEWMGIIYPDDSDTRYS PSFQGQVTISADKSINTAYLQWSSLKASDTAIYYCATAPGDYWGQGTLVTVSSGGGGSGG GGSGGGGSQPVLTQPPSASGTPGQRISISCSGGGSNIGTNSAHWHRQVPGAAPKLLFYRGD QRYAA VPERFS ASRS GS S ASLVINGLQSEDEATY YCS S WDDRLS S WAFGGGTKVTVL (SEQ ID NO: 102, R4P1-D5), and in some embodiments, the anti-TRPl scFv comprises an amino acid sequence: QPVLTQPPSASGTPGQRISISCSGGGSNIGTNSAHWHRQVPGAAPKLLFYRGDQRYAAVPE RFSASRSGSSASLVINGLQSEDEATYYCSSWDDRLSSWAFGGGTKVTVLGGGGSGGGGSG GGGSQVQLVQSGAEVKKPGESLK1SCEASGYTFTTTW1GWVRQLPGKGLEWMG1IYPDDS DTRYSPSFQGQVTISADKSINTAYLQWSSLKASDTAIYYCATAPGDYWGQGTLVTVSS (SEQ ID NO: 103, R4P1-D5).In some embodiments, the anti-TRPl scFv comprises an amino acid sequence: QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNNVAWNWIRQSPSRGLEWLGRTYYRSKWY NDYAESVKSRIIINPDTSNNQFSLQLNSVTPEDTAVYYCAREEATVADAFDIWGQGTMVTV SSGGGGSGGGGSGGGGSQPVLTQPPSVSVAPGETATIACEGDNIGATSVHWYQQKPGQPP VLFVYDYGDRASGIPERFSASSSGNTATLTISSVEAGDEADYYCQMWDIGSDEQLFGGGTQ LIIL (SEQ ID NO: 104, R4P1-E12), and in some embodiments, the anti-TRPl scFv comprises an amino acid sequence: QPVLTQPPSVSVAPGETATIACEGDNIGATSVHWYQQKPGQPPVLFVYDYGDRASGIPERF SASSSGNTATLTISSVEAGDEADYYCQMWDIGSDEQLFGGGTQLIILGGGGSGGGGSGGGG SQVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNNVAWNWIRQSPSRGLEWLGRTYYRSKW YNDYAESVKSRIIINPDTSNNQFSLQLNSVTPEDTAVYYCAREEATVADAFDIWGQGTMVT VSS (SEQ ID NO: 105, R4P1-E12).In some embodiments, the anti-TRPl scFv comprises an amino acid sequence: QVQLVQSGAEVKKPGESLKISCKVSGYNFGTYHIAWVRQMPGKGLEWMGIIYPGDSETRY SPSFQGHVTISADKSNSTAFLQWSSLKASDSAMYYCARQFPGYARQGMDVWGQGTLVTV45753670.1 45ATTORNEY DOCKET NO. MOE 24MB020 PCTSSGGGGSGGGGSGGGGSQPVLTQPPSVSVAPGKTARITCGGNNIGSKSVHWYQQKPGQAP VLVVYDDSDRPSGIPERFSGSNSGNTATLTISRVEAGDEADYYCQVWDSYVVIGGGTQLTV L (SEQ ID NO: 106, R4P2-D11), and in some embodiments, the anti-TRPl scFv comprises an amino acid sequence: QPVLTQPPSVSVAPGKTARITCGGNNIGSKSVHWYQQKPGQAPVLVVYDDSDRPSGIPERF SGSNSGNTATLTISRVEAGDEADYYCQVWDSYVVIGGGTQLTVLGGGGSGGGGSGGGGS QVQLVQSGAEVKKPGESLKISCKVSGYNFGTYHIAWVRQMPGKGLEWMGIIYPGDSETRY SPSFQGHVTISADKSNSTAFLQWSSLKASDSAMYYCARQFPGYARQGMDVWGQGTLVTV SS (SEQ ID NO: 107, R4P2-D11).In some embodiments, the anti-TRPl scFv comprises an amino acid sequence: QVQLVQSGAEVKKPGASVKVSCKVSGYTLTELSMHWVRQAPGKGLEWMGGFDPEDGETI YAQKFQGRVTMTEDTSTDTAYMELSSLRSEDTAVYYCATDNSAVGYPHYYYYGMDVWG QGTMVTVSSGGGGSGGGGSGGGGSQPVLTQPPSMSKGLRQTATLTCTGTGSNVGDQGAL WLQLRRGLPPKLLSDRNYQRPSEISERFSASRSANTASLTITGLQPEDEADYYCSAWDNNLS AWVFGGGTKVTVL (SEQ ID NO: 108, R4P2-H4), and in some embodiments, the anti-TRPl scFv comprises an amino acid sequence: QPVLTQPPSMSKGLRQTATLTCTGTGSNVGDQGALWLQLRRGLPPKLLSDRNYQRPSEISE RFSASRSANTASLTITGLQPEDEADYYCSAWDNNLSAWVFGGGTKVTVLGGGGSGGGGS GGGGSQVQLVQSGAEVKKPGASVKVSCKVSGYTLTELSMHWVRQAPGKGLEWMGGFDP EDGETIYAQKFQGRVTMTEDTSTDTAYMELSSLRSEDTAVYYCATDNSAVGYPHYYYYG MDVWGQGTMVTVSS (SEQ ID NO: 109, R4P2-H4).In some embodiments, the anti-TRPl scFv comprises an amino acid sequence: QLQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHPGKGLEWIGYIYYSGSTYY NPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARMGYGGNFDYWGQGTLVTVSSGG GGSGGGGSGGGGSQSVLTQPPSVSAAPGQRVTISCSGSNSNIGSNSVSWYQHLPGTAPKLLI YDNNKRPSGIPDRFSASKSGTSATLGITGLQTGDEADYYCGTWDTSLSAEVFGGGTELTVL (SEQ ID NO: 110, R4P4-B11), and in some embodiments, the anti-TRPl scFv comprises an amino acid sequence: QSVLTQPPSVSAAPGQRVTISCSGSNSNIGSNSVSWYQHLPGTAPKLLIYDNNKRPSGIPDRF SASKSGTSATLGITGLQTGDEADYYCGTWDTSLSAEVFGGGTELTVLGGGGSGGGGSGGG GSQLQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHPGKGLEWIGYIYYSGSTY YNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARMGYGGNFDYWGQGTLVTVSS (SEQ ID NO: 111, R4P4-B 11).45753670.1 46ATTORNEY DOCKET NO. MOE 24MB020 PCTIn some embodiments, the anti-TRPl scFv comprises an amino acid sequence: EVQLVQS GAEVKKPGS S VKVSCKAS GGTFS S Y AS WVRQAPGQGLEWMGGIIPIFGTAN Y A QKFQGRVT1TADESTSTAYMELSSLRSEDTAVYYCASGVV1MPYDAFD1WGQGTTVTVSSG GGGSGGGGSGGGGSQPVLTQPPSVSVAPGETARIACEGDNIGATSVHWYQQKPGQPPILFV YDYGDRASGIPERFSASSSGSTATLTISSVEAGDEADYYCQAWDIGSDEQMFGGGTQLIIL (SEQ ID NO: 112, R4P1-C4), and in some embodiments, the anti-TRPl scFv comprises an amino acid sequence:QPVLTQPPSVSVAPGETARIACEGDNIGATSVHWYQQKPGQPPILFVYDYGDRASGIPERFS ASSSGSTATLTISSVEAGDEADYYCQAWDIGSDEQMFGGGTQLIILGGGGSGGGGSGGGGS EVQLVQS GAEVKKPGS S VKVSCKAS GGTFS S YAS WVRQAPGQGLEWMGGIIPIFGTAN YA QKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCASGVVIMPYDAFDIWGQGTTVTVSS (SEQ ID NO: 113, R4P1-C4).In some embodiments, the anti-TRPl scFv comprises an amino acid sequence: QVQLVQSGAEVKKPGSSVKVSCKASGGASSSNAFSWVRQAPGQGLEWMGGITPIFDTTNY AQRFQGRVTITADDSTSTSYMELSSLRSDDTAVYYCARDGRRGLGGFFDSWGQGTLVTVS SGGGGSGGGGSGGGGSQPVLTQPPSVSVSPGQTASVTCSGDKLGEKYVSWYQQRPGQSPL MVIYQDNKRPSGIPERFSGSNSGNTATLTISGTQAMDEADYYCQAWDSSTYVFGAGTKLT VL (SEQ ID NO: 114, R4P1-H4), and in some embodiments, the anti-TRPl scFv comprises an amino acid sequence:QPVLTQPPSVSVSPGQTASVTCSGDKLGEKYVSWYQQRPGQSPLMVIYQDNKRPSGIPERF SGSNSGNTATLTISGTQAMDEADYYCQAWDSSTYVFGAGTKLTVLGGGGSGGGGSGGGG SQVQLVQSGAEVKKPGSSVKVSCKASGGASSSNAFSWVRQAPGQGLEWMGGITPIFDTTN YAQRFQGRVTITADDSTSTSYMELSSLRSDDTAVYYCARDGRRGLGGFFDSWGQGTLVTV SS (SEQ ID NO:115, R4P1-H4).In some embodiments, the anti-TRPl scFv comprises an amino acid sequence: QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNIASWNWIRQSPSRGLEWLGRTYYRSKWYN DYAVSVKSRITINPDTSKNQFSLQLNSMTPEDSAVYYCARGDGSTFDYWGQGTLVTVSSG GGGSGGGGSGGGGSQPVLTQPPSASGTPGQRVTISCSGISSNIGSNSVHWYQQVPGTAPKLL IYGNNHRPSGLPDRFSGSKSGTSASLAISGLQSEDEADYYCAAWDDSLNGWVFGGGTQLT VL (SEQ ID NO: 116, R4P2-D8), and in some embodiments, the anti-TRPl scFv comprises an amino acid sequence:QPVLTQPPSASGTPGQRVTISCSGISSNIGSNSVHWYQQVPGTAPKLLIYGNNHRPSGLPDRF SGSKSGTSASLAISGLQSEDEADYYCAAWDDSLNGWVFGGGTQLTVLGGGGSGGGGSGG45753670.1 47ATTORNEY DOCKET NO. MOE 24MB020 PCTGGSQVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNIASWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSKNQFSLQLNSMTPEDSAVYYCARGDGSTFDYWGQGTLVTVSS (SEQ ID NO:117, R4P2-D8).In some embodiments, the anti-TRPl scFv comprises an amino acid sequence: QLQLQES GPGLVKPSQTLSLTCTVS GGSISS GGYYWS WIRQHPGKGLEWIG YIYYS GSTY Y NPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARMGYGGNFDYWGQGTLVTVSSGG GGSGGGGSGGGGSQSVLTQPPSVSAAPGQRVTISCSGSNSNIGSNSVSWYQHLPGTAPKLLI YDNNKRPSGIPDRFSASKSGTSATLGITGLQTGDEADYYCGTWDTSLSAEVFGGGTELTVL (SEQ ID NO: 118, R4P3-H9), and in some embodiments, the anti-TRPl scFv comprises an amino acid sequence: QSVLTQPPSVSAAPGQRVTISCSGSNSNIGSNSVSWYQHLPGTAPKLLIYDNNKRPSGIPDRF SASKSGTSATLGITGLQTGDEADYYCGTWDTSLSAEVFGGGTELTVLGGGGSGGGGSGGG GSQLQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHPGKGLEWIGYIYYSGSTY YNPSLKSRVTIS VDTS KNQFSLKLS S VTAADTAVYYCARMGYGGNFD YWGQGTLVTVS S (SEQ ID NO: 119, R4P3-H9).In some embodiments, the anti-TRPl scFv comprises an amino acid sequence: QVQLQESGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYA QKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARDKMGFGVRSPYYYGMDVWGQGT LVTVSSGGGGSGGGGSGGGGSDIVMTQSPSSLSAFVGDRVSITCRASQTVSNYLNWYQQK PGKAPKVLIYAAATLQSGVPSRFSGSGSGTEFTLTISSLQPEDVASYFCQQSYSGPLTFGGGT KVEIK (SEQ ID NO: 120, R3P1-A10), and in some embodiments, the anti-TRPl scFv comprises an amino acid sequence: DIVMTQSPSSLSAFVGDRVSITCRASQTVSNYLNWYQQKPGKAPKVLIYAAATLQSGVPSR FSGSGSGTEFTLTISSLQPEDVASYFCQQSYSGPLTFGGGTKVEIKGGGGSGGGGSGGGGSQ VQLQESGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQ KFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARDKMGFGVRSPYYYGMDVWGQGTL VTVSS (SEQ ID NO:121, R3P1-A10).In some embodiments, the anti-TRPl scFv comprises an amino acid sequence: QVQLVQSGGALVRPGRSLRLSCTGSGFVFPNYAFNWVRQAPGKGLEWVGFIRGQSYNGTT DYAASVNGRFTISRDDSKRVVYLQMNSLKSEDTATYYCYTRPLTSLQIWGPGTLVTVSSGG GGSGGGGSGGGGSEIVLTQSPDSLAVSLGERATINCKSSQSILYSPSNKNYLAWYQQKPGQ PPQ VLITWASTRES G VPDRFS GSGSGTDFTLTIS SLQAED V AVYYCQQYYTTYPTFGQGTK VEIK (SEQ ID NO: 122, R3P1-C8), and in some embodiments, the anti-TRPl scFv comprises an45753670.1 48ATTORNEY DOCKET NO. MOE 24MB020 PCT amino acid sequence: EIVLTQSPDSLAVSLGERATINCKSSQSILYSPSNKNYLAWYQQKPGQPPQVLITWASTRES GVPDRFSGSGSGTDFTLT1SSLQAEDVAVYYCQQYYTTYPTFGQGTKVEIKGGGGSGGGGS GGGGSQVQLVQSGGALVRPGRSLRLSCTGSGFVFPNYAFNWVRQAPGKGLEWVGFIRGQS YNGTTDYAASVNGRFTISRDDSKRVVYLQMNSLKSEDTATYYCYTRPLTSLQIWGPGTLVTVSS (SEQ ID NO: 123, R3P1-C8).In some embodiments, the anti-TRPl scFv comprises an amino acid sequence: EVQLLESGGGLIQPGGSLRLSCAASGFTFSSYWINWVRQVPGKGLVWVSRINGDGSQTDY ADSVKGRFTISRDNAKNTVDLQMNSLRAEDTALYYCARMASYDRSGYYGFFQHWGQATP VTVSSGGGGSGGGGSGGGGSDIVMTQPPSSLSASVGDRLTITCRASQYINTYLNWFQQKPG KAPNLLIYGASTLQSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQSFSTPRTFGPGTKV DIK (SEQ ID NO: 124, R3P1-D7), and in some embodiments, the anti-TRPl scFv comprises an amino acid sequence:DIVMTQPPSSLSASVGDRLTITCRASQYINTYLNWFQQKPGKAPNLLIYGASTLQSGVPSRF SGSGSGTEFTLTISSLQPEDFATYYCQQSFSTPRTFGPGTKVDIKGGGGSGGGGSGGGGSEV QLLESGGGL1QPGGSLRLSCAASGFTFSSYW1NWVRQVPGKGLVWVSR1NGDGSQTDYAD SVKGRFTISRDNAKNTVDLQMNSLRAEDTALYYCARMASYDRSGYYGFFQHWGQATPVT VSS (SEQ ID NO: 125, R3P1-D7).In some embodiments, the anti-TRPl scFv comprises an amino acid sequence:QVQLVQSGPEVKKPGTTVKVSCKASGYSFSDRYMHWLRQAPGKGPEWMGLIDPEDGETR YAEKFLGRLTISADTSSDTAYMELNGLRSDDTAVYYCGRDIQTYGGSPRNWIDPWGQGTL VTVSSGGGGSGGGGSGGGGSQAVLTQPPSASGTPGQRVTISCSGSSSNIGSNTVNWYQQLP GTAPKLLIYSNNQRPSGVPDRFSGSKSGTSASLAISGLQSEDEADYYCAAWDDSLNGYVFG TGTKVTVL (SEQ ID NO:126, R3P1-E2), and in some embodiments, the anti-TRPl scFv comprises an amino acid sequence:QAVLTQPPSASGTPGQRVTISCSGSSSNIGSNTVNWYQQLPGTAPKLLIYSNNQRPSGVPDR FSGSKSGTSASLAISGLQSEDEADYYCAAWDDSLNGYVFGTGTKVTVLGGGGSGGGGSGG GGSQVQLVQSGPEVKKPGTTVKVSCKASGYSFSDRYMHWLRQAPGKGPEWMGLIDPEDG ETRYAEKFLGRLTISADTSSDTAYMELNGLRSDDTAVYYCGRDIQTYGGSPRNWIDPWGQ GTLVTVSS (SEQ ID NO: 127, R3P1-E2).In some embodiments, the anti-TRPl scFv comprises an amino acid sequence:EVQLVESGAEVKKPGASVKVSCKASGYTFTSYDINWVRQATGQGLEWMGWMNPNSGNT GYAQKFQGRVTMTRNTSISTAYMELSSLRSEDTAVYYCARANGRSLGSGWNSLYYYYYG45753670.1 49ATTORNEY DOCKET NO. MOE 24MB020 PCTMDVWGQGTTVTVSSGGGGSGGGGSGGGGSAIRMTQSPSSLSASVGDRVTITCRASQTISPY LNWYQQKPGKAPKLLISSASTLQSGVPSRFTGSGSGTVFTLTISRLEPEDSATYYCQQSSSS WTFGQGTKLE1K (SEQ ID NO: 128, R3P1-H1), and in some embodiments, the anti-TRPl scFv comprises an amino acid sequence: AIRMTQSPSSLSASVGDRVTITCRASQTISPYLNWYQQKPGKAPKLLISSASTLQSGVPSRFT GSGSGTVFTLTISRLEPEDSATYYCQQSSSSWTFGQGTKLEIKGGGGSGGGGSGGGGSEVQ LVESGAEVKKPGASVKVSCKASGYTFTSYDINWVRQATGQGLEWMGWMNPNSGNTGYA QKFQGRVTMTRNTSISTAYMELSSLRSEDTAVYYCARANGRSLGSGWNSLYYYYYGMDV WGQGTTVTVSS (SEQ ID NO: 129, R3P1-H1).In some embodiments, the anti-TRPl scFv comprises an amino acid sequence: EVQLVESGAEVRKPGESLKISCKASGYDFTASSIAWVRQMPDEGLEWMGIIFPDDSDVRYS PSFQGQVTISADKSINTAYLHWTRLKAADTAIYSCARLRDYGNGHWYFDLWGRGTLVTVS SGGGGSGGGGSGGGGSSYELTQPASVSGSPGQSITISCTGTSSDVGGYKYVSWYQQHPGKA PKLLIYEVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSTTTYIFGTGTELT VL (SEQ ID NO: 130, R3P1-H5), and in some embodiments, the anti-TRPl scFv comprises an amino acid sequence: SYELTQPASVSGSPGQSITISCTGTSSDVGGYKYVSWYQQHPGKAPKLLIYEVSNRPSGVSN RFSGSKSGNTASLTISGLQAEDEADYYCSSYTSTTTYIFGTGTELTVLGGGGSGGGGSGGGG SEVQLVESGAEVRKPGESLKISCKASGYDFTASSIAWVRQMPDEGLEWMGIIFPDDSDVRY SPSFQGQVTISADKSINTAYLHWTRLKAADTAIYSCARLRDYGNGHWYFDLWGRGTLVTV SS (SEQ ID NO:131, R3P1-H5).E. Immune Effector CellsAlso disclosed are immune effector cells that are engineered to express the disclosed CARs (also referred to herein as “CAR-T cells.” These cells are preferably obtained from the subject to be treated (i.e. are autologous). However, in some embodiments, immune effector cell lines or donor effector cells (allogeneic) are used. Immune effector cells can be obtained from a number of sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, cord blood, thymus tissue, tissue from a site of infection, ascites, pleural effusion, spleen tissue, and tumors. Immune effector cells can be obtained from blood collected from a subject using any number of techniques known to the skilled artisan, such as Ficoll™ separation. For example, cells from the circulating blood of an individual may be obtained by apheresis. In some embodiments, immune effector cells are isolated from peripheral blood lymphocytes by lysing the red blood cells and depleting the monocytes, for example, by centrifugation through a PERCOLL™ gradient or by45753670.1 50ATTORNEY DOCKET NO. MOE 24MB020 PCT counterflow centrifugal elutriation. A specific subpopulation of immune effector cells can be further isolated by positive or negative selection techniques. For example, immune effector cells can be isolated using a combination of antibodies directed to surface markers unique to the positively selected cells, e.g., by incubation with antibody-conjugated beads for a time period sufficient for positive selection of the desired immune effector cells. Alternatively, enrichment of immune effector cells population can be accomplished by negative selection using a combination of antibodies directed to surface markers unique to the negatively selected cells.In some embodiments, the immune effector cells comprise any leukocyte involved in defending the body against infectious disease and foreign materials. For example, the immune effector cells can comprise lymphocytes, monocytes, macrophages, dentritic cells, mast cells, neutrophils, basophils, eosinophils, or any combinations thereof. For example, the immune effector cells can comprise T lymphocytes.T cells or T lymphocytes can be distinguished from other lymphocytes, such as B cells and natural killer cells (NK cells), by the presence of a T-cell receptor (TCR) on the cell surface. They are called T cells because they mature in the thymus (although some also mature in the tonsils). There are several subsets of T cells, each with a distinct function.T helper cells (TH cells) assist other white blood cells in immunologic processes, including maturation of B cells into plasma cells and memory B cells, and activation of cytotoxic T cells and macrophages. These cells are also known as CD4+ T cells because they express the CD4 glycoprotein on their surface. Helper T cells become activated when they are presented with peptide antigens by MHC class II molecules, which are expressed on the surface of antigen-presenting cells (APCs). Once activated, they divide rapidly and secrete small proteins called cytokines that regulate or assist in the active immune response. These cells can differentiate into one of several subtypes, including TH1, TH2, TH3, TH17, TH9, or TFH, which secrete different cytokines to facilitate a different type of immune response.Cytotoxic T cells (TC cells, or CTLs) destroy virally infected cells and tumor cells, and are also implicated in transplant rejection. These cells are also known as CD8+ T cells since they express the CD8 glycoprotein at their surface. These cells recognize their targets by binding to antigen associated with MHC class I molecules, which are present on the surface of all nucleated cells. Through IL- 10, adenosine and other molecules secreted by regulatory T cells, the CD8+ cells can be inactivated to an anergic state, which prevents autoimmune diseases.Memory T cells are a subset of antigen-specific T cells that persist long-term after an infection has resolved. They quickly expand to large numbers of effector T cells upon re-exposure45753670.1 51ATTORNEY DOCKET NO. MOE 24MB020 PCT to their cognate antigen, thus providing the immune system with “memory” against past infections. Memory cells may be either CD4+ or CD8+. Memory T cells typically express the cell surface protein CD45RO.Regulatory T cells (Treg cells), formerly known as suppressor T cells, are crucial for the maintenance of immunological tolerance. Their major role is to shut down T cell-mediated immunity toward the end of an immune reaction and to suppress auto-reactive T cells that escaped the process of negative selection in the thymus. Two major classes of CD4+ Treg cells have been described — naturally occurring Treg cells and adaptive Treg cells.Natural killer T (NKT) cells (not to be confused with natural killer (NK) cells) bridge the adaptive immune system with the innate immune system. Unlike conventional T cells that recognize peptide antigens presented by major histocompatibility complex (MHC) molecules, NKT cells recognize glycolipid antigen presented by a molecule called CD Id.In some embodiments, the T cells comprise a mixture of CD4+ cells. In other embodiments, the T cells are enriched for one or more subsets based on cell surface expression. For example, in some cases, the T comprise are cytotoxic CD8+ T lymphocytes. In some embodiments, the T cells comprise y5 T cells, which possess a distinct T-cell receptor (TCR) having one y chain and one 5 chain instead of a and chains.Natural-killer (NK) cells are CD56+CD3- large granular lymphocytes that can kill virally infected and transformed cells, and constitute a critical cellular subset of the innate immune system (Godfrey J, et al. Leuk Lymphoma 2012 53: 1666-1676). Unlike cytotoxic CD8+ T lymphocytes, NK cells launch cytotoxicity against tumor cells without the requirement for prior sensitization, and can also eradicate MHC-I-negative cells (Nami-Mancinelli E, et al. Int Immunol 2011 23:427-431). NK cells are safer effector cells, as they may avoid the potentially lethal complications of cytokine storms (Morgan RA, et al. Mol Ther 2010 18:843-851), tumor lysis syndrome (Porter DL, et al. N Engl J Med 2011 365:725-733), and on-target, off-tumor effects. Although NK cells have a well- known role as killers of cancer cells, and NK cell impairment has been extensively documented as crucial for progression of MM (Godfrey J, et al. Leuk Lymphoma 2012 53: 1666-1676; Fauriat C, et al. Leukemia 2006 20:732-733), the means by which one might enhance NK cell-mediated anti- MM activity has been largely unexplored prior to the disclosed CARs.F. Nucleic Acids and VectorsAlso disclosed are polynucleotides and polynucleotide vectors encoding the disclosed TRPl-specific antibodies that allow expression of the TRPl-specific antibodies in the cells.45753670.1 52ATTORNEY DOCKET NO. MOE 24MB020 PCT

[0154] Nucleic acid sequences encoding the disclosed antibodies, and regions thereof, can be obtained using recombinant methods known in the art, such as, for example by screening libraries from cells expressing the gene, by deriving the gene from a vector known to include the same, or by isolating directly from cells and tissues containing the same, using standard techniques. Alternatively, the gene of interest can be produced synthetically, rather than cloned.Expression of nucleic acids encoding antibodies is typically achieved by operably linking a nucleic acid encoding the antibody polypeptide to a promoter, and incorporating the construct into an expression vector. Typical cloning vectors contain transcription and translation terminators, initiation sequences, and promoters useful for regulation of the expression of the desired nucleic acid sequence.The disclosed nucleic acid can be cloned into a number of types of vectors. For example, the nucleic acid can be cloned into a vector including, but not limited to a plasmid, a phagemid, a phage derivative, an animal virus, and a cosmid. Vectors of particular interest include expression vectors, replication vectors, probe generation vectors, and sequencing vectors.Further, the expression vector may be provided to a cell in the form of a viral vector. Viral vector technology is well known in the art and is described, for example, in Sambrook et al. (2001, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, New York), and in other virology and molecular biology manuals. Viruses, which are useful as vectors include, but are not limited to, retroviruses, adenoviruses, adeno-associated viruses, herpes viruses, and lentiviruses. In general, a suitable vector contains an origin of replication functional in at least one organism, a promoter sequence, convenient restriction endonuclease sites, and one or more selectable markers. In some embodiments, the polynucleotide vectors are lentiviral or retroviral vectors.A number of viral based systems have been developed for gene transfer into mammalian cells. For example, retroviruses provide a convenient platform for gene delivery systems. A selected gene can be inserted into a vector and packaged in retroviral particles using techniques known in the art. The recombinant virus can then be isolated and delivered to cells of the subject either in vivo or ex vivo.One example of a suitable promoter is the immediate early cytomegalovirus (CMV) promoter sequence. This promoter sequence is a strong constitutive promoter sequence capable of driving high levels of expression of any polynucleotide sequence operatively linked thereto. Another example of a suitable promoter is Elongation Growth Factor- la (EF-la). However, other constitutive promoter sequences may also be used, including, but not limited to the simian virus 40 (SV40) early promoter, MND (myeloproliferative sarcoma virus) promoter, mouse mammary tumor45753670.1 53ATTORNEY DOCKET NO. MOE 24MB020 PCT virus (MMTV), human immunodeficiency virus (HIV) long terminal repeat (LTR) promoter, MoMuLV promoter, an avian leukemia virus promoter, an Epstein-Barr virus immediate early promoter, a Rous sarcoma virus promoter, as well as human gene promoters such as, but not limited to, the actin promoter, the myosin promoter, the hemoglobin promoter, and the creatine kinase promoter. The promoter can alternatively be an inducible promoter. Examples of inducible promoters include, but are not limited to a metallothionine promoter, a glucocorticoid promoter, a progesterone promoter, and a tetracycline promoter.Additional promoter elements, e.g., enhancers, regulate the frequency of transcriptional initiation. Typically, these are located in the region 30-110 bp upstream of the start site, although a number of promoters have recently been shown to contain functional elements downstream of the start site as well. The spacing between promoter elements frequently is flexible, so that promoter function is preserved when elements are inverted or moved relative to one another.In order to assess the expression of an antibody polypeptide or portions thereof, the expression vector to be introduced into a cell can also contain either a selectable marker gene or a reporter gene or both to facilitate identification and selection of expressing cells from the population of cells sought to be transfected or infected through viral vectors. In other aspects, the selectable marker may be carried on a separate piece of DNA and used in a co-transfection procedure. Both selectable markers and reporter genes may be flanked with appropriate regulatory sequences to enable expression in the host cells. Useful selectable markers include, for example, antibiotic-resistance genes.Reporter genes are used for identifying potentially transfected cells and for evaluating the functionality of regulatory sequences. In general, a reporter gene is a gene that is not present in or expressed by the recipient organism or tissue and that encodes a polypeptide whose expression is manifested by some easily detectable property, e.g., enzymatic activity. Expression of the reporter gene is assayed at a suitable time after the DNA has been introduced into the recipient cells. Suitable reporter genes may include genes encoding luciferase, beta-galactosidase, chloramphenicol acetyl transferase, secreted alkaline phosphatase, or the green fluorescent protein gene. Suitable expression systems are well known and may be prepared using known techniques or obtained commercially. In general, the construct with the minimal 5' flanking region showing the highest level of expression of reporter gene is identified as the promoter. Such promoter regions may be linked to a reporter gene and used to evaluate agents for the ability to modulate promoter-driven transcription.45753670.1 54ATTORNEY DOCKET NO. MOE 24MB020 PCTMethods of introducing and expressing genes into a cell are known in the art. In the context of an expression vector, the vector can be readily introduced into a host cell, e.g., mammalian, bacterial, yeast, or insect cell by any method in the art. For example, the expression vector can be transferred into a host cell by physical, chemical, or biological means.Physical methods for introducing a polynucleotide into a host cell include calcium phosphate precipitation, lipof ection, particle bombardment, microinjection, electroporation, and the like. Methods for producing cells comprising vectors and / or exogenous nucleic acids are well- known in the art. See, for example, Sambrook et al. (2001, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, New York).Biological methods for introducing a polynucleotide of interest into a host cell include the use of DNA and RNA vectors. Viral vectors, and especially retroviral vectors, have become the most widely used method for inserting genes into mammalian, e.g., human cells.Chemical means for introducing a polynucleotide into a host cell include colloidal dispersion systems, such as macromolecule complexes, nanocapsules, microspheres, beads, and lipid-based systems including oil-in-water emulsions, micelles, mixed micelles, and liposomes. An exemplary colloidal system for use as a delivery vehicle in vitro and in vivo is a liposome (e.g., an artificial membrane vesicle).In the case where a non- viral delivery system is utilized, an exemplary delivery vehicle is a liposome. In another aspect, the nucleic acid may be associated with a lipid. The nucleic acid associated with a lipid may be encapsulated in the aqueous interior of a liposome, interspersed within the lipid bilayer of a liposome, attached to a liposome via a linking molecule that is associated with both the liposome and the oligonucleotide, entrapped in a liposome, complexed with a liposome, dispersed in a solution containing a lipid, mixed with a lipid, combined with a lipid, contained as a suspension in a lipid, contained or complexed with a micelle, or otherwise associated with a lipid. Lipid, lipid / DNA or lipid / expression vector associated compositions are not limited to any particular structure in solution. For example, they may be present in a bilayer structure, as micelles, or with a “collapsed” structure. They may also simply be interspersed in a solution, possibly forming aggregates that are not uniform in size or shape. Lipids are fatty substances which may be naturally occurring or synthetic lipids. For example, lipids include the fatty droplets that naturally occur in the cytoplasm as well as the class of compounds which contain long-chain aliphatic hydrocarbons and their derivatives, such as fatty acids, alcohols, amines, amino alcohols, and aldehydes. Lipids suitable for use can be obtained from commercial sources. For example, dimyristyl phosphatidylcholine (“DMPC”) can be obtained from Sigma, St. Louis, Mo.;45753670.1 55ATTORNEY DOCKET NO. MOE 24MB020 PCT dicetyl phosphate (“DCP”) can be obtained from K & K Laboratories (Plainview, N.Y.); cholesterol (“Choi”) can be obtained from Calbiochem-Behring; dimyristyl phosphatidylglycerol (“DMPG”) and other lipids may be obtained from Avanti Polar Lipids, Inc, (Birmingham, Ala.).G. Pharmaceutical CompositionAlso disclosed is a pharmaceutical composition comprising a disclosed molecule in a pharmaceutically acceptable carrier. Pharmaceutical carriers are known to those skilled in the art. These most typically would be standard carriers for administration of drugs to humans, including solutions such as sterile water, saline, and buffered solutions at physiological pH. For example, suitable carriers and their formulations are described in Remington: The Science and Practice of Pharmacy (21 ed.) ed. PP. Gerbino, Lippincott Williams & Wilkins, Philadelphia, PA. 2005. Typically, an appropriate amount of a pharmaceutically-acceptable salt is used in the formulation to render the formulation isotonic. Examples of the pharmaceutically-acceptable carrier include, but are not limited to, saline, Ringer's solution and dextrose solution. The pH of the solution is preferably from about 5 to about 8, and more preferably from about 7 to about 7.5. The solution should be RNAse free. Further carriers include sustained release preparations such as semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g., films, liposomes or microparticles. It will be apparent to those persons skilled in the art that certain carriers may be more preferable depending upon, for instance, the route of administration and concentration of composition being administered.Pharmaceutical compositions may include carriers, thickeners, diluents, buffers, preservatives, surface active agents and the like in addition to the molecule of choice. Pharmaceutical compositions may also include one or more active ingredients such as antimicrobial agents, anti-inflammatory agents, anesthetics, and the like.Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic / aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles include sodium chloride solution, Ringer’s dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and other additives may also be present such as, for example, antimicrobials, antioxidants, chelating agents, and inert gases and the like.45753670.1 56ATTORNEY DOCKET NO. MOE 24MB020 PCTSome of the compositions may potentially be administered as a pharmaceutically acceptable acid- or base- addition salt, formed by reaction with inorganic acids such as hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid, and phosphoric acid, and organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, and fumaric acid, or by reaction with an inorganic base such as sodium hydroxide, ammonium hydroxide, potassium hydroxide, and organic bases such as mono-, di-, trialkyl and aryl amines and substituted ethanolamines.III. Methods of Making / UsingAlso disclosed is a method for treating a TRP1 -expressing cancer in a subject by administering to the subject a therapeutically effective amount of the disclosed pharmaceutical composition.Immune effector cells expressing the disclosed CARs can elicit an anti-tumor immune response against TAA-expressing cancer cells. The anti-tumor immune response elicited by the disclosed CAR-modified immune effector cells may be an active or a passive immune response. In addition, the CAR-mediated immune response may be part of an adoptive immunotherapy approach in which CAR-modified immune effector cells induce an immune response specific to TAAAdoptive transfer of immune effector cells expressing chimeric antigen receptors is a promising anti-cancer therapeutic. Following the collection of a patient’s immune effector cells, the cells may be genetically engineered to express the disclosed CARs, then infused back into the patient.The disclosed CAR-modified immune effector cells may be administered either alone, or as a pharmaceutical composition in combination with diluents and / or with other components such as IL-2, IL-15, or other cytokines or cell populations. Briefly, pharmaceutical compositions may comprise a target cell population as described herein, in combination with one or more pharmaceutically or physiologically acceptable carriers, diluents or excipients. Such compositions may comprise buffers such as neutral buffered saline, phosphate buffered saline and the like; carbohydrates such as glucose, mannose, sucrose or dextrans, mannitol; proteins; polypeptides or amino acids such as glycine; antioxidants; chelating agents such as EDTA or glutathione; adjuvants (e.g., aluminum hydroxide); and preservatives. Compositions for use in the disclosed methods are in some embodiments formulated for intravenous administration. Pharmaceutical compositions may be administered in any manner appropriate treat MM. The quantity and frequency of administration will be determined by such factors as the condition of the patient, and the severity of the patient's disease, although appropriate dosages may be determined by clinical trials.45753670.1 57ATTORNEY DOCKET NO. MOE 24MB020 PCTWhen “an immunologically effective amount”, “an anti-tumor effective amount”, “an tumor-inhibiting effective amount”, or “therapeutic amount” is indicated, the precise amount of the compositions of the present invention to be administered can be determined by a physician with consideration of individual differences in age, weight, tumor size, extent of infection or metastasis, and condition of the patient (subject). It can generally be stated that a pharmaceutical composition comprising the T cells described herein may be administered at a dosage of 104to 109cells / kg body weight, such as 105to 106cells / kg body weight, including all integer values within those ranges. T cell compositions may also be administered multiple times at these dosages. The cells can be administered by using infusion techniques that are commonly known in immunotherapy (see, e.g., Rosenberg et al., New Eng. J. of Med. 319:1676, 1988). The optimal dosage and treatment regime for a particular patient can readily be determined by one skilled in the art of medicine by monitoring the patient for signs of disease and adjusting the treatment accordingly.In certain embodiments, it may be desired to administer activated T cells to a subject and then subsequently re-draw blood (or have an apheresis performed), activate T cells therefrom according to the disclosed methods, and reinfuse the patient with these activated and expanded T cells. This process can be carried out multiple times every few weeks. In certain embodiments, T cells can be activated from blood draws of from 10 cc to 400 cc. In certain embodiments, T cells are activated from blood draws of 20 cc, 30 cc, 40 cc, 50 cc, 60 cc, 70 cc, 80 cc, 90 cc, or 100 cc. Using this multiple blood draw / multiple reinfusion protocol may serve to select out certain populations of T cells.The disclosed compositions, including pharmaceutical composition, may be administered in a number of ways depending on whether local or systemic treatment is desired, and on the area to be treated. For example, the disclosed compositions can be administered intravenously, intraperitoneally, intramuscularly, subcutaneously, intracavity, or transdermally. The compositions may be administered orally, parenterally (e.g., intravenously), by intramuscular injection, by intraperitoneal injection, transdermally, extracorporeally, ophthalmically, vaginally, rectally, intranasally, topically or the like, including topical intranasal administration or administration by inhalant. In some embodiments, the disclosed compositions are administered to a patient by intradermal or subcutaneous injection. In some embodiments, the disclosed compositions are administered by intravenous injection. The compositions may also be injected directly into a tumor, lymph node, or site of infection.Parenteral administration of the composition, if used, is generally characterized by injection. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid45753670.1 58ATTORNEY DOCKET NO. MOE 24MB020 PCT forms suitable for solution of suspension in liquid prior to injection, or as emulsions. A revised approach for parenteral administration involves use of a slow release or sustained release system such that a constant dosage is maintained.The compositions disclosed herein may be administered prophylactically to patients or subjects who are at risk for a TRPl-expressing cancer. Thus, the method can further comprise identifying a subject at risk for a TRPl-expressing cancer prior to administration of the herein disclosed compositions.The exact amount of the compositions required will vary from subject to subject, depending on the species, age, weight and general condition of the subject, the severity of the allergic disorder being treated, the particular nucleic acid or vector used, its mode of administration and the like. Thus, it is not possible to specify an exact amount for every composition. However, an appropriate amount can be determined by one of ordinary skill in the art using only routine experimentation given the teachings herein. For example, effective dosages and schedules for administering the compositions may be determined empirically, and making such determinations is within the skill in the art. The dosage ranges for the administration of the compositions are those large enough to produce the desired effect in which the symptoms disorder are affected. The dosage should not be so large as to cause adverse side effects, such as unwanted cross -reactions, anaphylactic reactions, and the like. Generally, the dosage will vary with the age, condition, sex and extent of the disease in the patient, route of administration, or whether other drugs are included in the regimen, and can be determined by one of skill in the art. The dosage can be adjusted by the individual physician in the event of any counterindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. A typical daily dosage of the disclosed composition used alone might range from about 1 pg / kg to up to 100 mg / kg of body weight or more per day, depending on the factors mentioned above.In some embodiments, the molecule is administered in a dose equivalent to parenteral administration of about 0.1 ng to about 100 g per kg of body weight, about 10 ng to about 50 g per kg of body weight, about 100 ng to about 1 g per kg of body weight, from about Ipg to about 100 mg per kg of body weight, from about 1 pg to about 50 mg per kg of body weight, from about 1 mg to about 500 mg per kg of body weight; and from about 1 mg to about 50 mg per kg of body weight. Alternatively, the amount of molecule containing lenalidomide administered to achieve a therapeutic effective dose is about 0.1 ng, 1 ng, 10 ng, 100 ng, 1 pg, 10 pg, 100 pg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 1745753670.1 59ATTORNEY DOCKET NO. MOE 24MB020 PCT mg, 18 mg, 19 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 500 mg per kg of body weight or greater.The cancer of the disclosed methods can be any TRP1 -expressing cell in a subject undergoing unregulated growth, invasion, or metastasis. Cancers that express TRP1 include prostate cancer, ovarian cancer, adenocarcinoma of the lung, breast cancer, endometrial cancer, gastric cancer, colon cancer, and pancreatic cancer. TRP1 has also been found on Jurkat cells. In some aspects, the cancer is a gallbladder cancer, exocrine adenocarcinoma, or apocrine adenocarcinomas.In certain embodiments, the disclosed CAR-modified immune effector cells are administered to a patient in conjunction with (e.g., before, simultaneously or following) any number of relevant treatment modalities, including but not limited to thalidomide, dexamethasone, bortezomib, and lenalidomide. In further embodiments, the CAR-modified immune effector cells may be used in combination with chemotherapy, radiation, immunosuppressive agents, such as cyclosporin, azathioprine, methotrexate, mycophenolate, and FK506, antibodies, or other immunoablative agents such as CAM PATH, anti-CD3 antibodies or other antibody therapies, cytoxin, fludaribine, cyclosporin, FK506, rapamycin, mycophenolic acid, steroids, FR901228, cytokines, and irradiation. In some embodiments, the CAR- modified immune effector cells are administered to a patient in conjunction with (e.g., before, simultaneously or following) bone marrow transplantation, T cell ablative therapy using either chemotherapy agents such as, fludarabine, external-beam radiation therapy (XRT), cyclophosphamide, or antibodies such as OKT3 or CAMPATH. In another embodiment, the cell compositions of the present invention are administered following B-cell ablative therapy such as agents that react with CD20, e.g., Rituxan. For example, in some embodiments, subjects may undergo standard treatment with high dose chemotherapy followed by peripheral blood stem cell transplantation. In certain embodiments, following the transplant, subjects receive an infusion of the expanded immune cells of the present invention. In an additional embodiment, expanded cells are administered before or following surgery.The cancer of the disclosed methods can be any TAA-expressing cell in a subject undergoing unregulated growth, invasion, or metastasis. In some aspects, the cancer can be any neoplasm or tumor for which radiotherapy is currently used. Alternatively, the cancer can be a neoplasm or tumor that is not sufficiently sensitive to radiotherapy using standard methods. Thus, the cancer can be a sarcoma, lymphoma, leukemia, carcinoma, blastoma, or germ cell tumor. A representative but non-limiting list of cancers that the disclosed compositions can be used to treat include lymphoma, B cell lymphoma, T cell lymphoma, mycosis fungoides, Hodgkin’s Disease,45753670.1 60ATTORNEY DOCKET NO. MOE 24MB020 PCT myeloid leukemia, bladder cancer, brain cancer, nervous system cancer, head and neck cancer, squamous cell carcinoma of head and neck, kidney cancer, lung cancers such as small cell lung cancer and non-small cell lung cancer, neuroblastoma / glioblastoma, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, liver cancer, melanoma, squamous cell carcinomas of the mouth, throat, larynx, and lung, endometrial cancer, cervical cancer, cervical carcinoma, breast cancer, epithelial cancer, renal cancer, genitourinary cancer, pulmonary cancer, esophageal carcinoma, head and neck carcinoma, large bowel cancer, hematopoietic cancers; testicular cancer; colon and rectal cancers, prostatic cancer, and pancreatic cancer.The disclosed antibodies can be used in combination with any compound, moiety or group which has a cytotoxic or cytostatic effect. Drug moieties include chemotherapeutic agents, which may function as microtubulin inhibitors, mitosis inhibitors, topoisomerase inhibitors, or DNA intercalators, and particularly those which are used for cancer therapy.The disclosed antibodies can be used in combination with a checkpoint inhibitor. The two known inhibitory checkpoint pathways involve signaling through the cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed-death 1 (PD-1) receptors. These proteins are members of the CD28-B7 family of cosignaling molecules that play important roles throughout all stages of T cell function. The PD-1 receptor (also known as CD279) is expressed on the surface of activated T cells. Its ligands, PD-L1 (B7-H1; CD274) and PD-L2 (B7-DC; CD273), are expressed on the surface of APCs such as dendritic cells or macrophages. PD-L1 is the predominant ligand, while PD-L2 has a much more restricted expression pattern. When the ligands bind to PD-1, an inhibitory signal is transmitted into the T cell, which reduces cytokine production and suppresses T-cell proliferation. Checkpoint inhibitors include, but are not limited to antibodies that block PD-1 (Nivolumab (BMS- 936558 or MDX1106), CT-011, MK-3475), PD-L1 (MDX-1105 (BMS-936559), MPDL3280A, MSB0010718C), PD-L2 (rHIgM12B7), CTLA-4 (Ipilimumab (MDX-010), Tremelimumab (CP- 675,206)), IDO, B7-H3 (MGA271), B7-H4, TIM3, LAG-3 (BMS-986016).Human monoclonal antibodies to programmed death 1 (PD-1) and methods for treating cancer using anti-PD- 1 antibodies alone or in combination with other immunotherapeutics are described in U.S. Patent No. 8,008,449, which is incorporated by reference for these antibodies. Anti-PD-Ll antibodies and uses therefor are described in U.S. Patent No. 8,552,154, which is incorporated by reference for these antibodies. Anticancer agent comprising anti-PD- 1 antibody or anti-PD-Ll antibody are described in U.S. Patent No. 8,617,546, which is incorporated by reference for these antibodies.45753670.1 61ATTORNEY DOCKET NO. MOE 24MB020 PCTIn some embodiments, the PDL1 inhibitor comprises an antibody that specifically binds PDL1, such as BMS-936559 (Bristol-Myers Squibb) or MPDL3280A (Roche). In some embodiments, the PD1 inhibitor comprises an antibody that specifically binds PD1, such as lambrolizumab (Merck), nivolumab (Bristol-Myers Squibb), or MEDI4736 (AstraZeneca). Human monoclonal antibodies to PD-1 and methods for treating cancer using anti-PD-1 antibodies alone or in combination with other immunotherapeutics are described in U.S. Patent No. 8,008,449, which is incorporated by reference for these antibodies. Anti-PD-Ll antibodies and uses therefor are described in U.S. Patent No. 8,552,154, which is incorporated by reference for these antibodies. Anticancer agent comprising anti-PD-1 antibody or anti-PD-Ll antibody are described in U.S. Patent No. 8,617,546, which is incorporated by reference for these antibodies.The disclosed antibodies can be used in combination with other cancer immunotherapies. There are two distinct types of immunotherapy: passive immunotherapy uses components of the immune system to direct targeted cytotoxic activity against cancer cells, without necessarily initiating an immune response in the patient, while active immunotherapy actively triggers an endogenous immune response. Passive strategies include the use of the monoclonal antibodies (mAbs) produced by B cells in response to a specific antigen. The development of hybridoma technology in the 1970s and the identification of tumor-specific antigens permitted the pharmaceutical development of mAbs that could specifically target tumor cells for destruction by the immune system. Thus far, mAbs have been the biggest success story for immunotherapy; the top three best-selling anticancer drugs in 2012 were mAbs. Among them is rituximab (Rituxan, Genentech), which binds to the CD20 protein that is highly expressed on the surface of B cell malignancies such as non-Hodgkin’s lymphoma (NHL). Rituximab is approved by the FDA for the treatment of NHL and chronic lymphocytic leukemia (CLL) in combination with chemotherapy. Another important mAb is trastuzumab (Herceptin; Genentech), which revolutionized the treatment of HER2 (human epidermal growth factor receptor 2)-positive breast cancer by targeting the expression of HER2.Generating optimal “killer” CD8 T cell responses also requires T cell receptor activation plus co-stimulation, which can be provided through ligation of tumor necrosis factor receptor family members, including 0X40 (CD134) and 4-1BB (CD137). 0X40 is of particular interest as treatment with an activating (agonist) anti-OX40 mAb augments T cell differentiation and cytolytic function leading to enhanced anti-tumor immunity against a variety of tumors.45753670.1 62ATTORNEY DOCKET NO. MOE 24MB020 PCTIn some embodiments, such an additional therapeutic agent may be selected from an antimetabolite, such as methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, fludarabine, 5- fluorouracil, decarbazine, hydroxyurea, asparaginase, gemcitabine or cladribine.In some embodiments, such an additional therapeutic agent may be selected from an alkylating agent, such as mechlorethamine, thioepa, chlorambucil, melphalan, carmustine (BSNU), lomustine (CCNU), cyclophosphamide, busulfan, dibromomannitol, streptozotocin, dacarbazine (DTIC), procarbazine, mitomycin C, cisplatin and other platinum derivatives, such as carboplatin .In some embodiments, such an additional therapeutic agent may be selected from an antimitotic agent, such as taxanes, for instance docetaxel, and paclitaxel, and vinca alkaloids, for instance vindesine, vincristine, vinblastine, and vinorelbine.In some embodiments, such an additional therapeutic agent may be selected from a topoisomerase inhibitor, such as topotecan or irinotecan, or a cytostatic drug, such as etoposide and teniposide.In some embodiments, such an additional therapeutic agent may be selected from a growth factor inhibitor, such as an inhibitor of ErbBl (EGFR) (such as an EGFR antibody, e.g. zalutumumab, cetuximab, panitumumab or nimotuzumab or other EGFR inhibitors, such as gefitinib or erlotinib), another inhibitor of ErbB2 (HER2 / neu) (such as a HER2 antibody, e.g. trastuzumab, trastuzumab-DM 1 or pertuzumab) or an inhibitor of both EGFR and HER2, such as lapatinib).In some embodiments, such an additional therapeutic agent may be selected from a tyrosine kinase inhibitor, such as imatinib (Glivec, Gleevec STI571) or lapatinib.Therefore, in some embodiments, a disclosed antibody is used in combination with ofatumumab, zanolimumab, daratumumab, ranibizumab, nimotuzumab, panitumumab, hu806, daclizumab (Zenapax), basiliximab (Simulect), infliximab (Remicade), adalimumab (Humira), natalizumab (Tysabri), omalizumab (Xolair), efalizumab (Raptiva), and / or rituximab.In some embodiments, a therapeutic agent for use in combination with antibodies as described above may be an anti-cancer cytokine, chemokine, or combination thereof. Examples of suitable cytokines and growth factors include IFNy, IL-2, IL-4, IL-6, IL-7, IL-10, IL-12, IL-13, IL- 15, IL-18, IL-23, IL-24, IL-27, IL-28a, IL-28b, IL-29, KGF, IFNa (e.g., INFa2b), IFN , GM-CSF, CD40L, Flt3 ligand, stem cell factor, ancestim, and TNFa. Suitable chemokines may include Glu- Leu-Arg (ELR)- negative chemokines such as IP-10, MCP-3, MIG, and SDF-la from the human CXC and C-C chemokine families. Suitable cytokines include cytokine derivatives, cytokine variants, cytokine fragments, and cytokine fusion proteins.45753670.1 63ATTORNEY DOCKET NO. MOE 24MB020 PCTIn some embodiments, a therapeutic agent for use in combination with antibodies as described above may be a cell cycle control / apoptosis regulator (or "regulating agent"). A cell cycle control / apoptosis regulator may include molecules that target and modulate cell cycle control / apoptosis regulators such as (i) cdc-25 (such as NSC 663284), (ii) cyclin-dependent kinases that overstimulate the cell cycle (such as flavopiridol (L868275, HMR1275), 7- hydroxystaurosporine (UCN-01, KW-2401), and roscovitine (R-roscovitine, CYC202)), and (iii) telomerase modulators (such as BIBR1532, SOT-095, GRN163 and compositions described in for instance US 6,440,735 and US 6,713,055) . Non-limiting examples of molecules that interfere with apoptotic pathways include TNF-related apoptosis-inducing ligand (TRAIL) / apoptosis-2 ligand (Apo-2L), antibodies that activate TRAIL receptors, IFNs, and anti-sense Bcl-2.In some embodiments, a therapeutic agent for use in combination with antibodies as described above may be a hormonal regulating agent, such as agents useful for anti-androgen and anti-estrogen therapy. Examples of such hormonal regulating agents are tamoxifen, idoxifene, fulvestrant, droloxifene, toremifene, raloxifene, diethylstilbestrol, ethinyl estradiol / estinyl, an antiandrogene (such as flutaminde / eulexin), a progestin (such as such as hydroxyprogesterone caproate, medroxy- progesterone / provera, megestrol acepate / megace), an adrenocorticosteroid (such as hydrocortisone, prednisone), luteinizing hormone-releasing hormone (and analogs thereof and other LHRH agonists such as buserelin and goserelin), an aromatase inhibitor (such as anastrazole / arimidex, aminoglutethimide / cytraden, exemestane) or a hormone inhibitor (such as octree tide / s andos tatin) .In some embodiments, a therapeutic agent for use in combination with antibodies as described above may be an anti-cancer nucleic acid or an anti-cancer inhibitory RNA molecule.Combined administration, as described above, may be simultaneous, separate, or sequential. For simultaneous administration the agents may be administered as one composition or as separate compositions, as appropriate.In some embodiments, the disclosed antibodies are administered in combination with radiotherapy. Radiotherapy may comprise radiation or associated administration of radiopharmaceuticals to a patient is provided. The source of radiation may be either external or internal to the patient being treated (radiation treatment may, for example, be in the form of external beam radiation therapy (EBRT) or brachytherapy (BT)). Radioactive elements that may be used in practicing such methods include, e.g., radium, cesium-137, iridium-192, americium-241, gold-198, cobalt-57, copper-67, technetium-99, iodide-123, iodide-131, and indium-i ll.45753670.1 64ATTORNEY DOCKET NO. MOE 24MB020 PCTIn some embodiments, the disclosed antibodies are administered in combination with surgery.CAR-T cells may be designed in several ways that enhance tumor cytotoxicity and specificity, evade tumor immunosuppression, avoid host rejection, and prolong their therapeutic half-life. TRUCK (T-cells Redirected for Universal Cytokine Killing) T cells for example, possess a CAR but are also engineered to release cytokines such as IL- 12 that promote tumor killing. Because these cells are designed to release a molecular payload upon activation of the CAR once localized to the tumor environment, these CAR-T cells are sometimes also referred to as ‘armored CARs’. Several cytokines as cancer therapies are being investigated both pre-clinically and clinically, and may also prove useful when similarly incorporated into a TRUCK form of CAR-T therapy. Among these include IL-2, IL-3. IL-4, IL-5, IL-6, IL-7, IL-10, IL-12, IL-13, IL-15, IL-18, M-CSF, GM-CSF, IFN-a, IFN-y, TNF-a, TRAIL, FLT3 ligand, Lymphotactin, and TGF-0 (Dranoff 2004). “Self-driving” or “homing” CAR-T cells are engineered to express a chemokine receptor in addition to their CAR. As certain chemokines can be upregulated in tumors, incorporation of a chemokine receptor aids in tumor trafficking to and infiltration by the adoptive T-cell, thereby enhancing both specificity and functionality of the CAR-T (Moon 2011). Universal CAR-T cells also possess a CAR, but are engineered such that they do not express endogenous TCR (T-cell receptor) or MHC (major histocompatibility complex) proteins. Removal of these two proteins from the signaling repertoire of the adoptive T-cell therapy prevents graft- versus-host-disease and rejection, respectively. Armored CAR-T cells are additionally so named for their ability to evade tumor immunosuppression and tumor-induced CAR-T hypofunction. These particular CAR-Ts possess a CAR, and may be engineered to not express checkpoint inhibitors. Alternatively, these CAR-Ts can be co-administered with a monoclonal antibody (mAb) that blocks checkpoint signaling. Administration of an anti-PDLl antibody significantly restored the killing ability of CAR TILs (tumor infiltrating lymphocytes). While PD1-PDL1 and CTLA-4-CD80 / CD86 signaling pathways have been investigated, it is possible to target other immune checkpoint signaling molecules in the design of an armored CAR-T including LAG-3, Tim-3, IDO-1, 2B4, and KIR. Other intracellular inhibitors of TILs include phosphatases (SHP1), ubiquitin-ligases (i.e., cbl-b), and kinases (i.e., diacylglycerol kinase) . Armored CAR-Ts may also be engineered to express proteins or receptors that protect them against or make them resistant to the effects of tumor- secreted cytokines. For example, CTLs (cytotoxic T lymphocytes) transduced with the double negative form of the TGF-P receptor are resistant to the immunosuppression by lymphoma secreted45753670.1 65ATTORNEY DOCKET NO. MOE 24MB020 PCTTGF-p. These transduced cells showed notably increased antitumor activity in vivo when compared to their control counterparts.A tandem CAR contains two sequential antigen binding domains facing the extracellular environment connected to the intracellular costimulatory and stimulatory domains.One primary concern with CAR-T cells as a form of “living therapeutic” is their manipulability in vivo and their potential immune- stimulating side effects. To better control CAR- T therapy and prevent against unwanted side effects, a variety of features have been engineered including off-switches, safety mechanisms, and conditional control mechanisms. Both self-destruct and marked / tagged CAR-T cells for example, are engineered to have an “off-switch” that promotes clearance of the CAR-expressing T-cell. A self-destruct CAR-T contains a CAR, but is also engineered to express a pro-apoptotic suicide gene or “elimination gene” inducible upon administration of an exogenous molecule. A variety of suicide genes may be employed for this purpose, including HSV-TK (herpes simplex virus thymidine kinase), Fas, iCasp9 (inducible caspase 9), CD20, MYC tag, and truncated EGFR (endothelial growth factor receptor). HSK for example, will convert the prodrug ganciclovir (GCV) into GCV-triphosphate that incorporates itself into replicating DNA, ultimately leading to cell death. iCasp9 is a chimeric protein containing components of FK506-binding protein that binds the small molecule AP1903, leading to caspase 9 dimerization and apoptosis. A marked / tagged CAR-T cell however, is one that possesses a CAR but also is engineered to express a selection marker. Administration of a mAb against this selection marker will promote clearance of the CAR-T cell. Truncated EGFR is one such targetable antigen by the anti-EGFR mAb, and administration of cetuximab works to promotes elimination of the CAR-T cell. CARs created to have these features are also referred to as sCARs for ‘switchable CARs’, and RCARs for ‘regulatable CARs’. A “safety CAR”, also known as an “inhibitory CAR” (iCAR), is engineered to express two antigen binding domains. One of these extracellular domains is directed against a tumor related antigen and bound to an intracellular costimulatory and stimulatory domain. The second extracellular antigen binding domain however is specific for normal tissue and bound to an intracellular checkpoint domain such as CTLA4, PD1, or CD45. Incorporation of multiple intracellular inhibitory domains to the iCAR is also possible. Some inhibitory molecules that may provide these inhibitory domains include B7-H1, B7-1, CD160, PIH, 2B4, CEACAM (CEACAM-1. CEACAM-3, and / or CEACAM-5), LAG-3, TIGIT, BTLA, LAIR1, and TGFP-R. In the presence of normal tissue, stimulation of this second antigen binding domain will work to inhibit the CAR. It should be noted that due to this dual antigen specificity, iCARs are also a form of bi-specific CAR-T cells. The safety CAR-T engineering enhances specificity of the45753670.1 66ATTORNEY DOCKET NO. MOE 24MB020 PCTCAR-T cell for tumor tissue, and is advantageous in situations where certain normal tissues may express very low levels of a tumor associated antigen that would lead to off target effects with a standard CAR (Morgan 2010). A conditional CAR-T cell expresses an extracellular antigen binding domain connected to an intracellular costimulatory domain and a separate, intracellular costimulator. The costimulatory and stimulatory domain sequences are engineered in such a way that upon administration of an exogenous molecule the resultant proteins will come together intracellularly to complete the CAR circuit. In this way, CAR-T activation can be modulated, and possibly even 'fine-tuned’ or personalized to a specific patient. Similar to a dual CAR design, the stimulatory and costimulatory domains are physically separated when inactive in the conditional CAR; for this reason these too are also referred to as a “split CAR”.In some embodiments, two or more of these engineered features may be combined to create an enhanced, multifunctional CAR-T. For example, it is possible to create a CAR-T cell with either dual- or conditional- CAR design that also releases cytokines like a TRUCK. In some embodiments, a dual-conditional CAR-T cell could be made such that it expresses two CARs with two separate antigen binding domains against two distinct cancer antigens, each bound to their respective costimulatory domains. The costimulatory domain would only become functional with the stimulatory domain after the activating molecule is administered. For this CAR-T cell to be effective the cancer must express both cancer antigens and the activating molecule must be administered to the patient; this design thereby incorporating features of both dual and conditional CAR T cells.Typically, CAR-T cells are created using a-|3 T cells, however y-8 T cells may also be used. In some embodiments, the described CAR constructs, domains, and engineered features used to generate CAR-T cells could similarly be employed in the generation of other types of CAR- expressing immune cells including NK (natural killer) cells, B cells, mast cells, myeloid-derived phagocytes, and NKT cells. Alternatively, a CAR-expressing cell may be created to have properties of both T-cell and NK cells. In an additional embodiment, the transduced with CARs may be autologous or allogeneic.Several different methods for CAR expression may be used including retroviral transduction (including y-retro viral), lentiviral transduction, transposon / transposases (Sleeping Beauty and PiggyBac systems), and messenger RNA transfer-mediated gene expression. Gene editing (gene insertion or gene deletion / disruption) has become of increasing importance with respect to the possibility for engineering CAR-T cells as well. CRISPR-Cas9, ZFN (zinc finger nuclease), and45753670.1 67ATTORNEY DOCKET NO. MOE 24MB020 PCTTALEN (transcription activator like effector nuclease) systems are three potential methods through which CAR-T cells may be generated.A number of embodiments of the invention have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims. IV. EmbodimentsEmbodiment 1. A recombinant antibody that selectively binds TRP1 on tumor cells, comprising a variable heavy (VH) domain having CDR1, CDR2 and CDR3 sequences and a variable light (VL) domain having CDR1, CDR2 and CDR3 sequences, wherein the CDR1 sequence of the VH domain comprises the amino acid sequence GFTFSYYW (SEQ ID NO:1), CDR2 sequence of the VH domain comprises the amino acid sequence IKQDGNEK (SEQ ID NO:2), CDR3 sequence of the VH domain comprises the amino acid sequence ARGRRGRPPPDY (SEQ ID NOG), CDR1 sequence of VL comprises the amino acid sequence QGISNY (SEQ ID NO:4), CDR2 sequence of the VL domain comprises the amino acid sequence AAS, and CDR3 sequence of the VL domain comprises the amino acid sequence QKYNSAPRT (SEQ ID NOG); the CDR1 sequence of the VH domain comprises the amino acid sequence GYTFTGYY (SEQ ID NO:6), CDR2 sequence of the VH domain comprises the amino acid sequence INPNRGGT (SEQ ID NO:7), CDR3 sequence of the VH domain comprises the amino acid sequence ARDGGAAADGFDY (SEQ ID NOG), CDR1 sequence of the VL comprises the amino acid sequence QSIGNW (SEQ ID NO:9), CDR2 sequence of the VL domain comprises the amino acid sequence KAS, and CDR3 sequence of the VL domain comprises the amino acid sequence QQYDRYPQT (SEQ ID NO: 10); the CDR1 sequence of the VH domain comprises the amino acid sequence GFTFSDYY (SEQ ID NO: 11), CDR2 sequence of the VH domain comprises the amino acid sequence SRSRPNNYST (SEQ ID NO: 12), CDR3 sequence of the VH domain comprises the amino acid sequence TRGRSGTSFPFYYYGMDL (SEQ ID NO: 13), CDR1 sequence of the VL comprises the amino acid sequence QSISSN (SEQ ID NO: 14), CDR2 sequence of the VL domain comprises the amino acid sequence GAS, and CDR3 sequence of the VL domain comprises the amino acid sequence QQKYNTPPVT (SEQ ID NO: 15); the CDR1 sequence of the VH domain comprises the amino acid sequence GDSVSTNSAS (SEQ ID NO: 16), CDR2 sequence of the VH domain comprises the amino acid sequence TYYRSKWYN (SEQ ID NO: 17), CDR3 sequence of the VH domain comprises the amino acid sequence VRGSSGLNAFDI (SEQ ID NO: 18), CDR1 sequence of the VL comprises the amino45753670.1 68ATTORNEY DOCKET NO. MOE 24MB020 PCT acid sequence NSNIGGNT (SEQ ID NO: 19), CDR2 sequence of the VL domain comprises the amino acid sequence GRN, and CDR3 sequence of the VL domain comprises the amino acid sequence SAWDDSLKGPV (SEQ ID NO:20); the CDR1 sequence of the VH domain comprises the amino acid sequence GFTFSSYG (SEQ ID NO:21), CDR2 sequence of the VH domain comprises the amino acid sequence ITTAGDT (SEQ ID NO:22), CDR3 sequence of the VH domain comprises the amino acid sequence ARKFSSSWYDWYFDL (SEQ ID NO:23), CDR1 sequence of the VL comprises the amino acid sequence QDISNF (SEQ ID NO:24), CDR2 sequence of the VL domain comprises the amino acid sequence DAS, and CDR3 sequence of the VL domain comprises the amino acid sequence LQYHTYPYT (SEQ ID NO:25); the CDR1 sequence of the VH domain comprises the amino acid sequence GYTFTTTW (SEQ ID NO:26), CDR2 sequence of the VH domain comprises the amino acid sequence IYPDDSDT (SEQ ID NO:27), CDR3 sequence of the VH domain comprises the amino acid sequence ATAPGDY (SEQ ID NO:28), CDR1 sequence of the VL comprises the amino acid sequence GSNIGTNS (SEQ ID NO:29), CDR2 sequence of the VL domain comprises the amino acid sequence RGD, and CDR3 sequence of the VL domain comprises the amino acid sequence SSWDDRLSSWA (SEQ ID NQ:30); the CDR1 sequence of the VH domain comprises the amino acid sequence GDSVSSNNVA (SEQ ID NO:31), CDR2 sequence of the VH domain comprises the amino acid sequence TYYRSKWYN (SEQ ID NO:32), CDR3 sequence of the VH domain comprises the amino acid sequence AREEATVADAFDI (SEQ ID NO:33), CDR1 sequence of the VL comprises the amino acid sequence NIGATS (SEQ ID NO:34), CDR2 sequence of the VL domain comprises the amino acid sequence DYG, and CDR3 sequence of the VL domain comprises the amino acid sequence QMWDIGSDEQL (SEQ ID NO:35); the CDR 1 sequence of the VH domain comprises the amino acid sequence GYNFGTYH (SEQ ID NO:36), CDR2 sequence of the VH domain comprises the amino acid sequence IYPGDSET (SEQ ID NO: 37), CDR3 sequence of the VH domain comprises the amino acid sequence ARQFPGYARQGMDV (SEQ ID NO:38), CDR1 sequence of the VL comprises the amino acid sequence NIGSKS (SEQ ID NO:39), CDR2 sequence of the VL domain comprises the amino acid sequence DDS, and CDR3 sequence of the VL domain comprises the amino acid sequence QVWDSYVV (SEQ ID NO:40); the CDR1 sequence of the VH domain comprises the amino acid sequence GYTLTELS (SEQ ID NO:41), CDR2 sequence of the VH domain comprises the amino acid sequence45753670.1 69ATTORNEY DOCKET NO. MOE 24MB020 PCTFDPEDGET (SEQ ID NO:42), CDR3 sequence of the VH domain comprises the amino acid sequence ATDNSAVGYPHYYYYGMDV (SEQ ID NO:43), CDR1 sequence of the VL comprises the amino acid sequence GSNVGDQG (SEQ ID NO:44), CDR2 sequence of the VL domain comprises the amino acid sequence RYN, and CDR3 sequence of the VL domain comprises the amino acid sequence SAWDNNLSAWV (SEQ ID NO:45); the CDR1 sequence of the VH domain comprises the amino acid sequence GGSISSGGYY (SEQ ID NO:46), CDR2 sequence of the VH domain comprises the amino acid sequence IYYSGST (SEQ ID NO:47), CDR3 sequence of the VH domain comprises the amino acid sequence ARMGYGGNFDY (SEQ ID NO:48), CDR1 sequence of the VL comprises the amino acid sequence NSNIGSNS (SEQ ID NO:49), CDR2 sequence of the VL domain comprises the amino acid sequence DNN, and CDR3 sequence of the VL domain comprises the amino acid sequence GTWDTSLSAEV (SEQ ID NQ:50); the CDR1 sequence of the VH domain comprises the amino acid sequence GGTFSSYA (SEQ ID NO: 132), CDR2 sequence of the VH domain comprises the amino acid sequence IIPIFGTA (SEQ ID NO: 133), CDR3 sequence of the VH domain comprises the amino acid sequence ASGVVIMPYDAFDI (SEQ ID NO: 134), CDR1 sequence of the VL comprises the amino acid sequence NIGATS (SEQ ID NO:135), CDR2 sequence of the VL domain comprises the amino acid sequence DYG, and CDR3 sequence of the VL domain comprises the amino acid sequence QAWDIGSDEQM (SEQ ID NO:136); the CDR1 sequence of the VH domain comprises the amino acid sequence GGASSSNA (SEQ ID NO: 137), CDR2 sequence of the VH domain comprises the amino acid sequence ITPIFDTT (SEQ ID NO: 138), CDR3 sequence of the VH domain comprises the amino acid sequence ARDGRRGLGGFFDS (SEQ ID NO: 139), CDR1 sequence of the VL comprises the amino acid sequence KLGEKY (SEQ ID NO: 140), CDR2 sequence of the VL domain comprises the amino acid sequence QDN, and CDR3 sequence of the VL domain comprises the amino acid sequence QAWDSSTYV (SEQ ID NO: 141); the CDR1 sequence of the VH domain comprises the amino acid sequence GDSVSSNIAS (SEQ ID NO: 142), CDR2 sequence of the VH domain comprises the amino acid sequence TYYRSKWYN (SEQ ID NO: 143), CDR3 sequence of the VH domain comprises the amino acid sequence ARGDGSTFDY (SEQ ID NO: 144), CDR1 sequence of the VL comprises the amino acid sequence SSNIGSNS (SEQ ID NO: 145), CDR2 sequence of the VL domain comprises the amino acid sequence GNN, and CDR3 sequence of the VL domain comprises the amino acid sequence AAWDDSLNGWV (SEQ ID NO: 146); the CDR1 sequence of the VH domain comprises the amino acid sequence GGSISSGGYY (SEQ ID NO: 147), CDR2 sequence of the VH domain comprises the amino acid sequence IYYSGST (SEQ ID NO: 148), CDR3 sequence of the VH domain comprises the amino45753670.1 70ATTORNEY DOCKET NO. MOE 24MB020 PCT acid sequence ARMGYGGNFDY (SEQ ID NO: 149), CDR1 sequence of the VL comprises the amino acid sequence NSNIGSNS (SEQ ID NO: 150), CDR2 sequence of the VL domain comprises the amino acid sequence DNN, and CDR3 sequence of the VL domain comprises the amino acid sequence GTWDTSLSAEV (SEQ ID NO: 151); the CDR1 sequence of the VH domain comprises the amino acid sequence GGTFSSYA (SEQ ID NO: 152), CDR2 sequence of the VH domain comprises the amino acid sequence IIPIFGTA (SEQ ID NO: 153), CDR3 sequence of the VH domain comprises the amino acid sequence ARDKMGFGVRSPYYYGMDV (SEQ ID NO:154), CDR1 sequence of the VL comprises the amino acid sequence QTVSNY (SEQ ID NO: 155), CDR2 sequence of the VL domain comprises the amino acid sequence AAA, and CDR3 sequence of the VL domain comprises the amino acid sequence QQSYSGPLT (SEQ ID NO: 156); the CDR1 sequence of the VH domain comprises the amino acid sequence GFVFPNYA (SEQ ID NO: 157), CDR2 sequence of the VH domain comprises the amino acid sequence IRGQSYNGTT (SEQ ID NO:158), CDR3 sequence of the VH domain comprises the amino acid sequence YTRPLTSLQI (SEQ ID NO: 159), CDR1 sequence of the VL comprises the amino acid sequence QSILYSPSNKNY (SEQ ID NO: 160), CDR2 sequence of the VL domain comprises the amino acid sequence WAS, and CDR3 sequence of the VL domain comprises the amino acid sequence QQYYTTYPT (SEQ ID NO: 161); the CDR1 sequence of the VH domain comprises the amino acid sequence GFTFSSYW (SEQ ID NO: 162), CDR2 sequence of the VH domain comprises the amino acid sequence INGDGSQT (SEQ ID NO: 163), CDR3 sequence of the VH domain comprises the amino acid sequence ARMASYDRSGYYGFFQH (SEQ ID NO: 164), CDR1 sequence of the VL comprises the amino acid sequence QYINTY (SEQ ID NO: 165), CDR2 sequence of the VL domain comprises the amino acid sequence GAS, and CDR3 sequence of the VL domain comprises the amino acid sequence QQSFSTPRT (SEQ ID NO: 166); the CDR1 sequence of the VH domain comprises the amino acid sequence GFTFSSYW (SEQ ID NO: 162), CDR2 sequence of the VH domain comprises the amino acid sequence INGDGSQT (SEQ ID NO: 163), CDR3 sequence of the VH domain comprises the amino acid sequence ARMASYDRSGYYGFFQH (SEQ ID NO:164), CDR1 sequence of the VL comprises the amino acid sequence QYINTY (SEQ ID NO: 165), CDR2 sequence of the VL domain comprises the amino acid sequence GAS, and CDR3 sequence of the VL domain comprises the amino acid sequence QQSFSTPRT (SEQ ID NO: 166); the CDR1 sequence of the VH domain comprises the amino acid sequence GYSFSDRY (SEQ ID NO:167), CDR2 sequence of the VH domain comprises the amino acid sequence IDPEDGET (SEQ ID NO: 168), CDR3 sequence of the VH domain comprises the amino acid sequence GRDIQTYGGSPRNWIDP (SEQ ID NO: 169), CDR1 sequence of the VL comprises the amino acid45753670.1 71ATTORNEY DOCKET NO. MOE 24MB020 PCT sequence SSNIGSNT (SEQ ID NO: 170), CDR2 sequence of the VL domain comprises the amino acid sequence SNN, and CDR3 sequence of the VL domain comprises the amino acid sequence AAWDDSLNGYV (SEQ ID NO: 171); the CDR1 sequence of the VH domain comprises the amino acid sequence GYTFTSYD (SEQ ID NO: 172), CDR2 sequence of the VH domain comprises the amino acid sequence MNPNSGNT (SEQ ID NO: 173), CDR3 sequence of the VH domain comprises the amino acid sequence ARANGRSLGSGWNSLYYYYYGMDV (SEQ ID NO: 174), CDR1 sequence of the VL comprises the amino acid sequence QTISPY (SEQ ID NO: 175), CDR2 sequence of the VL domain comprises the amino acid sequence SAS, and CDR3 sequence of the VL domain comprises the amino acid sequence QQSSSSWT (SEQ ID NO: 176); or the CDR1 sequence of the VH domain comprises the amino acid sequence GYDFTASS (SEQ ID NO: 177), CDR2 sequence of the VH domain comprises the amino acid sequence IFPDDSDV (SEQ ID NO: 178), CDR3 sequence of the VH domain comprises the amino acid sequence ARLRDYGNGHWYFDL (SEQ ID NO: 179), CDR1 sequence of the VL comprises the amino acid sequence SSDVGGYKY (SEQ ID NO: 180), CDR2 sequence of the VL domain comprises the amino acid sequence EVS, and CDR3 sequence of the VL domain comprises the amino acid sequence SSYTSTTTYI (SEQ ID NO: 181).Embodiment 2. The recombinant antibody of embodiment 1, wherein the VH domain comprises the amino acid sequence SEQ ID NO:51, SEQ ID NO:53, SEQ ID NO:55, SEQ ID NO:57, SEQ ID NO:59, SEQ ID NO:61, SEQ ID NO:63, SEQ ID NO:65, SEQ ID NO:67, SEQ ID NO:69, SEQ ID NO:71, SEQ ID NO:73, SEQ ID NO:75, SEQ ID NO:77, SEQ ID NO:79, SEQ ID NO:81, SEQ ID NO:83, SEQ ID NO:85, SEQ ID NO:87, or SEQ ID NO:89.Embodiment 3. The recombinant antibody of embodiment 1, wherein the VL domain comprises the amino acid sequence SEQ ID NO:52, SEQ ID NO:54, SEQ ID NO:56, SEQ ID NO:58, SEQ ID NO:60, SEQ ID NO:62, SEQ ID NO:64, SEQ ID NO:66, SEQ ID NO:68, SEQ ID NO:70, SEQ ID NO:72, SEQ ID NO:74, SEQ ID NO:76, SEQ ID NO:78, SEQ ID NO:80, SEQ ID NO:82, SEQ ID NO:84, SEQ ID NO:86, SEQ ID NO:88, SEQ ID NO:90.Embodiment 4. The recombinant antibody of embodiment 1, wherein the antibody is a single chain antibody (scFv) comprising the amino acid sequence SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO: 100, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, SEQ ID NO: 104, SEQ ID NO: 105, SEQ ID NO: 106, SEQ ID NO: 107, SEQ ID NO: 108, SEQ ID NO: 109, SEQ ID NO: 110, SEQ ID NOT H, SEQ ID NO: 112, SEQ ID NO: 113, SEQ ID NO: 114, SEQ ID NO: 115, SEQ ID NO: 116, SEQ ID NO: 117, SEQ ID NO: 118, SEQ ID NO: 119, SEQ ID NO:120, SEQ ID NO:121,45753670.1 72ATTORNEY DOCKET NO. MOE 24MB020 PCTSEQ ID NO:122, SEQ ID NO:123, SEQ ID NO: 124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO: 127, SEQ ID NO: 128, SEQ ID NO: 129, SEQ ID NO: 130, SEQ ID NO: 131.Embodiment 5. A chimeric antigen receptor (CAR) polypeptide, comprising a TRP1 antigen binding domain, a transmembrane domain, an intracellular signaling domain, and a co-stimulatory signaling region, wherein the TRP1 antigen binding domain is a single-chain variable fragment (scFv) of an antibody comprising a variable heavy (VH) domain having CDR1, CDR2 and CDR3 sequences and a variable light (VL) domain having CDR1, CDR2 and CDR3 sequences, and wherein the CDR1 sequence of the VH domain comprises the amino acid sequence GFTFSYYW (SEQ ID NO:1), CDR2 sequence of the VH domain comprises the amino acid sequence IKQDGNEK (SEQ ID NO:2), CDR3 sequence of the VH domain comprises the amino acid sequence ARGRRGRPPPDY (SEQ ID NO:3), CDR1 sequence of VL VL comprises the amino acid sequence QGISNY (SEQ ID NO:4), CDR2 sequence of the VL domain comprises the amino acid sequence AAS, and CDR3 sequence of the VL domain comprises the amino acid sequence QKYNSAPRT (SEQ ID NO: 5); the CDR1 sequence of the VH domain comprises the amino acid sequence GYTFTGYY (SEQ ID NO:6), CDR2 sequence of the VH domain comprises the amino acid sequence INPNRGGT (SEQ ID NO:7), CDR3 sequence of the VH domain comprises the amino acid sequence ARDGGAAADGFDY (SEQ ID NO:8), CDR1 sequence of the VL comprises the amino acid sequence QSIGNW (SEQ ID NO:9), CDR2 sequence of the VL domain comprises the amino acid sequence KAS, and CDR3 sequence of the VL domain comprises the amino acid sequence QQYDRYPQT (SEQ ID NO: 10); the CDR1 sequence of the VH domain comprises the amino acid sequence GFTFSDYY (SEQ ID NO: 11), CDR2 sequence of the VH domain comprises the amino acid sequence SRSRPNNYST (SEQ ID NO: 12), CDR3 sequence of the VH domain comprises the amino acid sequence TRGRSGTSFPFYYYGMDL (SEQ ID NO: 13), CDR1 sequence of the VL comprises the amino acid sequence QSISSN (SEQ ID NO: 14), CDR2 sequence of the VL domain comprises the amino acid sequence GAS, and CDR3 sequence of the VL domain comprises the amino acid sequence QQKYNTPPVT (SEQ ID NO: 15); the CDR1 sequence of the VH domain comprises the amino acid sequence GDSVSTNSAS (SEQ ID NO: 16), CDR2 sequence of the VH domain comprises the amino acid sequence TYYRSKWYN (SEQ ID NO: 17), CDR3 sequence of the VH domain comprises the amino acid sequence VRGSSGLNAFDI (SEQ ID NO: 18), CDR1 sequence of the VL comprises the amino45753670.1 73ATTORNEY DOCKET NO. MOE 24MB020 PCT acid sequence NSNIGGNT (SEQ ID NO: 19), CDR2 sequence of the VL domain comprises the amino acid sequence GRN, and CDR3 sequence of the VL domain comprises the amino acid sequence SAWDDSLKGPV (SEQ ID NO:20); the CDR1 sequence of the VH domain comprises the amino acid sequence GFTFSSYG (SEQ ID NO:21), CDR2 sequence of the VH domain comprises the amino acid sequence ITTAGDT (SEQ ID NO:22), CDR3 sequence of the VH domain comprises the amino acid sequence ARKFSSSWYDWYFDL (SEQ ID NO:23), CDR1 sequence of the VL comprises the amino acid sequence QDISNF (SEQ ID NO:24), CDR2 sequence of the VL domain comprises the amino acid sequence DAS, and CDR3 sequence of the VL domain comprises the amino acid sequence LQYHTYPYT (SEQ ID NO:25); the CDR1 sequence of the VH domain comprises the amino acid sequence GYTFTTTW (SEQ ID NO:26), CDR2 sequence of the VH domain comprises the amino acid sequence IYPDDSDT (SEQ ID NO:27), CDR3 sequence of the VH domain comprises the amino acid sequence ATAPGDY (SEQ ID NO:28), CDR1 sequence of the VL comprises the amino acid sequence GSNIGTNS (SEQ ID NO:29), CDR2 sequence of the VL domain comprises the amino acid sequence RGD, and CDR3 sequence of the VL domain comprises the amino acid sequence SSWDDRLSSWA (SEQ ID NQ:30); the CDR1 sequence of the VH domain comprises the amino acid sequence GDSVSSNNVA (SEQ ID NO:31), CDR2 sequence of the VH domain comprises the amino acid sequence TYYRSKWYN (SEQ ID NO:32), CDR3 sequence of the VH domain comprises the amino acid sequence AREEATVADAFDI (SEQ ID NO:33), CDR1 sequence of the VL comprises the amino acid sequence NIGATS (SEQ ID NO:34), CDR2 sequence of the VL domain comprises the amino acid sequence DYG, and CDR3 sequence of the VL domain comprises the amino acid sequence QMWDIGSDEQL (SEQ ID NO:35); the CDR 1 sequence of the VH domain comprises the amino acid sequence GYNFGTYH (SEQ ID NO:36), CDR2 sequence of the VH domain comprises the amino acid sequence IYPGDSET (SEQ ID NO: 37), CDR3 sequence of the VH domain comprises the amino acid sequence ARQFPGYARQGMDV (SEQ ID NO:38), CDR1 sequence of the VL comprises the amino acid sequence NIGSKS (SEQ ID NO:39), CDR2 sequence of the VL domain comprises the amino acid sequence DDS, and CDR3 sequence of the VL domain comprises the amino acid sequence QVWDSYVV (SEQ ID NO:40); the CDR1 sequence of the VH domain comprises the amino acid sequence GYTLTELS (SEQ ID NO:41), CDR2 sequence of the VH domain comprises the amino acid sequence45753670.1 74ATTORNEY DOCKET NO. MOE 24MB020 PCTFDPEDGET (SEQ ID NO:42), CDR3 sequence of the VH domain comprises the amino acid sequence ATDNSAVGYPHYYYYGMDV (SEQ ID NO:43), CDR1 sequence of the VL comprises the amino acid sequence GSNVGDQG (SEQ ID NO:44), CDR2 sequence of the VL domain comprises the amino acid sequence RYN, and CDR3 sequence of the VL domain comprises the amino acid sequence SAWDNNLSAWV (SEQ ID NO:45); the CDR1 sequence of the VH domain comprises the amino acid sequence GGSISSGGYY (SEQ ID NO:46), CDR2 sequence of the VH domain comprises the amino acid sequence IYYSGST (SEQ ID NO:47), CDR3 sequence of the VH domain comprises the amino acid sequence ARMGYGGNFDY (SEQ ID NO:48), CDR1 sequence of the VL comprises the amino acid sequence NSNIGSNS (SEQ ID NO:49), CDR2 sequence of the VL domain comprises the amino acid sequence DNN, and CDR3 sequence of the VL domain comprises the amino acid sequence GTWDTSLSAEV (SEQ ID NQ:50); the CDR1 sequence of the VH domain comprises the amino acid sequence GGTFSSYA (SEQ ID NO: 132), CDR2 sequence of the VH domain comprises the amino acid sequence IIPIFGTA (SEQ ID NO: 133), CDR3 sequence of the VH domain comprises the amino acid sequence ASGVVIMPYDAFDI (SEQ ID NO: 134), CDR1 sequence of the VL comprises the amino acid sequence NIGATS (SEQ ID NO:135), CDR2 sequence of the VL domain comprises the amino acid sequence DYG, and CDR3 sequence of the VL domain comprises the amino acid sequence QAWDIGSDEQM (SEQ ID NO:136); the CDR1 sequence of the VH domain comprises the amino acid sequence GGASSSNA (SEQ ID NO: 137), CDR2 sequence of the VH domain comprises the amino acid sequence ITPIFDTT (SEQ ID NO: 138), CDR3 sequence of the VH domain comprises the amino acid sequence ARDGRRGLGGFFDS (SEQ ID NO: 139), CDR1 sequence of the VL comprises the amino acid sequence KLGEKY (SEQ ID NO: 140), CDR2 sequence of the VL domain comprises the amino acid sequence QDN, and CDR3 sequence of the VL domain comprises the amino acid sequence QAWDSSTYV (SEQ ID NO: 141); the CDR1 sequence of the VH domain comprises the amino acid sequence GDSVSSNIAS (SEQ ID NO: 142), CDR2 sequence of the VH domain comprises the amino acid sequence TYYRSKWYN (SEQ ID NO: 143), CDR3 sequence of the VH domain comprises the amino acid sequence ARGDGSTFDY (SEQ ID NO: 144), CDR1 sequence of the VL comprises the amino acid sequence SSNIGSNS (SEQ ID NO: 145), CDR2 sequence of the VL domain comprises the amino acid sequence GNN, and CDR3 sequence of the VL domain comprises the amino acid sequence AAWDDSLNGWV (SEQ ID NO: 146); the CDR1 sequence of the VH domain comprises the amino acid sequence GGSISSGGYY (SEQ ID NO: 147), CDR2 sequence of the VH domain comprises the amino acid sequence IYYSGST (SEQ ID NO: 148), CDR3 sequence of the VH domain comprises the amino45753670.1 75ATTORNEY DOCKET NO. MOE 24MB020 PCT acid sequence ARMGYGGNFDY (SEQ ID NO: 149), CDR1 sequence of the VL comprises the amino acid sequence NSNIGSNS (SEQ ID NO: 150), CDR2 sequence of the VL domain comprises the amino acid sequence DNN, and CDR3 sequence of the VL domain comprises the amino acid sequence GTWDTSLSAEV (SEQ ID NO: 151); the CDR1 sequence of the VH domain comprises the amino acid sequence GGTFSSYA (SEQ ID NO: 152), CDR2 sequence of the VH domain comprises the amino acid sequence IIPIFGTA (SEQ ID NO: 153), CDR3 sequence of the VH domain comprises the amino acid sequence ARDKMGFGVRSPYYYGMDV (SEQ ID NO:154), CDR1 sequence of the VL comprises the amino acid sequence QTVSNY (SEQ ID NO: 155), CDR2 sequence of the VL domain comprises the amino acid sequence AAA, and CDR3 sequence of the VL domain comprises the amino acid sequence QQSYSGPLT (SEQ ID NO: 156); the CDR1 sequence of the VH domain comprises the amino acid sequence GFVFPNYA (SEQ ID NO: 157), CDR2 sequence of the VH domain comprises the amino acid sequence IRGQSYNGTT (SEQ ID NO:158), CDR3 sequence of the VH domain comprises the amino acid sequence YTRPLTSLQI (SEQ ID NO: 159), CDR1 sequence of the VL comprises the amino acid sequence QSILYSPSNKNY (SEQ ID NO: 160), CDR2 sequence of the VL domain comprises the amino acid sequence WAS, and CDR3 sequence of the VL domain comprises the amino acid sequence QQYYTTYPT (SEQ ID NO: 161); the CDR1 sequence of the VH domain comprises the amino acid sequence GFTFSSYW (SEQ ID NO: 162), CDR2 sequence of the VH domain comprises the amino acid sequence INGDGSQT (SEQ ID NO: 163), CDR3 sequence of the VH domain comprises the amino acid sequence ARMASYDRSGYYGFFQH (SEQ ID NO: 164), CDR1 sequence of the VL comprises the amino acid sequence QYINTY (SEQ ID NO: 165), CDR2 sequence of the VL domain comprises the amino acid sequence GAS, and CDR3 sequence of the VL domain comprises the amino acid sequence QQSFSTPRT (SEQ ID NO: 166); the CDR1 sequence of the VH domain comprises the amino acid sequence GFTFSSYW (SEQ ID NO: 162), CDR2 sequence of the VH domain comprises the amino acid sequence INGDGSQT (SEQ ID NO: 163), CDR3 sequence of the VH domain comprises the amino acid sequence ARMASYDRSGYYGFFQH (SEQ ID NO:164), CDR1 sequence of the VL comprises the amino acid sequence QYINTY (SEQ ID NO: 165), CDR2 sequence of the VL domain comprises the amino acid sequence GAS, and CDR3 sequence of the VL domain comprises the amino acid sequence QQSFSTPRT (SEQ ID NO: 166); the CDR1 sequence of the VH domain comprises the amino acid sequence GYSFSDRY (SEQ ID NO:167), CDR2 sequence of the VH domain comprises the amino acid sequence IDPEDGET (SEQ ID NO: 168), CDR3 sequence of the VH domain comprises the amino acid sequence GRDIQTYGGSPRNWIDP (SEQ ID NO: 169), CDR1 sequence of the VL comprises the amino acid45753670.1 76ATTORNEY DOCKET NO. MOE 24MB020 PCT sequence SSNIGSNT (SEQ ID NO: 170), CDR2 sequence of the VL domain comprises the amino acid sequence SNN, and CDR3 sequence of the VL domain comprises the amino acid sequence AAWDDSLNGYV (SEQ ID NO: 171); the CDR1 sequence of the VH domain comprises the amino acid sequence GYTFTSYD (SEQ ID NO: 172), CDR2 sequence of the VH domain comprises the amino acid sequence MNPNSGNT (SEQ ID NO: 173), CDR3 sequence of the VH domain comprises the amino acid sequence ARANGRSLGSGWNSLYYYYYGMDV (SEQ ID NO: 174), CDR1 sequence of the VL comprises the amino acid sequence QTISPY (SEQ ID NO: 175), CDR2 sequence of the VL domain comprises the amino acid sequence SAS, and CDR3 sequence of the VL domain comprises the amino acid sequence QQSSSSWT (SEQ ID NO: 176); or the CDR1 sequence of the VH domain comprises the amino acid sequence GYDFTASS (SEQ ID NO: 177), CDR2 sequence of the VH domain comprises the amino acid sequence IFPDDSDV (SEQ ID NO: 178), CDR3 sequence of the VH domain comprises the amino acid sequence ARLRDYGNGHWYFDL (SEQ ID NO: 179), CDR1 sequence of the VL comprises the amino acid sequence SSDVGGYKY (SEQ ID NO: 180), CDR2 sequence of the VL domain comprises the amino acid sequence EVS, and CDR3 sequence of the VL domain comprises the amino acid sequence SSYTSTTTYI (SEQ ID NO: 181).Embodiment 6. The polypeptide of embodiment 5, wherein the VH domain comprises the amino acid sequence SEQ ID NO:51, SEQ ID NO:53, SEQ ID NO:55, SEQ ID NO:57, SEQ ID NO:59, SEQ ID NO:61, SEQ ID NO:63, SEQ ID NO:65, SEQ ID NO:67, SEQ ID NO:69, SEQ ID NO:71, SEQ ID NO:73, SEQ ID NO:75, SEQ ID NO:77, SEQ ID NO:79, SEQ ID NO:81, SEQ ID NO:83, SEQ ID NO:85, SEQ ID NO:87, or SEQ ID NO:89.Embodiment 7. The polypeptide of embodiment 5 or 6, wherein the VL domain comprises the amino acid sequence SEQ ID NO:52, SEQ ID NO:54, SEQ ID NO:56, SEQ ID NO:58, SEQ ID NO:60, SEQ ID NO:62, SEQ ID NO:64, SEQ ID NO:66, SEQ ID NO:68, SEQ ID NO:70, SEQ ID NO:72, SEQ ID NO:74, SEQ ID NO:76, SEQ ID NO:78, SEQ ID NO:80, SEQ ID NO:82, SEQ ID NO:84, SEQ ID NO:86, SEQ ID NO:88, SEQ ID NO:90.Embodiment 8. The polypeptide of embodiment 5, wherein the antibody is a single chain antibody (scFv) comprising the amino acid sequence SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID N0:100, SEQ ID NO:101, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO: 104, SEQ ID NO:105, SEQ ID NO: 106, SEQ ID NO: 107, SEQ ID NO: 108, SEQ ID NO: 109, SEQ ID NO: 110, SEQ ID NO: 111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115, SEQ ID NO:116, SEQ ID NO: 117, SEQ ID NO: 118, SEQ ID NO: 119, SEQ ID NO: 120, SEQ ID NO: 121, SEQ ID45753670.1 77ATTORNEY DOCKET NO. MOE 24MB020 PCTNO: 122, SEQ ID NO: 123, SEQ ID NO: 124, SEQ ID NO: 125, SEQ ID NO: 126, SEQ ID NO:127, SEQ ID NO: 128, SEQ ID NO: 129, SEQ ID NO: 130, SEQ ID NO: 131.Embodiment 9. The polypeptide of any one of embodiments 5 to 8, wherein the costimulatory signaling region comprises the cytoplasmic domain of a costimulatory molecule selected from the group consisting of CD27, CD28, 4-1BB, 0X40, CD30, CD40, PD-1, ICOS, lymphocyte function-associated antigen- 1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, a ligand that specifically binds with CD83, and any combination thereofEmbodiment 10. The polypeptide of any one of embodiments 5 to 9, wherein the CAR polypeptide is defined by the formula:SP-TRP1-HG-TM-CSR-ISD; orSP- TRP1-HG-TM-ISD-CSR wherein “SP” represents a signal peptide, wherein “TRP1” represents a TRP1 -binding region, wherein “HG” represents and optional hinge domain, wherein “TM” represents a transmembrane domain, wherein “CSR” represents a co-stimulatory signaling region, wherein “ISD” represents an intracellular signaling domain, and wherein represents a bivalent linker.Embodiment 11. The polypeptide of any one of embodiments 5 to 10, wherein the intracellular signaling domain comprises a CD3 zeta (CD3Q signaling domain.Embodiment 12. The polypeptide of any one of embodiments 5 to 10, wherein the intracellular signaling domain comprises an NK cell receptor intracellular domain.Embodiment 13. The polypeptide of any one of embodiments 5 to 11, wherein the polypeptide contains only an intracellular signaling domain or a co-stimulatory domain, but not both.Embodiment 14. An isolated nucleic acid sequence encoding the recombinant polypeptide of any one of embodiments 5 to 12.Embodiment 15. A vector comprising the isolated nucleic acid sequence of embodiment 13.Embodiment 16. A cell comprising the vector of embodiment 14.Embodiment 17. The cell of embodiment 15, wherein the cell is selected from the group consisting of an a|3T cell, y5T cell, a Natural Killer (NK) cells, a Natural Killer T (NKT) cell, a B cell, an innate lymphoid cell (ILC), a cytokine induced killer (CIK) cell, a cytotoxic T lymphocyte (CTL), a lymphokine activated killer (LAK) cell, a regulatory T cell, or any combination thereof.45753670.1 78ATTORNEY DOCKET NO. MOE 24MB020 PCTEmbodiment 18. A method of providing an anti-cancer immunity in a subject with a melanoma, the method comprising administering to the subject an effective amount of an immune effector cell genetically modified to express the CAR polypeptide of any one of embodiments 5 to 12, thereby providing an anti-tumor immunity in the mammal.Embodiment 19. The method of embodiment 17, wherein the immune effector cell is selected from the group consisting of an a T cell, yoT cell, a Natural Killer (NK) cells, a Natural Killer T (NKT) cell, a B cell, an innate lymphoid cell (ILC), a cytokine induced killer (CIK) cell, a cytotoxic T lymphocyte (CTL), a lymphokine activated killer (LAK) cell, a regulatory T (Treg) cell, or any combination thereof.Embodiment 20. The method of embodiments 17 or 18, further comprising administering to the subject a checkpoint inhibitor.Embodiment 21. The method of embodiment 19, wherein the checkpoint inhibitor comprises an anti-PD-1 antibody, anti-PD-Ll antibody, anti-CTLA-4 antibody, or a combination thereof.The disclosed compositions and methods can be further understood through the following numbered paragraphs.EXAMPLESA. Example 1:A CAR construct was produced using an scFv derived from a TA99 mAb. The signaling module was 41BB-CD3z. A cytotoxicity assay was performed at 10:1 and 5:1 E:T ratios using B16 and CHO-CD33 used as target cells. UT = untransduced. humTA99BBz = CAR T cell targeted against TRP1 (using humanized TA99 antibody), costim = 41BB, includes CD3zeta.Transduction efficiency was calculated by percentage of CD34 and GFP double positive cells. The transduction efficiency of the UT was 1.8 and of the humTA99BBz as 79.0.FIGs. 1A and IB show cytotoxicity of a 2nd generation CAR construct with an scFv derived from IMC-20D7S and a 41BB-CD3z cytoplasmic domain with B16 and CHO-CD33 used as target cells at 10:1 (FIG. 1A) and 5: 1 (FIG. IB) E:T ratios. Arrow indicates addition of T cells. humTA99 is specific for B 16 target cells and humTA99BBz shows effective killing.B. Example 2:FIG. 2 illustrates CAR constructs used in examples.45753670.1 79ATTORNEY DOCKET NO. MOE 24MB020 PCTFIG. 3 shows RTCA cytotoxicity of humLCl-TA99BBz. Arrow indicates addition of T cells. humTA99 is specific for B 16 target cells. humTA99BBz shows effective killing.FIG. 4 shows RTCA cytotoxicity hTA99LClBBz.FIG. 5 shows RTCA cytotoxicity hTA99LC2BBz.FIG. 6 shows RTCA cytotoxicity humTA99NKG2D. The effectortarget ratio is 1:5, this implies that one CAR has to kill more than once. This indicates that the CARs have the ability to conduct repetitive killing.FIG. 7 shows that while CTL killing was comparable, cytokine production (IL6) was reduced with humTA99BBz. This feature may help reduce the development of irAEs, like cytokine storm.FIG. 8 shows flank tumor growth in NSG mice challenged with B 16 melanoma, no preconditioning (CTX or TBI), and then treatment with 200K untransduced or LCl-BBz human ab- T cells.C. Example 3:FIG. 9 illustrates CAR constructs used in examples with (x) standing in for one of 10 different scFvs labeled a-j.Table 2 below shows transduction efficiency scFv variants against melanoma TRP1.FIG. 10 shows RTCA cytotoxicity scFv (variants against TRPl)-BBz melanoma targets.Cells are plated at a 5:1 ET ratio.FIG. 11 shows RTCA cytotoxicity where cells are plated at a 5:1 ET ratio. Cells are cultured in hypoxic conditions (0.5% 02).D. Example 4:FIG. 12 illustrates the functional activity of CD28-CD3^ CAR-T cells expressing a panel of affinity-optimized human anti-TRPl scFvs, following co-culture with melanoma target cells.45753670.1 80ATTORNEY DOCKET NO. MOF 24MB020 PCTTable 3 shows phage binding values showing reactivity of each clone (R3P1-R4P4 series) against immobilized TRP1 antigen (Ag), along with two controls (LC1 and LC2). Binding strength was measured as OD values from phage ELISA. Clones demonstrating strong TRP1 binding with maximal target reactivity were prioritized for CAR design.effectiveness for selected scFvs used in functional CAR-T constructs.FIG. 14 shows aggregate analysis of IFNy production across all tumor lines and donors.FIG. 15 reveals reproducibility of cytokine responses and donor-to-donor variation in magnitude.45753670.1 81ATTORNEY DOCKET NO. MOE 24MB020 PCTFIG. 16 shows real-time cell adhesion index of B16 melanoma cells treated with murine CAR-T cells expressing the TRPld scFv (mTRPld-CD28z), measured using xCELLigence platform. CAR-T cells were added at different effector-to-target (E:T) ratios (1:1, 1:5, 1: 10, 1:20).FIG. 17 shows Kaplan-Meier survival analysis of mice bearing leptomeningeal melanoma treated with murine CAR-T cells expressing TRPld-CD28z (mTRPld-CARs).FIG. 18 shows real-time killing of TRP1+canine melanoma cell lines by canine T cells expressing LCl-derived scFv CARs with CD28 signaling domains.FIG. 19 reveals both caninized LC1 and humanized LC1 scFvs test to assess cross-species reactivity and performance of donor 7.FIG. 20 reveals both caninized LC1 and humanized LC1 scFvs test to assess cross-species reactivity and performance of donor 9.FIG. 21 shows IFNy levels measured from CAR-T cells co-cultured with B16 (mouse), CMGD2 (canine), and TLM (canine) melanoma cell lines.FIG. 22 shows Kaplan-Meier survival analysis of tumor-bearing mice treated with CD3^- based or CD3^-less CAR-T cells, with isotype or anti-PD-l / PD-Ll ICI.FIG. 23 displays tumor growth curves.It is understood that the disclosed method and compositions are not limited to the particular methodology, protocols, and reagents described as these can vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims.Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, many equivalents to the specific embodiments of the method and compositions described herein. Such equivalents are intended to be encompassed by the following claims.45753670.1 82

Claims

ATTORNEY DOCKET NO. MOF 24MB020 PCTCLAIMSWe claim:1 . A recombinant antibody that selectively binds TRP1 on tumor cells, comprising a variable heavy (VH) domain having CDR1, CDR2 and CDR3 sequences and a variable light (VL) domain having CDR1, CDR2 and CDR3 sequences, wherein the CDR1 sequence of the VH domain comprises the amino acid sequence GFTFSYYW (SEQ ID NO: 1), CDR2 sequence of the VH domain comprises the amino acid sequence IKQDGNEK (SEQ ID NO:2), CDR3 sequence of the VH domain comprises the amino acid sequence ARGRRGRPPPDY (SEQ ID NO:3), CDR1 sequence of VL comprises the amino acid sequence QGISNY (SEQ ID NO:4), CDR2 sequence of the VL domain comprises the amino acid sequence AAS, and CDR3 sequence of the VL domain comprises the amino acid sequence QKYNSAPRT (SEQ ID NO:5); the CDR1 sequence of the VH domain comprises the amino acid sequence GYTFTGYY (SEQ ID NO:6), CDR2 sequence of the VH domain comprises the amino acid sequence INPNRGGT (SEQ ID NO:7), CDR3 sequence of the VH domain comprises the amino acid sequence ARDGGAAADGFDY (SEQ ID NO: 8), CDR1 sequence of the VL comprises the amino acid sequence QSIGNW (SEQ ID NO:9), CDR2 sequence of the VL domain comprises the amino acid sequence KAS, and CDR3 sequence of the VL domain comprises the amino acid sequence QQYDRYPQT (SEQ ID NO: 10); the CDR1 sequence of the VH domain comprises the amino acid sequence GFTFSDYY (SEQ ID NO: 11), CDR2 sequence of the VH domain comprises the amino acid sequence SRSRPNNYST (SEQ ID NO: 12), CDR3 sequence of the VH domain comprises the amino acid sequence TRGRSGTSFPFYYYGMDL (SEQ ID NO: 13), CDR1 sequence of the VLcomprises the amino acid sequence QSISSN (SEQ ID NO: 14), CDR2 sequence of the VL domain comprises the amino acid sequence GAS, and CDR3 sequence of the VL domain comprises the amino acid sequence QQKYNTPPVT (SEQ ID NO: 15); the CDR1 sequence of the VH domain comprises the amino acid sequence GDSVSTNSAS (SEQ ID NO: 16), CDR2 sequence of the VH domain comprises the amino acid sequence TYYRSKWYN (SEQ ID NO: 17), CDR3 sequence of the VH domain comprises the amino acid sequence VRGSSGLNAFDI (SEQ ID NO: 18), CDR1 sequence of the VL comprises the amino acid sequence NSNIGGNT (SEQ ID NO: 19), CDR2 sequence of the VL domain comprises the amino acid sequence GRN, and CDR3 sequence of the VL domain comprises the amino acid sequence SAWDDSLKGPV (SEQ ID NO:20);45753670.1 83ATTORNEY DOCKET NO. MOF 24MB020 PCT the CDR1 sequence of the VH domain comprises the amino acid sequence GFTFSSYG (SEQ ID NO:21), CDR2 sequence of the VH domain comprises the amino acid sequence ITTAGDT (SEQ ID NO:22), CDR3 sequence of the VH domain comprises the amino acid sequence ARKFSSSWYDWYFDL (SEQ ID NO:23), CDR1 sequence of the VL comprises the amino acid sequence QDISNF (SEQ ID NO:24), CDR2 sequence of the VL domain comprises the amino acid sequence DAS, and CDR3 sequence of the VL domain comprises the amino acid sequence LQYHTYPYT (SEQ ID NO:25); the CDR1 sequence of the VH domain comprises the amino acid sequence GYTFTTTW (SEQ ID NO:26), CDR2 sequence of the VH domain comprises the amino acid sequence IYPDDSDT (SEQ ID NO:27), CDR3 sequence of the VH domain comprises the amino acid sequence ATAPGDY (SEQ ID NO:28), CDR1 sequence of the VL comprises the amino acid sequence GSNIGTNS (SEQ ID NO:29), CDR2 sequence of the VL domain comprises the amino acid sequence RGD, and CDR3 sequence of the VL domain comprises the amino acid sequence SSWDDRLSSWA (SEQ ID NO:30); the CDR1 sequence of the VH domain comprises the amino acid sequence GDSVSSNNVA (SEQ ID NO:31), CDR2 sequence of the VH domain comprises the amino acid sequence TYYRSKWYN (SEQ ID NO:32), CDR3 sequence of the VH domain comprises the amino acid sequence AREEATVADAFDI (SEQ ID NO:33), CDR1 sequence of the VL comprises the amino acid sequence NIGATS (SEQ ID NO:34), CDR2 sequence of the VL domain comprises the amino acid sequence DYG, and CDR3 sequence of the VL domain comprises the amino acid sequence QMWDIGSDEQL (SEQ ID NO:35); the CDR1 sequence of the VH domain comprises the amino acid sequence GYNFGTYH (SEQ ID NO:36), CDR2 sequence of the VH domain comprises the amino acid sequence IYPGDSET (SEQ ID NO:37), CDR3 sequence of the VH domain comprises the amino acid sequence ARQFPGYARQGMDV (SEQ ID NO:38), CDR1 sequence of the VL comprises the amino acid sequence NIGSKS (SEQ ID NO:39), CDR2 sequence of the VL domain comprises the amino acid sequence DDS, and CDR3 sequence of the VL domain comprises the amino acid sequence QVWDSYVV (SEQ ID NQ:40); the CDR1 sequence of the VH domain comprises the amino acid sequence GYTLTELS (SEQ ID NO:41), CDR2 sequence of the VH domain comprises the amino acid sequence FDPEDGET (SEQ ID NO:42), CDR3 sequence of the VH domain comprises the amino acid sequence ATDNSAVGYPHYYYYGMDV (SEQ ID NO:43), CDR1 sequence of the VL comprises the amino acid sequence GSNVGDQG (SEQ ID NO:44), CDR2 sequence of the45753670.1 84ATTORNEY DOCKET NO. MOF 24MB020 PCTVL domain comprises the amino acid sequence RYN, and CDR3 sequence of the VL domain comprises the amino acid sequence SAWDNNLSAWV (SEQ ID NO:45); the CDR1 sequence of the VH domain comprises the amino acid sequence GGSISSGGYY (SEQ ID NO:46), CDR2 sequence of the VH domain comprises the amino acid sequence IYYSGST (SEQ ID NO:47), CDR3 sequence of the VH domain comprises the amino acid sequence ARMGYGGNFDY (SEQ ID NO:48), CDR1 sequence of the VL comprises the amino acid sequence NSNIGSNS (SEQ ID NO:49), CDR2 sequence of the VL domain comprises the amino acid sequence DNN, and CDR3 sequence of the VL domain comprises the amino acid sequence GTWDTSLSAEV (SEQ ID NO:50); the CDR1 sequence of the VH domain comprises the amino acid sequence GGTFSSYA (SEQ ID NO: 132), CDR2 sequence of the VH domain comprises the amino acid sequence IIPIFGTA (SEQ ID NO: 133), CDR3 sequence of the VH domain comprises the amino acid sequence ASGVVIMPYDAFDI (SEQ ID NO: 134), CDR1 sequence of the VL comprises the amino acid sequence NIGATS (SEQ ID NO: 135), CDR2 sequence of the VL domain comprises the amino acid sequence DYG, and CDR3 sequence of the VL domain comprises the amino acid sequence QAWDIGSDEQM (SEQ ID NO: 136); the CDR1 sequence of the VH domain comprises the amino acid sequence GGASSSNA (SEQ ID NO: 137), CDR2 sequence of the VH domain comprises the amino acid sequence ITPIFDTT (SEQ ID NO: 138), CDR3 sequence of the VH domain comprises the amino acid sequence ARDGRRGLGGFFDS (SEQ ID NO: 139), CDR1 sequence of the VL comprises the amino acid sequence KLGEKY (SEQ ID NO: 140), CDR2 sequence of the VL domain comprises the amino acid sequence QDN, and CDR3 sequence of the VL domain comprises the amino acid sequence QAWDSSTYV (SEQ ID NO: 141); the CDR1 sequence of the VH domain comprises the amino acid sequence GDSVSSNIAS (SEQ ID NO: 142), CDR2 sequence of the VH domain comprises the amino acid sequence TYYRSKWYN (SEQ ID NO: 143), CDR3 sequence of the VH domain comprises the amino acid sequence ARGDGSTFDY (SEQ ID NO: 144), CDR1 sequence of the VL comprises the amino acid sequence SSNIGSNS (SEQ ID NO: 145), CDR2 sequence of the VL domain comprises the amino acid sequence GNN, and CDR3 sequence of the VL domain comprises the amino acid sequence AAWDDSLNGWV (SEQ ID NO: 146); the CDR1 sequence of the VH domain comprises the amino acid sequence GGSISSGGYY (SEQ ID NO: 147), CDR2 sequence of the VH domain comprises the amino acid sequence IYYSGST (SEQ ID NO: 148), CDR3 sequence of the VH domain comprises the amino acid sequence ARMGYGGNFDY (SEQ ID NO: 149), CDR1 sequence of the VL comprises the amino acid sequence NSNIGSNS (SEQ ID NO: 150), CDR2 sequence of the VL domain comprises the 45753670.1 §5ATTORNEY DOCKET NO. MOF 24MB020 PCT amino acid sequence DNN, and CDR3 sequence of the VL domain comprises the amino acid sequence GTWDTSLSAEV (SEQ ID NO: 151); the CDR1 sequence of the VH domain comprises the amino acid sequence GGTFSSYA (SEQ ID NO: 152), CDR2 sequence of the VH domain comprises the amino acid sequence IIPIFGTA (SEQ ID NO: 153), CDR3 sequence of the VH domain comprises the amino acid sequence ARDKMGFGVRSPYYYGMDV (SEQ ID NO: 154), CDR1 sequence of the VL comprises the amino acid sequence QTVSNY (SEQ ID NO: 155), CDR2 sequence of the VL domain comprises the amino acid sequence AAA, and CDR3 sequence of the VL domain comprises the amino acid sequence QQSYSGPLT (SEQ ID NO: 156); the CDR1 sequence of the VH domain comprises the amino acid sequence GFVFPNYA (SEQ ID NO: 157), CDR2 sequence of the VH domain comprises the amino acid sequence IRGQSYNGTT (SEQ ID NO: 158), CDR3 sequence of the VH domain comprises the amino acid sequence YTRPLTSLQI (SEQ ID NO: 159), CDR1 sequence of the VL comprises the amino acid sequence QSILYSPSNKNY (SEQ ID NO: 160), CDR2 sequence of the VL domain comprises the amino acid sequence WAS, and CDR3 sequence of the VL domain comprises the amino acid sequence QQYYTTYPT (SEQ ID NO:161); the CDR1 sequence of the VH domain comprises the amino acid sequence GFTFSSYW (SEQ ID NO: 162), CDR2 sequence of the VH domain comprises the amino acid sequence INGDGSQT (SEQ ID NO: 163), CDR3 sequence of the VH domain comprises the amino acid sequence ARMASYDRSGYYGFFQH (SEQ ID NO: 164), CDR1 sequence of the VL comprises the amino acid sequence QYINTY (SEQ ID NO: 165), CDR2 sequence of the VL domain comprises the amino acid sequence GAS, and CDR3 sequence of the VL domain comprises the amino acid sequence QQSFSTPRT (SEQ ID NO: 166); the CDR1 sequence of the VH domain comprises the amino acid sequence GFTFSSYW (SEQ ID NO: 162), CDR2 sequence of the VH domain comprises the amino acid sequence INGDGSQT (SEQ ID NO: 163), CDR3 sequence of the VH domain comprises the amino acid sequence ARMASYDRSGYYGFFQH (SEQ ID NO: 164), CDR1 sequence of the VL comprises the amino acid sequence QYINTY (SEQ ID NO:165), CDR2 sequence of the VL domain comprises the amino acid sequence GAS, and CDR3 sequence of the VL domain comprises the amino acid sequence QQSFSTPRT (SEQ ID NO: 166); the CDR1 sequence of the VH domain comprises the amino acid sequence GYSFSDRY (SEQ ID NO: 167), CDR2 sequence of the VH domain comprises the amino acid sequence IDPEDGET (SEQ ID NO: 168), CDR3 sequence of the VH domain comprises the amino acid sequence GRDIQTYGGSPRNWIDP (SEQ ID NO: 169), CDR1 sequence of the VL comprises the amino acid sequence SSNIGSNT (SEQ ID NO: 170), CDR2 sequence 45753670.1 §gATTORNEY DOCKET NO. MOF 24MB020 PCT of the VL domain comprises the amino acid sequence SNN, and CDR3 sequence of the VL domain comprises the amino acid sequence AAWDDSLNGYV (SEQ ID NO: 171); the CDR1 sequence of the VH domain comprises the amino acid sequence GYTFTSYD (SEQ ID NO: 172), CDR2 sequence of the VH domain comprises the amino acid sequence MNPNSGNT (SEQ ID NO: 173), CDR3 sequence of the VH domain comprises the amino acid sequence ARANGRSLGSGWNSLYYYYYGMDV (SEQ ID NO: 174), CDR1 sequence of the VL comprises the amino acid sequence QTISPY (SEQ ID NO: 175), CDR2 sequence of the VL domain comprises the amino acid sequence SAS, and CDR3 sequence of the VL domain comprises the amino acid sequence QQSSSSWT (SEQ ID NO: 176); or the CDR1 sequence of the VH domain comprises the amino acid sequence GYDFTASS (SEQ ID NO: 177), CDR2 sequence of the VH domain comprises the amino acid sequence IFPDDSDV (SEQ ID NO: 178), CDR3 sequence of the VH domain comprises the amino acid sequence ARLRDYGNGHWYFDL (SEQ ID NO:179), CDR1 sequence of the VL comprises the amino acid sequence SSDVGGYKY (SEQ ID NO: 180), CDR2 sequence of the VL domain comprises the amino acid sequence EVS, and CDR3 sequence of the VL domain comprises the amino acid sequence SSYTSTTTYI (SEQ ID NO:181).

2. The recombinant antibody of claim 1, wherein the VH domain comprises the amino acid sequence SEQ ID NO:51, SEQ ID NO:53, SEQ ID NO:55, SEQ ID NO:57, SEQ ID NO:59, SEQ ID NO:61, SEQ ID NO:63, SEQ ID NO:65, SEQ ID NO:67, SEQ ID NO:69, SEQ ID NO:71, SEQ ID NO:73, SEQ ID NO:75, SEQ ID NO:77, SEQ ID NO:79, SEQ ID NO:81, SEQ ID NO:83, SEQ ID NO:85, SEQ ID NO:87, or SEQ ID NO:89.

3. The recombinant antibody of claim 1, wherein the VL domain comprises the amino acid sequence SEQ ID NO:52, SEQ ID NO:54, SEQ ID NO:56, SEQ ID NO:58, SEQ ID NQ:60, SEQ ID NO:62, SEQ ID NO:64, SEQ ID NO:66, SEQ ID NO:68, SEQ ID NO:70, SEQ ID NO:72, SEQ ID NO:74, SEQ ID NO:76, SEQ ID NO:78, SEQ ID NO:80, SEQ ID NO:82, SEQ ID NO:84, SEQ ID NO:86, SEQ ID NO:88, SEQ ID NO:90.

4. The recombinant antibody of claim 1, wherein the antibody is a single chain antibody (scFv) comprising the amino acid sequence SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:100, SEQ ID NQ:101, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO: 105, SEQ ID NO: 106, SEQ ID NO: 107, SEQ ID NO: 108, SEQ ID NO: 109, SEQ ID NO: 110, SEQ ID NO: 111, SEQ ID NO: 112, SEQ ID NO: 113, SEQ ID NO: 114, SEQ ID NO: 1 15, SEQ ID NO: 1 16, SEQ ID NO: 117, SEQ ID NO: 1 18, SEQ ID NO: 1 19, SEQ ID NO:120, SEQ ID NO:121, SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID45753670.1 87ATTORNEY DOCKET NO. MOF 24MB020 PCTNO: 125, SEQ ID NO: 126, SEQ ID NO: 127, SEQ ID NO: 128, SEQ ID NO: 129, SEQ ID NO:130, SEQ ID NO:131.

5. A chimeric antigen receptor (CAR) polypeptide, comprising a TRP1 antigen binding domain, a transmembrane domain, an intracellular signaling domain, and a co-stimulatory signaling region, wherein the TRP1 antigen binding domain is a single-chain variable fragment (scFv) of an antibody comprising a variable heavy (VH) domain having CDR1, CDR2 and CDR3 sequences and a variable light (VL) domain having CDR1, CDR2 and CDR3 sequences, and wherein the CDR1 sequence of the Vn domain comprises the amino acid sequence GFTFSYYW (SEQ ID NO: 1), CDR2 sequence of the Vn domain comprises the amino acid sequence IKQDGNEK (SEQ ID NO:2), CDR3 sequence of the Vn domain comprises the amino acid sequence ARGRRGRPPPDY (SEQ ID NO:3), CDR1 sequence of VL VL comprises the amino acid sequence QGISNY (SEQ ID NO:4), CDR2 sequence of the VL domain comprises the amino acid sequence AAS, and CDR3 sequence of the VL domain comprises the amino acid sequence QKYNSAPRT (SEQ ID NO:5); the CDR1 sequence of the Vn domain comprises the amino acid sequence GYTFTGYY (SEQ ID NO:6), CDR2 sequence of the VH domain comprises the amino acid sequence INPNRGGT (SEQ ID NO:7), CDR3 sequence of the Vn domain comprises the amino acid sequence ARDGGAAADGFDY (SEQ ID NO: 8), CDR1 sequence of the VL comprises the amino acid sequence QSIGNW (SEQ ID NO:9), CDR2 sequence of the VL domain comprises the amino acid sequence KAS, and CDR3 sequence of the VL domain comprises the amino acid sequence QQYDRYPQT (SEQ ID NO: 10); the CDR1 sequence of the Vn domain comprises the amino acid sequence GFTFSDYY (SEQ ID NO: 11), CDR2 sequence of the Vn domain comprises the amino acid sequence SRSRPNNYST (SEQ ID NO: 12), CDR3 sequence of the Vn domain comprises the amino acid sequence TRGRSGTSFPFYYYGMDL (SEQ ID NO: 13), CDR1 sequence of the VL comprises the amino acid sequence QSISSN (SEQ ID NO: 14), CDR2 sequence of the VL domain comprises the amino acid sequence GAS, and CDR3 sequence of the VL domain comprises the amino acid sequence QQKYNTPPVT (SEQ ID NO: 15); the CDR1 sequence of the VH domain comprises the amino acid sequence GDSVSTNSAS (SEQ ID NO: 16), CDR2 sequence of the VH domain comprises the amino acid sequence TYYRSKWYN (SEQ ID NO: 17), CDR3 sequence of the VH domain comprises the amino acid sequence VRGSSGLNAFDI (SEQ ID NO: 18), CDR1 sequence of the VL comprises the amino acid sequence NSNIGGNT (SEQ ID NO: 19), CDR2 sequence of the VL domain45753670.1 88ATTORNEY DOCKET NO. MOF 24MB020 PCT comprises the amino acid sequence GRN, and CDR3 sequence of the VL domain comprises the amino acid sequence SAWDDSLKGPV (SEQ ID NO:20); the CDR1 sequence of the VH domain comprises the amino acid sequence GFTFSSYG (SEQ ID NO:21), CDR2 sequence of the VH domain comprises the amino acid sequence ITTAGDT (SEQ ID NO:22), CDR3 sequence of the VH domain comprises the amino acid sequence ARKFSSSWYDWYFDL (SEQ ID NO:23), CDR1 sequence of the VL comprises the amino acid sequence QDISNF (SEQ ID NO:24), CDR2 sequence of the VL domain comprises the amino acid sequence DAS, and CDR3 sequence of the VL domain comprises the amino acid sequence LQYHTYPYT (SEQ ID NO:25); the CDR1 sequence of the VH domain comprises the amino acid sequence GYTFTTTW (SEQ ID NO:26), CDR2 sequence of the VH domain comprises the amino acid sequence IYPDDSDT (SEQ ID NO:27), CDR3 sequence of the VH domain comprises the amino acid sequence ATAPGDY (SEQ ID NO:28), CDR1 sequence of the VL comprises the amino acid sequence GSNIGTNS (SEQ ID NO:29), CDR2 sequence of the VL domain comprises the amino acid sequence RGD, and CDR3 sequence of the VL domain comprises the amino acid sequence SSWDDRLSSWA (SEQ ID NO:30); the CDR1 sequence of the VH domain comprises the amino acid sequence GDSVSSNNVA (SEQ ID NO:31), CDR2 sequence of the VH domain comprises the amino acid sequence TYYRSKWYN (SEQ ID NO: 32), CDR3 sequence of the VH domain comprises the amino acid sequence AREEATVADAFDI (SEQ ID NO:33), CDR1 sequence of the VL comprises the amino acid sequence NIGATS (SEQ ID NO:34), CDR2 sequence of the VL domain comprises the amino acid sequence DYG, and CDR3 sequence of the VL domain comprises the amino acid sequence QMWDIGSDEQL (SEQ ID NO: 35); the CDR1 sequence of the VH domain comprises the amino acid sequence GYNFGTYH (SEQ ID NO:36), CDR2 sequence of the VH domain comprises the amino acid sequence IYPGDSET (SEQ ID NO:37), CDR3 sequence of the VH domain comprises the amino acid sequence ARQFPGYARQGMDV (SEQ ID NO:38), CDR1 sequence of the VL comprises the amino acid sequence NIGSKS (SEQ ID NO:39), CDR2 sequence of the VL domain comprises the amino acid sequence DDS, and CDR3 sequence of the VL domain comprises the amino acid sequence QVWDSYVV (SEQ ID NO:40); the CDR1 sequence of the VH domain comprises the amino acid sequence GYTLTELS (SEQ ID NO:41), CDR2 sequence of the VH domain comprises the amino acid sequence FDPEDGET (SEQ ID NO:42), CDR3 sequence of the VH domain comprises the amino acid sequence ATDNSAVGYPHYYYYGMDV (SEQ ID NO:43), CDR1 sequence of the VL45753670.1 89ATTORNEY DOCKET NO. MOF 24MB020 PCT comprises the amino acid sequence GSNVGDQG (SEQ ID NO:44), CDR2 sequence of the Vi. domain comprises the amino acid sequence RYN, and CDR3 sequence of the VL domain comprises the amino acid sequence SAWDNNLSAWV (SEQ ID NO:45); the CDR1 sequence of the VH domain comprises the amino acid sequence GGSISSGGYY (SEQ ID NO:46), CDR2 sequence of the VH domain comprises the amino acid sequence IYYSGST (SEQ ID NO:47), CDR3 sequence of the VH domain comprises the amino acid sequence ARMGYGGNFDY (SEQ ID NO:48), CDR1 sequence of the VL comprises the amino acid sequence NSNIGSNS (SEQ ID NO:49), CDR2 sequence of the VL domain comprises the amino acid sequence DNN, and CDR3 sequence of the VL domain comprises the amino acid sequence GTWDTSLSAEV (SEQ ID NO:50); the CDR1 sequence of the VH domain comprises the amino acid sequence GGTFSSYA (SEQ ID NO: 132), CDR2 sequence of the VH domain comprises the amino acid sequence IIPIFGTA (SEQ ID NO:133), CDR3 sequence of the VH domain comprises the amino acid sequence ASGVVIMPYDAFDI (SEQ ID NO: 134), CDR1 sequence of the VL comprises the amino acid sequence NIGATS (SEQ ID NO: 135), CDR2 sequence of the VL domain comprises the amino acid sequence DYG, and CDR3 sequence of the VL domain comprises the amino acid sequence QAWDIGSDEQM (SEQ ID NO: 136); the CDR1 sequence of the VH domain comprises the amino acid sequence GGASSSNA (SEQ ID NO: 137), CDR2 sequence of the VH domain comprises the amino acid sequence ITPIFDTT (SEQ ID NO: 138), CDR3 sequence of the VH domain comprises the amino acid sequence ARDGRRGLGGFFDS (SEQ ID NO: 139), CDR1 sequence of the VL comprises the amino acid sequence KLGEKY (SEQ ID NO: 140), CDR2 sequence of the VL domain comprises the amino acid sequence QDN, and CDR3 sequence of the VL domain comprises the amino acid sequence QAWDSSTYV (SEQ ID NO: 141); the CDR1 sequence of the VH domain comprises the amino acid sequence GDSVSSNIAS (SEQ ID NO: 142), CDR2 sequence of the VH domain comprises the amino acid sequence TYYRSKWYN (SEQ ID NO: 143), CDR3 sequence of the VH domain comprises the amino acid sequence ARGDGSTFDY (SEQ ID NO: 144), CDR1 sequence of the VL comprises the amino acid sequence SSNIGSNS (SEQ ID NO: 145), CDR2 sequence of the VL domain comprises the amino acid sequence GNN, and CDR3 sequence of the VL domain comprises the amino acid sequence AAWDDSLNGWV (SEQ ID NO: 146); the CDR1 sequence of the VH domain comprises the amino acid sequence GGSISSGGYY (SEQ ID NO: 147), CDR2 sequence of the VH domain comprises the amino acid sequence IYYSGST (SEQ ID NO: 148), CDR3 sequence of the VH domain comprises the amino acid sequence ARMGYGGNFDY (SEQ ID NO: 149), CDR1 sequence of the VL comprises the amino acid 45753670.1 90ATTORNEY DOCKET NO. MOF 24MB020 PCT sequence NSNIGSNS (SEQ ID NO: 150), CDR2 sequence of the VL domain comprises the amino acid sequence DNN, and CDR3 sequence of the VL domain comprises the amino acid sequence GTWDTSLSAEV (SEQ ID NO:151); the CDR1 sequence of the VH domain comprises the amino acid sequence GGTFSSYA (SEQ ID NO: 152), CDR2 sequence of the VH domain comprises the amino acid sequence IIPIFGTA (SEQ ID NO: 153), CDR3 sequence of the VH domain comprises the amino acid sequence ARDKMGFGVRSPYYYGMDV (SEQ ID NO: 154), CDR1 sequence of the VL comprises the amino acid sequence QTVSNY (SEQ ID NO: 155), CDR2 sequence of the VL domain comprises the amino acid sequence AAA, and CDR3 sequence of the VL domain comprises the amino acid sequence QQSYSGPLT (SEQ ID NO: 156); the CDR1 sequence of the VH domain comprises the amino acid sequence GFVFPNYA (SEQ ID NO: 157), CDR2 sequence of the VH domain comprises the amino acid sequence IRGQSYNGTT (SEQ ID NO: 158), CDR3 sequence of the VH domain comprises the amino acid sequence YTRPLTSLQI (SEQ ID NO: 159), CDR1 sequence of the VL comprises the amino acid sequence QSILYSPSNKNY (SEQ ID NO: 160), CDR2 sequence of the VL domain comprises the amino acid sequence WAS, and CDR3 sequence of the VL domain comprises the amino acid sequence QQYYTTYPT (SEQ ID NO: 161); the CDR1 sequence of the VH domain comprises the amino acid sequence GFTFSSYW (SEQ ID NO: 162), CDR2 sequence of the VH domain comprises the amino acid sequence INGDGSQT (SEQ ID NO: 163), CDR3 sequence of the VH domain comprises the amino acid sequence ARMASYDRSGYYGFFQH (SEQ ID NO: 164), CDR1 sequence of the VL comprises the amino acid sequence QYINTY (SEQ ID NO: 165), CDR2 sequence of the VL domain comprises the amino acid sequence GAS, and CDR3 sequence of the VL domain comprises the amino acid sequence QQSFSTPRT (SEQ ID NO: 166); the CDR1 sequence of the VH domain comprises the amino acid sequence GFTFSSYW (SEQ ID NO: 162), CDR2 sequence of the VH domain comprises the amino acid sequence INGDGSQT (SEQ ID NO: 163), CDR3 sequence of the VH domain comprises the amino acid sequence ARMASYDRSGYYGFFQH (SEQ ID NO: 164), CDR1 sequence of the VL comprises the amino acid sequence QYINTY (SEQ ID NO:165), CDR2 sequence of the VL domain comprises the amino acid sequence GAS, and CDR3 sequence of the VL domain comprises the amino acid sequence QQSFSTPRT (SEQ ID NO: 166); the CDR1 sequence of the VH domain comprises the amino acid sequence GYSFSDRY (SEQ ID NO: 167), CDR2 sequence of the VH domain comprises the amino acid sequence IDPEDGET (SEQ ID NO: 168), CDR3 sequence of the VH domain comprises the amino acid sequence GRDIQTYGGSPRNWIDP (SEQ ID NO: 169), CDR1 sequence of 45753670.1 91ATTORNEY DOCKET NO. MOF 24MB020 PCT the VL comprises the amino acid sequence SSNIGSNT (SEQ ID NO: 170), CDR2 sequence of the VL domain comprises the amino acid sequence SNN, and CDR3 sequence of the VL domain comprises the amino acid sequence AAWDDSLNGYV (SEQ ID NO: 171); the CDR1 sequence of the VH domain comprises the amino acid sequence GYTFTSYD (SEQ ID NO: 172), CDR2 sequence of the VH domain comprises the amino acid sequence MNPNSGNT (SEQ ID NO: 173), CDR3 sequence of the VH domain comprises the amino acid sequence ARANGRSLGSGWNSLYYYYYGMDV (SEQ ID NO: 174), CDR1 sequence of the VL comprises the amino acid sequence QTISPY (SEQ ID NO: 175), CDR2 sequence of the VL domain comprises the amino acid sequence SAS, and CDR3 sequence of the VL domain comprises the amino acid sequence QQSSSSWT (SEQ ID NO: 176); or the CDR1 sequence of the VH domain comprises the amino acid sequence GYDFTASS (SEQ ID NO: 177), CDR2 sequence of the VH domain comprises the amino acid sequence IFPDDSDV (SEQ ID NO: 178), CDR3 sequence of the VH domain comprises the amino acid sequence ARLRDYGNGHWYFDL (SEQ ID NO: 179), CDR1 sequence of the VL comprises the amino acid sequence SSDVGGYKY (SEQ ID NO: 180), CDR2 sequence of the VL domain comprises the amino acid sequence EVS, and CDR3 sequence of the VL domain comprises the amino acid sequence SSYTSTTTYI (SEQ ID NO:181).

6. The polypeptide of claim 5, wherein the Vn domain comprises the amino acid sequence SEQ ID NO:51, SEQ ID NO:53, SEQ ID NO:55, SEQ ID NO:57, SEQ ID NO:59, SEQ ID NO:61, SEQ ID NO:63, SEQ ID NO:65, SEQ ID NO:67, SEQ ID NO:69, SEQ ID NO:71, SEQ ID NO:73, SEQ ID NO:75, SEQ ID NO:77, SEQ ID NO:79, SEQ ID NO:81, SEQ ID NO:83, SEQ ID NO:85, SEQ ID NO:87, or SEQ ID NO:89.

7. The polypeptide of claim 5, wherein the VL domain comprises the amino acid sequence SEQ ID NO:52, SEQ ID NO:54, SEQ ID NO:56, SEQ ID NO:58, SEQ ID NO:60, SEQ ID NO:62, SEQ ID NO:64, SEQ ID NO:66, SEQ ID NO:68, SEQ ID NO:70, SEQ ID NO:72, SEQ ID NO:74, SEQ ID NO:76, SEQ ID NO:78, SEQ ID NO:80, SEQ ID NO:82, SEQ ID NO:84, SEQ ID NO:86, SEQ ID NO:88, SEQ ID NO:90.

8. The polypeptide of claim 5, wherein the antibody is a single chain antibody (scFv) comprising the amino acid sequence SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO: 100, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, SEQ ID NO: 104, SEQ ID NO: 105, SEQ ID NO: 106, SEQ ID NO: 107, SEQ ID NO: 108, SEQ ID NO: 109, SEQ ID NO: 1 10, SEQ ID NO: 1 1 1 , SEQ ID NO: 112, SEQ ID NO: 1 13, SEQ ID NO: 1 14, SEQ ID NO:115, SEQ ID NO:116, SEQ ID NO:117, SEQ ID NO:118, SEQ ID NO:119, SEQ ID45753670.1 92ATTORNEY DOCKET NO. MOF 24MB020 PCTNO: 120, SEQ ID NO: 121, SEQ ID NO: 122, SEQ ID NO: 123, SEQ ID NO: 124, SEQ ID NO: 125, SEQ ID NO: 126, SEQ ID NO: 127, SEQ ID NO: 128, SEQ ID NO: 129, SEQ ID NO:130, SEQ ID NO:131.

9. The polypeptide of claim 5, wherein the costimulatory signaling region comprises the cytoplasmic domain of a costimulatory molecule selected from the group consisting of CD27, CD28, 4-1BB, 0X40, CD30, CD40, PD-1, 1C0S, lymphocyte function- associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, a ligand that specifically binds with CD83, and any combination thereof10. The polypeptide of claim 5, wherein the CAR polypeptide is defined by the formula:SP-TRP1-HG-TM-CSR-ISD; orSP- TRP1-HG-TM-ISD-CSR wherein “SP” represents the signal peptide, wherein “TRP1” represents the TRPl-binding region, wherein “HG” represents the optional hinge domain, wherein “TM” represents the transmembrane domain, wherein “CSR” represents the co-stimulatory signaling region, wherein “ISD” represents the intracellular signaling domain, and whereinrepresents the bivalent linker.

11. The polypeptide of claim 5, wherein the intracellular signaling domain comprises a CD3 zeta (CD3Q signaling domain.

12. The polypeptide of claim 5, wherein the intracellular signaling domain comprises an NK cell receptor intracellular domain.

13. The polypeptide of claim 5, wherein the polypeptide contains only an intracellular signaling domain or a co-stimulatory domain, but not both.

14. An isolated nucleic acid sequence encoding the recombinant polypeptide of claim 5.

15. A vector comprising the isolated nucleic acid sequence of claim 13.

16. A cell comprising the vector of claim 14.

17. The cell of claim 15, wherein the cell is selected from the group consisting of an a[lT cell, y5T cell, a Natural Killer (NK) cells, a Natural Killer T (NKT) cell, a B cell, an innate lymphoid cell (ILC), a cytokine induced killer (CIK) cell, a cytotoxic T lymphocyte (CTL), a lymphokine activated killer (LAK) cell, a regulatory T cell, or any combination thereof.

18. A method of providing an anti-cancer immunity in a subject with a melanoma, the method comprising administering to the subject an effective amount of an immune effector45753670.1 93ATTORNEY DOCKET NO. MOF 24MB020 PCT cell genetically modified to express the CAR polypeptide of claim 5, thereby providing an anti-tumor immunity in the mammal.

19. The method of claim 17, wherein the immune effector cell is selected from the group consisting of an aPT cell, y5T cell, a Natural Killer (NK) cells, a Natural Killer T (NKT) cell, a B cell, an innate lymphoid cell (ILC), a cytokine induced killer (CIK) cell, a cytotoxic T lymphocyte (CTL), a lymphokine activated killer (LAK) cell, a regulatory T (Treg) cell, or any combination thereof.

20. The method of claim 17 or 18, further comprising administering to the subject a checkpoint inhibitor.

21. The method of claim 19, wherein the checkpoint inhibitor comprises an anti-PD-1 antibody, anti-PD-Ll antibody, anti-CTLA-4 antibody, or a combination thereof.

22. A chimeric antigen receptor (CAR) polypeptide, comprising an anti-TRPl binding domain, a hinge domain, a transmembrane domain, and an endodomain that comprises an NK cell receptor intracellular domain, or fragment thereof capable of activating the target killing pathway.

23. The polypeptide of claim 22, wherein the NK cell receptor is hNKG2D, hCD16, hNKp30, hNKG2C, h2B4, hDNAM-1, hCD137, hOX-40, hCD27, KIR2DS5, KIR3DS1, or NKp80 / KLRFl.

24. The polypeptide of claim 22, wherein the intracellular domain comprises the amino acid sequence SEQ ID NO:1, SEQ ID NO:4, SEQ ID NO:7, SEQ ID NO:10, SEQ ID NO: 13, SEQ ID NO: 16, SEQ ID NO: 19, SEQ ID NO:22, SEQ ID NO:25, SEQ ID NO:28, SEQ ID NO:31, or SEQ ID NO:34.

25. The polypeptide of claim 22, wherein the transmembrane domain comprises the amino acid sequence SEQ ID NO:2, SEQ ID NO:5, SEQ ID NO:8, SEQ ID NO:11, SEQ ID NO: 14, SEQ ID NO: 17, SEQ ID NO:20, SEQ ID NO:23, SEQ ID NO:26, SEQ ID NO:29, SEQ ID NO:32, or SEQ ID NO:35.

26. The polypeptide of claim 22, wherein the intracellular and transmembrane domain comprise the amino acid sequence SEQ ID NO:3, SEQ ID NO:6, SEQ ID NO:9, SEQ ID NO: 12, SEQ ID NO: 15, SEQ ID NO: 18, SEQ ID NO:21, SEQ ID NO:24, SEQ ID NO:27, SEQ ID NO:30, SEQ ID NO:33, or SEQ ID NO:36.

27. The polypeptide of claim 22, wherein the endodomain does not contain a CD3 zeta (CD3Q signaling domain.45753670.1 94

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