Various antigen binding domains, new platforms, and other improvements for cell therapy

Abstract

The present invention relates to various antigen-binding domains and platforms for constructing conventional and next-generation chimeric antigen receptors for adoptive cell therapies for cancer, infections, allergic, degenerative, and immune disorders. Approaches for the activation and expansion of immune T cells for adoptive cell therapies for cancer, infections, allergic, degenerative, and immune disorders are also provided.

Description

VARIOUS ANTIGEN-BINDING DOMAINS, NEW PLATFORMS AND OTHER IMPROVEMENTS FOR CELL THERAPY CROSS REFERENCE TO RELATED REQUESTS This application claims priority to US Provisional Application No. 62 / 679,741, filed June 1, 2018, the descriptions of which are incorporated herein for all purposes. FIELD OF INVENTION Various antigen binding domains and novel platforms for the construction of conventional and next generation chimeric antigen receptors for adoptive cell therapies for cancer, infections, allergic, degenerative and immune disorders are provided herein. Novel approaches for immune T cell activation and expansion are also provided for adoptive cell therapies for cancer, infections, allergic, degenerative and immune disorders. INCORPORATION BY SEQUENCE LISTING REFERENCE Accompanying this presentation is a Sequence Listing titled Sequence_ST25.txt, created June 1, 2019 and containing 80,373,218 bytes of data, machine-formatted on IBM-PC, MS-Windows operating system. The sequence listing is incorporated herein by reference in its entirety for all purposes. BACKGROUND OF THE INVENTION CARs are synthetic immunoreceptors, which can redirect T cells to selectively kill tumor cells. Unlike the physiological T cell receptor (TCR), which binds to HLA-peptide complexes, CARs bind to molecules that do not require peptide processing or HLA expression to be recognized. Initial first-generation CARs were constructed by fusing an scFv-based antigen-binding domain (single-chain variable fragment) to an inert CD8 transmembrane domain, linked to a / zRZLn / nznz / E receptor chain-derived cytoplasmic signaling domain. / Yi Fc-γ or CD3-z. To overcome the lack of T-cell costimulation, first-generation CARs were further modified to incorporate the cytoplasmic signaling domains of T-cell costimulatory receptors. Despite the success with CAR-T cells, there are several limitations to this approach, including toxicities such as cytokine release syndrome (CRS) and neurotoxicities. The inclusion of the costimulatory domain in the CAR construct results in non-physiological tonic signaling through the receptor, which in turn could contribute to its toxicity and lack of persistence. To overcome some of the design limitations of conventional second-generation CARs, several alternative designs, collectively referred to as next-generation CARs, have been described, including Ab-TCR (WO 2017 / 070608 A1 incorporated herein by reference), TCR or TFP receptor fusion (WO 2016 / 187349 A1 incorporated herein by reference), synthetic immune receptors (SIRs) (see WO 2018 / 102795 A1 , incorporated herein by reference), trifunctional T cell antigen coupler ( Tri-TAC) (see WO 2015 / 117229 A1, incorporated herein by reference). These alternative CAR designs generally lack a costimulatory domain. SUMMARY OF THE INVENTION The following embodiments and aspects thereof are described and illustrated in conjunction with systems, compositions, and methods that are intended to be exemplary and illustrative, without limiting their scope. In certain embodiments, the disclosure provides compositions comprising genetically modified effector cells (such as NK cells and T cells) that include polynucleotides encoding chimeric antigen receptors, synthetic immune receptors (SIRs), and the like that can be used in adoptive cell therapy for the treatment of cancer, infectious, autoimmune and degenerative diseases. In certain embodiments, the disclosure provides a platform of synthetic immune / zRZLn / nznz / B / Yi receptors, referred to as zSIRs, that contain two CD3z chains. Polynucleotide sequences of CD3z chains that can be used in the construction of zSIR are provided, for example, in SEQ ID NO: 67 and 71. The corresponding amino acid sequences are provided in SEQ ID NO: 4066 and 4070, respectively. The disclosure states that the vL fragment of an antibody can bind to one of the two CD3z chains and the vH fragment can bind to the other CD3z chain. When two such chains (for example, vL-CD3z and vH-CD3z) are co-expressed in the same cell, the vL and vH fragments can bind to their cognate antigen and transmit a T-cell signal. T cells expressing such a zSIR when exposed to a cell line expressing the related target antigen can activate NFAT signaling, induce IL2 production, promote T cell proliferation, promote T cell activation, and exert cytotoxicity. The expression and activity of the zSIR can be further increased by incorporating a linker between the vL / vH and CD3z fragments. In particular, antibody-derived IgCL (SEQ ID NO: 28 and 4027) and IgCH (SEQ ID NO: 29 and 4028) domains serve as useful linkers between vL / vH and CD3z fragments. The disclosure further provides several novel antigen-binding domains that can be used in the generation of conventional CARs (eg, second-generation CARs containing the 41BB costimulatory domain) as well as next-generation CARs such as SIR, zSIR, Ab-TCR , Tri-TAC and TFP, for applications in adoptive cell therapy. In some embodiments, these antigen-binding domains are derived from antibodies and target antigens expressed in both hematologic malignancies and solid tumors. The SEQ ID NOs of the vL, vH and scFv fragments of these antigen-binding domains are shown in Table 3. The SEQ ID NOs of the complementary determining regions (CDRs) of the light (vL) and heavy (vH) chains are shown in Table 4. SEQ IDs of exemplary conventional CAR nucleic acids and amino acids (ie, second-generation CARs containing / zRZLn / nznz / B / Yi 41BB costimulatory domains) and next-generation CARs (eg, SIR , zSIR, Ab-TCR, and TFP) based on these antigen-binding domains are provided in Table 6 and 7. CARs containing these antigen-binding domains display various properties in vitro and in vivo, such as binding affinity. to target antigens, cytokine secretion, proliferation, cytotoxicity, depletion, and long-term persistence. As such, CARs containing these target antigens can be used to generate a diverse immune response. The polynucleotide, polypeptides, expression constructs, CAR-expressing recombinant engineered cells comprising the antigen-binding domains of the disclosure, as well as the method of making and using said polypeptides, polynucleotides, and cells are described in Methods Known in the Art. technique and methods described in PCT / US2017 / 024843, WO 2014 / 160030 A2, WO 2016 / 187349 A1, PCT / US2016 / 058305, WO 2015 / 117229 A1 and PCT / US17 / 64379, which are incorporated herein by reference in their entirety . Immune cells expressing CARs, both conventional and next-generation CARs, comprising these antigen-binding domains can be generated and used for adoptive cell therapy of cancer, infectious and immune diseases using methods known in the art and methods described in PCT / US2017 / 024843., WO 2014 / 160030 A2, WO 2016 / 187349 A1, PCT / US2016 / 058305, WO 2015 / 117229 A1 and PCT / US17 / 64379, which are incorporated herein by reference in their entireties. The disclosure also provides a method of enhancing gene transfer using lentiviral vectors by co-expressing the Vif protein and a CAR (eg, a conventional CAR, SIR, Ab-TCR, Tri-TAC or a recombinant TCR and the like) or Vif and any other therapeutic gene (for example, β-globin gene for the treatment of sickle cell anemia). An exemplary lentiviral vector encoding a CAR is provided in SEQ ID NO: 11268 ((pLenti-EF1a-CD8SP-hu-CD19-USC1LH4-vH-Gly-Ser-Ligator-vL-Myc-CD8TM-BBz-2A-Vif ) and coexpects Vif. In some embodiments, the Vif protein is provided in trans by co-expression of Vif in the / zRZLn / nznz / B / Yi packaging cells at the time of lentiviral vector packaging. In such embodiment, the Vif protein it is packaged together with the RNA encoding the lentiviral vector into the viral particles and transferred into the target cells The Vif protein can be expressed in the packaging cells by methods known in the art. In an exemplary embodiment, the Vif protein is expressed in packaging cells by cotransfecting a mammalian expression vector (eg, PCDNA3-Vif; SEQ ID NO: 11269) encoding Vif with the lentiviral transfer vector encoding the gene or genes of interest (for example, pLenti-EF1a-CD8SP-MYC3-WT1Ab13-vL-V5-[hTCRb-KACIAH]-F-P2A-SP-WT1-Ab13-vH-Myc4-[hTCRa-CSDVP]-F-F2APAC -DWPRE; SEQ ID NO: 151) and lentiviral packaging vector(s). Exemplary lentiviral packaging vector includes pMDLg / pRRE (Addgene plasmid 12251), which is a third generation lentiviral packaging plasmid encoding Gag and Pol and also requires pRSV-Rev (Addgene #12253) and the envelope expression plasmid. pMD2.G (Addgene #12259) for efficient packaging. Another lentiviral packaging vector is psPAX2 (Addgene plasmid #12260), which is a second generation lentiviral packaging plasmid and can be used with the envelope expression plasmid pMD2.G (Addgene #12259) to package oesn't lentiviral vectors. 2nd or 3rd generation. In an exemplary embodiment, a plasmid encoding Vif can be cotransfected with plasmids psPAX2 and pMD2.G to package a 2nd or 3rd generation lentiviral vector. In an alternate exemplary embodiment, a plasmid encoding Vif can be cotransfected with plasmids pMDLg / pRRE, pRSV-Rev, and pMD2.G to package a 3rd generation lentiviral vector. Vif can also be co-expressed from the same vector(s) encoding other lentiviral packaging proteins (eg gag, Pol and Rev). In an exemplary embodiment, the psPAX2 packaging plasmid is modified to also co-express Vif by methods known in the art. In an alternate exemplary embodiment, a 3a / zRZLn / nznz / B / Yi generation lentiviral packaging plasmid encoding Gag and Pol is modified to also express Vif by fusing the nucleic acid sequence encoding Vif in frame with the nucleic acid sequence encoding Pol and separated from it by a linker sequence cleaved by P2A. In some embodiment, Vif is expressed in packaging cells in a transient manner while in other embodiments Vif is expressed in packaging cells in a stable manner. In some embodiment, Vif is expressed in the target cells transiently while in other embodiments Vif is expressed in the target cells in a stable manner. In one embodiment, Vif is expressed in target cells (eg, T cells or stem cells) transiently by electroporation of a mammalian expression vector (eg, pCDNA3-Vif; SEQ ID NO: 11269) encoding Vif. or by electroporation of the Vif polypeptide. Target cells (eg, T cells or stem cells) transiently expressing Vif are subsequently infected with a lentiviral vector encoding a CAR or any therapeutic gene of interest (eg, β-globin). The polyclonal nature of the immune response is key to its success in controlling various infections. In contrast, current CAR therapies are generally based on the targeting of a single antigen and / or a single epitope of a single antigen. Loss of target antigen or target epitope is a frequent cause of failure of current CAR therapies. To overcome this limitation, the disclosure provides CAR against multiple antigens and against multiple epitopes of a single antigen. These CARs can be used in suitable combinations to provide a diverse polyclonal adaptive immune response for the prevention or treatment of diseases, such as cancer, infectious diseases, autoimmune diseases, allergic diseases, and degenerative diseases. The disclosure also provides accessory modules that can be expressed in adoptively transferred T cells (eg, CAR-T cells, TCRT and TIL cells) to affect their survival, proliferation, activation, effector functions (eg, cytokine secretion, cytotoxicity, etc.), exhaustion and persistence in vivo. / zRZLn / nznz / B / Yu The disclosure provides at least one recombinant polynucleotide encoding at least one first- or next-generation chimeric antigen receptor (CAR), the at least one recombinant polynucleotide comprising: (a) a first nucleic acid domain encoding a partial transmembrane or complete and / or a cytoplasmic domain and optionally the extracellular domain of an endogenous protein, wherein the endogenous protein is expressed on the surface of lymphocytes and triggers activation and / or proliferation of the lymphocyte; (b) optionally a polynucleotide linker; and (c) a second nucleic acid domain operably linked to the first nucleic acid domain, wherein the second nucleic acid domain encodes one or more unnatural TCR antigen binding domains wherein the binding domain is selected from a binding domain set forth in Table 3; (d) an optional third nucleic acid domain encoding a costimulatory domain; and an optional additional nucleic acid domain encoding an accessory module. In one embodiment, the first nucleic acid partially or fully encodes at least one T cell receptor (TCR) chain as set forth in Table 13. In another or additional embodiment, the first nucleic acid encodes at least one transmembrane domain in Table 13 operably linked to the TCR-like cytoplasmic domain. In another embodiment, the polynucleotide encodes a CAR, wherein the CAR comprises: (i) a partial or full T cell receptor (TCR) constant chain having an amino acid sequence having at least 75% sequence identity to a sequence selected from SEQ ID NO: 4038 to 4063, 12602-12638, and may comprise an optional costimulator module; (ii) an optional linker; and (iii) one or more unnatural TCR antigen binding domains linked to (a) selected from a binding domain set forth in Table 3; (iv) an optional access module; and (v) a dimer of a polypeptide comprising (i)-(iv). In another one or more embodiments, the recombinant polynucleotide comprises a sequence encoding any of the sequences in Table 2. In another one or more embodiments, the accessory module comprises a / zRZLn / nznz / E / Yi amino acid sequence selected from SEQ ID NO : 4103-4117 and 4090-4096. In another or more embodiments, the encoded CAR comprises (1) any of CARs 1-16 from Table 1 and / or (2) a Table 2 backbone; and (3) a binding domain of Table 3. In yet another embodiment, (i) is a CD3z TCR ​​constant chain. In another or additional embodiment, the polynucleotide provides two first generation or next generation chimeric antigen receptors. In another or additional embodiment, the polynucleotide encodes a dimer of CD3z constant strands.

[00698] The disclosure also provides at least one recombinant polynucleotide encoding at least one next-generation chimeric antigen receptor (CAR), the at least one recombinant polynucleotide comprising: (a) a first nucleic acid domain encoding a partial transmembrane or complete and / or cytoplasmic domain and, optionally, the extracellular domain of an endogenous CD3z protein having a sequence selected from the group consisting of SEQ ID NO: 4064-4066, 4070-4072 and 4075-4078, wherein the protein endogenous is expressed on the surface of lymphocytes and triggers lymphocyte activation and / or proliferation; (b) optionally a polynucleotide or a linker; and (c) a second nucleic acid domain operatively linked to the first nucleic acid domain, wherein the second nucleic acid domain encodes one or more non-natural TCR antigen binding domains wherein the binding domain is selected from a binding domain set forth in Table 3; and (d) an optional third nucleic acid domain encoding a costimulatory module; and an optional additional nucleic acid encoding an accessory module. In another or additional embodiment, the nucleic acid sequences encoding the endogenous CD3z protein are selected from the group consisting of SEQ ID NO: 67 and 71. In another or in an additional embodiment, the at least one next generation CAR comprises two CAR, each of which comprises a CD3z strand. In another or a further embodiment, a vL fragment of an antibody is operably linked to one of the two CD3z chains and a vH fragment of the antibody is operably linked to the other CD3z chain. In a further / zRZLn / nznz / B / Yi embodiment, the vL and vH chains are selected from pairs in Table 3 and 4 for a specific target antigen. In another or additional embodiment, a linker is provided between the vL / vH and / or CD3z chains. In another embodiment, an encoded linker is selected from the group consisting of IgCL (SEQ ID NO (DNA): 28 and SEQ ID NO (PRT): 4027) and IgCH domains (SEQ ID NO (DNA): 29 and SEQ ID NO (PRT): 4028). In yet another embodiment, it further comprises the third nucleic acid domain encoding a costimulatory module. In another or additional embodiment, the costimulatory module comprises a 41BB or CD28 protein. In another or more embodiments, the costimulatory module comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 4067 and 4068. In another or more embodiments, the costimulatory module comprises a signaling domain from one or more of CD134 (OX40 ), Dap10, CD27, CD2, CD5, ICAM1, LFA-1, Lck, TNFR-I, TNFR-II, Fas, CD30, CD40 and combinations thereof. In another or more embodiments, it further comprises the accessory module, wherein the accessory module comprises an amino acid sequence selected from SEQ ID NO: 4103-4117 and 4090-4096. The disclosure also provides a recombinant cell expressing a first-generation or next-generation chimeric antigen receptor (CAR) homo or heterodimer, the homo or heterodimer comprising: (a) a first nucleic acid domain encoding a partial transmembrane or the entire and / or cytoplasmic domain and, optionally, the extracellular domain of an endogenous protein, where the endogenous protein is expressed on the surface of lymphocytes and triggers activation and / or proliferation of the lymphocyte; (b) optionally a peptide linker; and (c) a second domain operatively linked to the first domain, wherein the second domain comprises one or more unnatural TCR antigen binding domains wherein the binding domain is selected from a binding domain set forth in Table 3. ; and (d) an optional third domain encoding a costimulatory module, and wherein the cell optionally comprises an accessory module, wherein the / zRZLn / nznz / B / Yi homo or heterodimer associates on the surface of the recombinant cell. . In another or more embodiments, the cell is transformed with at least one recombinant polynucleotide as described herein. In another or more embodiments, the cell is a T lymphocyte (T cell). In another or more embodiments, the cell is a naive T cell, a core memory T cell, an effector memory T cell, Treg, or a combination thereof. In one or more other embodiments, the cell is a natural killer (NK) cell, a hematopoietic stem cell (HSC), an embryonic stem cell, or a pluripotent stem cell. In another or additional embodiment, the accessory module comprises an amino acid sequence selected from SEQ ID NO: 4103-4117 and 4090-4096. In one or more other embodiments, the recombinant cell expresses or is engineered to express HIV1-vif. The disclosure provides a chimeric antigen receptor (CAR) comprising (a) a first domain encoding a partial or complete transmembrane and / or cytoplasmic domain and, optionally, the extracellular domain of an endogenous protein, wherein the endogenous protein is expressed on the surface of lymphocytes and triggers activation and / or proliferation of the lymphocyte; (b) optionally a peptide linker; and (c) a second domain operatively linked to the first domain, wherein the second domain comprises one or more unnatural TCR antigen binding domains wherein the binding domain is selected from a binding domain set forth in Table 3. ; and (d) an optional third domain encoding a costimulatory module. In another or more embodiment, the endogenous protein comprises a sequence selected from the group consisting of SEQ ID NO: 4064-4066, 4070-4072, 4075-4078 and 12637. In another or more embodiment, the first nucleic acid partially or fully encodes at least one T-Cell Receptor (TCR) chain as set forth in Table 13. In yet another embodiment, the first comprises a transmembrane domain in Table 13 operably linked to the cytoplasmic domain of a corresponding TCR type. In another or more embodiments, the CAR comprises: (i) a complete or partial T cell receptor (TCR) constant chain having an amino acid sequence having at least 75% / zRZLn / nznz / B / Yi identity of sequence with a sequence selected from SEQ ID NO: 4038 to 4063, 12602-12638, and which may comprise an optional costimulator module. The disclosure provides a polynucleotide encoding the chimeric antigen receptor as described above and herein. The disclosure also provides a vector comprising the polynucleotides described herein. The disclosure also provides a virus comprising the polynucleotide(s) as described herein. In another or additional embodiment, the virus is a retrovirus, an adenovirus, an adeno-associated virus, a lentivirus, a smallpox virus, or a herpes virus. The disclosure also provides a pharmaceutical composition comprising: any one or more of the inventions described herein and a pharmaceutically acceptable carrier. The disclosure also provides a method of treating cancer comprising: providing the composition, a recombinant cell of the disclosure, and administering a therapeutically effective amount of the composition or cell to the subject to treat cancer. In another or more embodiments, the cancer is blood cancer. In another embodiment, the blood cancer is one or more of acute myeloid leukemia, chronic myeloid leukemia, myelodysplastic syndrome, lymphoma, multiple myeloma, and acute lymphocytic leukemia. In another embodiment, the cancer is a solid tumor. In one embodiment, provided herein is an isolated nucleic acid encoding a SIR (i.e., a next-generation CAR), wherein the antigen-specific domain of the SIR targets CD19 and the SIR optionally expresses a codon-optimized variant. from K13-vFLIP (K13-opt). In exemplary embodiments, the sequences of isolated nucleic acid fragments that target CD19 are set forth in SEQ ID NO: 14056-14059 and 14109-14112. In exemplary embodiments, the isolated polypeptide sequences that target CD19 and optionally co-express K13-vFLIP are / zRZLn / nznz / B / Yi described in SEQ ID NO: 15800-15803 and 15853-15856. In some embodiments, the vL and vH fragments that target CD19 are described in Table 3 and set forth in SEQ ID NOs(DNA): 12662, 12693 and 12656 and 12687 and SEQ ID NOs (PRT): 14406, 14437 and 14400 and 14431. Also provided herein are polypeptides encoded by SIR-encoding nucleic acids and optionally encoding K13-vFLIP, wherein the antigen-specific domain of the SIR targets CD19. In addition, vectors encoding nucleic acids encoding SIR and K13-vFLIP are provided, wherein the Antigen-specific domain of the SIR targets CD19. In exemplary embodiments, a vector encoding a SIR that targets CD19 is provided in SEQ ID NO: 12641. Also provided herein are genetically engineered cells (such as T cells, NT cells) comprising vectors encoding nucleic acids that encode SIR and K13-vFLIP, where the antigen-specific domain of the SIR targets CD19. Also provided are methods for treating and preventing a disease wherein cells causing the disease or cells associated with the disease express CD19. In one embodiment, provided herein is an isolated nucleic acid encoding a SIR, wherein the antigen-specific domain of the SIR targets MPL and the SIR optionally expresses a codon-optimized variant of K13-vFLIP (K13-opt). In exemplary embodiments, the sequences of isolated nucleic acid fragments that target MPL are set forth in SEQ ID NO: 13791-13792 and 13844-13845. In exemplary embodiments, the isolated polypeptide sequences targeting MPL and optionally co-expressing K13-vFLIP are as follows in SEQ ID NOs: 15535-15536 ​​and 15588-15589. In some embodiments, the vL and vH fragments that target MPL are described in Table 3 and set forth in SEQ ID NOs (DNA): 12665, 12696 and 12658 and 12689 and SEQ ID NOs (PRT): 14409, 14440 and 14402 and 14433. Also provided herein are polypeptides encoded by nucleic acids encoding SIRs and optionally encoding K13-vFLIP, wherein the antigen-specific domain of the SIR targets / zRZLn / nznz / B / Yu mpl. Also provided herein are vectors encoding SIR and K13-vFLIP-encoding nucleic acids, in which the antigen-specific domain of the SIR targets MPL. In exemplary embodiments, a vector encoding a SIR that targets MPL is provided in SEQ ID NO: 14384. Also provided herein are genetically engineered cells (such as T cells, NKT cells) comprising vectors encoding nucleic acids encoding SIR and optionally encoding K13-vFLIP, wherein the antigen-specific domain of the SIR targets MPL. Also provided are methods for treating and preventing a disease in which cells causing the disease or cells associated with the disease express MPL. In one embodiment, provided herein is an isolated nucleic acid encoding a SIR, wherein the antigen-specific domain of the SIR targets BCMA and the SIR optionally expresses a codon-optimized variant of K13-vFLIP (K13-opt). In exemplary embodiments, the sequences of isolated nucleic acid fragments that target BCMA are set forth in SEQ ID NOs: 12890-12893, 12943-12946, 1299612999, 13049-13052, and 12837-12840. In exemplary embodiments, the isolated polypeptide sequences that target BCMA and optionally coexpress K13-vFLIP are as follows in SEQ ID NOs: 14634-14637, 14687-14690, 14740-14743, 14793-14796, and 14581-14584. In some embodiments, the vL and vH fragments that target BCMA are described in Table 3 and set forth in SEQ ID NOs (DNA): 12670 and 12701, 12669 and 12700, 12671-12702, 12657 and 12688, 12654 and 12685 and SEQ ID NOs. (PRT): 14414 and 14445, 14413 and 14444, 14415 and 14446, 14398 and 14429, and 14401 and 14432. Also provided herein are polypeptides encoded by SIR-encoding nucleic acids and optionally encoding K13-vFLIP, wherein the antigen-specific domain of the SIR targets BCMA. Also provided herein are vectors encoding SIR-encoding nucleic acids and K13-vFLIP, in which the antigen-specific domain of the SIR targets BCMA. In exemplary embodiments, / zRZLn / nznz / B / Yi is provided for a vector encoding a SIR that targets BCMA in SEQ ID NO: 14378 and 14385. Also provided herein are genetically modified cells (such as T cells, NKT cells ) comprising vectors encoding SIR-encoding nucleic acids and optionally encoding K13-vFLIP, wherein the antigen-specific domain of the SIR targets BCMA. Also provided are methods for treating and preventing a disease in which cells causing the disease or cells associated with the disease express BCMA. In one embodiment, provided herein is an isolated nucleic acid encoding a SIR, wherein the antigen-specific domain of the SIR targets MSLN and the SIR optionally expresses a codon-optimized variant of K13-vFLIP (K13-opt). In exemplary embodiments, the sequences of isolated nucleic acid fragments that target MSLN are set forth in SEQ ID NO: 14268-14269, 14321-14322, and 14374-14375. In exemplary embodiments, the isolated polypeptide sequences that target MSLN and optionally co-express K13-vFLIP are as follows in SEQ ID NOs: 1601216013, 16065-16066, and 16118-16119. In some embodiments, the vL and vH fragments targeting MSLN are described in Table 3 and set forth in SEQ ID NOs (DNA): 12668 and 12699, 12667 and 12698, and 12666-12697 and SEQ ID NOs (PRT): 14412 and 14443, 14411 and 14442, and 14410 and 14441. Also provided herein are polypeptides encoded by SIR-encoding nucleic acids and optionally encoding K13vFLIP, wherein the antigen-specific domain of the SIR targets MSLN. Also provided herein are vectors encoding SIR-encoding nucleic acids and K13-vFLIP, in which the antigen-specific domain of the SIR targets MSLN. In exemplary embodiments, a vector encoding a SIR that targets MSLN is provided in SEQ ID NO: 14381 and 14383. Genetically modified cells (such as T cells, NKT cells) comprising vectors encoding nucleic acids are also provided herein. encoding SIR and optionally encoding K13-vFLIP, wherein the antigen-specific domain of the SIR targets MSLN. Also provided are / zRZLn / nznz / B / Yi methods for the treatment and prevention of a disease in which cells causing the disease or associated with the disease express MSLN. In one embodiment, provided herein is an isolated nucleic acid encoding a SIR, wherein the antigen-specific domain of the SIR targets CD22 and the SIR optionally expresses a codon-optimized vanant of K13-VFLIP (K13-opt). In exemplary embodiments, the sequences of isolated nucleic acid fragments that target CD22 are set forth in SEQ ID NOs: 13314-13317, 13420-13423, 13473-13476, and 14215-14218. In exemplary embodiments, the isolated polypeptide sequences that target CD22 and optionally co-express K13-vFLIP are as follows in SEQ ID NO: 15058-15061, 15164-15167, 15217-15220, and 15959-15962. In some embodiments, the vL and vH fragments that target CD22 are described in Table 3 and set forth in SEQ ID NOs (DNA): 12663 and 12694, 12655 and 12686, 12643 and 12674, 12652 and 12683 and SEQ ID NOs (PRT): 14407 and 14438, 14399 and 14430, 14387 and 14418, 14396 and 14427. Also provided herein are polypeptides encoded by SIR-encoding nucleic acids and optionally encoding K13-vFLIP, wherein the antigen-specific domain of the SIR targets CD22. Also provided herein are vectors encoding SIR and K13-vFLIP-encoding nucleic acids, in which the antigen-specific domain of SIR targets CD22. In exemplary embodiments, a vector encoding a SIR that targets CD22 is provided in SEQ ID NO: 12640. Also provided herein are genetically modified cells (such as T cells, NK cells) comprising vectors encoding nucleic acids that encode SIR and optionally encode K13-vFLIP, wherein the antigen-specific domain of the SIR targets CD22. Also provided are methods for treating and preventing a disease in which cells causing the disease or cells associated with the disease express CD22. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows a schematic representation of different zSIRs. CD3z / zAZLn / nznz / B / Yi ECD, CD3z-TM, CD3z-CP refers to the extracellular, transmembrane, and cytoplasmic domains of CD3z. 4-1 BB and CD28 refer to the cytoplasmic costimulatory domains of 4-1 BB and CD28. Figure 2A-B depicts the induction of IFNγ following cocultivation of CAR-T cells of the disclosure with RAJI cells (Figure 2A) and Nalm6 cells (Figure 2B). Figure 3 depicts the in vivo efficacy of CAR-T cells of the disclosure in a RAJI cell xenograft model as measured using bioluminescence imaging. Figure 4 depicts the in vivo efficacy of CAR-T cells of the disclosure in a Nalm6 cell xenograft model as measured using bioluminescence imaging. DETAILED DESCRIPTION OF THE INVENTION As used herein and in the appended claims, the singular forms a / an and the / the include plural referents unless the context clearly indicates otherwise. Thus, for example, reference to a cell includes a plurality of such cells and reference to polynucleotide includes reference to one or more polynucleotides, and so on. Also, the use of or means and / or unless otherwise indicated. Similarly, comprises, comprises, includes, and includes are used interchangeably and are not intended to be limiting. It is further to be understood that when descriptions of various embodiments use the term comprising, those in the mid-level trade will understand that, in some specific cases, an embodiment may alternatively be described by use of expressions consisting essentially of or consisting of Unless otherwise defined, all technical and scientific terms used herein have the same meaning as is commonly understood by a / zRZLn / nznz / B / Yi person in the mid-level trade to which this invention pertains. The term around when referring to a value when referring to an average value such as an amount, a duration of time, and the like, is intended to encompass variations of ±20%, or in some cases ±10%, or in some cases ± 5%, or in some cases ±1%, or in some cases ±0.1% of the specified value, as such variations are appropriate for carrying out the methods described or describing the compositions herein. The term Ab-TCR or AbTCR refers to a next generation CAR platform as described in WO 2017 / 070608 A1 which is incorporated herein by reference. In one embodiment, a TCR-Ab comprises an antibody portion that specifically binds to a target antigen fused to a TCR module capable of recruiting at least one TCR signaling module. Example TCR modules that can be used in the construction of Ab-TCR are provided in SEQ ID NO: 959-964 (Table 6D) and in WO 2017 / 070608 A1 which is incorporated herein by reference. Exemplary BCMA-targeting Ab-TCRs that co-express an accessory module encoding NEMO-K277A are provided in SEQ ID NO: 4382-4383 (Table 6). However, the accessory module that encodes NEMO-K277A is optional. Ab-TCRs with the antigen-binding domains (ie, vL and vH fragments, ligands and receptors, etc.) described in the present disclosure can be constructed without NEMO-K277A. As such, this accessory module together with the upstream Furin-SGSG-F2A sequence can be removed from the Ab-TCR. Alternatively, the accessory module encoding NEMOK277A can be replaced by accessory modules encoding other proteins, such as hNEMO-K277A-deltaV249-K555, mNEMQ-K270A, K13-opt, IKK2-S177E-S181E, or IKK1-S176E- S180E, and MyD88-L265P, FKBPx2-NEMO, NEMQ-L600-FKBPx2, etc. Furthermore, the TCR modules present in the Ab-TCR can be replaced by other TCR modules described in WO 2017 / 070608 A1. The term accessory module refers to an element that is co-expressed with / zRZLn / nznz / B / Yi a CAR (including next generation CAR such as SIR, zSIR, Ab-TCR, Tri-TAC, TFP, etc.) and / or rTCR to increase, decrease, regulate, or modify the expression or activity of cells expressing CAR / rTCR or CAR / rTCR. Exemplary accessory modules include one or more of 41BBL, CD40L, HIV1-Vif, vFLIP K13, MC159, cFLIP-L / MRITa, cFLIP-p22, HTLV1 Tax, HTLV2 Tax, HTLV2 Tax-RS mutant, FKBPx2-K13, FKBPx2HTLV2- ltax, FKBPx2-HTLV2-ltax-RS, IL6R-304-vHH-Alb8-vHH, IL12f, PD1-4H1 scFV, PD1-5C4 scFV, PD1-4H1-Alb8-vHH, PD1-5C4-Alb8-vHH, CTLA4- lpilimumab-scFv, CTLA4-lpilimumab-Alb8-vHH, IL6-19A-scFV, IL6-19A-scFV-Alb8-vHH, sHVEM, sHVEMAlb8-vHH, hTERT, Fx06, hNEMO-K277A targeting Brd4 and shRNA combination thereof . The accessory module can be coexpressed with the CAR / rTCR and the like using a single vector or using two or more different vectors. In some embodiments, accessory modules reduce or prevent toxicity associated with CARs and / or TCRs and the like. In some embodiments, the accessory module enhances the efficiency of lentiviral-mediated gene transfer. The term "antibody" as used herein refers to a protein or polypeptide sequence derived from an immunoglobulin molecule that specifically binds to an antigen. Antibodies can be monoclonal or polyclonal immunoglobulins, single or multiple chain or intact, and can be derived from natural sources or from recombinant sources. Antibodies can be tetramers of immunoglobulin molecules. The antibody can be humanized, chimeric, or non-human. The term "antibody fragment" refers to at least a portion of an antibody that retains the ability to specifically interact (eg, by binding, spherical hindrance, stabilization / destabilization, spatial distribution) with an epitope of an antigen. Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab'h, Fv fragments, scFv, disulfide-linked Fv (sdFv) antibody fragments, an Fd fragment consisting of the VH and CH1 domains, / zRZLn / nznz / B / Yi linear antibodies, single domain antibodies (sdAb) such as vL or vH, camelid vHH domains, multispecific antibodies formed from antibody fragments, such as a bivalent fragment comprising two ligated Fab fragments via a disulfide bridge at the hinge region, and an isolated CDR or other epitope-binding fragment of an antibody.An antigen-binding fragment can also be incorporated into single domain, maxibody, minibody, nanobody, intrabody, diabody, triabodies, tetrabodies, v-NAR and bis-scFv (see, for example, Hollinger and Hudson, Nature Biotechnology 23:1126-1136, 2005).Antigen-binding fragments can also be grafted onto scaffolds based on polypeptides such as a fibronectin type III (Fn3) (see US Patent No. 6,703,199, which describes fibronectin polypeptide minibodies). The term antibody heavy chain refers to the larger of the two types of polypeptide chains present in antibody molecules in their natural conformations, and which normally determine the class to which the antibody belongs. The term antibody light chain refers to the smaller of the two types of polypeptide chains present in antibody molecules in their natural conformations. Kappa (κ) and lambda (Λ) light chains refer to the two main light chain isotypes of antibodies. The term anticancer effect refers to a biological effect that can be manifested by various means, including, but not limited to, a decrease in tumor volume, a decrease in the number of cancer cells, a decrease in the number of metastases, an increase in in life expectancy, decreased cancer cell proliferation, decreased cancer cell survival, or amelioration of various physiological symptoms associated with the cancerous condition. An anti-cancer effect can also be manifested by the ability of a CAR, SIR, TFP, Ab-TCR, Tri-Tac, zSIR and the like in preventing the occurrence of cancer in the first place. / zRZLn / nznz / B / Yi "Anti-cancer agent" refers to agents that inhibit abnormal cell growth and division, inhibit neoplastic cell migration, inhibit invasiveness, or prevent cancer growth and metastasis. The term antigen or Ag refers to a molecule that elicits an immune response. The term "antigen-presenting cell" or "APC" refers to any cell that expresses on its surface an antigen that can be recognized by an immune cell or an antibody that binds to an immune cell. For example, a B cell expressing CD19 can serve as an antigen presenting cell for a T cell expressing a CAR directed against CD19. An APC can present an antigen independent of an MHC molecule or in the context of an MHC molecule. The APC can present the antigen in a complex with major histocompatibility complexes (MHC). T cells can recognize these MHC-antigen complexes using their T cell receptors (TCRs). In an alternative embodiment, an APC may present an antigen on its surface that is recognized by a natural (eg, CD28 or 41BB) or synthetic (eg, CAR, SIR, zSIR, Ab-TCR, Tri-Tac, or TFP, etc.) receptor expressed on MHC independent T cells. The term antigen presenting substrate or APS refers to any substrate such as a bead, microbead, plate, or any matrix that presents a foreign antigen on its surface. In one embodiment, an APS may present an antigen on its surface that is recognized by a natural receptor (eg, CD28 or 41BB) or synthetic receptor (eg, a conventional CAR, a SIR, a zSIR, an Ab-TCR, etc.). a TFP) expressed on T cells. In an exemplary embodiment, beads coated with the extracellular domain of CD19 on their surface can serve as APS for T cells expressing a CAR, SIR, zSIR, Ab-TCR, or conventional TFP directed at CD19. The term anti-infective effect refers to a biological effect that can be manifested by various means, including, but not limited to, for example, a decrease in / zRZLn / nznz / B / Yi titer of the infectious agent, a decrease in counts of colonies of the infectious agent, amelioration of various physiological symptoms associated with the infectious condition. An anti-infective effect can also be manifested by the ability of the peptides, polynucleotides, cells, and antibodies to prevent infection from occurring in the first place. As used herein, affinity is used to describe a measure of binding strength. Affinity, in some cases, depends on the closeness of the stereochemical match between a binding agent and its target (for example, between an antibody and an antigen that includes epitopes specific to the binding domain), the size of the contact area between them, and the distribution of charged and hydrophobic groups. Affinity generally refers to the ability of the binding agent to bind to its target. There are numerous ways used in the art to measure affinity. For example, methods for calculating the affinity of an antibody for an antigen are known in the art, and include the use of binding experiments to calculate affinity. Binding affinity can be determined by various techniques known in the art, for example, surface plasmon resonance, biolayer interferometry, dual polarization interferometry, static light scattering, dynamic light scattering, isothermal titration calorimetry, ELISA, analytical ultracentrifugation. and flow cytometry. An exemplary method for determining binding affinity employs surface plasmon resonance. Surface plasmon resonance is an optical phenomenon that allows the analysis of biospecific interactions in real time by detecting alterations in protein concentrations within a biosensor array, for example, using the BIAcore system (Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, NJ). An antigen-binding domain or antigen-binding module or antigen-binding segment or antigen-specific domain (ASD) refers to a polypeptide or peptide that, due to its primary, secondary, or tertiary sequence, / zRZLn / nznz / B / Yi post-translational modifications and / or charge binds to antigen with a high degree of specificity. The antigen binding domain can be derived from different sources, for example, an antibody, a non-immunoglobulin binding protein, a ligand or a receptor. "Avidity" refers to the strength of the interaction between a binding agent and its target (eg, the strength of the interaction between an antibody and its antigenic target, a receptor and its cognate, and the like). Antibodies and affinities can be characterized phenotypically and compared by functional assays (eg, flow cytometric assay and Topanga assay). The association constant term (Ka) is defined as the equilibrium constant for the association of a receptor and ligand or antibody and antigen. The term "autoantigen" refers to an endogenous antigen that stimulates the production of an autoimmune response, such as the production of autoantibodies. Examples of autoantigens include, but are not limited to, desmoglein 1, desmoglein 3, and fragments thereof. As used herein, the term backbone refers to the specific combination of CARs (Table 1) and accessory modules as described in Table 2. In example embodiments, specific combinations of CARs (Table 1) are described in Table 2. CAR and accessory modules comprising several main strings. In one embodiment, the CAR and the accessory module are encoded by a single nucleic acid molecule. In another embodiment, the CAR is encoded by the first nucleic acid molecule and the accessory module is encoded by a second nucleic acid molecule. In some embodiments, the accessory module is encoded by more than one nucleic acid molecule, depending on the number of components in the accessory modules. As used herein, beneficial results may include, but are not limited to, lessening or alleviating the severity of the disease, preventing the disease from worsening, / zRZLn / nznz / B / Yi curing the disease, preventing the development of the disease, decrease the chances that a patient will develop the disease, and prolong the life or life expectancy of a patient. As used herein, the term "binding domain" or "antibody molecule" refers to a protein, eg, immunoglobulin chain or fragment thereof, comprising at least one domain, eg, immunoglobulin variable domain sequence. , which can bind to a target with a higher affinity than a non-specific domain. The term encompasses antibodies and antibody fragments. Binds to the same epitope meaning the ability of an antibody, scFv or other antigen-binding domain to bind to a target antigen and having the same epitope as an exemplified antibody, scFv or other antigen-binding domain. As an example, the epitopes of the exemplified antibody, scFv or other binding agent and other antibodies can be determined by standard epitope mapping techniques. The epitope bound by the antigen-binding domain of a conventional CAR or a next-generation CAR (eg, SIR, zSIR, TFP, Tri-Tac, or Ab-TCR) can also be determined by the Epitope Binning assay. Epitope presorting is a competitive immunoassay used to characterize and then screen a library of monoclonal antibodies against a target protein. Antibodies against a similar target are tested against all other antibodies in the library in pairs to see if the antibodies block the binding of the other antibodies to the epitope of an antigen. After each antibody is profiled against all other antibodies in the library, a competitive blocking profile is created for each antibody against the others in the library. Closely related presort profiles indicate that the antibodies have the same epitope or a closely related epitope and are clustered together. Similarly, conformational epitopes are readily identified by determination of the spatial conformation of amino acids, eg, by hydrogen / deuterium exchange, / zRZLn / nznz / B / Yu X-ray crystallography, and three-dimensional nuclear magnetic resonance. See, eg, Epitope Mapping Protocols, supra. Antigenic regions of proteins can also be identified by standard antigenicity and hydropathy plots, such as those calculated with, for example, the Omiga version 1.0 software program available from the Oxford Molecular Group. This computer program employs the Hopp / Woods method, Hopp et al, (1981) Proc. nati. Acad. Sci USA 78:3824-3828; to determine antigenicity profiles, and the Kyte-Doolittle technique, Kyte et al, (1982) J.Mol. Bioi. 157: 105-132; for hydropathy plots. To determine whether selected monoclonal antibodies against a target (eg, CD19) bind to unique epitopes, each antibody can be biostained with commercially available reagents (Pierce, Rockford, III.). Competition studies using unlabeled monoclonal antibodies and biotinylated monoclonal antibodies can be performed with CD19 extracellular domain-coated ELISA plates. Biotinylated mAb binding can be detected with a strep-avidin-alkaline phosphatase probe. As used herein, the term "CDR" or "complementarity determining region" means the non-contiguous antigen combining sites that lie within the variable region of heavy and light chain polypeptides. These particular regions were described by Kabat et al., J. Bioi. chern. 252:6609-6616 (1977); Kabat et al., U.S. Dept. of Health and Human Services, Sequences of proteins of immunological interest (1991); Chothia et al., J. Mol. Bioi. 196:901-917 (1987); and MacCallum et al., J. Mol. Bioi. 25 262:732-745 (1996), where the definitions include overlapping or subsets of amino acid residues when compared to one another. However, the application of any of the definitions to refer to a CDR of a grafted antibody or antibodies or variants thereof is intended to be within the scope of the term as defined and used herein. As used herein, the different CDRs of an antibody could also be defined by a combination of the different definitions. For example, vHCDRI could be defined based on Kabat and / zRZLn / nznz / B / Yi VHCDR2 could be defined based on Chothia. The amino acid residues encompassed by the CDRs defined by each of the references cited above are as follows: CDR DEFINITIONS / zRZLn / nznz / B / Yi Kabat Chothia MacCallum VHCDR1 31-35 26-32 30-35 VHCDR2 50-65 53-55 47-58 VHCDR3 95-102 96-10 193-101 VLCDR1 24-34 26-32 30-36 VLCDR2 50-56 50-52 46-55 VLCDR3 89-97 91-96 89-96 (The residue numbers correspond to the identified reference). The term framework region refers to the parts recognized in the art of an antibody variable region that exists between the most divergent (ie, hypervariable) CDRs. Modifications in the amino acid sequence of the binding molecules described herein are contemplated. For example, it may be desirable to improve the binding affinity and / or other biological properties of vL and / or vH fragments of a conventional CAR or a next-generation CAR (eg, SIR, zSIR, and the like). Such modifications include, for example, deletions and / or insertions and / or substitutions of residues within the amino acid sequences of the binding molecules. Any combination of deletion, insertion, and substitution can be performed to arrive at the final construct, as long as the final construct possesses the desired characteristics. Amino acid changes can also alter post-translational processes of binding molecules, such as changing the number or position of glycosylation sites. Preferably, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids may be substituted in a CDR, while 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 , 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 25 amino acids may be substituted in the framework regions (FR). The substitutions are preferably conservative substitutions as described herein. Additionally, or alternatively, 1, 2, 3, 4, 5 or 6 amino acids can be inserted or deleted in each of the CDRs (of course, depending on their length), while 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 25 amino acids can be inserted or deleted in each of the FRs. Preferably, amino acid sequence insertions include amino- and / or carboxyl-terminal fusions ranging in length from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 residues to polypeptides containing one hundred or more. residues, as well as intrasequence insertions of single or multiple amino acid residues. A variant insertion of the binding molecule includes fusing the N- or C-terminus of the antibody with an enzyme or a fusion with a polypeptide that increases the serum half-life of the antibody. Another type of variant is an amino acid substitution variant. These variants preferably have at least 1,2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid residues in the linker replaced by a different residue. Sites of greatest interest for substitution mutagenesis include the heavy and / or light chain CDRs, particularly the hypervariable regions, but heavy and / or light chain FR alterations are also contemplated. For example, if a CDR sequence comprises 6 amino acids, one, two, or three of these amino acids are expected to be substituted. Similarly, if a CDR sequence comprises 15 amino acids, one, two, three, four, five, or six of these amino acids are expected to be substituted. Generally, if the amino acids are substituted in one or more or all of the CDRs of the heavy and / or light chain, it is preferred that the substituted sequence then obtained is at least 60%, more preferably 65%, even more preferably 70%, particularly preferably 75%, more particularly preferably 80% identical to / zRZLn / nznz / B / Yi the original CDR sequence. This means that it depends on the length of the CDR to what extent it is identical to the substituted sequence. For example, a CDR that is 5 amino acids long is preferably 80% identical to its substituted sequence in order to have at least one amino acid substituted. Consequently, the CDRs of the binding molecule can have different degrees of identity with their substituted sequences, for example, CDRL1 can have 80%, whereas CDRL3 can have 90%.

[00699] Preferred substitutions (or replacements) are conservative substitutions. However, any substitution (including non-conservative substitution or one or more of the exemplary substitutions listed below) is envisioned as long as the binding molecule retains its ability to bind to the target antigen and / or its CDRs have an identity with the sequence then substituted (at least 60%, greater than 65%, greater than 70%, typically greater than 75%, or greater than 80% identical to the original CDR sequence). Non-conservative substitutions will involve exchanging a member of one for another class. Any cysteine ​​residues that are not involved in maintaining the proper conformation of the binding molecule can be substituted, generally with serine, to improve the oxidative stability of the molecule and prevent aberrant crosslinking. Conversely, cysteine ​​bonds can be added to the antibody to improve its stability (particularly when the antibody is an antibody fragment, such as an Fv fragment). The SEQ IDs of the CDRs of the exemplary vL and vH segments that can be used to constitute the antigen-binding domains of a CAR (eg, a second generation CAR, a SIR, a zSIR, an Ab-TCR, Tri - Tac or a TFP) of the disclosure directed to different antigens are provided in Table 4. In some embodiments, reference to an antigen-binding module (such as a Fab or Fv-type antigen-binding module) that specifically binds to a target antigen means that the antigen-binding module binds / zRZLn / nznz / E / Yi to the target antigen with (a) an affinity that is at least about 10 (for example, about 10, 20, 30, 40, 50, 75, 100, 200, 300, 400, 500, 750 , 1000 or more) times its binding affinity for other molecules; or (b) a Kd of not more than about 1 / 10 (for example, 1 / 10, 1 / 20, 1 / 30, 1 / 40, 1 / 50, 1175, 1 / 100,1 / 200, 1 / 300, 1 / 400, 1 / 500, 1 / 750, 1 / 1000 or less) times its Kd to bind to other molecules. Binding affinity can be determined by methods known in the art, such as ELISA, fluorescence activated cell sorting (FACS) analysis, or radioimmunoprecipitation assay (RIA). Kd can be determined by methods known in the art, such as the surface plasmon resonance (SPR) assay with, for example, Biacore instruments, or the kinetic exclusion assay (KinExA) with, for example, Sapidyne instruments. Cancer and cancerous refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. Examples of cancer include, but are not limited to, B-cell lymphomas (Hodgkin's lymphomas and / or non-Hodgkin's lymphomas), testicular cancer, lung cancer, and leukemia. Other cancers and cell proliterative disorders will be readily recognized in the art. The terms tumor and cancer are used interchangeably herein, eg, both terms encompass solid and liquid tumors, eg, diffuse or circulating tumors. As used herein, the term "cancer" or "tumor" includes premalignant as well as malignant cancers and tumors. Chemotherapeutic agents are compounds known to be useful in cancer chemotherapy. "Chimeric antigen receptors" (CARs) are artificial T cell receptors contemplated for use as a therapy for cancer, using a technique called adoptive cell transfer. CARs are specifically constructed to stimulate T cell activation and proliferation in response to a specific antigen to which the CAR binds. Generally, a CAR refers to a set of / zRZLn / nznz / B / Yi polypeptides, typically two in the simplest embodiments, which when expressed in an immune effector cell, provides the cell with specificity for a target cell, typically a cancer cell, and with intracellular signal generation. In some embodiments, a CAR comprises at least an extracellular antigen-binding domain, a transmembrane domain, and a cytoplasmic signaling domain (also referred to herein as an intracellular signaling domain) comprising a functional signaling domain derived from a stimulatory molecule and / or costimulatory molecule. In one aspect, the cytoplasmic signaling domain further comprises one or more functional signaling domains derived from at least one costimulatory molecule as defined below. In one embodiment, the costimulatory molecule is selected from the costimulatory molecules described herein, for example, 4-1BB (ie, CD137), CD27, and / or CD28. In one embodiment, the CAR comprises an optional leader sequence at the amino (N-ter) terminus of the CAR fusion protein. In one embodiment, the CAR further comprises a leader sequence at the N-terminus of the extracellular antigen-binding domain, wherein the leader sequence is optionally excised from the antigen-binding domain (eg, a scFv) during cellular processing. and the localization of CAR to the cell membrane. Typically, CAR-T cells are used, which refers to T cells that have been engineered to contain a chimeric antigen receptor. Therefore, T cells carrying such CARs are generally referred to as CAR-T cells. A second-generation CAR that targets CD19 and comprises a CD8 signal peptide, a CD19-AM1 scFv-based antigen-binding domain, a CD8 transmembrane and hinge domain, a 4-1BB costimulatory domain, and a CD3z stimulatory domain is represented by SEQ ID NO: 799. A CAR in which the 4-1 BB costimulatory domain is replaced by a different costimulatory domain (eg, CD28 or CD27) is also called a conventional CAR. To overcome the limitation of conventional CARs, several alternative designs or next generation CARs have been described, / zRZLn / nznz / B / Yi including TCR or TFP receptor fusion proteins (WO 2016 / 187349 A1), antibodies TCR or AbTCR (PCT / US2016 / 058305). Tri-TAC (WO 2015 / 117229 A1) and synthetic immune receptors or SIRs (US 62 / 429,597 and PCT / US17 / 64379). As used herein, the term CAR or CAR also encompasses newer approaches (ie, TFP, AbTCR, Tri-Tac, SIR and zSIR, etc.) for conferring antigen specificity to cells. The present disclosure provides several new antigen-binding domains that can be used for CAR generation. Although not explicitly described, it is envisioned that these antigen-binding domains (eg, scFv, vL, vH or vHH, etc.) can be used to generate conventional first- and second-generation CARs, as well as newer approaches ( ie, TFP, AbTCR, Tri-Tac, SIR and zSIR, etc.) to confer antigen specificity to cells. Therefore, the vL and vH fragments of a given antigen-binding domain can be used to generate a double-stranded SIR, a double-stranded Ab-TCR or a double-stranded zSIR when these fragments are fused to the two constant strands. (eg, TCRa / b or TCRg / d) comprising a SIR, Ab-TCR, or zSIR. The vL and vH fragment of the same antigen-binding domain can be joined by a flexible linker to generate an scFv which in turn can be used to generate a conventional first- or second-generation CAR, a TFP, or a Tri-TAC using methods known in art. Codon optimization or species codon bias control refers to the preferred codon usage of a particular host cell. As used herein, co-express refers to the expression of two or more genes. Genes can be nucleic acids encoding, for example, a single protein or a chimeric protein as a single polypeptide chain. For example, the zSIR described herein can be encoded by a single polynucleotide chain and synthesized as a single polypeptide chain, which is subsequently cleaved into different polypeptides, each representing a different functional unit. In some embodiments, where the zSIR consists of two or more / zRZLn / nznz / B / Yu functional polypeptide units, the different functional units are co-expressed using one or more polynucleotide chains. In another embodiment, the different polynucleotide strands are linked by nucleic acid sequences encoding cleavage linkers (eg, T2A, F2A, P2A, E2A, etc.). In another embodiment, a Ser-Gly-Ser-Gly (SGSG) motif (SEQ ID NO: 86-87 and 4085-86) is also added upstream of the cleavable linker sequences to improve cleavage efficiency. A potential drawback of cleaved linkers is the possibility that the small 2A tag remaining at the end of the N-terminal protein may affect the function of the protein or contribute to the antigenicity of the proteins. To overcome this, in some embodiments, a furin cleavage site (RAKR) (SEQ ID NO: 88-90 and 40874089) is added upstream of the SGSG motifs to facilitate cleavage of residual 2A peptide after translation. Polynucleotides encoding the different units of a zSIR can be linked by IRES (internal ryosomal entry site) sequences. Alternatively, the different functional units of a zSIR are encoded by two different polynucleotides that are not linked by a linker but are encoded by, for example, two different vectors. Nucleic acid sequences of cleavable linkers are provided in SEQ ID NO: 80 to SEQ ID NO: 85. It will be recognized that proteins may have identity or homology to one another and retain similar or identical functions. For example, the disclosure includes CD3z strands that have 85%, 90%, 95%, 97%, 98%, 98.5%, 99%, or 99.9% identity to any of the sequences described herein while retaining oiological activity. The term costimulatory molecule or costimulatory receptor refers to a cognate binding partner on a T cell that specifically binds with a costimulatory ligand, thereby to measure a T cell costimulatory response, such as, but not limited to, proliferation. Costimulatory molecules include, but are not limited to, an MHC class I molecule, BTLA, and a Toll receptor ligand, as well as OX40, Dap10, CD27, CD28, / zRZLn / nznz / B / Yi CD2, CD5, CD8, ICAM-1, LFA-1 (CD11a / CD18), ICOS (CD278), Lck, TNFR-I, TNFR-II, Fas, CD30, CD40 and 4-1BB (CD137). Other examples of such costimulatory molecules include CD8, ICAM-1, GITR, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD160, CD19, CD4, CD8alpha, CD8beta, IL2R beta, IL2R gamma , IL7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CDIId, ITGAE, CD103, ITGAL, CDIIa, LFA-1, ITGAM, CDIIb, ITGAX, CDIIc, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, NKG2D, NKG2C, TNFR2, TRANCE / RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRT AM, Ly9 (CD229) , CD160 (BY55), PSGL1, CDIOO (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, ​​LAT, GADS , SLP-76, PAG / Cbp, CD19a, and a ligand that specifically binds to CD83. A costimulatory intracellular signaling domain may be the intracellular portion of a costimulatory molecule. A costimulatory molecule can be represented by the following families of proteins: TNF receptor proteins, immunoglobulin-like proteins, cytokine receptors, integrins, signaling lymphocyte activation molecules (SLAM proteins), and activating NK cell receptors. Examples of such molecules include CD27, CD28, 4-1BB (CD137), 0X40, GITR, CD30, CD40, ICOS, BAFFR, HVEM, ICAM-1, lymphocyte function associated antigen 1 (LFA-1), CD2 , CD8, CD7, CD287, LIGHT, NKG2C, NKG2D, SLAMF7, NKp80, NKp30, NKp44, NKp46, CD160, B7-H3 and a ligand that specifically binds to CD83 and the like. The intracellular signaling domain may comprise the entire intracellular portion, or the entire native intracellular signaling domain, of the molecule from which it is derived, or a functional fragment or derivative thereof. The term "disease-specific antigen" or "disease-associated antigen" or "disease-causing antigen" refers to an antigen expressed in cells that contribute to the development of a disease. The term "disease-causing cell" or "disease-associated cell" refers to a cell that contributes to the development of a disease. Exemplary / zRZLn / nznz / B / Yi disease-causing cells include cancer cells and virus-infected cells. Non-cancerous cells, such as B lymphocytes and T lymphocytes, have been associated with the pathogenesis of immune, allergic, degenerative, and infectious diseases and are also considered disease-causing cells. The term "disease-supporting antigen" refers to an antigen expressed in cells that promotes the survival, proliferation, persistence, or activity of disease-causing cells. In some embodiments, the disease-supporting antigen is an antigen present on stromal cells. Without wishing to be bound by theory, in some embodiments, CAR-expressing cells kill disease-bearing cells, thereby indirectly blocking the growth or survival of disease-causing cells. Exemplary stromal cell antigens include bone marrow stromal cell antigen 2 (BST2), fibroblast activation protein (FAP), and tenascin. The term degenerative disorders refers to a disease that is the result of an ongoing process of degenerative cellular changes, affecting tissues or organs, that will deteriorate more and more over time, either due to normal bodily wear and tear or choices of care. lifestyle, such as exercise or eating habits. Exemplary degenerative diseases include Alzheimer's disease, Charcot-Marie-Tooth disease, Creutzfeldt-Jakob disease, Friedreich's ataxia, diabetes mellitus (type II) and atherosclerosis. The term "derived from", as used herein, indicates a relationship between a first and a second molecule. It generally refers to structural similarity between the first molecule and a second molecule and does not connote or include a process or source limitation on a first molecule being derived from a second molecule. For example, in the case of an antigen-binding domain that is derived from an antibody molecule, the antigen-binding domain retains sufficient antibody structure so that it has the required function, i.e., the ability to bind to an antigen. antigen. / zRZLn / nznz / B / Yi The phrase disease associated with the expression of a target antigen or antigen associated with disease as described herein includes, but is not limited to, a disease associated with the expression of a target antigen as described herein or a condition associated with cells that express a target antigen as described herein, including, for example, proliferative diseases such as cancer or neoplasia, or a precancerous condition, such as myelodysplasia, myelodysplastic syndrome, or preleukemia; or a non-cancer related indication associated with cells expressing a target antigen as described herein. In one aspect, a cancer associated with the expression of a tumor antigen as described herein is a hematological cancer. In one aspect, a cancer associated with the expression of a tumor antigen as described herein is a solid cancer. Additional diseases associated with the expression of a tumor antigen described herein include, but are not limited to, atypical and / or non-classical cancers, neoplasms, precancerous conditions, or proliferative diseases associated with the expression of a tumor antigen as described in the present. Non-cancer indications associated with expression of a target antigen as described herein include, for example, autoimmune disease (eg, lupus), inflammatory disorders (allergy and asthma), and transplantation. In some embodiments, the cells that express the target antigen express, or at any time express, mRNA encoding the target antigen. In another embodiment, the cells expressing the target antigen produce the target antigen protein (eg, wild-type or mutant), and the target antigen protein may be present at normal levels or reduced levels. In another embodiment, cells expressing the target antigen produced detectable levels of a target antigen protein at one point, and subsequently produced substantially no detectable target antigen protein. Disease directed by genetically modified cells, as used herein, encompasses the targeting of any cell involved in any way / zAZLn / nznz / B / Yi in any disease by a genetically modified cell that is adapted to the disease or a tissue or target cell type, regardless of whether the modified cells target diseased cells or healthy cells to achieve a therapeutically beneficial result. The dissociation constant term (Kd) is defined as the equilibrium constant for dissociation of a receptor-ligand interaction. The term coding refers to the inherent property of specific nucleotide sequences in a polynucleotide, such as a gene, cDNA, or mRNA, to serve as templates for the synthesis of other polymers and macromolecules in biological processes that have a defined nucleotide sequence. (eg, rRNA, tRNA, and mRNA) or a defined sequence of amino acids and the resulting biological properties thereof. Thus, a gene, cDNA, or RNA encodes a protein if transcription and translation of the mRNA corresponding to that gene produces the protein in a cell or other biological system. Both the coding strand, whose nucleotide sequence is identical to the mRNA sequence and is usually provided in sequence listings, and the non-coding strand, used as a template for transcription of a gene or cDNA, can be referred to as protein-coding or other product of that gene or cDNA. Unless otherwise specified, a nucleotide sequence encoding an amino acid sequence includes all nucleotide sequences that are degenerate versions of each other and that encode the same amino acid sequence. The phrase nucleotide sequence encoding a protein or RNA may also include trans to the extent that the nucleotide sequence encoding the protein may contain intron(s) in some version. / zRZLn / nznz / B / Yi The terms "effective amount" or "therapeutically effective amount" are used interchangeably herein and refer to an amount of a compound, formulation, material, or composition, as described herein, effective to achieve a particular biological result. The term endogenous, native, or naturally occurring refers to any material from or produced within an organism, cell, tissue, or system. It also refers to a gene, protein, nucleic acid (eg, DNA, RNA, etc.) or a fragment thereof that is native to a cell or naturally expressed in a cell. The term exogenous refers to any material introduced into or produced outside of an organism, cell, tissue, or system. The term "expression" refers to the transcription and / or translation of a particular nucleotide sequence directed by a promoter and / or other regulatory elements. The term transfer vector refers to a composition of matter that comprises an isolated nucleic acid and that can be used to deliver the isolated nucleic acid into a cell. Thus, the term transfer vector includes an autonomously replicating plasmid or virus. The term should also be construed to further include non-plasmid and non-viral compounds that facilitate the transfer of nucleic acid into cells, such as, for example, a polylysine compound, liposomes, and the like. Examples of viral transfer vectors include, but are not limited to, adenoviral vectors, adeno-associated virus vectors, retroviral vectors, lentiviral vectors, and the like. Expression vectors include all those known in the art, including cosmids, plasmids (eg, naked or contained in liposomes), and viruses (eg, lentiviruses, retroviruses, adenoviruses, and adeno-associated viruses) that incorporate the recombinant polynucleotide. / zRZLn / nznz / B / Yi As used herein, an epitope is defined as the portion of an antigen capable of eliciting an immune response, or the portion of an antigen that binds to an antibody or antibody fragment. The epitopes can be a sequence or subsequence of proteins. The term "expression vector" refers to a vector comprising a recombinant polynucleotide comprising expression control sequences operably linked to a nucleotide sequence to be expressed. Expression vectors include all those known in the art, including cosmids, plasmids (eg, naked or contained in liposomes), and viruses (eg, lentiviruses, retroviruses, adenoviruses, and adena-associated viruses) incorporating the recombinant polynucleotide. The term "functional polypeptide unit (FPU)" of, for example, a zSIR, refers to a polypeptide comprising an amino-terminal signal sequence operably linked to an antigen-binding domain and, for example, a CD3z chain. For example, the antigen binding domain is located between the signal sequence and the CD3z chain. The term "functional portion" when used in reference to, for example, a zSIR refers to any part or fragment of a polypeptide, for example, the zSIR, which part or fragment retains the biological activity of the desired molecule, for example, of the zSIR, of which it is a part (ie, the parent zSIR). Functional portions encompass, for example, those parts of a zSIR that retain the ability to recognize target cells, or detect, treat, or prevent disease, to a similar extent, to the same extent, or to a greater extent, as the parental zSIR. Referring to the parent zSIR, the functional portion may comprise, for example, about 10%, 25%, 30%, 50%, 68%, 80%, 90%, 95% or more of the parent zSIR. Genetically modified cells, redirected cells, genetically engineered cells, or modified cells as used in this / zRZLn / nznz / B / Yu document refer to cells that have been modified to express a CAR (for example, a Second generation conventional CAR, TFP, AbTCR, SIR, Tri-Tacy zSIR) or a recombinant TCR. For example, a genetically modified T cell that expresses a CAR or a zSIR is a genetically modified cell. The term immune disorder refers to a disease characterized by dysfunction of the immune system. An autoimmune disease is a condition that arises from an abnormal immune response to a normal part of the body. There are at least 80 types of autoimmune diseases. Immune effector cell, as used herein, refers to a cell that is involved in an immune response, eg, in promoting an immune effector response. Examples of immune effector cells include T cells, eg, alpha / beta T cells and gamma / delta T cells, B cells, and natural killer T (NKT) cells. Immune receptor-expressing cell, as the term is used herein, refers to a cell that is involved in an immune response, for example, in promoting an effector immune response, and expresses one or more immune receptors, such such as, for example, an endogenous TCR, a recombinant TCR or a CAR. Examples of cells that express immune receptors include T cells, eg, alpha / beta T cells and gamma / delta T cells, and NKT cells. Immune effector function or immune effector response, as used herein, refers to the function or response, eg, of an immune effector cell, that ameliorates or promotes an immune attack by a cell. Effector function or response refers to a property of a T or NK cell that promotes the death or inhibition of growth or proliferation of a target cell. In the case of a T cell, primary stimulation and costimulation are examples of effector immune response or function. / zRZLn / nznz / B / Yi An intracellular signaling domain, as the term is used herein, refers to an intracellular signaling portion of a molecule. The intracellular signaling domain generates a signal that promotes, for example, an immune effector function of the CAR-containing cell (eg, CAR 2nd generation, TFP, AbTCR, SIR, Tri-TAC and / or zSIR). Examples of immune effector function include cytolytic activity and auxiliary activity, including cytokine secretion. The TCRa / β / and / δ chains do not have an intracellular signaling domain of their own, but transmit a signal by associating with other chains of the TCR signaling complex (for example, CD3z, CD3e, CD3d, and CD3g) that possess an intracellular signaling domain. Signaling. In another embodiment, the intracellular signaling domain may comprise a primary intracellular signaling domain. Exemplary primary intracellular signaling domains include those derived from the molecules responsible for antigen-dependent primary stimulation or simulation. In another embodiment, the intracellular signaling domain may comprise a costimulatory intracellular domain. Exemplary costimulatory intracellular signaling domains include those derived from molecules responsible for costimulatory signals, or antigen-independent stimulation. For example, a primary intracellular signaling domain may comprise a CD3z cytoplasmic sequence, and a costimulatory intracellular signaling domain may comprise a co-receptor cytoplasmic sequence or costimulatory molecule, such as CD28 or 41BB. A primary intracellular signaling domain may comprise a signaling motif that is known as an immunoreceptor tyrosine-based activation motif or ITAM. Examples of ITAMs that contain primary cytoplasmic signal sequences include, but are not limited to, derivatives of CD3 zeta, common FeR gamma (FCER1G), Fe gamma Rila, FeR beta (Fe Epsilon R1b), CD3 gamma, CD3 delta, CD3 epsilon, CD79a, CD79b, DAPIO and DAP12. As used herein, the term "linker" (also linker domain or linker region) refers to an oligo or polypeptide that joins two or more / zRZLn / nznz / B / Yi domains or regions of a CAR (eg, CAR of second generation, TFP, AbTCR, SIR and zSIR) described herein. The linker can be between 1 and 500 amino acids in length. In some embodiments, the linker is cleaved or not cleaved. Unless otherwise specified, the term "linker" used herein means a linker that did not cleave it. Such non-cleavable linkers may be composed of flexible residues that allow free movement of adjacent protein domains relative to one another. Non-limiting examples of such residues include glycine and serine. In some embodiments, the linkers include non-flexible residues. Exemplary embodiments of linkers with non-flexible linkers are EAAAK (SEQ ID NO: 4011), E-coil (SEQ ID NO: 4009), K-coil (SEQ ID NO: 4010), or PG4SP (SEQ ID NO: 4007). In other embodiments, the linker joining the antigen-binding domain and the CD3z chains of a zSIR share a similar length. In other embodiments, the linker joining the antigen-binding domain and the CD3z chains of a zSIR differ in length by no more than 20 amino acids, typically no more than 10 amino acids, preferably no more than 5 amino acids, more preferably no more than 5 amino acids. no more than 2 amino acids. In some embodiments, the linker joining the antigen-binding domain and the CD3z strands of a zSIR have the same or similar amino acid composition. Exemplary linkers with identical composition are PG4SP (SEQ ID NO: 4007) and PG4SP-v2 (SEQ ID NO: 4008). In some embodiments, the linkers that join the antigen-binding domain and the CD3z strands of a zSIR are PG4SP (DNA SEQ ID NO: 8; PRT SEQ ID NO: 4007) and PG4SP-V2 (DNA SEQ ID NO: 9; PRT SEQ ID NO: 4008). In some embodiments, the linkers that bind to the antigen-binding domains and CD3z chains of a zSIR are derived from antibodies. In one embodiment, the linker that joins a vL region and a CD3z chain of a zSIR is IgCL (DNA SEQ ID NO: 28; PRT SEQ ID NO: 4027) and the linker that joins a vH region and a CD3z chain of a zSIR is lgG1-CH1 (DNA SEQ ID NO: 29 and PRT SEQ ID NO: 4028). In some / zRZLn / nznz / E / Yi embodiments, the linker joining the respective antigen-binding domain and the CD3z chain of a zSIR are IgCL (DNA SEQ ID NO: 28; PRT SEQ ID NO: 4027) and IgG2- 0C-CH1 (DNA SEQ ID NO: 30; PRT SEQ ID NO: 4029). In some embodiments, the linker may comprise an epitope tag. In some embodiments, the epitope tag is selected from the group consisting of a MYC tag, a V5 tag, an AcV5 tag, a Streptagll, a FLAG or HA tag. In some embodiments, the uncleaved linker is of sufficient length to ensure that two adjacent domains do not spherically interfere with each other. In one embodiment of the disclosure, three amino acid residues (Gly-Ser-Gly) are added to the carboxy-terminus of linkers (eg, Myc tag or V5 tag) that lie between the antigen-binding domain and the strands. CD3z from the zSIR. In certain embodiments, the linkers can carry additional sequences, such as restriction enzyme sites. The term flexible polypeptide linker, as used herein, refers to a peptide linker consisting of amino acids such as glycine and / or serine residues used alone or in combination, to ligate polypeptide chains (eg, regions of variable light and variable heavy chain). In one embodiment, the flexible polypeptide linker is a Gly / Ser linker and comprises the amino acid sequence (Gly-Gly-Gly-Ser)n where n is a positive integer equal to or greater than 1. For example , n=1, n=2, n=3, n=4, n=5 and n=6, n=7, n=8, n=9 and n=10. In one embodiment, flexible polypeptide linkers include, but are not limited to, (Gly4Ser)4 or (Gly4Ser)3 (SEQ ID NO:5). In another embodiment, the linkers include multiple repeats of (Gly2Ser), (GlySer) or (Gly3Ser). Also included within the scope of the disclosure are the linkers described in W02012 / 138475, incorporated herein by reference. The term lentivirus refers to a genus in the Retroviridae family. HIV, SIV, and FIV are all examples of lentiviruses. The term "lentiviral vector" refers to a vector derived from at least one / zRZLn / nznz / B / Yi portion of a lentivirus genome, including especially a self-inactivating lentiviral vector as provided in Milone et al., Mol. ther. 17(8): 1453-1464 (2009). Other examples of lentivirus vectors that can be used in the clinic include, but are not limited to, for example, Oxford BioMedica's LENTIVECTOR® gene delivery technology, Lentigen's LENTIMAX™ vector system, and the like. Other examples of lentivirus vectors are pLENTI-EF1a (SEQ ID NO: 129), pLENTI-EF1a-DWPRE (SEQ ID NO: 130) and pCCLc-MNDU3 (SEQ ID NO: 12639). As used herein, a non-natural TCR antigen-binding domain refers to a binding domain operatively linked to a TCR constant region or CD3z chain that is chimeric and non-natural to a TCR that is present. In nature. . Stated differently, the non-naturally occurring TCR antigen-binding domain is modified by recombinant molecular biology techniques to be operably linked to a TCR constant chain or CD3z chain and, furthermore, that the antigen-binding domain it is obtained or derived from a molecule that is other than a TCR found in nature. An antigen-binding domain that is other than a TCR in nature includes vH and vL antibody fragments, humanized antibody fragments, chimeric antibody fragments, receptor ligands, and the like. The term "operably linked" or "functionally linked" refers to the functional link or association between a first component and a second component such that each component can be functional. For example, "operably linked" includes the association between a regulatory sequence and a heterologous nucleic acid sequence that results in the expression of the latter. For example, a first nucleic acid sequence is operatively linked to a second nucleic acid sequence when the first nucleic acid sequence is placed into a functional relationship with the second nucleic acid sequence. In the context of two polypeptides that are operably linked, a first polypeptide functions independently of any / zRZLn / nznz / B / Yi linkage and the second polypeptide functions as if absent a link between the two. Percent identity, in the context of two or more nucleic acid or polypeptide sequences, refers to two or more sequences that are the same. Two sequences are substantially identical if two sequences have a specified percentage of amino acid residues or nucleotides that are the same (for example, 60% identity, optionally 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%,81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92% , 93%, 94%, 95%, 96%, 97%, 98%, 99% identity in a specific region or, when not specified, in the entire sequence), compared and aligned for maximum correspondence over a comparison window, or designated region as measured by one of the following sequence comparison algorithms or by manual alignment and visual inspection. Optionally, the identity exists over a region that is at least about 50 nucleotides (or 10 amino acids) in length, or more preferably, over a region that is 100 to 500 or 1000 or more nucleotides (or 20, 50, 200 or more amino acids) in length. The term polynucleotide, nucleic acid or recombinant nucleic acid refers to polymers of nucleotides such as deoxyribonucleic acid (DNA) and, where appropriate, ribonucleic acid (RNA). A protein or polypeptide, the terms of which are used interchangeably herein, comprises one or more chains of chemical building blocks called amino acids that are linked together by chemical bonds called peptide bonds. Refractory as used herein refers to a disease, eg, cancer, that does not respond to treatment. In embodiments, a refractory cancer may be resistant to treatment prior to or at the start of treatment. In other embodiments, the refractory cancer can become resistant during a / zRZLn / nznz / B / Yi treatment. A refractory cancer is also called a resistant cancer. Relapse, as used herein, refers to the return of a disease (eg, cancer) or the signs and symptoms of a disease such as cancer after a period of improvement, eg, after prior treatment with a therapy eg cancer therapy Ranges: Throughout this description, various aspects of the invention may be presented in a range format. It is to be understood that the description in range format is merely for convenience and brevity and is not to be construed as inflexibly limiting the scope of the invention. The term "retroviral vector" or "retroviral vector" refers to a vector derived from at least a part of a retroviral genome. Examples of retroviral vector include MSCVneo, MSCV-pac (or MSCV-puro), MSCV-hygro available from Addgene or Clontech. Another example of a retrovirus vector is MSCV-Bgl2-Avrll-Bam-EcoR1-XhoBstB1-Mlu-Sal-Clal.103 (SEQ ID NO: 131). The term "sleeping beauty transposon" or "sleeping beauty transposon vector" refers to a vector derived from at least a portion of the sleeping beauty transposon genome. An example of a sleeping beauty transposon vector is pSBbi-Pur (SEQ ID NO: 133). Other examples of sleeping beauty transposon vectors encoding a SIR are provided in SEQ ID NO: 134 and SEQ ID NO: 135. The term "scFv" refers to a fusion protein comprising at least one antibody fragment comprising a light chain variable region and at least one antibody fragment comprising a heavy chain variable region, wherein the variable regions of the heavy chain are contiguously linked, eg, via a synthetic linker, eg, a short flexible polypeptide linker, and capable of expression as a single-chain polypeptide, and wherein the scFv retains the specificity of the intact antibody from which it is derived. drift. Unless specified, as used herein, a scFv may have the variable regions of vL / zRZLn / nznz / B / Yi and vH in any order, eg, with respect to the N-terminal and C-terminal ends. of the polypeptide, the scFv may comprise vl_-linker-vH or may comprise vH-linkervL. In this invention, a scFv is also described as vL-Gly-Ser-linker-vH. For example, FMC63-vL-Gly-Ser-Linker-FMC63-vH refers to a scFv containing the vL and vH fragments of the FMC63 monoclonal antibody linked through a linker consisting of Gly and Ser residues. Alternatively, a scFv it is also described as (vL + vH). For example, FMC6-(vL + vH) refers to a scFv containing the vL and vH fragments of the FMC63 antibody linked by a linker in which the vL fragment is at the N-terminus. The term "signaling domain" refers to the functional region of a protein that conveys information within the cell to regulate cellular activity through signaling pathways defined by the generation of second messengers or that function as effectors that respond to such messengers. The term "Synthetic Immune Receptor" or alternatively a SIR refers to a polypeptide, typically two polypeptides (eg, a heterodimer or homodimer) in some embodiments, that when expressed in an effector cell, provides the cell with specificity for a target cell. , typically a cancer cell, and with intracellular signal generation. SIRs have been described in PCT / US17 / 64379. In a typical embodiment, a SIR comprises one or more antigen-binding domains (eg, Antibody or antibody fragment, a ligand, or a receptor) that bind to antigens or cognate ligand as described herein, and attached to one or more T cell receptor chains or constant regions via an optional linker. In some embodiments, the set of polypeptides is contiguous with one another. In some embodiments, a SIR comprises two or more sets of two or more polypeptides. Polypeptides from each set of SIRs are contiguous with each other (functional polypeptide unit 1) but are not contiguous with polypeptides from the other set (functional polypeptide unit 2). In some aspects, the SIR T cell receptor constant chains (or regions) are selected from the human T cell receptor alpha constant chain (TCR-alpha or TCRa or TCRa or hTCR- alpha or hTCRa ​​or hTCRa ​​or Ca), human T cell receptor beta1 (TCR-beta1 or TCRpi or TCRbl or hTCR-beta1 or hTCRpi or hTCRbl or Οβ1), human T cell receptor beta 2 (TCR-beta2 or TCRP2 or TCRb2 or hTCR-beta2 or hTCRp2 or hTCRb2 or Οβ2 also called TCR-beta, TCRp or TCRb or Οβ), pre-human T cell receptor alpha ((preTCR-alpha or preTCRo or preTCRa or preCa), human T cell receptor gamma (TCR-gamma or TCRy or TCRg or hTCRgamma or hTCRy or hTCRg or hTCRyl or hTCRgammal, or Cy), or human T cell receptor delta (TCR-delta or TCRd or TCRó or hTCR-delta or hTCRd or hTCRó or Có). In some embodiments, the SIR TCR constant strings are encoded by their wild-type nucleotide sequences, while in other aspects the strings with SIR TCR constants are encoded by nucleotide sequences that are not wild-type. In some embodiments, the SIR TCR constant chains are encoded by their codon-optimized sequences. In some embodiments, the SIR TCR constant chains encode wild-type polypeptide sequences, while in other embodiments, the SIR TCR constant chains encode polypeptides carrying one or more mutations. In some embodiments, the SIR TCR constant chains are encoded by their codon-optimized sequences carrying one or more mutations. A SIR comprising an antigen-binding domain (eg, a scFv or vHH) that targets a specific tumor generator X, such as those described herein, is also known as an X-SIR or XSIR. For example, a SIR comprising an antigen-binding domain that targets CD19 is referred to as CD19-SIR or CD19SIR. The TCR constant chain / domain of a SIR may be derived from the same species in which the SIR will ultimately be used. For example, for use in humans, it may be beneficial if the TCR constant chain of the SIR is derived from or comprised of human TCR constant chains. However, in some cases, it is beneficial if the TCR constant chain is derived from / zRZLn / nznz / B / Yi the same species in which the SIR will ultimately be used, but modified to carry amino acid substitutions that improve expression. of the constant chains of TCR. For example, for use in humans, it may be beneficial if the SIR TCR constant chain is derived from or comprised of or composed of human TCR constant chains, but where certain amino acids are replaced by the corresponding amino acids of the constant chains. murine TCR constants. Such murinized TCR constant chains provide increased expression of the SIR. Exemplary TCR constant strand nucleic acid sequences are provided in SEQ ID NO: 39-64 (Table 5). Exemplary TCR constant chain amino acid sequences are provided in SEQ ID NO: 4038-4063 (Table 5).The SIR, or the functional portion thereof, may include additional amino acids at the amino or carboxyl terminus, or at both termini, which additional amino acids are not found in the amino acid sequence of the TCR or antigen-binding domain that make up the SIR. Desirably, the additional amino acids do not interfere with the biological function of the SIR or the functional portion, eg, recognizing target cells, detecting cancer, treating or preventing cancer, etc. More desirably, the additional amino acids enhance the biological activity compared to the biological activity of the parental SIR. The term stimulation refers to a primary response induced by the binding of a stimulatory molecule (for example, a TCR / CD3 complex) to its cognate ligand (or target antigen), thus mediating a signal transduction event, such as , among others, signal transduction through the TCR / CD3. Stimulation can mediate the altered expression of certain molecules. The term TCR receptor or TFP fusion proteins refers to a next generation CAR platform as described in WO 2016 / 187349 A1, which is incorporated herein by reference. In one embodiment, a TFP comprises an antibody portion that specifically binds to a target antigen fused to a TCR chain such as CD3c, CD3y, CD3Ó, TCRa, or TCRp. In the document WO / zRZLn / nznz / B / Yi 2017 / 070608 Α1, which is incorporated herein by reference, exemplary TCR chains are provided that can be used in the construction of TFP. A TFP that incorporates the CD3c chain is called a CD3c TFP. A TFP that incorporates the CD3y chain is called a CD3y TFP. A TFP that incorporates the CD3ó chain is called a CD3ó TFP. TFP incorporating CD3c, CD3y or CD3S chains is collectively referred to as CD3c / y / or TFP. Exemplary TFPs incorporating the BCMA-AmO6-HL antigen-binding domain that targets BCMA described in this disclosure and co-expressing an accessory module encoding NEMO-K277A are provided in SEQ ID NO: 4384-4387 (Table 6). Examples of TFPs incorporating different antigen-binding domains described in this disclosure and co-expressing an accessory module encoding NEMOK277A are provided in Table 7. The SEQ ID NOs, antigen-binding domains, and target antigens of these TFPs can be determined by referring to Table 6 since the order of the different constructs (i.e., CAR class) listed in Table 7 is the same as the order of constructs (ie CAR class) listed in Table 6. The accessory module encoding NEMO-K277A is optional. TFPs with the antigen-binding domains (ie, vL and vH fragments, ligands and receptors, etc.) described in the present disclosure can be constructed without NEMO-K277A. As such, this accessory module along with the upstream Furin-SGSG-F2A sequence can be removed from the TFPs represented by SEQ ID NO: 1900-3123. Alternatively, the accessory module encoding NEMO-K277A can be replaced by accessory modules encoding other signaling proteins, such as hNEMO-K277A-deltaV249-K555, mNEMQ-K270A, K13-opt, IKK2-S177E-S181E, or IKK1-S176E-S180E, and MyD88-L265P, FKBPx2-NEMO, NEMOL600-FKBPx2, and CMV-141, etc. The term "stimulatory molecule" refers to a molecule expressed by an immune cell (eg, T cell, NK cell, B cell) that provides the cytoplasmic signaling sequences that regulate immune cell activation in a stimulatory manner for at least some aspect. of the / zRZLn / nznz / B / Yu immune cell signaling pathway. The term "subject" is intended to include living organisms in which an immune response can be elicited (eg, any domesticated mammal or a human). The terms T cell and T lymphocyte are used interchangeably and synonymously herein. Examples include, but are not limited to, naïve T cells (lymphocyte progenitors), central memory T cells, effector memory T cells, stem memory T cells (Scm), tissue-resident T cells, Τα / β cells , T, and / δ cells, ¡PSC-derived T cells, synthetic T cells, or combinations thereof. The term therapeutic effect refers to a biological effect that can be manifested by various means, including, but not limited to, decreased tumor volume, decreased number of cancer cells, decreased colony count of the infectious agent, enhancement of various physiological symptoms associated with a disease, preventing the onset of the disease in the first place, or preventing the relapse of the disease. Treatment and treating, as used herein, refer to both therapeutic treatment and prophylactic or preventative measures. Those who need treatment include those who already have the condition, as well as those likely to have the condition or those in whom the condition is to be prevented. The term zeta (or defined by the Greek symbol ζ) or alternatively zeta chain, CD3-zeta or TCR-zeta is defined as the protein provided as GenBan Ace. No. BAG36664.1, or the equivalent residues from a non-human species, eg, mouse, rodent, monkey, ape, and the like, and a zeta-stimulatory domain or, alternatively, a CD3-zeta-stimulatory domain or a zeta-stimulatory domain. TCRzeta stimulator is defined as amino acid residues in the cytoplasmic domain of the zeta chain, or functional derivatives thereof, that are sufficient to functionally convey / zRZLn / nznz / B / Yi an initial signal necessary for T cell activation. In one aspect, the cytoplasmic domain of zeta comprises residues 52 to 164 of GenBank Ace. No. BAG36664.1 or the equivalent residues from a non-human species, eg, mouse, rodent, monkey, ape, and the like, which are functional orthologs thereof. In one aspect, the zeta stimulating domain or a CD3-zeta stimulating domain is the sequence provided as DNA SEQ ID NO: 101 and PRT SEQ ID NO: 4100. Provided herein are compositions comprising a CAR and one or more optional accessory modules and a method of using them to treat diseases, including cancer. As described in this document, specific combinations of CARs (Table 1) and accessory modules as described in Table 2 define a master string (Table 2). Table 1: CAR architectures. First-generation CARs (conventional CAR1 or CAR I) have an antigen-specific domain (ASD), an intracellular signaling domain (ISD) (eg, CD3z), and no costimulatory domain. TCR fusion proteins (TFPs) are next-generation CARs that are described in WO 2016 / 187349 A1 but resemble conventional CAR1 in having an antigen-specific domain (ASD) and an intracellular signaling domain. Second-generation CARs (conventional CAR 2 or CAR II) have an antigen-specific domain (ASD), a costimulatory domain (eg, 41BB or CD28), and an intracellular signaling domain (ISD) (eg, CD3z). Third-generation CARs (conventional CAR 3 or CAR III) have an antigen-specific domain (ASD), two costimulatory domains (eg, 41 BB and CD28), and an intracellular signaling domain (ISD) (eg, CD3z). . AbTCRs are duel-chain receptors and have been described in PCT / US2016 / 058305. cTCRs are single-chain, one-and-a-half-chain, or double-chain receptors that consist of an antigen-binding domain derived from a vL fragment. and vH that fuse with a constant chain TCR and result in activation of T cell signaling. Synthetic immune receptors are / zRZLn / nznz / B / Yi next generation cTCRs and are described in US 62 / 429,597 and PCT / US017 / 064379. SIRs can be single-chain, 1.5-chain, or double-chain receptors that consist of one or more antigen-binding domains that are fused to one or more TCR constant chains and result in activation of TCR signaling. T cells by binding to the ligand. The zSIRs are described in this application. zSIRs are a new platform of synthetic immune receptors (SIRs) that contain two CD3-zeta chains (CD3z). The nucleic acid and amino acid sequences of the CD3z strands that can be used in the construction of zSIR are provided in SEQ ID NOs: 67 and 71 and PRT SEQ ID NOs: 4066 and 4072. The disclosure provides that the vL fragment of a antibody can bind to one of the two CD3z chains and the vH fragment can bind to the other CD3z chain. When two such chains (for example, vL-CD3z and vH-CD3z) are coexpressed in the same cell, the vL and vH fragments can associate, recognize their cognate antigen or binding partner, and transmit a T-cell signal. In particular, T cells expressing such a zSIR when exposed to a cell line expressing the target antigen can activate NFAT signaling, induce IL2 production, and exert cytotoxicity. The expression and activity of the zSIR can be further increased by incorporating a linker between the vL / vH and CD3z fragments. In particular, antibody-derived IgCL and IgCH domains serve as useful linkers between vL / vH and CD3z fragments. Exemplary linkers that can be used in the construction of zSIR are provided in SEQ ID NO: 4004 to 4037 (Table 5). Schematic examples of zSIRs contemplated by the disclosure are provided in Figure 1. For example, zSIR1, the vL fragment of one scFV binds to a CD3z-ECD-TM-CP (extracellular, transmembrane and cytoplasmic domain) and the vH fragment binds to a second CD3zECDTMCP. An example of zSIR1 is provided in SEQ ID NO: 425. In zSIR2, one ASD (eg, a scFV fragment) binds to a CD3zECDTMCP (extracellular, transmembrane, and cytoplasmic / zRZLn / nznz / B / Yi domain) and the second ASD binds to a second CD3zECDTMCP. An exemplary zlR2 is provided in SEQ ID NO: 3961. The two ASDs can target the same or different antigens or different epitopes on the same antigen. An example of zSIR2 in which the two ASDs target two different antigens is provided in SEQ ID NO: 3962. An example of zSIR2 in which the two ASDs target two epitopes of the same antigens is provided in SEQ ID NO: 3961. In zSIR3, the vL of a scFV fragment binds to a CD3zECDTMCP (extracellular, transmembrane, and cytoplasmic domain) via the cL linker (SEQ ID NO: 28 and 4027) derived from an immunoglobulin and the vH fragment binds to a second CD3zECDTMCP via a CH1 linker (SEQ ID NOs: 29 and 4028). An example of zSIR3 is CD8hCD19-EUK5-13-vL-lgCL-Bam-CD3zECDTMCP-opt-F-P2A-Spe-SP-Bst-hCD19-EUK5-13vH-lgG1-CH1-KPN-CD3zECDTMCP-opt2-F-F2A -Xba-PAC (SEQ ID NO: 3955). Other linkers that can be used in the construction of a zSIR are listed in Table 5. In another embodiment, a costimulatory domain is also incorporated into the CD3z strand(s) of a zSIR. Exemplary costimulatory domains include costimulatory domains from 41BB (SEQ ID NO: 69 and SEQ ID NO: 4068) and CD28 (SEQ ID NO: 69 and SEQ ID NO: 4067). CD3z chains containing 41 BB (BB) (see, scheme O, above) and CD28 (see, scheme D, above) costimulatory domains are presented in SEQ ID NO (DNA): 76-79 and SEQ ID NO: (PRT ): 4075-4078. CD8SP-BCMA-AmO6-HL-vL-[CD3zECDTM28z-opt]-F-P2A-SP-BCMA-Am06-HL-vH-[CD3zECDTM-28z-opt2] (SEQ ID NO (DNA): 3971 and SEQ ID NO (PRT): 7971) presents an example of a zSIR with CD3z containing CD28 stimulatory domains. An example of a zSIR with CD3z containing 41 BB stimulatory domains is presented by CD8SP-BCMA-AmO6-HL-vL-[CD3zECDTMBBz-opt]-F-P2A-SP-BCMA-Am06-HL-vH-[CD3zECDTMBz-BBz- opt2] (SEQ ID NO (DNA): 3972 and SEQ ID NO (PRT): 7972). zSIRs 4-9 resemble zSIRs 1-3 except for the replacement of CD3zECDTMCP with CD3zECDTM-BBz or CD3zECDTM-28z domains. / zAZLn / nznz / B / Yi Table 1 Table 1 Exemplary CARs CAR 1 CAR 1 or CAR I (including TFP) ASD HR TMD ISD CAR 2 CAR 2 (CAR II) ASD HR TMD CSD ISD CAR 3 CAR 3 (CAR III) ASD HR TMD CSD-I CSD-II ISD CAR 4 AbTCR vL-cL TCRD(1) 2A vH-CH1 TCRD (II) CAR 5 double-chain cTCR / SIR vL TCR-C(1) 2A vH TCR-C (II) CAR 6 y-chain cTCR / SIR mean TCR-C(1) 2A ASD TCR-C (II) CAR 7 zSIR1 vL CD3zECD TMCP 2A vH CD3zECD TMCP CAR 8 zSIR2 ASD CD3zECD TMCP 2A ASD CD3zECD TMCP CAR 9 zSIR3 vL-cL CD3zECD TMCP 2A vH-CH1 CD3zECD TMCP CAR 10 zSIR4 vL CD3zECD TM-BBz 2A vH CD3zECD TM-BBz CAR 11 zSIR5 vL CD3zECD TM-28z 2A vH CD3zECD TM-28z CAR 12 zSIR6 ASD CD3zECD TM-BBz 2A ASD CD3zECD TM-BBz CAR 13 zSIR7 ASD-2zECD 2 ASD CD3zECD TM-28z CAR 14 zSIR8 vL-cL CD3zECD TM-BBz 2A vH-CH1 CD3zECD TM-BBz CAR 15 zSIR9 vL-cL CD3zECD TM-28z 2A vH-CH1 CD3zECD TM-28z / zRZLn / nznz / E / Yu

[00700] Table 2: Example parent strings Main Chain CAR Component Accessory Module NAME SEQ ID (ADN) SEQ ID (PRT) Main Chain 1 CAR I K13-VFLIP 108 4107 Main Chain 2 CAR I FKBPX2-K13 113 4112 Main Chain 3 CAR I tBCMA 97 4096 Main Chain 4 CAR I HIV-1 Vif 118 4117 Main chain 5 CAR II K13-VFLIP 108 4107 Main chain 6 CAR II FKBPX2-K13 113 4112 Main chain 7 CAR II tBCMA 97 4096 Main chain 8 CAR II HIV-1 Vif 118 4117 Main chain 9 CAR III K13-VFLIP 108 4107 Main Chain 10 CAR III FKBPX2-K13 113 4112 Main Chain 11 CAR III tBCMA 97 4096 Main chain 12 CAR III HIV-1 Vif 118 4117 Main chain 13 AbTCR K13-vFLIP 108 4107 Main chain 14 AbTCR FKBPX2-K13 113 4112 Main chain 15 AbTCR tBCMA 97 4096 Main chain 16 AbTCR HIV-1 Vif 118 4117 Main chain 17 DC -cTCR / SIR K13-VFLIP 108 4107 Main chain 18 DC-cTCR / SIR FKBPX2-K13 113 4112 Main chain 19 DC-cTCR / SIR tBCMA 97 4096 Main chain 20 DC-cTCR / SIR HIV-1 Vif 118 4117 Main chain 21 OHC-cTCR / SIR K13-VFLIP 108 4107 Main chain 22 OHC-cTCR / SIR FKBPX2-K13 113 4112 Main chain 23 OHC-cTCR / SIR tBCMA 97 4096 Main chain 24 OHC-cTCR / SIR HIV-1 Vif 118 4117 Main chain 25 zSIR1 K13-VFLIP 108 4107 Parent 26 zSIR1 FKBPX2-K13 113 4112 Parent 27 zSIR1 tBCMA 97 4096 Parent 28 zSIR1 HIV-1 Vif 118 4117 Parent 29 zSIR2 K13-VFLIP 108 3-4107 3KB1 FKB1 3 4112 Main chain 31 zSIR2 tBCMA 97 4096 Main chain 32 zSIR2 HIV-1 Vif 118 4117 Main chain 33 z SIR3 K13-VFLIP 108 4107 Main Chain 34 zSIR3 FKBPX2-K13 113 4112 Main Chain 35 zSIR3 tBCMA 97 4096 Main Chain 36 zSIR3 HIV-1 Vif 118 4117 Main Chain 37 zSIR4 K13-VFLIP 108 4107 Main Chain 38 zS12IR1K3 KB3P121K3 Main chain 39 zSIR4 tBCMA 97 4096 Main chain 40 zSIR4 HIV-1 Vif 118 4117 Main chain 41 zSIR5 K13-VFLIP 108 4107 Main chain 42 zSIR5 FKBPX2-K13 113 4112 Main chain 43 zSIR5 tBCMA 97 4096 Main chain 44 HIV-1zfSIR 118 4117 Main Chain 45 zSIR6 K13-VFLIP 108 4107 Main Chain 46 zSIR6 FKBPX2-K13 113 4112 Main Chain 47 zSIR6 tBCMA 97 4096 Main Chain 48 zSIR6 HIV-1 Vif 118 4117 Main Chain 49 zSIR7 K13-VFLIP0 7 13-VFLIP0 118 FKBPX2-K13 113 4112 Main Chain 51 zSIR7 tBCMA 97 4096 Main Chain 52 zSIR7 HIV-1 Vif 118 4117 Main Chain 53 zSIR8 K13-VFLIP 108 4107 Main Chain 54 zSIR8 FKBPX2-K13 113 4112 Main Chain 5BC 908 zSIR7 / zRZLn / nznz / B / Yi Main chain 56 zSIR8 HIV-1 Vif 118 4117 Main chain 57 zSIR9 K13-vFLIP 108 4107 Main chain 58 zSIR9 FKBPX2-K13 113 4112 Main chain 59 zSIR9 tBCMA 97 4096 Main chain 60 zSIR9 HIV-1 Vif 118 4117 / zRZLn / nznz / B / Yu TABLE 3: List of sequences of vL, vH and scFv fragments directed to different antigens that are used in the construction of CAR vL vH scFv Antigen target Antigen binding domain DNA SEQ ID PRT SEQ ID DNA SEQ ID PRT SEQ ID DNA SEQ ID PRT SEQ ID BCMA BCMA-Am14-HL 155 4118 229 4192 303 4266 BCMA BCMA-AmO8-HL 156 4119 230 4193 304 4267 BCMA BCMA66-HL 157 4120 231 4194 305 4268 CD19 HU-CAT18-1-HL 158 4121 232 4195 306 4269 CD19 CAT17-HL 159 412 233 4196 307 4270 CD22 HU-HA22-1 160 4123 4271 CD19 CD19-DART1 161 4124 235 4198 309 4272 CD20 HU-UBLI-1-V4 162 4125 236 4199 310 4273 INTEGRINA B7 HU-LNTB7-MMG49 163 4126 237 4200 311 4274 BCMA BCMA-BBCAR02 164 4127 -169 165 4128 239 4202 313 4276 HER2 HER2-XMT-1520 166 4129 240 4203 314 4277 HER2 HER2-XMT-1518 167 4130 241 4204 315 4278 HER2 HER2-HUMAB4D5- D98W 168 4131 242 4205 316 4279 TSHR TSHR TSHR 169 4132 243 4206 317 4280 PSMA PSMA-83A12- HL-AM 170 4133 244 4207 318 4281 PSMA PSMA-76-HL-AM 171 4134 245 4208 319 4282 PSMA HU106MSMA-4HL 172 4135 246 4209 320 4283 MSLN MSLN MSLN-3-HL -AM 173 4136 247 4210 321 4284 MSL N MSLN-5-HL 174 4137 248 4211 322 4285 EGFRviii EGFRviii-2-ΑΜHL 175 4138 249 4212 323 4286 EGFRviii EGFRviiiH2M1863N2-HL 176 4139 250 4213 324 4287 EGFRviii EGFRviiiH2M1915N-HL 177 4140 251 4214 325 4288 EGFRviii EGFRv¡¡¡- 131-2 178 4141 252 4215 326 4289 DLL3 DLL3-AM6-HL 179 4142 253 4216 327 4290 DLL3 DLL3-AM14-HL 180 4143 254 4217 328 4291 vL vH scFv Antigen target Antigen binding domain DNA SEQ ID PRT SEQ ID DNA SEQ ID PRT SEQ ID DNA SEQ ID PRT SEQ ID Nectin4 Nectin4-66-HL 181 4144 255 4218 329 4292 MSLN MSLN-237-HL 182 4145 256 4219 330 4293 MSLN MSLN-HUAM15 183 4146 257 4220 331 4294 MSLN MSLN76923-HL 184 4147 258 4221 332 4295 PROLR-CN PROLACTIVE RECEIVE 185 4148 259 4222 333 4296 MUC17 MUC17 AM1 187 4150 261 4224 335 4298 CD19 CD19-9B7 188 4151 262 4225 336 4299 CD20 CD20-HL 189 4152 263 4226 337 4300 CD70 CD70-HL-AM13 190 4153 264 4227 338 4301 CDH19 CDH19 4302 CDH19 CDH19-Usec2HL 192 4155 266 4229 340 4303 CD160R F54 C16ORF54- USC1-V4 193 4156 267 4230 341 4304 VIEVISTA HUVISTA-Usec1V4 194 4157 268 4231 342 430 -HL- V4 196 4159 270 4233 344 4307 GPC3 GPC3-USC2-HL- V4 197 4160 271 4234 345 4308 PRLR PRLR-USC2-HL- V4 198 4161 272 4235 346 4309 Muc5USAc1 Muc5HAcL- 4 199 4162 273 4236 347 4310 FCHR5 FCh5-Usec1- HL-V4 200 4163 274 4237 348 4311 LYPD1 LYPD1-HL-V4 201 4164 275 4238 349 4312 EMR2 EMR2-USC1-V4 202 4165 276 4239 V4 203 4166 277 4240 351 4314 EMR2 MEMR2-USC3- V4 204 4167 278 4241 352 4315 GPNMB M-GPNMBUSC1-HL-V4 205 4168 279 4242 353 4316 RNF43 RNF43-Usec1- HL4 206 4169 280 4243 HL4 207 4170 281 4244 355 4318 CD44v6 CD44v6-USC1HL4 208 4171 282 4245 356 4319 / zRZLn / nznz / B / Yi vL vH scFv Antigen target Antigen binding domain DNA SEQ ID PRT SEQ ID DNA SEQ ID PRT SEQ ID DNA SEQ ID PRT SEQ ID Robo4 Robo4-USC1 209 4172 283 4246 357 4320 CEA CEA-USC1-HL4 210 4173 284 4247 358 4321 HER3 HER3-UUSC1-HL4 211 4174 285 4248 359 4322 folr1 folr1-USC1- HL4 212 4175 286 4249 360 4323 folr1 folr1 -usc2- HL4 213 4176 287 4250 361 4324 CLDN6 CLDN6-Usec1- LH4 214 CLDN6-USC2LH4 215 4178 289 4252 363 4326 MMP16 hMMP16-USC-1LH4 216 4179 290 4253 364 4327 UPK1B hUPK1 B-USC1LH4 217 4180 291 4254 365 4328 UPK1B hUPK1 B-USC2LH4 218 4181 292 4255 366 4329 BMPR1B hBMPRIBUSC1-LH4 219 4182 293 4256 367 4330 BMPR1B hBMPRIBUSC2-LH4 220 4183 294 4257 368 4331 Ly6E Ly6E-USC1-HL4 221 4184 295 4258 369 4332 STEAP1 STEAP1-USC1HL4 222 4185 296 4259 370 4333 CD79b CD79b-USC1LH4 223 4186 297 4260 371 4334 WISP1 hu-UISP1- USC1LH4 224 4187 298 4261 372 4335 WISP1 hu-UISP1-USC2LH4 225 4188 299 4262 373 4336 SLC34A2 huMX35-LH4 226 4189 300 4263 374 4337 CD19 hu-CD1 9-USC1LH4 227 4190 301 4264 375 4338 CD22 CD22-HA22 8000 9631 8031 ​​9662 8062 9693 STEAP1 STEAP1-hu120 8001 9632 8032 9663 8063 9694 Liv1 hLiv1-mAb2 8002 9633 8033 9664 8064 9695 Nectin4 hu-Nectin4-mAb1 8003 9634 8034 9665 8065 9696 HU-CRIPT-L1H2 8004 9635 8035 9666 8066 9697 GPA33 HU-GPA3 8005 9636 8036 9667 8067 9698 R0R1 ROR1-DART4 8006 9637 8037 9668 8068 9699 BCMA BCMA BCMA BCMA BCMA 9670 8070 9701 BCMA BCMA-AJ 8009 9640 8040 9671 8071 9702 BCMA BCMA-NM 8010 9641 8041 9672 8072 9703 / zRZLn / nznz / B / Yi vL vH scFv Antigen target Antigen binding domain DNA SEQ ID PRT SEQ ID DNA SEQ ID PRT SEQ ID DNA SEQ ID PRT SEQ ID BOMA BCMA-TS 8011 9642 8042 9673 8073 9704 BOMA BCMA-PP 8012 9643 8043 9674 8074 9705 BOMA BCMA-RD 8013 9644 8044 9675 8075 9706 BCMA BCMA-BBCAR02 8014 9645 8045 9676 8076 9707 CLL1 CLL1-24C8 8015 9646 8046 9677 8077 9708 CLL1 CLL1-24C1 8016 9647 8047 9678 8078 9709 FLT3 FLT3-10E3 8017 9648 8048 9679 8079 9710 FLT3 FLT3-8B5 8018 9649 8049 9680 8080 9711 IL1RAP IL1RAP-IAPB57 8019 9650 8050 9681 8081 9712 IL1RAP IL1RAP-IAPB63 8020 9651 8051 9682 8082 9713 IL1RAP hu-IL1RAP- CANO4 8021 9652 8052 9683 8083 9714 MSLN MSLN-7D9-V3 8022 9653 8053 9684 8084 9715 MSLN MSLN-HU22A10 8023 9654 8054 9685 8085 9716 CD19 HU-BU13 8024 9655 8055 9686 8086 9717 BST1 HU-BST1-A1 8025 9656 8056 9687 8087 9718 BST1 HUST1 HUST1 HUST1 BST1-A3 8027 9658 8058 9689 8089 9720 Her2 Her2-XMT-1519 8028 9659 8059 9690 8090 9721 Her2 Her2-XMT-1517 8029 9660 8060 969 1 8091 9722 CD133 CD133-RW03 11300 11460 1130 4 11464 1130 8 11468 CD133 CD133- W6B3H10 11301 11461 1130 5 11465 1130 9 11469 CD133 CD133293AC1C3B9 11302 11462 1130 6 11466 1131 0 11470 IL113Ra2 hu-IL13Ra2mAb47 12642 14386 1267 3 14417 1270 4 14448 CD22 CD22-INO 12643 14387 1267 4 14418 1270 5 14449 CD22 CD22-CELL4 12644 14388 1267 5 14419 1270 6 14450 CD22 CD22-CELL13 12645 14389 1267 6 14420 1270 7 14451 CD22 CD22 CD22 VM1011 12647 14391 1267 8 14422 1270 9 14453 CD22 CD22-RAB-4120 12648 14392 1267 9 14423 1271 0 14454 CD22 CD22-MED12C5-HL 12649 14393 1268 0 14424 1271 1 14455 / zRZLn / nznz / E / Yi vL vH scFv Antigen target Antigen binding domain DNA SEQ ID PRT SEQ ID DNA SEQ ID PRT SEQ ID DNA SEQ ID PRT SEQ ID CD22 CD22-Med-19A3 12650 14394 1268 1 14425 1271 2 14456 CD22 CD22-Med-16F7 12651 14395 1268 2 14426 1271 3 14457 CD22 HU-RFB4 12652 14396 1268 3 14427 1271 4 14458 BCMA BCMA-MJ22-9 12653 14397 1268 4 14428 1271 5 14459 BCMA BCMA-HUJ22-10 12654 14398 1268 126 HU-HA22-2 12655 14399 1268 6 14430 1271 7 14461 CD19 HUCD19-USC3 12656 14400 1268 7 14431 1271 8 14462 CD22 BCMA-HU72 12657 14401 1268 8 14432 1271 9 14463 MPL HU-161-3 1265 14464 BAFF-R HU-BAFFRUSC90 12659 14403 1269 0 14434 1272 1 14465 BAFF-R HU-BAFFRUSC55 12660 14404 1269 1 14435 1272 2 14466 BAFF-R HU-BFRMOR6654 12661 14405 1269 2 14436 1272 3 14467 CD19 14406 1269 3 14437 1272 4 14468 CD22 CD22-H10F4V2 12663 14407 1269 4 14438 1272 5 14469 CD22 CD22-HA22 12664 14408 1269 5 14439 1272 6 14470 MPL HU-161-2 12665 ​​14409 1269 440 1272 7 14471 MSLN MSLN-HU22A10 12666 14410 1269 7 14441 1272 8 14472 MSLN MSLN-7D9-HL 12667 14411 1269 8 14442 1272 9 14473 MSLN MSLN-5 12668 14412 1269 9 14443 1273 1270 0 14444 1273 1 14475 BCMA BCMA-huC12A3- L3H3 12670 14414 1270 1 14445 1273 2 14476 BCMA BCMA-J6M0 12671 14415 1270 2 14446 1273 7 1270 TABLE 4: LISTING OF SEQUENCES OF VARIOUS CDRs of vL REGIONS and / zRZLn / nznz / B / Yi vH BELONGING TO DIFFERENT ANTIGEN-BINDING DOMAINS DIRECTED TO DIFFERENT / zRZLn / nznz / B / Yi ANTIGENS ANTIGEN OBJECTIVE ANTIGEN UNIVENE MASTER VLCDR1 VLCDR 2 VLCDR 3 VHCDR 1 VHCDR2 VHCDR3 BCMA BCMA-AM14-HL 11961 1206 8 1217 5 1228 2 12389 12497 BCMA BCMA-RAMO8-HL 11962 1206 9 1217 6 1228 3 123 AMO6-HL 11963 1207 0 1217 7 1228 4 12391 12499 CD19 HU-CAT18-1-HL 11964 1207 1 1217 8 1228 5 12392 12500 CD19 Cat17-HL 11965 1207 2 1217 9 1228 6 12393 12501 CD22 HU-HA22-1 11966 1207 3 1218 0 1228 7 12394 12502 CD19 CD19-DART1 11967 1207 4 1218 1 1228 8 12395 12503 CD20 HU-UBLI-1-V4 11968 1207 5 1218 2 1228 9 12396 12504 INTEGRINE B7 HU-LNTB7-MMG49 11969 1207 6 12 12 12 0 12397 12505 BCMA BCMA-BB-CAR02 11970 1207 7 1218 4 1229 1 12398 12506 HER2 HER2-169 11971 1207 8 1218 5 1229 2 12399 12507 HER2 HER2-XMT-1520 11972 1207 9 1218 6 1229 3 12400 12508 HER2 HER2 HER2 HER2 HER2 HER2 HER2 HER2 HER2 HER2 -1518 11973 1208 0 1218 7 1229 4 12401 12509 HER2 HER2-HUMAB4D5- D98W 11974 1208 1 1218 8 1229 5 12402 12510 TSHR TSHR-HU-3BD10 11975 1208 2 1218 9 1229 6 12403 12511 PSMA PSMA PSMA PSMA PSMA 1219 0 1 229 7 12404 12512 PSMM PSMA-76-HL-AM 11977 1208 4 1219 1 1229 8 12405 12513 PSMA HU106MSMA-4HL 11978 1208 5 1219 2 1229 9 12406 12514 MSLN MSLN-3-HL-HL-AM 11979 1208 6 1219 3 12 12 12 12515 MSLN MSLN-5-HL 11980 1208 7 1219 4 1230 1 12408 12516 EGFRVIII EGFRVIII-2-AM-HL 11981 1208 8 1219 5 1230 2 12409 12517 EGFRVIII EGFRVIIH2M1863N2-HL 11982 1208 9 1219 EGFRVIII EGFRVIIH2M1915N-HL 11983 1209 0 1219 7 1230 4 12411 12519 EGFRIZ -HL 11986 1209 3 1220 0 1230 7 12414 12522 NECTIN4 NECTIN4-66-HL 11987 1209 4 1220 1 1230 8 12415 12523 MSLN MSLN-237-HL 11988 1209 5 1220 230 9 12416 12524 MSLN MSLN-HUAM15 119 1231 0 12417 12525 MSLN MSLN76923-HL 11990 1209 7 1220 4 1231 1 12418 12526 PROLR-CN PROLACTINE RECEIVE 11991 1209 8 1220 5 1231 2 12419 12527 MUC17 MUC17-11-CN 11992 1209 9 1220 6 12 12 AM1 11993 1210 0 1220 7 1231 4 12421 12529 CD19 CD19-9B7 11994 1210 1 1220 8 1231 5 12422 12530 CD20 CD20-HL 11995 1210 2 1220 9 1231 6 12423 12531 CD70 CD70-HL-AM13 11996 1210 3 1221 0 1231 12532 CDH19 CDH19-USC1HLV4 11997 1210 4 1221 1 1231 8 12425 12533 ​​CDH19 CDH19-Usec2-HL 11998 1210 5 1221 2 1231 9 12426 12534 CD16ORF5 4 C16ORF54-USC1V4 11999 1210 Huvista-Usec1-V4 12000 1210 7 1221 4 1232 1 12428 12536 Huvista-JJ-Usec2V4 12001 1210 8 1221 5 1232 2 12429 12537 GPC3 GPC3-Usec1-HL- V4 12002 1210 9 1221 6 1232 3 12430 12538 GPC3 GPC3- USC2-HL- V4 12003 1211 0 1221 7 1232 4 12431 12539 PRLR PRLR -USC2-HL-V4 12004 1211 1 1221 8 1232 5 12432 12540 MUC5AC MUC5AC-Usec1-HL- V4 12005 1211 2 1221 9 1232 6 12433 12541 FCH5 -USC1-HL-V4 12006 1211 3 1222 0 1232 7 12434 12542 LYPD1 LYPD1-HL-V4 12007 1211 4 1222 1 1232 8 12435 12543 EMR2 EMR2-USC1-V4 12008 2211 242 3 / zRZLn / nznz / B / Yi 5 2 9 EMR2 EMR2 -USC2-V4 12009 1211 6 1222 3 1233 0 12437 12545 EMR2 MEMR2 -USC3-V4 12010 1211 7 1222 4 1233 1 12438 12546 GPNMB M-GPNMB -usC1HL-V4 12011 1211 8 1222 5 1233 2 12439 12547 RNF43 RNF43-USC1-HL4 12012 1211 9 1222 6 1233 3 12440 12548 RNF43 RNF43-Usec2-HL4 12013 1212 0 1222 7 1233 4 12441 12549 CD44V6 CD44V6-Usec1-HL4 12014 1212 1 122 1 1222 8 1233 5 12442 1212 2 1222 9 1233 6 12443 12551 CEA CEA -USC1-HL4 12016 1212 3 1223 0 1233 7 12444 12552 Her3 Her3-Usec1-HL4 12017 1212 4 1223 1 1233 8 12445 12553 F0LR1 F0LR1-USC1-HL4 12018 1212 9 12446 12554 F0LR1 folr1-USC2-HL4 12019 1212 6 1223 3 1234 0 12447 12555 CLDN6 CLDN6-Usec1-LH4 12020 1212 7 1223 4 1234 1 12448 12556 CLDN6 CLDN6 -USC2-LH4 12021 1212 8 1223 -USC-1LH4 12022 1212 9 1223 6 1234 3 12450 12558 UPK1B HUPK1B-USC1LH4 12023 1213 0 1223 7 1234 4 12451 12559 UPK1B HUPK1B -USC2LH4 12024 1213 1 1223 8 1234 5 12452 12560 BMPR1B 1234 6 12453 12561 BMPR1B HBMPRI B -USC2LH4 12026 1213 3 1224 0 1234 7 12454 12562 LY6E LY6E-Usec1-HL4 12027 1213 4 1224 1 1234 8 12455 12563 Steap1 Steap1-Usec1HL4 12028 1213 5 1224 2 124 -LH4 12029 1213 6 1224 3 1235 0 12457 12565 WISP1 HU-UISP1-Usec1LH4 12030 1213 7 1224 4 1235 1 12458 12566 WISP1 HU-UISP1-Usec2LH4 12031 1213 8 1224 5 1235 2 12459 12567 SLC34A2 HUMX35 1235 3 12460 12568 CD19 hu-CD19-USC1LH4 12033 1214 0 1224 7 1235 4 12461 12569 / zRZLn / nznz / B / Yi CD22 CD22-HA22 12034 1214 1 1224 8 1235 5 12462 12570 Steap1 Steap1-HU120 12035 1214 2 1224 9 1235 6 ​​12463 12571 LIV1 HLIV1-MAB2 12036 1214 3 1225 0 1235 7 12464 12572 NECTIN4 HU-Nectin4 1235 8 12465 12573 CRIPT HU-CRIPT-L1H2 12038 1214 5 1225 2 1235 9 12466 12574 GPA33 HU-GPA33 12039 1214 6 1225 3 1236 0 12467 12575 R0R1 R0R1-Dart4 12040 1214 7 1225 4 1236 1 1246 1214 8 1225 5 1236 2 12469 12577 BCMA BCMA-PC 12042 1214 9 1225 6 1236 3 12470 12578 BCMA BCMA-AJ 12043 1215 0 1225 7 1236 4 12471 12579 BCMA BCMA-NM TS 12045 1215 2 1225 9 1236 6 12473 12581 BCMA BCMA-PP 12046 1215 3 1226 0 1236 7 12474 12582 BCMA BCMA-RD 12047 1215 4 1226 1 1236 8 12475 12583 BCMA BCMA-BB-CAR02 12048 1215 12584 CLL1 CLL1-24C8 12049 1215 6 1226 3 1237 0 12477 12585 CLL1 CLL1-24C1 12050 1215 7 1226 4 1237 1 12478 12586 FLT3 FLT3-10E3 12051 1215 8 1226 5 1237 2 12479 12587 FLT3 FLT3 FLT3-8B5 1 2052 1215 9 1226 6 1237 3 12480 12588 IL1RAP IL1RAP-PB57 12053 1216 0 1226 7 1237 4 12481 12589 IL1RAP IL1RAP-PB63 12054 1216 1 1226 8 1237 5 12482 12590 IL1rap MSLN MSLN-7D9-V3 12056 1216 3 1227 0 1237 7 12484 12592 MSLN MSLN-HU22A10 12057 1216 4 1227 1 1237 8 12485 12593 CD19 HU-BU13 12058 1216 5 1227 2 1237 9 12486 12594 BST1 HUST1 HU-BST1 1238 12487 12595 / zRZLn / nznz / B / Yi 6 3 0 BST1 HU-BST1-A2 12060 1216 7 1227 4 1238 1 12488 12596 BST1 HU-BST1-A3 12061 1216 8 1227 5 1238 2 12489 12597 HER2 HER2-XMT-1519 12062 1216 9 1227 6 1238 3 12490 1259 -XMT-1517 12063 1217 0 1227 7 1238 4 12491 12599 CD133 CD133-RW03 12064 1217 1 1227 8 1238 5 12492 12600 CD133 CD133-W6B3H10 12065 1217 2 1227 9 1238 6 12493 12601 CD133 IL113RA2 HU-CA13RA2-MAB47 16126 1615 7 1618 8 1621 9 16250 16281 CD22 CD22-INO 16127 1615 8 1618 9 1622 0 16251 16282 CD22 CD22-CELL4 16128 1615 9 1619 0 1622 1 16252 16283 CD22 1622 2 16253 16284 CD22 CD22-CELL7 16130 1616 1 1619 2 1622 3 16254 16285 CD22 CD22-VM1011 16131 1616 2 1619 3 1622 4 16255 16286 CD22 CD22-RAB-4120 16132 1616 3 1619 4 162 4 1622 5 162 12C5HL 16133 1616 4 1619 5 1622 6 16257 16288 CD22 CD22-MED-199 1616 7 1619 8 1622 9 16260 16291 BCMA BCMA-MJ22-9 16137 1616 8 1619 9 1623 0 16261 16292 BCMA BCMA-HUJ22-10 16138 1616 9 1620 0 1623 1 16262 16293 CD22 CD22-HU-HA22-2 1 1623 2 16263 16294 CD19 HUCD19-Usec3 16140 1617 1 1620 2 1623 3 16264 16295 CD22 BCMA-HU72 16141 1617 2 1620 3 1623 4 16265 16296 MPL HU-161-3 16142 1617 3 1620 4 1623 5 162666 1626 1629 -BAFFR-USC90 16143 1617 4 1620 5 1623 6 16267 16298 / zRZLn / nznz / B / Yi BAFF-R HU-BAFFR-UUSC55 16144 1617 5 1620 6 1623 7 16268 16299 BAFF-R HU-BAFFRMOR654 16145 1617 6 1620 7 1623 8 16269 16300 CD19 CD19-HU-MROO51 16146 1617 7 1620 8 1623 9 16270 16 H10F4V2 16147 1617 8 1620 9 1624 0 16271 16302 CD22 CD22-HA22 16148 1617 9 1621 0 1624 1 16272 16303 MPL HU-161-2 16149 1618 0 1621 1 1624 2 16273 16304 m. 16305 MSLN MSLN-7D9-HL 16151 1618 2 1621 3 1624 4 16275 16306 MSLN MSLN-5 16152 1618 3 1621 4 1624 5 16276 16307 BCMA BCMA-HUC13-F12 16153 1618 4 1621 5 1624 6 16277 16308 16308 16154 1618 5 1621 6 1624 7 16278 16309 BCMA BCMA-J6M0 16155 1618 6 1621 7 1624 8 16279 16310 / zRZLn / nznz / B / Yi TABLE 5 COMPONENT OF CAR DNA SEQ ID PRT SEQ ID CD8 signal peptide 1 4000 CD8 signal peptide 2 4001 IgH signal peptide 3 4002 IgH signal peptide 4 4003 (GGGGS)x3_linker 5 4004 DDAKKJigator 6 4005 GGGSG-Streptagx2-T ag 7 4006 PG4SP-ligator 8 4007 PG4SP-v2-ligator 9 4008 E-coil-ligator 10 4009 K-coil-ligator 11 4010 EAAAK-ligator 12 4011 EAAAK-v2-ligator 13 4012 Myc-(P)-TAG 14 4013 Myc -TAG 15 4014 MYC-TAG 16 4015 MYC2-TAG 17 4016 MYC4-TAG 18 4017 V5-TAG 19 4018 HA-TAG 20 4019 HIS-TAG 21 4020 AVIG-DELTA-GSG 22 4021 G4SX2-TAG 23 4022 G4SX2-TAG 24 4023 STREPTAGLL 25 4024 STREPTAGLL 26 4025 FLAG-TAG 27 4026 IGCL 28 4027 LGG1-CH1 29 4028 LGG2-0C-CHI 30 4029 lgG2-IC-CHI 31 4030 lgG3-CHI 32 4031 lgG4-CHI 33 4032 IgAI-CHI 34 4033 lgA2-CHI 35 4034 IgD-CHI 36 4035 IgE-CHI 37 4036 IgM-CHI 38 4037 hTCR-constant-alpha_X0383 4038 HTCRA-WT 40 4039 HTCRA-CSDVP 41 4040 HTCRA-OT2 42 4041 HTCRA-T48C-OT 43 4042 HTCRA-T48C-OT1 44 4043 HTCRA-SDVP 45 4044 HTCRA-S61 R 46 4045 HTCRA-SDVPR 47 404 opt2 48 4047 hTC R- b 1 - constant reg ion_X00437.1 49 4048 hTCR-b2-constant region_L34740 50 4049 hTCRb-WT 51 4050 hTCRb-S57C-opt1 52 4051 hTCRb-KACIAH 53 4052 hTCRb-4b05 KACIA5 4b05 4054 HTCRB-R79G 56 4055 HTCRBECD-CD3ZECDTMCP-OT 57 4056 PRETCRA_GB_U38996.1 58 4057 PRE-PRE-PRE-59 4058 PRE-PRE-DEL48 60 4059 HTCR-GAMMA 64 4063 / zRZLn / nznz / B / Yi CD3zECDTM-opt 65 4064 CD3zCP-opt 66 4065 CD3zECDTMCP-opt 67 4066 CD28-CP-opt 68 4067 41BB-CP-opt 69 4068 CD3e-CP-opt 70 4069 CD3zECDTM-opt2 71 4070 CD3zCP2-opt27 CD3zCP4opt2 70 4072 CD28-CP-OT2 74 4073 41BB-CP-OT2 75 4074 CD3ZECDTM-28Z-OT 76 4075 CD3ZECDTM-BBZ-PE 82 4081 P2A 83 4082 Variant P2A 84 4083 E2A 85 4084 SGSG 86 4085 SGSG 87 4086 Place of Furin tEGFR 94 4093 tEGFRviii 95 4094 tCD19 96 4095 tBCMA 97 4096 hCD8-Hinge-TM 98 4097 hCD8-Hinge-TM-BBz 99 4098 hCD8TM-Hinge-BB 100 4099 Cytosolic domain CD3z 101 4100 CD3z 1Cytosolic domain TM- Hinge2 100 -Cytosolic domain 103 4102 Myr-MYD88-CD40-Fv'-Fv 104 4103 IL12F 105 4104 41BB-L 106 4105 CD40L 107 4106 K13 108 4107 / zRZLn / nznz / B / Yi MC159 109 4108 CFLIP-L / MRIT-ALPHA 110 4109 CFLIP-P22 111 4110 FKBP-K13 112 4111 FKBPX2-K13 113 4112 HTLV1-TAX 114 4113 HTLV2-TAX 115 4114 HTLV2-TAX-RERS 116 4115 ICASPASE-9 -1 Vif 118 4117 i7R7 Ln / nznz / E / YiAi TABLE 6: LIST OF SEQUENCES OF DIFFERENT CAR classes according to the BCMA-AmO6-HL antigen-binding domain. The CAR type and accessory modules are also displayed. The CAR classes 16 and 17 represent a string of a double-stranded SIRs and show biological activity only when co-expressed with their complementary strand (ie, CAR classes 18 and 19, respectively). CAR classes 13-15 (single-stranded SIR) show only weak activity. CAR class SEQ ID (ADN ) SEQ ID (PRT) NAME TYPE OF CAR Class 1 CAR accessory module 377 4340 CD8SP-BCMA-AmO6-HL-vL-V5[hTCRb-KACIAH]-F-P2A-SP-BCMAAmO6 -HL-vH-Myc-[hTCRa-CSDVP]-FF2A-PAC SIR double chain PAC CAR Class 2 378 4341 CD8SP-BCMA-AmO6-HL-vL-V5- [hTCRb-KACIAH]-F-P2A-SP- BCMAAmO6-HL-vH-Myc-[preTCRa-Del48]-FF2A-PAC SIR double chain PAC CAR Class 3 379 4342 CD8SP-V5-[hTCRb-KACIAH]-F-P2ACD8SP-BCMA-AmO6-HL-vL-Gly -SerLigador-BCMA-Am06-HL-vH-Myc[hTCRa-CSDVP]-F-F2A-PAC SIR one and a half chain PAC CAR Class 4 380 4343 CD8SP-V5-[hTCRb-KACIAH]-F-P2ACD8SP-BCMA -Am06-HL-vL-Gly-SerLigador-BCMA-Am06-HL-vH-Myc4[preTCRa-Del48]-F-F2A-PAC SIR one and a half chain PAC CAR Class 5 381 4344 CD8SP-MYC-[hTCRa- T48C-opt1]-FF2A-SP-BCMA-AmO6-HL-vL-Gly-SerLigator-BCMA-Am06-HL-vH-V5[hTCRb-S57C-opt1]-F-P2A-PAC Double-chain SIR PAC CAR Class 6 382 4345 CD8SP-BCMA-AmO6-HL-vL-V5[hTCRb-S57C-opt]-F-P2A-SP-BCMAAm06-HL-vH-Myc-[hTCRa-T48C-opt]-FF2A-PAC SIR double chain PAC CAR Class 7 383 4346 CD8SP-BCMA-AmO6-HL-vL-[hTCRbopt2]-F-P2A-SP-BCMA-Am06-HL-vH[hTC Ra-opt2]- F- F2A- PAC SIR of double chain PAC CAR Class 8 384 4347 CD8SP-BCMA-AmO6-HL-vL-[hTCRbopt2]-F-P2A-SP-BCMA-Am06-HL-vHMyc-[preTCRa-Del48]-F-F2A-PAC double SIR chain PAC CAR Class 9 385 4348 CD8SP-[hTCRb-opt2]-F-P2A-CD8SPBCMA-Am06-HL-vL-Gly-Ser-LigadorBCMA-AmO6-HL-vH-Myc4-[preTCRaDel48]-F-F2A-PAC 1.5-chain SIR PAC CAR Class 10 386 4349 CD8SP-BCMA-AmO6-HL-vL-V5[hTCRg 1 -opt]-F- P2A-SP- BCMA-AmO6HL-vH-Myc-[hTCRd-opt]- F-F2A-PAC SIR double chain PAC CAR Class 11 387 4350 CD8SP-V5-[hTCRg1-opt]-F-P2A- CD8SP-BCMA-AmO6-HL-vL-Gly-SerLigador-BCMA-Am06-HL-vH -Myc[hTCRd-opt]-F-F2A-PAC SIR one and a half chain PAC CAR Class 12 388 4351 CD8SP-G4Sx2-[hTCRa-S61 R-opt]-FF2A-SP-BCMA-AmO6-HL-vl_- Gly-SerLigador-BCMA-Am06-HL-vH-G4Sx2[hTCRb-R79G-opt]-F-P2A-PAC SIR one and a half chain PAC CAR Class 13 389 4352 CD8SP-BCMA-AmO6-HL-vL-Gly-SerLigador-BCMA-Am06-HL-vH-[hTCRaSDVP]-F-F2A-PAC SIR single chain PAC CAR Class 14 390 4353 CD8SP-BCMA-AmO6-HL-vL-Gly-SerLigador-BCMA-Am06-HL-vH-[hTCRb- KAIAH]-F-P2A-PAC SIR single chain PAC CAR Class 15 391 4354 CD8SP-BCMA-AmO6 -HL-vL-Gly-SerLigador-BCMA-Am06-HL-vH-Myc4[preTCRa-Del48]-F-F2A-PAC SIR single chain PAC CAR Class 16 392 4355 CD8SP-BCMA-AmO6-HL-vL-V5 [hTC Rb-S57C-opt]- F- P2A- PAC One chain of a double chain SIR PAC CAR Class 17 393 4356 CD8SP-BCMA-AmO6-HL-vL-V5[hTCRb-S57C-opt] One chain of a CAR Class 18 double-chain SIR 394 4357 lgHSP-BCMA-AmO6-HL-vH-Myc[hTCRa-T48C-opt]-F-F2A-BlastR One chain of a double-chain SIR !7R7 Ln / nznZ / Ε / ΥΙΛΙ CAR Class 19 395 4358 lgHSP-BCMA-AmO6-HL-vH-Myc[hTCRa-T48C-opt] One strand of a double stranded SIR CAR Class 20 396 4359 CD8SP-BCMA-AmO6-HL-vl_-Gly-SerLigator- BCMA-Am06-HL-vH-MycCD8TM-BBZ CAR II CAR Class 21 397 4360 CD8SP-BCMA-AmO6-HL-vH-Gly-Ser- Ligador-vL-Myc-CD8TM-BBz CAR II CAR Class 22 398 4361 CD8SP- BCMA-AmO6-HL-vL-Gly-Ser- Ligador-BCMA-Am06-HL-vH-MycCD8TM-Z-P2A-K13-FLAG-T2A-PAC CAR 1 K13 and PAC CAR Class 23 399 4362 CD8SP-BCMA-AmO6 -HL-vl_-[hTCRaCSDVP]-F-F2A-SP-BCMA-AmO6-HLvH-[hTCRb-KACIAH]-F-P2A-Xba-PAC SIR double chain PAC CAR Class 24 400 4363 CD8SP-BCMA-Am06- HL-vL-PG4SPv2-[hTCRb-KACIAH]-F-P2A-SP-BCMAAmO6-HL-vH-PG4SP-[hTCRa-CSDVP]F-F2A-PAC Dual Chain SIR PAC CAR Class 25 401 4364 CD8SP-BCMA- Am06-HL-vL-E-Coil[hTCRb-KACIAH]-F-P2A-SP-BCMAAm06-HL-vH-K-Coil-[hTCRa-CSDVP]F-F2A-PAC Dual Chain SIR PAC CAR Class 26 402 4365 CD8SP-BCMA-AmO6-HL-vl_-EAAAK[hTCRb-KACIAH]-F-P2A-SP-BCMAAmO6-HL-vH-EAAAK-v2-[hTCRaCSDVP]-F-F2A-PAC Dual-chain SIR PAC CAR Class 27 403 4366 CD 8SP-BCMA-Am06-HL-vL-V5[hTCRb-KACIAH]-F-P2A-SP-BCMAAmO6-HL-vH-Myc4-[hTCRa-CSDVP]-FF2A-PAC Dual Chain SIR PAC CAR Class 28 404 4367 CD8SP-BCMA-Am06-HL-vL-Myc2[hTCRb-KACIAH]-F-P2A-SP-BCMAAmO6-HL-vH-Myc4-[hTCRa-CSDVP]-FF2A-PAC SIR Dual Chain PAC CAR Class 29 405 4368 CD8SP-BCMA-AmO6-HL-vL-[hTCRbKACIAH]-F-P2A-SP-BCMA-AmO6-HLvH-[hTCRa-CSDVP]-F-F2A-PAC Dual Chain SIR PAC CAR Class 30 406 4369 CD8-BCMA -AmO6-HL-vl_4gCL- CD3zECDTMCP-opt-F-P2A-SP-Bst- BCMA-AmO6-HL-vH-lgGTCH1- CD3zECDTMCP-opt2-F-F2A-PAC zSIR PAC CAR Class 31 407 4370 CD8SP-BCMA-AmO6 -HL-vL-[hTCRbECD-Bam-CD3zECDTMCPopt]-F-P2A-SP-BCMA-Am06-HL-vH[hTCRaECD-Kpn-CD3zECDTMCPopt2] zSIR !7R7 Ln / nznZ / Ε / ΥΙΛΙ CAR Class 32 408 4371 CD8SP-BCMA-AmO6-HL-vL-[hTCRbKAC-ECD-Bam-CD3zECDTMCP-opt]F-P2A-SP-BCMA-AmO6-HL-vH[hTCRa-CSDVP-ECD-KpnCD3zECDTMCP-opt2] SIR CAR Class 33 409 4372 CD8SP-BCMA-AmO6-HL-vl_-V5[hTCRbECD-Bam-CD3zECDTMCPopt]-F-P2A-SP-BCMA-Am06-HL-vHMyc-[hTCRaECD-Kpn-CD3zECDTM28z-opt2] SIR PAC CAR Class 34 410 4373 CD8SP-BCMA-AmO6-HL-vL-V5[hTCRbECD-Bam-CD3zECDTM-28zopt]- F- P2A-S P- BCM A- Am 06- H L-vHMyc-[hTCRaECD-Kpn-CD3zECDTM28z -opt2] SIR CAR Class 35 411 4374 CD8SP-BCMA-AmO6-HL-vl_-V5- [hTCRbECD-Bam-CD3zECDTMCPopt]- F- P2 A-S P- BC M A-Am 06- H L-v H Myc4-[hTCRaECD- Kpn-CD3zECDTMBz-opt2] SIR CAR Class 36 412 4375 CD8SP-BCMA-AmO6-HL-vL-V5[hTCRbECD-Bam-CD3zECDTM-BBzopt]- F- P2A-S P- BCM A-Am 06- H L-vHMyc4 -[hTCRaECD-Kpn-CD3zECDTMBBz-opt2] SIR CAR Class 37 413 4376 CD8-BCMA-Am06-HL-vL-lgCL-Xho-CD3zECDTMCP-opt-F-P2A-Spe-SP- Bst-BCMA-AmO6-HL- vH-lgG1-CH1- Mlu-CD3zECDTMCP-opt2-F-F2A-PACDeltaWPRE zSIR CAR Class 38 414 4377 CD8SP-BCMA-AmO6-HL-(vL-vH)-Mycz-P2A-hNEMO-K277A-Flag-T2A-PAC CAR I HNE MOK277AFlag and PAC CAR Class 39 415 4378 CD8SP-BCMA-AmO6-HL-(vL-vH)- CD3e-ECDTMCP-opt2-P2A-hNEMO- K277A-Flag-T2A-PAC TFP hNEMOK277AFlag and PAC CAR Class 40 416 4379 CD8SP- BCMA-AmO6-HL-(vL-vH)- CD3d-ECDTMCP-opt2-P2A-hNEMO- K277A-Flag-T2A-PAC TFP hNEMOK277AFlag and PAC CAR Class 41 417 4380 CD8SP-BCMA-AmO6-HL-(vL-vH )- CD3g-ECDTMCP-opt2-P2A-hNEMO- K277A-Flag-T2A-PAC TFP hNEMOK277AFlag and PAC CAR Class 42 418 4381 CD8SP-BCMA-AmO6-HL-(vL-vH)- CD3z-ECDTMCP-opt2-P2A- hNEMO-K277A-Flag-T2A-PAC TFP hNEMOK277AFlag and PAC !7R7 Ln / nznZ / Ε / ΥΙΛΙ CAR Class 43 419 4382 CD8SP-BCMA-AmO6-HL-vL-[lgCLTCRg-6MD]-F-P2A-SP-BCMA-AmO6HL-vH-[lgG1-CH1-TCRd-6MD]-F-F2AhNEMO-K277A Ab- TCR hNEMOK277AFlag CAR Class 44 420 4383 CD8SP-BCMA-AmO6-HL-vL-[lgCL- TCRb-IAH-6MD]-F-P2A-SP-BCMAAmO6-HL-vH-[lgG1-CH1-TCRa-SDVP6MD]-F -F2A-hNEMO-K277A Ab-TCR hNEMOK277AFlag CAR Class 45 421 4384 CD8SP-BCMA-AmO6-HL-(vH-vL)- CD3e-ECDTMCP-opt2-P2A-hNEMO- K277A-Flag-T2A-PAC TFP hNEMOK277AFlag and PAC CAR Class 46 422 4385 CD8SP-BCMA-AmO6-HL-(vH-vL)- CD3d-ECDTMCP-opt2-P2A-hNEMO- K277A-Flag-T2A-PAC TFP hNEMOK277A- Flag and PAC CAR Class 47 423 4386 CD8SP-BCMA -AmO6-HL-(vH-vL)CD3g-ECDTMCP-opt2-P2A-hNEMOK277A-Flag-T2A-PAC TFP hNEMOK277AFlag and PAC CAR Class 48 424 4387 CD8SP-BCMA-AmO6-HL-(vH-vL)- CD3z- ECDTMCP-opt2-P2A-hNEMO- K277A-Flag-T2A-PAC TFP hNEMOK277AFlag and PAC CAR Class 49 425 4388 CD8SP-BCMA-Am06-HL-vL-Xho- CD3zECDTMCP-opt-F-P2A-Spe-SP- BCMA- AmO6-HL-vH-Mlu- CD3zECDTMCP-opt2-F-F2A-PAC zSIR PAC CAR Class 50 1278 4 1452 8 CD8SP-BCMA-AmO6-vL-[hTCRbS57C]- F- P2A-S P- BCMA-Am 06-vH[hTCRa-T48C] CAR Class 51 Dual Chain SIR 1278 5 1452 9 CD8SP-BCMA-AmO6-vL-[hTCRbS57C]-F-P2A-SP-BCMA-AmO6-vH[hTCRa-T48C]-F- F2A-K13-opt Dual Chain SIR K13vFLIP CAR Class 52 1278 6 1453 0 CD8SP-BCMA-AmO6-vL-[hTCRaT48C]-F-P2A-SP-BCMA-AmO6-vH[hTCRa-S57C] Dual Chain CAR SIR Class 53 1278 7 1453 1 CD8SP-BCMA-AmO6-vL-[hTCRaT48C]-F-P2A-SP-BCMA-AmO6-vH[hTCRa-S57C]-F-P2A-K13-opt Dual-chain SIR K13vFLIP !7R7 Ln / nznZ / Ε / ΥΙΛΙ TABLE 7: LIST OF SEQUENCES OF DIFFERENT CONSTRUCTIONS OF CARS CONTAINING DIFFERENT BINDING DOMAINS OF ANTIGENS. THE ORDER OF THE DIFFERENT CONSTRUCTIONS OF CARS IS AS SHOWN IN TABLE 6 FOR CARS BASED ON BCMA-AmO6-HL. / zAZLn / nznz / B / Yi CARs Antigen target Antigen-binding domain SEQ ID NO (DNA) SEQ ID NO (PRT) 1 BCMA BCMA-Am14-HL 475-523 4438-4486 2 BCMA BCMA-AmO8-HL 426-474 4389-4437 3 BCMA BCMA -AmO6-HL 377-425; 1278412787 4340-4388; 14528-14531 4 CD19 hu-CAT18-1-HL 867-915 4830-4871 5 CD19 CAT17-HL 818-866 4781-4829 6 CD22 hu-HA22-1 1112-1160 5068-5115 7 CD19 CD19-DART1 916-964 4872-4920 8 CD20 hu-Ubli-1-v4 1063-1111 5019-5067 9 Hu Hu-lntB7-MMG49 2533-2581 6489-6537 10 BCMA BCMA-BB-CAR02 524-572 4487-4535 11 Her2 Her2-169 2288 -2336 6244-6292 12 Her2 Her2-XMT-1520 2435-2483 6391-6439 13 Her2 Her2-XMT-1518 2386-2434 6342-6390 14 Her2 Her2-huMab4D5-D98W 2337-2385 6293-6341 TSHR-huTSHR 3BD10 3611-3659 7567-7615 16 PSMA PSMA-83A12-HL-AM 3317-3365 7273-7321 17 PSMA PSMA-76-HL-AM 3268-3316 7224-7272 18 PSMA hu106mPSMA-4-HL 3219-37567 223 19 MSLN MSLN-3-HL-AM 2729-2777 6685-6733 20 MSLN MSLN-5-HL 2778-2826 6734-6782 21 EGFRviii EGFRviii-2-AM-HL 1651-1699 5607-5655 22 EGFRviii EGFR1863-H2MLviii 1749-1797 5705-5753 23 EGFRVIII EGFRVIII-H2M1915N-HL 1798-1846 5754-5802 24 EGFRVIII EGFRVIII-131-2 1700-1748 5656-5704 25 DLL3 DLL3-AM6-HL 1553-1601 5509-5557 -HL 1602-1650 5558-5606 27 Nectin 4 Nectin 4-66-HL 3072-3120 7028-7076 28 MSLN MSLN-237-HL 2827-2875 6783-6831 29 MSLN MSLN-HuAM15 2925-2973 6881-6929 30 MSLN MSLN76923-HL 2876-29324 PR08 PR08 CN 3121-3169 7077-7125 32 Muc17 Muc17-11-CN 3023-3071 6979-7027 33 CD19 CD19-AM1 769-817 4732-4780 34 CD19 CD19-9B7 720-768 4683-4731 35 CDHL1020204 4970-5018 36 CD70 CD70-HL-AM13 1210-1258 5166-5214 37 CDH19 CDH19-USC1-HLv4 1308-1356 5264-5312 38 CDH19 CDH19-USC2-HL 1357-1405 5313-5361 39 C16ORF54 C16ORF54-USC1-V4 671-719 4634-4682 40 VISTA huVISTA-USC1-v4 3807-3855 7763-7811 41 VISTA huVISTA-75-JvJ4- 3806 7714-7762 42 GPC3 GPC3-USC1-HL-V4 2141-2189 6097-6145 43 GPC3 GPC3-USC2-HL-V4 2190-2238 6146-6194 44 PRLR PRLR-USC2-HL-V4 3170-3218 712 655 Muc5Ac Muc5Ac-USC1-HL-V4 2974-3022 6930-6978 46 FCRH5 FCRH5-USC1-HL-V4 1994-2042 5950-5998 47 LYPD1 LYPD1-HL-V4 2631-2679 6587-6635 48 EMR2 EMR2-V4-US187 -1895 5803-5851 49 EMR2 EMR2-USC2-V4 1896-1944 5852-5900 50 EMR2 mEMR2-USC3-V4 1945-1993 5901-5949 51 gPNMB m-gPNMB-USC1-HL-v4 2239-2287 6195-62RN432F4 RNF43-USC1-HL4 3366-3414 7322-7370 53 RNF43 RNF43-Usec2-HL4 3415-3463 7371-7419 54 CD44V6 CD44V6-Usec1-HL4 1161-1209 5117-5165 55 ROBO4 ROBO4 ROBO4 ROBO4 CEA-USC1-HL4 1406-1454 5362-5410 57 Her3 Her3-USC1-HL4 2484-2532 6440-6488 58 FOLR1 FOLR1-USC1-HL4 2043-2091 5999-6047 59 FOLR1 FOLR1-USC2-2-HL2 1409 209-604 60 CLDN6 CLDN6-USC1-LH4 1455-1503 5411-5459 61 CLDN6 CLDN6 -USC2-LH4 1504-1552 5460-5508 62 MMP16 HMMP16 -USC-1-LH4 2680-2728 6636-6684 63 UPK1B HUPK1B -US -USC1-LH4 3660-3708 7616-7664 64 LH4 3709-3757 7665-7713 65 BMPR1B HBMPR1B-Usec1-LH4 573-621 4536-4584 66 BMPR1B HBMPR1B-USC2-LH4 622-670 4585-4633 67 LY6E LY6E LY6E-Use-Use-USC1-HL4 2582 USC1-HL4 3513-3561 7469-7517 69 CD79b CD79b-USC1-LH4 1259-1307 5215-5263 70 WISP1 hu-UISP1-USC1-LH4 3856-3904 7812-7860 71 WISP1 hu-UISP1-USC3905-LH4 79305 79305 -7909 72 SLC34A2 HUMX35-LH4 3562-3610 7518-7566 73 CD19 HU-CD19-USC1-LH4 965-1013 4921-4969 74 CD22 CD22-HA22830-8778 10361-10409 75 Steap1 Steap1 Steap1 Steap1 Steap1 76 LIV1 HLIV1-MAB2 9318-9366 10949-10997 77 Nectin 4 HU-Nectin4-MAB1 9465-9513 11096-11144 78 Crypt HU-CRIPT-L1H2 8877-8925 10508-10556 79 GPA33 HU-GPA ROR1 ROR1-DART4 9514-9562 11145-11193 81 BCMA BCMA-FS 8191-8239 9822-9870 / zRZLn / nznz / B / Yi 82 BCMA BCMA-PC 8289-8337 9920-9968 83 BCMA BCMA-AJ 8093-8141 9724-9772 84 BCMA BCMA-NM 8240-8288 9871-9919 85 BCMA BCMA-TS 8436-8484 10057-101 BCMA38 -8386 9969-10017 87 BCMA BCMA-RD 8387-8435 10018-10066 88 BCMA BCMA-BB-CAR02 8142-8190 9773-9821 89 CLL1 CLL1-24C8 8828-8876 10459-10507 90 CLL1 CLL1 CLL1 CLL1 CLL1 10458 91 FLT3 FLT3-10E3 8975-9023 10606-10654 92 FLT3 FLT3-8B5 8926-8974 10557-10605 93 IL1RAP IL1RAP-PB57 9171-9219 10802-10850 94 IL1RAP IL1RAP IL1RAP IL1RAP -CANO4 9269-9317 10900-10948 96 MSLN MSLN-7D9-V3 9367-9415 10998-11046 97 MSLN MSLN-HU22A10 9416-9464 11047-11095 98 CD19 HU-BU13 8632-8680 10263-10311 99 BST1 8485-8533 10116-10164 100 BST1 hu-BST1-A2 8534-8582 10165-10212 101 BST1 hu-BST1-A3 8583-8631 10213-10262 102 Her2 Her2-XMT-1519 9122-9170-10871 Her2XMT1 -1517 9073-9121 10704-10752 104 CD133 CD133-RW03 11312-11360 11472-11520 105 CD133 CD133-W6B3H10 11361-11409 11521-11569 106 CD1 33 CD133-293AC1C3B9 11410-11458 11570-11618 107 IL113RA2 HU-IL13RA2-MAB47 14113-14165 15857-15909 108 CD22 CD22-INO 13424-13476 15168-15220 109 CD22 CD22 CD22 13211 13477-13529 15221-15273 115 CD22 CD22-MED-199 13053-13105 14797-14849 119 BCMA BCMA-HUJ22-10 12947-12999 14691-14743 120 CD22 CD22-HU-HA22-2 13371-13423 15115-15167 121 CD19 HUCD19 -usC3 14060-14112 15804-15856 12788-12840 14532-14584 123 MPL hu-161-3 13795-13847 15539-15591 124 BAFF-R hu-BAFFR-USC90 13954-14006 15698-15750 125 BAFF-R hu-BAFFR-USC55-136951 / zRZLn / nznz / B / Yi 126 BAFF-R HU-BAFFFR-MOR6654 13848-13900 15592-15644 127 CD19 CD19-HU-MROO5-1 14007-14059 15751-15803 128 CD22 CD22-H10F4V2 13265-13317 15009-15061 129 CD22 CD22 -15114 130 MPL HU-161-2 13742-13794 15486-15538 131 MSLN MSLN-HU22A10 14325-14377 16069-16021 132 MSLN MSLN-7D9-HL 14272-14324 16016-16068 133 MSLN MSLN 134 BCMA BCMA-huC13-F12 12894-12946 14638-14690 135 BCMA BCMA-huC12A3-L3H3 12841-12893 14585-14637 136 BCMA BCMA-J6M0 13000-13052 14744-1479 i7R7 Ln / nznz / E / YiAi Table 8. zSIR, SIR and miscellaneous exemplary constructs SEQ ID (ADN) SEQ ID (PRT) NAME 3955 7955 CD8SP-hCD19-EUK5-13-vL-lgCL-Bam-CD3zECDTMCP-opt-F-P2A-SPBst-hCD19-EUK5-13-vH-lgG1-CH1-KPN -CD3zECDTMCP-opt2-F-F2APAC 3956 7956 CD8-hCD19-EUK5-13-vL-lgCL-Xho-CD3zECDTMCP-opt-F-P2A-SpeSP-Bst-hCD19-EUK5-13-vH-lgG1-CH1-Mlu- CD3zECDTMCP-opt2-FF2A-PAC 3957 7957 CD8SP-hCD19-EUK5-13-vL-Xho-CD3zECDTMCP-opt-F-P2A-Spe-SPhCD19-EUK5-13-vH-Mlu-CD3zECDTMCP-opt2-F-F2A-PAC 3958 7958 3959 7959 CD8SP-FMC63-vL-Xho-CD3zECDTMCP-opt-F-P2A-Spe-SP-FMC63vH-Mlu-CD3zECDTMCP-opt2-F-F2A-PAC 3960 7960 hCD19-Bu12-Xho-CD3zECDTMCP-opt-F -P2A-Pac 3961 7961 CD8SP-CD19Bu12-scFv-Xho-CD3zECDTMCP-opt-F-P2A-SPCD19MM-scFv-Mlu-CD3zECDTMCP-opt2-F-F2A-PAC 3962 7962 CD8SP-CD19Bu12-scFv-Xho-CD3zECDTMCP-opt -F-P2A-SP-CD123DART2-scFv-Mlu-CD3zECDTMCP-opt2-F-F2A-PAC 3963 7963 CD8SP-CD19Bu12-scFv-Xho-CD3zECDTMCP-opt-F-P2A-SP-CD202F2-scFv-Mlu-CD3zECDTMCP- opt2-F-F2A-PAC 3964 7964 CD8SP-CD19Bu12-scFv-Xho-CD3zECDTMCP-opt-F-P2A-SP-AFP-61scF v-M I u-C D3z EC DT M C P- opt2- F- F2 A- P AC 3965 7965 CD8SP- CD19Bu12-scFv-Xho-CD3zECDTMCP-opt-F-P2A-SP-CD22h10F4v2-scFv-Mlu-CD3zECDTMCP-opt2-F-F2A-PAC 3966 7966 CD8SP-CD19Bu12-scFv-Xho-CD3zECDTMCP-opt-F-P2A-SP -hSC2210- H L-scF v- ΜI u-C D3zEC DTM C P-opt2- F- F2 A- PAC 3967 7967 CD8SP-CD19Bu12-scFv-Xho-CD3zECDTMCP-opt-F-P2A-SP-CD123DART1-scFv-Mlu- CD3zECDTMCP-opt2-F-F2A-PAC 3968 7968 CD8SP-CD19Bu12-scFv-Xho-CD3zECDTMCP-opt-F-P2A-SP-WT1Ab5-scFv-Mlu-CD3zECDTMCP-opt2-F-F2A-PAC SEQ ID (ADN) SEQ ID (PRT) NAME 3969 7969 CD8SP-CD19-USC2-vL-[hTCRb-KACIAH]-F-P2A-SP-CD19-USC2-vH[hTCRa-CSDVP]-F-F2A-PAC 3971 7971 CD8SP-BCMA-Am06-HL-vL-[CD3zECDTM-28z-opt]-F-P2A-SP-BCMAAm06-HL-vH-[CD3zECDTM-28z-opt2] 3972 7972 CD8SP-BCMA-Am06-HL-vL- [CD3zECDTM-BBz-opt]-F-P2A-SP-BCMAAm06-HL-vH-[CD3zECDTM-BBz-opt2] 16311 16335 CD8SP-FMC63-BBZ 16312 16336 CD8SP-MSLN-hu22A10-BBz 16313 16337 CD8SP-MSLN-7D9 -HL-BBZ 16314 16338 CD8SP-MSLN-5-HL-BBZ 16315 16339 CD8SP-MPL-hu-161-2-BBz 16316 16340 CD8SP-BCMA-huC13-F12-BBz 16317 16341 CD8SP-huCD19-mROO5-1-BBz 16318 16342 CD8SP-huCD19-mROO5-1-vL-[hTCRb-KACIAH]-F-P2A-SP-huCD19mROO5-1-vH-[hTCRa-CSDVP]-F-F2A-K13-opt 16319 16343 CD8SP-CD22-INO -vL-[hTCRb-S57C]-F-P2A-SP-CD22-INO-vH-[hTCRaT48C]-F-F2A-PAC 16320 16344 CD8SP-CD22-hu-HA22-2-vL-[hTCRa-T48C]- F-P2A-SP-CD22-hu-HA222-vH-[hTCRa-S57C]- F- F2A-Pac 16321 16345 CD8SP-CD22-Med-12C5-HL-vH-[hTCRb-S57C]-F-P2A-SP -CD22-Med12C5-HL-vL-[hTCRa-T48C]-F-F2A-PAC 16322 16346 CD8SP-hu-RFB4-vL-[hTCRb-S57C]-F-P2A-SP-hu -RFB4-vH-[hTCRaT48C]-F-F2A-PAC 16323 16347 CD8SP-CD22-CELL7-vH-[hTCRb-S57C]-F-P2A-SP-CD22-CELL7-vL[hTCRa-T48C]-F-F2A -PAC 16324 16348 CD8SP-CD22-HA22-vL-[hTCRb-S57C]-F-P2A-SP-CD22-HA22-vH[hTCRa-T48C]-F-F2A-PAC 16325 16349 CD8SP-MSLN-7D9-HL- vH-[hTCRa-T48C]-F-P2A-SP-MSLN-7D9-HL-vL[hTCRa-S57C] 16326 16350 CD8SP-MSLN-7D9-HL-vH-[hTCRb-S57C]-F-P2A-SP- MSLN-7D9-HL-vL[hTCRa-T48C] 16328 16351 CD8SP-huCD19-mROO5-1-(vL-vH)-CD3e-ECDTMCP-opt2-T2A-PAC 16329 16352 CD8SP-huCD19-mROO5-1-(vL- vH)-CD3d-ECDTMCP-opt2-T2A-PAC 16330 16353 CD8SP-huCD19-mROO5-1-vL-[hTCRb-KACIAH]-F-P2A-SP-huCD19mROO5-1-vH-[hTCRa-CSDVP] 16331 16354 CD8SP -MSLN-hu22A10-vL-[hTCRb-KACIAH]-F-P2A-SP-MSLNhu22A10-vH-[hTCRa-CSDVP]-F-F2A-K13-Opt 16332 16355 CD8SP-MSLN-hu22A10-vL-[hTCRb-KACIAH ]-F-P2A-SP-MSLNhu22A10-vH-[hTCRa-CSDVP] 16333 16356 CD8SP-MSLN-7D9-HL-vH-[hTCRb-KACIAH]-F-P2A-SP-MSLN-7D9-HLvL-[hTCRa- CSDVP]-F-F2A-K13-opt !7R7 Ln / nznZ / Ε / ΥΙΛΙ SEQ ID (ADN) SEQ ID (PRT) NAME 16334 16357 CD8SP-MSLN-7D9-HL-vH-[hTCRb-KACIAH]-F-P2A-SP-MSLN-7D9vL-[hTCRa-CSDVP] HL- 16361 16358 CD8SP- MSLN-5-HL-vH-[hTCRa-CSDVP]-F-F2A-SP-MSLN-5-HL-vL[hTCRb-KACIAH] 16362 16359 CD8SP-MSLN-7D9-HL-vH-[hTCRa-CSDVP]- F-F2A-SP-MSLN-7D9-HLvL-[hTCRb-KACIAH] 16363 16360 CD8SP-MSLN-hu22A10-vL-[hTCRa-CSDVP]-F-F2A-SP-MSLNhu22A10-vH-[hTCRb-KACIAH] [00701 ] Table 9: Exemplary Vif Constructs SEQ ID (DNA) SEQ ID (PRT) NAME 11243 11270 HIV 1-Vif 11244 11271 CD8SP-FMC63-(vl_-vH)-Myc-BBz-T2A-PAC 11245 11272 CD8SP-FMC63-( vL-vH)-Myc-BBz-F-P2A-Vif-F-P2A-PAC 11246 11273 CD8SP-hu-CD19-USC1-LH4-vL-V5-[hTCRb-KACIAH]-F-P2A-SPhu-CD19- USC1-LH4-vH-Myc-[hTCRa-CSDVP]-F-F2A-Vif 11247 11274 CD8SP-hu-CD19-USC1-LH4-vL-V5-[hTCRb-KACIAH]-F-P2A-SPhu-CD19-USC1 -LH4-vH-Myc-[preTCRa-Del48]-F-F2A-Vif 11248 11275 CD8SP-V5-[hTCRb-KACIAH]-F-P2A-CD8SP-hu-CD19-USC1-LH4vL-Gly-Ser-Ligator- hu-CD19-USC1-LH4-vH-Myc-[hTCRa-CSDVP]F-F2A-V¡f 11249 11276 CD8SP-hu-CD19-USC1-LH4-vL-V5-[hTCRg1-opt]-F-P2A- S P-huCD19-USC1-LH4-vH-Myc-[hTCRd-opt]-F-F2A-Vif 11250 11277 CD8SP-V5-[hTCRg1-opt]-F-P2A-CD8SP-hu-CD19-USC1-LH4-vLGly -Ser-Ligator-hu-CD19-USC1-LH4-vH-Myc-[hTCRd-opt]-F-F2A- Vif 11251 11278 CD8SP-hu-CD19-USC1-LH4-vL-Gly-Ser-Ligator-hu- CD19-USC1LH4-vH-Myc-CD8TM-z-P2A-K13-FLAG-T2A-Vif 11252 11279 CD8SP-hu-CD19-USC1-LH4-vL-[hTCRa-CSDVP]-F-F2A-SP-huCD19-USC1 -LH4-vH-[hTCRb-KACIAH]-F-P2A-Vif 11253 11280 CD8-hu-CD19-USC1-LH4-vL-lgCL-Bam-CD3zECDTMCP-opt-FP2A-Spe-SP-Bst-hu-CD19- USC1-LH4-vH-lgG1-CH1-KPNCD3zECDTMCP-opt2-F-F2A-Xba-Vif 11254 11281 CD8-hu-CD19-USC1-LH4-vL-lgCL-Xho-CD3zECDTMCP-opt-FP2A-Spe-SP-Bst -hu-CD19-USC1-LH4-vH-lgG1-CH1-MluCD3zECDTMCP-opt2-F-F2A-Vif 11255 11282 CD8SP-hu-CD19-USC1-LH4-(vL-vH)-Myc-z-P2A-hNEMO- K277AFlag-T2A-Vif 11256 11283 CD8SP-hu-CD19-USC1-LH4-(vL-vH)-CD3e-ECDTMCP-opt2-P2AhNEMO-K277A-Flag-T2A-Vif 11257 11284 CD8SP-hu-CD19-USC1-LH4- (vL-vH)-CD3d-ECDTMCP-opt2-P2AhNEMO-K277A-Flag-T2A-Vif I7R7. Ln / nznZ / Ε / ΥΙΛΙ SEQ ID (ADN) SEQ ID (PRT) NAME 11258 11285 CD8SP-hu-CD19-USC1-LH4-(vL-vH)-CD3g-ECDTMCP-opt2-P2AhNEMO-K277A-Flag-T2A-Vif 11259 11286 CD8SP-hu- CD19-USC1-LH4-(vL-vH)-CD3z-ECDTMCP-opt2-P2AhNEMO-K277A-Flag-T2A-Vif 11260 11287 CD8SP-hu-CD19-USC1-LH4-vL-[lgCL-TCRg-6MD]-F -P2A-SP-huCD19-USC1-LH4-vH-[lgG1-CH1-TCRd-6MD]-F-F2A-V¡f 11261 11288 CD8SP-hu-CD19-USC1-LH4-vL-[lgCL-TCRb-IAH -6MD]-F-P2A-SPhu-CD19-USC1-LH4-vH-[lgG1-CH1-TCRa-SDVP-6MD]-F-F2A-Vif 11262 11289 CD8SP-hu-CD19-USC1-LH4-(vH- vL)-CD3e-ECDTMCP-opt2-P2AVif 11263 11290 CD8SP-hu-CD19-USC1-LH4-(vH-vL)-CD3d-ECDTMCP-opt2-P2AhNEMO-K277A-Flag-T2A-Vif 11264 11291 CD8SP-hu-CD19 -USC1-LH4-(vH-vL)-CD3g-ECDTMCP-opt2-P2AhNEMO-K277A-Flag-T2A-Vif 11265 11292 CD8SP-hu-CD19-USC1-LH4-(vH-vL)-CD3z-ECDTMCP-opt2- P2AhNEMO-K277A-Flag-T2A-Vif 11266 11293 CD8SP-hu-CD19-USC1-LH4-vL-Xho-CD3zECDTMCP-opt-F-P2ASpe-SP-hu-CD19-USC1-LH4-vH-Mlu-CD3zECDTMCP-opt2 -FF2A-Vif 11267 11294 CD8SP-hu-CD19-USC1-LH4-vH-Gly-Ser-Ligator-vL-Myc-CD8TMBBz-2A-Vif 11268 pLent¡-EF1a-CD8SP- hu-CD19-USC1-LH4-vH-Gly-Ser-Lgador-vLMyc-CD8TM-BBz-2A-Vif 11269 pCDNA3-Vif i7R7 Ln / nznz / E / YiAi Table 10. Exemplary bispecific antibodies targeting different antigens Ag x CD3 Ag x CD28 Ag x 41BB Antigen or (Ag) Antigen binding domain SEQ ID NO (DNA) SEQ ID NO (PRT) SEQ ID NO (DNA) SEQ ID NO (PRT) SEQ ID NO (DNA) SEQ ID NO (PRT) CD19 FMC63 11620 11790 11676 11846 11732 11902 CD19 huFMC63-11 11621 11791 11677 11847 11733 11903 CD19 huFMC63-11N203Q 11622 11792 11678 11848 11734 11904 CD19 CD19Bu12 11623 11793 11679 11849 11735 11905 CD19 CD19MM 11624 11794 11680 11850 11736 11906 CD19 Ritx-CD19MOR0028 11625 11795 11681 11851 11737 11907 CD19 CD19-humR005-1 11626 11796 11682 11852 11738 11908 BCMA BCMA-J6M0 11627 11739 11738 11853 Ag x CD3 Ag x CD28 Ag x 41BB BOMA BCMAhuC12A3- L3H3 11628 11798 11684 11854 11740 11910 BCMA BCMAhuC11.D5.3L1 H3 11629 11799 11685 11855 11741 11911 BCMA BCMAhuC13-F12 11630 11800 11686 11856 11742 11912 CD20 CD20-2F2 11631 11801 11687 11857 11743 11913 CD20 CD20-GA101 11632 11802 11688 11858 11744 11914 CD20 CD20-2H7 11633 11803 11689 11859 11745 11915 CD20 CD20-Ubli-v4 11634 11804 11690 11860 11746 11916 CD20 CD20-2H7 11635 11805 11691 11861 11747 11917 CD20 CD20-7D8 11636 11806 11692 11862 11748 11918 CD22 CD22h10F4v2 11637 11807 11693 11863 11749 11919 CD22 CD22H22Rhov2A 11638 11808 11694 11864 11750 11920 CD22 CD22-m971HL 11639 11809 11695 11865 11751 11921 CD22 CD22-5-HL 11640 11810 11696 11866 11752 11922 CD22 CD22-10-HL 11641 11811 11697 11867 11753 11923 CD22 CD22-HA22 11642 11812 11698 11868 11754 11924 CD30 CD30-5F11 11643 11813 11699 11869 11755 11925 CD30 CD30-Ac10 11644 11814 11700 11870 11756 11926 CD32 CD32-Med9 11645 11815 11701 11871 11757 11927 CD33 CD33-AF5 11646 11 816 11702 11872 11758 11928 CD33 CD33-huMyc9 11647 11817 11703 11873 11759 11929 CD33 CD33-Him3-4 11648 11818 11704 11874 11760 11930 CD33 CD33- SGNh2H12 11649 11819 11705 11875 11761 11931 CD33 CD33-15G1533 11650 11820 11706 11876 11762 11932 CD33 CD33- 33H4 11651 11821 11707 11877 11763 11933 CD123 CD123- CSL362 11652 11822 11708 11878 11764 11934 CD123 CD123-1172 11653 11823 11709 11879 11765 11935 CD123 CD123DART-1 11654 11824 11710 11880 11766 11936 CD123 CD123- DART-2 11655 11825 11711 11881 11767 11937 CD123 CD123-9D7 11656 11826 11712 11882 11768 11938 CD123 CD123-3B10 11657 11827 11713 11883 11769 11939 / zRZLn / nznz / B / Yi Ag x CD3 Ag x CD28 Ag x 41 BB CD138 CD138 11658 11828 11714 11884 11770 11940 CS1 CS1-HuLuc64 11659 11829 11715 11885 11771 11941 CS1 CS1-huLuc90 11660 11830 11716 11886 11772 11942 FLT3 FLT3-NC7 11661 11831 11717 11887 11773 11943 MPL MPL -175 11662 11832 11718 11888 11774 11944 MPL MPL-161 11663 11833 11719 11889 11775 11945 MPL MPL-111 11664 11834 11720 11890 1176 11946 MPL HU-161-2 11665 11835 11721 11891 1177 117 11722 11892 11778 11948 MPL MPL-hu-111-2 11667 11837 11723 11893 11779 11949 Lym1 Lym1 11668 11838 11724 11894 11780 11950 Lym2 Lym2 11669 11839 11725 11895 11781 11951 CD70 CD70-h1F6 11670 11840 11726 11896 11782 11952 CD79b CD79b-2F2 11671 11841 11727 11897 11783 11953 CD179B CD179B 11672 11842 11728 11898 11784 11954 GPRC5 D GPRC5DET150-5 11673 11843 11729 11899 11785 / zRZLn / nznz / B / Yi Table 11: CAR “X” TARGET DISEASE EXAMPLES TARGET CARS (i.e. conventional CARs and next generation CARs. For example, SIR, Ab-TCR, TFP and zSIR) CD19 ALL, CLL, lymphoma, lymphoid blast crisis CML, Multiple Myeloma, Immune Disorders ALK Non-Small Cell Lung Cancer (NSCLC), ALCL (Anaplastic Large Cell Lymphoma), IMT (Inflammatory Myofibroblastic Tumor), or Neuroblastoma CD45 Hematologic Cancers BCMA Myeloma, PEL, Leukemia plasma cells, Waldenstrom's macroglobulinemia CD5 Blood cancer, T-cell leukemia, T-cell lymphoma BAFF-R Blood cancer, chronic lymphocytic leukemia, B-ALL CD20 Blood cancers, leukemia, ALL, CLL, lymphoma, immune disorders CD22 Hematologic cancers, leukemia, ALL, CLL, lymphoma, gross CML lymphoid blasts, immune disorders CD23 Hematologic cancers, leukemia, ALL, CLL, lymphoma, autoimmune disorders CD30 Hodgkins lymphoma, cutaneous T-cell lymphoma CD32 Solid tumors CD33 Hematologic cancers, AML, MDS CAR “X” TARGET DISEASE EXAMPLES TARGET CARS (i.e., conventional CARs and next-generation CARs. For example, SIR, Ab-TCR, TFP, and zSIR) CD34 Hematologic Cancer Types, AML, MDS CD44v6 Types Blood Cancers, AML, MDS CD70 Blood Cancers, Lymphoma, Myeloma, Waldenstrom's Macroglobulinemia CD79b Blood Cancers, ALL, Lymphoma CD123 Blood Cancers, AML, MDS CD138 Blood Cancers, Myeloma, PEL, Leukemia Plasma cell tumors, Waldenstrom's macroglobulinemia CD179b Hematologic cancers, ALL, CD276 / B7-H3 lymphoma Ewing's sarcoma, neuroblastoma, rhabdomyosarcoma, ovarian, colorectal, and lung cancers CD324 Solid tumors, esophageal cancers, prostate, colorectal, breast and lung CDH6 Solid tumors, types of kidney, ovarian, thyroid cancers CDH17 Adenocarciniomas, types of gastrointestinal, lung, ovarian, endometrial cancers CDH19 Solid tumor, me lanoma EGFR Colon cancer, lung cancer CLEC5A Blood cancers, leukemia, AML GR / LHR Prostate cancer, ovarian cancer, or breast cancer CLL1 Blood cancer, leukemia CMVpp65 CMV infection, CMV colitis, CMV pneumonitis CS1 Hematologic Cancers, Myeloma, PEL, Plasma Cell Leukemia CSF2RA AML, CML, MDS CD123 Hematologic Cancers, AML, MDS DLL3 Melanoma, Lung Cancer, or Ovarian Cancer EBNA3C / MHC I Epstein Barr Virus Infection and Diseases related cancers including EBV-gp350 Epstein Barr virus infection and related diseases EGFR Solid tumors, colon cancer, lung cancer EGFRviii Solid tumors, glioblastoma EpCaml Gastrointestinal cancer FLT3 Hematological cancers, AML, MDS, ALL Folate receptor alpha (FR1 or FOLR1) Ovarian cancer, NSCLC, endometrial cancer, kidney cancer, or other solid tumors FSHR Prostate cancer, ovarian cancer, or breast cancer GD2 Neur oblastoma GD3 Melanoma GFRa4 Cancer, medullary thyroid cancer Fucosyl- GM1(GM1) Small cell lung cancer GPRC5D Myeloma, PEL, plasma cell leukemia, macroglobulinemia of CAR “X” TARGET DISEASE EXAMPLES TARGET CARS (i.e. conventional CARs and next generation CARs. For example, SIR, Ab-TCR, TFP and zSIR) Waldenstrom gpioo Melanoma GPC3 Solid tumors, lung cancer gpNMB Melanoma, brain tumors, brain cancer types GRP78 Myeloma Her2 Solid tumors, breast cancer, stomach cancer Her3 Colorectal cancer, breast cancer HMW-MAA Melanoma HTLV1- TAX / MHC I Diseases associated with HTLV1 infection, leukemia- adult T-cell lymphoma IL11Ra Hematologic cancers, AML, ALL, CML, MDS, sarcomas IL6Ra Solid tumors, liver cancer IL13Ra2 Glioblastomas KSHV-K8.1 Kaposi's sarcoma, PEL, multicentric Castleman disease LAMP1 Hematologic cancers , AML, ALL, MDS, CLL, CML LewisY Cancer types L1CAM Solid tumors, cancers of the ovary, breast, endometrium, melanoma LHR Prostate cancer, ovarian cancer, or breast cancer Lym1 Blood cancer, leukemia, lymphoma Lym2 Blood cancer, leukemia, CD79b lymphoma Blood cancers, lymphoma MART1 / MHC I Melanoma Mesothelin Mesothelioma, ovarian cancer, pancreatic cancer Muc1 / MHC I Breast cancer, gastric cancer, colorectal cancer, lung cancer and other solid tumors Muc16 Ovarian cancer NKG2D Leukemia, lymphoma or myeloma NYBR1 Breast cancer PSCA Prostate cancer PR1 / MHC I Hematological cancer, leukemia Prolactin receptor Breast cancer, chromophobe renal cell cancer PSMA Prostate cancer PTK7 Melanoma, lung cancer or cancer ROR1 Hematologic cancer, B-cell neoplasm, lymphoma, CLL SLea Pancreatic cancer, colon cancer SSEA4 Pancreatic cancer Tyrosinase / MHC I Melanoma TCRB1 T-cell leukemias and lymphomas, autoimmune disorders TCRB2 T-cell leukemias and lymphomas, autoimmune disorders TARGET “X” CARS TARGET AUTOMOBILE DISEASE EXAMPLES (i.e., conventional CARs and next-generation CARs. For example, SIR, Ab-TCR, TFP, and zSIR) TCRgd T-cell leukemias and lymphomas, hTERT autoimmune disorders Solid tumors, hematologic cancers TGFBR2 Solid tumors, keloid TIM1 / HAVCR1 Kidney cancer, liver cancer TROP2 Solid tumors, breast cancer, prostate cancer TSHR Thyroid cancer, T-cell leukemia, T-cell lymphoma TSLPR Types of hematologic cancers, leukemias, AML, MDS Tyrosinase / MHC I VEGFR3 melanoma WT1 / MHC solid tumors I Hematologic cancers, AML β-folate receptor AML, myeloma B7H4 Breast cancer or ovarian cancer CD23 Hematologic cancers, leukemias, CLL GCC Gastrointestinal cancer CD200R Hematologic cancers, AML, MDS AFP / MHC I Solid tumors, liver cancer CD99 Liver cancer GPRC5D Myeloma, Waldenstrom macroglobinemia HPV16-E7 / MHC I Types of HPV16-associated cancer, cervical cancer, head and neck cancers Tissue Factor 1 (TF1) Tn-Muc1 solid tumors Solid tumors and hematological cancers Igk light chain Myeloma, plasma cell leukemia Ras G12V / MHC I Solid tumors and hematologic cancers CLD18A2 (Claudin 18.2) Gastric, pancreatic, esophageal, ovarian, or lung cancer CD43 Hematologic cancers, AML NY-ESO1 / MHC I MPL / TPO-R Myeloma Hematologic cancer, AML, MDS , CML, ALL P-glycoprotein (MDR1) Kidney cancer, liver cancer, myeloma CD179a Hematologic cancers, acute leukemia, CLL, ALL, lymphoma STEAP1 Gastric or prostate cancer or lymphoma Liv1 (SLC39A6) Breast or prostate cancer Nectin 4 (PVRL4) Bladder, kidney, cervical, lung, head and neck, or breast cancer Cripto (TDGF1) Colorectal, endometrial, or ovarian cancer CAR “X” TARGET DISEASE EXAMPLES TARGET CARS (i.e. conventional CARs and next generation CARs. For example, SIR, Ab-TCR, TFP and zSIR) gpA33 Colorectal or endometrial or ovarian cancer FLT3 Blood cancers, AML, ALL, MDS BST1 / CD157 Blood cancers, AML, MDS IL1RAP Liver, colorectal, cervical, lung, or ovarian cancer Chloride channel Glioma igE HLA-A2 allergy Graft-versus-host disease , tissue rejection (SIR expressed on regulatory T cells) Amyloid Amyloidosis, Alzheimer's disease HIV1 envelope HIV / AIDS and related conditions HIV1-gag HIV1 / SI AD and related conditions Influenza A HA Influenza A infection B7 integrin Plasma cell neoplasms , primary effusion lymphoma Muc17 Pancreatic cancer, colon cancer CD16ORF54 Hematologic cancers VISTA Hematologic cancers Muc5Ac Pancreatic cancer, stomach cancer, colon cancer FCRH5 Neopl Plasma cell asia LYPD1 Ovarian cancer, endometrial cancer, melanoma EMR2 Acute leukemia, lymphoma, breast cancer, colon cancer gpNMB Melanoma, brain cancer, breast cancer, solid tumors RNF43 Colorectal cancer, breast cancer, colon cancer endometrial CD44v6 Epithelial cancers Robo4 Kidney cancer, colon cancer, breast cancer, solid tumors GPC3 Liver cancer, lung cancer, breast cancer FOLR1 Ovarian cancer, lung cancer, kidney cancer, solid tumors CLDN6 Ovarian cancer, cancer MMP16 Melanoma, brain cancer, small lung cancer, neuroblastoma BMPR1B Prostate cancer, breast cancer, ovarian cancer Ly6E Breast, ovarian, pancreatic, lung WISP1 Glioblastoma, breast cancer SLC34A2 Lung cancer, ovarian cancer, endometrial cancer CD133 Lung cancer, brain cancer Table 12: Ag x CD3 Ag x CD28 Ag x 41BB Antigen or (Ag) Antigen binding domain SEQ ID NO (DNA) SEQ I NO (PRT) D SEQ ID NO (DNA) SEQ I NO (PRT) D SEQ ID NO (DNA) ) SEQ ID NO (PRT) CD19 FMC63 11620 11790 11676 11846 11732 11902 CD19 huFMC63-11 11621 11791 11677 11847 11733 11903 CD19 huFMC63-11- N203Q 11622 11792 11678 11848 11734 11904 CD19 CD19Bu12 11623 11793 11679 11849 11735 11905 CD19 CD19MM 11624 11794 11680 11850 11736 11906 CD19 Ritx-CD19MOR0028 11625 11795 11681 11851 11737 11907 CD19 CD19-humR005-1 11626 11796 11682 11852 11738 11908 BCMA BCMA-J6M0 11627 11797 11683 11853 11739 11909 BCMA BCMAhuC12A3- L3H3 11628 11798 11684 11854 11740 11910 BCMA BCMAhuC11.D5.3L1 H3 11629 11799 11685 11855 11741 11911 BCMA BCMAhuC13-F12 11630 11800 11686 11856 11742 11912 CD20 CD20-2F2 11631 11801 11687 11857 ​​11743 11913 CD20 CD20-GA101 11632 11802 11688 11858 11744 11914 CD20 CD20-2H7 11633 11803 11689 11859 11745 11915 CD20 CD20-Ubli-v4 11634 11804 11690 11860 11746 11916 CD20 CD20-2H7 11635 11805 11691 11861 11747 11917 CD20 CD20-7D8 11636 11806 11692 11862 11748 11918 CD22 CD22h10F4v2 11637 11807 11693 11863 11749 11919 CD22 CD22H22Rhov2A 11638 11808 11694 11864 11 750 11920 CD22 CD22-m971HL 11639 11809 11695 11865 11751 11921 CD22 CD22-5-HL 11640 11810 11696 11866 11752 11922 CD22 CD22-10-HL 11641 11811 11697 11867 11753 11923 CD22 CD22-HA22 11642 11812 11698 11868 11754 11924 CD30 CD30-5F11 11643 11813 11699 11869 11755 11925 CD30 CD30-AC10 11644 11814 11700 11870 11756 11926 CD32 CD32-Med9 11645 11815 11701 11871 11757 11927 CD33 CD33-AF5 11646 11816 11702 11872 11758 11928 CD33 CD33-huMyc9 11647 11817 11703 11873 11759 11929 CD33 CD33-Him3 -4 11648 11818 11704 11874 11760 11930 CD33 CD33- SGNH2H12 11649 11819 11705 11875 11761 11931 CD33 CD33-15G1533 11650 11820 11706 11876 11762 11932 CD33 CD33 CD33 / zRZLn / nznz / B / Yi CD123 CD123- CSL362 11652 11822 11708 11878 11764 11934 CD123 CD123-1172 11653 11823 11709 11879 11765 11935 CD123 CD123DART-1 11654 11824 11710 11880 11766 11936 CD123 CD123- DART-2 11655 11825 11711 11881 11767 11937 CD123 CD123-9D7 11656 11826 11712 11882 11768 11938 CD123 CD123-3B10 11657 11827 11713 11883 11769 11939 CD138 CD138 11658 11828 11714 11884 11770 11940 CS1 CS1-HuLuc64 11659 11829 11715 11885 11771 11941 CS1 CS1-huLuc90 11660 11830 11716 11886 11772 11942 FLT3 FLT3-NC7 11661 11831 11717 11887 11773 11943 MPL MPL-175 11662 11832 11718 11888 11774 11944 MPL MPL-161 11663 11833 11719 11889 11775 11945 MPL MPL-111 11664 11834 11720 11890 11776 11946 MPL HU-161-2 11665 11835 11721 11891 1177 11666 11836 11722 11892 11778 11948 MPL MPL-hu-111-2 11667 11837 11723 11893 11779 11949 Lym1 Lym1 11668 11838 11724 11894 11780 11950 Lym2 Lym2 11669 11839 11725 11895 11781 11951 CD70 CD70-h1F6 11670 11840 11726 11896 11782 11952 CD79b CD79b-2F2 11671 11841 1172 7 11897 11783 11953 CD179B CD179B 11672 11842 11728 11898 11784 11954 GPRC5 D GPRC5DET150-5 11673 11843 11729 11899 11785 11955 GPRC5 D GPRC5DET150-18 11674 Table 13: TCR chains useful in various embodiments: / zRZLn / nznz / B / Yi SEQ ID NO (PRT) TCR chains 4038 hTCR-alpha-constant-region_X02883.1 4039 hTCRa-WT 4040 hTCRa-CSDVP 4041 hTCRa-opt2 4042 hTCRa-T48C-opt 4043 hTCRa-T48C-opt1 4044 hTCRa-SDVP 4045 hTCRa-S61 R 4046 hTCRa-SDVPR 4047 hTCRaECD-CD3zECDTMCP-opt2 4048 region-constant-of-hTCR-b1_X00437.1 4049 hTCR-b2 constant 4050 hTCRb-WT 4051 hTCRb-S57C-opt1 4052 hTCRb-KACIAH 4053 hTCRb-opt2 4054 hTCRb-KAIAH 4055 hTCRb-R79G 4056 hTCRbECD-CD3zECDTMCP-opt 4057 preTCRa_gb_U38996.1 4058 preTCRa 4059 preTCRa-del48 4060 hTCR-gama_M27331.1 4061 hTCR-Gama-Opt 4062 hTCR-Delta 4063 hTCR-Delta-Opt 12602 TCRa transmembrane domain 12603 TCRb transmembrane domain 12604 TCRd transmembrane domain 12605 TCRg transmembrane domain 12606 TCRa connecting peptide 12607 TCRb connecting peptide 12608 TCRd connecting peptide TCR160 connecting peptide TCR16de connecting peptide connection MD 12611 TCRb connection peptide MD 12612 TCRd connection peptide MD 12613 TCRy connection peptide MD 12614 TCRb intracellular domain 12615 TCRy intracellular domain 12616 TCRD alpha 12617 TCRD beta 12618 TCRD alpha MD 12619 TCRD beta MD 12620 TCRD21 delta6 TCRD21 gamma delta MD 12623 TCRD gamma MD 12624 CD3e-ECDTMCP 12625 CD3e-ECD 12626 CD3e-TM 12627 CD3e-CP 12628 CD3d-ECDTMCP 12629 CD3d-ECD 12630 CD3d-TM 12631 CD3d-CP 12632 CD3g-ECDTMCP / zRZLn / nznz / B / Yi 12633 CD3g-ECD 12634 CD3g-TM 12635 CD3g-CP 12636 CD3zECDTMCP 12637 CD3z-TM 12638 CD3z-CP / zRZLn / nznz / B / Yu In some embodiments, the compositions comprise nucleic acids encoding CARs 1-15 (Table 1), wherein the antigen-specific domain of the CAR targets one or more specific antigens as described in Tables 3 or Tables 5-6 of PCT / US2017 / 064379, which are incorporated herein by reference. In some embodiments, compositions comprise nucleic acids encoding one or more of strands 1-60 (Table 2) where the encoded CAR antigen-specific domain is targeted to one or more specific antigens as described herein and in Table 3 or Tables 5-6 of PCT / US2017 / 064379. In some embodiments, the compositions comprise nucleic acids encoding backbone-1, where the CAR antigen-specific domain in backbone-1 targets one or more cancer-specific antigens as described herein and in Table 3 or Tables 5-6 of PCT / US2017 / 064379. In some embodiments, the compositions comprise backbone-8-encoding nucleic acids, wherein the CAR antigen-specific domain in backbone-1 targets one or more cancer-specific antigens as described herein and in Table 3 or Tables 5-6 of PCT / US2017 / 064379. In various embodiments, the isolated nucleic acid molecules encoding the CAR components of the backbones described herein encode one, two, three, or more antigen-specific domains (ASDs). In various embodiments, isolated nucleic acid molecules encoding the CAR components of the backbones described herein encode zero, one, two, three, or more costimulatory domains. In various embodiments, isolated nucleic acid molecules encoding the CAR components of the backbones described herein encode zero, one, two, three, or more intracellular signaling domains. In various embodiments, the isolated nucleic acid molecules encoding the CAR and backbones described herein encode zero, one, two, three, or more accessory modules. Nucleic acid sequences encoding the desired components of the CARs and accessory modules described herein can be obtained using recombinant methods known in the art. Alternatively, the nucleic acid of interest can be produced synthetically, rather than cloned. In some embodiments, the genetically modified cells described herein that express the CARs and accessory components described herein also express agents that reduce the toxicity of the CARs. In some embodiments, the genetically modified cells described herein that express the CARs and accessory components described herein also express agents that enhance the activity of the CARs. In some embodiments, the genetically modified cells described herein that express the CARs and accessory components described herein also express agents that enhance the persistence of the CARs. In some embodiments, the genetically modified cells described herein that express the CARs and accessory components described herein also express agents that prevent CAR depletion. Compositions comprising multiple backbones as described herein comprise CARs that comprise one or more ASDs that specifically bind to a cancer-associated antigen as described herein. ASD sequences are contiguous and in the same reading frame as a nucleic acid sequence encoding the remainder of one or more / zRZLn / nznz / B / Yi strands CHAR. The polynucleotides, polypeptides, expression constructs, CAR-expressing recombinant engineered cells comprising the antigen-binding domains of the disclosure, as well as the method of making and using said polypeptides, polynucleotides and cells are described in methods known in the art. technique and methods described in PCT / US2017 / 024843, WO 2014 / 160030 A2, WO 2016 / 187349 A1, PCT / US2016 / 058305, WO 2015 / 117229 A1 and PCT / US17 / 64379, which are incorporated herein by reference in their entirety . The disclosure provides several antigen-binding domains that can be used in the generation of CARs (eg, CAR 1-15 and backbones 1-60) for adoptive cell therapy applications. In some embodiments, these antigen-binding domains are derived from target antibodies and antigens that are expressed in cancer, non-cancerous proliterative disorders (eg, endometriosis), and / or immune disorders. The target antigens, SEQ ID (DNA) and SEQ ID (PRT) of the vL, vH and scFv fragments of these antigen binding domains are shown in Table 3. The CDRs of the vL and vH fragments of the binding domains to antigen that target different antigens are shown in Table 4. In some embodiments, the encoded antigen-binding domain(s) of the CAR polypeptide that targets a specific antigen comprises one or more light chain variable domain (vL or VL) amino acid sequences of SEQ IDs NO 4118 to 4190, 9631 to 9660 and 11460 to 11462, 14386 to 14415 targeting that antigen as listed in Table 3 in which up to 9 amino acid residues but not more than 10 amino acid residues are replaced by any other amino acid residue, or sequences with 80-100% identity to amino acid sequences as set forth in any of SEQ ID NOs 4118 to 4190, 9631 to 9660, or 11460 to 11462 and 14386 to 14415, or sequences with 85-100% identity to those complementarity determining regions (CDRs) of any of SEQ ID NO SEQ ID NO 4118 to 4190, 9631 to 9660, or 11460 to 11462 and !7R7 Ln / nznZ / Ε / ΥΙΛΙ 14386 to 14415. The CDR1, CDR2 and CDR3 of the vL fragments with SEQ ID NO: 4118 to 4190, 9631 to 9660 or 11460 to 11462 are represented by SEQ ID NO: 11961 to 12066, 12068 to 12173, 12175 to 12280, respectively (Table 4). In some embodiments, the polypeptide encoded for one or more antigen-binding domains of CARs (conventional CARs and next-generation CARs, eg, SIR, zSIR, Ab-TCR, Tri-Tac, and TFP) comprises one or more domains heavy chain variables. (vH or VH) amino acid sequences of SEQ ID NOs 4192 to 4264, 9662 to 9691, 11464 to 11466 and 14417 to 14446 directed to that antigen as listed in Table 3 in which up to 9 amino acid residues are found but no more than 10 replaced by any other residue or amino acid sequence with 80-100% identity to the amino acid sequences of SEQ ID NO 4192 to 4264, 9662 to 9691, 11464 to 11466 and 14417 to 14446 or sequences with 85-100% of identity with the complementarity determining regions (CDRs) of any of SEQ ID NOs 4192 to 4264, 9662 to 9691, 11464 to 11466 and 14417 to 14446. The CDR1, CDR2 and CDR3 of the vH fragments with SEQ ID NO: 4192 to 4264, 9662 to 9691, 11464 to 11466 and 14417 to 14446 are represented by SEQ ID NOs: 12282 to 12387, 12389 to 12494, 12497 to 12602, 16219-16310 respectively (Table 4). In some embodiments, one or more CAR polypeptide-encoded antigen-binding domains 1-15 and backbones 1-60 comprise one or more single-chain variable fragment (scFv) amino acid sequences of SEQ ID NOs 4266 to 4338. 9693 to 9722, 11468 to 11470 and 14448-14477 in which up to 9 amino acid residues but not more than 10 amino acids are replaced by any other amino acid residue or sequence with 80-100% identity to the amino acid sequences of SEQ ID NO 4266 to 4338, 9693 to 9722, 11468 to 11470 and 14448-14477 or sequences with 85-100% identity to the complementarity determining regions (CDRs) of SEQ ID NO 4266 to 4338, 9693 to 9722, 11468 to 11470 and 14448-14477. The CDRI, CDR2 and CDR3 of the vL regions of the scFv fragments with SEQ ID NOs: 4266 to 4338, 9693 / zRZLn / nznz / B / Yi to 9722, 11468 to 11470 and 14448-14477 are represented by SEQ ID NOs: 11961 to 12066, 12068 to 12173, 12175 to 12280, 16126-16217 respectively (Table 4). The CDR1, CDR2 and CDR3 of the vH regions of the scFv fragments with SEQ ID NO: 4266 to 4338, 9693 to 9722, 11468 to 11470 and 14448-14477 are represented by SEQ ID NO: 12282 to 12387, 12389 to 12494 and 12497 to 12602 and 16219-16310 respectively (Table 4). It should be understood that the order of the vL and vH fragments in a scFv fragment can be vL-vH or vH-vL. Therefore, although the exemplary scFv fragments shown in Table 3 represent the vL-vH or vH-vL orientation, scFv fragments with the complementary orientation (i.e., vH-vL and vL-vH) can also be used in the methods. or disclosure compositions. DNA and PRT SEQ IDs of exemplary elements that can be used in the construction of different CARs 1-15 and backbones 1-60 are listed in Table 5. Nucleic acid and amino acid SEQ IDs of exemplary standard CARs ( for example, second-generation CARs containing 41 BB costimulatory domains) and next-generation CARs (for example, SIR, zSIR, Ab-TCR, and TFP) based on the vL and vH fragments derived from a BCMA-AM06-HL scFv are are provided in Table 6. Nucleic acid and amino acid SEQ IDs of exemplary conventional CARs (eg, second-generation CARs containing 41 BB costimulatory domains) and next-generation CARs (eg, SIR, zSIR, Ab-TCR and TFP) based on the vL and vH fragments derived from other scFv fragments can be derived by replacing the vL and vH fragments of the BCMA-AM06-HL scFv with the vL and vH fragments of the scFv fragments listed in Table 3. The sequence of constructs of CAR examples q ue containing different antigen-binding domains are referenced in Table 7. The order of the different CAR constructs in Table 7 is as shown in Table 6 for the BCMA-AmO6-HL based CARs. Thus, the CAR construct represented by SEQ ID NO: 475 resembles the CAR construct represented by SEQ ID / zRZLn / nznz / B / Yi NO: 377 with the exception that the vL and vH fragments corresponding to the BCMA-AmO6-HL antigen binding domain are replaced with vL and vH fragments corresponding to the BCMA-Am14-HL antigen binding domain. Similarly, the CAR construct represented by SEQ ID NO: 476 resembles the CAR construct represented by SEQ ID NO: 378 with the exception that the vL and vH fragments corresponding to the BCMA-AmO6-HL antigen-binding domain are replaced. with vL and vH fragments corresponding to the BCMA-Am14-HL antigen-binding domain. In various embodiments, the antigen-binding domains of the disclosure display superior properties in vitro and in vivo, such as binding affinity to target antigens, cytokine secretion, proliferation, cytotoxicity, depletion, and long-term persistence, when used. in the construction of CARs (i.e. conventional CARs and next generation CARs). In various embodiments, these antigen-binding domains display various properties in vitro and in vivo, such as binding affinity to target antigens, cytokine secretion, proliferation, cytotoxicity, depletion, and long-term persistence, when used in the construct. of CARs (i.e. conventional CARs and next generation CARs). In various embodiments, CARs containing these target antigens can be used to generate a diverse immune response. The disclosure further contemplates CARs that target the same antigen but with different antigen-binding domains and may possess various biological properties depending in part on the epitope of the antigen targeted by them. Thus, the two groups of CARs that target Her2 represented by SEQ ID NO: 2435-2483 and SEQ ID NO: 2386-2434, see rows 12-13 of Table 7, show different biological properties, such as activation of T cells, secretion of cytokines and cytotoxicity. In some embodiments, the antigen-specific domain of the encoded CAR molecule comprises an antibody, an antibody fragment, a scFv, an Fv, a Fab, / zRZLn / nznz / B / Yi an (Fab')2, an antibody of single domain (SDAB), a VH or VL domain, or a camelid VHH domain. In some embodiments, the CAR antigen-binding domain is an scFv antibody fragment that is humanized in comparison to the murine sequence of the scFv from which it is derived. In some cases, scFvs can be prepared according to methods known in the art (eg, Bird et al., (1988) Science 242:423-426 and Huston et al., (1988) Proc.Natl. Acad. Sci USA 85:5879-5883). ScFv molecules can be produced by ligating the VH and VL regions together via flexible polypeptide linkers. The scFv molecules comprise a linker (eg, a Ser-Gly linker) with an optimized length and / or amino acid composition (eg, to optimize folding, etc.). Linker length can greatly affect how the variable regions of an scFv fold and interact. For example, if a short polypeptide linker is used (eg, between 5-10 amino acids) intrachain folding is avoided. Interstrand folding may be useful to join the two variable regions to form a functional epitope binding site. For examples of linker size and orientation, see, for example, Hollinger et al. 1993 Proc Nati Acad. Sci.U.S.A. 90: 6444-6448, US Patent Application Publications NOs. 2005 / 0100543, 2005 / 0175606, 2007 / 0014794, and PCT Publication NOs. WO2006 / 020258 and WO2007 / 024715, the disclosure of which is incorporated herein by reference. An scFv can comprise a linker of at least 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25 , 30, 35, 40, 45, 50 or more amino acid residues between its VL and VH regions. The linker sequence can comprise any naturally occurring amino acid. In some embodiments, the linker sequence comprises the amino acids glycine and serine. In another embodiment, the linker sequence comprises sets of glycine and serine repeats such as (Gly4Ser)n, where n is a positive integer equal to or greater than 1. In one embodiment, the linker may be (Gly4Ser)s or (Gly4Ser) s or Whitlow linker. Variation in the length of the / zRZLn / nznz / B / Yi linker may retain or enhance activity, leading to superior efficacy in activity studies. In one embodiment, the antigen-specific domain of a CAR that targets a specific antigen comprises one, two, or all three of the vH CDRs (heavy chain) (i.e., vH-CDRI, VH-CDR2, and VH-CDR3) of an antigen-binding domain listed herein (Table 4) (Table 4), and / or one, two, or all three vL CDRs (light chain) (ie, vL-CDR1, vL-CDR2, and vL-CDR3) of an antigen binding domain listed herein (Table 4). In another embodiment, the antigen-specific domain comprises a humanized antibody or antibody fragment. In some embodiments, the antigen-specific domain of a CAR described herein is an scFv antibody fragment. In other embodiments, the antibody fragment has a lower binding affinity for antigen compared to the antibody from which it is derived, but is functional in that it provides a biological response described herein. In one embodiment, the CAR molecule comprises an antibody fragment having a KD binding affinity of 10.4M to 10-8M, 10.5M to 10-7M, 10-6M or 10.8M, for the target antigen. . In some embodiments, the antigen-specific domain of a CAR described herein binds to an MHC-presented peptide. TCR-type antibodies have been described that target peptides derived from viral or tumor antigens in the context of human leukocyte antigen (HLA)-A1 or HLA-A2. For example, a TCR-like antibody can be identified from a library screen, such as a human scFv phage-displayed library. In some embodiments, when CARs comprising functional fragments of antibodies (including scFv fragments), as described herein, bind to the target antigen, a biological response is induced such as activation of an immune response, production of cytokines, cytotoxicity and the like, / zRZLn / nznz / B / Yi as will be understood by one skilled in the art. In some embodiments, disease-specific antigens that can be targeted by conventional CARs (eg, second-generation CARs), next-generation CARs (eg, zSIR, SIR, Ab-TCR, Tri-TAC, TFP, etc. .) and rTCR when expressed alone or with accessory modules, as described herein, include, but are not limited to, any one or more of CD5, CD19; CD123; CD22; CD30; CD171; CS-1 (also called CD2 subset 1, CRACC, SLAMF7, CD319 and 19A24); BAFF-R, C-type lectin-like molecule 1 (CLL-1 or CLECL1); CD33; mpl; epidermal growth factor receptor variant III (EGFRviii); G2 ganglioside (GD2); GD3 ganglioside (aNeu5Ac(2-8) aNeu5Ac(2-3)bDGalp(1-4)bDGIcp(1-1)Cer); B cell maturation of members of the TNF receptor family (BCMA); Tn Antigen ((Tn Ag) or (GalNAca-Ser / Thr)); prostate specific membrane antigen (PSMA); Receptor orphan receptor tyrosine kinase 1 (ROR1); Fms-like tyrosine kinase 3 (FLT3); Tumor-associated glycoprotein 72 (TAG72); CD38; CD44v6; a glycosylated CD43 epitope expressed on acute leukemia or lymphoma but not on hematopoietic progenitors, a glycosylated CD43 epitope expressed on non-hematopoietic cancers, carcinoembryonic antigen (CEA); Epithelial Cell Adhesion Molecule (EPCAM); B7H3 (CD276); KIT (CD117); Interleukin-13 receptor alpha2 subunit (IL-13Ra2 or CD213A2); Mesothelin; Interleukin 11 receptor alpha (IL-HRa); prostate stem cell antigen (PSCA); Protease Serine 21 (Testisin or PRSS21); vascular endothelial growth factor receptor 2 (VEGFR2); Lewis (Y) antigen; CD24; Platelet-derived growth factor receptor beta (PDGFR-beta); Stage-specific embryonic antigen 4 (SSEA-4); CD20; Alpha folate receptor; Receptor tyrosine-protein kinase ERBB2 (Her2 / neu); Mucin 1, associated with the cell surface (MUC1); epidermal growth factor receptor (EGFR); neural cell adhesion molecule (NCAM); prostasis; prosthetic acid phosphatase (PAP); elongation factor 2 mutated (ELF2M); Ephrin B2; alpha / zRZLn / nznz / B / Yu fibroblast activation protein (FAP); insulin-like growth factor receptor 1 (IGF-I receptor), carbonic anhydrase IX (CAIX); Proteasome subunit (prosome, macropain), type beta, 9 (LMP2); glycoprotein 100 (gp100); oncogene fusion protein consisting of breakpoint clustering region (BCR) and Abelson murine leukemia (Abl) viral oncogene homologue 1 (bcr-abl); tyrosinase; ephrin receptor 2 type A (EphA2); Fucosyl GM1; sialyl Lewis adhesion molecule (sLe); GM3 ganglioside (aNeu5Ac(2-3)bDCIalp(1-4)bDGIcp(1-1)Cer); transglutaminase 5 (TGS5); High Molecular Weight Melanoma Associated Antigen (HMWMAA); o-acetyl-GD2 ganglioside (OAcGD2); tumoral endothelial marker 1 (TEM1 / CD248); related to endothelial tumor marker 7 (TEM7R); claudin 6 (CLDN6); thyroid stimulating hormone receptor (TSHR); Group 5 class C G protein-coupled receptor, member D (GPRC5D); X chromosome open reading frame 61 (CXORF61); CD97; CD179a; anaplastic lymphoma kinase (ALK); Polysalic acid; 1 placenta-specific (PLACI); hexasaccharide portion of globoH glycoceramide (GloboH); mammary gland differentiation antigen (NY-BR-1); uroplakin 2 (UPK2); Hepatitis A virus cell receptor 1 (HAVCR1); beta 3 adrenoceptor (ADRB3); pannexin 3 (PANX3); G protein-coupled receptor 20 (GPR20); lymphocyte antigen complex 6, locus K 9 (LY6K); Olfactory receptor 51E2 (OR51E2); TCR gamma alternative reading frame protein (TARP); Wilms tumor protein (WT1); cancer / testicular antigen 1 (NY-ES0-1); Cancer / testicular antigen 2 (LAGE-1a); Melanoma-associated antigen 1 (MAGE-A1); ETS translocation variant gene 6, located on chromosome 12p (ETV6-AML); sperm protein 17 (SPA17); Family X antigens, member IA (XAGEI); angiopoietin-binding cell surface receptor 2 (Tie 2); melanoma cancer testicular antigen 1 (MAD-CT-1); melanoma cancer testicular antigen 2 (MAD-CT-2); Fos-related antigen 1; p53 tumor protein (p53); p53 mutant; prostein; survivor; telomerase; prostate carcinoma tumor antigen 1 (PCT A-1 or Galectin 8), melanoma antigen recognized by T cells 1 (MelanA or MARTI); / zRZLn / nznz / B / Yi Rat sarcoma mutant (Ras); human telomerase reverse transcriptase (hTERT); sarcoma translocation hotspots; melanoma inhibitor of apoptosis (MLIAP); ERG (Transmembrane protease, serine fusion gene 2 (TMPRSS2) ETS); N-acetylglucosaminyltransferase V (NA17); Pax-3 paired box protein (PAX3); Androgen receptor; Cyclin Bl; neuroblastoma-derived homologue of v-myc avian myelocytomatosis viral oncogene (MYCN); Member of the Ras Homolog C (RhoC) family; Tyrosinase-related protein 2 (TRP-2); Cytochrome P450 1B 1 (CYPIB 1); CCCTC (zinc finger protein) binding factor similar (BORIS or imprinted regulatory sibling), T-cell recognized squamous cell carcinoma antigen 3 (SART3); Pax-5 paired box protein (PAX5); proacrrosin binding protein sp32 (OY-TES1); lymphocyte-specific protein tyrosine kinase (LCK); A kinase anchor protein 4 (AKAP-4); synovial sarcoma, hotspot 2 of X (SSX2); Receptor for advanced glycation end products (RAGE-1); ubiquitous renal 1 (RU1); ubiquitous renal 2 (RU2); legumin; human papilloma virus E6 (HPV E6); human papilloma virus E7 (HPV E7); intestinal carboxyl esterase; mutated heat shock protein 70-2 (mut hsp702); CD79a; CD79b; CD72; Leukocyte-associated immunoglobulin-like receptor 1 (LAIR1); Fe fragment of the IgA receptor (FCAR or CD89); Leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2); Member f of the CD300 molecule-like family (CD300LF); C-type lectin domain family 12 member A (CLEC12A); bone marrow stromal cell antigen 2 (BST2); Mucin-like hormone receptor 2 (EMR2) containing an EGF-like module; lymphocyte antigen 75 (LY75); Glypican-3 (GPC3); Fe receptor-like 5 (FCRL5); and immunoglobulin lambda 1 (IGLL1) polypeptide, MPL, biotin, c-MYC epitope tag, CD34, LAMP1 TROP2, GFRalpha4, CDH17, CDH6, NYBR1, CDH19, CD200R, Slea (CA19.9; Sialil Lewis antigen) Fucosyl - GM1, PTK7, gpNMB, CDH1-CD324, DLL3, CD276 / B7H3, IL11Ra, IL13Ra2, CD179b-IGLI1, ALKTCRgamma-delta, NKG2D, CD32 (FCGR2A), CSPG4-HMWMAVRA, Tim1- / H2VRA-CSFR-alpha), TGFbetaR2, VEGFR2 / KDR, Lews Ag, TCR chain / zRZLn / nznz / B / Yi 100 betal, TCR-beta2 chain, TCR-gamma chain, TCR-delta chain, FITC, Luteinizing Hormone Receptor (LHR), Follicle Stimulating Hormone Receptor (FSHR), Chorionic Gonadotropin Hormone Receptor (CGHR), CCR4, SLAMF6, SLAMF4, HIV1 envelope glycoprotein, HTLV1-Tax, CMV pp65, EBV-EBNA3c, influenza A hemagglutinin (HA), GAD, PDL1, guanylyl cyclase C (GHVCC), K-Protein K8.1 , KSHV-gH protein, Desmoglein 3 (Dsg3) autoantibody, Desmoglein 1 (Dsg1) autoantibody, HLA, HLA-A, HLA-A2, HLA-B, HLA-C, HLA-DP , HLA-DM, HLA- DOA, HLA-DOB, HLA-DQ, HLA-DR, HLA-G, IGE, CD99, RAS G12V, tissue factor 1 (TF1), AFP, GPRC5D, claudin18.2 (CLD18A2 OR CLDN18A.2), P-glycoprotein , STEAP1, LIV1, NECTIN-4, CRYPTO, MPL, GPA33, BST1 / CD157, low conductance chloride channel, Integrin B7, Muc17, C16ORF54, VISTA, Muc5Ac, FCRH5, CLDN6, MMP16, UPK1B, BMPR1B, Ly6E, WISP1 and SLC34A2. In some embodiments, antigens associated with or specific to a disease that may be targeted by CARs, when expressed alone or with accessory modules as described herein, include, but are not limited to, one or more of 4 -1BB , 5T4, adenocarcinoma antigen, alpha-fetoprotein, BAFF, B lymphoma cells, C242 antigen, CA-125, carbonic anhydrase 9 (CA-IX), C-MET, CCR4, CD152, CD19, CD20, CD200, CD22 , CD221, CD23 (IgE receptor), CD28, CD30 (TNFRSF8), CD33, CD4, CD40, CD44 v6, CD51, CD52, CD56, CD74, CD80, CD123, CEA, CNTO888, CTLA4, DR5, EGFR, EpCAM, CD3 , FAP, fibronectin extra domain B, folate receptor 1, GD2, ganglioside GD3, glycoprotein 75, GPNMB, HER2 / neu, HGF, human shedding factor receptor kinase, IGF-1 receptor, IGF-I, lgG1, L1- CAM, IL-13, IL-6, insulin-like growth factor receptor I, α5β1 integrin, ανβ3 integrin, LAMP1, MORAb-009, MS4A1, MUC1, CanAg mucin, N-glycolylneuraminic acid, NPC-1C , PDGFR a , PDL192, phosphatidylserine, prosthetic carcinoma cells, RANKL, RON, ROR1, SCH 900105, SDC1, SLAMF7, TAG-72, tenascin C, TGF beta 2, TGF-β, TRAIL-R1, TRAIL-R2, antigen tumor CTAA16.88, VEGF-A, VEGFR-1, VEGFR2, vimentin, and / zRZLn / nznz / E / Yi combinations 101 the same. Other cancer-specific antigens will be apparent to those skilled in the art and may be used in connection with alternative embodiments of the disclosure. In some embodiments, cancer-associated or specific antigens that can be targeted by CARs, when expressed alone or with accessory modules as described herein, include, but are not limited to, one or more of BCMAs. , FLT3, CD19, CD20 (MS4A1), CD22, STEAP1, CD79b, Integrin B7, Her2, Her3, Liv1, TSHR (Thyroid-stimulating hormone receptor), PSMA, MSLN (Mesothelin), EGFRviii, Nectin 4, Receptor prolactin (PRLR), Muc17, Muc5Ac, CD70, CD179b, CDH19, CD16ORF54, VISTA (V-set receptor immunoregulatory or VSIR), GPC3 (glypican 3), DLL3 (canonical delta-like Notch 3 ligand), PTK7, FCRH5 ( Fe receptor as 5), LYPD1 (LY6 / PLAUR Domain containing 1), EMR2 (Adhesion G protein-coupled receptor E2 or ADGRE2), gpNMB (glycoprotein nmb), Ring finger protein 43 (RNF43), Robo4, CEA, Her3, folate receptor 1 (FOLR1), CLDN6 (Claudin 6), MMP16 (matrix metallopeptidase 16), uroplakin 1B (UPK1B), mor protein receptor bone phogenetics type 1B (BMPR1B), Ly6E, WISP1, SLC34A2, Cripto, gpA33, ROR1, CLL1, IL1RAP, BST1, CD133 and combinations thereof. In some embodiments, the antigen-specific domains of CARs are specific for BCMA, FLT3, CD19, CD20 (MS4A1), CD22, STEAP1, CD79b, Integrin B7, Her2, Her3, Liv1, TSHR (Thyroid Stimulating Hormone Receptor) , PSMA, MSLN (Mesothelin), EGFRviii, Nectin 4, Prolactin Receptor (PRLR), Muc17, Muc5Ac, CD70, CD179b, CDH19, CD16ORF54, VISTA (V-set immunoregulatory receptor or VSIR), GPC3 (glypican 3), DLL3 (canonical delta-like) Notch ligand 3), PTK7, FCRH5 (Fe receptor like 5), LYPD1 (LY6 / PLAUR domain containing 1), EMR2 (adhesion G protein-coupled receptor E2 or ADGRE2), gpNMB (glycoprotein nmb ), ring finger protein 43 (RNF43), Robo4, CEA, Her3, Folate receptor 1 (FOLR1), CLDN6 (Claudin 6), MMP16 (matrix metallopeptidase 16), uroplakin 1B (UPK1B), bone morphogenetic protein receptor type 1B (BMPR1B), Ly6E, WISP1, SLC34A2, Cripto, gpA33, ROR1, CLL1, IL1RAP, BST1 and CD133. / zRZLn / nznz / B / Yi 102 In some embodiments, the antigen-specific domains of CARs comprise scFv sequences whose SEQ IDs are set forth in Table 3. In some embodiments, the antigen-specific domains of CARs comprise CDR sequences whose SEQ IDs are set forth in Table 4. In various embodiments, immune cells expressing CARs, both conventional and next-generation CARs (eg, SIR, zSIR, Ab-TCR, TFP, and the like), comprising these antigen-binding domains can be generated and can be used for adoptive cell therapy of cancer, infectious and immune diseases using methods known in the art and using methods described in PCT / US2017 / 024843, WO 2014 / 160030 A2, WO 2016 / 187349 A1, PCT / US2016 / 058305 and PCT / US17 / 64379, which are incorporated herein by reference in their entirety. A CAR (eg, CAR II, SIR, zSIR, Ab-TCR, Tri-TAC, TFP, and the like), when used alone or with accessory modules as described herein, may comprise an antigen-binding domain ( eg, antibody or antibody fragment) that binds to a disease-supporting antigen (eg, a disease-supporting antigen as described herein). In some embodiments, the disease-supporting antigen is an antigen present on cells that supports the survival and proliferation of disease-causing cells. In some embodiments, the disease-supporting antigen is an antigen present on a stromal cell or a myeloid-derived suppressor cell (MDSC). Stromal cells can secrete growth factors and cytokines to promote cell proliferation in the microenvironment. MDSC cells can block the proliferation and activation of T lymphocytes. Without wishing to be limited by theory, in some embodiments, cells that express CAR (eg, CAR II, SIR, zSIR, AbTCR, Tri-TAC, TFP and the like) destroy disease-bearing cells, which indirectly blocks the growth or survival of disease-causing cells. / zRZLn / nznz / B / Yi 103 In certain embodiments, a stromal cell antigen is selected from one or more of: bone marrow stromal cell antigen 2 (BST2), fibroblast activation protein (FAP), and tenascin. In one embodiment, the FAP-specific antibody is, competes for binding to, or has the same CDRs as sibrotuzumab. In embodiments, the MDSC antigen is selected from one or more of: CD33, CDIIb, C14, CD15, and CD66b. Accordingly, in some embodiments, the disease-supporting antigen is selected from one or more of: bone marrow stromal cell antigen 2 (BST2), fibroblast activation protein (FAP) or tenascin, CD33, CDIIb, C14, CD15 and CD66b. In another embodiment, each CAR antigen-specific region (eg, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) may comprise a divalent (or bivalent) single-chain variable fragment (di-scFvs, bi-scFv) . In some embodiments, CARs (eg, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) comprising at least two antigen-specific targeting regions would express two scFvs specific for each of the two antigens. The resulting ASD binds to the costimulatory domain and the intracellular signaling domain through a hinge region and a transmembrane domain. An example of a CAR (a zSIR) that targets two antigens is represented by SEQ ID NO: 3962 and targets CD19 and CD123. In a further embodiment, each CAR ASD comprises a diabody. In some embodiments, the CAR ASD (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) comprises Vl fragments whose SEQ IDs and target antigens are listed in Table 3. In some embodiments, the CAR ASD (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) comprises Vh fragments whose SEQ IDs and target antigens are listed in Table 3. In some embodiments, the CAR ASD (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) comprises scFvs fragments whose SEQ ID and antigens / zRZLn / nznz / B / Yi 104 targets are listed in Table 3. In one embodiment, an antigen-specific domain of a CAR (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) against a target antigen is an antigen-binding portion, eg, CDR. , of vL and vH fragments directed to this antigen whose SEQ IDs are listed in Table 4. In one embodiment, an antigen-specific domain of a CAR (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) against a target antigen is an antigen-binding portion, eg, CDR. , of the vL and vH fragments of scFv directed to this antigen whose SEQ IDs are listed in Tables 4. In some embodiments, the CAR ASD (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) comprises VHH fragments (nanobodies). In one embodiment, an antigen-specific domain of a CAR (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) against a target antigen is an antigen-binding portion of a non-target scaffold. immunoglobulin targeting this antigen. In one embodiment, an antigen-specific domain of a CAR (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) against a target antigen is an antigen-binding portion of a receptor known by bind this target antigen. In one embodiment, a specific antigen-binding domain of a CAR (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) against a target antigen is an antigen-binding portion of a ligand. known to bind to this target antigen. The disclosure demonstrates that CARs that target the same antigen can have different biological properties depending on the particular epitope of the antigen to which they bind. Thus, two CD19-targeted CARs (eg, SEQ ID NO: 916 and 818) may have different biological properties (eg, cytotoxicity, proliferation or cytokine secretion, etc.) depending on the different CD19 epitopes they target. they join. In one embodiment, the disclosure provides CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that bind to the same epitope on the different / zRZLn / nznz / B / Yi targets. 105 listed in Tables 3 as any of the CARs (i.e., CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the disclosure that have the ability to cross-compete to bind to different targets with any of the CARs of the disclosure.In some embodiments, the antigen-specific domains of these CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) could be derived from vL fragments, vH fragments, or scFv fragments of antibodies In some embodiments, reference antibodies for cross-competition studies to determine the target epitope recognized by a CAR (eg, CAR I, CAR II, SIR, zSIR, Ab -TCR, TFP and the like) of the disclosure are scFvs targeting that antigen and having sequences as shown in SEQ ID NOs: 4266-4338, 9693-9722 and 1146811470 (Table 3).In an exemplary embodiment, the reference scFv BCMA-Am14-HL represented by SEQ ID NO: 4266 can be used in e cross-competition studies to determine the target epitope recognized by the BCMA-Am14-HL based CARs and the disclosure backbones. In some embodiments, the reference CARs for cross-competition studies against different targets are CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) whose SEQ IDs are shown in Table 7. In one embodiment, reference scFvs for cross-competition studies to determine target epitopes recognized by CD19-directed CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the disclosure are scFvs having sequences as shown in SEQ ID NOs: 4269-4270, 4272, 4298, 4299, 4338, 14462 (Table 3). In one embodiment, reference CARs for cross-competition studies to determine target epitopes recognized by CARs that target CD19 (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like). of the disclosure are CARs that target CD19 and have SEQ IDs 4830-4871, 4781-4829, 4872-4920, 4732-4780, 4683-4731,4970-5018, and 4921-4969 (Table 7). / zRZLn / nznz / E / Yii 106 In one embodiment, reference scFvs for cross-competition studies to determine target epitopes recognized by CD20-targeting CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of disclosure are scFvs targeting CD20 and having the SEQ IDs listed in Table 3. In one embodiment, reference CARs for cross-competition studies to determine target epitopes recognized by CARs that target CD20 (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like). of the disclosure are CARs that target CD20 and have SEQ IDs as listed in Table 7. In one embodiment, reference scFvs for cross-competition studies to determine target epitopes recognized by CD22-targeting CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of disclosure are scFvs targeting CD20 and having SEQ IDs 14449-14458, 14460, 14469-70 as listed in Table 3. In one embodiment, reference CARs for cross-competition studies to determine target epitopes recognized by CARs that target CD22 (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like). of the disclosure are CARs that target CD22 and have SEQ IDs as listed in Table 7. In one embodiment, reference scFvs for cross-competition studies to determine target epitopes recognized by CARs targeting BAFF-Rs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like). ) of the disclosure are scFvs targeting BAFF-R and having SEQ IDs: 14465-14467 as listed in Table 3. In one embodiment, reference CARs for cross-competition studies to determine target epitopes recognized by CARs that target BAFF-Rs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the disclosure are CARs targeting BAFF-R and having SEC IDs as listed in Table 7. In one embodiment, the reference scFvs for cross-competition studies / zRZLn / nznz / B / Yi 107 against CAR targeting DLL3 (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the disclosure are scFv targeting DLL3 and having SEQ ID as listed in FIG. Table 3. In one embodiment, the reference CARs for cross-competition studies against CARs targeting DLL3 (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the disclosure are CARs that are point to DLL3 and have the SEQ IDs listed in Table 7. In one embodiment, the reference scFvs for cross-competition studies against CAR targeting PTK7 (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the disclosure are scFv targeting to PTK7 and having SEQ ID as listed in Table 3. In one embodiment, the reference CARs for cross-competition studies against CARs targeting PTK7 (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the disclosure are CARs that are point to PTK7 and have the SEQ IDs listed in Table 7. In one embodiment, reference scFvs for cross-competition studies to determine target epitopes recognized by MSLN (mesothelin)-targeted CARs (e.g., CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like ) of the disclosure are scFvs targeting MSLN and having the SEQ IDs as listed in Table 3. In one embodiment, reference scFvs for cross-competition studies to determine target epitopes recognized by MSLN-targeting CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of disclosure are represented by SEQ ID NO: 4284-4285, 4293-4295, 9715 and 9716. In another embodiment, reference CARs for cross-competition studies to determine target epitopes recognized by CARs targeting MSLNs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of disclosure are CARs that address MSLN and have SEC IDs as listed in Table 7. / zRZLn / nznz / B / Yi 108 In one embodiment, reference scFvs for cross-competition studies to determine target epitopes recognized by Her2-directed CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the disclosure are scFvs targeting Her2 and having the SEQ IDs as listed in Table 3. In one embodiment, reference scFvs for cross-competition studies to determine target epitopes recognized by Her2-targeting CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of disclosure are represented by SEQ ID NO: 4276-4279. In another embodiment, reference CARs for cross-competition studies to determine target epitopes recognized by Her2-targeting CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the disclosure are Her2-CAR with SEQ ID NO: 6244-6292, 6391-6439, 6342-6390 and 6293-6341 (Table 7). In one embodiment, the reference scFv for cross-competition studies to determine target epitopes recognized by TSHR-targeting CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the disclosure is scFv directed to TSHR and having SEQ ID: 4280 as listed in Table 3. In another embodiment, reference CARs for cross-competition studies to determine target epitopes recognized by TSHR-targeting CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of disclosure are TSHR-CAR with SEQ ID NO: 7567-7615 (Table 7). In one embodiment, reference scFvs for cross-competition studies to determine target epitopes recognized by CARs that target EGFRviii (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of disclosure are scFvs targeting EGFRviii and having SEQ IDs as listed in Table 3. In another embodiment, reference CARs for cross-competition studies to determine target epitopes recognized by CARs targeting EGFRviii (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the disclosure are / zRZLn / nznz / B / Yi 109 EGFRviii -CAR with SEQ ID NO: 5607-5655, 5705-5753, 5754-5802 and 5656-5704. In one embodiment, reference scFvs for cross-competition studies to determine target epitopes recognized by PRLR (prolactin receptor) CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP and similar) of the disclosure are scFvs that target PRLR (Prolactin Receptor) and have SEQ IDs as listed in Table 3. In one embodiment, reference scFvs for cross-competition studies to determine recognized target epitopes for PRLR-targeting CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the disclosure are represented by SEQ ID NO: 4296 and 4309. In another embodiment, the PRLR-targeting CARs Reference CARs for cross-competition studies to determine target epitopes recognized by PRLR-targeting CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the disclosure are PRLR CAR with SEQ ID NOs: 7077-7125 and 7126-7174 as listed in Table 7. In another embodiment, reference scFvs for cross-competition studies to determine target epitopes recognized by PSMA (Prostate Specific Membrane Antigen) (e.g., CAR I, CAR II, SIR, zSIR, AbTCR) targeting CARs, TFP and the like) of the disclosure (eg, SEQ ID NO: 7273-7321, 7224-7272, and 7175-7223) are the PSMA-directed scFvs listed in Table 3 (eg, SEQ ID NO: 4281-4283). In one embodiment, reference scFvs for cross-competition studies to determine target epitopes recognized by CARs targeting PSMA (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of disclosure are represented by SEQ ID NO: 4281-4283. In another embodiment, reference CARs for cross-competition studies to determine target epitopes recognized by CARs targeting PSMA (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of disclosure are the PSMA CARs listed in Table 7 (eg, SEQ ID NO: 7273-7321, 7224-7272, and 7175-7223). / zRZLn / nznz / B / Yi 110 In another embodiment, reference scFvs for cross-competition studies to determine target epitopes recognized by DLL3-targeting CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the disclosure is the DLL3-directed scFvs listed in Table 3 (eg, SEQ ID NO: 4290-4291). In another embodiment, reference scFvs for cross-competition studies to determine target epitopes recognized by FOLR1-targeting CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the description (eg, SEQ ID NO: 5999-6047 and 6048-6096) are the FOLR1-targeting scFvs listed in Table 3 (eg, SEQ ID NO: 4323-4324). In one embodiment, reference scFvs for cross-competition studies to determine target epitopes recognized by CARs targeting FOLR1 of the disclosure are represented by SEQ ID NO: 5999-6047 and 6048-6096). In another embodiment, reference scFvs for cross-competition studies to determine target epitopes recognized by GPC3-targeting CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the description (eg, SEQ ID NO: 6097-6145 and 6146-6194) are the GPC3-directed scFvs listed in Table 3 (eg, SEQ ID NO: 4307-4308). In one embodiment, reference scFvs for cross-competition studies to determine target epitopes recognized by CARs that target GPC3 of the disclosure are represented by SEQ ID NO: 6097-6145 and 6146-6194). In another embodiment, reference scFvs for cross-competition studies to determine target epitopes recognized by WISP1-targeting CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the description (eg, SEQ ID NO: 7812-7860 and 7861-7909) are the WISP1-targeting scFvs listed in Table 3 (eg, SEQ ID NO: 4335 and 4336). In one embodiment, reference scFvs for cross-competition studies to determine target epitopes recognized by CARs that target WISP1 of the disclosure are / zRZLn / nznz / B / Yi 111 represented by SEQ ID NO: 7812-7860 and 7861-7909. In another embodiment, reference scFvs for cross-competition studies to determine target epitopes recognized by CARs targeting EMR2 (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the disclosure (eg, SEQ ID NO: 5803-5851, 5852-5900, and 5901-5949) are the EMR2-targeted scFvs listed in Table 3 (eg, SEQ ID NO: 4313, 4314, and 4315). In one embodiment, reference scFvs for cross-competition studies to determine target epitopes recognized by CARs targeting EMR2 of the disclosure are represented by SEQ ID NO: 4803-5851, 585-5900, 5901-5949. In another embodiment, reference scFvs for cross-competition studies to determine target epitopes recognized by UPK1B-targeted CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the disclosure (eg, SEQ ID NO: 7616-7664, 7665-7713) are the UPK1B-targeting scFvs listed in Table 3 (eg, SEQ ID NO: 4328 and 4329). In one embodiment, reference scFvs for cross-competition studies to determine target epitopes recognized by CARs targeting UPK1B of the disclosure are represented by SEQ ID NO: 7616-7664, 7665-7713. In another embodiment, reference scFvs for cross-competition studies to determine target epitopes recognized by CARs targeting BMPR1B (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the description (eg, SEQ ID NO: 4536-4584, 4585-4633) are the BMPR1B-targeting scFvs listed in Table 3 (eg, SEQ ID NO: 4330 and 4331). In one embodiment, reference scFvs for cross-competition studies to determine target epitopes recognized by CARs targeting BMPR1B of the disclosure are represented by SEQ ID NO: 4536-4584, 4585-4633. In another embodiment, reference CARs for cross-competition studies to determine target epitopes recognized by CARs targeting / zRZLn / nznz / B / Yi 112 BMPR1B (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the disclosure are the CARs of BMPR1B listed in Table 7 (eg, SEQ ID NO: 4536-4584, 4585- 4633). In another embodiment, reference scFvs for cross-competition studies to determine target epitopes recognized by CDH19-targeting CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the disclosure (eg, SEQ ID NO: 5264-5312, 5313-5361) are the CDH19-directed scFvs listed in Table 3 (eg, SEQ ID NO: 4302 and 4303). In one embodiment, reference scFvs for cross-competition studies to determine target epitopes recognized by the CDH19-targeting CARs of the disclosure are represented by SEQ ID NO: 5264-5312, 5313-5361. In another embodiment, reference CARs for cross-competition studies to determine target epitopes recognized by CDH19-targeting CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the disclosure is the CDH19 CARs listed in Table 7 (eg, SEQ ID NO: 5264-5312, 53135361). In another embodiment, the reference scFvs for cross-competition studies to determine target epitopes recognized by the VISTA-targeting CARs of the disclosure (eg, SEQ ID NO: 7763-7811, 7714-7762) are those of VISTA - targeting scFvs listed in Table 3 (eg, SEQ ID NO: 4305 and 4306). In one embodiment, reference scFvs for cross-competition studies to determine target epitopes recognized by VISTA-targeting CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of disclosure are represented by SEQ ID NO: 7763-7811, 7714-7762. In another embodiment, reference CARs for cross-competition studies to determine target epitopes recognized by VISTA-targeting CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of disclosure / zRZLn / nznz / B / Yi 113 are the VISTA CARs listed in Table 7 (eg, SEQ ID NO: 7763-7811, 7714-7762). In another embodiment, the reference scFv for cross-competition studies to determine target epitopes recognized by CARs that target IL13Ra2 (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the disclosure are IL13Ra2 scFv listed in Table 3 (eg, SEQ ID NO: 14448). In another embodiment, reference CARs for cross-competition studies to determine target epitopes recognized by CARs that target IL13Ra2 (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the disclosure is the IL13Ra2 CARs listed in Table 7 (eg, SEQ ID NO: 1585715909). In another embodiment, reference scFvs for cross-competition studies to determine target epitopes recognized by FLT3-targeted CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the description (eg, SEQ ID NO: 10606-10654, 10557-10605) are the FLT3-targeting scFvs listed in Table 3 (eg, SEQ ID NO: 9710 and 9711). In one embodiment, reference scFvs for cross-competition studies to determine target epitopes recognized by CARs that target FLT3 (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the disclosure are represented by SEQ ID NO: 10557-10605, 1060610654. In another embodiment, reference CARs for cross-competition studies to determine target epitopes recognized by CARs targeting FLT3 (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the disclosure are FLT3 CARs that are listed in Table 7 (eg, SEQ ID NO: 10557-10605, 1060610654). In another embodiment, reference scFvs for cross-competition studies to determine target epitopes recognized by CARs targeting CLDN6 / zRZLn / nznz / E / Yii 114 (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the disclosure (eg, SEQ ID NO: 5411-5459, 5460-5508) are the scFvs targeting CLDN6 listed in Table 3 (eg, SEQ ID NO: 4325 and 4326). In one embodiment, reference scFvs for cross-competition studies to determine target epitopes recognized by CARs targeting CLDN6 (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the disclosure are represented by SEQ ID NO: 54115459, 5460-5508. In another embodiment, reference CARs for cross-competition studies to determine target epitopes recognized by CARs targeting CLDN6 (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the disclosure is the CLDN6 CARs listed in Table 7 (eg, SEQ ID NO: 5411-5459, 54605508). In another embodiment, reference scFvs for cross-competition studies to determine target epitopes recognized by ROBO4-targeted CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the disclosure (eg, SEQ ID NO: 7420-7468) are the ROBO4-targeted scFvs listed in Table 3 (eg, SEQ ID NO: 4320). In one embodiment, reference scFvs for cross-competition studies to determine target epitopes recognized by ROBO4-targeting CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of disclosure are represented by SEQ ID NO: 7420-7468. In another embodiment, reference CARs for cross-competition studies to determine target epitopes recognized by ROBO4-targeting CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the disclosure is the ROBO4 CARs listed in Table 7 (eg, SEQ ID NO: 7420-7468). In another embodiment, reference scFvs for cross-competition studies to determine target epitopes recognized by IL1RAP-targeted CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the description (by / zRZLn / nznz / B / Yi 115 example, SEQ ID NO: 10802-10850, 10851-10899, 10900-10948) are the IL1RAP-targeting scFvs listed in Table 3 (eg, SEQ ID NO: 9712, 9713 and 9714). In one embodiment, reference scFvs for cross-competition studies to determine target epitopes recognized by IL1RAP-targeting CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of disclosure are represented by SEQ ID NO: 10802-10850, 10851-10899, 10900-10948. In another embodiment, reference CARs for cross-competition studies to determine target epitopes recognized by IL1RAP-targeting CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the disclosure is the CAR IL1RAPs listed in Table 7 (eg, SEQ ID NO: 10802-10850, 10851-10899, 10900-10948). In another embodiment, reference scFvs for cross-competition studies to determine target epitopes recognized by CD22-directed CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the disclosure (eg, SEQ ID NO: 5068-5115, 10361-10409) are the CD22-targeting scFvs listed in Table 3 (eg, SEQ ID NO: 4271, 9693, 12502). In one embodiment, reference scFvs for cross-competition studies to determine target epitopes recognized by CD22-targeting CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the disclosure are represented by SEQ ID NO: 50685115, 10361-10409. In another embodiment, reference CARs for cross-competition studies to determine target epitopes recognized by CD22-targeting CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the disclosure is the CD22 CARs listed in Table 7 (eg, SEQ ID NO: 5068-5115,10361-10409). In another embodiment, reference scFvs for cross-competition studies to determine target epitopes recognized by CLL1-targeting CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the description (for / zRZLn / nznz / E / Yii 116 example, SEQ ID NO: 10459-10507, 10410-10458) are the CLL1-targeting scFvs listed in Table 3 (eg, SEQ ID NO: 9708 and 9703). In one embodiment, reference scFvs for cross-competition studies to determine target epitopes recognized by CLL1-targeting CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of disclosure are represented by SEQ ID NO: 10410-10458, 10459-10507. In another embodiment, reference CARs for cross-competition studies to determine target epitopes recognized by CARs targeting CLL1 (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the disclosure is the CAR CLL1s listed in Table 7 (eg, SEQ ID NO: 10410-10458, 1045910507). In another embodiment, reference scFvs for cross-competition studies to determine target epitopes recognized by CARs targeting BST1 (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the disclosure (eg, SEQ ID NO: 10116-10164, 10165-10212, 10213-10262) are the BST1-targeted scFvs listed in Table 3 (eg, SEQ ID NO: 9718, 9719 and 9720). In one embodiment, reference scFvs for cross-competition studies to determine target epitopes recognized by CARs targeting BST1 (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of disclosure are represented by SEQ ID NO: 10116-10164, 10165-10212, 10213-10262. In another embodiment, reference CARs for cross-competition studies to determine target epitopes recognized by CARs targeting BST 1 (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like). of the disclosure are CAR BST1 listed in Table 7 (eg, SEQ ID NO: 10116-10164, 1016510212, 10213-10262). In another embodiment, reference scFvs for cross-competition studies to determine target epitopes recognized by CARs targeting / zRZLn / nznz / B / Yi 117 NECTIN-4 (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the disclosure (eg, SEQ ID NO: 7028-7076, 11096-11242) are the scFvs targeting NECTIN-4 listed in Table 3 (eg, SEQ ID NO: 4292, 9696). In one embodiment, reference scFvs for cross-competition studies to determine target epitopes recognized by CARs that target NECTIN-4 (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like). ) of the disclosure is represented by SEQ ID NO: 7028-7076, 11096-11242. In another embodiment, reference CARs for cross-competition studies to determine target epitopes recognized by CARs that target NECTIN-4 (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the similar) of the disclosure are the NECTIN-4 CARs listed in Table 7 (eg, SEQ ID NO: 7028-7076, 11096-11242). In another embodiment, reference scFvs for cross-competition studies to determine target epitopes recognized by GPA33-targeting CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the disclosure (eg, SEQ ID NO: 10655-10703) are the GPA33-directed scFvs listed in Table 3 (eg, SEQ ID NO: 9698). In one embodiment, reference scFvs for cross-competition studies to determine target epitopes recognized by GPA33-targeting CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the disclosure are represented by SEQ ID NO: 10655-10703. In another embodiment, reference CARs for cross-competition studies to determine target epitopes recognized by CARs targeting GPA33 (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the disclosure is the CARs of GPA33 listed in Table 7 (eg, SEQ ID NO: 10655-10703). In another embodiment, reference scFvs for cross-competition studies to determine target epitopes recognized by CARs targeting ROR1 (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of disclosure (by / zRZLn / nznz / B / Yi 118 example, SEQ ID NO: 11145-11193) are the ROR1-targeted scFvs listed in Table 3 (eg, SEQ ID NO: 9699). In one embodiment, reference scFvs for cross-competition studies to determine target epitopes recognized by CARs targeting ROR1 (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the disclosure are represented by SEQ ID NO: 11145-11193. In another embodiment, reference CARs for cross-competition studies to determine target epitopes recognized by CARs targeting ROR1 (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the disclosure is the CAR ROR1s listed in Table 7 (eg, SEQ ID NO: 11145-11193). In another embodiment, reference scFvs for cross-competition studies to determine target epitopes recognized by CRIPTO-targeting CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the disclosure (eg, SEQ ID NO: 10508-10556) are the CRYPTO-directed scFvs listed in Table 3 (eg, SEQ ID NO: 9697). In one embodiment, reference scFvs for cross-competition studies to determine target epitopes recognized by CRIPTO-targeting CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the disclosure are represented by SEQ ID NO: 10508-10556. In another embodiment, reference CARs for cross-competition studies to determine target epitopes recognized by CRIPTO-targeting CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the disclosure is the CRIPTO CARS listed in Table 7 (eg, SEQ ID NO: 10508-10556). In some embodiments, two or more functional domains of CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) as described herein are separated by one or more linkers. Linkers are oligo or polypeptide regions of about 1 to 100 amino acids in length, which join any of the CAR domains / regions (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP and the like) of disclosure. In some embodiments, the / zRZLn / nznz / B / Yi linkers 119 may be, for example, 5-12 amino acids long, 5-15 amino acids long, or 5-20 amino acids long. Linkers can be made up of flexible residues like glycine and serine so that adjacent protein domains can move freely relative to each other. Longer linkers, eg, those longer than 100 amino acids, may be used in connection with alternative embodiments of the disclosure, and may be selected to, eg, ensure that two adjacent domains do not interfere spherically with each other. SEQ ID NOs of several exemplary linkers are listed in Table 5 (see, for example, SEQ ID NOs: 4007 to 4012. In some embodiments, the CARs (which are part of the backbones) described herein comprise a hinge or linker region between the antigen-specific domain and the transmembrane domain. In some embodiments, the hinge region comprises one or more of a human CD8a or Fc fragment of an antibody or a functional equivalent, fragment or derivative thereof, a hinge region of human CD8a or an antibody or a functional equivalent, fragment or derivative thereof. itself, an antibody CH2 region, an antibody CH3 region, an artificial spacer sequence, and combinations thereof. In exemplary embodiments, the hinge region comprises one or more of (i) an lgG4 hinge, CH2 and CH3 region, (ii) an lgG4 hinge region, (iii) an lgG4 hinge and CH2 region, (iv) a CD8a hinge region, (v) an lgG1 hinge, CH2 and CH3 region, (vi) an lgG1 hinge region, (vi) an lgG1 hinge and CH2 region, or (vii) combinations of these. As described herein, the CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) (which are part of backbones) described herein comprise a transmembrane domain. The transmembrane domain can comprise the transmembrane sequence of any protein that has a transmembrane domain, including any of the type I, type II, or type III transmembrane proteins. The CAR transmembrane domain (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP and the like) of the disclosure may also comprise a / zRZLn / nznz / B / Yi 120 artificial hydrophobic sequence. The transmembrane domains of CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) described herein can be selected such that the transmembrane domain does not dimerize. In some embodiments, the TMD-encoded CAR (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) comprising any of the backbones described herein comprises a transmembrane domain selected from the transmembrane domain of an alpha, beta or zeta chain of a T cell receptor, CD3e, ΰϋ3ζ, CD3y, CD3Ó, CD28, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, CD154, KIRDS2, 0X40, CD2, CD27, LFA-1 (CDI la, CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD40, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRFI ), CD160 , CD19, IL2R beta, IL2R gamma, IL7R a, ITGA1, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CDI Id, ITGAE, CD103, ITGAL, CDI la, LFA -1, ITGAM, CDI Ib, ITGAX, CDI le, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, TNFR2, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (touch), CEACAM1, CRT AM, Ly9 (CD229), CD160 (BY55), PSGL1, CDIOO (SEMA4D), SLAMF6 (NTB-A, Lyl08), SLAM (SLAMF1, CD150, IPO-3), GUILT (S LAMF8), SELPLG (CD162), LTBR, ​​PAG / Cbp, NKp44, NKp30, NKp 46, NKG2D, and / or NKG2C. A transmembrane domain can include one or more additional amino acids adjacent to the transmembrane region, for example, one or more amino acids associated with the extracellular region of the protein from which the transmembrane is derived (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 up to 15 amino acids from the extracellular region) and / or one or more additional amino acids associated with the intracellular region of the protein from which the transmembrane protein is derived (for example, 1, 2 , 3, 4, 5, 6, 7, 8, 9, 10 to 15 amino acids from the intracellular region). In one aspect, the transmembrane domain is contiguous with one of the other CAR domains (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like). In one embodiment, the transmembrane domain can be from the same protein from which the signaling domain, costimulatory domain, or / zRZLn / nznz / B / Yi is derived. 121 the hinge domain. In another aspect, the transmembrane domain is not derived from the same protein that any other CAR domain is derived from (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like). As described herein, the CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) (which are part of backbones) described herein comprise a domain of intracellular signaling. This domain may be cytoplasmic and may transduce the signal of effector function and direct the cell to perform its specialized function. Examples of intracellular signaling domains include, but are not limited to, T cell receptor C chain or any of its homologues (for example, η chain, CD3e, CD3y, CD3ó, FceRly and β chains, MB1 (Iga) chain, B29 (Igp ), etc.), CD3 polypeptides (Δ, δ and ε), syk family tyrosine kinases (Syk, ZAP 70, etc.), src family tyrosine kinases (Lck, Fyn, Lyn, etc.) and others molecules involved in the transduction of T lymphocytes, such as CD2, CD5 and CD28. Specifically, the intracellular signaling domain may be human CD3 zeta chain, FcyRIII, FccRI, Fe receptor cytoplasmic tails, immunoreceptor tyrosine-based activation motif (ITAM) bearing cytoplasmic receptors, or combinations thereof. Additional intracellular signaling domains will be apparent to the mid-level trade and may be used in connection with alternative embodiments of the invention. In some embodiments, the intracellular signaling domain comprises a signaling domain from one or more of a human CD3 zeta chain, FcgRIII, FceRI, a cytoplasmic tail of an Fe receptor, an immunoreceptor tyrosine-based activation motif (ITAM ) bearing cytoplasmic receptors, and combinations thereof. As described herein, the CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) (which are part of backbones) described herein comprise a costimulatory domain. In exemplary embodiments, the costimulatory domain comprises a signaling domain of / zRZLn / nznz / B / Yi 122 any one or more of CD28, CD137 (4-1BB), CD134 (0X40), Dap10, CD27, CD2, CD5, ICAM-1, LFA-1, Lck, TNFR-I, TNFR-II, Fas, CD30, CD40 and combinations thereof. Cleavable linkers as described herein include 2A linkers (eg T2A), 2A-type linkers or functional equivalents thereof, and combinations thereof. In some embodiments, linkers include the type 2A picornaviral linker, CHYSEL sequences from porcine teschovirus (P2A), Thosea virus (T2A), or combinations, variants, and functional equivalents thereof. In other embodiments, the linker sequences may comprise the Asp-Val / lle-Glu-X-Asn-Pro-Gly(2A)-Pro(2B) motif, which results in cleavage between glycine 2A and proline 2B. Nucleic sequences of several exemplary cleavage linkers are provided in SEQ ID NO: 80 to SEQ ID NO: 85 and amino acid sequences of several exemplary linkers are provided in SEQ ID NO: 4079 to SEQ ID NO: 4084. Other linkers will be apparent. for those skilled in the art and may be used in connection with alternative embodiments of the disclosure. In one embodiment, a Ser-Gly-Ser-Gly (SGSG) motif (SEQ ID NO: 931932 and SEQ ID NO: 4844-4845) is also added upstream of the cleaved linker sequences to improve cleavage efficiency. A potential drawback of cleaved linkers is the possibility that the small 2A tag remaining at the end of the N-terminal protein may affect the function of the protein or contribute to the antigenicity of the proteins. To overcome this limitation, in some embodiments, a furin cleavage site (RAKR) (SEQ ID NO: 88-90 and 4087-4089) is added upstream of the SGSG motifs to facilitate cleavage of residual 2A peptide after nucleation. translation. In one embodiment, cleavage linkers are placed between the CAR-encoding polypeptide and the accessory module-encoding polypeptide. Cleavage at the cleaved linker site results in the separation of the two polypeptides. Accessory modules as used herein refer to agents that enhance, reduce, or modify the activity of T cells expressing the / zRZLn / nznz / B / Yi 123 CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) or reduce toxicity associated with CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and similar) so as to improve the therapeutic response of CARs. An accessory module can also enhance gene transfer and / or expression of the CAR-encoding cassette in target cells, eg, an immune effector cell. In some embodiments, vectors comprising CAR-encoding polynucleotides (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) may further comprise polynucleotides encoding viral and cellular signaling proteins that (i) extend the lifespan of T cells expressing CARs (for example, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like), (ii) stimulate T cell proliferation, and / or (iii) ) protect T cells expressing CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) from apoptosis; (iv) enhancing the packaging, gene transfer and / or expression of CAR constructs (eg CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP and the like). In exemplary embodiments, such proteins include, but are not limited to, vFLIP-K13 (SEQ ID NO (DNA): 108; SEQ ID NO (PRT): 4107) from Kaposi's sarcoma-associated herpes virus and Vif from HIV- 1 (SEQ ID NO: 118 and 4117). In one embodiment, vectors encoding CAR (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) further encode VFLIP-K13. In one embodiment, the nucleotide sequence of vFLIP-K13 is codon optimized. An example of CAR (ie, SIR) coexpressing the vFLIP K13 optimized codon is represented by SEQ ID NO: 14057. In one embodiment, vectors encoding CAR additionally encode HIV-1 Vif. In an alternative embodiment, the CAR-encoding vectors further encode both vFLIP K13 and HIV-1 Vif. In some embodiments, the accessory molecules are encoded by vectors that are distinct from the CAR-encoding vectors (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) described herein. In some embodiments, effector cells comprising CAR-encoding vectors (for / zRZLn / nznz / B / Yi 124 example, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP and the like) also comprise vectors encoding accessory molecules. In some embodiments, accessory molecules are encoded by modifying the genomic locus that encodes the corresponding endogenous protein. In some embodiments, vectors comprising CAR-encoding polynucleotides (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) further comprise cytokine-specific scFv or siRNA-encoding polynucleotides. In exemplary embodiments, the cytokines are any one or more of IL-10, IL-6, IFN, or combinations thereof. In some embodiment, CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) are co-expressed with a secreted bispecific antibody fragment that binds to the IL6 α receptor and human serum albumin. . In some embodiment, CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) are co-expressed with a secreted scFv fragment that binds IL6. In some embodiments, CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) are co-expressed with the FX06 peptide to mitigate capillary leak associated with CAR therapy. In further embodiments, vectors comprising polynucleotides encoding CAR (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) further comprise polynucleotides encoding siRNA or a nuclease that targets TCR-α. endogenous, TCR. -β, TCR-γ, TCR-delta, CD3gamma, CD3zeta, CD3epsilon, CD3delta. In additional embodiments, polynucleotides encoding siRNA or a nuclease that targets endogenous TCR-α, TCR-β, TCR-γ, TCR-delta, CD3gamma, CD3zeta, CD3epsilon, CD3-delta are encoded by vectors other than vectors encoding CAR (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like). In further embodiments, vectors comprising CAR-encoding polynucleotides (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) further comprise polynucleotides encoding a selectable marker. In an exemplary embodiment, the selectable marker may encode a / zRZLn / nznz / B / Yu resistance gene. 125 drugs, such as a gene that confers resistance to inhibitors of puromycin or calcineurin (eg, CNB30). In some embodiment, the selectable marker can encode extracellular and transmembrane domains of human CD30, CD20, CD19 (SEQ ID NO: 96 and 4095), BCMA (SEQ ID NO: 97 and 4096), EGFR (SEQ ID NO: 95 and 4094 ), CD34, or any protein or protein fragment that is expressed on the cell surface and can be recognized by an antibody that can be used to kill cells expressing its target antigen. In an exemplary embodiment, cetuximab, an anti-EGFR monoclonal, is used to eliminate CAR-expressing cells of the disclosure that co-express a truncated EGFR. Selectable markers can be used to enrich for cells expressing CAR (eg CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP and the like), to select for cells expressing high levels of CAR (eg , CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) and / or to reduce the clonal diversity of cells expressing the CAR (for example, CAR I, CAR II, SIR, zSIR, Ab- TCR, TFP and the like). In further embodiments, CAR-encoding polynucleotides (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) can encode epitope tags (eg, Myc Tag) that are expressed in the extracellular domain. of the CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) and can be used to enrich for cells expressing CAR (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR , TFP, and the like), to select for cells expressing high levels of CAR (e.g., CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) and / or to reduce the clonal diversity of cells expressing the CAR (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP and the like). Reducing the clonal diversity of allogeneic T cells expressing CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) will in turn lead to a reduction in the incidence of cancer disease. graft-versus-host (GVHD), thus allowing the use of allogeneic T cells for CAR-T cell therapy. It should be noted that accessory modules are optional for CAR activity (eg CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP and the like). The / zRZLn / nznz / B / Yi 126 polypeptides and polynucleotides of various examples of CAR constructs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) (ie, backbones) in Table 6 and Table 7 contain modules accessories such as PAC, K13 and / or hNEMOK277A-Flag. In alternate embodiments of the disclosure, these CAR constructs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) can be used without the presence of the accessory modules and intermediate divisible liner (eg , P2A or F2A or T2A). In certain embodiments, the disclosure provides a new platform of synthetic immune receptors, called zSIRs, that contain two CD3z chains. Nucleic acid sequences of CD3z strands that can be used in the construction of zSIR are provided in SEQ ID NO: 67 and 71. The corresponding amino acid sequences are provided in SEQ ID NO: 4066 and 4070, respectively. The disclosure states that the vL fragment of an antibody can bind to one of the two CD3z chains and the vH fragment can bind to the other CD3z chain. When two such chains (for example, vL-CD3z and vH-CD3z) are co-expressed in the same cell, the vL and vH fragments can bind to their cognate antigen and transmit a T-cell signal. T cells expressing such a zSIR when exposed to a cell line expressing the related target antigen can activate NFAT signaling, induce IL2 production, promote T cell proliferation, promote T cell activation, and exert cytotoxicity. The expression and activity of zSIR can be further increased by incorporating a linker between the vL / vH and CD3z fragments. In particular, the IgCL domains (SEQ ID NO (DNA): 28 and SEQ ID NO (PRT): 4027) and IgCH (SEQ ID NO (DNA): 29 and SEQ ID NO (PRT): 4028) derived from antibodies serve as useful linkers between vL / vH and CD3z fragments. In another embodiment, a costimulatory domain is also incorporated into the CD3z chain(s) of zSIR. Exemplary costimulatory domains include costimulatory domains from 41BB and CD28. CD3z chains containing / zRZLn / nznz / E / Yii domains 127 costimulators 41 BB and CD28 are presented in SEQ ID NO: 4076, 4078 and 4075, 4077, respectively (Table 5). Taken together, the above results provide a novel platform for adoptive cell therapy that overcomes some of the design limitations of SIRs and also provides a complementary approach to SIRs. The two zSIR chains described herein can be encoded by a single polynucleotide chain and translated into a single polypeptide chain, which is subsequently cleaved into different proteins. The two zSIR chains described herein can be expressed using two different promoters and encoded by two separate polynucleotide chains. The two zSIR chains described herein may be encoded by a single vector. The two zSIR chains described in this document may be encoded by two different vectors. The nucleic acid molecule encoding a zSIR may comprise one or more leader sequences (also known as signal peptides). In one embodiment, each functional unit (eg, an antigen-binding domain linked to a CD3z chain plus a Furine-SGSG cleaved linker) of a zSIR may be preceded by a leader sequence that directs the zSIR to the cell surface as a type I transmembrane protein. In one embodiment, the antigen-binding domain of zSIR is extracellular oriented. In some embodiments, the leader sequence comprises the nucleic acid sequence from any of SEQ ID NO: 1 to 4 and amino acid sequences from SEQ ID NO: 4000 to SEQ ID NO: 4003. In some embodiments, short nucleic acid sequences ( 3-9 nucleic acids) comprising restriction enzyme sites are located between the different subunits of a zSIR, for example, between a signal sequence and the antigen-binding domain of the zSIR or between the antigen-binding and CD3z strand. Provided herein are one or more polypeptides encoded by one or more CAR-encoding nucleic acid molecules (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) 1 to 15 (Table 1 ) or any one or more of the strings / zRZLn / nznz / B / Yi 128 main ones 1-60 described in the present document (Table 2). In some embodiments, the antigen-specific domain of CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) is specific for one, two, three, or more antigens on target cells, such like cancer cells. As described herein, in some embodiments, each component of the CAR (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) is contiguous and in the same reading frame with the others. CAR components (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP and the like). In some embodiments, if the structure comprising CAR (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) comprises more than one antigen-specific domain, each of the antigen-specific domains is contiguous and in the same reading frame as the other antigen-specific domains in the same CAR (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like). Also provided herein is one or more polypeptides encoded by one or more nucleic acid molecules encoding backbone-1 comprising CAR I and K13-vFLIP as described herein. In some embodiments, the CAR antigen-specific domain comprising backbone-1 is specific for one, two, three, or more antigens on target cells, such as cancer cells. As described herein, in some embodiments, each CAR component is contiguous and in the same reading frame with each of the other CAR components comprising the I-backbone. In some embodiments, the CAR comprising backbone-1 comprises more than one antigen-specific domain, each of the antigen-specific domains being contiguous and in the same reading frame as the other antigen-specific domains in the same CAR. Also provided herein is one or more polypeptides encoded by one or more nucleic acid molecules encoding the HIV-1 CAR II (CAR 2) and Vif comprising backbone-8 as described herein. In some / zRZLn / nznz / B / Yi 129 embodiments, the CAR antigen-specific domain comprising backbone 8 is specific for one, two, three or more antigens on target cells, such as cancer cells. As described herein, each component of the CAR is contiguous and in the same reading frame with each of the other components of the CAR. In some embodiments, the CAR comprising backbone-8 comprises more than one antigen-specific domain, each of the antigen-specific domains being contiguous and in the same reading frame as the other antigen-specific domains in the same CAR. . In various embodiments, polypeptides encoded by CAR-encoding nucleic acid molecules (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that are part of CARs 1 through 15 (see, Table 1) or part of the backbones described herein, such as backbone 1, backbone 2, backbone 32 or backbone 60, comprise two, three or more antigen-specific domains. In various embodiments, polypeptides encoded by CAR-encoding nucleic acid molecules (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that are part of CARs 1 through 15 (see, Table 1) or part of the lead chains described herein, such as lead 1, lead 2, lead 32 or lead 60, comprise two, three or more costimulatory domains. In various embodiments, polypeptides encoded by CAR-encoding nucleic acid molecules (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that are part of CARs 1 through 15 (see, Table 1) or part of the backbones described herein, such as backbone 1, backbone 2, backbone 32 or backbone 60, comprise zero, one, two, three or more intracellular signaling domains . In various embodiments, the polypeptides encoded by the / zRZLn / nznz / B / Yi molecules 130 CAR-encoding nucleic acids (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that are part of the backbones described herein, such as backbone-1, backbone-2 , skeleton-32 or skeleton-60, comprise one, two, three or more viral and / or cellular signaling proteins. Nucleic acid sequences encoding the desired components of CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) described herein can be obtained using recombinant methods known in the art. , such as, for example, by screening libraries of cells that express the nucleic acid molecule, deriving the nucleic acid molecule from a vector known to include it, or isolating directly from cells and tissues that contain it, using standard techniques . Alternatively, the nucleic acid of interest can be produced synthetically, rather than cloned. In some embodiments, provided herein are polypeptides encoded by CAR-encoding nucleic acid molecules (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that are part of the CAR 1 to 15. (see, Table 1) or are part of the lead chains described herein, such as lead 1, lead 2, lead 32, or lead 60, where the antigen-specific domain of CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) are target-specific as described in Table 3. In one embodiment, an antigen-specific domain of a CAR (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) against a target antigen is an antigen-binding portion, eg, CDR. , of vL and vH fragments directed to this antigen whose SEQ ID is shown in Tables 3 and 4. In one embodiment, an antigen-specific domain of a CAR (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) against a target antigen is an antigen-binding portion, eg, CDR. , of vHH fragments directed to this antigen. / zRZLn / nznz / E / Yii 131 In one embodiment, an antigen-specific domain of a CAR (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) against a target antigen is an antigen-binding portion of a non-immunoglobulin scaffold. directed at this antigen. In one embodiment, an antigen-specific domain of a CAR (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) against a target antigen is an antigen-binding portion of a receptor known by bind this target antigen. In one embodiment, an antigen-specific domain of a CAR (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) against a target antigen is an antigen-binding portion of a ligand known by bind this target antigen. In one embodiment, an antigen-specific domain of a CAR (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) against a target antigen is an antigen-binding portion, eg, CDR. , of vL and vH fragments of a scFV directed to this antigen whose SEQ ID is shown in Table 3. The SEQ ID NO of the CDRs are shown in Table 4. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that are part of CAR. 1 to 15 (see, for example, Table 1) or are part of the strands described herein, such as strand 1, strand 2, strand 32, or strand 60, wherein the antigen-specific domain of the CARs are specific to the targets shown in Table 3. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that are part of CAR. 1 to 15 (see, for example, Table 1) or are part of the strands described herein, such as strand 1, strand 2, strand 32, or strand 60, wherein the antigen-specific domain of CARs is specific for CD19. / zRZLn / nznz / B / Yi 132 In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that are part of CAR. 1 to 15 (see, for example, Table 1) or are part of the strands described herein, such as strand 1, strand 2, strand 32, or strand 60, wherein the antigen-specific domain of CARs is specific for CD20. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that are part of CAR. 1 to 15 (see, for example, Table 1) or are part of the strands described herein, such as strand 1, strand 2, strand 32, or strand 60, wherein the antigen-specific domain of CARs is specific for CD22. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that are part of CAR. 1 to 15 (see, for example, Table 1) or are part of the strands described herein, such as strand 1, strand 2, strand 32, or strand 60, wherein the antigen-specific domain of the CARs is specific to BCMA. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that are part of CAR. 1 to 15 (see, for example, Table 1) or are part of the strands described herein, such as strand 1, strand 2, strand 32, or strand 60, wherein the antigen-specific domain of the CARs is specific for Integrin B7. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that are part of CAR. 1 to 15 (see, for / zRZLn / nznz / E / Yii 133 example, Table 1) or are part of the lead chains described herein, such as lead 1, lead 2, lead 32, or lead 60, where the antigen-specific domain of CARs is specific for Her2. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that are part of CAR. 1 to 15 (see, for example, Table 1) or are part of the strands described herein, such as strand 1, strand 2, strand 32, or strand 60, wherein the antigen-specific domain of CARs is specific to TSHR. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that are part of CAR. 1 to 15 (see, for example, Table 1) or are part of the strands described herein, such as strand 1, strand 2, strand 32, or strand 60, wherein the antigen-specific domain of the CARs is specific to PSMA. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that are part of CAR. 1 to 15 (see, for example, Table 1) or are part of the strands described herein, such as strand 1, strand 2, strand 32, or strand 60, wherein the antigen-specific domain of the CARs is specific to MSLN. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that are part of CAR. 1 to 15 (see, for example, Table 1) or are part of the strands described herein, such as strand 1, strand 2, strand 32, or strand 60, wherein the antigen-specific domain of CARs is specific for EGFR viii. / zRZLn / nznz / B / Yi 134 In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that are part of CAR. 1 to 15 (see, for example, Table 1) or are part of the strands described herein, such as strand 1, strand 2, strand 32, or strand 60, wherein the antigen-specific domain of the CARs is specific to DLL3. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that are part of CAR. 1 to 15 (see, for example, Table 1) or are part of the strands described herein, such as strand 1, strand 2, strand 32, or strand 60, wherein the antigen-specific domain of the CARs is specific for Nectin-4. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that are part of CAR. 1 to 15 (see, for example, Table 1) or are part of the strands described herein, such as strand 1, strand 2, strand 32, or strand 60, wherein the antigen-specific domain of CARs is specific for Prolactin Receptor (PRLR). In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that are part of CAR. 1 to 15 (see, for example, Table 1) or are part of the strands described herein, such as strand 1, strand 2, strand 32, or strand 60, wherein the antigen-specific domain of the CARs is specific for Muc17. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding CARs (for example, CAR / zRZLn / nznz / B / Yi 135 I, CAR II, SIR, zSIR, Ab-TCR, TFP and the like) that are part of CAR 1 to 15 (see, for example, Table 1) or are part of the backbones described herein, such as backbone 1, backbone 2, backbone 32, or backbone 60, where the antigen-specific domain of the CARs is specific for CD70. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that are part of CAR. 1 to 15 (see, for example, Table 1) or are part of the strands described herein, such as strand 1, strand 2, strand 32, or strand 60, wherein the antigen-specific domain of CARs is specific for prolactin receptor CDH19. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that are part of CAR. 1 to 15 (see, for example, Table 1) or are part of the strands described herein, such as strand 1, strand 2, strand 32, or strand 60, wherein the antigen-specific domain of the CARs is specific for CD16ORF54. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that are part of CAR. 1 to 15 (see, for example, Table 1) or are part of the strands described herein, such as strand 1, strand 2, strand 32, or strand 60, wherein the antigen-specific domain of CARs is VISTA specific. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that are part of CAR. 1 to 15 (see, for example, Table 1) or are part of the backbones described herein, such / zRZLn / nznz / B / Yi 136 as lead 1, lead 2, lead 32, or lead 60, where the antigen-specific domain of the CARs is specific for GPC3. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that are part of CAR. 1 to 15 (see, for example, Table 1) or are part of the strands described herein, such as strand 1, strand 2, strand 32, or strand 60, wherein the antigen-specific domain of CARs is specific for Muc5Ac. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that are part of CAR. 1 to 15 (see, for example, Table 1) or are part of the strands described herein, such as strand 1, strand 2, strand 32, or strand 60, wherein the antigen-specific domain of the CARs is specific for FCRH5. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that are part of CAR. 1 to 15 (see, for example, Table 1) or are part of the strands described herein, such as strand 1, strand 2, strand 32, or strand 60, wherein the antigen-specific domain of CARs is specific for LYPD1 In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that are part of CAR. 1 to 15 (see, for example, Table 1) or are part of the strands described herein, such as strand 1, strand 2, strand 32, or strand 60, wherein the antigen-specific domain of the CARs is specific to EMR2. In some embodiments, / zRZLn / nznz / B / Yi polypeptides are provided herein. 137 encoded by the nucleic acid molecules encoding the CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that are part of CARs 1 to 15 (see, eg, Table 1 ) or are part of the backbones described herein, such as backbone 1, backbone 2, backbone 32, or backbone 60, where the antigen-specific domain of the CARs is specific for gpNMB. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that are part of CAR. 1 to 15 (see, for example, Table 1) or are part of the strands described herein, such as strand 1, strand 2, strand 32, or strand 60, wherein the antigen-specific domain of the CARs is specific for RNF43. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that are part of CAR. 1 to 15 (see, for example, Table 1) or are part of the strands described herein, such as strand 1, strand 2, strand 32, or strand 60, wherein the antigen-specific domain of the CARs is specific for CD44v6. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that are part of CAR. 1 to 15 (see, for example, Table 1) or are part of the strands described herein, such as strand 1, strand 2, strand 32, or strand 60, wherein the antigen-specific domain of the CARs is specific to Robo4. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that are part of CAR. 1 to 15 (see, for example, Table 1) or are part of the backbones described herein, such / zRZLn / nznz / B / Yi 138 as lead 1, lead 2, lead 32, or lead 60, where the antigen-specific domain of the CARs is specific for CEA. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that are part of CAR. 1 to 15 (see, for example, Table 1) or are part of the strands described herein, such as strand 1, strand 2, strand 32, or strand 60, wherein the antigen-specific domain of the CARs is specific for Her3. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that are part of CAR. 1 to 15 (see, for example, Table 1) or are part of the strands described herein, such as strand 1, strand 2, strand 32, or strand 60, wherein the antigen-specific domain of the CARs is specific for FOLR1. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that are part of CAR. 1 to 15 (see, for example, Table 1) or are part of the strands described herein, such as strand 1, strand 2, strand 32, or strand 60, wherein the antigen-specific domain of the CARs is specific for CLDN6. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that are part of CAR. 1 to 15 (see, for example, Table 1) or are part of the strands described herein, such as strand 1, strand 2, strand 32, or strand 60, wherein the antigen-specific domain of CARs is specific for MMP16. In some embodiments, / zRZLn / nznz / E / Yii polypeptides are provided herein. 139 encoded by the nucleic acid molecules encoding the CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that are part of CARs 1 to 15 (see, eg, Table 1 ) or are part of the strands described herein, such as strand 1, strand 2, strand 32, or strand 60, where the antigen-specific domain of the CARs is specific for UPK1B. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that are part of CAR. 1 to 15 (see, for example, Table 1) or are part of the strands described herein, such as strand 1, strand 2, strand 32, or strand 60, wherein the antigen-specific domain of CARs is specific for BMPR1B. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that are part of CAR. 1 to 15 (see, for example, Table 1) or are part of the strands described herein, such as strand 1, strand 2, strand 32, or strand 60, wherein the antigen-specific domain of CARs is specific for Ly6E. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that are part of CAR. 1 to 15 (see, for example, Table 1) or are part of the strands described herein, such as strand 1, strand 2, strand 32, or strand 60, wherein the antigen-specific domain of the CARs is specific for CD79b. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that are part of CAR. 1 to 15 (see, for example, Table 1) or are part of the backbones described herein, such / zRZLn / nznz / B / Yi 140 as lead 1, lead 2, lead 32, or lead 60, where the antigen-specific domain of the CARs is specific for WISP1. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that are part of CAR. 1 to 15 (see, for example, Table 1) or are part of the strands described herein, such as strand 1, strand 2, strand 32, or strand 60, wherein the antigen-specific domain of the CARs is specific to SLC34A2. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that are part of CAR. 1 to 15 (see, for example, Table 1) or are part of the strands described herein, such as strand 1, strand 2, strand 32, or strand 60, wherein the antigen-specific domain of the CARs is specific to Liv1. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that are part of CAR. 1 to 15 (see, for example, Table 1) or are part of the strands described herein, such as strand 1, strand 2, strand 32, or strand 60, wherein the antigen-specific domain of the CARs is specific to Crypto. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that are part of CAR. 1 to 15 (see, for example, Table 1) or are part of the strands described herein, such as strand 1, strand 2, strand 32, or strand 60, wherein the antigen-specific domain of CARs is specific for gpA33. In some embodiments, / zRZLn / nznz / B / Yi polypeptides are provided herein. 141 encoded by the nucleic acid molecules encoding the CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that are part of CARs 1 to 15 (see, eg, Table 1 ) or are part of the strands described herein, such as strand 1, strand 2, strand 32, or strand 60, where the antigen-specific domain of the CARs is specific for ROR1. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that are part of CAR. 1 to 15 (see, for example, Table 1) or are part of the strands described herein, such as strand 1, strand 2, strand 32, or strand 60, wherein the antigen-specific domain of the CARs is specific for CLL1. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that are part of CAR. 1 to 15 (see, for example, Table 1) or are part of the strands described herein, such as strand 1, strand 2, strand 32, or strand 60, wherein the antigen-specific domain of the CARs is specific for FLT3. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that are part of CAR. 1 to 15 (see, for example, Table 1) or are part of the strands described herein, such as strand 1, strand 2, strand 32, or strand 60, wherein the antigen-specific domain of the CARs is specific for IL1RAP. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that are part of CAR. 1 to 15 (see, for example, Table 1) or are part of the backbones described herein, such / zRZLn / nznz / B / Yi 142 as lead 1, lead 2, lead 32, or lead 60, where the antigen-specific domain of the CARs is specific for BST1. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that are part of CAR. 1 to 15 (see, for example, Table 1) or are part of the strands described herein, such as strand 1, strand 2, strand 32, or strand 60, wherein the antigen-specific domain of CARs is specific for CD133. In some embodiments, provided herein are polypeptides encoded by zSIR-encoding nucleic acid molecules that are part of CARs 7-15 (see, eg, Table 1), wherein the antigen-specific domains are antigen-specific. CD200R. In some embodiments, provided herein are polypeptides encoded by zSIR-encoding nucleic acid molecules that are part of CARs 7-15 (see, eg, Table 1), wherein the antigen-specific domains are antigen-specific. CD276. In some embodiments, provided herein are polypeptides encoded by zSIR-encoding nucleic acid molecules that are part of CARs 7-15 (see, eg, Table 1), wherein the antigen-specific domains are antigen-specific. CD324. In some embodiments, provided herein are polypeptides encoded by zSIR-encoding nucleic acid molecules that are part of CARs 7-15 (see, eg, Table 1), wherein the antigen-specific domains are antigen-specific. CS1. In some embodiments, provided herein are polypeptides encoded by zSIR-encoding nucleic acid molecules that are part of CARs 7-15 (see, eg, Table 1), wherein the specific domains of / zRZLn / nznz / B / Yi 143 antigen are specific for ALK1. In some embodiments, provided herein are polypeptides encoded by zSIR-encoding nucleic acid molecules that are part of CARs 7-15 (see, eg, Table 1), wherein the antigen-specific domains are antigen-specific. ROR1. In some embodiments, provided herein are polypeptides encoded by zSIR-encoding nucleic acid molecules that are part of CARs 7-15 (see, eg, Table 1), wherein the antigen-specific domains are antigen-specific. CDH6 In some embodiments, provided herein are polypeptides encoded by zSIR-encoding nucleic acid molecules that are part of CARs 7-15 (see, eg, Table 1), wherein the antigen-specific domains are antigen-specific. CDH16. In some embodiments, provided herein are polypeptides encoded by zSIR-encoding nucleic acid molecules that are part of CARs 7-15 (see, eg, Table 1), wherein the antigen-specific domains are antigen-specific. CDH17. In some embodiments, provided herein are polypeptides encoded by zSIR-encoding nucleic acid molecules that are part of CARs 7-15 (see, eg, Table 1), wherein the antigen-specific domains are antigen-specific. Beta folate receptor. In some embodiments, provided herein are polypeptides encoded by zSIR-encoding nucleic acid molecules that are part of CARs 7-15 (see, eg, Table 1), wherein the antigen-specific domains are antigen-specific. CLEC5A. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding zSIRs that / zRZLn / nznz / B / Yu 144 are part of CARs 7-15 (see, for example, Table 1), in which the antigen-specific domains are specific for the NY-ESO / MHC class I complex. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding zSIRs that are part of CARs 7-15 (see, for example, Table 1), in which the antigen-specific domains they are specific for the WT1 / MHC class I complex. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding zSIRs that are part of CARs 7-15 (see, for example, Table 1), in which the antigen-specific domains they are specific for the AFP / MHC class I complex. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding zSIRs that are part of CARs 7-15 (see, for example, Table 1), in which the antigen-specific domains they are specific for the HPV16-E7 / MHC class I complex. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding zSIRs that are part of CARs 7-15 (see, for example, Table 1), in which the antigen-specific domains they are specific for the gp100 / MHC class I complex. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding zSIRs that are part of CARs 7-15 (see, for example, Table 1), in which the antigen-specific domains they are specific for hTERT / MHC class I complex. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding zSIRs that are part of CARs 7-15 (see, for example, Table 1), in which the antigen-specific domains they are specific to the MARTI / MHC class I complex. In some embodiments, / zRZLn / nznz / E / Yii are provided herein 145 polypeptides encoded by the nucleic acid molecules encoding the zSIRs that are part of CARs 7-15 (see, for example, Table 1), in which the antigen-specific domains are specific for the HTLV1-Tax / MHC complex of class I In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding zSIRs that are part of CARs 7-15 (see, for example, Table 1), in which the antigen-specific domains they are specific for the PR1 / MHC class I complex. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding zSIRs that are part of CARs 7-15 (see, for example, Table 1), in which the antigen-specific domains they are specific for the HIV1-gag / MHC class I complex. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding zSIRs that are part of CARs 7-15 (see, for example, Table 1), in which the antigen-specific domains are specific to gp120 that involve HIV 1 In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding zSIRs that are part of CARs 7-15 (see, for example, Table 1), in which the antigen-specific domains they are specific to PTK7. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding zSIRs that are part of CARs 7-15 (see, for example, Table 1), in which the antigen-specific domains They are TROP2 specific. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding zSIRs that are part of CARs 7-15 (see, for example, Table 1), in which the antigen-specific domains they are specific to BAFF-R. / zRZLn / nznz / B / Yi 146 In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding zSIRs that are part of CARs 7-15 (see, for example, Table 1), in which the antigen-specific domains they are specific to LAMP1. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding zSIRs that are part of CARs 7-15 (see, for example, Table 1), in which the antigen-specific domains they are specific to Tim1. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding zSIRs that are part of CARs 7-15 (see, for example, Table 1), in which the antigen-specific domains they are specific for gamma-delta TCR. In some embodiments, provided herein are polypeptides encoded by zSIR-encoding nucleic acid molecules that are part of CARs 7-15 (see, for example, Table 1), wherein the antigen-specific domains are specific to the TCR betal constant chain. In some embodiments, provided herein are polypeptides encoded by zSIR-encoding nucleic acid molecules that are part of CARs 7-15 (see, for example, Table 1), wherein the antigen-specific domains are specific to the TCR beta2 constant chain. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding zSIRs that are part of CARs 7-15 (see, for example, Table 1), in which the antigen-specific domains they are specific to GCC. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding zSIRs that are part of CARs 7-15 (see, for example, Table 1), in which the / zRZLn / domains nznz / B / Yi 147 antigen-specific are specific for B7H4. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding zSIRs that are part of CARs 7-15 (see, for example, Table 1), in which the antigen-specific domains they are LHR-specific. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding zSIRs that are part of CARs 7-15 (see, for example, Table 1), in which the antigen-specific domains they are Tn-Muc1 specific. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding zSIRs that are part of CARs 7-15 (see, for example, Table 1), in which the antigen-specific domains they are specific to TSLPR. In some embodiments, provided herein are polypeptides encoded by zSIR-encoding nucleic acid molecules that are part of CARs 7-15 (see, for example, Table 1), wherein the antigen-specific domains are tissue factor specific. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding zSIRs that are part of CARs 7-15 (see, for example, Table 1), in which the antigen-specific domains they are specific to SSEA-4. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding zSIRs that are part of CARs 7-15 (see, for example, Table 1), in which the antigen-specific domains they are specific to SLea. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding zSIRs that / zRZLn / nznz / B / Yi 148 are part of CARs 7-15 (see, for example, Table 1), in which the antigen-specific domains are specific for the Muc1 / MHC class I complex. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding zSIRs that are part of CARs 7-15 (see, for example, Table 1), in which the antigen-specific domains they are specific to Muc16. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding zSIRs that are part of CARs 7-15 (see, for example, Table 1), in which the antigen-specific domains they are specific to NYBR-1. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding zSIRs that are part of CARs 7-15 (see, for example, Table 1), in which the antigen-specific domains they are specific for IL13Ra2. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding zSIRs that are part of CARs 7-15 (see, for example, Table 1), in which the antigen-specific domains they are specific for IL11Ra. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding zSIRs that are part of CARs 7-15 (see, for example, Table 1), in which the antigen-specific domains they are specific to L1CAM. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding zSIRs that are part of CARs 7-15 (see, for example, Table 1), in which the antigen-specific domains they are specific to EpCAMI. In some embodiments, / zRZLn / nznz / E / Yii are provided herein 149 polypeptides encoded by the nucleic acid molecules encoding the zSIRs that are part of the CARs 7-15 (see, for example, Table 1), in which the antigen-specific domains are gpNMB-specific. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding zSIRs that are part of CARs 7-15 (see, for example, Table 1), in which the antigen-specific domains they are specific to GRP78. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding zSIRs that are part of CARs 7-15 (see, for example, Table 1), in which the antigen-specific domains they are specific to GPC3. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding zSIRs that are part of CARs 7-15 (see, for example, Table 1), in which the antigen-specific domains they are specific to GRPC5D. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding zSIRs that are part of CARs 7-15 (see, for example, Table 1), in which the antigen-specific domains they are specific for GFRa4. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding zSIRs that are part of CARs 7-15 (see, for example, Table 1), in which the antigen-specific domains they are specific to FITC. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding zSIRs that are part of CARs 7-15 (see, for example, Table 1), in which the antigen-specific domains they are specific for CD79b. / zRZLn / nznz / B / Yi 150 In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding zSIRs that are part of CARs 7-15 (see, for example, Table 1), in which the antigen-specific domains they are Lym1 specific. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding zSIRs that are part of CARs 7-15 (see, for example, Table 1), in which the antigen-specific domains they are specific to Lym2. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding zSIRs that are part of CARs 7-15 (see, for example, Table 1), in which the antigen-specific domains they are specific for CLD18A2. In some embodiments, provided herein are polypeptides encoded by zSIR-encoding nucleic acid molecules that are part of CARs 7-15 (see, for example, Table 1), in which the antigen-specific domains are specific for the CD43 epitope expressed in leukemia cells. In some embodiments, provided herein are polypeptides encoded by nucleic acid molecules encoding zSIRs that are part of CARs 7-15 (see, for example, Table 1), in which the antigen-specific domains they are specific for CD179a. In some embodiments, provided herein are polypeptides encoded by the nucleic acid molecules encoding CARs 1-6 (see, for example, Table 1) or are part of the backbones described herein such as backbone- 1, skeleton-2, skeleton-32 or skeleton-60, wherein the antigen-specific domain is as described in Table 3. In some embodiments, the nucleic acid molecule encoding CAR (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) and / or / zRZLn / nznz / B / Yi molecules 151 accessory described herein is provided as a messenger RNA (mRNA) transcript. In another embodiment, the nucleic acid molecule encoding the CARs and / or accessory molecules described herein is provided as a DNA construct. Vectors comprising the polynucleotides described herein are also provided. In some embodiments, the vectors are viral vectors. Examples of viral vectors include, but are not limited to, a retrovirus, an adenovirus, an adeno-associated virus, a lentivirus, a smallpox virus, a herpes virus vector, or a sleeping beauty transposon vector. In various embodiments, the disclosure includes retroviral and lentiviral vector constructs that express the CAR (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) and accessory molecules that can be directly transduced into a cell. . The disclosure also includes an RNA construct that can be directly transfected into a cell. One method of generating mRNA for use in transfection involves in vitro transcription (IVT) of a template with specially designed primers, followed by addition of poly A, to produce a construct containing the 3' untranslated sequence ('UTR'). and 5' (eg, a 3' and / or 5' UTR described herein), a 5' cap (eg, a 5' cap described herein), and / or an internal ribosome entry site ( IRES) (eg, an IRES described herein), the nucleic acid to be expressed, and a poly A tail, typically 50-2000 bases in length. The RNA thus produced can efficiently transfect different types of cells. In one embodiment, the template includes sequences for the CAR (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like). In one embodiment, a next-generation CAR RNA or CAR vector is transduced into a cell, eg, a T cell or NK cell, by electroporation. In another embodiment, a next-generation CAR RNA or CAR vector is transduced into a cell, eg, a T cell or NK cell, causing transient perturbations in the cell membrane using a / zRZLn / nznz / E / microfluidic device. yii 152 as described in the patent application WO 2013 / 059343 A1 (PCT / US2012 / 060646). Polynucleotide sequences encoding the desired molecules can be obtained using recombinant methods known in the art, for example, by screening for libraries of cells that express the gene, deriving the gene from a vector known to include the gene, or isolating it directly from cells and tissues containing the same, using standard techniques. Alternatively, the gene of interest can be produced synthetically, rather than cloned. The disclosure also provides vectors into which is inserted a DNA encoding the CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the disclosure. Retrovirus-derived vectors such as the lentivirus are suitable tools to achieve long-term gene transfer, as they allow long-term stable integration of a transgene and its propagation in daughter cells. Lentiviral vectors have the added advantage over vectors derived from oncoretroviruses such as murine leukemia viruses in that they can transduce non-proliferating cells, such as hepatocytes. Examples of lentiviral vectors are provided in SEQ ID NO: 129-130 and 12639. A retroviral vector can also be, for example, a gammaretroviral vector. A gamma retroviral vector can include, for example, a promoter, a packaging signal (ψ), a primer binding site (PBS), one or more (for example, two) long terminal repeats (LTRs), and a transgene of interest. eg a gene encoding a CAR (eg CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP and the like). Exemplary gamma retroviral vectors include murine leukemia virus (MLV), spleen foci-forming virus (SFFV), and myeloproliferative sarcoma virus (MPSV), and vectors derived therefrom. In another embodiment, the vector comprising the nucleic acid encoding the desired CAR (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the disclosure is an adenoviral vector (A5 / 35) . / zRZLn / nznz / B / Yi The expression of natural or synthetic nucleic acids encoding CAR (for 153 example, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) is typically achieved by operably linking a CAR-encoding nucleic acid (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP and the like) polypeptide or parts thereof to a promoter, and incorporating the construct into an expression vector. The exemplary CAR-encoding lentiviral vector of the disclosure is provided in SEQ ID NOs: 12640-41 and 14378, 14380-85. The vectors may be suitable for replication and integration in eukaryotes. Typical cloning vectors contain transcription and translation terminators, initiation sequences, and promoters useful for regulation of expression of the desired nucleic acid sequence. The vector may contain a single promoter or more than one promoter. In some embodiments, the two or more functional units of a CAR (eg, nucleotides encoding two functional polypeptide units of a SIR or a zSIR or an Ab-TCR) are under the control of separate promoters. The expression constructs of the disclosure can also be used for nucleic acid immunization and gene therapy, using standard gene delivery protocols. Methods for gene delivery are known in the art. See, for example, US Patent NOs. 5,399,346, 5,580,859, 5,589,466, incorporated herein by reference in their entirety. Methods of cloning and expression will be apparent to one skilled in the art. Physical methods for introducing polynucleotides into host cells such as calcium phosphate transfection and the like are well known in the art and will be apparent to one skilled in the art. In another embodiment, a CAR vector (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) is transduced into a cell, eg, a T cell or NK cell, causing transient perturbations in cell membrane using a microfluidic device as described in patent application WO 2013 / 059343 A1 (PCT / US2012 / 060646) and in Ding X et al., Nat. Biomed. Ing. 1, 0039 (2017), the contents of each of which are incorporated herein as / zRZLn / nznz / B / Yi 154 reference in their entirety as if they were established here. In various embodiments, the cells for CAR modifications (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) described herein, including T cells or NK cells, can be obtained from a subject desiring therapy. T cells can be obtained from a variety of sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, umbilical cord blood, placenta, thymus tissue, tissue from an infection site, ascites, pleural effusion, tissue from the spleen and tumors. The T cells could be tissue-resident gamma-delta T cells, which can be cultured and expanded in vitro prior to CAR expression (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP and the like). In one aspect, the disclosure provides a series of CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that comprise an antigen-binding domain (eg, Antibody or Antibody Fragment , TCR or TCR fragment) designed for specific binding to a disease-associated antigen, eg, a tumor antigen described herein. In one aspect, the disclosure provides an immune effector cell (eg, T cell, NKT cell) engineered to express a CAR (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like), in which the engineered immune effector cell exhibits a therapeutic property. In one aspect, the disclosure provides an immune effector cell (eg, T cell, NKT cell) engineered to express a CAR (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like), in which the genetically engineered immune effector cell exhibits an anti-cancer property. In one embodiment, a cell is transformed with both CAR (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) and CAR (eg, CAR I, CAR II, SIR, zSIR, Ab -TCR, TFP and the like) is expressed on the cell surface. In some embodiments, the cell (eg, T cell, NKT cell) is transduced with a viral vector encoding a CAR (eg, SIR, zSIR, Ab-TCR, TFP, and the like). In some embodiments, the viral vector is a retroviral vector. In some implementations, the / zRZLn / nznz / B / Yi 155 viral vector is a lentiviral vector. In some such embodiments, the cell can stably express the CAR (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like). In another embodiment, the cell (eg, T cell, NKT cell) is transfected with a nucleic acid, eg, mRNA, cDNA, DNA, encoding a CAR or next generation CAR (eg, CAR I, CAR II , SIR, zSIR, Ab-TCR, TFP and the like). In some such embodiments, the cell may transiently express the CAR (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like). The disclosure provides immune effector cells (eg, T cells, NKT or NK cells) that are engineered to contain one or more CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that direct immune effector cells to diseased cells or disease-associated cells, such as cancer cells. This is accomplished by an antigen-binding domain in the CAR (eg, SIR, zSIR, AbTCR, Tri-Tac, TFP, and the like) that is specific for a cancer-associated antigen. There are two classes of cancer-associated antigens (tumor antigens) that can be targeted by CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, Tri-Tac, TFP, and the like) of the disclosure: ( 1) cancer-associated antigens that are expressed on the surface of cancer cells; and (2) cancer-associated antigens that are themselves intracellular; however, a fragment of said antigen (peptide) is presented on the surface of cancer cells by the MHC (major histocompatibility complex). Furthermore, the disclosure provides CAR- expressing cells (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) and their use in medicaments or methods for treating, among other diseases, cancer or any malignancy or autoimmune disease or infectious disease or degenerative disease or allergic disease involving cells or tissues expressing a tumor antigen or disease-associated antigen as described herein. In one aspect, the disclosure provides an immune effector cell (eg, T cell, NKT, or NK cell) engineered to express a CAR or proximal CAR / zRZLn / nznz / B / Yi 156 generation (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP and the like), wherein the modified immune effector cell exhibits an anti-disease property, such as an anti-tumor property. In one embodiment, the antigen is a cancer-associated antigen (ie, a tumor antigen) described herein. In one aspect, the antigen-binding domain of CAR (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) comprises a partially humanized antibody fragment. In one aspect, the antigen-binding domain of the CAR (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) comprises a partially humanized scFv. Accordingly, the disclosure provides CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) that comprise a humanized antigen-binding domain and are engineered into a cell, eg, a cell. T or NK cell, and methods for their use for adoptive therapy. Also provided herein are genetically engineered cells, comprising the polynucleotides and / or the CAR (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) described herein. In some embodiments, the cell is a T lymphocyte (T cell). In some embodiment, the cell is a naive T cell, a core memory T cell, an effector memory T cell, a regulatory T cell (Treg), or a combination thereof. In some embodiments, the cell is a natural killer (NK) cell, a hematopoietic stem cell (HSC), an embryonic stem cell, or a pluripotent stem cell. Genetically engineered cells capable of comprising and expressing the CARs of the disclosure include, but are not limited to, T lymphocytes (T cells), naive T cells (TN), memory T cells (e.g., central memory T cells (MCT), effector memory (TEM) cells), natural killer cells, hematopoietic stem cells and / or embryonic / induced pluripotent stem cells capable of giving rise to therapeutically relevant progeny. In one embodiment, the genetically engineered cells are autologous cells. In one embodiment, the engineered cells are allogeneic cells. / zRZLn / nznz / B / Yi 157 By way of example, the individual T cells of the disclosure may be CD4+ / CD8-, CD4- / CD8+, CD4- / CD8-, or CD4+ / CD8+. T cells can be a mixed population of CD4+ / CD8- and CD4- / CD8+ cells or a single clone population. The CD4+ T cells of the disclosure can produce IL-2, IFN, TNF, and other T cell effector cytokines when co-cultivated in vitro with cells expressing the target antigens (for example, CD20+ and / or CD19+ tumor cells ). The CD8 + T cells of the disclosure can lyse antigen-specific target cells when co-cultivated in vitro with the target cells. In some embodiments, the T cells can be one or more of CD45RA + CD62L + naive cells, CD45RO + CD62L + core memory cells, CD62L effector memory cells, or a combination thereof (Berger et al. Cellular Immunity, Curr Opin Immunol, 2009, 21 (2) 224-232). Genetically modified cells can be produced by stably transfecting cells with DNA encoding the CAR (eg, SIR, zSIR, Ab-TCR, TFP, and the like) of the disclosure. The engineered cells can be engineered to abrogate the expression of endogenous TCR chains, eg, TCRa, TCRp, TCRy, TCRÓ or pre-TCRa chains. Inactivation of endogenous TCRa, TCRP, TCRy, TCRó or pre-TCRa chains can be achieved using a number of techniques known in the art, such as the use of CRISP / Cas9 and Zn finger nucleases. In an exemplary embodiment, gRNAs targeting the TCRa and TCRp loci can be introduced into T cells or ¡PSCs or stem cells together with Cas9 mRNA to abrogate the expression of endogenous TCRa and TCRp chains. Such TCRa / β deficient cells can be used to introduce the CARs of the disclosure. The T cell lacking a functional endogenous TCR can be designed so that it does not express any functional endogenous TCR on its surface, for example, it can be designed so that it does not express one or more subunits (for example, constant chains of TCRa , TCRpi, TCRP2, endogenous TCRy). , TCRó or pre-TCRa) comprising a functional endogenous TCR or designed in a way that produces very little functional endogenous TCR / zRZLn / nznz / B / Yu 158 on its surface. Alternatively, the T cell may express a substantially altered endogenous TCR, for example, by expressing mutated or truncated forms of one or more of the TCR subunits. The term "substantially altered TCR" means that this TCR will not cause an adverse immune reaction in a host. In one embodiment, the allogeneic T cell or allogeneic NKT cell lacks expression or has low expression of a functional TCR and / or a functional HLA. Various methods produce stable transfectants that express the CARs (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the disclosure. In one embodiment, a method of stably transfecting and redirecting cells is by electroporation using naked DNA. By using naked DNA, the time required to produce redirected cells can be significantly reduced. Additional methods for genetically engineering cells using naked DNA encoding the CAR (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the disclosure include, but are not limited to, transformation methods. chemical (eg, using calcium phosphate, dendrimers, liposomes, and / or cationic polymers), non-chemical transformation methods (eg, electroporation, optical transformation, electrotransfer of genes, transient perturbation in cell membranes, and / or hydrodynamic delivery ) and / or particle-based methods (for example, impalefection, using a gene gun and / or magnetofection). Transfected cells that demonstrate the presence of a single unrearranged integrated vector and expression of CAR (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) can be expanded ex vivo. In one embodiment, the cells selected for ex vivo expansion are CD8+ and demonstrate the ability to specifically recognize and lyse antigen-specific target cells. Viral transduction methods can also be used to generate redirected cells that express the CAR (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the disclosure. Cell types that can be used to generate / zRZLn / nznz / B / Yi cells 159 genetically modified cells that express the CAR (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the disclosure include but are not limited to T lymphocytes (T cells), natural killer cells, cells hematopoietic stem and / or embryonic / induced pluripotent stem cells capable of giving rise to therapeutically relevant progeny. Stimulation of T cells by an antigen under suitable conditions results in the proliferation (expansion) of the cells and / or the production of IL-2. Cells comprising the CAR (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the disclosure will expand in number in response to binding of one or more antigens to the targeting regions. specific to the CAR antigen (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP and the like). The disclosure also provides a method for making and expanding cells that express a CAR (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like). The method comprises transfecting or transducing the cells with the CAR-expressing vector (for example, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) and stimulating the cells with cells expressing the target antigens, target antigens recombinants, or an antibody against the receptor to cause the cells to proliferate, to produce and expand the T cells. In one embodiment, the cells can be any one or more of T lymphocytes, natural killer (NK) T cells, hematopoietic stem cells (HSC) or embryonic / induced pluripotent stem cells capable of giving rise to therapeutically relevant progeny. In some embodiments, the genetically modified cells described herein express the various backbone chains described herein, wherein the CAR component (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like) of the the backbone determines the target specificity based on the antigen-specific domain of the CAR (eg, CAR I, CAR II, SIR, zSIR, Ab-TCR, TFP, and the like). In one embodiment, the genetically engineered cells comprise nucleic acid molecules encoding CARs 1 to 15 (see, for example, Table 1) that / zRZLn / nznz / B / Yi 160 are part of the backbones described herein, such as backbone-1, backbone-2, backbone-32, or backbone-60, where the antigen-specific domain of CARs is specific to a target of antigen in Table 3 and / or 7 and comprises the antigen-binding domain sequences set forth in Table 3 and / or 7. In one embodiment, the genetically engineered cells comprise zSIR-encoding nucleic acid molecules that are part of CARs 7-15 (see, for example, Table 1), wherein the antigen-specific domains are MPL-specific. In one embodiment, the genetically engineered cells comprise nucleic acid molecules encoding CARs 1 through 15 that are part of the lead strands described herein, such as lead 1, lead 2, lead 32, or lead 32. 60 backbone, in which the antigen-specific domain of CARs is MPL-specific. In one embodiment, the genetically engineered cells comprise zSIR-encoding nucleic acid molecules that are part of CARs 7-15 (see, for example, Table 1), wherein the antigen-specific domains are CD19-specific. In one embodiment, the genetically engineered cells comprise nucleic acid molecules encoding CARs 1 through 15 that are part of the lead strands described herein, such as lead 1, lead 2, lead 32, or lead 32. backbone 60, in which the antigen-specific domain of the CAR is specific for CD19. In one embodiment, the genetically engineered cells comprise nucleic acid molecules encoding CARs 1 through 15 that are part of the lead strands described herein, such as lead 1, lead 2, lead 32, or lead 32. backbone 60, in which the antigen-domain / zRZLn / nznz / E / Yii 161 specific to CAR is specific to CD19. In one embodiment, the genetically engineered cells comprise zSIR-encoding nucleic acid molecules that are part of CARs 7-15 (see, for example, Table 1), where the antigen-specific domains are CD20-specific. In one embodiment, the genetically engineered cells comprise nucleic acid molecules encoding CARs 1 through 15 that are part of the lead strands described herein, such as lead 1, lead 2, lead 32, or lead 32. backbone 60, in which the antigen-specific domain of the CAR is specific for CD20. In one embodiment, the genetically engineered cells comprise zSIR-encoding nucleic acid molecules that are part of CARs 7-15 (see, eg, Table 1), where the antigen-specific domains are BCMA-specific. In one embodiment, the genetically engineered cells comprise nucleic acid molecules encoding CARs 1 through 15 that are part of the lead strands described herein, such as lead 1, lead 2, lead 32, or lead 32. backbone 60, in which the antigen-specific domain of the CAR is specific for BCMA. In one embodiment, the genetically engineered cells comprise zSIR-encoding nucleic acid molecules that are part of CARs 7-15 (see, eg, Table 1), wherein the antigen-specific domains are CD22-specific. In one embodiment, the genetically engineered cells comprise nucleic acid molecules encoding CARs 1 through 15 that are part of the lead strands described herein, such as lead 1, lead 2, lead 32, or lead 32. main chain 60, in which the antigen-domain / zRZLn / nznz / B / Yi 162 specific to CAR is specific to CD22. In one embodiment, the genetically engineered cells comprise zSIR-encoding nucleic acid molecules that are part of CARs 7-15 (see, eg, Table 1), wherein the antigen-specific domains are BAFF-R-specific. In one embodiment, the genetically engineered cells comprise nucleic acid molecules encoding CARs 1 through 15 that are part of the lead strands described herein, such as lead 1, lead 2, lead 32, or lead 32. backbone 60, in which the antigen-specific domain of the CAR is specific for BAFF-R. In one embodiment, the genetically engineered cells comprise nucleic acid molecules encoding CARs 1 through 15 that are part of the lead strands described herein, such as lead 1, lead 2, lead 32, or lead 32. backbone 60, in which the antigen-specific domain of the CAR is specific for Integrin B7. In one embodiment, the genetically engineered cells comprise nucleic acid molecules encoding CARs 1 through 15 that are part of the lead strands described herein, such as lead 1, lead 2, lead 32, or lead 32. main chain 60, in which the antigen-specific domain of the CAR is specific for Nectin 4. In one embodiment, the genetically engineered cells comprise nucleic acid molecules encoding CARs 1 through 15 that are part of the lead strands described herein, such as lead 1, lead 2, lead 32, or lead 32. main chain 60, in which the antigen-specific domain of the CAR is specific for Prolactin Receptor. In one embodiment, the genetically engineered cells comprise nucleic acid molecules encoding CARs 1 through 15 that are part of the / zRZLn / nznz / B / Yi chains. 163 major chains described herein, such as lead 1, lead 2, lead 32, or lead 60, in which the antigen-specific domain of the CAR is Muc17-specific. In one embodiment, the genetically engineered cells comprise zSIR-encoding nucleic acid molecules that are part of CARs 7-15 (see, for example, Table 1), where the antigen-specific domains are CD70-specific. In one embodiment, the genetically engineered cells comprise nucleic acid molecules encoding CARs 1 through 15 that are part of the lead strands described herein, such as lead 1, lead 2, lead 32, or lead 32. backbone 60, in which the antigen-specific domain of the CAR is specific for CD70. In one embodiment, the genetically engineered cells comprise nucleic acid molecules encoding CARs 1 through 15 that are part of the lead strands described herein, such as lead 1, lead 2, lead 32, or lead 32. 60 backbone, in which the antigen-specific domain of the CAR is VISTA specific. In one embodiment, the genetically engineered cells comprise zSIR-encoding nucleic acid molecules that are part of CARs 7-15 (see, eg, Table 1), wherein the antigen-specific domains are GPC3-specific. In one embodiment, the genetically engineered cells comprise nucleic acid molecules encoding CARs 1 through 15 that are part of the lead strands described herein, such as lead 1, lead 2, lead 32, or lead 32. backbone 60, in which the antigen-specific domain of the CAR is specific for GPC3. In one embodiment, the genetically engineered cells comprise / zRZLn / nznz / B / Yi 164 zSIR-encoding nucleic acid molecules that are part of CARs 7-15 (see, for example, Table 1), where the antigen-specific domains are EMR2-specific. In one embodiment, the genetically engineered cells comprise nucleic acid molecules encoding CARs 1 through 15 that are part of the lead strands described herein, such as lead 1, lead 2, lead 32, or lead 32. backbone 60, in which the antigen-specific domain of the CAR is specific for EMR2. In one embodiment, the genetically engineered cells comprise zSIR-encoding nucleic acid molecules that are part of CARs 7-15 (see, for example, Table 1), where the antigen-specific domains are gpNMB-specific. In one embodiment, the genetically engineered cells comprise nucleic acid molecules encoding CARs 1 through 15 that are part of the lead strands described herein, such as lead 1, lead 2, lead 32, or lead 32. backbone 60, in which the antigen-specific domain of the CAR is specific for RNF43. In one embodiment, the genetically engineered cells comprise nucleic acid molecules encoding CARs 1 through 15 that are part of the lead strands described herein, such as lead 1, lead 2, lead 32, or lead 32. main chain 60, in which the antigen-specific domain of the CAR is specific for STEAP1. In one embodiment, the genetically engineered cells comprise nucleic acid molecules encoding CARs 1 through 15 that are part of the lead strands described herein, such as lead 1, lead 2, lead 32, or lead 32. backbone 60, in which the antigen-specific domain of the CAR is specific for Robo4. / zRZLn / nznz / B / Yi 165 In one embodiment, the genetically engineered cells comprise zSIR-encoding nucleic acid molecules that are part of CARs 7-15 (see, eg, Table 1), wherein the antigen-specific domains are CLDN6-specific. In one embodiment, the genetically engineered cells comprise zSIR-encoding nucleic acid molecules that are part of CARs 7-15 (see, eg, Table 1), where the antigen-specific domains are CD44v6-specific. In one embodiment, the genetically engineered cells comprise nucleic acid molecules encoding CARs 1 through 15 that are part of the lead strands described herein, such as lead 1, lead 2, lead 32, or lead 32. main chain 60, in which the antigen-specific domain of the CAR is specific for MMP16. In one embodiment, the genetically engineered cells comprise nucleic acid molecules encoding CARs 1 through 15 that are part of the lead strands described herein, such as lead 1, lead 2, lead 32, or lead 32. backbone 60, in which the antigen-specific domain of the CAR is specific for UPK1B. In one embodiment, the genetically engineered cells comprise nucleic acid molecules encoding CARs 1 through 15 that are part of the lead strands described herein, such as lead 1, lead 2, lead 32, or lead 32. backbone 60, in which the antigen-specific domain of the CAR is specific for BMPR1B. In one embodiment, the genetically engineered cells comprise nucleic acid molecules encoding CARs 1 through 15 that are part of the lead strands described herein, such as lead 1, lead 2, lead 32, or lead 32. main chain 60, in which the antigen-domain / zRZLn / nznz / B / Yi 166 specific to CAR is specific to Ly6E. In one embodiment, the genetically engineered cells comprise zSIR-encoding nucleic acid molecules that are part of CARs 7-15 (see, eg, Table 1), wherein the antigen-specific domains are CD79b-specific. In one embodiment, the genetically engineered cells comprise nucleic acid molecules encoding CARs 1 through 15 that are part of the lead strands described herein, such as lead 1, lead 2, lead 32, or lead 32. backbone 60, in which the antigen-specific domain of the CAR is specific for CD79b. In one embodiment, the genetically engineered cells comprise nucleic acid molecules encoding CARs 1 through 15 that are part of the lead strands described herein, such as lead 1, lead 2, lead 32, or lead 32. backbone 60, in which the antigen-specific domain of the CAR is specific for WISP1. In one embodiment, the genetically engineered cells comprise nucleic acid molecules encoding CARs 1 through 15 that are part of the lead strands described herein, such as lead 1, lead 2, lead 32, or lead 32. backbone 60, in which the antigen-specific domain of the CAR is specific for Cripto. In one embodiment, the genetically engineered cells comprise nucleic acid molecules encoding CARs 1 through 15 that are part of the lead strands described herein, such as lead 1, lead 2, lead 32, or lead 32. backbone 60, in which the antigen-specific domain of the CAR is specific for gpA33. In one embodiment, the genetically engineered cells comprise nucleic acid molecules encoding CARs 1 through 15 that are part of the / zRZLn / nznz / E / Yii chains. 167 major chains described herein, such as lead 1, lead 2, lead 32, or lead 60, in which the antigen-specific domain of the CAR is specific for IL1RAP. In one embodiment, the genetically engineered cells comprise nucleic acid molecules encoding CARs 1 through 15 that are part of the lead strands described herein, such as lead 1, lead 2, lead 32, or lead 32. backbone 60, in which the antigen-specific domain of the CAR is specific for BST1. In one embodiment, the genetically engineered cells comprise nucleic acid molecules encoding CARs 1 through 15 that are part of the lead strands described herein, such as lead 1, lead 2, lead 32, or lead 32. backbone 60, in which the antigen-specific domain of the CAR is specific for CD133. In one embodiment, the genetically engineered cells comprise zSIR-encoding nucleic acid molecules that are part of CARs 7-15 (see, eg, Table 1), wherein the antigen-specific domains are CD123-specific. In one embodiment, the genetically engineered cells comprise nucleic acid molecules encoding CARs 1 through 15 that are part of the lead strands described herein, such as lead 1, lead 2, lead 32, or lead 32. backbone 60, in which the antigen-specific domain of the CAR is specific for CD123. In one embodiment, the genetically engineered cells comprise zSIR-encoding nucleic acid molecules that are part of CARs 7-15 (see, eg, Table 1), wherein the antigen-specific domains are CD138-specific. / zRZLn / nznz / B / Yi In one embodiment, the genetically engineered cells comprise 168 nucleic acid molecules encoding CARs 1 through 15 that are part of the lead strands described herein, such as lead 1, lead 2, lead 32, or lead 60, where the antigen-specific domain of CAR is specific for CD138. In one embodiment, the genetically engineered cells comprise zSIR-encoding nucleic acid molecules that are part of CARs 7-15 (see, eg, Table 1), wherein the antigen-specific domains are CLL1-specific. In one embodiment, the genetically engineered cells comprise nucleic acid molecules encoding CARs 1 through 15 that are part...

Claims

CLAIMS 1. At least one recombinant polynucleotide encoding at least one first- or next-generation chimeric antigen receptor (CAR), the at least one recombinant polynucleotide comprising: (a) a first nucleic acid domain encoding a partial or complete transmembrane and / or cytoplasmic domain and, optionally, the extracellular domain of an endogenous protein, wherein the endogenous protein is expressed on the surface of lymphocytes and triggers lymphocyte activation and / or proliferation; (b) optionally a linker polynucleotide; and (c) a second nucleic acid domain operatively linked to the first nucleic acid domain, wherein the second nucleic acid domain encodes one or more non-natural TCR antigen-binding domains, the binding domain being selected from a binding domain established in Table 3; (d) an optional third nucleic acid domain encoding a costimulatory domain;and an optional additional nucleic acid domain that encodes an accessory module.

2. The at least one recombinant polynucleotide of claim 1, wherein the first nucleic acid partially or totally encodes at least one T cell receptor (TCR) chain as set out in Table 13.

3. The at least one recombinant polynucleotide of claim 2, wherein the first nucleic acid encodes at least one transmembrane domain in Table 13 operatively linked to the cytoplasmic domain of the TCR type.

4. The at least one recombinant polynucleotide of claim 1, wherein the polynucleotide encodes a CAR, wherein the CAR comprises: (i) a partial or complete T cell receptor (TCR) constant chain having an amino acid sequence having at least 75% sequence identity with a sequence selected from SEQ ID NO: 4038 to 4063, 12602-12638, and which may comprise an optional costimulatory module; (i) an optional linker; and (iii) one or more non-natural TCR antigen-binding domains linked to (a) selected from a binding domain established in Table 3; (iv) an optional access module; and (v) a polypeptide dimer comprising (i) - (iv).

5. The at least one recombinant polynucleotide of claim 4, wherein the recombinant polynucleotide comprises a sequence encoding any of the sequences in Table 2.

6. The at least one recombinant polynucleotide of any of claims 1-5, wherein the accessory module comprises an amino acid sequence selected from SEQ ID NO: 4103-4117 and 4090-4096.

7. The at least one recombinant polynucleotide of any of claims 1-6, wherein the encoded CAR comprises (1) any of CARs 1-16 of Table 1 and / or (2) a backbone of Table 2; and (3) a binding domain of Table 3.

8. The at least one recombinant polynucleotide of claim 4, wherein (i) is a CD3z TCR ​​constant chain.

9. The at least one recombinant polynucleotide of any of claims 1-6 encoding two first-generation or next-generation chimeric antigen receptors.

10. The at least one recombinant polynucleotide of any of claims 1-6, encoding a CD3z constant chain dimer.

11. At least one recombinant polynucleotide encoding at least one next-generation chimeric antigen receptor (CAR), the at least one recombinant polynucleotide comprising: (a) a first nucleic acid domain encoding a partial or complete transmembrane and / or cytoplasmic domain and, optionally, the extracellular domain of an endogenous CD3z protein having a sequence selected from the group consisting of SEQ ID / zRZLn / nznz / B / Yi 302 NO: 4064-4066, 4070-4072, and 4075-4078, wherein the endogenous protein is expressed on the surface of lymphocytes and triggers lymphocyte activation and / or proliferation; (b) optionally a polynucleotide linker; and (c) a second nucleic acid domain operatively linked to the first nucleic acid domain, wherein the second nucleic acid domain encodes one or more non-natural TCR antigen-binding domains, wherein the binding domain is selected from a binding domain established in Table 3;and (d) an optional third nucleic acid domain encoding a costimulatory module; and an additional optional nucleic acid encoding an accessory module.; 12. The at least one recombinant polynucleotide of claim 11, wherein the nucleic acid sequences encoding the endogenous CD3z protein are selected from the group consisting of SEQ ID NO: 67 and 71.

13. The at least one recombinant polynucleotide of claim 11 or 12, wherein the at least one next-generation CAR comprises two CARs, each CAR comprising a CD3z chain.

14. The at least one recombinant polynucleotide of claim 13, wherein a vL fragment of an antibody is operatively linked to one of the two CD3z chains and a vH fragment of the antibody is operatively linked to the other CD3z chain.

15. The at least one recombinant polynucleotide of claim 14, wherein the vL and vH chains are selected from pairs in Tables 3 and 4 for a specific target antigen.

16. At least one recombinant polynucleotide of claim 14 or 15, wherein a linker is provided between the vL / vH and / or CD3z chains.

17. The at least one recombinant polynucleotide of claim 16, wherein a coded linker is selected from the group consisting of IgCL (SEQ ID NO (DNA): 28 and SEQ ID NO (PRT): 4027) and IgCH domains (SEQ ID NO (DNA): 29 and SEQ ID NO (PRT): 4028). / zRZLn / nznz / B / Yi 303 18. At least one recombinant polynucleotide of claim 11, further comprising the third nucleic acid domain encoding a costimulatory module.

19. At least one recombinant polynucleotide of claim 17, wherein the stimulating module comprises a 41 BB or CD28 protein.

20. The at least one recombinant polynucleotide of claim 18 or 19, wherein the costimulatory module comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 4067 and 4068.

21. The at least one recombinant polynucleotide of claim 18, wherein the constructor module comprises a signaling domain of any one or more of CD134 (OX40), Dap 10, CD27, CD2, CD5, ICAM-1, LFA-1, Lck, TNFR-I, TNFR-II, Fas, CD30, CD40 and combinations thereof.

22. The at least one recombinant polynucleotide of any of claims 1121, further comprising the accessory module, wherein the accessory module comprises an amino acid sequence selected from SEQ ID NO: 4103-4117 and 4090-4096.

23. A recombinant cell expressing a homo- or heterodimer of a first- or next-generation chimeric antigen receptor (CAR), the homo- or heterodimer comprising: (a) a first domain encoding a partial or complete transmembrane and / or cytoplasmic domain and, optionally, the extracellular domain of an endogenous protein, wherein the endogenous protein is expressed on the surface of lymphocytes and triggers lymphocyte activation and / or proliferation; (b) optionally a linker peptide; and (c) a second domain operatively linked to the first domain, wherein the second domain comprises one or more non-natural TCR antigen-binding domains, the binding domain being selected from a binding domain listed in Table 3;and (d) an optional third domain encoding a costimulatory module, and wherein the cell optionally comprises an accessory module, / zRZLn / nznz / B / Yi 304 in which the homo or heterodimer is associated on the surface of the recombinant cell.; 24. Recombinant cell according to claim 23, wherein the cell is transformed with at least one recombinant polynucleotide or any of claims 1-22.

25. The recombinant cell of claim 23 or 24, wherein the cell is a T lymphocyte (T cell).

26. The recombinant cell of claim 25, wherein the cell is a naïve T cell, a central memory T cell, an effector memory T cell, Treg or a combination thereof.

27. The recombinant cell of claim 23, wherein the cell is a natural killer (NK) cell, a hematopoietic stem cell (HSC), an embryonic stem cell, or a pluripotent stem cell.

28. The recombinant cell of any of claims 23-27, wherein the accessory module comprises an amino acid sequence selected from SEQ ID NO: 41034117 and 4090-4096.

29. A chimeric antigen receptor (CAR) comprising: (a) a first domain encoding a partial or complete transmembrane and / or cytoplasmic domain and, optionally, the extracellular domain of an endogenous protein, wherein the endogenous protein is expressed on the surface of lymphocytes and triggers lymphocyte activation and / or proliferation; (b) optionally a linker peptide; and (c) a second domain operatively linked to the first domain, wherein the second domain comprises one or more non-natural TCR antigen-binding domains, the binding domain being selected from a binding domain listed in Table 3; and (d) an optional third domain encoding a costimulatory module.

30. The chimeric antigen receptor of claim 29, wherein the endogenous protein comprises a sequence selected from the group consisting of SEQ ID NO: 4064-4066, 4070-4072, 4075-4078 and 12637. / zRZLn / nznz / E / Yii 305 31. The at least one recombinant polynucleotide of claim 29, wherein the first nucleic acid partially or totally encodes at least one T cell receptor (TCR) chain as set out in Table 13.

32. The chimeric antigen receptor of claim 31, wherein the first comprises a transmembrane domain in Table 13 operatively linked to the cytoplasmic domain of a corresponding TCR type.

33. The chimeric antigen receptor of claim 29, wherein the CAR comprises: (i) a partial or complete T cell receptor (TCR) constant chain having an amino acid sequence having at least 75% sequence identity with a sequence selected from SEQ ID NO: 4038 to 4063, 12602-12638, and which may comprise an optional costimulatory module.

34. A polynucleotide encoding the chimeric antigen receptor of any of claims 29-33.

35. A vector comprising the polynucleotide of claim 34.

36. A virus comprising the polynucleotide of claim 35.

37. The virus of claim 36, wherein the virus is a retrovirus, an adenovirus, an adeno-associated virus, a lentivirus, a smallpox virus, or a herpes virus.

38. A pharmaceutical composition comprising: one or more of the at least one polynucleotide of claims 1-22, the recombinant cell of claims 23-28, the CAR of claim 29-33, the vector of claim 35, or the virus of claim 36.

39. A method for treating cancer comprising: providing the composition of claim 38 or a recombinant cell of claim 23; and administering a therapeutically effective amount of the composition or cell to the subject to treat cancer.

40. The method of claim 39, wherein the cancer is blood cancer.

41. The method of claim 40, wherein the blood cancer is one or more of acute myeloid leukemia, chronic myeloid leukemia, myelodysplastic syndrome, lymphoma, multiple myeloma, and acute lymphocytic leukemia.

42. The at least one recombinant cell of claim 21, wherein the at least one recombinant polynucleotide comprises a sequence encoding HIV-1-vif.

43. The recombinant cell of claim 42, wherein the cell further comprises 5 HIV-1-vif.