Synthetic immunoreceptors and methods of use thereof

Abstract

To provide a recombinant polynucleotide encoding a synthetic immune receptor.SOLUTION: At least one recombinant polynucleotide encoding at least one synthetic immune receptor (SIR), the at least one SIR comprising a T cell receptor constant chain having a particular amino acid sequence, an optional linker, and one or more non-naturally occurring TCR antigen binding domains selected from the group consisting of antibodies and the like, wherein the synthetic immune receptor, when expressed in a lymphocyte, expresses both the antigen binding domain and the T cell receptor constant chain in one or more contiguous chains on the surface of the lymphocyte; As a result, the lymphocyte is triggered to modulate (induce or suppress) activation, proliferation, secretion of cytokines and / or killing of target cells when the expressed antigen binding domain binds to its antigen, and has both MHC-restricted and MHC-unrestricted antibody type specificities.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. §119 to U.S. Provisional Application No. 62 / 429,619, filed December 2, 2016, and U.S. Provisional Application No. 62 / 429,597, filed December 2, 2016, the disclosures of which are incorporated herein by reference.

[0002] The present invention relates to synthetic immune receptor (SIR) polypeptides, polynucleotides, expression constructs, and the use of immune effector cells (e.g., T cells, NKT cells) and stem cells engineered to express the synthetic immune receptors (SIRs). The present disclosure also provides methods of using such polypeptides, polynucleotides, expression constructs, and recombinant cells to treat diseases and disorders, including, but not limited to, cancer, infectious diseases, allergic diseases, autoimmune diseases, degenerative diseases, or combinations thereof.

[0003] Incorporation by Reference of Sequence Listing This application is accompanied by a Sequence Listing entitled "Sequence_ST25.txt," created on December 2, 2017, machine-formatted for IBM-PC, MS Windows OS, containing 77,085,242 bytes of data, which is hereby incorporated by reference in its entirety for all purposes. [Background technology]

[0004] Cancer immunotherapy, a strategy that activates immune cells to selectively recognize and destroy tumors, offers a powerful approach to cancer treatment. Immunotherapy using tumor-specific T cells and adoptive transfer of chimeric antigen receptor (CAR)-modified T cells (CAR-T cells) mediates durable and complete disease regression in a subset of patients with metastatic cancer.

[0005] Despite the success of CAR T cells, this approach has several limitations. In the majority of patients who respond to engineered CAR T cells, the excessive release of pro-inflammatory cytokines causes symptoms including fever, hypotension, hypoxemia, cardiac dysfunction, renal failure, and electrolyte abnormalities (collectively referred to as "cytokine release syndrome" (CRS)). In some cases, CAR therapy can lead to neurological symptoms, including tremors and seizures, which can be fatal. Strategies to counteract CRS include treatment with immunosuppressants and antibodies against cytokines to block cytokine release.

[0006] In addition, one of the most important challenges for successful cancer immunotherapy is the persistence of such genetically modified T cells for several months or more after transfer, which has proven to be even more challenging for T cells modified with CAR genes.

[0007] Recent molecular design of CAR constructs incorporating the costimulatory domains CD28 or 41BB has achieved improved persistence. However, the inclusion of costimulatory domains in CAR constructs results in nonphysiological receptor-mediated signaling. Some CARs exhibit persistent antigen-independent signaling, resulting in unlimited cell activation ultimately leading to apoptosis, excessive cytokine release independent of the cognate antigen, and immune exhaustion. Expression of some CARs containing the CD28 and LCD3z tandem signaling domains results in constitutive activation and proliferation of transduced primary human T cells, which is associated with poor in vivo efficacy (Frigault et al., 2015). One mechanism found to result in a CAR phenotype associated with sustained T cell proliferation is high cell surface CAR density (Frigault et al., 2015).

[0008] T cell receptors (TCRs) are expressed on the surface of T cells. In humans, these receptors recognize complexes formed between human leukocyte antigen (HLA) molecules and antigenic peptides. Recognition of such peptides leads to activation of the immune function of T cells.

[0009] In most T cells, the TCR is a heterodimer of an alpha (α) chain and a beta (β) chain. The β chain has two isoforms, Cβ2 (80% of human T cells) and Cβ1 (20% of human T cells). Each chain of the TCR contains an N-terminal immunoglobulin (Ig)-like variable (V) domain and an Ig-like constant (C) domain, which contain a transmembrane region and a short cytoplasmic tail at the C-terminus. Summary of the Invention

[0010] The present disclosure provides at least one recombinant polynucleotide encoding at least one synthetic immunoreceptor (SIR), the at least one SIR comprising: (a) a T cell receptor (TCR) constant chain having (i) an amino acid sequence at least 98% identical to SEQ ID NO: 3010 and having one or more mutations at positions 48, 61, 91, 92, 93, and / or 94, and optionally including an optional accessory module; (ii) an amino acid sequence at least 98% identical to SEQ ID NO: 3024 and having one or more mutations at positions 18, 22, 57, 79, 133, 136, and / or 139; (iii) an amino acid sequence that is at least 98% identical to SEQ ID NO: 3025 and has one or more mutations at positions 18, 22, 57, 79, 133, 136, and / or 139, and may include an optional accessory module; (iv) an amino acid sequence that is at least 98% identical to SEQ ID NO: 3046, 3047, or 3048, and may include an optional accessory module; (v) an amino acid sequence that is at least 98% identical to SEQ ID NO: 3049, and has one or more mutations at positions 18, 22, 57, 79, 133, 136, and / or 139, and may include an optional accessory module. (vi) an amino acid sequence at least 98% identical to SEQ ID NO: 3051 or 3052, which may include an optional accessory module; and (vii) a dimeric combination of two TCR constant chains selected from (i) and (ii), (i) and (iii), (iv) and (ii), (iv) and (iii), and (v) and (vi), (b) an optional linker; and (c) one or more non-natural TCR antigen binding domains linked to (a). (1) antibodies, (2) antibody fragments (e.g., Fv, Fab, (Fab')2), (3) antibody heavy chain variable regions (vH domains) or fragments thereof, (4) antibody light chain variable regions (vL domains) or fragments thereof, (5) single-chain variable fragments (scFv) or fragments thereof, (6) single-domain antibodies (SDABs) or fragments thereof, (7) camelid-derived VHH domains or fragments thereof, (8) antibody monomeric variable regions, (9) DARPINs, affibodies, affilins, adnectins, affitins, obodies, lipibodies, finomers, alphabodies,and one or more non-natural TCR antigen-binding domains selected from the group consisting of a non-immunoglobulin antigen-binding scaffold, such as an avimer, an atrimer, a centilin, a pronectin, an anticalin, a Kunitz domain, an armadillo repeat protein, or a fragment thereof; (10) a receptor or a fragment thereof; (11) a ligand or a fragment thereof; (12) a bispecific antibody, a bispecific antibody fragment, a bispecific scFV, a bispecific vHH, a bispecific SDAB, a bispecific non-immunoglobulin antigen-binding scaffold, a bispecific receptor, or a bispecific ligand; and (13) an autoantigen or a fragment thereof, The variants of (iii) and dimers of (a)(vii) provide diverse binding affinities of the antigen-binding domain to the target antigen, said affinity being at least 5% greater than the binding affinity of a cTCR having the same binding domain, and the synthetic immunoreceptor, when expressed in a lymphocyte, expresses both the antigen-binding domain and a T cell receptor constant chain in one or more contiguous chains on the surface of the lymphocyte, such that when the expressed antigen-binding domain binds to its antigen, the lymphocyte is triggered to activate, proliferate, secrete cytokines and / or coordinate (induce or suppress) killing of target cells, and has MHC-restricted and MHC-unrestricted antibody-type specificity. In one embodiment, the non-native TCR binding domain comprises the variable regions of an antibody heavy and light chain or fragment thereof specific for a predetermined target antigen, wherein when expressed, one of the antibody heavy and light chains or fragments thereof is attached to one of the two chains of the T cell constant region of (a)(vii) and the other of the antibody heavy and light chains or fragments thereof is attached to the other of the two chains of the T cell constant region; and two single chain variable fragments (scFvs) specific for one or more predetermined target antigens, wherein when expressed, one of the scFvs is attached to one of the two chains of the T cell constant region of (a)(vii) and the other scFv is attached to the other of the two chains of the T cell constant region; and two antibody fragments specific for one or more predetermined target antigens, wherein when expressed, one of the antibody fragments isand two single domain antibody (SDAB) fragments specific for one or more predetermined target antigens, wherein, when expressed, one of the SDAB fragments is attached to one of the two chains of (a)(vii) of the T cell constant region and the other of the SDAB fragment is attached to the other of the two chains of the T cell constant region; and two camelid single domain antibody fragments specific for one or more predetermined target antigens. and two non-immunoglobulin antigen-binding scaffolds specific for one or more predetermined target antigens, wherein, when expressed, one of the non-immunoglobulin antigen-binding scaffolds is attached to one of the two chains of (a)(vii) of the T cell constant region, and the other of the vHH domains is attached to another of the two chains of the T cell constant region; and two non-immunoglobulin antigen-binding scaffolds specific for one or more predetermined target antigens, wherein, when expressed, one of the non-immunoglobulin antigen-binding scaffolds is attached to one of the two chains of (a)(vii) of the T cell constant region, and the non-immunoglobulin antigen-binding scaffold domains are a non-immunoglobulin antigen-binding scaffold attached to another of the two chains of the T cell constant region, and two receptors or fragments thereof specific for one or more predetermined target antigens, wherein, when expressed, one of the receptors or fragments thereof is attached to one of the two chains of (a)(vii) of the T cell constant region, and the other of the receptors or fragments thereof is attached to the other of the two chains of the T cell constant region, and two ligands or fragments thereof specific for one or more predetermined target antigens, wherein, when expressed, a receptor or fragment thereof, wherein one of the ligand or fragment thereof is attached to one of the two chains in (a)(vii) of the T cell constant region and the other of the ligand or fragment thereof is attached to the other of the two chains of the T cell constant region; and two structurally distinct antigen-binding fragments specific for one or more predetermined target antigens, wherein, when expressed, one of the antigen-binding fragments is attached to one of the two chains in (a)(vii) of the T cell constant region and the other of the antigen-binding fragments is attached to the other of the two chains of the T cell constant region.two binding fragments, either or both of which are bispecific or multispecific, and when expressed, one of the antigen-binding fragments is attached to one of the two chains in (a)(vii) of the T cell constant region and the other of the antigen-binding fragments is attached to the other of the two chains of the T cell constant region; and two autoantigens or fragments thereof, when expressed, one of the autoantigens or fragments thereof is attached to one of the two chains in (a)(vii) of the T cell constant region and the other of the autoantigens or fragments thereof is attached to the other of the two chains of the T cell constant region. a receptor or fragment thereof, wherein, when expressed, one of the vL or fragment thereof is attached to one of the two chains in (a)(vii) of the T cell constant region and the other of the vL or fragment thereof is attached to the other of the two chains of the T cell constant region; and two vH or fragment thereof, wherein, when expressed, one of the vH or fragment thereof is attached to one of the two chains in (a)(vii) of the T cell constant region and the other of the vH or fragment thereof is attached to the other of the two chains of the T cell constant region. In another or further embodiment of any of the foregoing, the TCR constant chain of (a)(iv) is selected from the group consisting of a variable region of an antibody heavy chain (vH) specific for a predetermined target antigen, or a fragment thereof, a variable region of an antibody light chain (vL) specific for a predetermined target antigen, or a fragment thereof, a single chain variable fragment (scFv) or a fragment thereof specific for a predetermined target antigen, an antibody fragment (e.g., Fv, Fab, (Fab')2) specific for a predetermined target antigen, a single domain (SDAB) fragment specific for a predetermined target antigen, and a camelid fragment specific for a predetermined target antigen. an animal-derived vHH domain; a non-immunoglobulin antigen-binding scaffold specific for a predetermined target antigen; a receptor or fragment thereof specific for a predetermined target antigen; a ligand or fragment thereof specific for a predetermined target antigen; a bispecific antibody, bispecific antibody fragment, bispecific scFV, bispecific vHH, bispecific SDAB, bispecific non-immunoglobulin antigen-binding scaffold, bispecific receptor, or bispecific ligand specific for one or more predetermined target antigens; and an autoantigen or fragment thereof.In yet another embodiment, the non-natural TCR binding domain comprises a polynucleotide encoding (i), (ii), (iii), (iv), (v), or (vi), wherein the non-natural TCR binding domain comprises a variable region of an antibody heavy chain (vH) specific for a predetermined target antigen, a variable region of an antibody light chain (vL) specific for a predetermined target antigen, a single chain variable fragment (scFv) specific for a predetermined target antigen, an antibody fragment (e.g., Fv, Fab, (Fab')2) specific for a predetermined target antigen, a single domain (SDAB) fragment (SDAB) specific for a predetermined target antigen, and a camelid fragment (SCFv) specific for a predetermined target antigen. the polynucleotide encoding the TCR constant chain is selected from the group consisting of a vHH domain derived from a human subject, a non-immunoglobulin antigen-binding scaffold specific for a predetermined target antigen, a receptor or fragment thereof specific for a predetermined target antigen, a ligand or fragment thereof specific for a predetermined target antigen, a bispecific antibody, a bispecific antibody fragment, a bispecific scFV, a bispecific vHH, a bispecific SDAB, a bispecific non-immunoglobulin antigen-binding scaffold, a bispecific receptor, or a bispecific ligand specific for one or more predetermined target antigens, and an autoantigen or fragment thereof. In another or further embodiment of any of the foregoing, the polynucleotide encoding the TCR constant chain is a codon-optimized sequence. In another or further embodiment of any of the foregoing, the polynucleotide encoding the TCR constant chain of (a) encodes a TCR constant chain having a mutation that improves expression and / or pairing of the TCR constant chain and a mutation that reduces pairing with an endogenous T cell receptor chain. In alternative or further embodiments of any of the foregoing, the polynucleotide encoding the TCR constant chain of (a) is a nucleic acid sequence with 1-40 modifications of the nucleic acid sequence of SEQ ID NOs: 730-743, or a sequence at least 70% identical to the nucleic acid sequence of SEQ ID NOs: 730-743, and has a sequence capable of dimerizing with the TCR β1 or TCR β2 chain. In alternative or further embodiments of any of the foregoing, the polynucleotide encoding the TCR constant chain of (b) or (c) is a nucleic acid sequence with 1-40 modifications of the nucleic acid sequence of SEQ ID NOs: 744-765, or a sequence at least 70% identical to the nucleic acid sequence of SEQ ID NOs: 744-765,In another or further embodiment of any of the foregoing, the polynucleotide encoding the TCR constant chain of (v) is selected from SEQ ID NOs: 769 to 770, The polynucleotide encoding the TCR constant chain of (vi) has a nucleic acid sequence with 1 to 40 modifications of the nucleic acid sequence of SEQ ID NOs: 770 or a sequence at least 70% identical to the nucleic acid sequence of SEQ ID NOs: 769 to 770, and has a sequence capable of dimerizing with a TCR δ chain. In another or further embodiment of any of the foregoing, the polynucleotide encoding the TCR constant chain of (vi) has a nucleic acid sequence with 1 to 40 modifications of the nucleic acid sequence of SEQ ID NOs: 771 to 772, or a sequence at least 70% identical to the nucleic acid sequence of SEQ ID NOs: 771 to 772, and has a sequence capable of dimerizing with a TCR γ chain. In another or further embodiment of any of the foregoing, the polynucleotide encoding the TCR constant chain of (iv) has a nucleic acid sequence with 1 to 40 modifications of the nucleic acid sequence of SEQ ID NOs: 766 to 768, or a sequence at least 70% identical to the nucleic acid sequence of SEQ ID NOs: 766 to 768, and has a sequence capable of dimerizing with a TCR β1 or TCR β2 chain. In alternative or further embodiments of any of the foregoing, the one or more non-native TCR antigen binding domains that bind one or more disease-associated antigens are selected from the group consisting of CD19; CD123; CD22; CD30; CD171; CS-1 (CD2 subset 1, also known as CRACC, SLAMF7, CD319, and 19A24); C-type lectin-like molecule 1 (CLL-1 or CLECL1); CD33; epidermal growth factor receptor variant III (EGFRviii); ganglioside G2 (GD2); ganglioside GD3 (aNeu5Ac(2-8)aNeu5Ac(2-3)bDGalp(1-4)bDGlcp(1-1)Cer); TNF receptor family member B-cell maturation (BCMA); Tn antigen ((Tn Ag) or (GalNAcα-Ser / Thr); prostate-specific membrane antigen (PSMA); receptor tyrosine kinase-like orphan receptor 1 (ROR1); FMS-like tyrosine kinase 3 (FLT3); tumor-associated glycoprotein 72 (TAG72); CD38; CD44v6; glycosylated CD43 epitope expressed in acute leukemia or lymphoma but not in hematopoietic progenitor cells,Glycosylated CD43 epitopes expressed in non-hematopoietic cancers; carcinoembryonic antigen (CEA); epithelial cell adhesion molecule (EPCAM); B7H3 (CD276); KIT (CD117); interleukin-13 receptor subunit alpha 2 (IL-13Ra2 or CD213A2); mesothelin; interleukin-11 receptor alpha (IL-11Ra); 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-β) ); stage-specific embryonic antigen 4 (SSEA-4); CD20; folate receptor α; receptor tyrosine protein kinase ERBB2 (Her2 / neu); mucin 1, cell surface associated (MUC1); epidermal growth factor receptor (EGFR); neural cell adhesion molecule (NCAM); prostase; prostatic acid phosphatase (PAP); elongation factor 2 mutated (ELF2M); ephrin B2; fibroblast activation protein α (FAP); insulin-like growth factor 1 receptor (IGF-1 receptor), carbonic anhydrase IX (CAIX); proteasome (prosome, macropain) subunits,beta-type 9 (LMP2); glycoprotein 100 (gp100); oncogene fusion protein (bcr-abl) consisting of a cleavage-prone region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (Abl); tyrosinase; ephrin type A receptor 2 (EphA2); fucosyl GM1; sialyl Lewis adhesion molecule (sLe); ganglioside GM3 (aNeu5Ac(2-3)bClalp(1-4)bDGlcp(1-1)Cer); transglutaminase 5 (TGS5); high-molecular-weight melanoma-associated antigen (HMWMAA); O-a Cetyl-GD2 ganglioside (OAcGD2); folate receptor beta; tumor endothelial marker 1 (TEM1 / CD248); tumor endothelial marker 7-related (TEM7R); claudin 6 (CLDN6); thyroid-stimulating hormone receptor (TSHR); G protein-coupled receptor class C group 5 member D (GPRC5D); chromosome X open reading frame 61 (CXORF61); CD97; CD179a; anaplastic lymphoma kinase (ALK); polysialic acid; placenta-specific 1 (PLAC1); globoH glycoceramide hexasaccharide moiety (G loboH); mammary differentiation antigen (NY-BR-1); uroplakin 2 (UPK2); hepatitis A virus cell receptor 1 (HAVCR1); adrenergic receptor β3 (ADRB3), pannexin 3 (PANX3); G protein-coupled receptor 20 (GPR20), lymphocyte antigen 6 complex locus K9 (LY6K), olfactory receptor 51E2 (OR51E2); TCRγ alternative reading frame protein (TARP); Wilms tumor protein (WT1); cancer / testis antigen 1 (NY-ES0-1); cancer / testis 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); X antigen family member 1A (XAGE1); angiopoietin-binding cell surface receptor 2 (Tie2); melanoma cancer-testis antigen 1 (MAD-CT-1); melanoma cancer-testis antigen 2 (MAD-CT-2); Fos-related antigen 1; tumor protein p53 (p53); p53 mutant; prostein; survivin; telomerase; prostate carcinoma antigen 1 (PCT A-1 or galectin 8),Melanoma antigen 1 recognized by T cells (MelanA or MARTI); rat sarcoma (Ras) mutant; human telomerase reverse transcriptase (hTERT); sarcoma translocation breakpoints; melanoma inhibitor of apoptosis (ML-IAP); ERG (transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene); N-acetylglucosaminyltransferase V (NA17); paired box protein Pax-3 (PAX3); androgen receptor; cyclin B1; neuroblastoma-derived homolog of v-myc avian myelocytomatosis viral oncogene (MYCN); Ras homolog family member C (RhoC); tyrosinase-related protein 2 (TRP-2); cytochrome P4501B1 (CYP1B1); CCCTC-binding factor (zinc finger protein)-like (BORIS or Brother of the Regulator of Imprinted Sites), squamous cell carcinoma antigen 3 recognized by T cells (SART3); paired box protein Pax-5 (PAX5); proacrosin-binding protein sp32 (OY-TES1); lymphocyte-specific protein tyrosine kinase (LCK); A-kinase anchor protein 4 (AKAP-4); synovial sarcoma, X-breakpoint 2 (SSX2); receptor for advanced glycation end products (RAGE-1); renal ubiquitous 1 (RU1); renal ubiquitous 2 (RU2); legumain; human papillomavirus E6 (HPV E6); human papillomavirus E7 (HPV E7); intestinal carboxylesterase; heat shock protein 70-2 mutant (mut hsp 70-2); CD79a; CD79b; CD72; leukocyte-associated immunoglobulin-like receptor 1 (LAIR1); Fc fragment of IgA receptor (FCAR or CD89); leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2); CD300 molecule-like family member f (CD300LF); C-type lectin domain family 12 member A (CLEC12A); bone marrow stromal cell antigen 2 (BST2); EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2); lymphocyte antigen 75 (LY75); glypican 3 (GPC3); Fc receptor-like 5 (FCRL5); and immunoglobulin lambda-like polypeptide 1 (IGLL1), MPL, biotin, c-MYC epitope tag, CD34,LAMP1, TROP2, GFRα4, CDH17, CDH6, NYBR1, CDH19, CD200R, Slea (CA19.9; sialyl Lewis antigen), fucosyl GM1, PTK7, gpNMB, CDH1-CD324, DLL3, CD276 / B7H3, IL11Ra, IL13Ra2, CD179b-IGL11, ALK, TCRγδ, NKG2D, CD32 (FCGR2A), Tn Ag, CSPG4-HMW-MAA, Timl- / HVCR1, CSF2RA (GM-CSFRα), TGFβR2, VEGFR2 / KDR, Lewis Ag, TCRβ chain, TCRβ2 chain, TCRγ chain, TCRδ chain, FITC, luteinizing hormone receptor (LHR), follicle-stimulating hormone receptor (FSHR), chorionic gonadotropin receptor (CGHR), CCR4, GD3, SLAMF6, SLAMF4, HIV1 envelope glycoprotein, HTLV1-Tax, CMVpp65, EBV-EBNA3c, influenza Enza A hemagglutinin (HA), GAD, PDL1, guanylyl cyclase C (GCC), KSHV-K8.1 protein, KSHV-gH protein, autoantibodies to desmoglein 3 (Dsg3), autoantibodies to desmoglein 1 (Dsg1), autoantibodies to desmoglein 1 (Dsg1), 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 In another or further embodiment of any of the foregoing, the one or more non-native TCR antigen-binding domains are selected from the group consisting of an antibody, an antibody fragment, an scFv, an Fv, an Fab, an (Fab')2, a single domain antibody (SDAB), a vH or vL domain, a camelid-derived vHH domain, a non-immunoglobulin antigen-binding scaffold, e.g., a DARPIN, an affibody, an affilin, an adnectin, an afftin, an obodies, a lipibody, a finomer,In another or further embodiment of any of the foregoing, the one or more non-natural TCR antigen-binding domains comprise: (i) a heavy chain variable region (vH) encoded by a polynucleotide having the sequence of any of SEQ ID NOs: 226-400 or 10203-10321, or a sequence at least 98% identical thereto, wherein the polynucleotide encodes a polypeptide that binds to an antigen; (ii) a light chain variable region (vL) encoded by a polynucleotide having the sequence of any of SEQ ID NOs: 16-191 or 10085-10202, or a sequence at least 98% identical thereto, wherein the polynucleotide encodes a polypeptide that binds to an antigen; and (iii) a polynucleotide having the sequence of any of SEQ ID NOs: 488-657, 10346-10400, or 18098-18160, or a sequence at least 98% identical thereto. (iv) a camelid VHH domain encoded by a polynucleotide encoding an antigen-binding polypeptide, wherein the polynucleotide has the sequence of any of SEQ ID NOs: 421 to 445 or 10322 to 10337, or a sequence at least 98% identical thereto, and wherein the polynucleotide encodes an antigen-binding polypeptide; (v) a non-immunoglobulin scaffold encoded by a polynucleotide encoding an antigen-binding polypeptide, wherein the polynucleotide has the sequence of any of SEQ ID NOs: 439 to 443, or a sequence at least 98% identical thereto; and (vi) a polynucleotide having the sequence of any of SEQ ID NOs: 456 to 468, or a sequence at least 98% identical thereto, and wherein the polynucleotide encodes an antigen-binding polypeptide. and (vii) a receptor encoded by a polynucleotide encoding SEQ ID NO: 476 to 486 or 10402 to 10404. and a ligand encoded by the polynucleotide having the sequence of any of SEQ ID NOs: 10404 or a sequence at least 98% identical thereto, wherein the polynucleotide encodes a polypeptide that binds to an antigen. In alternative or further embodiments of any of the foregoing, the one or more non-natural TCR antigen binding domains comprise one or more light chain complementarity determining regions for a selected target antigen set forth in any one of SEQ ID NOs: 13999-14879 or 14880, and / or one or more light chain complementarity determining regions for a selected target antigen set forth in any one of SEQ ID NOs: 14881-15761 or 15762. In alternative or further embodiments of any of the foregoing, the one or more non-natural TCR antigen-binding domains comprise a variable light chain (vL) domain having a sequence set forth in any one of SEQ ID NOs: 2307-2482 or 12042-12159 with up to 10 conservative amino acid substitutions, and / or a variable heavy chain (vH) domain having a sequence set forth in any one of SEQ ID NOs: 2506-2680 or 12160-12278 with up to 10 conservative amino acid substitutions. In alternative or further embodiments of any of the foregoing, the one or more non-natural TCR antigen-binding domains comprise one or more camelid vHH complementarity determining regions for a selected antigen set forth in any one of SEQ ID NOs: 2701-2725 or 12279-12294 with up to 10 conservative amino acid substitutions. In alternative or further embodiments related to any of the foregoing, the one or more non-natural TCR antigen-binding domains comprise a non-immunoglobulin antigen-binding domain having the amino acid sequence set forth in any one of SEQ ID NOs: 2728-2732 or 12296-12301, and including up to 10 conservative amino acid substitutions. In alternative or further embodiments related to any of the foregoing, the one or more non-natural TCR antigen-binding domains comprise an scFv domain comprising one or more light chain complementarity determining regions of a variable light chain (vL) domain having the sequence of any one of SEQ ID NOs: 2307-2482 or 12042-12159, and one or more heavy chain complementarity determining regions of a variable heavy chain (vH) domain having the sequence of any one of SEQ ID NOs: 2506-2680 or 12160-12278.In alternative or further embodiments of any of the foregoing, the one or more non-natural TCR antigen-binding domains comprise scFv fragments comprising a sequence selected from the group consisting of SEQ ID NOs: 2770-2939, 12303-12357, and 18162-18224, each with up to 10 conservative amino acid substitutions. In alternative or further embodiments of any of the foregoing, the one or more non-natural TCR antigen-binding domains comprise one or more receptors consisting of the amino acid sequence of any of SEQ ID NOs: 2736-2748 with up to 10 conservative amino acid substitutions. In alternative or further embodiments of any of the foregoing, the one or more non-natural TCR antigen-binding domains comprise one or more ligands consisting of the sequence of any of SEQ ID NOs: 2758-2768 or 12359-12361 with up to 10 conservative amino acid substitutions. In alternative or further embodiments of any of the foregoing, the one or more non-natural TCR antigen-binding domains comprise the extracellular domain of CD16A, NKG2D, CD4, PD1, desmoglein 3 (Dsg3), or CD4-DC-SIGN. In alternative or further embodiments of any of the foregoing, the one or more non-natural TCR antigen-binding domains comprise the extracellular domain of one or more of hTPO, mTPO, CGH α chain, CGH β chain, FH β chain, LH β chain, TSH β chain, APRIL, or a combination thereof.In another or further embodiment of any of the foregoing, the one or more non-native TCR antigen binding domains are selected from the group consisting of: any single chain variable fragment (scFv) comprising the sequence of any one of SEQ ID NOs: 2770-2939, 12303-12357, or 18162-18224, and having up to 10 conservative amino acid substitutions; and a) any camelid vHH as set forth in any of SEQ ID NOs: 2701-2725 or 12279-12294, and having up to 10 conservative amino acid substitutions; or b) any camelid vHH as set forth in any of SEQ ID NOs: 2701-2725 or 12279-12294, and having up to 10 conservative amino acid substitutions. or c) any non-immunoglobulin antigen-binding domain having the sequence set forth in any of SEQ ID NOs: 2736 to 2748, and having up to 10 conservative amino acid substitutions; or d) any extracellular domain of a ligand having any of the sequences set forth in SEQ ID NOs: 2758 to 2768, 12359 to 12361, and having up to 10 conservative amino acid substitutions. In another or further embodiment of any of the foregoing, the one or more non-natural TCR antigen binding domains comprise a camelid vHH having up to 10 conservative amino acid substitutions and set forth in any of SEQ ID NOs: 2701-2725 or 12279-12294, and a single chain variable fragment (scFv) having the sequence of any of SEQ ID NOs: 2770-2939, 12303-12357, or 18162-18224, and having up to 10 conservative amino acid substitutions; or b) a single chain variable fragment (scFv) having the sequence of any of SEQ ID NOs: 2728-2739, 12303-12357, or 18162-18224, and having up to 10 conservative amino acid substitutions. or c) any non-immunoglobulin antigen-binding domain having the sequence set forth in any of SEQ ID NOs: 32 or 12296 to 12301 and having up to 10 conservative amino acid substitutions; or c) any extracellular domain of a receptor consisting of any amino acid sequence set forth in SEQ ID NOs: 2736 to 2748 and having up to 10 conservative amino acid substitutions; or d) any extracellular domain of a ligand having any sequence set forth in SEQ ID NOs: 2758 to 2768 or 12359 to 12361 and having up to 10 conservative amino acid substitutions.In another or further embodiment of any of the foregoing, the one or more non-natural TCR antigen-binding domains are optionally connected to each of the TCR constant regions by a linker region, wherein the nucleic acid of the linker region encodes an amino acid sequence selected from the group consisting of SEQ ID NOs: 2981-2992 and any combination thereof, or a sequence at least 98% identical thereto, or the linker is encoded by a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 701-714, or a sequence at least 98% identical thereto. In another or further embodiment of any of the foregoing, the one or more non-natural TCR antigen-binding domains have a binding affinity for the target antigen that is at least 5-fold less than the antibody from which they are derived. In another or further embodiment of any of the foregoing, the polynucleotide encoding the SIR further comprises a leader sequence or signal peptide present at the N-terminus of each chain and having a sequence selected from the group consisting of SEQ ID NOs: 1-9 and 10. In another or further embodiment of any of the foregoing, at least one polynucleotide encodes two SIRs. In another or further embodiment of any of the foregoing, the polynucleotide encodes two SIRs connected by a nucleotide sequence encoding a cleavable linker. In another or further embodiment of any of the foregoing, the cleavable linker is a self-cleaving cleavable linker. In another or further embodiment of any of the foregoing, the cleavable linker is any one or more of a 2A linker, a 2A-like linker, or functional equivalents thereof. In another or further embodiment of any of the foregoing, the cleavable linker is any one or more of a T2A linker, a P2A, an F2A, an E2A linker, or functional equivalents thereof. In another or further embodiment of any of the foregoing, the cleavable linker has the sequence of any one or more of SEQ ID NOs: 780-785. In another or further embodiment of any of the foregoing, the polynucleotide sequence encoding the cleavable linker is optionally preceded by a nucleotide sequence encoding a furin cleavage site, a furin-like cleavage site, or functional equivalents thereof.In further or further embodiments of any of the foregoing, the furin cleavage site preceding the cleavable linker has the sequence of any one or more of SEQ ID NOs: 788-790. In further or further embodiments of any of the foregoing, the polynucleotide sequence encoding the cleavable linker is preceded by a nucleotide sequence encoding a flexible linker. In further or further embodiments of any of the foregoing, the flexible linker preceding the cleavable linker encodes one or more of a Ser-Gly linker, a Ser-Gly-Ser-Gly linker, or functional equivalents thereof. In further or further embodiments of any of the foregoing, the flexible linker preceding the cleavable linker has the sequence of SEQ ID NOs: 786-787. In further or further embodiments of any of the foregoing, the polynucleotide sequence encoding the furin cleavage site is followed by a polynucleotide encoding a flexible linker, which is followed by a polynucleotide encoding the cleavable linker, in the order: furin cleavage site, flexible linker, cleavable linker. In another or further embodiment of any of the foregoing, the polynucleotide encoding the cleavable linker precedes a sequence encoding a leader sequence (signal peptide) encoding a second SIR. In another or further embodiment of any of the foregoing, the SIR can be designed to have diverse binding affinities for selected antigens. In another or further embodiment of any of the foregoing, the SIR comprises an accessory module. In another or further embodiment of any of the foregoing, the accessory module comprises a CD3z domain. In another or further embodiment of any of the foregoing, the TCR constant chain is selected from the group consisting of: (viii) an amino acid sequence at least 98% identical to SEQ ID NO: 12401, 12402, 12403, 12408, or 12409; (ix) an amino acid sequence at least 98% identical to SEQ ID NO: 12421, 12422, 12423, 12427, or 12428; and (x) a dimeric combination of the two TCR constant chains of (viii) and (ix).In alternative or further embodiments of any of the foregoing, the one or more non-native TCR antigen-binding domains bind to CD19. In alternative or further embodiments related to any of the foregoing, the one or more non-natural TCR antigen binding domains are selected from the group consisting of: a polypeptide having a sequence at least 98% identical to, or a complementarity determining region (CDR) comprised in, any one of SEQ ID NOs: 2318-2324, 12060-12068, 12108, 12127, and 12156; a polypeptide having a sequence at least 98% identical to, or a complementarity determining region (CDR) comprised in any one of SEQ ID NOs: 2517-2523, 12178-12186, 1227, 12246, and 12275; a polypeptide having a sequence at least 98% identical to, SEQ ID NO: 12288; and a polypeptide having a sequence at least 98% identical to, any one of SEQ ID NOs: 2770-2774, 12325, 12308, 18162-18170, and 12354. In another or further embodiment of any of the foregoing, the recombinant polynucleotide is selected from the group consisting of SEQ ID NOs: 3135-3235, 3250-3346, 3396, 3401-3403, 3406, 3429-3432, 3435-3439, 3540, 3855-3859, 12431-12489, 12491-. 12493, 12495~12530, 12534, 13195~13203, 13250, 13267, 13289, 13429-13437, 13483, 13501, and 13523. In alternative or further embodiments of any of the foregoing, the one or more non-native TCR antigen-binding domains bind to CD20. In alternative or further embodiments related to any of the foregoing, the one or more non-natural TCR antigen binding domains are selected from the group consisting of: a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2325-2326, 12069-12077, and 12078, or any complementarity determining region (CDR) contained in any of the polypeptides; a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2524-2525, 12187-12195, and 12196, or any complementarity determining region (CDR) contained in any of the polypeptides; a polypeptide having a sequence at least 98% identical to SEQ ID NO: 12289 or 12290; and a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2787-2788, 18177-18186, and 18187. In alternative or further embodiments of any of the foregoing, the recombinant polynucleotide encodes a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 3263, 3348, 3456-3457, 3876-3877, 12464-12465, 12477-12482, 12492, 12534, 13204-13213, 13438-13446, and 13447. In alternative or further embodiments of any of the foregoing, the one or more non-native TCR antigen-binding domains bind to CD22.In alternative or further embodiments related to any of the foregoing, the one or more non-natural TCR antigen binding domains are selected from the group consisting of: a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2327-2329, 12122-12126, and 12132, or any complementarity determining region (CDR) contained in any of the polypeptides; a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2526-2528, 12241-12245, and 12251, or any complementarity determining region (CDR) contained in any of the polypeptides; and a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2789-2791, 12320-12330, and 18188. In alternative or further embodiments of any of the foregoing, the recombinant polynucleotide encodes a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 3332, 3433, 3458-3460, 3878-3880, 12483, 12485, 12488-12490, 13241-13245, 13268, 13475-13479, and 13502. In alternative or further embodiments of any of the foregoing, the one or more non-native TCR antigen binding domains bind BCMA.In alternative or further embodiments related to any of the foregoing, the one or more non-natural TCR antigen binding domains comprise a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2310-2313, 12046-12048, 12118-12119, 12139-12145, and 12146, or any complementarity determining region (CDR) contained in any of the polypeptides, and any CDR(s) contained in any of SEQ ID NOs: 2509-2512, 12164-12166, 12237-12238, 12258-12264, and 12265. a polypeptide having a sequence at least 98% identical to one of, or any complementarity determining region (CDR) contained in any of the polypeptides, and a polypeptide having a sequence at least 98% identical to SEQ ID NOs: 12279-12281, 12283-12285, 12287, 12291-12292, 12293, or 12294; and a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2780-2783, 12237-12344, 18174-18175, and 18176. In alternative or further embodiments of any of the foregoing, the recombinant polynucleotide encodes a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 3445-3449, 3866-3869, 12463, 12533, 12535-12536, 13181-13183, 13261-13262, 13277-13284, 13415-13417, 13495-13496, 13511-13517, and 13518. In alternative or further embodiments of any of the foregoing, the one or more non-native TCR antigen-binding domains bind to MPL.In alternative or further embodiments related to any of the foregoing, the one or more non-natural TCR antigen binding domains are selected from the group consisting of: a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2414-2421, 12120, 12128, and 12129, or any complementarity determining region (CDR) contained in any of the polypeptides; a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2611-2618, 12239, 12247, and 12248, or any complementarity determining region (CDR) contained in any of the polypeptides; and a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2871-2878, 12326-12327, and 12318. In alternative or further embodiments of any of the foregoing, the one or more non-native TCR antigen-binding domains encode a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 3347, 3373, 3427-3428, 3495, 3556-3562, 3979-3985, 4025, 12454, 12456, 12458, 12462, 12532, 13259, 13265-13266, 13493, 13499, and 13500. In alternative or further embodiments of any of the foregoing, the one or more non-native TCR antigen-binding domains bind to CS1. In alternative or further embodiments related to any of the foregoing, the one or more non-natural TCR antigen binding domains are selected from the group consisting of: a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2355-2358, 12090-12094, and 12095, or any complementarity determining region (CDR) contained in any of the polypeptides; a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2553-2555, 12209-12213, and 12214, or any complementarity determining region (CDR) contained in any of the polypeptides; and a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2817-2819, 18211-18215, and 18216.In alternative or further embodiments of any of the foregoing, the recombinant polynucleotide encodes a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 3376, 3487, 3489, 3907-3909, 12455, 12457, 12459, 12461, 12476, 13226-13231, 13460-13464, and 13465. In alternative or further embodiments of any of the foregoing, the one or more non-native TCR antigen-binding domains bind to CD33. In alternative or further embodiments related to any of the foregoing, the one or more non-natural TCR antigen binding domains are selected from the group consisting of: a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2336-2337, 12079-12084, and 12085, or any complementarity determining region (CDR) contained in any of the polypeptides; a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2535-2536, 12197-12202, and 12203, or any complementarity determining region (CDR) contained in any of the polypeptides; and a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2795-2796, 18189-18193, and 18194. In alternative or further embodiments of any of the foregoing, the recombinant polynucleotide encodes a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 3464-3465, 3884-3885, 12460, 12473, 12479, 13214-13220, 13448-13453, and 13454. In alternative or further embodiments of any of the foregoing, the one or more non-native TCR antigen-binding domains bind to CD123.In alternative or further embodiments related to any of the foregoing, the one or more non-natural TCR antigen binding domains are selected from the group consisting of: a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2315, 2472, 12049-12058, and 12059, or any complementarity determining region (CDR) contained in any of the polypeptides; a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2514, 2670, 12167-12176, and 12177, or any complementarity determining region (CDR) contained in any of the polypeptides; a polypeptide having a sequence at least 98% identical to SEQ ID NO: 2716 or 2717; and a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2801, 2929, 18196-18205, and 18206. In alternative or further embodiments of any of the foregoing, the recombinant polynucleotide encodes a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 3266-3267, 3366-3368, 3375, 3378, 3405, 3409, 3434, 3470, 3492-3497, 3617, 3890, 3912-3913, 4041, 12480, 13184-13194, 13418-13427, and 13428. In alternative or further embodiments of any of the foregoing, the one or more non-native TCR antigen binding domains bind to folate receptor 1. In alternative or further embodiments of any of the foregoing, the one or more non-native TCR antigen binding domains are selected from the group consisting of: a polypeptide having a sequence at least 98% identical to SEQ ID NO: 2373, or any complementarity determining region (CDR) contained in any of the polypeptides; a polypeptide having a sequence at least 98% identical to SEQ ID NO: 2570, or any complementarity determining region (CDR) contained in any of the polypeptides; and a polypeptide having a sequence at least 98% identical to SEQ ID NO: 2833. In alternative or further embodiments of any of the foregoing, the recombinant polynucleotide encodes a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 3511 and 3928.In another or further embodiment of any of the foregoing, the one or more non-natural TCR antigen-binding domains bind to mesothelin. In another or further embodiment of any of the foregoing, the one or more non-natural TCR antigen-binding domains bind to at least any one of SEQ ID NOs: 2413, 12154, and 12155. a polypeptide having a sequence at least 98% identical to, or any complementarity determining region (CDR) contained in, any of the polypeptides, a polypeptide having a sequence at least 98% identical to, any one of SEQ ID NOs: 2609-2610, 12273, and 12274, or any complementarity determining region (CDR) contained in any of the polypeptides, a polypeptide having a sequence at least 98% identical to, SEQ ID NOs: 2713-2714 or 2725, and a polypeptide having a sequence at least 98% identical to, any one of SEQ ID NOs: 2870, 2899, 12352, and 12353. In another or further embodiment of any of the foregoing, the recombinant polynucleotide encodes a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 3414, 3419, 3554, 3585, 3976, 4008, 13287-13288, 13521, and 13522. In another or further embodiment of any of the foregoing, the one or more non-natural TCR antigen-binding domains bind to IL13Ra2. In another or further embodiment of any of the foregoing, the one or more non-natural TCR antigen-binding domains are selected from the group consisting of: a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2399 and 2400, or any complementarity determining region (CDR) contained in any of the polypeptides, and a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2595 and 2596, or any complementarity determining region (CDR) contained in any of the polypeptides, and a sequence at least 98% identical to any one of SEQ ID NOs: 2858 and 2859. In another or further embodiment of any of the foregoing, the recombinant polynucleotide encodes a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 3541-3542, 3542, 3963, and 3964. In alternative or further embodiments of any of the foregoing, the one or more non-native TCR antigen-binding domains bind to CD138.In alternative or further embodiments of any of the foregoing, the one or more non-naturally occurring TCR antigen binding domains are selected from the group consisting of: a polypeptide having a sequence at least 98% identical to SEQ ID NO: 2316, or any complementarity determining region (CDR) contained in any of the polypeptides; a polypeptide having a sequence at least 98% identical to SEQ ID NO: 2515, or any complementarity determining region (CDR) contained in any of the polypeptides; and a polypeptide having a sequence at least 98% identical to SEQ ID NO: 2802. In alternative or further embodiments of any of the foregoing, the recombinant polynucleotide encodes a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 3268, 3374, 3404, 3471, and 3891. In alternative or further embodiments of any of the foregoing, the one or more non-naturally occurring TCR antigen binding domains bind to TCRgd. In alternative or further embodiments of any of the foregoing, the one or more non-natural TCR antigen-binding domains are selected from the group consisting of: a polypeptide having a sequence at least 98% identical to SEQ ID NO: 2449, or any complementarity determining region (CDR) contained in any of the polypeptides; a polypeptide having a sequence at least 98% identical to SEQ ID NO: 2646, or any complementarity determining region (CDR) contained in any of the polypeptides; and a polypeptide having a sequence at least 98% identical to SEQ ID NO: 2907. The recombinant polynucleotide encodes a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 3594 and 4017. In alternative or further embodiments of any of the foregoing, the one or more non-natural TCR antigen-binding domains bind to TCRB1.In alternative or further embodiments of any of the foregoing, the one or more non-natural TCR antigen-binding domains are selected from the group consisting of: a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2445 and 2446, or any complementarity determining region (CDR) contained in any of the polypeptides; a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2642 and 2643, or any complementarity determining region (CDR) contained in any of the polypeptides; and a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2903 and 2904. The recombinant polynucleotide encodes a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 3590-3591, 4013, and 4014. In alternative or further embodiments of any of the foregoing, the one or more non-natural TCR antigen-binding domains bind to TCRB2. In alternative or further embodiments related to any of the foregoing, the one or more non-natural TCR antigen binding domains are selected from the group consisting of: a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2447 and 2448, or any complementarity determining region (CDR) contained in any of the polypeptides; a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2644 and 2645, or any complementarity determining region (CDR) contained in any of the polypeptides; and a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2905 and 2906. The recombinant polynucleotide encodes a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 3353-3364, 3592-3593, 4015, and 4016.

[0011] A recombinant expression system having a recombinant polynucleotide described herein co-expressed with a therapeutic control, wherein the therapeutic control is selected from the group consisting of truncated epidermal growth factor receptor (tEGFR), truncated epidermal growth factor receptor viii (tEGFRviii), cleaved CD30 (tCD30), cleaved BCMA (tBCMA), cleaved CD19 (tCD19), CD34, thymidine kinase, cytosine deaminase, nitroreductase, xanthine guanine phosphoribosyltransferase, human caspase 8, human caspase 9, and inducible caspase 9 (ic Caspase 9), purine nucleoside phosphorylase, linamarase / linamarin glucose oxidase, deoxynucleoside kinase, horseradish peroxidase (HRP) / indole-3-acetic acid (IAA), gamma glutamylcysteine ​​synthase, CD20 / alpha CD20, CD34 / thymidine kinase chimera, dox-dependent caspase 2, mutant thymidine kinase (HSV-TKSR39), AP1903 / Fas system, chimeric cytokine receptor (CCR), selectable marker, and combinations thereof. In one embodiment, the tEGFR and tEGFRviii bind to any one or more of an EGFR-specific siRNA, a small molecule compound, an anti-EGFR antibody or a fragment thereof, or a combination thereof. In another embodiment, the tCD30 binds to any one or more of a CD30-specific siRNA, a small molecule compound, an anti-CD30 antibody or a fragment thereof, and a combination thereof. In another embodiment, the tCD19 binds to any one or more of a CD19-specific siRNA, a small molecule compound, an anti-CD19 antibody or a fragment thereof, and a combination thereof. In another embodiment, the CD34 binds to any one or more of a CD34-specific siRNA, a small molecule compound, an anti-CD34 antibody or a fragment thereof, and a combination thereof.In another embodiment, the selectable marker binds to any one or more of dihydroxyfolate receptor, mutant DHFR, methylated DNA-protein cysteine ​​methyltransferase, inosine monophosphate dehydrogenase II (IMDHP2), puromycin acetyltransferase (PAC), blasticidin resistance gene, mutant calcineurin a / b (Can / b), CNa12, CNb30, and combinations thereof. In yet another embodiment, the CCR comprises any one or more of (i) an IL-7 cytokine linker IL7Ra, (ii) an IL-7 cytokine linker extracellular domain of the cytoplasmic domain of IL2Rβ, the IL-7Ra transmembrane domain of IL-7Ra, (iii) an IL-7 cytokine linker IL2Rβ, and (iv) combinations thereof. In another embodiment, the recombinant expression system comprises a recombinant polynucleotide of the disclosure co-expressed with an accessory module, wherein the accessory module is 41BBL, CD40L, K13, MC159, cFLIP-L / MRITα, cFLIP-p22, HTLV1 Tax, HTLV2 Tax, HTLV2 Tax2-RS mutant, FKBPx-K13, FKBPx-HTLV2-Tax, FKBPx-HTLV2-Tax-RS, IL6R-304-vHH-Alb8-vHH, IL12f, PD1-4H1 scFV, PD1-5C4 scFV, PD1-4H1-Alb8-vHH, PD1-5C4-Alb8-vHH, CTLA4 ipilimumab scFV, CTLA4 ipilimumab Alb8-vHH, IL6-19A-scFV, IL6-19A-scFV-Alb8-vHH, sHVEM, sHVEM-Alb8-vHH, hTERT, Fx06, CD3z, CD3z-GGGS-41BB, CD3-BBz, CD3-CD28z, CD3-CD28-Lck fusion protein, shRNA targeting Brd4, chimeric antigen receptor (CAR), hTERT, heparinase, CAR, inhibitory CAR, and combinations thereof.In another or further embodiment of any of the foregoing, the recombinant polynucleotide encoding the SIR, one or more therapeutic controls, and / or one or more accessory modules are linked by a nucleotide sequence encoding a cleavable linker. In another or further embodiment of any of the foregoing, the cleavable linker is a self-cleaving cleavable linker. In another or further embodiment of any of the foregoing, the polynucleotide sequence encoding the cleavable linker is preceded by a nucleotide sequence encoding a furin cleavage site, a furin-like cleavage site, or a functional equivalent thereof. In another or further embodiment of any of the foregoing, the polynucleotide sequence encoding the cleavable linker is optionally preceded by a nucleotide sequence encoding a flexible linker.

[0012] The present disclosure further provides at least one vector comprising a recombinant polynucleotide described herein, the vector being selected from the group consisting of a DNA vector, an RNA vector, a plasmid, a lentiviral vector, an adenoviral vector, a retroviral vector, a baculoviral vector, a sleeping beauty transposon vector, and a piggybac transposon vector. In one embodiment, the backbone of the vector has a sequence selected from the group consisting of SEQ ID NOs: 870-875 and 876. In another embodiment, the vector has a promoter selected from the EF-1 promoter, the CMV IE gene promoter, the EF-1a promoter, the ubiquitin C promoter, the MSCV LTR promoter, and the phosphoglycerate kinase (PGK) promoter. In a further embodiment, the EF-1 promoter has the sequence of SEQ ID NO: 877, or a sequence 80-99% identical thereto. In another or further embodiment of any of the foregoing, the vector is an in vitro transcription vector, or the vector further comprises a poly(A) tail or a 3'UTR.

[0013] The present disclosure provides at least one polypeptide encoded by at least one recombinant polynucleotide of the present disclosure.

[0014] Additionally, the present disclosure provides recombinant cells that express at least one recombinant polynucleotide described herein.

[0015] The present disclosure also provides an isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer, comprising: (a) a T cell receptor (TCR) constant chain comprising: (i) an amino acid sequence at least 98% identical to SEQ ID NO: 3010, having one or more mutations at positions 48, 61, 91, 92, 93, and / or 94, and optionally an accessory module; (ii) an amino acid sequence at least 98% identical to SEQ ID NO: 3024, having one or more mutations at positions 18, 22, 57, 79, 133, 136, and / or 139, and optionally an accessory module; and (iii) an amino acid sequence at least 98% identical to SEQ ID NO: 3025, having one or more mutations at positions 18, 22, 57, 79, 133, 136, and / or 139, and optionally an accessory module. (iv) an amino acid sequence at least 98% identical to SEQ ID NO: 3046, 3047, or 3048, optionally with an optional accessory module; (v) an amino acid sequence at least 98% identical to SEQ ID NO: 3049, optionally with an optional accessory module; (vi) an amino acid sequence at least 98% identical to SEQ ID NO: 3051 or 3052, optionally with an optional accessory module; (vii) a dimeric combination of two TCR constant chains selected from (i) and (ii), (i) and (iii), (iv) and (ii), (iv) and (iii), (v) and (vi); (b) an optional linker; and (c) one or more non-natural TCR antigen binding domains linked to (a), comprising: (1) an antibody; (2) antibody fragments (e.g., Fv, Fab, (Fab')2); (3) antibody heavy chain variable regions (vH domains) or fragments thereof; (4) antibody light chain variable regions (vL domains) or fragments thereof; (5) single-chain variable fragments (scFv) or fragments thereof; (6) single-domain antibodies (SDABs) or fragments thereof; (7) camelid-derived VHH domains or fragments thereof; (8) antibody monomeric variable regions; (9) DARPINs, affibodies, affilins, adnectins,(10) a non-immunoglobulin antigen-binding scaffold such as an afftin, obodies, lipibodies, finomers, alphabodies, avimers, atrimers, centrins, pronectins, anticalins, Kunitz domains, armadillo repeat proteins, or fragments thereof; (11) a receptor or a fragment thereof; (12) a bispecific antibody, a bispecific antibody fragment, a bispecific scFV, a bispecific vHH, a bispecific SDAB, a bispecific non-immunoglobulin antigen-binding scaffold, a bispecific receptor, or a bispecific ligand; and (13) an autoantigen. or a fragment thereof; and a non-natural TCR antigen-binding domain selected from the group consisting of (a)(i) through (a)(iii), wherein the variants of (a)(i) through (a)(iii) have diverse binding affinities for the target antigen of the antigen-binding domain, and the synthetic immunoreceptor, when expressed in a lymphocyte, expresses both the antigen-binding domain and the T cell receptor constant chain in one or more contiguous chains on the surface of the lymphocyte, is triggered to activate, proliferate, and secrete cytokines and / or modulate (induce or suppress) killing of the target cell when the expressed antigen-binding domain binds to its antigen, and has MHC-restricted and MHC-unrestricted antibody-type specificity. In another or further embodiment of any of the foregoing, the TCR constant chain of (a)(vii) above has a non-native TCR binding domain, which is a variable region of an antibody heavy and light chain or fragment thereof specific for a predetermined target antigen, wherein, when expressed, one of the antibody heavy and light chains or fragment thereof is attached to one of the two chains of (a)(vii) of the T cell constant region, and the other of the antibody heavy and light chains or fragment thereof is attached to the other of the two chains of the T cell constant region. and two single chain variable fragments (scFvs) specific for one or more predetermined target antigens, wherein, when expressed, one of the scFvs is attached to one of the two chains of (a)(vii) of the T cell constant region and the other scFv is attached to the other of the two chains of the T cell constant region; and two antibody fragments specific for one or more predetermined target antigens, wherein, when expressed, one of the antibody fragments is attached to one of the two chains of (a)(vii) of the T cell constant region;an antibody fragment, wherein another of the antibody fragments is attached to another of the two chains of a T-cell constant region; and two single domain antibody (SDAB) fragments specific for one or more predetermined target antigens, wherein, when expressed, one of the SDAB fragments is attached to one of the two chains of the T-cell constant region of (a)(vii) and the other of the SDAB fragments is attached to another of the two chains of the T-cell constant region; and two camelid-derived vHH domains specific for one or more predetermined target antigens, wherein, when expressed, the vHH domains one of the vHH domains is attached to one of the two chains of (a)(vii) of the T cell constant region and the other of the vHH domains is attached to the other of the two chains of the T cell constant region; and two non-immunoglobulin antigen-binding scaffolds specific for one or more predetermined target antigens, wherein when expressed, one of the non-immunoglobulin antigen-binding scaffolds is attached to one of the two chains of (a)(vii) of the T cell constant region and the other of the non-immunoglobulin antigen-binding scaffold domains is attached to the other of the two chains of the T cell constant region. a non-immunoglobulin antigen-binding scaffold, two receptors or fragments thereof specific for one or more predetermined target antigens, wherein when expressed, one of the receptors or fragments thereof is attached to one of the two chains of (a)(vii) of the T-cell constant region and the other of the receptors or fragments thereof is attached to another of the two chains of the T-cell constant region; and two ligands or fragments thereof specific for one or more predetermined target antigens, wherein when expressed, one of the ligands or fragments thereof is attached to the T-cell constant region. a receptor or fragment thereof, wherein one of the ligand or fragment thereof is attached to one of the two chains of (a)(vii) of the T cell constant region and the other of the ligand or fragment thereof is attached to another of the two chains of the T cell constant region; and two structurally distinct antigen-binding fragments specific for one or more predetermined target antigens, wherein, when expressed, one of the antigen-binding fragments is attached to one of the two chains of (a)(vii) of the T cell constant region and the other of the antigen-binding fragments is attached to another of the two chains of the T cell constant region; and two structurally distinct antigen-binding fragments, whereina receptor or fragment thereof, and two autoantigens or fragments thereof, either or both of which are bispecific or multispecific, and when expressed, one of the antigen-binding fragments is attached to one of the two chains of (a)(vii) of the T cell constant region and the other of the antigen-binding fragments is attached to the other of the two chains of the T cell constant region; and a receptor or fragment thereof, and two autoantigens or fragments thereof, and when expressed, one of the autoantigens or fragments is attached to one of the two chains of (a)(vii) of the T cell constant region and the other of the autoantigens or fragments is attached to the other of the two chains of the T cell constant region. a receptor or fragment thereof, wherein, when expressed, one of the vL or fragment thereof is attached to one of the two chains in (a)(vii) of the T cell constant region and the other of the vL or fragment thereof is attached to the other of the two chains of the T cell constant region; and two vH or fragment thereof, wherein, when expressed, one of the vH or fragment thereof is attached to one of the two chains in (a)(vii) of the T cell constant region and the other of the vH or fragment thereof is attached to the other of the two chains of the T cell constant region. In another or further embodiment of any of the foregoing, the TCR constant chain of (a)(iv) comprises a non-native TCR binding domain, the non-native TCR binding domain comprising a variable region of an antibody heavy chain (vH) or fragment thereof specific for a predetermined target antigen, a variable region of an antibody light chain (vL) or fragment thereof specific for a predetermined target antigen, a single chain variable fragment (scFv) or fragment thereof specific for a predetermined target antigen, an antibody fragment (e.g., Fv, Fab, (Fab')2) specific for a predetermined target antigen, and a single chain variable fragment (scFv) or fragment thereof specific for a predetermined target antigen. a single domain (SDAB) fragment, a camelid-derived vHH domain specific for a predetermined target antigen, a non-immunoglobulin antigen-binding scaffold specific for a predetermined target antigen, a receptor or fragment thereof specific for a predetermined target antigen, a ligand or fragment thereof specific for a predetermined target antigen, a bispecific antibody, a bispecific antibody fragment, a bispecific scFV, a bispecific vHH, a bispecific SDAB, a bispecific non-immunoglobulin antigen-binding scaffold, a bispecific receptor specific for one or more predetermined target antigens,In another or further embodiment of any of the foregoing, the non-native TCR binding domain comprises a TCR constant domain of (i), (ii), (iii), (iv), (v), or (vi) above, and the non-native TCR binding domain is selected from the group consisting of a variable region of an antibody heavy chain (vH) specific for a predetermined target antigen, a variable region of an antibody light chain (vL) specific for a predetermined target antigen, a single chain variable fragment (scFv) specific for a predetermined target antigen, an antibody fragment (e.g., Fv, Fab, (Fab')2) specific for a predetermined target antigen, a single domain (SDAB) fragment specific for a predetermined target antigen, and a non-native TCR constant domain (vL) specific for a predetermined target antigen. and a bispecific antibody, bispecific antibody fragment, bispecific scFV, bispecific vHH, bispecific SDAB, bispecific non-immunoglobulin antigen-binding scaffold, bispecific receptor, or bispecific ligand specific for one or more predetermined target antigens, and an autoantigen or fragment thereof. In another or further embodiment of any of the foregoing, the TCR constant chain(s) comprises a mutation that improves expression and / or pairing of the TCR constant chain and reduces pairing with endogenous T cell receptor chains. In another or further embodiment of any of the foregoing, the constant region of the TCR comprises a sequence selected from the group consisting of SEQ ID NOs: 3010-3023, or SEQ ID NOs: 3010-3024. 3023。 In another or further embodiment related to any of the foregoing, the constant region of the TCR is a TCR receptor β chain (Cβ) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 3024-3044, or an amino acid sequence at least 98% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 3024-3044. In another or further embodiment related to any of the foregoing, the constant region of the TCR is a TCR receptor γ chain (Cγ) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 3049-3050, or an amino acid sequence at least 98% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 3049-3050. In another or further embodiment of any of the foregoing, the constant region of the TCR is a TCR receptor δ chain (Cδ) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 3051-3052, or comprising 1-40 amino acid substitutions or mutations relative to a sequence at least 98% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 3051-3052. In another or further embodiment of any of the foregoing, the constant region of the TCR is a pre-TCR receptor α chain (pre-Cα) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 3046-3048, or comprising 1-40 amino acid substitutions or mutations relative to a sequence at least 98% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 3046-3048. In another or further embodiment of any of the foregoing, the one or more non-native TCR antigen-binding domains that bind the one or more disease-associated antigens are selected from the group consisting of CD19; CD123; CD22; CD30; CD171; CS-1 (CD2 subset 1), CRACC, SLAMF7, CD319,and 19A24); C-type lectin-like molecule 1 (CLL-1 or CLECL1); CD33; epidermal growth factor receptor variant III (EGFRviii); ganglioside G2 (GD2); ganglioside GD3 (aNeu5Ac(2-8)aNeu5Ac(2-3)bDGalp(1-4)bDGlcp(1-1)Cer); TNF receptor family member B cell maturation (BCMA); Tn antigen ((Tn Ag) or (GalNAcα-Ser / Thr); prostate-specific membrane antigen (PSMA); receptor tyrosine kinase-like orphan receptor 1 (ROR1); FMS-like tyrosine kinase 3 (FLT3); tumor-associated glycoprotein 72 (TAG72); CD38; CD44v6; glycosylated CD43 epitope expressed in acute leukemia or lymphoma but not in hematopoietic progenitor cells, glycosylated CD43 epitope expressed in non-hematopoietic cancers; carcinoembryonic antigen (CEA); epithelial cell adhesion molecule (EPCAM); B7H3 (CD276); KIT (CD117); interleukin-13 receptor subunit alpha 2 (IL-13Ra2 or CD213A2); mesothelin; interleukin-11 receptor alpha (IL-11Ra); prostate stem cell antigen (PSCA); protein ase serine 21 (testisin or PRSS21); vascular endothelial growth factor receptor 2 (VEGFR2); Lewis (Y) antigen; CD24; platelet-derived growth factor receptor beta (PDGFR-β); stage-specific embryonic antigen 4 (SSEA-4); CD20; folate receptor α; receptor tyrosine protein kinase ERBB2 (Her2 / neu); mucin 1, cell surface associated (MUC1); epidermal growth factor receptor (EGFR); neural cell adhesion molecule (NCAM); prostase; prostatic acid phosphatase (PAP); elongation factor 2 mutated (ELF2M); ephrin B2; fibroblast activation protein α (FAP); insulin-like growth factor 1 receptor (IGF-1 receptor), carbonic anhydrase IX (CAIX); proteasome (prosome, macropain) subunits,beta-type 9 (LMP2); glycoprotein 100 (gp100); oncogene fusion protein (bcr-abl) consisting of a cleavage-prone region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (Abl); tyrosinase; ephrin type A receptor 2 (EphA2); fucosyl GM1; sialyl Lewis adhesion molecule (sLe); ganglioside GM3 (aNeu5Ac(2-3)bClalp(1-4)bDGlcp(1-1)Cer); transglutaminase 5 (TGS5); high-molecular-weight melanoma-associated antigen (HMWMAA); O-acetyl-GD2 ganglioside (OAcGD2); folate receptor beta; tumor endothelial marker 1 (TEM1 / CD248); tumor endothelial marker 7-related (TEM7R); claudin 6 (CLDN6); thyroid-stimulating hormone receptor (TSHR); G protein-coupled receptor class C group 5 member D (GPRC5D); chromosome X open reading frame 61 (CXORF61); CD97; CD179a; anaplastic lymphoma kinase (ALK); polysialic acid; placenta-specific 1 (PLAC1); globoglycoceramide Hexasaccharide moiety (GloboH); mammary differentiation antigen (NY-BR-1); uroplakin 2 (UPK2); hepatitis A virus cellular receptor 1 (HAVCR1); adrenergic receptor β3 (ADRB3), pannexin 3 (PANX3); G protein-coupled receptor 20 (GPR20), lymphocyte antigen 6 complex locus K9 (LY6K), olfactory receptor 51E2 (OR51E2); TCRγ alternative reading frame protein (TARP); Wilms tumor protein (WT1); cancer / testis antigen 1 (NY-ES0-1); cancer / testis antigen Origin 2 (LAGE-1a); melanoma-associated antigen 1 (MAGE-A1); ETS translocation variant gene 6 located on chromosome 12p (ETV6-AML); sperm protein 17 (SPA17); X antigen family member 1A (XAGE1); angiopoietin-binding cell surface receptor 2 (Tie2); melanoma cancer-testis antigen 1 (MAD-CT-1); melanoma cancer-testis antigen 2 (MAD-CT-2); Fos-related antigen 1; tumor protein p53 (p53); p53 mutant; prostein; survivin; telomerase; prostate carcinoma antigen 1 (PCT A-1 or galectin 8),Melanoma antigen 1 recognized by T cells (MelanA or MARTI); rat sarcoma (Ras) mutant; human telomerase reverse transcriptase (hTERT); sarcoma translocation breakpoints; melanoma inhibitor of apoptosis (ML-IAP); ERG (transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene); N-acetylglucosaminyltransferase V (NA17); paired box protein Pax-3 (PAX3); androgen receptor; cyclin B1; neuroblastoma-derived homolog of v-myc avian myelocytomatosis viral oncogene (MYCN); Ras homolog family member C (RhoC); tyrosinase-related protein 2 (TRP-2); cytochrome P4501B1 (CYP1B1); CCCTC-binding factor (zinc finger protein)-like (BORIS or Brother of the Regulator of Imprinted Sites), squamous cell carcinoma antigen 3 recognized by T cells (SART3); paired box protein Pax-5 (PAX5); proacrosin-binding protein sp32 (OY-TES1); lymphocyte-specific protein tyrosine kinase (LCK); A-kinase anchor protein 4 (AKAP-4); synovial sarcoma, X-breakpoint 2 (SSX2); receptor for advanced glycation end products (RAGE-1); renal ubiquitous 1 (RU1); renal ubiquitous 2 (RU2); legumain; human papillomavirus E6 (HPV E6); human papillomavirus E7 (HPV E7); intestinal carboxylesterase; heat shock protein 70-2 mutant (mut hsp 70-2); CD79a; CD79b; CD72; leukocyte-associated immunoglobulin-like receptor 1 (LAIR1); Fc fragment of IgA receptor (FCAR or CD89); leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2); CD300 molecule-like family member f (CD300LF); C-type lectin domain family 12 member A (CLEC12A); bone marrow stromal cell antigen 2 (BST2); EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2); lymphocyte antigen 75 (LY75); glypican 3 (GPC3); Fc receptor-like 5 (FCRL5); and immunoglobulin lambda-like polypeptide 1 (IGLL1), MPL, biotin, c-MYC epitope tag, CD34,LAMP1, TROP2, GFRalpha4, CDH17, CDH6, NYBR1, CDH19, CD200R, Slea (CA19.9; sialyl Lewis antigen), fucosyl GM1, PTK7, gpNMB, CDH1-CD324, DLL3, CD276 / B7H3, IL11Ra, IL13Ra2, CD179b-IGL11, ALK, TCRγδ, NKG2D, CD32 (FCGR2A), Tn ag, CSPG4-HMW-MAA, Timl- / HVCR1, CSF2RA (GM-CSFRα), TGFβR2, VEGFR2 / KDR, Lewis Ag, TCRβ chain, TCRβ2 chain, TCRγ chain, TCRδ chain, FITC, luteinizing hormone receptor (LHR), follicle-stimulating hormone receptor (FSHR), chorionic gonadotropin receptor (CGHR), CCR4, GD3, SLAMF6, SLAMF4, HIV1 envelope glycoprotein, HTLV1-Tax, CMVpp65, EBV- EBNA3c, influenza A hemagglutinin (HA), GAD, PDL1, guanylyl cyclase C (GCC), KSHV-K8.1 protein, KSHV-gH protein, autoantibodies to desmoglein 3 (Dsg3), autoantibodies to desmoglein 1 (Dsg1), 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 In another or further embodiment of any of the foregoing, the one or more non-native TCR antigen-binding domains are selected from the group consisting of antigens recognized by antibodies, such as G12V, tissue factor 1 (TF1), AFP, GPRC5D, claudin 18.2 (CLD18A2 or CLDN18A.2), P-glycoprotein, STEAP1, LIV1, NECTIN-4, CRIPTO, GPA33, BST1 / CD157, small conductance chloride channel, and TNT. In another or further embodiment of any of the foregoing, the one or more non-native TCR antigen-binding domains are selected from the group consisting of antibodies, antibody fragments, scFv, Fv, Fab, (Fab')2, single domain antibodies (SDAB), vH or vL domains, camelid-derived vHH domains, non-immunoglobulin antigen-binding scaffolds, such as DARPINs, affibodies, affilins, adnectins, affitins, obodies, lipibodies, finomers, alphabodies, avimers, atrimers, centirins,In another or further embodiment of any of the foregoing, the one or more non-natural TCR antigen-binding domains comprise (i) a heavy chain variable region (vH) encoding a polypeptide that binds to an antigen having the sequence set forth in any of SEQ ID NOs: 2506-2680 or 12160-12278, or a sequence at least 98% identical thereto; (ii) a light chain variable region (vL) encoding a polypeptide that binds to an antigen having the sequence set forth in any one of SEQ ID NOs: 2307-2482 or 12042-12159, or a sequence at least 98% identical thereto; (iii) a single chain variable fragment (scFv) encoding a polypeptide that binds to an antigen having the sequence set forth in any one of SEQ ID NOs: 2770-2939, 12303-12357, or 18162-18224, or a sequence at least 98% identical thereto; and (iv) a sequence set forth in SEQ ID NOs: A sequence set forth in any one of Nos. 2701 to 2725 or 12279 to 12294, or at least (v) a non-immunoglobulin scaffold encoded by the sequence set forth in any one of SEQ ID NOs: 439 to 443 or a sequence at least 98% identical thereto and encoding a polypeptide that binds to a cognate species; (vi) a receptor encoded by the sequence set forth in any one of SEQ ID NOs: 2736 to 2748 or a sequence at least 98% identical thereto and encoding a polypeptide that binds to a cognate species; and (vii) a ligand encoded by the sequence set forth in any one of SEQ ID NOs: 2758 to 2768 or 12359 to 12361 or a sequence at least 98% identical thereto and encoding a polypeptide that binds to a cognate species. In alternative or further embodiments of any of the foregoing, the one or more non-natural TCR antigen-binding domains comprise one or more light chain complementarity determining regions for a selected target antigen set forth in any of SEQ ID NOs: 13999-14879 or 14880, and / or one or more heavy chain complementarity determining regions for a selected target antigen set forth in any of SEQ ID NOs: 14881-15761 or 15762. In alternative or further embodiments of any of the foregoing, the one or more non-natural TCR antigen-binding domains comprise a variable light chain (vL) domain having up to 10 conservative amino acid substitutions and comprising the sequence of any one of SEQ ID NOs: 2307-2482 or 12042-12159, and / or a variable heavy chain (vH) domain having up to 10 conservative amino acid substitutions and comprising the sequence of any one of SEQ ID NOs: 2506-2680 or 12160-12278. The one or more non-natural TCR antigen binding domains have one or more camelid vHH complementarity determining regions for a selected antigen with up to 10 conservative amino acid substitutions as set forth in any of SEQ ID NOs: 2701-2725 or 12279-12294. In alternative or further embodiments related to any of the foregoing, the one or more non-natural TCR antigen binding domains have a sequence set forth in any of SEQ ID NOs: 2728-2732 or 12296-12301 and comprise a non-immunoglobulin antigen binding domain with up to 10 conservative amino acid substitutions.In alternative or further embodiments related to any of the foregoing, the one or more non-natural TCR antigen-binding domains comprise an scFv domain comprising one or more light chain complementarity determining regions of a variable light chain (vL) domain having the sequence of any one of SEQ ID NOs: 2307 to 2482 or 12042 to 12159, and one or more heavy chain complementarity determining regions of a variable heavy chain (vH) domain having the sequence of any one of SEQ ID NOs: 2506 to 2680 or 12160 to 12278. In alternative or further embodiments related to any of the foregoing, the one or more non-natural TCR antigen-binding domains comprise an scFv fragment comprising a sequence selected from the group consisting of SEQ ID NOs: 2770 to 2939, 12303 to 12357, or 18162 to 18224, each with up to 10 conservative amino acid substitutions. In further or alternative embodiments of any of the foregoing, the one or more non-natural TCR antigen-binding domains comprise one or more receptors with up to 10 conservative amino acid substitutions and consisting of the amino acid sequence of any of SEQ ID NOs: 2736-2748. In further or alternative embodiments of any of the foregoing, the one or more non-natural TCR antigen-binding domains comprise one or more ligands with up to 10 conservative amino acid substitutions and comprising the sequence of any of SEQ ID NOs: 2758-2768 or 12359-12361. In further or alternative embodiments of any of the foregoing, the one or more non-natural TCR antigen-binding domains comprise the extracellular domain of CD16A, NKG2D, CD4, PD1, desmoglein 3 (Dsg3), or CD4-DC-SIGN. In further or alternative embodiments of any of the foregoing, the one or more non-natural TCR antigen-binding domains comprise the extracellular domain of one or more of hTPO, mTPO, CGH α chain, CGH β chain, FH β chain, TSH β chain, APRIL, or a combination thereof.In another or further embodiment of any of the foregoing, the one or more non-natural TCR antigen binding domains comprise any single chain variable fragment (scFv) having the sequence of any of SEQ ID NOs: 2770 to 2939, 12303 to 12357, or 18162 to 18224, and having up to 10 conservative amino acid substitutions; and a) a camelid vHH having up to 10 conservative amino acid substitutions and set forth in any of SEQ ID NOs: 2701 to 2725 or 12279 to 12294; or b) a camelid vHH having the sequence of SEQ ID NOs: 2728 to 2729. or c) any non-immunoglobulin antigen-binding domain having the sequence set forth in any of SEQ ID NOs: 32 or 12296 to 12301 and having up to 10 conservative amino acid substitutions; or c) any extracellular domain of a receptor consisting of any amino acid sequence set forth in SEQ ID NOs: 2736 to 2748 and having up to 10 conservative amino acid substitutions; or d) any extracellular domain of a ligand having any sequence set forth in SEQ ID NOs: 2758 to 2768 or 12359 to 12361 and having up to 10 conservative amino acid substitutions. In another or further embodiment of any of the foregoing, the one or more non-natural TCR antigen binding domains comprise a camelid vHH having up to 10 conservative amino acid substitutions and set forth in any of SEQ ID NOs: 2701-2725 or 12279-12294, and a single chain variable fragment (scFv) having the sequence of any of SEQ ID NOs: 2770-2939, 12303-12357, or 18162-18224, and having up to 10 conservative amino acid substitutions; or b) a single chain variable fragment (scFv) having the sequence of any of SEQ ID NOs: 2728-2739, 12303-12357, or 18162-18224, and having up to 10 conservative amino acid substitutions. or c) any non-immunoglobulin antigen-binding domain having the sequence set forth in any of SEQ ID NOs: 32 or 12296 to 12301 and having up to 10 conservative amino acid substitutions; or c) any extracellular domain of a receptor consisting of any amino acid sequence set forth in SEQ ID NOs: 2736 to 2748 and having up to 10 conservative amino acid substitutions; or d) any extracellular domain of a ligand having any sequence set forth in SEQ ID NOs: 2758 to 2768 or 12359 to 12361 and having up to 10 conservative amino acid substitutions.In another or further embodiment of any of the foregoing, the one or more non-natural TCR antigen-binding domains are optionally connected to each of the TCR constant regions by a linker region, wherein the nucleic acid of the linker region encodes an amino acid sequence selected from the group consisting of SEQ ID NOs: 2981-3003 and any combination thereof, or a sequence at least 98% identical thereto, or the linker is encoded by a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 701-725, or a sequence at least 98% identical thereto. In another or further embodiment of any of the foregoing, the one or more non-natural TCR antigen-binding domains have a binding affinity for the target antigen that is at least 5-fold less than the antibody from which they are derived. In another or further embodiment of any of the foregoing, the polynucleotide encoding the SIR further comprises a leader sequence or signal peptide present at the N-terminus of each chain and having a sequence selected from the group consisting of SEQ ID NOs: 1-9 and 10. In another or further embodiment of any of the foregoing, the SIR comprises an SIR heterodimer. In another or further embodiment of any of the foregoing, the polypeptide comprises two SIRs connected by a cleavable linker. In another or further embodiment of any of the foregoing, the cleavable linker is a self-cleaving cleavable linker. In another or further embodiment of any of the foregoing, the cleavable linker is any one or more of a 2A linker, a 2A-like linker, or functional equivalents thereof. In another or further embodiment of any of the foregoing, the cleavable linker is any one or more of a T2A linker, a P2A, an F2A, an E2A linker, or functional equivalents thereof. In further embodiments, the cleavable linker has the sequence of any one or more of SEQ ID NOs: 780-785. In any of the foregoing embodiments, the cleavable linker is optionally preceded by a furin cleavage site, a furin-like cleavage site, or functional equivalents thereof. In further embodiments, the furin cleavage site preceding the cleavable linker has the sequence of any one or more of SEQ ID NOs: 788-790.In further embodiments, the cleavable linker is preceded by a flexible linker. In further embodiments, the flexible linker preceding the cleavable linker encodes one or more of a Ser-Gly linker, a Ser-Gly-Ser-Gly linker, or functional equivalents thereof. The flexible linker preceding the cleavable linker has the sequence of SEQ ID NOs: 786-787. In further embodiments, the furin cleavage site is followed by a flexible linker, which is followed by a cleavable linker, in the order: furin cleavage site, flexible linker, cleavable linker. In another or further embodiment of any of the foregoing, the SIR is designed to have diverse binding affinities for selected antigens.

[0016] The present disclosure also provides immune effector or stem cells comprising at least one polypeptide or heterodimer described herein.

[0017] The present disclosure also provides immune effector or stem cells comprising at least one recombinant polynucleotide described herein.

[0018] The present disclosure also provides immune effector or stem cells described herein that comprise at least one vector of the present disclosure.

[0019] In another or further embodiment of any of the foregoing, the immune effector cell or stem cell comprises a plurality of SIR polypeptides. In another or further embodiment of any of the foregoing, at least one SIR polypeptide of the plurality targets a different antigen than at least one other SIR polypeptide. In another or further embodiment of any of the foregoing, at least one SIR polypeptide of the plurality targets the same antigen. In another or further embodiment of any of the foregoing, at least one SIR polypeptide of the plurality has a different binding affinity for an antigen than at least one other SIR polypeptide. In another or further embodiment of any of the foregoing, the immune cell further comprises at least one chimeric antigen receptor (CAR) polypeptide. In another or further embodiment of any of the foregoing, the antigen-binding domain of the SIR polypeptide targets a different antigen than the antigen-binding domain of the CAR polypeptide. In another or further embodiment of any of the foregoing, the CAR polypeptide has an intracellular signaling domain that includes a costimulatory signaling domain but not the first signaling domain, or an intracellular signaling domain that includes the first signaling domain but not the costimulatory signaling domain. In alternative or further embodiments of any of the foregoing, the CAR polypeptide has a costimulatory signaling domain that comprises a functional signaling domain of a protein selected from the group consisting of 4-1BB, CD28, CD27, or OX-40, or the CAR polypeptide has a first signaling domain that comprises a functional signaling domain of CD3ζ.In another or further embodiment of any of the foregoing, the CAR polypeptide is an inhibitory CAR polypeptide, the inhibitory CAR polypeptide having the antigen-binding domain, transmembrane domain, and intracellular domain of an inhibitory molecule, the inhibitory molecule being selected from the group consisting of PD1, PD-L1, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, TGFRβ, CEACAM-1, CEACAM-3, and CEACAM-5. In another or further embodiment of any of the foregoing, the CAR polypeptide further has an intracellular signaling domain and / or an intracellular signaling domain comprising a first signaling domain, the intracellular signaling domain comprising a first signaling domain comprising a functional domain of CD3ζ and a costimulatory signaling domain comprising a functional domain of 4-1BB and / or CD28. In another or further embodiment of any of the foregoing, the CAR polypeptide has the amino acid sequence of SEQ ID NO:3077 to SEQ ID NO:3083. In alternative or further embodiments of any of the foregoing, the immune effector cells are optionally human T cells, human NKT cells, or synthetic T cells, or stem cells capable of generating immune effector cells, and the T cells are diacylglycerol kinase (DGK) and / or Ikaros deficient and / or Brd4 deficient.

[0020] The present disclosure provides methods for generating SIR-expressing immune effector cells, the methods comprising introducing at least one vector of the present disclosure or at least one recombinant polynucleotide of the present disclosure into immune effector cells, or hematopoietic stem or progenitor cells capable of developing into immune effector cells, under conditions in which the SIR polypeptide is expressed. In alternative or further embodiments of any of the foregoing, the methods further comprise the steps of: a) providing a population of immune effector cells; and b) depleting restricted T cells from the population, thereby providing restricted T-depleted cells, wherein steps a) and b) are performed prior to introducing the vector or recombinant polynucleotide encoding the SIR into the population. In alternative or further embodiments of any of the foregoing, the restricted T cells are depleted from the cell population using an anti-CD25 antibody or an anti-GITR antibody. In alternative or further embodiments of any of the foregoing, the method further comprises the steps of: a) providing a population of immune effector cells; and b) enriching the population for P-glycoprotein (P-gp or Pgp, MDR1, ABCB1, CD243) positive cells, thereby providing a population of P-glycoprotein (P-gp or Pgp, MDR1, ABCB1, CD243) enriched cells, wherein steps a) and b) are performed before or after introducing a vector or recombinant polynucleotide encoding the SIR.In another or further embodiment of any of the foregoing, the P-glycoprotein positive cells are identified by: i) immunoselection using one or more of a cocktail of steps specific for P-glycoprotein; ii) staining with one or more fluorescent dyes that are substrates of P-glycoprotein, such as tetramethylrhodamine methyl ester (TMRM), adriamycin, and actinomycin D, under conditions in which P-glycoprotein is active as a pump, to enrich for cells that are poorly stained by the dyes; and iii) staining with a phototoxic compound that is a substrate of P-glycoprotein, such as TH9402, 2-(4,5-dibromo-6-amino-3-imino-3H-xanthen-9-yl)benzoic acid methyl ester hydrochloride, or 2-(4,5-dibromo-6-amino-3-imino-3H-xanthen-9-yl)benzoic acid ethyl ester salt. and iv) selection of cells resistant to any one or more of 2-(4,5-dibromo-6-amino-3-imino-3H-xanthen-9-yl)benzoic acid n-butyl ester hydrochloride, 2-(4,5-dibromo-6-amino-3-imino-3H-xanthen-9-yl)benzoic acid n-butyl ester hydrochloride, 2-(6-ethylamino-3-ethylimino-3H-xanthen-9-yl)benzoic acid n-butyl ester hydrochloride, or derivatives thereof, or combinations thereof; and iv) selection of cells resistant to cytotoxic compounds that are substrates of P-glycoprotein, such as vincristine, vinblastine, taxol, paclitaxel, mitoxantrone, etoposide, adriamycin, daunorubicin, and actinomycin D.

[0021] The present disclosure provides methods for generating a population of RNA-modified cells, the methods comprising introducing in vitro transcribed RNA(s) or synthetic RNA(s) into a cell or population of cells, wherein the RNA(s) comprise a recombinant polynucleotide(s) described herein.

[0022] The present disclosure provides a method of providing disease-fighting immunity to a subject, the method comprising administering to the subject an effective amount of immune effector cells or stem cells capable of generating immune effector cells of the disclosure, wherein the cells are autologous T cells, allogeneic T cells, autologous NKT cells, allogeneic NKT cells, autologous or allogeneic hematopoietic stem cells, or autologous or allogeneic iPSCs capable of generating immune effector cells. In one embodiment, the allogeneic T cells or allogeneic NK cells lack or have reduced expression of a functional TCR or functional HLA.

[0023] The present disclosure provides compositions comprising immune effector cells or stem cells capable of generating immune effector cells having one or more synthetic immune receptors (SIRs), for use in combination with an agent that increases the efficacy of the immune effector cells in treating a subject having a disease associated with expression of a disease-associated antigen, or in preventing a disease in a subject at increased risk for the disease associated with expression of a disease-associated antigen, wherein (i) the SIR molecules comprise one or more T cell receptor constant chains linked, via an optional linker, to one or more antigen-binding domains that bind to the disease-associated antigen, and The immune-associated antigens are CD5, CD19; CD123; CD22; CD30; CD171; CS-1 (CD2 subset 1, also known as CRACC, SLAMF7, CD319, and 19A24); C-type lectin-like molecule 1 (CLL-1 or CLECL1); CD33; epidermal growth factor receptor variant III (EGFRviii); ganglioside G2 (GD2); ganglioside GD3 (aNeu5Ac(2-8)aNeu5Ac(2-3)bDGalp(1-4)bDGlcp(1-1)Cer); TNF receptor family member B cell maturation (BCMA); Tn antigen ((Tn Ag) or (GalNAcα-Ser / Thr); prostate-specific membrane antigen (PSMA); receptor tyrosine kinase-like orphan receptor 1 (ROR1); FMS-like tyrosine kinase 3 (FLT3); tumor-associated glycoprotein 72 (TAG72); CD38; CD44v6; glycosylated CD43 epitope expressed in acute leukemia or lymphoma but not in hematopoietic progenitor cells, glycosylated CD43 epitope expressed in non-hematopoietic cancers; carcinoembryonic antigen (CEA); epithelial cell adhesion molecule (EPCAM); B7H3 (CD 276); KIT (CD117); interleukin-13 receptor subunit alpha 2 (IL-13Ra2 or CD213A2); mesothelin; interleukin-11 receptor alpha (IL-11Ra); 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-β); stage-specific fetal antigen 4 (SSEA-4); CD20; folate receptor alpha;Receptor tyrosine protein kinase ERBB2 (Her2 / neu); mucin 1, cell surface associated (MUC1); epidermal growth factor receptor (EGFR); neural cell adhesion molecule (NCAM); prostase; prostatic acid phosphatase (PAP); elongation factor 2 mutated (ELF2M); ephrin B2; fibroblast activation protein α (FAP); insulin-like growth factor 1 receptor (IGF-1 receptor), carbonic anhydrase IX (CAIX); proteasome (prosome, macropain) subunit, beta type 9 (LMP2); glycoprotein 100 (gp100); cleavage-prone Oncogene fusion protein (bcr-abl) consisting of the BCR region and Abelson murine leukemia viral oncogene homolog 1 (Abl); tyrosinase; ephrin type A receptor 2 (EphA2); fucosyl-GM1; sialyl Lewis adhesion molecule (sLe); ganglioside GM3 (aNeu5Ac(2-3)bClalp(1-4)bDGlcp(1-1)Cer); transglutaminase 5 (TGS5); high-molecular-weight melanoma-associated antigen (HMWMAA); O-acetyl-GD2 ganglioside (OAcGD2); tumor endothelial marker 1 (TEM1 / CD248) ); tumor endothelial marker 7-related (TEM7R); claudin 6 (CLDN6); thyroid-stimulating hormone receptor (TSHR); G protein-coupled receptor class C group 5 member D (GPRC5D); chromosome X open reading frame 61 (CXORF61); CD97; CD179a; anaplastic lymphoma kinase (ALK); polysialic acid; placenta-specific 1 (PLAC1); hexasaccharide moiety of globo-H glycoceramide (GloboH); mammary differentiation antigen (NY-BR-1); uroplakin 2 (UPK2); hepatitis A virus cellular receptor 1 (HAVCR1); Ad renal receptor beta 3 (ADRB3), pannexin 3 (PANX3); G protein-coupled receptor 20 (GPR20), lymphocyte antigen 6 complex locus K9 (LY6K), olfactory receptor 51E2 (OR51E2); TCRγ alternative reading frame protein (TARP); Wilms tumor protein (WT1); cancer / testis antigen 1 (NY-ES0-1); cancer / testis 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);X antigen family member 1A (XAGE1); angiopoietin-binding cell surface receptor 2 (Tie2); melanoma cancer testis antigen 1 (MAD-CT-1); melanoma cancer testis antigen 2 (MAD-CT-2); Fos-related antigen 1; tumor protein p53 (p53); p53 mutant; prostein; survivin; telomerase; prostate carcinoma antigen 1 (PCT A-1 or galectin-8), melanoma antigen 1 recognized by T cells (MelanA or MARTI); rat sarcoma (Ras) mutant; human telomerase reverse transcriptase (hTERT); sarcoma translocation breakpoint; melanoma inhibitor of apoptosis (ML-IAP); ERG (transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene); N-acetylglucosaminyltransferase V (NA17); paired box protein Pax-3 (PAX3); androgen receptor; cyclin B1; neuroblastoma-derived homolog of v-myc avian myelocytomatosis viral oncogene (MYCN); Ras homolog family member C (RhoC); tyrosinase-related protein 2 (TRP-2); cytochrome P4501B1 (CYP1B1); CCCTC-binding factor (zinc finger protein)-like (BORIS or Brother of the Regulator of Imprinted Sites), squamous cell carcinoma antigen 3 recognized by T cells (SART3); paired box protein Pax-5 (PAX5); proacrosin-binding protein sp32 (OY-TES1); lymphocyte-specific protein tyrosine kinase (LCK); A-kinase anchor protein 4 (AKAP-4); synovial sarcoma, X-breakpoint 2 (SSX2); receptor for advanced glycation end products (RAGE-1); renal ubiquitous 1 (RU1); renal ubiquitous 2 (RU2); legumain; human papillomavirus E6 (HPV E6); human papillomavirus E7 (HPV E7); intestinal carboxylesterase; heat shock protein 70-2 mutant (mut hsp 70-2); CD79a; CD79b; CD72; leukocyte-associated immunoglobulin-like receptor 1 (LAIR1): Fc fragment of IgA receptor (FCAR or CD89); leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2); CD300 molecule-like family member f (CD300LF);C-type lectin domain family 12 member A (CLEC12A); bone marrow stromal cell antigen 2 (BST2); EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2); lymphocyte antigen 75 (LY75); glypican 3 (GPC3); Fc receptor-like 5 (FCRL5); and immunoglobulin lambda-like polypeptide 1 (IGLL1), MPL, biotin, c-MYC epitope tag, CD34, LAMP1 TROP2, GFRalpha4, CDH17, CDH6, NYBR1, CDH19, CD200R, Slea (CA19.9);Sialyl Lewis antigen) fucosyl GM1, PTK7, gpNMB, CDH1-CD324, DLL3, CD276 / B7H3, IL11Ra, IL13Ra2, CD179b-IGL11, ALK, TCRγδ, NKG2D, CD32 (FCGR2A), CSPG4-HMW-MAA, Timl- / HVCR1, CSF2RA (GM-CSFRα), TGFβR2, VEGFR2 / KDR, Lewis antigen, TCRβ chain, TCRβ2 chain, TCRγ chain, TCRδ chain, FITC, luteinizing hormone receptor (LHR), follicle-stimulating hormone receptor (FSHR), chorionic gonadotropin receptor (CGHR), CCR4, SLAMF6, SLAMF4, HIV1 envelope glycoprotein, HTLV-1-Tax, CMV pp65, EBV-EBNA3c, influenza A hemagglutinin (HA), GAD, PDL1, guanylyl cyclase C (GCC), KSHV-K8.1 protein, KSHV-gH protein, autoantibodies to desmoglein 3 (Dsg3), autoantibodies to desmoglein 1 (Dsg1), 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, claudin 18.2 (CLD18A2 or CLDN18A.2), P-glycoprotein, STEAP1, LIV1, NECTIN-4, CRIPTO, GPA33, BST1 / CD157, small conductance chloride channel, and an antigen recognized by a TNT antibody, wherein (ii) the agent for increasing the effect of said immune cells is selected from the group consisting of a protein phosphatase inhibitor, a kinase inhibitor (e.g., a P13K / AKT inhibitor, an mTOR inhibitor, an LCK inhibitor, or a BTK inhibitor), a cytokine, an inhibitor of an immunosuppressive molecule, and T; REGThe agent is selected from one or more of: an agent that reduces the level or activity of SIR-modified cells; an agent that increases the proliferation and maintenance of SIR-modified cells; a chemokine; an agent that increases the expression of SIR; an agent that enables modulation of the expression or activity of SIR; an agent that enables control of the survival and / or maintenance of SIR-modified cells; an agent that controls the side effects of SIR-modified cells; a Brd4 inhibitor; an agent that delivers a therapeutic agent (e.g., sHVEM) or a prophylactic agent to the site of the disease; an agent that increases the expression of an antigen targeted by SIR; and an adenosine A2a receptor antagonist.

[0024] The present disclosure provides a method for treating or preventing a disease associated with expression of a disease-associated antigen in a subject, the method comprising administering to the subject an effective amount of immune effector cells having synthetic immune receptor (SIR) molecules in combination with an agent that enhances the effectiveness of the immune cells, wherein (i) the SIR molecules have one or more T cell receptor constant chains linked, via an optional linker, to one or more antigen-binding domains that bind to the disease-associated antigen, the disease-associated antigen being selected from the group consisting of CD5, CD19; CD123; CD22; CD30; ; CD171; CS-1 (CD2 subset 1, also known as CRACC, SLAMF7, CD319, and 19A24); C-type lectin-like molecule 1 (CLL-1 or CLECL1); CD33; epidermal growth factor receptor variant III (EGFRviii); ganglioside G2 (GD2); ganglioside GD3 (aNeu5Ac(2-8)aNeu5Ac(2-3)bDGalp(1-4)bDGlcp(1-1)Cer); TNF receptor family member B cell maturation (BCMA); Tn antigen ((Tn Ag) or (GalNAcα-Ser / Thr); prostate-specific membrane antigen (PSMA); receptor tyrosine kinase-like orphan receptor 1 (ROR1); FMS-like tyrosine kinase 3 (FLT3); tumor-associated glycoprotein 72 (TAG72); CD38; CD44v6; glycosylated CD43 epitope expressed in acute leukemia or lymphoma but not in hematopoietic progenitor cells, glycosylated CD43 epitope expressed in non-hematopoietic cancers; carcinoembryonic antigen (CEA); epithelial cell adhesion molecule (EPCAM); B7H3 (CD276); KIT (CD117); interleukin-13 receptor subunit alpha 2 ( IL-13Ra2 or CD213A2); mesothelin; interleukin-11 receptor alpha (IL-11Ra); 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-β); stage-specific embryonic antigen 4 (SSEA-4); CD20; folate receptor alpha; receptor tyrosine protein kinase ERBB2 (Her2 / neu); mucin 1, cell surface associated (MUC1); epidermal growth factor receptor (EGFR); neural cell adhesion molecule (NCAM);Prostase; prostatic acid phosphatase (PAP); elongation factor 2 mutated (ELF2M); ephrin B2; fibroblast activation protein alpha (FAP); insulin-like growth factor 1 receptor (IGF-1 receptor); carbonic anhydrase IX (CAIX); proteasome (prosome, macropain) subunit, beta type 9 (LMP2); glycoprotein 100 (gp100); oncogene fusion protein (bcr-abl) consisting of a cleavage-prone region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (Abl); tyrosinase; ephrin type A receptor 2 (EphA2); fucosyl GM1; sialyl Lewis adhesion molecule (sLe); ganglioside GM3 (aNeu5Ac(2-3)bClalp(1-4)bDGlcp(1-1)Cer); transglutaminase 5 (TGS5); high molecular weight melanoma-associated antigen (HMWMAA); O-acetyl-GD2 ganglioside (OAcGD2); folate receptor β; tumor endothelial marker 1 (TEM1 / CD248); tumor endothelial marker 7-related (TEM7R); claudin 6 (CLDN6); thyroid-stimulating hormone receptor (TSHR); G protein-coupled receptor class C Loop 5 member D (GPRC5D); chromosome X open reading frame 61 (CXORF61); CD97; CD179a; anaplastic lymphoma kinase (ALK); polysialic acid; placenta-specific 1 (PLAC1); hexasaccharide moiety of globo-H glycoceramide (GloboH); mammary differentiation antigen (NY-BR-1); uroplakin 2 (UPK2); hepatitis A virus cellular receptor 1 (HAVCR1); adrenergic receptor β3 (ADRB3), pannexin 3 (PANX3); G protein-coupled receptor 20 (GPR20), lymphocyte antigen 6 complex gene Locus K9 (LY6K), olfactory receptor 51E2 (OR51E2); TCRγ alternative reading frame protein (TARP); Wilms tumor protein (WT1); cancer / testis antigen 1 (NY-ES0-1); cancer / testis 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); X antigen family member 1A (XAGE1); angiopoietin-binding cell surface receptor 2 (Tie2); melanoma cancer-testis antigen 1 (MAD-CT-1);Melanoma cancer testis antigen 2 (MAD-CT-2); Fos-related antigen 1; tumor protein p53 (p53); p53 mutant; prostein; survivin; telomerase; prostate carcinoma antigen 1 (PCT A-1 or galectin-8), melanoma antigen 1 recognized by T cells (MelanA or MARTI); rat sarcoma (Ras) mutant; human telomerase reverse transcriptase (hTERT); sarcoma translocation breakpoint; melanoma inhibitor of apoptosis (ML-IAP); ERG (transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene); N-acetylglucosaminyltransferase V (NA17); paired box protein Pax-3 (PAX3); androgen receptor; cyclin B1; neuroblastoma-derived homolog of v-myc avian myelocytomatosis viral oncogene (MYCN); Ras homolog family member C (RhoC); tyrosinase-related protein 2 (TRP-2); cytochrome P4501B1 (CYP1B1); CCCTC-binding factor (zinc finger protein)-like (BORIS or Brother of the Regulator of Imprinted Sites), squamous cell carcinoma antigen 3 recognized by T cells (SART3); paired box protein Pax-5 (PAX5); proacrosin-binding protein sp32 (OY-TES1); lymphocyte-specific protein tyrosine kinase (LCK); A-kinase anchor protein 4 (AKAP-4); synovial sarcoma, X-breakpoint 2 (SSX2); receptor for advanced glycation end products (RAGE-1); renal ubiquitous 1 (RU1); renal ubiquitous 2 (RU2); legumain; human papillomavirus E6 (HPV E6); human papillomavirus E7 (HPV E7); intestinal carboxylesterase; heat shock protein 70-2 mutant (mut hsp 70-2); CD79a; CD79b; CD72; leukocyte-associated immunoglobulin-like receptor 1 (LAIR1): Fc fragment of IgA receptor (FCAR or CD89); leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2); CD300 molecule-like family member f (CD300LF); C-type lectin domain family 12 member A (CLEC12A); bone marrow stromal cell antigen 2 (BST2); EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2);Lymphocyte antigen 75 (LY75); glypican 3 (GPC3); Fc receptor-like 5 (FCRL5); and immunoglobulin lambda-like polypeptide 1 (IGLL1), MPL, biotin, c-MYC epitope tag, CD34, LAMP1 TROP2, GFRalpha4, CDH17, CDH6, NYBR1, CDH19, CD200R, Slea (CA19.9; sialyl Lewis antigen) fucosyl GM1, PTK7, gpNMB, CDH1-CD324, DLL3, CD276 / B7H3, IL11Ra, IL13Ra2, CD179b-IGL11, ALK TCRγδ, NKG2D, CD32 (FCGR2A), CSPG4-HMW-MAA, Timl- / HVCR1, CSF2RA (GM-CSFRα), TGFβR2, VEGFR2 / KDR, Lewis Ag, TCRβ chain, TCRβ2 chain, TCRγ chain, TCRδ chain, FITC, luteinizing hormone receptor (LHR), follicle-stimulating hormone receptor (FSHR), chorionic gonadotropin receptor (CGHR), CCR4, SLAMF6, SLAMF4, HIV1 envelope glycoprotein, HTLV-1-Tax, CMV pp65, EBV-EBNA3c, influenza A hemagglutinin (HA), GAD, PDL1, guanylyl cyclase C (GCC), KSHV-K8.1 protein, KSHV-gH protein, autoantibodies to desmoglein 3 (Dsg3), autoantibodies to desmoglein 1 (Dsg1), 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 (ii) the agent for increasing the effect of the immune cells is selected from the group consisting of an antigen recognized by G12V, tissue factor 1 (TF1), AFP, GPRC5D, claudin 18.2 (CLD18A2 or CLDN18A.2), P-glycoprotein, STEAP1, LIV1, NECTIN-4, CRIPTO, GPA33, BST1 / CD157, a small conductance chloride channel, and a TNT antibody; and (iii) the agent for increasing the effect of the immune cells is selected from the group consisting of a protein phosphatase inhibitor, a kinase inhibitor (e.g., a P13K / AKT inhibitor, an mTOR inhibitor, an LCK inhibitor, or a BTK inhibitor), a cytokine, an inhibitor of an immunosuppressive molecule, and T; REGThe therapeutic agent is selected from one or more of an agent that reduces the level or activity of SIR-modified cells, an agent that increases the proliferation and maintenance of SIR-modified cells, a chemokine, an agent that increases the expression of SIR, an agent that enables modulation of the expression or activity of SIR, an agent that enables control of the survival and / or maintenance of SIR-modified cells, an agent that controls the side effects of SIR-modified cells, a Brd4 inhibitor, an agent that delivers a therapeutic agent (e.g., sHVEM) or a prophylactic agent to the site of the disease, an agent that increases the expression of an antigen targeted by SIR, and an adenosine A2a receptor antagonist, thereby treating the subject or preventing disease in the subject.

[0025] The present disclosure provides a method for treating or preventing a disease associated with expression of a disease-associated antigen in a subject, the method comprising administering to the subject an effective amount of immune effector cells comprising a synthetic immune receptor (SIR) molecule, wherein (i) the SIR molecule comprises one or more T cell receptor constant chains linked, via an optional linker, to one or more antigen-binding domains that bind to the disease-associated antigen, wherein the disease-associated antigens include CD5, CD19; CD123; CD22; CD23; CD30; CD171; CS -1 (CD2 subset 1, also known as CRACC, SLAMF7, CD319, and 19A24); C-type lectin-like molecule 1 (CLL-1 or CLECL1); CD33; epidermal growth factor receptor variant III (EGFRviii); ganglioside G2 (GD2); ganglioside GD3 (aNeu5Ac(2-8)aNeu5Ac(2-3)bDGalp(1-4)bDGlcp(1-1)Cer); TNF receptor family member B cell maturation (BCMA); Tn antigen ((Tn Ag) or (GalNAcα-Ser / Thr); prostate-specific membrane antigen (PSMA); receptor tyrosine kinase-like orphan receptor 1 (ROR1); FMS-like tyrosine kinase 3 (FLT3); tumor-associated glycoprotein 72 (TAG72); CD38; CD44v6; glycosylated CD43 epitope expressed in acute leukemia or lymphoma but not in hematopoietic progenitor cells, glycosylated CD43 epitope expressed in non-hematopoietic cancers; carcinoembryonic antigen (CEA); epithelial cell adhesion molecule (EPCAM); B7H3 (CD276); KIT (CD117); interleukin-13 receptor subunit alpha 2 (IL-1 3Ra2 or CD213A2); mesothelin; interleukin-11 receptor alpha (IL-11Ra); 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-β); stage-specific embryonic antigen 4 (SSEA-4); CD20; folate receptor alpha (FRa or FR1); folate receptor beta (FRb); receptor tyrosine protein kinase ERBB2 (Her2 / neu); mucin 1, cell surface associated (MUC1); epidermal growth factor receptor (EGFR);Neural cell adhesion molecule (NCAM); prostase; prostatic acid phosphatase (PAP); elongation factor 2 mutated (ELF2M); ephrin B2; fibroblast activation protein alpha (FAP); insulin-like growth factor 1 receptor (IGF-1 receptor), carbonic anhydrase IX (CAIX); proteasome (prosome, macropain) subunit, beta type 9 (LMP2); glycoprotein 100 (gp100); oncogene fusion protein (bcr-abl) consisting of a cleavage-prone region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (Abl); tyrosine enzymes; ephrin type A receptor 2 (EphA2); fucosyl GM1; sialyl Lewis adhesion molecule (sLe); ganglioside GM3 (aNeu5Ac(2-3)bClalp(1-4)bDGlcp(1-1)Cer); transglutaminase 5 (TGS5); high molecular weight melanoma-associated antigen (HMWMAA); O-acetyl-GD2 ganglioside (OAcGD2); tumor endothelial marker 1 (TEM1 / CD248); tumor endothelial marker 7-related (TEM7R); claudin 6 (CLDN6); thyroid-stimulating hormone receptor (TSHR); G protein-coupled receptor cleavage RasC group 5 member D (GPRC5D); chromosome X open reading frame 61 (CXORF61); CD97; CD179a; anaplastic lymphoma kinase (ALK); polysialic acid; placenta-specific 1 (PLAC1); hexasaccharide moiety of globo-H glycoceramide (GloboH); mammary differentiation antigen (NY-BR-1); uroplakin 2 (UPK2); hepatitis A virus cellular receptor 1 (HAVCR1); adrenergic receptor β3 (ADRB3), pannexin 3 (PANX3); G protein-coupled receptor 20 (GPR20), lymphocyte antigen 6 complex gene Locus K9 (LY6K), olfactory receptor 51E2 (OR51E2); TCRγ alternative reading frame protein (TARP); Wilms tumor protein (WT1); cancer / testis antigen 1 (NY-ES0-1); cancer / testis 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); X antigen family member 1A (XAGE1); angiopoietin-binding cell surface receptor 2 (Tie2); melanoma cancer-testis antigen 1 (MAD-CT-1);Melanoma cancer testis antigen 2 (MAD-CT-2); Fos-related antigen 1; tumor protein p53 (p53); p53 mutant; prostein; survivin; telomerase; prostate carcinoma antigen 1 (PCT A-1 or galectin-8), melanoma antigen 1 recognized by T cells (MelanA or MARTI); rat sarcoma (Ras) mutant; human telomerase reverse transcriptase (hTERT); sarcoma translocation breakpoint; melanoma inhibitor of apoptosis (ML-IAP); ERG (transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene); N-acetylglucosaminyltransferase V (NA17); paired box protein Pax-3 (PAX3); androgen receptor; cyclin B1; neuroblastoma-derived homolog of v-myc avian myelocytomatosis viral oncogene (MYCN); Ras homolog family member C (RhoC); tyrosinase-related protein 2 (TRP-2); cytochrome P4501B1 (CYP1B1); CCCTC-binding factor (zinc finger protein)-like (BORIS or Brother of the Regulator of Imprinted Sites), squamous cell carcinoma antigen 3 recognized by T cells (SART3); paired box protein Pax-5 (PAX5); proacrosin-binding protein sp32 (OY-TES1); lymphocyte-specific protein tyrosine kinase (LCK); A-kinase anchor protein 4 (AKAP-4); synovial sarcoma, X-breakpoint 2 (SSX2); receptor for advanced glycation end products (RAGE-1); renal ubiquitous 1 (RU1); renal ubiquitous 2 (RU2); legumain; human papillomavirus E6 (HPV E6); human papillomavirus E7 (HPV E7); intestinal carboxylesterase; heat shock protein 70-2 mutant (mut hsp 70-2); CD79a; CD79b; CD72; leukocyte-associated immunoglobulin-like receptor 1 (LAIR1): Fc fragment of IgA receptor (FCAR or CD89); leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2); CD300 molecule-like family member f (CD300LF); C-type lectin domain family 12 member A (CLEC12A); bone marrow stromal cell antigen 2 (BST2); EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2);Lymphocyte antigen 75 (LY75); glypican 3 (GPC3); Fc receptor-like 5 (FCRL5); and immunoglobulin lambda-like polypeptide 1 (IGLL1), MPL, biotin, c-MYC epitope tag, CD34, LAMP1 TROP2, GFRalpha4, CDH17, CDH6, NYBR1, CDH19, CD200R, Slea (CA19.9; sialyl Lewis antigen) fucosyl GM1, PTK7, gpNMB, CDH1-CD324, DLL3, CD276 / B7H3, IL11Ra, IL13Ra2, CD179b-IGL11, TCRγδ, NKG2D, CD32 (FCGR2A), Timl- / HVCR1, CS F2RA (GM-CSFRα), TGFβR2, Lewis Ag, TCRβ chain, TCRβ2 chain, TCRγ chain, TCRδ chain, FITC, luteinizing hormone receptor (LHR), follicle-stimulating hormone receptor (FSHR), chorionic gonadotropin receptor (CGHR), CCR4, SLAMF6, SLAMF4, HIV1 envelope glycoprotein, HTLV1-Tax, CMVpp65, EBV-EBNA3c, KSHV K8.1, KSHV-gH, influenza A hemagglutinin (HA), GAD, PDL1, guanylyl cyclase C (GCC), KSHV-K8.1 protein, KSHV-gH protein, autoantibodies to desmoglein 3 (Dsg3), autoantibodies to desmoglein 1 (Dsg1), 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 selected from the group consisting of antigens recognized by G12V, tissue factor 1 (TF1), AFP, GPRC5D, claudin 18.2 (CLD18A2 or CLDN18A.2), P-glycoprotein, STEAP1, LIV1, NECTIN-4, CRIPTO, GPA33, BST1 / CD157, small conductance chloride channel, and TNT antibodies, and (ii) the antigen-binding domain of the SIR molecule has a binding affinity that is at least 5-fold less than that of the antibody to which the antigen-binding domain is derived;

[0026] In another or further embodiment of any of the aforementioned methods or uses, the disease associated with expression of the disease-associated antigen is selected from the group consisting of a hyperplasia, a precancerous condition, a cancer, and a non-cancer related indication associated with said disease-associated expression. In another or further embodiment of any of the aforementioned methods or uses, the cancer is selected from the group consisting of chronic lymphocytic leukemia (CLL), acute leukemia, acute lymphocytic leukemia (ALL), B-cell acute lymphocytic leukemia (B-ALL), T-cell acute lymphocytic leukemia (T-ALL), chronic myeloid leukemia (CML), B-cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt's lymphoma, diffuse large B-cell lymphoma, primary effusion lymphoma, and the like. and hematological malignancies selected from one or more of: myeloma, follicular lymphoma, hairy cell lymphoma, small cell or large cell follicular lymphoma, malignant lymphoproliferative conditions, MALT lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndromes, non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom's macroglobulinemia, and preleukemia. In another or further embodiment of any of the aforementioned methods or uses, the cancer is selected from the group consisting of colon cancer, rectal cancer, renal cell carcinoma, liver cancer, non-small cell lung cancer, small intestine cancer, esophageal cancer, melanoma, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, endocrine The cancer is selected from the group consisting of: cancer of the bladder, cancer of the kidney or ureter, cancer of the renal pelvis, tumors of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, Merkel cell carcinoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancers, combinations of the above cancers, and metastases of the above cancers.In another or further embodiment of any of the aforementioned methods or uses, the disease is associated with a viral infection, including but not limited to, HIV1, HIV2, HTLV1, Epstein-Barr virus (EBV), cytomegalovirus, adenovirus, adeno-associated virus, BK virus, human herpesvirus 6, human herpesvirus 8, influenza virus, parainfluenza virus, avian influenza virus, MERS and SARS coronavirus, Crimean-Congo hemorrhagic fever virus, rhinovirus, enterovirus, dengue virus, West Nile virus These include Ebola virus, Marburg virus, Lassa fever virus, Zika virus, RSV, measles virus, mumps virus, rhinovirus, varicella virus types 1 and 2, varicella-zoster virus, HIV-1, HTLV-1, hepatitis viruses, enteroviruses, hepatitis B virus, hepatitis C virus, Nipah and Rift Valley fever virus, Japanese encephalitis virus, viruses associated with Merkel cell polyomavirus or Mycobacterium tuberculosis infection, atypical mycobacterial species, Pneumocystis jiroveci, toxoplasmosis, Rickettscherichia, Nocardia, Aspergillus, Mucor, and Candida. In alternative or further embodiments of any of the aforementioned methods or uses, the disease is an immune disease or a degenerative disease, including but not limited to diabetes mellitus, multiple sclerosis, rheumatoid arthritis, pemphigus vulgaris, ankylosing spondylitis, Hashimoto's thyroiditis, SLE, sarcoidosis, scleroderma, mixed connective tissue disease, graft-versus-host disease, and Alzheimer's disease.In another or further embodiment of any of the aforementioned methods or uses, (i) the protein phosphatase inhibitor is an SHP-1 inhibitor and / or an SHP-2 inhibitor; (ii) the kinase inhibitor is selected from one or more of a CDK4 inhibitor, a CDK4 / 6 inhibitor, an mTOR inhibitor, an MNK inhibitor, and a dual P13K / mTOR inhibitor; and (iii) the agent that inhibits an immunosuppressive factor is an antibody or antibody fragment, an inhibitory nucleic acid, a clustered, regularly spaced, short (iv) the agent that reduces the level or activity of TREG cells is selected from cyclophosphamide, an anti-GITR antibody, CD25 depletion, or a combination thereof; and / or (v) the Brd4 inhibitor is selected from JQ1, MS417, OTXO15, LY303511, and a Brd4 inhibitor described in U.S. Patent No. 20140256706A1, or a derivative thereof. In another or further embodiment of any of the aforementioned methods or uses, the immunosuppressant is selected from the group consisting of PD1, PD-L1, CTLA-4, TIM-3, LAG-3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, TGFRβ, CEACAM-1, CEACAM-3, and CEACAM-5. In another or further embodiment of any of the aforementioned methods or uses, the agent that inhibits the inhibitory molecule comprises a first polypeptide comprising the inhibitory molecule or a fragment thereof and a second polypeptide that provides a positive signal to a cell, wherein the first and second polypeptides are expressed on the SIR-containing immune cell, and (i) the first polypeptide is PD1, PD-L1, CTLA-4, TIM-3, LAG-3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, TGFRβ, CEACAM-1, CEACAM-3, and CEACAM-5, or a fragment thereof, and / or the second polypeptide has an intracellular signaling domain comprising a first signaling domain and / or a costimulatory signaling domain.In another or further embodiment of any of the aforementioned methods or uses, the first signaling domain comprises a functional domain of CD3ζ, and / or the costimulatory signaling domain comprises a functional domain of a protein selected from 41BB, CD27, and CD28. In another or further embodiment of any of the aforementioned methods or uses, the cytokine is selected from IL-15 and / or IL-21. In another or further embodiment of any of the aforementioned methods or uses, the immune effector cells comprising the SIR molecule(s) and the agent that enhances the efficacy of the immune effector cells are administered substantially simultaneously or sequentially. In another or further embodiment of any of the aforementioned methods or uses, the SIR molecule is administered in combination with a molecule that targets GITR and / or a molecule that modulates GITR function. In another or further embodiment of any of the aforementioned methods or uses, the molecule that targets GITR and / or the molecule that modulates GITR function is administered prior to the SIR-expressing cells or cell population or prior to apheresis. In another or further embodiment of any of the aforementioned methods or uses, the subject is a human.

[0027] The present disclosure also provides a composition having at least one polynucleotide of this disclosure, a SIR polypeptide molecule of this disclosure, a vector of this disclosure, or a cell of this disclosure, and a pharmaceutically acceptable excipient.

[0028] The present disclosure also provides kits having at least one polynucleotide of this disclosure, a SIR polypeptide molecule of this disclosure, a vector of this disclosure or a cell of this disclosure, and / or a composition of this disclosure.

[0029] The present disclosure relates to a method for producing a nucleic acid fragment having a sequence selected from the group consisting of SEQ ID NOs: 900-2264, 4531-6013, 7519-8160, 8803-9230, 9659-9856, 10474-12041, 15786-16011, 16240-16465, 16694-16926, 17162-17394, 17864-17979, 18321-18322, 18242-18259, 18280-18588, 18899, and 18915-18916, or SEQ ID NOs: 900-2264, 4531-6013, Also provided is a recombinant polynucleotide encoding a synthetic immunoreceptor having a sequence at least 75% identical to a nucleotide sequence encoding a synthetic immunoreceptor set forth in any one of SEQ ID NOs: 7519-8160, 8803-9230, 9659-9856, 10474-12041, 15786-16011, 16240-16465, 16694-16926, 17162-17394, 17864-17979, 18321-18322, 18242-18259, 18280-18588, 18899, and 18915-18916.

[0030] The present disclosure provides an amino acid sequence encoding a synthetic immunoreceptor polypeptide selected from the group consisting of SEQ ID NOs: 3135-4498, SEQ ID NOs: 6044-7518, SEQ ID NOs: 8161-8802, SEQ ID NOs: 9231-9658, SEQ ID NOs: 9873-10070, SEQ ID NOs: 12431-13998, SEQ ID NOs: 16013-16238, SEQ ID NOs: 16467-16692, SEQ ID NOs: 16928-17160, SEQ ID NOs: 17396-17628, SEQ ID NOs: 17981-18096, SEQ ID NOs: 18239-18240, SEQ ID NOs: 18261-18278, SEQ ID NOs: 18590-18898, SEQ ID NO: 18900, and SEQ ID NOs: 18919-18920, or SEQ ID NO: 3 Also provided are sequences at least 75% identical to the amino acid sequence encoding the synthetic immunoreceptor polypeptides set forth in any one of SEQ ID NOs: 135-4498, 6044-7518, 8161-8802, 9231-9658, 9873-10070, 12431-13998, 16013-16238, 16467-16692, 16928-17160, 17396-17628, 17981-18096, 18239-18240, 18261-18278, 18590-18898, 18900, and 18919-18920. The present invention also relates to the following: [Item 1] at least one recombinant polynucleotide encoding at least one synthetic immunoreceptor (SIR), The at least one SIR is (a) a T cell receptor (TCR) constant chain, (i) an amino acid sequence at least 98% identical to SEQ ID NO: 3010 and having one or more mutations at positions 48, 61, 91, 92, 93 and / or 94, which may include an optional accessory module; (ii) an amino acid sequence at least 98% identical to SEQ ID NO: 3024 and having one or more mutations at positions 18, 22, 57, 79, 133, 136 and / or 139, which may include an optional accessory module; (iii) an amino acid sequence at least 98% identical to SEQ ID NO: 3025 and having one or more mutations at positions 18, 22, 57, 79, 133, 136 and / or 139, which may include an optional accessory module; (iv) an amino acid sequence at least 98% identical to SEQ ID NO: 3046, 3047, or 3048, which may include an optional accessory module; (v) an amino acid sequence at least 98% identical to SEQ ID NO: 3049, which may include an optional accessory module; (vi) an amino acid sequence at least 98% identical to SEQ ID NO: 3051 or 3052, which may include an optional accessory module; and (vii) a dimeric combination of two TCR constant chains selected from (i) and (ii), (i) and (iii), (iv) and (ii), (iv) and (iii), and (v) and (vi); a T cell receptor constant chain having an amino acid sequence selected from the group consisting of: (b) an optional linker; and (c) one or more non-native TCR antigen-binding domains linked to (a), (1) Antibodies, (2) antibody fragments (e.g., Fv, Fab, (Fab')2), (3) an antibody heavy chain variable region (vH domain) or a fragment thereof; (4) an antibody light chain variable region (vL domain) or a fragment thereof; (5) a single-chain variable fragment (scFv) or a fragment thereof; (6) Single domain antibodies (SDABs) or fragments thereof; (7) a VHH domain derived from a camelid or a fragment thereof; (8) a monomeric variable region of an antibody; (9) Non-immunoglobulin antigen-binding scaffolds, such as DARPINs, affibodies, affilins, adnectins, affitins, obodies, lipibodies, finomers, alphabodies, avimers, atrimers, centilins, pronectins, anticalins, Kunitz domains, armadillo repeat proteins, or fragments thereof; (10) a receptor or a fragment thereof; (11) a ligand or a fragment thereof; (12) Bispecific antibodies, bispecific antibody fragments, bispecific scFVs, bispecific vHHs, bispecific SDABs, bispecific non-immunoglobulin antigen-binding scaffolds, bispecific receptors, or bispecific ligands; and (13) an autoantigen or a fragment thereof; one or more non-native TCR antigen-binding domains selected from the group consisting of: Including, the variants of (a)(i) through (a)(iii) and the dimer of (a)(vii) confer diverse binding affinities of the antigen-binding domains to the target antigen, which affinities are at least 5% greater than the binding affinity of a cTCR having the same binding domain; and the synthetic immunoreceptors, when expressed in lymphocytes, express both the antigen-binding domains and the T cell receptor constant chains in one or more contiguous chains on the surface of the lymphocyte, such that, upon binding of the expressed antigen-binding domain to its antigen, the lymphocyte is triggered to activate, proliferate, secrete cytokines and / or modulate (induce or suppress) killing of target cells, and have MHC-restricted and MHC-unrestricted antibody-type specificities. Recombinant polynucleotides. [Item 2] 2. The recombinant polynucleotide of claim 1, comprising a TCR constant chain of (a)(vii), wherein the non-native TCR binding domain is: - variable regions of antibody heavy and light chains or fragments thereof specific for a predetermined target antigen, wherein, when expressed, one of the antibody heavy and light chains or fragments thereof is attached to one of the two chains of (a)(vii) of the T cell constant region, and the other of the antibody heavy and light chains or fragments thereof is attached to the other of the two chains of the T cell constant region; - two single chain variable fragments (scFvs) specific for one or more predetermined target antigens, wherein, when expressed, one of the scFvs is attached to one of the two chains of (a)(vii) of the T cell constant region and the other of the scFvs is attached to the other of the two chains of the T cell constant region; - two antibody fragments specific for one or more predetermined target antigens, wherein when expressed, one of the antibody fragments is attached to one of the two chains of (a)(vii) of the T cell constant region and the other of the antibody fragments is attached to the other of the two chains of the T cell constant region; - two single domain antibody (SDAB) fragments specific for one or more predetermined target antigens, wherein, when expressed, one of the SDAB fragments is attached to one of the two chains of (a)(vii) of the T cell constant region and the other of the SDAB fragments is attached to the other of the two chains of the T cell constant region; - two camelid-derived vHH domains specific for one or more predetermined target antigens, wherein, when expressed, one of the vHH domains is attached to one of the two chains of (a)(vii) of the T-cell constant region and the other of the vHH domains is attached to the other of the two chains of the T-cell constant region; - two non-immunoglobulin antigen-binding scaffolds specific for one or more predetermined target antigens, wherein, when expressed, one of the non-immunoglobulin antigen-binding scaffolds is attached to one of the two chains of (a)(vii) of the T-cell constant region and the other of the non-immunoglobulin antigen-binding scaffold domains is attached to the other of the two chains of the T-cell constant region; - two receptors or fragments thereof specific for one or more predetermined target antigens, wherein, when expressed, one of the receptors or fragments thereof is attached to one of the two chains of (a)(vii) of the T cell constant region and the other of the receptors or fragments thereof is attached to the other of the two chains of the T cell constant region; - two ligands or fragments thereof specific for one or more predetermined target antigens, wherein, when expressed, one of the ligands or fragments thereof is attached to one of the two chains of (a)(vii) of the T cell constant region and the other of the ligands or fragments thereof is attached to the other of the two chains of the T cell constant region; - two structurally distinct antigen-binding fragments specific for one or more predetermined target antigens, wherein, when expressed, one of the antigen-binding fragments is attached to one of the two chains of (a)(vii) of the T-cell constant region and the other of the antigen-binding fragments is attached to the other of the two chains of the T-cell constant region; two binding fragments, either or both of which are bispecific or multispecific, and when expressed, one of the antigen-binding fragments is attached to one of the two chains of (a)(vii) of the T-cell constant region and the other of the antigen-binding fragments is attached to the other of the two chains of the T-cell constant region; and two autoantigens or fragments thereof, wherein, when expressed, one of the autoantigens or fragments thereof is attached to one of the two chains of (a)(vii) of the T cell constant region and the other of the autoantigens or fragments thereof is attached to the other of the two chains of the T cell constant region; two vLs or fragments thereof, wherein, when expressed, one of the vLs or fragments thereof is attached to one of the two chains of (a)(vii) of the T cell constant region and another of the vLs or fragments thereof is attached to the other of the two chains of the T cell constant region; two vHs or fragments thereof, wherein, when expressed, one of the vHs or fragments thereof is attached to one of the two chains of (a)(vii) of the T cell constant region and the other of the vHs or fragments thereof is attached to the other of the two chains of the T cell constant region; and A recombinant polynucleotide selected from the group consisting of: [Item 3] 2. The recombinant polynucleotide of claim 1, comprising a TCR constant chain of (a)(iv), wherein the non-natural TCR binding domain is: the variable region of the heavy chain (vH) of an antibody specific for a predetermined target antigen, or a fragment thereof; the variable region of the light chain (vL) of an antibody specific for a predetermined target antigen, or a fragment thereof; a single-chain variable fragment (scFv) or a fragment thereof specific for a predetermined target antigen, - antibody fragments (e.g. Fv, Fab, (Fab')2) specific for a predetermined target antigen; - single domain (SDAB) fragments specific for a predetermined target antigen; a camelid-derived vHH domain specific for a predetermined target antigen; a non-immunoglobulin antigen-binding scaffold specific for a predetermined target antigen; a receptor or a fragment thereof specific for a predetermined target antigen; a ligand or a fragment thereof specific for a predetermined target antigen; a bispecific antibody, bispecific antibody fragment, bispecific scFV, bispecific vHH, bispecific SDAB, bispecific non-immunoglobulin antigen-binding scaffold, bispecific receptor, or bispecific ligand specific for one or more predetermined target antigens; an autoantigen or a fragment thereof, A recombinant polynucleotide selected from the group consisting of: [Item 4] 2. The recombinant polynucleotide of claim 1, comprising a polynucleotide encoding (i), (ii), (iii), (iv), (v) or (vi), wherein the non-native TCR binding domain is the variable region of the heavy chain (vH) of an antibody specific for a predetermined target antigen; the variable region of the light chain (vL) of an antibody specific for a predetermined target antigen; a single-chain variable fragment (scFv) specific for a predetermined target antigen; - antibody fragments (e.g. Fv, Fab, (Fab')2) specific for a predetermined target antigen; - single domain (SDAB) fragments specific for a predetermined target antigen; a camelid-derived vHH domain specific for a predetermined target antigen; a non-immunoglobulin antigen-binding scaffold specific for a predetermined target antigen; a receptor or a fragment thereof specific for a predetermined target antigen; a ligand or a fragment thereof specific for a predetermined target antigen; a bispecific antibody, bispecific antibody fragment, bispecific scFV, bispecific vHH, bispecific SDAB, bispecific non-immunoglobulin antigen-binding scaffold, bispecific receptor, or bispecific ligand specific for one or more predetermined target antigens; an autoantigen or a fragment thereof, A recombinant polynucleotide selected from the group consisting of: [Item 5] 2. The recombinant polynucleotide of item 1, wherein the polynucleotide encoding the TCR constant chain is a codon-optimized sequence. [Item 6] 2. The recombinant polynucleotide of Item 1, wherein the polynucleotide encoding the TCR constant chain of (a) encodes a TCR constant chain(s) that includes a mutation that improves expression and / or pairing of the TCR constant chain and a mutation that reduces pairing with an endogenous T cell receptor chain. [Item 7] 2. The recombinant polynucleotide according to Item 1, wherein the polynucleotide encoding the TCR constant chain (a) is a nucleic acid sequence that is modified by 1 to 40 of the nucleic acid sequence of SEQ ID NOs: 730 to 743 or a sequence that is at least 70% identical to the nucleic acid sequence of SEQ ID NOs: 730 to 743, and includes a sequence that can dimerize with the TCR β1 chain or the TCR β2 chain. [Item 8] 2. The recombinant polynucleotide according to Item 1, wherein the polynucleotide encoding the TCR constant chain of (b) or (c) is a nucleic acid sequence having 1 to 40 modifications of the nucleic acid sequence of SEQ ID NOs: 744 to 765 or a sequence at least 70% identical to the nucleic acid sequence of SEQ ID NOs: 744 to 765, and comprises a sequence capable of dimerizing with the TCR α chain. [Item 9] 2. The recombinant polynucleotide according to Item 1, wherein the polynucleotide encoding the TCR constant chain (v) is a nucleic acid sequence that is modified by 1 to 40 of the nucleic acid sequence of SEQ ID NOs: 769 to 770 or a sequence that is at least 70% identical to the nucleic acid sequence of SEQ ID NOs: 769 to 770, and comprises a sequence that can pair with the TCR δ chain. [Item 10] (vi) The recombinant polynucleotide according to Item 1, wherein the polynucleotide encoding the TCR constant chain is a nucleic acid sequence that is modified by 1 to 40 of the nucleic acid sequence of SEQ ID NOs: 771 to 772 or a sequence that is at least 70% identical to the nucleic acid sequence of SEQ ID NOs: 771 to 772, and comprises a sequence that can dimerize with the TCR gamma chain. [Item 11] (iv) The recombinant polynucleotide according to Item 1, wherein the polynucleotide encoding the TCR constant chain is a nucleic acid sequence that is modified by 1 to 40 of the nucleic acid sequence of SEQ ID NOs: 766 to 768 or a sequence that is at least 70% identical to the nucleic acid sequence of SEQ ID NOs: 766 to 768, and includes a sequence that can dimerize with the TCR β1 chain or the TCR β2 chain. [Item 12] The one or more non-natural TCR antigen-binding domains may be selected from the group consisting of CD19; CD123; CD22; CD30; CD171; CS-1 (CD2 subset 1, also known as CRACC, SLAMF7, CD319, and 19A24); C-type lectin-like molecule 1 (CLL-1 or CLECL1); CD33; epidermal growth factor receptor variant III (EGFRviii); ganglioside G2 (GD2); ganglioside GD3 (aNeu5Ac(2-8)aNeu5Ac(2-3)bDGalp(1-4)bDGlcp(1-1)Cer); TNF receptor family member B cell maturation (BCMA); Tn antigen ((Tn Ag) or (GalNAcα-Ser / Thr); prostate-specific membrane antigen (PSMA); receptor tyrosine kinase-like orphan receptor 1 (ROR1); FMS-like tyrosine kinase 3 (FLT3); tumor-associated glycoprotein 72 (TAG72); CD38; CD44v6; glycosylated CD43 epitope expressed in acute leukemia or lymphoma but not in hematopoietic progenitor cells, glycosylated CD43 epitope expressed in non-hematopoietic cancers; carcinoembryonic antigen (CEA); epithelial cell adhesion molecule (EPCAM); B7H3 (CD276); KIT (CD117); interleukin-13 receptor subunit alpha 2 (IL-13Ra2 or CD213A2); mesothelin; interleukin-11 receptor alpha (IL-11Ra); prostate stem cell antigen (PSCA); protease serine 21 (testis rRNA or PRSS21); vascular endothelial growth factor receptor 2 (VEGFR2); Lewis (Y) antigen; CD24; platelet-derived growth factor receptor beta (PDGFR-β); stage-specific embryonic antigen 4 (SSEA-4); CD20; folate receptor α; receptor tyrosine protein kinase ERBB2 (Her2 / neu); mucin 1, cell surface associated (MUC1); epidermal growth factor receptor (EGFR); neural cell adhesion molecule (NCAM); prostase; prostatic acid phosphatase (PAP); elongation factor 2 mutated (ELF2M); ephrin B2; fibroblast activation protein α (FAP); insulin-like growth factor 1 receptor (IGF-1 receptor), carbonic anhydrase IX (CAIX); proteasome (prosome, macropain) subunit, beta type 9 (LMP2); glycoprotein 100 (gp100);Oncogene fusion protein (bcr-abl) consisting of a cleavage-prone region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (Abl); tyrosinase; ephrin type A receptor 2 (EphA2); fucosyl GM1; sialyl Lewis adhesion molecule (sLe); ganglioside GM3 (aNeu5Ac(2-3)bClalp(1-4)bDGlcp(1-1)Cer); transglutaminase 5 (TGS5); high-molecular-weight melanoma-associated antigen (HMWMAA); O-acetyl-GD2 ganglioside (OAc GD2); folate receptor beta; tumor endothelial marker 1 (TEM1 / CD248); tumor endothelial marker 7-related (TEM7R); claudin 6 (CLDN6); thyroid-stimulating hormone receptor (TSHR); G protein-coupled receptor class C group 5 member D (GPRC5D); chromosome X open reading frame 61 (CXORF61); CD97; CD179a; anaplastic lymphoma kinase (ALK); polysialic acid; placenta-specific 1 (PLAC1); hexasaccharide moiety of globoH glycoceramide (GloboH); breast Glandular differentiation antigen (NY-BR-1); uroplakin 2 (UPK2); hepatitis A virus cell receptor 1 (HAVCR1); adrenergic receptor beta 3 (ADRB3), pannexin 3 (PANX3); G protein-coupled receptor 20 (GPR20), lymphocyte antigen 6 complex locus K9 (LY6K), olfactory receptor 51E2 (OR51E2); TCR gamma alternative reading frame protein (TARP); Wilms tumor protein (WT1); cancer / testis antigen 1 (NY-ES0-1); cancer / testis 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); X antigen family member 1A (XAGE1); angiopoietin-binding cell surface receptor 2 (Tie2); melanoma cancer-testis antigen 1 (MAD-CT-1); melanoma cancer-testis antigen 2 (MAD-CT-2); Fos-related antigen 1; tumor protein p53 (p53); p53 mutant; prostein; survivin; telomerase; prostate carcinoma antigen 1 (PCT A-1 or galectin-8), melanoma antigen 1 recognized by T cells (MelanA or MARTI); rat sarcoma (Ras) mutant; human telomerase reverse transcriptase (hTERT); sarcoma translocation breakpoints;Melanoma inhibitor of apoptosis (ML-IAP); ERG (transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene); N-acetylglucosaminyltransferase V (NA17); paired box protein Pax-3 (PAX3); androgen receptor; cyclin B1; neuroblastoma-derived homolog of v-myc avian myelocytomatosis viral oncogene (MYCN); Ras homolog family member C (RhoC); tyrosinase-related protein 2 (TRP-2); cytochrome P450 1B1 (CYP1B1); CCCTC-binding factor (zinc finger protein)-like (BORIS, or Brother of the Regulator of Imprinted Ribosomal Proteins) Sites), squamous cell carcinoma antigen 3 recognized by T cells (SART3); paired box protein Pax-5 (PAX5); proacrosin-binding protein sp32 (OY-TES1); lymphocyte-specific protein tyrosine kinase (LCK); A-kinase anchor protein 4 (AKAP-4); synovial sarcoma, X-breakpoint 2 (SSX2); receptor for advanced glycation end products (RAGE-1); renal ubiquitous 1 (RU1); renal ubiquitous 2 (RU2); legumain; human papillomavirus E6 (HPV E6); human papillomavirus E7 (HPV E7); gut-derived carboxylesterase; heat shock protein 70-2 mutant (mut hsp 70-2); CD79a; CD79b; CD72; leukocyte-associated immunoglobulin-like receptor 1 (LAIR1): Fc fragment of IgA receptor (FCAR or CD89); leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2); CD300 molecule-like family member f (CD300LF); C-type lectin domain family 12 member A (CLEC12A); bone marrow stromal cell antigen 2 (BST2); EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2); lymphocyte antigen 75 (LY75); glypican 3 (GPC3); Fc receptor-like 5 (FCRL5); and immunoglobulin lambda-like polypeptide 1 (IGLL1), MPL, biotin, c-MYC epitope tag, CD34, LAMP1 TROP2, GFRalpha4, CDH17, CDH6, NYBR1, CDH19, CD200R, Slea (CA19.9;Sialyl Lewis antigen) fucosyl GM1, PTK7, gpNMB, CDH1-CD324, DLL3, CD276 / B7H3, IL11Ra, IL13Ra2, CD179b-IGL11, ALK, TCRγ-δ, NKG2D, CD32 (FCGR2A), Tn ag, CSPG4-HMW-MAA, Timl- / HVCR1, CSF2RA (GM-CSFRα), TGFβR2, VEGFR2 / KDR, Lewis antigen, TCRβ chain, TCRβ2 chain, TCRγ chain, TCRδ chain, FITC, luteinizing hormone receptor (LHR), follicle-stimulating hormone receptor (FSHR), chorionic gonadotropin receptor (CGHR), CCR4, GD3, SLAMF6, SLAMF4, HIV1 envelope glycoprotein, HTLV1-Tax, CMVpp65, EBV- EBNA3c, influenza A hemagglutinin (HA), GAD, PDL1, guanylyl cyclase C (GCC), KSHV-K8.1 protein, KSHV-gH protein, autoantibodies to desmoglein 3 (Dsg3), autoantibodies to desmoglein 1 (Dsg1), 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 Item 13: The recombinant polynucleotide of Item 1, which binds to one or more disease-associated antigens selected from the group consisting of G12V, tissue factor 1 (TF1), AFP, GPRC5D, claudin 18.2 (CLD18A2 or CLDN18A.2), P-glycoprotein, STEAP1, LIV1, NECTIN-4, CRIPTO, GPA33, BST1 / CD157, small-conductance chloride channel, and an antigen recognized by the TNT antibody; 13. The recombinant polynucleotide of claim 12, wherein the one or more non-natural TCR antigen-binding domains comprise an antibody; an antibody fragment; an scFv; an Fv; an Fab; an (Fab')2; a single-domain antibody (SDAB); a vH domain or a vL domain; a camelid-derived vHH domain; a non-immunoglobulin antigen-binding scaffold such as a DARPIN, an affibody, an affilin, an adnectin, an affitin, an obody, a lipibody, a finomer, an alphabody, an avimer, an atrimer, a centilin, a pronectin, an anticalin, a Kunitz domain, or an armadillo repeat protein; a receptor; or a ligand. [Item 14] the one or more non-native TCR antigen-binding domains (i) a heavy chain variable region (vH) encoded by a polynucleotide having any one of SEQ ID NOs: 226 to 400 or 10203 to 10321 or a sequence at least 98% identical thereto, wherein the polynucleotide encodes a polypeptide that binds to the antigen; (ii) a light chain variable region (vL) encoded by a polynucleotide having any one of SEQ ID NOs: 16 to 191 or 10085 to 10202 or a sequence at least 98% identical thereto, wherein the polynucleotide encodes a polypeptide that binds to the antigen; (iii) a single-chain variable fragment (scFv) encoded by a polynucleotide having any one of SEQ ID NOs: 488 to 657, 10346 to 10400, or 18098 to 18160, or a sequence at least 98% identical thereto, wherein the polynucleotide encodes a polypeptide that binds to the antigen; (iv) a camelid VHH domain encoded by a polynucleotide having any one of SEQ ID NOs: 421 to 445 or 10322 to 10337, or a sequence at least 98% identical thereto, and encoding a polypeptide that binds to the antigen; (v) a non-immunoglobulin scaffold encoded by a polynucleotide having any one of SEQ ID NOs: 439 to 443 or a sequence at least 98% identical thereto, wherein the polynucleotide encodes a polypeptide that binds to the antigen; (vi) a polynucleotide having any one of SEQ ID NOs: 456 to 468 or a sequence at least 98% identical thereto, wherein the polynucleotide encodes a polypeptide that binds to its cognate; (vii) a polynucleotide having any one of SEQ ID NOs: 476 to 486 or 10402 to 10404, or a sequence at least 98% identical thereto, wherein the polynucleotide encodes a polypeptide that binds to its cognate; 13. The recombinant polynucleotide of item 12, selected from the group consisting of: [Item 15] 2. The recombinant polynucleotide of Item 1, wherein the one or more non-natural TCR antigen-binding domains comprise one or more light chain complementarity determining regions for a selected target antigen set forth in any of SEQ ID NOs: 13999 to 14879 or 14880, and / or one or more heavy chain complementarity determining regions for a selected target antigen set forth in any of SEQ ID NOs: 14881 to 15761 or 15762. [Item 16] 2. The recombinant polynucleotide according to Item 1, wherein the one or more non-natural TCR antigen-binding domains have a variable light chain (vL) domain having a sequence set forth in any one of SEQ ID NOs: 2307 to 2482 or 12042 to 12159 with up to 10 conservative amino acid substitutions, and / or a variable heavy chain (vH) domain having a sequence set forth in any one of SEQ ID NOs: 2506 to 2680 or 12160 to 12278 with up to 10 conservative amino acid substitutions. [Item 17] 2. The recombinant polynucleotide of item 1, wherein the one or more non-natural TCR antigen-binding domains comprise one or more camelid vHH complementarity-determining regions for a selected antigen set forth in any one of SEQ ID NOs: 2701-2725 or 12279-12294 with up to 10 conservative amino acid substitutions. [Item 18] 2. The recombinant polynucleotide according to Item 1, wherein the one or more non-natural TCR antigen-binding domains have the amino acid sequence set forth in any one of SEQ ID NOs: 2728 to 2732 or 12296 to 12301 and a non-immunoglobulin antigen-binding domain containing up to 10 conservative amino acid substitutions. [Item 19] 2. The polynucleotide according to Item 1, wherein the one or more non-natural TCR antigen-binding domains have an scFv domain comprising one or more light chain complementarity-determining regions of a variable light chain (vL) domain having the sequence of any one of SEQ ID NOs: 2307 to 2482 or 12042 to 12159 and one or more heavy chain complementarity-determining regions of a variable heavy chain (vH) domain having the sequence of any one of SEQ ID NOs: 2506 to 2680 or 12160 to 12278. [Item 20] 2. The recombinant polynucleotide according to item 1, wherein the one or more non-natural TCR antigen-binding domains comprise an scFv fragment comprising a sequence selected from the group consisting of SEQ ID NOs: 2770 to 2939, 12303 to 12357, and 18162 to 18224, each having up to 10 conservative amino acid substitutions. [Item 21] 2. The recombinant polynucleotide according to Item 1, wherein the one or more non-natural TCR antigen-binding domains have one or more receptors consisting of the amino acid sequence of any one of SEQ ID NOs: 2736 to 2748 with up to 10 conservative amino acid substitutions. [Item 22] 2. The recombinant polynucleotide of item 1, wherein the one or more non-natural TCR antigen-binding domains have one or more ligands consisting of any of SEQ ID NOs: 2758 to 2768 or 12359 to 12361 with up to 10 conservative amino acid substitutions. [Item 23] 2. The recombinant polynucleotide of claim 1, wherein the one or more non-native TCR antigen-binding domains comprise the extracellular domain of CD16A, NKG2D, CD4, PD1, desmoglein 3 (Dsg3), or CD4-DC-SIGN. [Item 24] 2. The recombinant polynucleotide of claim 1, wherein the one or more non-native TCR antigen-binding domains comprise one or more extracellular domains of hTPO, mTPO, CGH α chain, CGH β chain, FH β chain, LH β chain, TSH β chain, APRIL, or a combination thereof. [Item 25] the one or more non-natural TCR antigen-binding domains are any single-chain variable fragment (scFv) comprising any one of SEQ ID NOs: 2770-2939, 12303-12357, or 18162-18224, with up to 10 conservative amino acid substitutions; a) any camelid vHH as set forth in any of SEQ ID NOs: 2701 to 2725 or 12279 to 12294, with up to 10 conservative amino acid substitutions; or b) any non-immunoglobulin antigen-binding domain having a sequence as set forth in any of SEQ ID NOs: 2728 to 2732 or 12296 to 12301, with up to 10 conservative amino acid substitutions; or c) any extracellular domain of a receptor consisting of any of the amino acid sequences set forth in SEQ ID NOs: 2736 to 2748, with up to 10 conservative amino acid substitutions; or d) any extracellular domain of a ligand having any of SEQ ID NOs: 2758-2768 or 12359-12361, with up to 10 conservative amino acid substitutions; 2. The recombinant polynucleotide according to item 1, comprising: [Item 26] the one or more non-natural TCR antigen-binding domains have up to 10 conservative amino acid substitutions and are selected from the group consisting of a camelid vHH set forth in any of SEQ ID NOs: 2701 to 2725 or 12279 to 12294; a) any single chain variable fragment (scFv) having any of SEQ ID NOs: 2770 to 2939, 12303 to 12357, or 18162 to 18224, and having up to 10 conservative amino acid substitutions; or b) any non-immunoglobulin antigen-binding domain having a sequence set forth in any of SEQ ID NOs: 2728 to 2732 or 12296 to 12301 and having up to 10 conservative amino acid substitutions; or c) any extracellular domain of a receptor consisting of any of the amino acid sequences set forth in SEQ ID NOs: 2736 to 2748, with up to 10 conservative amino acid substitutions; or d) any extracellular domain of a ligand having any of SEQ ID NOs: 2758-2768 or 12359-12361, with up to 10 conservative amino acid substitutions; 2. The recombinant polynucleotide according to item 1, comprising: [Item 27] 2. The recombinant polynucleotide of item 1, wherein the one or more non-natural TCR antigen-binding domains are optionally connected to each of the TCR constant regions by a linker region, and the nucleic acid of the linker region encodes an amino acid sequence selected from the group consisting of SEQ ID NOs: 2981 to 3003 and any combination thereof, or a sequence at least 98% identical thereto, or the linker is encoded by a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 701 to 725, or a sequence at least 98% identical thereto. [Item 28] 2. The recombinant polynucleotide of item 1, wherein the one or more non-native TCR antigen-binding domains have a binding affinity for the target antigen that is at least 5-fold less than the antibody from which they are derived. [Item 29] 2. The recombinant polynucleotide of item 1, wherein the polynucleotide encoding the SIR further comprises a leader sequence or signal peptide present at the N-terminus of each chain and having a sequence selected from the group consisting of SEQ ID NOs: 1 to 9 and 10. [Item 30] 2. The recombinant polynucleotide of item 1, wherein at least one polynucleotide encodes two SIRs. [Item 31] 31. The recombinant polynucleotide of claim 30, wherein the polynucleotide encodes two SIRs linked by a nucleotide sequence encoding a cleavable linker. [Item 32] 32. The recombinant polynucleotide of claim 31, wherein the cleavable linker is a self-cleaving cleavable linker. [Item 33] 32. The recombinant polynucleotide of claim 31, wherein the cleavable linker is any one or more of a 2A linker, a 2A-like linker, or functional equivalents thereof. [Item 34] 32. The recombinant polynucleotide of item 31, wherein the cleavable linker is any one or more of a T2A linker, a P2A, an F2A, an E2A linker, or functional equivalents thereof. [Item 35] 32. The recombinant polynucleotide according to Item 31, wherein the cleavable linker has any one or more sequences selected from SEQ ID NOs: 780 to 785. [Item 36] 32. The recombinant polynucleotide of claim 31, wherein the polynucleotide sequence encoding the cleavable linker is optionally preceded by a nucleotide sequence encoding a furin cleavage site, a furin-like cleavage site, or a functional equivalent thereof. [Item 37] 37. The recombinant polynucleotide according to Item 36, wherein the furin cleavage site preceding the cleavable linker has any one or more sequences selected from SEQ ID NOs: 788 to 790. [Item 38] 38. The recombinant polynucleotide of any one of items 31 to 37, wherein the polynucleotide sequence encoding the cleavable linker is preceded by a nucleotide sequence encoding a flexible linker. [Item 39] 39. The recombinant polynucleotide of claim 38, wherein the flexible linker preceding the cleavable linker encodes one or more of a Ser-Gly linker, a Ser-Gly-Ser-Gly linker, or a functional equivalent thereof. [Item 40] 39. The recombinant polynucleotide of claim 39, wherein the flexible linker preceding the cleavable linker has the sequence of SEQ ID NOs: 786-787. [Item 41] 39. The recombinant polynucleotide of Item 38, wherein the polynucleotide sequence encoding the furin cleavage site is followed by a polynucleotide encoding the flexible linker, which is followed by a polynucleotide encoding the cleavable linker, in the order of furin cleavage site, flexible linker, cleavable linker. [Item 42] 32. The recombinant polynucleotide of claim 31, wherein the polynucleotide encoding the cleavable linker precedes a sequence encoding a leader sequence (signal peptide) encoding a second SIR. [Item 43] 2. The recombinant polynucleotide of item 1, wherein the SIR can be designed to have diverse binding affinities for a selected antigen. [Item 44] The SIR is a recombinant polynucleotide having an accessory module. [Item 45] 45. The recombinant polynucleotide of claim 1, wherein the accessory module comprises a CD3z domain. [Item 46] The TCR constant chain (viii) an amino acid sequence that is at least 98% identical to SEQ ID NO: 12401, 12402, 12403, 12408, or 12409; (ix) an amino acid sequence that is at least 98% identical to SEQ ID NO: 12421, 12422, 12423, 12427, or 12428; (x) a dimeric combination of two TCR constant chains of (viii) and (ix); 46. ​​The recombinant polynucleotide according to item 45, selected from the group consisting of: [Item 47] 13. The recombinant polynucleotide of claim 12, wherein the one or more non-natural TCR antigen-binding domains bind to CD19. [Item 48] the one or more non-native TCR antigen-binding domains - a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2318-2324, 12060-12068, 12108, 12127, and 12156, or any complementarity determining region (CDR) contained in any of said polypeptides; - a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2517-2523, 12178-12186, 1227, 12246, and 12275, or any complementarity determining region (CDR) contained in any of the aforementioned polypeptides; - a polypeptide having a sequence at least 98% identical to SEQ ID NO: 12288; - a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2770-2774, 12325, 12308, 18162-18170, and 12354; 48. The recombinant polynucleotide according to item 47, selected from the group consisting of: [Item 49] 48. The recombinant polynucleotide of Item 47, encoding a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 3135-3235, 3250-3346, 3396, 3401-3403, 3406, 3429-3432, 3435-3439, 3540, 3855-3859, 12431-12489, 12491-12493, 12495-12530, 12534, 13195-13203, 13250, 13267, 13289, 13429-13437, 13483, 13501, and 13523. [Item 50] 13. The recombinant polynucleotide of claim 12, wherein the one or more non-natural TCR antigen-binding domains bind to CD20. [Item 51] the one or more non-native TCR antigen-binding domains - a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2325-2326, 12069-12077, and 12078, or any complementarity determining region (CDR) contained in any of said polypeptides; - a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2524-2525, 12187-12195, and 12196, or any complementarity determining region (CDR) contained in any of said polypeptides; - a polypeptide having a sequence at least 98% identical to SEQ ID NO: 12289 or 12290; - a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2787-2788, 18177-18186, and 18187; 51. The recombinant polynucleotide of item 50, selected from the group consisting of: [Item 52] 51. The recombinant polynucleotide of Item 50, encoding a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 3263, 3348, 3456-3457, 3876-3877, 12464-12465, 12477-12482, 12492, 12534, 13204-13213, 13438-13446, and 13447. [Item 53] 13. The recombinant polynucleotide of claim 12, wherein the one or more non-natural TCR antigen-binding domains bind to CD22. [Item 54] the one or more non-native TCR antigen-binding domains - a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2327-2329, 12122-12126, and 12132, or any complementarity determining region (CDR) contained in any of said polypeptides; - a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2526-2528, 12241-12245, and 12251, or any complementarity determining region (CDR) contained in any of said polypeptides; - a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2789-2791, 12320-12330, and 18188; 54. The recombinant polynucleotide of item 53, selected from the group consisting of: [Item 55] 54. The recombinant polynucleotide of Item 53, encoding a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 3332, 3433, 3458-3460, 3878-3880, 12483, 12485, 12488-12490, 13241-13245, 13268, 13475-13479, and 13502. [Item 56] 13. The recombinant polynucleotide of claim 12, wherein the one or more non-native TCR antigen-binding domains bind to BCMA. [Item 57] the one or more non-native TCR antigen-binding domains - a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2310-2313, 12046-12048, 12118-12119, 12139-12145, and 12146, or any complementarity determining region (CDR) contained in any of said polypeptides; - a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2509-2512, 12164-12166, 12237-12238, 12258-12264, and 12265, or any complementarity determining region (CDR) contained in any of the aforementioned polypeptides; - a polypeptide having a sequence at least 98% identical to SEQ ID NOs: 12279-12281, 12283-12285, 12287, 12291-12292, 12293, or 12294; - a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2780-2783, 12237-12344, 18174-18175, and 18176; 57. The recombinant polynucleotide of item 56, selected from the group consisting of: [Item 58] 57. The recombinant polynucleotide of Item 56, encoding a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 3445-3449, 3866-3869, 12463, 12533, 12535-12536, 13181-13183, 13261-13262, 13277-13284, 13415-13417, 13495-13496, 13511-13517, and 13518. [Item 59] 13. The recombinant polynucleotide of claim 12, wherein the one or more non-natural TCR antigen-binding domains bind to MPL. [Item 60] the one or more non-native TCR antigen-binding domains - a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2414 to 2421, 12120, 12128, and 12129, or any complementarity determining region (CDR) contained in any of said polypeptides; - a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2611 to 2618, 12239, 12247, and 12248, or any complementarity determining region (CDR) contained in any of said polypeptides; - a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2871-2878, 12326-12327, and 12318; 60. The recombinant polynucleotide of item 59, selected from the group consisting of: [Item 61] 60. The recombinant polynucleotide of Item 59, encoding a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 3347, 3373, 3427-3428, 3495, 3556-3562, 3979-3985, 4025, 12454, 12456, 12458, 12462, 12532, 13259, 13265-13266, 13493, 13499, and 13500. [Item 62] 13. The recombinant polynucleotide of claim 12, wherein the one or more non-native TCR antigen-binding domains bind to CS1. [Item 63] the one or more non-native TCR antigen-binding domains - a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2355-2358, 12090-12094, and 12095, or any complementarity determining region (CDR) contained in any of said polypeptides; - a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2553-2555, 12209-12213, and 12214, or any complementarity determining region (CDR) contained in any of said polypeptides; - a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2817-2819, 18211-18215, and 18216; 63. The recombinant polynucleotide of item 62, selected from the group consisting of: [Item 64] 63. The recombinant polynucleotide of Item 62, encoding a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 3376, 3487, 3489, 3907-3909, 12455, 12457, 12459, 12461, 12476, 13226-13231, 13460-13464, and 13465. [Item 65] 13. The recombinant polynucleotide of claim 12, wherein the one or more non-natural TCR antigen-binding domains bind to CD33. [Item 66] the one or more non-native TCR antigen-binding domains - a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2336-2337, 12079-12084, and 12085, or any complementarity determining region (CDR) contained in any of said polypeptides; - a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2535-2536, 12197-12202, and 12203, or any complementarity determining region (CDR) contained in any of said polypeptides; - a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2795-2796, 18189-18193, and 18194; 66. The recombinant polynucleotide of item 65, selected from the group consisting of: [Item 67] 66. The recombinant polynucleotide of Item 65, encoding a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 3464-3465, 3884-3885, 12460, 12473, 12479, 13214-13220, 13448-13453, and 13454. [Item 68] 13. The recombinant polynucleotide of item 12, wherein the one or more non-natural TCR antigen-binding domains bind to CD123. [Item 69] the one or more non-native TCR antigen-binding domains - a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2315, 2472, 12049-12058, and 12059, or any complementarity determining region (CDR) contained in any of said polypeptides; - a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2514, 2670, 12167-12176, and 12177, or any complementarity determining region (CDR) contained in any of said polypeptides; - a polypeptide having a sequence at least 98% identical to SEQ ID NO: 2716 or 2717; - a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2801, 2929, 18196-18205, and 18206; 69. The recombinant polynucleotide of item 68, selected from the group consisting of: [Item 70] 69. The recombinant polynucleotide of Item 68, encoding a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 3266-3267, 3366-3368, 3375, 3378, 3405, 3409, 3434, 3470, 3492-3497, 3617, 3890, 3912-3913, 4041, 12480, 13184-13194, 13418-13427, and 13428. [Item 71] 13. The recombinant polynucleotide of claim 12, wherein the one or more non-natural TCR antigen-binding domains bind to folate receptor 1. [Item 72] the one or more non-native TCR antigen-binding domains - a polypeptide having a sequence at least 98% identical to SEQ ID NO: 2373, or any complementarity determining region (CDR) contained in any of said polypeptides; - a polypeptide having a sequence at least 98% identical to SEQ ID NO: 2570, or any complementarity determining region (CDR) contained in any of said polypeptides; - a polypeptide having a sequence at least 98% identical to SEQ ID NO: 2833; 72. The recombinant polynucleotide of item 71, selected from the group consisting of: [Item 73] 72. The recombinant polynucleotide of item 71, encoding a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 3511 and 3928. [Item 74] 13. The recombinant polynucleotide of claim 12, wherein the one or more non-natural TCR antigen-binding domains bind to mesothelin. [Item 75] the one or more non-native TCR antigen-binding domains - a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2413, 12154, and 12155, or any complementarity determining region (CDR) contained in any of said polypeptides; - a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2609-2610, 12273, and 12274, or any complementarity determining region (CDR) contained in any of the above polypeptides; - a polypeptide having a sequence at least 98% identical to SEQ ID NO: 2713-2714 or 2725; - a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2870, 2899, 12352, and 12353; 75. The recombinant polynucleotide of item 74, selected from the group consisting of: [Item 76] 75. The recombinant polynucleotide of Item 74, encoding a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 3414, 3419, 3554, 3585, 3976, 4008, 13287-13288, 13521, and 13522. [Item 77] 13. The recombinant polynucleotide of claim 12, wherein the one or more non-natural TCR antigen-binding domains bind to IL13Ra2. [Item 78] the one or more non-native TCR antigen-binding domains - a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2399 and 2400, or any complementarity determining region (CDR) contained in any of said polypeptides; - a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2595 and 2596, or any complementarity determining region (CDR) contained in any of said polypeptides; - a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2858 and 2859; 78. The recombinant polynucleotide of item 77, selected from the group consisting of: [Item 79] 78. The recombinant polynucleotide of Item 77, encoding a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 3541-3542, 3963, and 3964. [Item 80] 13. The recombinant polynucleotide of claim 12, wherein the one or more non-natural TCR antigen-binding domains bind to CD138. [Item 81] the one or more non-native TCR antigen-binding domains - a polypeptide having a sequence at least 98% identical to SEQ ID NO: 2316, or any complementarity determining region (CDR) contained in any of said polypeptides; - a polypeptide having a sequence at least 98% identical to SEQ ID NO: 2515, or any complementarity determining region (CDR) contained in any of said polypeptides; - a polypeptide having a sequence at least 98% identical to SEQ ID NO: 2802; 81. The recombinant polynucleotide of item 80, selected from the group consisting of: [Item 82] 81. The recombinant polynucleotide of item 80, encoding a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 3268, 3374, 3404, 3471, and 3891. [Item 83] 13. The recombinant polynucleotide of claim 12, wherein the one or more non-natural TCR antigen-binding domains bind to TCRgd. [Item 84] the one or more non-native TCR antigen-binding domains - a polypeptide having a sequence at least 98% identical to SEQ ID NO: 2449, or any complementarity determining region (CDR) contained in any of said polypeptides; - a polypeptide having a sequence at least 98% identical to SEQ ID NO: 2646, or any complementarity determining region (CDR) contained in any of said polypeptides; - a polypeptide having a sequence at least 98% identical to SEQ ID NO: 2907; 84. The recombinant polynucleotide of item 83, selected from the group consisting of: [Item 85] 84. The recombinant polynucleotide of Item 83, encoding a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 3594 and 4017. [Item 86] 13. The recombinant polynucleotide of claim 12, wherein the one or more non-natural TCR antigen-binding domains bind to TCRB1. [Item 87] the one or more non-native TCR antigen-binding domains - a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2445 and 2446, or any complementarity determining region (CDR) contained in any of said polypeptides; - a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2642 and 2643, or any complementarity determining region (CDR) contained in any of said polypeptides; - a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2903 and 2904; 87. The recombinant polynucleotide of item 86, selected from the group consisting of: [Item 88] 87. The recombinant polynucleotide of Item 86, encoding a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 3590-3591, 4013, and 4014. [Item 89] 13. The recombinant polynucleotide of claim 12, wherein the one or more non-natural TCR antigen-binding domains bind to TCRB2. [Item 90] the one or more non-native TCR antigen-binding domains - a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2447 and 2448, or any complementarity determining region (CDR) contained in any of said polypeptides; - a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2644 and 2645, or any complementarity determining region (CDR) contained in any of said polypeptides; - a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2905 and 2906; 90. The recombinant polynucleotide of item 89, selected from the group consisting of: [Item 91] 89. The recombinant polynucleotide of Item 89, encoding a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 3353-3364, 3592-3593, 4015, and 4016. [Item 92] A recombinant expression system comprising the recombinant polynucleotide of item 1 co-expressed with a therapeutic control, The therapeutic controls include truncated epidermal growth factor receptor (tEGFR), truncated epidermal growth factor receptor viii (tEGFRviii), truncated CD30 (tCD30), truncated BCMA (tBCMA), truncated CD19 (tCD19), CD34, thymidine kinase, cytosine deaminase, nitroreductase, xanthine guanine phosphoribosyltransferase, human caspase 8, human caspase 9, inducible caspase 9 (icaspase 9), and purine nucleoside phosphorylase. , linamarase / linamarin glucose oxidase, deoxynucleoside kinase, horseradish peroxidase (HRP) / indole-3-acetic acid (IAA), gamma glutamylcysteine ​​synthase, CD20 / alpha CD20, CD34 / thymidine kinase chimera, dox-dependent caspase 2, mutant thymidine kinase (HSV-TKSR39), AP1903 / Fas system, chimeric cytokine receptor (CCR), selection marker, and combinations thereof, Recombinant expression systems. [Item 93] 93. The recombinant expression system of item 92, wherein the tEGFR and tEGFRviii are conjugated to any one or more of an EGFR-specific siRNA, a small molecule compound, an anti-EGFR antibody or fragment thereof, and a combination thereof. [Item 94] 93. The recombinant expression system of claim 92, wherein the tCD30 is conjugated to any one or more of a CD30-specific siRNA, a small molecule compound, an anti-CD30 antibody or fragment thereof, and a combination thereof. [Item 95] 93. The recombinant expression system of claim 92, wherein the tCD19 is conjugated to any one or more of a CD19-specific siRNA, a small molecule compound, an anti-CD19 antibody or fragment thereof, and a combination thereof. [Item 96] 93. The recombinant expression system of item 92, wherein the CD34 is conjugated to any one or more of a CD34-specific siRNA, a small molecule compound, an anti-CD34 antibody or fragment thereof, and a combination thereof. [Item 97] 93. The recombinant expression system of claim 92, wherein the selectable marker binds any one or more of a dihydroxyfolate receptor, a mutant DHFR, a methylated DNA-protein cysteine ​​methyltransferase, inosine monophosphate dehydrogenase II (IMDHP2), puromycin acetyltransferase (PAC), a blasticidin resistance gene, a mutant calcineurin a / b (Can / b), CNa12, CNb30, and combinations thereof. [Item 98] 93. The recombinant expression system of claim 92, wherein the CCR comprises any one or more of: (i) an IL-7 cytokine linker (IL7Ra); (ii) an IL-7 cytokine linker (IL-Ra) extracellular domain of an IL-7Ra transmembrane domain of the cytoplasmic domain of an IL2Rβ; (iii) an IL-7 cytokine linker (IL2Rβ); and (iv) combinations thereof. [Item 99] 2. A recombinant expression system comprising the recombinant polynucleotide of item 1 co-expressed with an accessory module, The accessory modules include 41BBL, CD40L, K13, MC159, cFLIP-L / MRITα, cFLIP-p22, HTLV1 Tax, HTLV2 Tax, HTLV2 Tax2-RS mutant, FKBPx-K13, FKBPx-HTLV2-Tax, FKBPx-HTLV2-Tax-RS, IL6R-304-vHH-Alb8-vHH, IL12f, PD1-4H1 scFV, and PD1-5C4 scFV, PD1-4H1-Alb8-vHH, PD1-5C4-Alb8-vHH, CTLA4 ipilimumab scFV, CTLA4 ipilimumab Alb8-vHH, IL6-19A-scFV, IL6-19A-scFV-Alb8-vHH, sHVEM, sHVEM-Alb8-vHH, hTERT, Fx06, CD3z, CD3z-GGGS-41BB, CD3-BBz, CD3-CD28z, CD3-CD28-Lck fusion protein, shRNA targeting Brd4, chimeric antigen receptor (CAR), hTERT, heparinase, CAR, inhibitory CAR, and combinations thereof. Recombinant expression systems. [Item 100] 101. The recombinant expression system of claim 92 or 99, wherein the recombinant polynucleotide encoding the SIR, one or more therapeutic controls, and / or one or more accessory modules are linked by a nucleotide sequence encoding a cleavable linker. 101. The recombinant expression system of claim 100, wherein the cleavable linker is a self-cleaving cleavable linker. [Item 102] 102. The recombinant expression system of claim 101, wherein the polynucleotide sequence encoding the cleavable linker is preceded by a nucleotide sequence encoding a furin cleavage site, a furin-like cleavage site, or a functional equivalent thereof. [Item 103] 101. The recombinant expression system of claim 100, wherein the polynucleotide sequence encoding the cleavable linker is optionally preceded by a nucleotide sequence encoding a flexible linker. [Item 104] At least one vector carrying the recombinant polynucleotide of item 1, selected from the group consisting of a DNA vector, an RNA vector, a plasmid, a lentiviral vector, an adenoviral vector, a retroviral vector, a baculoviral vector, a sleeping beauty transposon vector, and a piggybac transposon vector; vector. [Item 105] Item 105. The vector according to Item 104, wherein the backbone of the vector has a sequence selected from the group consisting of SEQ ID NOs: 870 to 875 and 876. [Item 106] 105. The vector of item 104, having a promoter selected from the group consisting of an EF-1 promoter, a CMV IE gene promoter, an EF-1a promoter, a ubiquitin C promoter, an MSCV LTR promoter, and a phosphoglycerate kinase (PGK) promoter. [Item 107] 107. The vector according to Item 106, wherein the EF-1 promoter has the sequence of SEQ ID NO: 877 or a sequence that is 80 to 99% identical thereto. [Item 108] 105. The vector according to item 104, wherein the vector is an in vitro transcription vector or a vector further comprising a poly(A) tail or a 3'UTR. [Item 109] At least one polypeptide encoded by at least one recombinant polynucleotide of item 1. [Item 110] A recombinant cell expressing at least one recombinant polynucleotide according to item 1. [Item 111] 1. An isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer, comprising: (a) a T cell receptor (TCR) constant chain, (i) an amino acid sequence at least 98% identical to SEQ ID NO: 3010, having one or more mutations at positions 48, 61, 91, 92, 93, and / or 94, and optionally having an accessory module; (ii) an amino acid sequence at least 98% identical to SEQ ID NO: 3024, having one or more mutations at positions 18, 22, 57, 79, 133, 136, and / or 139, and optionally having an accessory module; (iii) an amino acid sequence at least 98% identical to SEQ ID NO: 3025, having one or more mutations at positions 18, 22, 57, 79, 133, 136, and / or 139, and optionally having an accessory module; (iv) an amino acid sequence at least 98% identical to SEQ ID NO: 3046, 3047, or 3048, optionally with any accessory module; (v) an amino acid sequence at least 98% identical to SEQ ID NO: 3049, optionally with an optional accessory module; (vi) an amino acid sequence at least 98% identical to SEQ ID NO: 3051 or 3052, optionally with an accessory module; (vii) a dimeric combination of two TCR constant chains selected from (i) and (ii), (i) and (iii), (iv) and (ii), (iv) and (iii), (v) and (vi); a T cell receptor constant chain having an amino acid sequence selected from the group consisting of: (b) an optional linker; and (c) one or more non-native TCR antigen-binding domains linked to (a), (1) an antibody; (2) antibody fragments (e.g., Fv, Fab, (Fab')2); (3) an antibody heavy chain variable region (vH domain) or a fragment thereof; (4) an antibody light chain variable region (vL domain) or a fragment thereof; (5) a single-chain variable fragment (scFv) or a fragment thereof; (6) a single domain antibody (SDAB) or a fragment thereof; (7) a VHH domain derived from a camel or a fragment thereof; (8) a monomeric variable region of an antibody; (9) Non-immunoglobulin antigen-binding scaffolds, such as DARPINs, affibodies, affilins, adnectins, affitins, obodies, lipibodies, finomers, alphabodies, avimers, atrimers, centilins, pronectins, anticalins, Kunitz domains, armadillo repeat proteins, or fragments thereof; (10) A receptor or a fragment thereof, (11) A ligand or a fragment thereof; (12) A bispecific antibody, bispecific antibody fragment, bispecific scFV, bispecific vHH, bispecific SDAB, bispecific non-immunoglobulin antigen-binding scaffold, bispecific receptor, or bispecific ligand; (13) an autoantigen or a fragment thereof; and a non-native TCR antigen-binding domain selected from the group consisting of: The variants of (a)(i) to (a)(iii) have diverse binding affinities for the target antigen of the antigen-binding domain, and the synthetic immunoreceptors, when expressed in lymphocytes, express both the antigen-binding domain and the T cell receptor constant chain in one or more contiguous chains on the surface of the lymphocyte, are triggered to activate, proliferate, and secrete cytokines and / or modulate (induce or suppress) killing of the target cell when the expressed antigen-binding domain binds to its antigen, and have MHC-restricted and MHC-unrestricted antibody-type specificities. An isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer. (a)(vii), wherein the non-native TCR binding domain comprises: - variable regions of antibody heavy and light chains or fragments thereof specific for a predetermined target antigen, wherein, when expressed, one of the antibody heavy and light chains or fragments thereof is attached to one of the two chains of (a)(vii) of the T cell constant region, and the other of the antibody heavy and light chains or fragments thereof is attached to the other of the two chains of the T cell constant region; - two single chain variable fragments (scFvs) specific for one or more predetermined target antigens, wherein, when expressed, one of the scFvs is attached to one of the two chains of (a)(vii) of the T cell constant region and the other of the scFvs is attached to the other of the two chains of the T cell constant region; - two antibody fragments specific for one or more predetermined target antigens, wherein, when expressed, one of the antibody fragments is attached to one of the two chains of (a)(vii) of the T cell constant region and the other of the antibody fragments is attached to the other of the two chains of the T cell constant region; - two single domain antibody (SDAB) fragments specific for one or more predetermined target antigens, wherein, when expressed, one of the SDAB fragments is attached to one of the two chains of (a)(vii) of the T cell constant region and the other of the SDAB fragments is attached to the other of the two chains of the T cell constant region; - two camelid-derived vHH domains specific for one or more predetermined target antigens, wherein, when expressed, one of the vHH domains is attached to one of the two chains of (a)(vii) of the T cell constant region and the other vHH domain is attached to the other of the two chains of the T cell constant region; - two non-immunoglobulin antigen-binding scaffolds specific for one or more predetermined target antigens, wherein, when expressed, one of the non-immunoglobulin antigen-binding scaffolds is attached to one of the two chains of (a)(vii) of the T-cell constant region and the other of the non-immunoglobulin antigen-binding scaffold domains is attached to the other of the two chains of the T-cell constant region; two receptors or fragments thereof specific for one or more predetermined target antigens, wherein, when expressed, one of the receptors or fragments thereof is attached to one of the two chains of (a)(vii) of the T cell constant region and the other of the receptors or fragments thereof is attached to the other of the two chains of the T cell constant region; - two ligands or fragments thereof specific for one or more predetermined target antigens, wherein, when expressed, one of the ligands or fragments thereof is attached to one of the two chains of (a)(vii) of the T cell constant region and the other of the ligands or fragments thereof is attached to the other of the two chains of the T cell constant region; and two structurally distinct antigen-binding fragments specific for one or more predetermined target antigens, wherein, when expressed, one of the antigen-binding fragments is attached to one of the two chains of (a)(vii) of the T cell constant region and the other of the antigen-binding fragments is attached to the other of the two chains of the T cell constant region; two binding fragments, either or both of which are bispecific or multispecific, wherein, when expressed, one of the antigen-binding fragments is attached to one of the two chains of (a)(vii) of the T cell constant region and the other of the antigen-binding fragments is attached to the other of the two chains of the T cell constant region; - two autoantigens or fragments thereof, wherein, when expressed, one of the autoantigens or fragments thereof is attached to one of the two chains of (a)(vii) of the T cell constant region and another of the autoantigens or fragments thereof is attached to the other of the two chains of the T cell constant region; two vLs or fragments thereof, wherein, when expressed, one of the vLs or fragments thereof is attached to one of the two chains of (a)(vii) of the T cell constant region and another of the vLs or fragments thereof is attached to the other of the two chains of the T cell constant region; two vHs or fragments thereof, wherein, when expressed, one of the vHs or fragments thereof is attached to one of the two chains of (a)(vii) of the T cell constant region and the other of the vHs or fragments thereof is attached to the other of the two chains of the T cell constant region; and 112. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of item 111, selected from the group consisting of: [Item 113] (a)(iv) a TCR constant chain, wherein the non-native TCR binding domain comprises: the variable region of the heavy chain (vH) of an antibody specific for a predetermined target antigen, or a fragment thereof; the variable region of the light chain (vL) of an antibody specific for a predetermined target antigen, or a fragment thereof; a single-chain variable fragment (scFv) or a fragment thereof specific for a predetermined target antigen, - antibody fragments (e.g. Fv, Fab, (Fab')2) specific for a predetermined target antigen; - single domain (SDAB) fragments specific for a predetermined target antigen; a camelid-derived vHH domain specific for a predetermined target antigen; a non-immunoglobulin antigen-binding scaffold specific for a predetermined target antigen; a receptor or a fragment thereof specific for a predetermined target antigen; a ligand or a fragment thereof specific for a predetermined target antigen; a bispecific antibody, bispecific antibody fragment, bispecific scFV, bispecific vHH, bispecific SDAB, bispecific non-immunoglobulin antigen-binding scaffold, bispecific receptor, or bispecific ligand specific for one or more predetermined target antigens; an autoantigen or a fragment thereof, 112. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of item 111, selected from the group consisting of: [Item 114] (i), (ii), (iii), (iv), (v), or (vi), wherein the non-native TCR binding domain comprises: the variable region of the heavy chain (vH) of an antibody specific for a predetermined target antigen; the variable region of the light chain (vL) of an antibody specific for a predetermined target antigen; a single-chain variable fragment (scFv) specific for a predetermined target antigen; - antibody fragments (e.g. Fv, Fab, (Fab')2) specific for a predetermined target antigen; - single domain (SDAB) fragments specific for a predetermined target antigen; a camelid-derived vHH domain specific for a predetermined target antigen; a non-immunoglobulin antigen-binding scaffold specific for a predetermined target antigen; a receptor or a fragment thereof specific for a predetermined target antigen; a ligand or a fragment thereof specific for a predetermined target antigen; a bispecific antibody, bispecific antibody fragment, bispecific scFV, bispecific vHH, bispecific SDAB, bispecific non-immunoglobulin antigen-binding scaffold, bispecific receptor, or bispecific ligand specific for one or more predetermined target antigens; an autoantigen or a fragment thereof, 112. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of item 111, selected from the group consisting of: [Item 115] 112. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 111, wherein the TCR constant chain(s) have a mutation that promotes expression and / or pairing of the TCR constant chain and a mutation that reduces pairing with an endogenous T cell receptor chain. [Item 116] 112. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of Item 111, wherein the constant region of the TCR is a TCR receptor alpha chain (Cα) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 3010 to 3023, or an amino acid sequence comprising 1 to 40 amino acid substitutions or mutations relative to a sequence that is at least 98% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 3010 to 3023. [Item 117] 112. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of Item 111, wherein the constant region of the TCR is a TCR receptor beta chain (Cβ) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 3024 to 3044, or an amino acid sequence comprising 1 to 40 amino acid substitutions or mutations relative to a sequence that is at least 98% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 3024 to 3044. [Item 118] 112. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of Item 111, wherein the constant region of the TCR is a TCR receptor gamma chain (Cγ) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 3049-3050, or an amino acid sequence comprising 1 to 40 amino acid substitutions or mutations relative to a sequence that is at least 98% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 3049-3050. [Item 119] 112. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of Item 111, wherein the constant region of the TCR is a TCR receptor δ chain (Cδ) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 3051-3052, or an amino acid sequence comprising 1 to 40 amino acid substitutions or mutations relative to a sequence that is at least 98% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 3051-3052. [Item 120] 112. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of Item 111, wherein the constant region of the TCR is a pre-TCR receptor alpha chain (pre-Cα) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 3046-3048, or an amino acid sequence comprising 1 to 40 amino acid substitutions or variants relative to a sequence at least 98% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 3046-3048. [Item 121] The one or more non-natural TCR antigen-binding domains that bind one or more disease-associated antigens may be selected from the group consisting of CD19; CD123; CD22; CD30; CD171; CS-1 (CD2 subset 1, also known as CRACC, SLAMF7, CD319, and 19A24); C-type lectin-like molecule 1 (CLL-1 or CLECL1); CD33; epidermal growth factor receptor variant III (EGFRviii); ganglioside G2 (GD2); ganglioside GD3 (aNeu5Ac(2-8)aNeu5Ac(2-3)bDGalp(1-4)bDGlcp(1-1)Cer); TNF receptor family member B-cell maturation (BCMA); Tn antigen ((Tn Ag) or (GalNAcα-Ser / Thr); prostate-specific membrane antigen (PSMA); receptor tyrosine kinase-like orphan receptor 1 (ROR1); FMS-like tyrosine kinase 3 (FLT3); tumor-associated glycoprotein 72 (TAG72); CD38; CD44v6; glycosylated CD43 epitope expressed in acute leukemia or lymphoma but not in hematopoietic progenitor cells, glycosylated CD43 epitope expressed in non-hematopoietic cancers; carcinoembryonic antigen (CEA); epithelial cell adhesion molecule (EPCAM); B7H3 (CD276); KIT (CD117); interleukin-13 receptor subunit alpha 2 (IL-13Ra2 or CD213A2); mesothelin; interleukin-11 receptor alpha (IL-11Ra); prostate stem cell antigen (PSCA); protease serine 21 (testis rRNA or PRSS21); vascular endothelial growth factor receptor 2 (VEGFR2); Lewis (Y) antigen; CD24; platelet-derived growth factor receptor beta (PDGFR-β); stage-specific embryonic antigen 4 (SSEA-4); CD20; folate receptor α; receptor tyrosine protein kinase ERBB2 (Her2 / neu); mucin 1, cell surface associated (MUC1); epidermal growth factor receptor (EGFR); neural cell adhesion molecule (NCAM); prostase; prostatic acid phosphatase (PAP); elongation factor 2 mutated (ELF2M); ephrin B2; fibroblast activation protein α (FAP); insulin-like growth factor 1 receptor (IGF-1 receptor), carbonic anhydrase IX (CAIX); proteasome (prosome, macropain) subunit, beta type 9 (LMP2); glycoprotein 100 (gp100);Oncogene fusion protein consisting of a cleavage-prone region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (Ab1) (bcr-ab1); tyrosinase; ephrin type A receptor 2 (EphA2); fucosyl GM1; sialyl Lewis adhesion molecule (sLe); ganglioside GM3 (aNeu5Ac(2-3)bClalp(1-4)bDGlcp(1-1)Cer); transglutaminase 5 (TGS5); high-molecular-weight melanoma-associated antigen (HMWMAA); O-acetyl-GD2 ganglioside (OAc GD2); folate receptor beta; tumor endothelial marker 1 (TEM1 / CD248); tumor endothelial marker 7-related (TEM7R); claudin 6 (CLDN6); thyroid-stimulating hormone receptor (TSHR); G protein-coupled receptor class C group 5 member D (GPRC5D); chromosome X open reading frame 61 (CXORF61); CD97; CD179a; anaplastic lymphoma kinase (ALK); polysialic acid; placenta-specific 1 (PLAC1); hexasaccharide moiety of globoH glycoceramide (GloboH); breast Glandular differentiation antigen (NY-BR-1); uroplakin 2 (UPK2); hepatitis A virus cell receptor 1 (HAVCR1); adrenergic receptor beta 3 (ADRB3), pannexin 3 (PANX3); G protein-coupled receptor 20 (GPR20), lymphocyte antigen 6 complex locus K9 (LY6K), olfactory receptor 51E2 (OR51E2); TCR gamma alternative reading frame protein (TARP); Wilms tumor protein (WT1); cancer / testis antigen 1 (NY-ES0-1); cancer / testis 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); X antigen family member 1A (XAGE1); angiopoietin-binding cell surface receptor 2 (Tie2); melanoma cancer-testis antigen 1 (MAD-CT-1); melanoma cancer-testis antigen 2 (MAD-CT-2); Fos-related antigen 1; tumor protein p53 (p53); p53 mutant; prostein; survivin; telomerase; prostate carcinoma antigen 1 (PCT A-1 or galectin-8), melanoma antigen 1 recognized by T cells (MelanA or MARTI); rat sarcoma (Ras) mutant; human telomerase reverse transcriptase (hTERT); sarcoma translocation breakpoints;Melanoma inhibitor of apoptosis (ML-IAP); ERG (transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene); N-acetylglucosaminyltransferase V (NA17); paired box protein Pax-3 (PAX3); androgen receptor; cyclin B1; neuroblastoma-derived homolog of v-myc avian myelocytomatosis viral oncogene (MYCN); Ras homolog family member C (RhoC); tyrosinase-related protein 2 (TRP-2); cytochrome P4501B1 (CYP1B1); CCCTC-binding factor (zinc finger protein)-like (BORIS or Brother of the Regulator of Imprinted Sites), squamous cell carcinoma antigen 3 recognized by T cells (SART3); paired box protein Pax-5 (PAX5); proacrosin-binding protein sp32 (OY-TES1); lymphocyte-specific protein tyrosine kinase (LCK); A-kinase anchor protein 4 (AKAP-4); synovial sarcoma, X-breakpoint 2 (SSX2); receptor for advanced glycation end products (RAGE-1); renal ubiquitous 1 (RU1); renal ubiquitous 2 (RU2); legumain; human papillomavirus E6 (HPV E6); human papillomavirus E7 (HPV E7); intestinal carboxylesterase; heat shock protein 70-2 mutant (mut hsp 70-2); CD79a; CD79b; CD72; leukocyte-associated immunoglobulin-like receptor 1 (LAIR1): Fc fragment of IgA receptor (FCAR or CD89); leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2); CD300 molecule-like family member f (CD300LF); C-type lectin domain family 12 member A (CLEC12A); bone marrow stromal cell antigen 2 (BST2); EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2); lymphocyte antigen 75 (LY75); glypican 3 (GPC3); Fc receptor-like 5 (FCRL5); and immunoglobulin lambda-like polypeptide 1 (IGLL1), MPL, biotin, c-MYC epitope tag, CD34, LAMP1 TROP2, GFRalpha4, CDH17, CDH6, NYBR1, CDH19, CD200R, Slea (CA19.9;Sialyl Lewis antigen) fucosyl GM1, PTK7, gpNMB, CDH1-CD324, DLL3, CD276 / B7H3, IL11Ra, IL13Ra2, CD179b-IGL11, ALK, TCRγδ, NKG2D, CD32 (FCGR2A), Tn ag, CSPG4-HMW-MAA, Timl- / HVCR1, CSF2RA (GM-CSFRα), TGFβR2, VEGFR2 / KDR, Lewis antigen, TCRβ chain, TCRβ2 chain, TCRγ chain, TCRδ chain, FITC, luteinizing hormone receptor (LHR), follicle-stimulating hormone receptor (FSHR), chorionic gonadotropin receptor (CGHR), CCR4, GD3, SLAMF6, SLAMF4, HIV1 envelope glycoprotein, HTLV1-Tax, CMVpp65, EBV- EBNA3c, influenza A hemagglutinin (HA), GAD, PDL1, guanylyl cyclase C (GCC), KSHV-K8.1 protein, KSHV-gH protein, autoantibodies to desmoglein 3 (Dsg3), autoantibodies to desmoglein 1 (Dsg1), 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 112. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 111, wherein the polypeptide or polypeptide heterodimer is selected from the group consisting of G12V, tissue factor 1 (TF1), AFP, GPRC5D, claudin 18.2 (CLD18A2 or CLDN18A.2), P-glycoprotein, STEAP1, LIV1, NECTIN-4, CRIPTO, GPA33, BST1 / CD157, small conductance chloride channel, and an antigen recognized by the TNT antibody. [Item 122] 122. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 121, wherein the one or more non-natural TCR antigen-binding domains comprise an antibody, antibody fragment, scFv, Fv, Fab, (Fab')2, single domain antibody (SDAB), vH or vL domain, camelid-derived vHH domain, non-immunoglobulin antigen-binding scaffold, e.g., a DARPIN, an affibody, an affilin, an adnectin, an affitin, an obody, a lipibody, a fynomer, an alphabody, an avimer, an atrimer, a centilin, a pronectin, an anticalin, a Kunitz domain, an armadillo repeat protein, a receptor, or a ligand. [Item 123] the one or more non-native TCR antigen-binding domains (i) a heavy chain variable region (vH) encoding a polypeptide that binds to an antigen, the heavy chain variable region having a sequence set forth in any one of SEQ ID NOs: 2506 to 2680 or 12160 to 12278 or a sequence at least 98% identical thereto; (ii) a light chain variable region (vL) encoding a polypeptide that binds to an antigen, the light chain variable region having a sequence set forth in any one of SEQ ID NOs: 2307 to 2482 or 12042 to 12159 or a sequence at least 98% identical thereto; (iii) a single-chain variable fragment (scFv) encoding an antigen-binding polypeptide having a sequence set forth in any one of SEQ ID NOs: 2770 to 2939, 12303 to 12357, or 18162 to 18224, or a sequence at least 98% identical thereto; and (iv) a camelid VHH encoding a polypeptide that binds to an antigen and has a sequence set forth in any one of SEQ ID NOs: 2701 to 2725 or 12279 to 12294 or a sequence at least 98% identical thereto; (v) a non-immunoglobulin scaffold encoded by a sequence set forth in any one of SEQ ID NOs: 439 to 443 or a sequence at least 98% identical thereto, wherein the non-immunoglobulin scaffold encodes a polypeptide that binds to a cognate molecule; (vi) a receptor encoding a polypeptide that binds to an antigen, the polypeptide having a sequence set forth in any one of SEQ ID NOs: 2736 to 2748 or a sequence at least 98% identical thereto; and (vii) a ligand encoding a polypeptide that binds to a cognate sequence, the polypeptide having a sequence set forth in any one of SEQ ID NOs: 2758 to 2768 or 12359 to 12361 or a sequence at least 98% identical thereto. 122. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of item 121, selected from the group consisting of: [Item 124] 12. The isolated synthetic immune receptor (SIR) polypeptide or polypeptide heterodimer of claim 111, wherein the one or more non-natural TCR antigen-binding domains have one or more light chain complementarity determining regions for a selected target antigen set forth in any of SEQ ID NOs: 13999-14879 or 14880, and / or one or more heavy chain complementarity determining regions for a selected target antigen set forth in any of SEQ ID NOs: 14881-15761 or 15762. [Item 125] 12. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 111, wherein the one or more non-naturally occurring TCR antigen-binding domains comprise a variable light chain (vL) domain having up to 10 conservative amino acid substitutions and comprising the sequence of any one of SEQ ID NOs: 2307-2482 or 12042-12159, and / or a variable heavy chain (vH) domain having up to 10 conservative amino acid substitutions and comprising the sequence of any one of SEQ ID NOs: 2506-2680 or 12160-12278. [Item 126] 12. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 111, wherein the one or more non-natural TCR antigen-binding domains have up to 10 conservative amino acid substitutions and comprise one or more camelid vHH complementarity determining regions for a selected antigen as set forth in any of SEQ ID NOs: 2701-2725 or 12279-12294. [Item 127] 112. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 111, wherein the one or more non-naturally occurring TCR antigen-binding domains have a sequence set forth in any of SEQ ID NOs: 2728-2732 or 12296-12301 and have a non-immunoglobulin antigen-binding domain containing up to 10 conservative amino acid substitutions. [Item 128] 12. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer according to Item 111, wherein the one or more non-natural TCR antigen-binding domains have an scFv domain comprising one or more light chain complementarity determining regions of a variable light chain (vL) domain having the sequence of any one of SEQ ID NOs: 2307 to 2482 or 12042 to 12159 and one or more heavy chain complementarity determining regions of a variable heavy chain (vH) domain having the sequence of any one of SEQ ID NOs: 2506 to 2680 or 12160 to 12278. [Item 129] 112. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of Item 111, wherein the one or more non-native TCR antigen-binding domains comprise an scFv fragment comprising a sequence selected from the group consisting of SEQ ID NOs: 2770-2939, 12303-12357, or 18162-18224, each with up to 10 conservative amino acid substitutions. [Item 130] 112. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of Item 111, wherein the one or more non-natural TCR antigen-binding domains have up to 10 conservative amino acid substitutions and comprise one or more receptors consisting of the amino acid sequence of any of SEQ ID NOs: 2736 to 2748. [Item 131] 112. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 111, wherein the one or more non-naturally occurring TCR antigen-binding domains have up to 10 conservative amino acid substitutions and have one or more ligands comprising the sequence of any of SEQ ID NOs: 2758-2768 or 12359-12361. [Item 132] 112. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 111, wherein the one or more non-native TCR antigen-binding domains have an extracellular domain of CD16A, NKG2D, CD4, PD1, desmoglein 3 (Dsg3), or CD4-DC-SIGN. [Item 133] 112. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 111, wherein the one or more non-native TCR antigen-binding domains comprise one or more extracellular domains of hTPO, mTPO, CGH α chain, CGH β chain, FH β chain, TSH β chain, APRIL, or a combination thereof. [Item 134] the one or more non-native TCR antigen-binding domains Any single-chain variable fragment (scFv) having any of SEQ ID NOs: 2770 to 2939, 12303 to 12357, or 18162 to 18224, and having up to 10 conservative amino acid substitutions; a) a camelid vHH as set forth in any of SEQ ID NOs: 2701-2725 or 12279-12294, having up to 10 conservative amino acid substitutions; or b) any non-immunoglobulin antigen-binding domain having a sequence set forth in any of SEQ ID NOs: 2728 to 2732 or 12296 to 12301 and having up to 10 conservative amino acid substitutions; or c) any extracellular domain of a receptor consisting of any of the amino acid sequences set forth in SEQ ID NOs: 2736 to 2748, with up to 10 conservative amino acid substitutions; or d) any extracellular domain of a ligand having any of SEQ ID NOs: 2758-2768 or 12359-12361, with up to 10 conservative amino acid substitutions; 112. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 111, having the following structure: [Item 135] the one or more non-native TCR antigen-binding domains A camelid vHH having up to 10 conservative amino acid substitutions and set forth in any of SEQ ID NOs: 2701 to 2725 or 12279 to 12294; a) any single chain variable fragment (scFv) having any of SEQ ID NOs: 2770 to 2939, 12303 to 12357, or 18162 to 18224, and having up to 10 conservative amino acid substitutions; or b) any non-immunoglobulin antigen-binding domain having a sequence set forth in any of SEQ ID NOs: 2728 to 2732 or 12296 to 12301 and having up to 10 conservative amino acid substitutions; or c) any extracellular domain of a receptor consisting of any of the amino acid sequences set forth in SEQ ID NOs: 2736 to 2748, with up to 10 conservative amino acid substitutions; or d) any extracellular domain of a ligand having any of SEQ ID NOs: 2758-2768 or 12359-12361, with up to 10 conservative amino acid substitutions; 112. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 111, having the following structure: [Item 136] 12. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 111, wherein the one or more non-natural TCR antigen-binding domains are optionally connected to each of the TCR constant regions by a linker region, wherein the nucleic acid of the linker region encodes an amino acid sequence selected from the group consisting of SEQ ID NOs: 2981-3003 and any combination thereof, or a sequence at least 98% identical thereto, or the linker is encoded by a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 701-725, or a sequence at least 98% identical thereto. [Item 137] 112. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 111, wherein the one or more non-natural TCR antigen-binding domains have a binding affinity for the target antigen that is at least 5-fold less than the antibody from which it is derived. [Item 138] 112. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 111, wherein the polynucleotide encoding the SIR further comprises a leader sequence or signal peptide present at the N-terminus of each chain and having a sequence selected from the group consisting of SEQ ID NOs: 1-9 and 10. [Item 139] 112. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 111, wherein the SIR comprises a SIR heterodimer. [Item 140] 112. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 111, wherein the polypeptide has two SIRs joined by a cleavable linker. [Item 141] 142. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 140, wherein the cleavable linker is a self-cleaving cleavable linker. 141. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 140, wherein the cleavable linker is any one or more of a 2A linker, a 2A-like linker, or functional equivalents thereof. [Item 143] 141. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 140, wherein the cleavable linker is any one or more of a T2A linker, a P2A, an F2A, an E2A linker, or functional equivalents thereof. [Item 144] 141. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of Item 140, wherein the cleavable linker has any one or more sequences of SEQ ID NOs: 780-785. [Item 145] 141. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 140, wherein the cleavable linker is optionally preceded by a furin cleavage site, a furin-like cleavage site, or a functional equivalent thereof. [Item 146] 146. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of Item 145, wherein the furin cleavage site preceding the cleavable linker has any one or more sequences of SEQ ID NOs: 788-790. [Item 147] 147. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of any one of items 140 to 146, wherein the cleavable linker is preceded by a flexible linker. [Item 148] 148. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 147, wherein the flexible linker preceding the cleavable linker encodes one or more of a Ser-Gly linker, a Ser-Gly-Ser-Gly linker, or a functional equivalent thereof. [Item 149] 148. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 147, wherein the flexible linker preceding the cleavable linker has the sequence of SEQ ID NOs: 786-787. [Item 150] 148. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of Item 147, wherein the furin cleavage site is followed by the flexible linker, which is followed by the cleavable linker, in the following order: furin cleavage site, flexible linker, cleavable linker. [Item 151] 112. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 111, wherein the SIRs are engineered to have diverse binding affinities for selected antigens. [Item 152] 112. An immune effector cell or stem cell comprising at least one polypeptide or heterodimer according to item 111. [Item 153] 2. An immune effector cell or stem cell comprising at least one recombinant polynucleotide according to item 1. [Item 154] 105. An immune effector or stem cell comprising at least one vector according to item 104. [Item 155] 155. The immune effector or stem cell of any one of items 152 to 154, comprising multiple SIR polypeptides. [Item 156] 156. The immune cell or stem cell of claim 155, wherein at least one SIR polypeptide of the plurality of SIR polypeptides targets a different antigen than at least one other SIR polypeptide. [Item 157] 156. The immune cell or stem cell of claim 155, wherein at least one SIR polypeptide of the plurality of SIR polypeptides targets the same antigen. [Item 158] 158. The immune cell or stem cell of claim 157, wherein at least one SIR polypeptide of the plurality of SIR polypeptides has a binding affinity for an antigen that is different from at least one other SIR polypeptide. [Item 159] 155. The immune cell or stem cell according to any one of items 152 to 154, wherein the immune cell further comprises at least one chimeric antigen receptor (CAR) polypeptide. [Item 160] 160. The immune cell or stem cell of item 159, wherein the antigen-binding domain of the SIR polypeptide targets a different antigen than the antigen-binding domain of the CAR polypeptide. [Item 161] 160. The immune cell or stem cell of paragraph 159, wherein the CAR polypeptide has an intracellular signaling domain that includes a costimulatory signaling domain but not the first signaling domain, or has an intracellular signaling domain that includes the first signaling domain but not the costimulatory signaling domain. [Item 162] 162. The immune cell or stem cell of paragraph 161, wherein the CAR polypeptide has a costimulatory signaling domain comprising a functional signaling domain of a protein selected from the group consisting of 4-1BB, CD28, CD27, or OX-40, or wherein the CAR polypeptide has a first signaling domain comprising a functional signaling domain of CD3ζ. [Item 163] 160. The immune cell or stem cell of item 159, wherein the CAR polypeptide is an inhibitory CAR polypeptide, which has an antigen-binding domain, a transmembrane domain, and an intracellular domain of an inhibitory molecule, and the inhibitory molecule is selected from the group consisting of PD1, PD-L1, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, TGFRβ, CEACAM-1, CEACAM-3, and CEACAM-5. [Item 164] 160. The immune cell or stem cell of paragraph 159, wherein the CAR polypeptide further comprises an intracellular signaling domain and / or an intracellular signaling domain comprising a first signaling domain, the intracellular signaling domain comprising a first signaling domain comprising a functional domain of CD3ζ and a costimulatory signaling domain comprising a functional domain of 4-1BB and / or CD28. [Item 165] Item 159. The immune cell or stem cell according to Item 159, wherein the CAR polypeptide has the amino acid sequence of SEQ ID NO: 3077 to SEQ ID NO: 3083. [Item 166] 155. The immune cell or stem cell according to any one of items 152 to 154, wherein the immune effector cell is optionally a human T cell, a human NKT cell, or a synthetic T cell capable of generating an immune effector cell, or a stem cell, and the T cell is diacylglycerol kinase (DGK) and / or Ikaros deficient and / or Brd4 deficient. [Item 167] 153. The population of immune cells or effector cells of paragraph 152, wherein the population of immune cells or effector cells comprises a plurality of different SIR polypeptides. [Item 168] 168. The population of immune cells or effector cells of paragraph 167, wherein the plurality of different SIR polypeptides have different sequences but bind to the same target antigen. [Item 169] 168. The population of immune or effector cells of paragraph 167, wherein the population of cells has SIR polypeptides that target different antigens present in a particular disease type. [Item 170] 10. A method for producing a SIR-expressing immune effector cell, the method comprising introducing at least one vector of paragraph 104 or at least one recombinant polynucleotide of paragraph 1 into an immune effector cell, or a hematopoietic stem or progenitor cell capable of developing into an immune effector cell, under conditions in which the SIR polypeptide is expressed. [Item 171] a) providing a population of immune effector cells; b) removing restricted T cells from said population, thereby providing restricted T-depleted cells; and steps a) and b) are performed prior to introducing the vector or a recombinant polynucleotide encoding the SIR into the population; Item 170. The method according to item 170. [Item 172] 172. The method of claim 171, wherein the restricted T cells are removed from the cell population using an anti-CD25 antibody or an anti-GITR antibody. [Item 173] a) providing a population of immune effector cells; b) enriching P-glycoprotein (P-gp or Pgp, MDR1, ABCB1, CD243) positive cells from said population, thereby providing a population of P-glycoprotein (P-gp or Pgp, MDR1, ABCB1, CD243) enriched cells; and 171. The method of claim 170, wherein steps a) and b) are performed before or after introducing the vector or a recombinant polynucleotide encoding the SIR. [Item 174] P-glycoprotein positive cells i) immunoselection using one or more of a cocktail of steps specific for P-glycoprotein; ii) staining with one or more fluorescent dyes that are substrates of P-glycoprotein, such as tetramethylrhodamine methyl ester (TMRM), adriamycin, and actinomycin D, under conditions in which P-glycoprotein is active as a pump, and enriching for cells that are poorly stained by the dyes; iii) selecting cells resistant to any one or more of the phototoxic compounds that are substrates of P-glycoprotein, such as TH9402, 2-(4,5-dibromo-6-amino-3-imino-3H-xanthen-9-yl)benzoic acid methyl ester hydrochloride, 2-(4,5-dibromo-6-amino-3-imino-3H-xanthen-9-yl)benzoic acid ethyl ester hydrochloride, 2-(4,5-dibromo-6-amino-3-imino-3H-xanthen-9-yl)benzoic acid octyl ester hydrochloride, 2-(4,5-dibromo-6-amino-3-imino-3H-xanthen-9-yl)benzoic acid n-butyl ester hydrochloride, 2-(6-ethylamino-3-ethylimino-3H-xanthen-9-yl)benzoic acid n-butyl ester hydrochloride, or derivatives thereof, or combinations thereof; iv) Selection of cells resistant to cytotoxic compounds that are substrates of P-glycoprotein, such as vincristine, vinblastine, taxol, paclitaxel, mitoxantrone, etoposide, adriamycin, daunorubicin, and actinomycin D; 174. The method of claim 173, wherein the analyte is concentrated using any one or more of the methods selected from the group consisting of: [Item 175] 1. A method for generating a population of RNA recombinant cells, comprising: 1. A method for the production of a recombinant polynucleotide comprising introducing in vitro transcribed RNA(s) or synthetic RNA(s) into a cell or a population of cells, wherein said RNA(s) comprise the recombinant polynucleotide(s) of item 1. method. [Item 176] 1. A method of providing disease-resistant immunity to a subject, comprising: Administering to the subject an effective amount of immune effector cells or stem cells capable of generating immune effector cells according to any one of Items 152 to 154, wherein the cells are autologous T cells, allogeneic T cells, autologous NKT cells, allogeneic NKT cells, autologous or allogeneic hematopoietic stem cells, or autologous or allogeneic iPSCs capable of generating immune effector cells. method. [Item 177] 177. The method of claim 176, wherein the allogeneic T cells, or allogeneic NKT cells, or hematopoietic stem cells, or iPSCs lack or have low expression of a functional TCR or functional HLA. [Item 178] 1. A composition comprising immune effector cells or stem cells capable of generating immune effector cells having one or more synthetic immune receptors (SIRs), for use in combination with an agent that increases the effectiveness of immune effector cells in treating a subject having a disease associated with expression of a disease-associated antigen, or in preventing a disease in a subject at increased risk for the disease associated with expression of a disease-associated antigen, comprising: (i) The SIR molecule comprises one or more T cell receptor constant chains linked, via an optional linker, to one or more antigen-binding domains that bind to disease-associated antigens, including CD5, CD19; CD123; CD22; CD30; CD171; CS-1 (also known as CD2 subset 1, CRACC, SLAMF7, CD319, and 19A24); C-type lectin-like molecule 1 (CLL-1 or CLECL1); CD33; epidermal growth factor receptor variant III (EGFRviii); ganglioside G2 (GD2); ganglioside GD3 (aNeu5Ac(2-8)aNeu5Ac(2-3)bDGalp(1-4)bDGlcp(1-1)Cer); TNF receptor family member B cell maturation (BCMA); Tn antigen ((Tn Ag) or (GalNAcα-Ser / Thr); prostate-specific membrane antigen (PSMA); receptor tyrosine kinase-like orphan receptor 1 (ROR1); FMS-like tyrosine kinase 3 (FLT3); tumor-associated glycoprotein 72 (TAG72); CD38; CD44v6; glycosylated CD43 epitope expressed in acute leukemia or lymphoma but not in hematopoietic progenitor cells, glycosylated CD43 epitope expressed in non-hematopoietic cancers; carcinoembryonic antigen (CEA); epithelial cell adhesion molecule (EPCAM); B7H3 (CD276); KIT (CD117); interleukin-13 receptor subunit alpha 2 (IL-13Ra2 or CD213A2); mesothelin; interleukin-11 receptor alpha (IL-11Ra); prostate stem cell Protease serine 21 (testisin or PRSS21); vascular endothelial growth factor receptor 2 (VEGFR2); Lewis (Y) antigen; CD24; platelet-derived growth factor receptor beta (PDGFR-β); stage-specific embryonic antigen 4 (SSEA-4); CD20; folate receptor α; receptor tyrosine protein kinase ERBB2 (Her2 / neu); mucin 1, cell surface associated (MUC1); epidermal growth factor receptor (EGFR); neural cell adhesion molecule (NCAM); prostase; prostatic acid phosphatase (PAP); elongation factor 2 mutated (ELF2M); ephrin B2; fibroblast activation protein α (FAP); insulin-like growth factor 1 receptor (IGF-1 receptor), carbonic anhydrase IX (CAIX);Proteasome (prosome, macropain) subunit, beta type 9 (LMP2); glycoprotein 100 (gp100); oncogene fusion protein consisting of the cleavage-prone region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (Ab1) (bcr-ab1); tyrosinase; ephrin type A receptor 2 (EphA2); fucosyl GM1; sialyl Lewis adhesion molecule (sLe); ganglioside GM3 (aNeu5Ac(2-3)bClalp(1-4)bDGlcp(1-1)Cer); transglutaminase 5 (T GS5); high molecular weight melanoma-associated antigen (HMWMAA); O-acetyl-GD2 ganglioside (OAcGD2); tumor endothelial marker 1 (TEM1 / CD248); tumor endothelial marker 7-related (TEM7R); claudin 6 (CLDN6); thyroid-stimulating hormone receptor (TSHR); G protein-coupled receptor class C group 5 member D (GPRC5D); chromosome X open reading frame 61 (CXORF61); CD97; CD179a; anaplastic lymphoma kinase (ALK); polysialic acid; placenta-specific 1 (PLA C1); hexasaccharide moiety of GloboH glycoceramide (GloboH); mammary differentiation antigen (NY-BR-1); uroplakin 2 (UPK2); hepatitis A virus cellular receptor 1 (HAVCR1); adrenergic receptor beta 3 (ADRB3), pannexin 3 (PANX3); G protein-coupled receptor 20 (GPR20), lymphocyte antigen 6 complex locus K9 (LY6K), olfactory receptor 51E2 (OR51E2); TCR gamma alternative reading frame protein (TARP); Wilms tumor protein (WT1); cancer / testis antigen 1 (N Y-ES0-1); cancer / testis 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); X antigen family member 1A (XAGE1); angiopoietin-binding cell surface receptor 2 (Tie2); melanoma cancer-testis antigen 1 (MAD-CT-1); melanoma cancer-testis antigen 2 (MAD-CT-2); Fos-related antigen 1; tumor protein p53 (p53); p53 mutant; prostein; survivin; telomerase;Prostate carcinoma antigen 1 (PCT A-1 or galectin-8), melanoma antigen 1 recognized by T cells (MelanA or MARTI); rat sarcoma (Ras) mutants; human telomerase reverse transcriptase (hTERT); sarcoma translocation breakpoints; melanoma inhibitor of apoptosis (ML-IAP); ERG (transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene); N-acetylglucosaminyltransferase V (NA17); paired box protein Pax-3 (PAX3); androgen receptor; cyclin B1; neuroblastoma-derived homolog of v-myc avian myelocytomatosis viral oncogene (MYCN); Ras homolog family member C (RhoC); tyrosinase-related protein 2 (TRP-2); cytochrome P4501B1 (CYP1B1); CCCTC-binding factor (zinc finger protein)-like (BORIS or Brother of the Regulator of Imprinted Ribosomal Proteins) Sites), squamous cell carcinoma antigen 3 recognized by T cells (SART3); paired box protein Pax-5 (PAX5); proacrosin-binding protein sp32 (OY-TES1); lymphocyte-specific protein tyrosine kinase (LCK); A-kinase anchor protein 4 (AKAP-4); synovial sarcoma, X-breakpoint 2 (SSX2); receptor for advanced glycation end products (RAGE-1); renal ubiquitous 1 (RU1); renal ubiquitous 2 (RU2); legumain; human papillomavirus E6 (HPV E6); human papillomavirus E7 (HPV E7); intestinal carboxylesterase; heat shock protein 70-2 mutant (mut hsp 70-2); CD79a; CD79b; CD72; leukocyte-associated immunoglobulin-like receptor 1 (LAIR1); Fc fragment of IgA receptor (FCAR or CD89); leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2); CD300 molecule-like family member f (CD300LF); C-type lectin domain family 12 member A (CLEC12A); bone marrow stromal cell antigen 2 (BST2); EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2); lymphocyte antigen 75 (LY75); glypican 3 (GPC3); Fc receptor-like 5 (FCRL5);and immunoglobulin lambda-like polypeptide 1 (IGLL1), MPL, biotin, c-MYC epitope tag, CD34, LAMP1 TROP2, GFRalpha4, CDH17, CDH6, NYBR1, CDH19, CD200R, Slea (CA19.9; sialyl Lewis antigen) fucosyl GM1, PTK7, gpNMB, CDH1-CD324, DLL3, CD276 / B7H3, IL11Ra, IL13Ra2, CD179b-IGL11, ALK TCRγδ, NKG2D, CD32 (FCGR2A), CSPG4-HMW-MAA, Timl- / HVCR1, CSF2RA (GM-CSFRα), TGFβR2, VEGFR2 / KDR, Lewis Ag, TCRβ chain, TCRβ2 chain, TCRγ chain, TCRδ chain, FITC, luteinizing hormone receptor (LHR), follicle-stimulating hormone receptor (FSHR), chorionic gonadotropin receptor (CGHR), CCR4, SLAMF6, SLAMF4, HIV 1 envelope glycoprotein, HTLV1-Tax, CMVpp65, EBV-EBNA3c, influenza A hemagglutinin (HA), GAD, PDL1, guanylyl cyclase C (GCC), KSHV-K8.1 protein, KSHV-gH protein, autoantibodies against desmoglein 3 (Dsg3), autoantibodies against desmoglein 1 (Dsg1), HLA, HLA-A, HLA-A2, HLA-B, HLA-C, HLA-DP; selected from the group consisting of antigens recognized by HLA-DM, HLA-DOA, HLA-DOB, HLA-DQ, HLA-DR, HLA-G, IGE, CD99, RAS G12V, tissue factor 1 (TF1), AFP, GPRC5D, claudin 18.2 (CLD18A2 or CLDN18A.2), P-glycoprotein, STEAP1, LIV1, NECTIN-4, CRIPTO, GPA33, BST1 / CD157, small conductance chloride channel, and TNT antibodies; (ii) an agent for increasing the effect of the immune cells, a protein phosphatase inhibitor, a kinase inhibitor (e.g., a P13K / AKT inhibitor, an mTOR inhibitor, an LCK inhibitor, or a BTK inhibitor), -Cytokines and -inhibitors of immunosuppressive molecules, -T REG an agent that reduces the level or activity of a cell; - an agent that increases the proliferation and maintenance of SIR-modified cells; - Chemokines and an agent that increases the expression of SIR; - an agent that allows for modulation of the expression or activity of a SIR; - an agent that allows for the control of survival and / or maintenance of SIR-modified cells; - an agent that controls the side effects of SIR-modified cells; -Brd4 inhibitors, - an agent that delivers a therapeutic (e.g., sHVEM) or prophylactic agent to the site of disease; - an agent that increases the expression of the antigen targeted by the SIR; an adenosine A2a receptor antagonist; Selected from one or more of composition. [Item 179] 1. A method of treating or preventing a disease associated with expression of a disease-associated antigen in a subject, comprising: administering to the subject an effective amount of immune effector cells having a synthetic immune receptor (SIR) molecule in combination with an agent that increases the effectiveness of the immune cells; (i) The SIR molecule comprises one or more T cell receptor constant chains linked, via an optional linker, to one or more antigen-binding domains that bind to disease-associated antigens, including CD5, CD19; CD123; CD22; CD30; CD171; CS-1 (also known as CD2 subset 1, CRACC, SLAMF7, CD319, and 19A24); C-type lectin-like molecule 1 (CLL-1 or CLECL1); CD33; epidermal growth factor receptor variant III (EGFRviii); ganglioside G2 (GD2); ganglioside GD3 (aNeu5Ac(2-8)aNeu5Ac(2-3)bDGalp(1-4)bDGlcp(1-1)Cer); TNF receptor family member B cell maturation (BCMA); Tn antigen ((Tn Ag) or (GalNAcα-Ser / Thr); prostate-specific membrane antigen (PSMA); receptor tyrosine kinase-like orphan receptor 1 (ROR1); FMS-like tyrosine kinase 3 (FLT3); tumor-associated glycoprotein 72 (TAG72); CD38; CD44v6; glycosylated CD43 epitope expressed in acute leukemia or lymphoma but not in hematopoietic progenitor cells, glycosylated CD43 epitope expressed in non-hematopoietic cancers; carcinoembryonic antigen (CEA); epithelial cell adhesion molecule (EPCAM); B7H3 (CD276); KIT (CD117); interleukin-13 receptor subunit alpha 2 (IL-13Ra2 or CD213A2); mesothelin; interleukin-11 receptor alpha (IL-11Ra); prostate stem cell Protease serine 21 (testisin or PRSS21); vascular endothelial growth factor receptor 2 (VEGFR2); Lewis (Y) antigen; CD24; platelet-derived growth factor receptor beta (PDGFR-β); stage-specific embryonic antigen 4 (SSEA-4); CD20; folate receptor α; receptor tyrosine protein kinase ERBB2 (Her2 / neu); mucin 1, cell surface associated (MUC1); epidermal growth factor receptor (EGFR); neural cell adhesion molecule (NCAM); prostase; prostatic acid phosphatase (PAP); elongation factor 2 mutated (ELF2M); ephrin B2; fibroblast activation protein α (FAP); insulin-like growth factor 1 receptor (IGF-1 receptor), carbonic anhydrase IX (CAIX);Proteasome (prosome, macropain) subunit, beta type 9 (LMP2); glycoprotein 100 (gp100); oncogene fusion protein consisting of the cleavage-prone region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (Ab1) (bcr-ab1); tyrosinase; ephrin type A receptor 2 (EphA2); fucosyl GM1; sialyl Lewis adhesion molecule (sLe); ganglioside GM3 (aNeu5Ac(2-3)bClalp(1-4)bDGlcp(1-1)Cer); transglutaminase 5 (TG S5); high-molecular-weight melanoma-associated antigen (HMWMAA); O-acetyl-GD2 ganglioside (OAcGD2); folate receptor beta; tumor endothelial marker 1 (TEM1 / CD248); tumor endothelial marker 7-related (TEM7R); claudin 6 (CLDN6); thyroid-stimulating hormone receptor (TSHR); G protein-coupled receptor class C group 5 member D (GPRC5D); chromosome X open reading frame 61 (CXORF61); CD97; CD179a; anaplastic lymphoma kinase (ALK); polysialic acid; placenta-specific 1 (PLAC1); hexasaccharide moiety of GloboH glycoceramide (GloboH); mammary differentiation antigen (NY-BR-1); uroplakin 2 (UPK2); hepatitis A virus cell receptor 1 (HAVCR1); adrenergic receptor beta 3 (ADRB3), pannexin 3 (PANX3); G protein-coupled receptor 20 (GPR20), lymphocyte antigen 6 complex locus K9 (LY6K), olfactory receptor 51E2 (OR51E2); TCR gamma alternative reading frame protein (TARP); Wilms tumor protein (WT1); cancer / testis antigen 1 (NY-ES0-1); cancer / testis 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); X antigen family member 1A (XAGE1); angiopoietin-binding cell surface receptor 2 (Tie2); melanoma cancer-testis antigen 1 (MAD-CT-1); melanoma cancer-testis antigen 2 (MAD-CT-2); Fos-related antigen 1; tumor protein p53 (p53); p53 mutant; prostein; survivin; telomerase;Prostate carcinoma antigen 1 (PCT A-1 or galectin-8), melanoma antigen 1 recognized by T cells (MelanA or MARTI); rat sarcoma (Ras) mutants; human telomerase reverse transcriptase (hTERT); sarcoma translocation breakpoints; melanoma inhibitor of apoptosis (ML-IAP); ERG (transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene); N-acetylglucosaminyltransferase V (NA17); paired box protein Pax-3 (PAX3); androgen receptor; cyclin B1; neuroblastoma-derived homolog of v-myc avian myelocytomatosis viral oncogene (MYCN); Ras homolog family member C (RhoC); tyrosinase-related protein 2 (TRP-2); cytochrome P4501B1 (CYP1B1); CCCTC-binding factor (zinc finger protein)-like (BORIS or Brother of the Regulator of Imprinted Ribosomal Proteins) Sites), squamous cell carcinoma antigen 3 recognized by T cells (SART3); paired box protein Pax-5 (PAX5); proacrosin-binding protein sp32 (OY-TES1); lymphocyte-specific protein tyrosine kinase (LCK); A-kinase anchor protein 4 (AKAP-4); synovial sarcoma, X-breakpoint 2 (SSX2); receptor for advanced glycation end products (RAGE-1); renal ubiquitous 1 (RU1); renal ubiquitous 2 (RU2); legumain; human papillomavirus E6 (HPV E6); human papillomavirus E7 (HPV E7); intestinal carboxylesterase; heat shock protein 70-2 mutant (mut hsp 70-2); CD79a; CD79b; CD72; leukocyte-associated immunoglobulin-like receptor 1 (LAIR1); Fc fragment of IgA receptor (FCAR or CD89); leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2); CD300 molecule-like family member f (CD300LF); C-type lectin domain family 12 member A (CLEC12A); bone marrow stromal cell antigen 2 (BST2); EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2); lymphocyte antigen 75 (LY75); glypican 3 (GPC3); Fc receptor-like 5 (FCRL5);and immunoglobulin lambda-like polypeptide 1 (IGLL1), MPL, biotin, c-MYC epitope tag, CD34, LAMP1 TROP2, GFRalpha4, CDH17, CDH6, NYBR1, CDH19, CD200R, Slea (CA19.9; sialyl Lewis antigen) fucosyl GM1, PTK7, gpNMB, CDH1-CD324, DLL3, CD276 / B7H3, IL11Ra, IL13Ra2, CD179b-IGL11, ALK TCRγδ, NKG2D, CD32 (FCGR2A), CSPG4-HMW-MAA, Timl- / HVCR1, CSF2RA (GM-CSFRα), TGFβR2, VEGFR2 / KDR, Lewis Ag, TCRβ chain, TCRβ2 chain, TCRγ chain, TCRδ chain, FITC, luteinizing hormone receptor (LHR), follicle-stimulating hormone receptor (FSHR), chorionic gonadotropin receptor (CGHR), CCR4, SLAMF6, SLAMF4, HIV1 envelope glycoprotein, HTLV-1-Tax, CMV pp65, EBV-EBNA3c, influenza A hemagglutinin (HA), GAD, PDL1, guanylyl cyclase C (GCC), KSHV-K8.1 protein, KSHV-gH protein, autoantibodies to desmoglein 3 (Dsg3), autoantibodies to desmoglein 1 (Dsg1), 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 selected from the group consisting of antigens recognized by G12V, tissue factor 1 (TF1), AFP, GPRC5D, claudin 18.2 (CLD18A2 or CLDN18A.2), P-glycoprotein, STEAP1, LIV1, NECTIN-4, CRIPTO, GPA33, BST1 / CD157, small conductance chloride channel, and TNT antibodies; (ii) an agent for increasing the effect of the immune cells, a protein phosphatase inhibitor, a kinase inhibitor (e.g., a P13K / AKT inhibitor, an mTOR inhibitor, an LCK inhibitor, or a BTK inhibitor), -Cytokines and -inhibitors of immunosuppressive molecules, -T REG an agent that reduces the level or activity of a cell; - an agent that increases the proliferation and maintenance of SIR-modified cells; - Chemokines and an agent that increases the expression of SIR; - an agent that allows for modulation of the expression or activity of a SIR; - an agent that allows for the control of survival and / or maintenance of SIR-modified cells; - an agent that controls the side effects of SIR-modified cells; -Brd4 inhibitors, - an agent that delivers a therapeutic (e.g., sHVEM) or prophylactic agent to the site of disease; - an agent that increases the expression of the antigen targeted by the SIR; an adenosine A2a receptor antagonist; thereby treating said subject or preventing disease in said subject; method. [Item 180] 1. A method of treating or preventing a disease associated with expression of a disease-associated antigen in a subject, comprising: administering to the subject an effective amount of immune effector cells comprising a synthetic immune receptor (SIR) molecule; (i) The SIR molecule comprises one or more T cell receptor constant chains linked, via an optional linker, to one or more antigen-binding domains that bind to disease-associated antigens, including CD5, CD19; CD123; CD22; CD23; CD30; CD171; CS-1 (also known as CD2 subset 1, CRACC, SLAMF7, CD319, and 19A24); C-type lectin-like molecule 1 (CLL-1 or CLECL1); CD33; epidermal growth factor receptor variant III (EGFRviii); ganglioside G2 (GD2); ganglioside GD3 (aNeu5Ac(2-8)aNeu5Ac(2-3)bDGalp(1-4)bDGlcp(1-1)Cer); TNF receptor family member B cell maturation (BCMA); Tn antigen ((Tn Ag) or (GalNAcα-Ser / Thr); prostate-specific membrane antigen (PSMA); receptor tyrosine kinase-like orphan receptor 1 (ROR1); FMS-like tyrosine kinase 3 (FLT3); tumor-associated glycoprotein 72 (TAG72); CD38; CD44v6; glycosylated CD43 epitope expressed in acute leukemia or lymphoma but not in hematopoietic progenitor cells, glycosylated CD43 epitope expressed in non-hematopoietic cancers; carcinoembryonic antigen (CEA); epithelial cell adhesion molecule (EPCAM); B7H3 (CD276); KIT (CD117); interleukin-13 receptor subunit alpha 2 (IL-13Ra2 or CD213A2); mesothelin; interleukin-11 receptor alpha (IL-11 Ra); 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-β); stage-specific embryonic antigen 4 (SSEA-4); CD20; folate receptor alpha (FRa or FR1); folate receptor beta (FRb); receptor tyrosine protein kinase ERBB2 (Her2 / neu); mucin 1, cell surface associated (MUC1); epidermal growth factor receptor (EGFR); neural cell adhesion molecule (NCAM); prostase; prostatic acid phosphatase (PAP); elongation factor 2 mutated (ELF2M); ephrin B2; fibroblast activation protein alpha (FAP);Insulin-like growth factor 1 receptor (IGF-1 receptor), carbonic anhydrase IX (CAIX); proteasome (prosome, macropain) subunit, beta type 9 (LMP2); glycoprotein 100 (gp100); oncogene fusion protein consisting of the cleavage-prone region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (Ab1) (bcr-ab1); tyrosinase; ephrin type A receptor 2 (EphA2); fucosyl GM1; sialyl Lewis adhesion molecule (sLe); ganglioside GM3 (aNeu5Ac(2-3)bClalp(1-4)) bDGlcp(1-1)Cer; transglutaminase 5 (TGS5); high-molecular-weight melanoma-associated antigen (HMWMAA); O-acetyl-GD2 ganglioside (OAcGD2); tumor endothelial marker 1 (TEM1 / CD248); tumor endothelial marker 7-related (TEM7R); claudin 6 (CLDN6); thyroid-stimulating hormone receptor (TSHR); G protein-coupled receptor class C group 5 member D (GPRC5D); chromosome X open reading frame 61 (CXORF61); CD97; CD179a; anaplastic lymphoma kinase (ALK) K); polysialic acid; placenta-specific 1 (PLAC1); hexasaccharide moiety of globo-H glycoceramide (GloboH); mammary differentiation antigen (NY-BR-1); uroplakin 2 (UPK2); hepatitis A virus cellular receptor 1 (HAVCR1); adrenergic receptor beta 3 (ADRB3), pannexin 3 (PANX3); G protein-coupled receptor 20 (GPR20), lymphocyte antigen 6 complex locus K9 (LY6K), olfactory receptor 51E2 (OR51E2); TCR gamma alternative reading frame protein (TARP); Wilms tumor protein (WT1) ; cancer / testis antigen 1 (NY-ES0-1); cancer / testis 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); X antigen family member 1A (XAGE1); angiopoietin-binding cell surface receptor 2 (Tie2); melanoma cancer-testis antigen 1 (MAD-CT-1); melanoma cancer-testis antigen 2 (MAD-CT-2); Fos-related antigen 1; tumor protein p53 (p53); p53 mutant; prostein; survivin; telomerase;Prostate carcinoma antigen 1 (PCT A-1 or galectin-8), melanoma antigen 1 recognized by T cells (MelanA or MARTI); rat sarcoma (Ras) mutants; human telomerase reverse transcriptase (hTERT); sarcoma translocation breakpoints; melanoma inhibitor of apoptosis (ML-IAP); ERG (transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene); N-acetylglucosaminyltransferase V (NA17); paired box protein Pax-3 (PAX3); androgen receptor; cyclin B1; neuroblastoma-derived homolog of v-myc avian myelocytomatosis viral oncogene (MYCN); Ras homolog family member C (RhoC); tyrosinase-related protein 2 (TRP-2); cytochrome P4501B1 (CYP1B1); CCCTC-binding factor (zinc finger protein)-like (BORIS or Brother of the Regulator of Imprinted Ribosomal Proteins) Sites), squamous cell carcinoma antigen 3 recognized by T cells (SART3); paired box protein Pax-5 (PAX5); proacrosin-binding protein sp32 (OY-TES1); lymphocyte-specific protein tyrosine kinase (LCK); A-kinase anchor protein 4 (AKAP-4); synovial sarcoma, X-breakpoint 2 (SSX2); receptor for advanced glycation end products (RAGE-1); renal ubiquitous 1 (RU1); renal ubiquitous 2 (RU2); legumain; human papillomavirus E6 (HPV E6); human papillomavirus E7 (HPV E7); intestinal carboxylesterase; heat shock protein 70-2 mutant (mut hsp 70-2); CD79a; CD79b; CD72; leukocyte-associated immunoglobulin-like receptor 1 (LAIR1); Fc fragment of IgA receptor (FCAR or CD89); leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2); CD300 molecule-like family member f (CD300LF); C-type lectin domain family 12 member A (CLEC12A); bone marrow stromal cell antigen 2 (BST2); EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2); lymphocyte antigen 75 (LY75); glypican 3 (GPC3); Fc receptor-like 5 (FCRL5);and immunoglobulin lambda-like polypeptide 1 (IGLL1), MPL, biotin, c-MYC epitope tag, CD34, LAMP1 TROP2, GFRalpha4, CDH17, CDH6, NYBR1, CDH19, CD200R, Slea (CA19.9; sialyl Lewis antigen) fucosyl GM1, PTK7, gpNMB, CDH1-CD324, DLL3, CD276 / B7H3, IL11Ra, IL13Ra2, CD179b-IGL11, TCRγδ, NKG2D, CD32(FCGR2A), Timl- / HVCR1, CS F2RA (GM-CSFRα), TGFβR2, Lewis Ag, TCRβ chain, TCRβ2 chain, TCRγ chain, TCRδ chain, FITC, luteinizing hormone receptor (LHR), follicle-stimulating hormone receptor (FSHR), chorionic gonadotropin receptor (CGHR), CCR4, SLAMF6, SLAMF4, HIV1 envelope glycoprotein, HTLV1-Tax, CMVpp65, EBV-EBNA3c, KSHV K8.1, KSHV-gH, influenza A hemagglutinin (HA), GAD, PDL1, guanylyl cyclase C (GCC), KSHV-K8.1 protein, KSHV-gH protein, autoantibodies to desmoglein 3 (Dsg3), autoantibodies to desmoglein 1 (Dsg1), 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 selected from the group consisting of antigens recognized by G12V, tissue factor 1 (TF1), AFP, GPRC5D, claudin 18.2 (CLD18A2 or CLDN18A.2), P-glycoprotein, STEAP1, LIV1, NECTIN-4, CRIPTO, GPA33, BST1 / CD157, small conductance chloride channel, and TNT antibodies; (ii) the antigen-binding domain of the SIR molecule has a binding affinity that is at least 5-fold less than that of the antibody from which the antigen-binding domain was derived; method. [Item 181] 181. The use or method of any one of items 178 to 180, wherein the disease associated with expression of said disease-associated antigen is selected from the group consisting of hyperplasia, precancerous conditions, cancer, and non-cancer related indications associated with said disease-associated expression. [Item 182] The cancers include chronic lymphocytic leukemia (CLL), acute leukemia, acute lymphoblastic leukemia (ALL), B-cell acute lymphoblastic leukemia (B-ALL), T-cell acute lymphoblastic leukemia (T-ALL), chronic myeloid leukemia (CML), B-cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt's lymphoma, diffuse large B-cell lymphoma, primary effusion lymphoma, follicular lymphoma, hairy cell lymphoma, small cell lymphoma, and the like. 184. The use or method of item 183, wherein the hematological cancer is selected from one or more of: small cell or large cell follicular lymphoma, malignant lymphoproliferative conditions, MALT lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndromes, non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom's macroglobulinemia, and preleukemia. [Item 183] The cancers include colon cancer, rectal cancer, renal cell carcinoma, liver cancer, non-small cell lung cancer, small intestine cancer, esophageal cancer, melanoma, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, 184. The use or method of item 183, wherein the cancer is selected from the group consisting of: carcinoma, penile cancer, pediatric solid tumors, bladder cancer, cancer of the kidney or ureter, renal pelvis cancer, tumors of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, Merkel cell carcinoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancers, combinations of said cancers, and metastases of said cancers. [Item 184] The disease is associated with a viral infection, including, but not limited to, HIV1, HIV2, HTLV1, Epstein-Barr virus (EBV), cytomegalovirus, adenovirus, adeno-associated virus, BK virus, human herpesvirus 6, human herpesvirus 8, influenza virus, parainfluenza virus, avian influenza virus, MERS and SARS coronavirus, Crimean-Congo hemorrhagic fever virus, rhinovirus, enterovirus, dengue virus, West Nile virus, Ebola virus, Marburg virus, and Lassa fever. [Item 185] The use or method of item 183, including viruses, Zika virus, RSV, measles virus, mumps virus, rhinovirus, varicella virus types 1 and 2, varicella zoster virus, HIV-1, HTLV-1, hepatitis viruses, enteroviruses, hepatitis B virus, hepatitis C virus, Nipah and Rift Valley fever virus, Japanese encephalitis virus, Merkel cell polyomavirus or viruses associated with Mycobacterium tuberculosis infection, atypical mycobacterial species, Pneumocystis jiroveci, toxoplasmosis, rickettsii, Nocardia, Aspergillus, Mucor, and Candida. 184. The use or method of item 183, wherein the disease is an immune disease or a degenerative disease, including but not limited to diabetes mellitus, multiple sclerosis, rheumatoid arthritis, pemphigus vulgaris, ankylosing spondylitis, Hashimoto's thyroiditis, SLE, sarcoidosis, scleroderma, mixed connective tissue disease, graft-versus-host disease, and Alzheimer's disease. [Item 186] (i) the protein phosphatase inhibitor is an SHP-1 inhibitor and / or an SHP-2 inhibitor; (ii) the kinase inhibitor is selected from one or more of a CDK4 inhibitor, a CDK4 / 6 inhibitor, an mTOR inhibitor, an MNK inhibitor, and a redundant P13K / mTOR inhibitor; (iii) the agent that inhibits the immunosuppressive factor comprises an antibody or antibody fragment, an inhibitory nucleic acid, a clustered regularly interspaced short palindromic repeats (CRISPR), a TAL effector nuclease (TALEN), or a zinc finger endonuclease (ZFN), which inhibits expression of the inhibitory molecule; (iv) the agent that decreases the level or activity of TREG cells is selected from cyclophosphamide, an anti-GITR antibody, CD25 depletion, or a combination thereof; and / or (v) The Brd4 inhibitor is selected from JQ1, MS417, OTXO15, LY303511, and Brd4 inhibitors described in U.S. Patent No. 20140256706A1, or derivatives thereof; 175. The use or method according to any of items 178 to 180 or 182 to 184. [Item 187] 185. The use or method of any of items 178 to 180 or 182 to 184, wherein the immunosuppressant is selected from the group consisting of PD1, PD-L1, CTLA-4, TIM-3, LAG-3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, TGFRβ, CEACAM-1, CEACAM-3, and CEACAM-5. [Item 188] 185. The use or method of any of items 178-180 or 182-184, wherein the agent that inhibits the inhibitory molecule comprises a first polypeptide comprising the inhibitory molecule or a fragment thereof and a second polypeptide that provides a positive signal to the cell, the first and second polypeptides being expressed on the SIR-containing immune cell, and (i) the first polypeptide is PD1, PD-L1, CTLA-4, TIM-3, LAG-3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, TGFRβ, CEACAM-1, CEACAM-3, and CEACAM-5, or a fragment thereof, and / or the second polypeptide has an intracellular signaling domain comprising a first signaling domain and / or a costimulatory signaling domain. [Item 189] 189. The use or method of paragraph 188, wherein the first signaling domain comprises a functional domain of CD3ζ and / or the costimulatory signaling domain comprises a functional domain of a protein selected from 41BB, CD27, and CD28. [Item 190] 185. The use or method according to any of items 178 to 180 or 182 to 184, wherein the cytokine is selected from IL-15 and / or IL-21. [Item 191] 185. The use or method of any of paragraphs 178-180 or 182-184, wherein the immune effector cells comprising the SIR molecule(s) and the agent that increases the effect of the immune effector cells are administered substantially simultaneously or sequentially. [Item 192] 192. The use or method of item 191, wherein the SIR molecule is administered in combination with a molecule that targets GITR and / or modulates GITR function. [Item 193] 193. The use or method of item 192, wherein the molecule targeting GITR and / or the molecule modulating GITR function is administered prior to the SIR-expressing cell or cell population or prior to apheresis. [Item 194] 185. The use or method of any of items 178-180 or 182-184, wherein the subject is a human. [Item 195] 1. A composition comprising: A method for producing a recombinant human SIR cell comprising: at least one polynucleotide according to item 1; an SIR polypeptide molecule according to item 111; a vector according to item 104 or a cell according to any one of items 152 to 153; and a pharmaceutically acceptable excipient. composition. [Item 196] A kit comprising: comprising at least one polynucleotide according to item 1, an SIR polypeptide molecule according to item 111, a vector according to item 104 or a cell according to any one of items 152-153, and / or a composition according to item 144; kit. [Item 197] 1. A recombinant polynucleotide comprising: or having a sequence selected from the group consisting of SEQ ID NOs: 900 to 2264, 4531 to 6013, 7519 to 8160, 8803 to 9230, 9659 to 9856, 10474 to 12041, 15786 to 16011, 16240 to 16465, 16694 to 16926, 17162 to 17394, 17864 to 17979, 18321 to 18322, 18242 to 18259, 18280 to 18588, 18899, and 18915 to 18916, and 19248 to 19246, or having a sequence selected from the group consisting of SEQ ID NOs: 900 to 2264, SEQ ID NO: 4531 a nucleotide sequence encoding a synthetic immunoreceptor having a sequence at least 75% identical to a nucleotide sequence encoding a synthetic immunoreceptor set forth in any one of SEQ ID NOs: 16013, 16240, 16465, 16694, 16926, 17162, 17394, 17864, 17979, 18321, 18322, 18242, 18259, 18280, 18588, 18899, 18915, 18916, and 19248, 19246; Recombinant polynucleotides. [Item 198] An amino acid sequence comprising: an amino acid sequence encoding a synthetic immunoreceptor polypeptide selected from the group consisting of SEQ ID NOs: 3135 to 4498, SEQ ID NOs: 6044 to 7518, SEQ ID NOs: 8161 to 8802, SEQ ID NOs: 9231 to 9658, SEQ ID NOs: 9873 to 10070, SEQ ID NOs: 12431 to 13998, SEQ ID NOs: 16013 to 16238, SEQ ID NOs: 16467 to 16692, SEQ ID NOs: 16928 to 17160, SEQ ID NOs: 17396 to 17628, SEQ ID NOs: 17981 to 18096, SEQ ID NOs: 18239 to 18240, SEQ ID NOs: 18261 to 18278, SEQ ID NOs: 18590 to 18898, SEQ ID NO: 18900, and SEQ ID NOs: 18919 to 18920, and SEQ ID NOs: 19248 to 19246, or a sequence that is at least 75% identical to an amino acid sequence encoding the synthetic immunoreceptor polypeptide set forth in any one of SEQ ID NOs: 35 to 4498, 6044 to 7518, 8161 to 8802, 9231 to 9658, 9873 to 10070, 12431 to 13998, 16013 to 16238, 16467 to 16692, 16928 to 17160, 17396 to 17628, 17981 to 18096, 18239 to 18240, 18261 to 18278, 18590 to 18898, 18900, 18919 to 18920, and 19248 to 19246. Amino acid sequence. [Brief explanation of the drawings]

[0031] The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description, drawings, and claims.

[0032] [Figure 1] Figure 1 shows a schematic diagram of different generations of antibodies, TCRs, dual-chain chimeric receptors, and CARs. [Figure 2] FIG. 2 shows an exemplary vector construct of the present disclosure. [Figure 3]Figures 3A-3Q show diagrams of various formats that the SIRs of the present disclosure may take upon expression. In such diagrams, each TCR of a TCR pair is linked to a vH or vL binding domain. In other embodiments, each TCR is linked to a vHH domain rather than a vH or vL. [Figure 4] Figures 4A-4Q. Figures 4A-4Q show diagrams of various formats that the SIRs of the present disclosure may take upon expression. In these diagrams, one TCR of a TCR pair is linked to a vH or vL, which in turn is linked to the opposite vH or vL. In (A), the vL is shown linked to the TCRb chain, but it will be recognized that in all diagrams (A)-(Q), the orientation is interchangeable (e.g., in (A), the vL is linked to the TCRa). [Figure 5] Figures 5A-5Q show diagrams of various formats that the SIRs of the present disclosure can take. In such constructs, the SIRs are based on a single-domain antibody (vHH) that binds only one of the two TCR constant chains, leaving the other chain free. An exemplary such construct is CD8SP-V5-[hTCRb-KACIAH]-F-P2A-CD8SP-Her3-17B05So-vHH-Myc-[hTCRa-CSDVP]-F-F2A-PAC [SEQ ID NO: 1715]. Similar constructs can also be made based on other non-immunoglobulin binding domains instead of the vHH domain. For example, such non-immunoglobulin binding domains can be based on affibodies, DARPINs, autoantigens (e.g., Dsg3), ligands (e.g., MPL or TRAIL), or receptors (e.g., CD16). [Figure 6]Figures 6A-6Q. Figures 6A-Q show diagrams of various formats that the SIR of the present disclosure can take. In such constructs, the SIR contains two structurally distinct types of antigen-binding domains. In one example, one antigen-binding domain consists of a single-domain antibody, and the other antigen-binding domain consists of an scFV fragment in a vL / linker / vH or vH / linker / vL orientation. In another example, one antigen-binding domain consists of a single-domain antibody, and the other antigen-binding domain consists of a receptor (e.g., CD16). In another example, one antigen-binding domain consists of a single-domain antibody, and the other antigen-binding domain consists of an affibody. The advantage of using two different types of antigen-binding domains is that they are less likely to interfere with each other. The first antigen-binding domain (e.g., a vHH) can be directed against one antigen, and the second antigen-binding domain (e.g., an scFV fragment) can be directed against a different antigen. Alternatively, both can be directed against the same antigen to increase avidity. [Figure 7] Figures 7A-7Q show diagrams of various formats that the SIR of the present disclosure can take. In such constructs, the SIR is based on two dcFv fragments. The two scFv fragments may be directed against two different antigens (e.g., CD8SP-CD19Bu12-scFv-V5-[hTCRb-KACIAH]-F-P2A-SP-CD20-2F2-scFv-Myc-[hTCRa-CSDVP]-F-F2A-PAC(040716-B04) (SEQ ID NO: 1028)). Alternatively, to increase avidity, both may be directed against the same antigen (e.g., CD8SP-CD19Bu12-scFv-V5-[hTCRb-KACIAH]-F-P2A-SP-FMC63-scFv-Myc-[hTCRa-CSDVP]-F-F2A-PAC(020216-B07) (SEQ ID NO: 1026)). The scFv may be in the format vH / linker / vL or vL / linker / vH. [Figure 8]Figures 8A-8T. Figures 8A-T show diagrams of various formats that the SIRs of the present disclosure can take. In some SIR constructs, an scFv fragment consisting of a signal peptide (e.g., derived from the human CD8 signal peptide) is fused in frame to the vL region through a Gly-Ser linker (GGGGSx3), and the vH region is fused to the Cα, Cβ, pre-Cα, Cδ, or Cγ chain, with no complementary chain present. [Figure 9A] Figures 9A-9B. Figures 9A-B show NLuc assays measuring CAR expression in 293FT cells. Untransduced 293FT cells and cells transduced with CD19 (FMC63-BBZ-PAC) and 161-BBZ-PAC CARs were cultured with CD19-GGSG-NLuc-AcV5 and MPL-GGSG-NLuc-AcV5 supernatants, washed with PBS, and NLuc activity was measured with coelenterazine (CTZ:Nanolight) diluted in PBS. Luminescence was quantified using a BioTek plate reader. Data represent the mean of triplicate wells + / - standard deviation (SD). [Figure 9B] Continued from Figure 9A. [Figure 10A] Figure 10 shows strong binding of T cells expressing the 161(vL+vH)-Myc-BBz-PAC R07, 175(vL+vH)-Myc-28z-PAC Q04, VB22(vL+vH)-Myc-28z-PAC B06 CARs, and moderate binding of T cells expressing 161(vL+vH)-Myc-28z-PAC Z07, AB317(vL+vH)-Myc-28z-PAC T04, and 12E10(vL+vH)-Myc-28z-PAC B06 to MPL-GGSG-NLuc AcV5 supernatant; no significant binding was observed with untransduced T cells or cells expressing the 4C3(vL+vH)-Myc-28z-PAC control CAR. Similarly, no specific binding was observed with MPL CAR-T cells with CD19-GGSG-NLuc-AcV5 supernatant, demonstrating the specificity of the assay. [Figure 10B]Figure 10 shows strong binding of T cells expressing the 161(vL+vH)-Myc-BBz-PAC R07, 175(vL+vH)-Myc-28z-PAC Q04, VB22(vL+vH)-Myc-28z-PAC B06 CARs, and moderate binding of T cells expressing 161(vL+vH)-Myc-28z-PAC Z07, AB317(vL+vH)-Myc-28z-PAC T04, and 12E10(vL+vH)-Myc-28z-PAC B06 to MPL-GGSG-NLuc AcV5 supernatant; no significant binding was observed with untransduced T cells or cells expressing the 4C3(vL+vH)-Myc-28z-PAC control CAR. Similarly, no specific binding was observed with MPL CAR-T cells with CD19-GGSG-NLuc-AcV5 supernatant, demonstrating the specificity of the assay. [Figure 10C] Figure 10 shows strong binding of T cells expressing the 161(vL+vH)-Myc-BBz-PAC R07, 175(vL+vH)-Myc-28z-PAC Q04, VB22(vL+vH)-Myc-28z-PAC B06 CARs, and moderate binding of T cells expressing 161(vL+vH)-Myc-28z-PAC Z07, AB317(vL+vH)-Myc-28z-PAC T04, and 12E10(vL+vH)-Myc-28z-PAC B06 to MPL-GGSG-NLuc AcV5 supernatant; no significant binding was observed with untransduced T cells or cells expressing the 4C3(vL+vH)-Myc-28z-PAC control CAR. Similarly, no specific binding was observed with MPL CAR-T cells with CD19-GGSG-NLuc-AcV5 supernatant, demonstrating the specificity of the assay. [Figure 11A]Figure 11 shows that SIRs containing TCRα and TCRβ constant regions encoded by wild-type nucleotide sequences are not efficiently expressed in human primary T cells. In contrast, SIRs containing codon-optimized human TCRα / β constant chains with additional cysteine ​​groups to promote interchain disulfide bonds were efficiently expressed. As seen in the (081415-D06) (SEQ ID NO: 992) SIR, murineization of the human TCRα / β constant chains further increased SIR expression. Furthermore, as seen in the (082815-G07) (SEQ ID NO: 1620) and (082815-E05) (SEQ ID NO: 1622) constructs, scFv fragments can be expressed by fusion with the TCRβ constant region when coexpressed with the TCRβ constant chain, even if the TCRβ does not contain any antigen-binding moiety. [Figure 11B] Figure 11 shows that SIRs containing TCRα and TCRβ constant regions encoded by wild-type nucleotide sequences are not efficiently expressed in human primary T cells. In contrast, SIRs containing codon-optimized human TCRα / β constant chains with additional cysteine ​​groups to promote interchain disulfide bonds were efficiently expressed. As seen in the (081415-D06) (SEQ ID NO: 992) SIR, murineization of the human TCRα / β constant chains further increased SIR expression. Furthermore, as seen in the (082815-G07) (SEQ ID NO: 1620) and (082815-E05) (SEQ ID NO: 1622) constructs, scFv fragments can be expressed by fusion with the TCRβ constant region when coexpressed with the TCRβ constant chain, even if the TCRβ does not contain any antigen-binding moiety. [Figure 12] FIG. 12 illustrates a method for generating a pool of SIRs with desired or diverse binding affinities. [Figure 13A-1]Figures 13A-B show representative FACS analyses. (A) Jurkat-NFAT-GFP cells or cells expressing SIRs targeting CD19 (clone ID: 051716-108), MPL (clone ID: 040716-A07), and BCMA (clone ID: 011116-A07) were cultured with RAJI cells (top), HEL cells (middle), and U266 cells (bottom), respectively. Coculture of SIR-expressing Jurkat-NFAT-GFP cells with each target cell clearly induces GFP expression. (B) Jurkat-NFAT-GFP cells expressing SIRs targeting CDH6 (clone ID: 051716-J05), CD276 (clone ID: 050516-Q06), and Her2 / neu (clone ID: 050516-I03) were cocultured with SKOV3 cells (top) and MC7 cells (middle and bottom). The induction of GFP expression is evident upon coculture of SIR-expressing Jurkat-NFAT-GFP cells with their respective target cells. [Figure 13A-2] This is a continuation of Figure 13A-1. [Figure 13B-1] This is a continuation of Figure 13A-2. [Figure 13B-2] This is a continuation of Figure 13B-1. [Figure 14] FIG. 14 shows exemplary results of retroviral vectors used to express SIRs of the present disclosure. [Figure 15] Figure 15 shows results using the Sleeping Beauty transposon vector, demonstrating that Jurkat-NFAT-GFP cells transduced with the construct pSBbi-puro-FMC63vL-V5-[TCRb-KACIAH]-F-P2A-FMC63vH-MYC-[TCRa-CSDVP]-F-F2A(010616-B01) (SEQ ID NO: 875) induce GFP upon co-culture with the corresponding RAJI target cell line. [Figure 16]Figure 16 shows that cell surface expression of Bu12 SIR (CD8SP-CD19Bu12-vL-V5-[TCRb-S57C-optl]-F-P2A-SP-CD19Bu12-vH-Myc-[TCRa-T48C-optl]-F-F2A-PAC(070215-M03) (SEQ ID NO: 1021)) on T cells was reduced compared to Bu12 CAR CD8SP-CD19Bu12-(vL-vH)-Myc-BBz-T2A-PAC(082815-P08) (SEQ ID NO: 4503), as determined by staining with APC-MYC-APC and biotin protein L plus APC streptavidin, respectively. [Figure 17] Figure 17 shows NSG mice injected with RAJI cells and administered T cells expressing CD19-mediated SIR (CD8SP-FMC63-vL-V5-[TCRb-S57C-optl]-F-P2A-SP-FMC63-vH-Myc-[TCRa-T48C-optl]-F-F2A-PAC(050515-L05) (SEQ ID NO: 900)), and T cells expressing SIR (CD8SP-CD19Bu12-vL-V5-"TCRb-S57C-optl"-F-P2A-SP-CD19Bu12-vH Figure 1 shows survival of NSG mice receiving T cells expressing CD8SP-MPL-161-vL-V5-[hTCRb-S57C-opt1]-F-P2A-MPL-161-vH-Myc-[hTCRa-T48C-opt1]-F-F2A-PAC(070215-M03) (SEQ ID NO: 1021)) compared to the MPL-mediated control SIR (CD8SP-MPL-161-vL-V5-[hTCRb-S57C-opt1]-F-P2A-MPL-161-vH-Myc-[hTCRa-T48C-opt1]-F-F2A-PAC(040315-U02) (SEQ ID NO: 1112)). [Figure 18] FIG. 18 shows GFP induction by co-culturing Jurkat-NFAT-GFP cells expressing constructs of the present disclosure with Protein L beads. [Figure 19A]Figures 19A-D show that co-culture with 239ProteinL-II cells induced the expression of (B) CD8SP-FMC63(vL-vH)-Myc-BBz-T2A-PAC(112014-A13) (SEQ ID NO: 4501) CAR, (C) CD8SP-HuLuc64-vL-V5-[hTCRb-KACIAH]-F-P2A-SP-Huluc64-vH-Myc-[hTCRa-CSDVP]-F-F2A-PAC(092916-E07) (SEQ ID NO: 4502) CAR. No. 1253), and (D) CD8SP-V5-[hTCRb-KACIAH]-F-P2-CD8SP-CD19Bu12-vL-Gly-Ser-Linker-CD19Bu12-vH-Myc-[hTCRa-CSDVP]-F-F2A-PAC(082815-E05) (SEQ ID NO: 1622) SIR constructs. [Figure 19B] This is a continuation of Figure 19A. [Figure 19C] This is a continuation of Figure 19B. [Figure 19D] This is a continuation of Figure 19C. DETAILED DESCRIPTION OF THE INVENTION

[0033] As used herein and in the appended claims, the singular forms "a," "an," and "the" include the plural unless the context clearly dictates otherwise. Thus, for example, the term "a cell" includes a plurality of such cells, and the term "a polypeptide" includes one or more polynucleotides.

[0034] Additionally, unless otherwise noted, the term "or" means "and / or." Similarly, the terms "have," "having," "including," and "including" are synonymous with each other and do not have a limiting meaning.

[0035] It should be further appreciated that where the term "comprising" is used in describing various embodiments, those skilled in the art will understand that in certain instances, an embodiment may instead be described using the terms "consisting essentially of" or "consisting of."

[0036] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Allen et al., Remington: The Science and Practice of Pharmacy 22nd ed., Pharmaceutical Press (September 15, 2012), Homyak et al., Introduction to Nanoscience and Nanotechnology, CRC Press (2008), Singleton and Sainsbury, Dictionary of Microbiology and Molecular Biology 3rd ed., revised edition, J. Wiley & Sons (New York, NY 2006), Smith, March's Advanced Organic Chemistry Reactions, Mechanism and Structure 7th ed., J. Wiley & Sons (New York, NY 2013), Singleton, Dictionary of DNA and Genome Technology 3rd ed., Wiley-Blackwell (November 28, 2012), and Green and Sambrook, Molecular Cloning: A Laboratory Manual 4th ed., Cold Spring Harbor Laboratory Press (Cold Spring Harbor, NY 2012) provides those skilled in the art with general guidance regarding many of the terms used in this application.For references regarding antibody preparation methods, see Greenfield, Antibodies A Laboratory Manual 2nd ed., Cold Spring Harbor Press (Cold Spring Harbor, NY 2013); Koehler and Milstein, Derivation of Specific Antibody-Producing Tissue Culture and Tumor Lines by Cell Fusion, Eur. J. Immunol. 1976 July 6(7):511-9; Queen and Selick, Humanized Immunoglobulins, U.S. Pat. No. 5,585,089; and Riechmann et al., Reshaping Human Antibodies for Therapy, Nature 1988 March 24, 332(6162):323-7. All headings and subheadings provided herein are for ease of reading only and should not be construed as limiting the invention. Although methods and materials similar or equivalent to those described herein can also be used in the practice and testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated herein by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and specific examples are illustrative only and are not intended to be limiting.

[0037] The synthetic immunoreceptors (SIRs) of the present disclosure have, for example, an antigen-binding domain (e.g., an antibody or antibody fragment) capable of binding to an antigen in an MHC-dependent or MHC-independent manner. Typically, peptides derived from endogenous proteins fill the pocket of major histocompatibility complex (MHC) class I molecules and are recognized by T cell receptors (TCRs) on CD8+ T lymphocytes. MHC class I complexes are constitutively expressed by all nucleated cells. In cancer, virus-specific and / or tumor-specific peptide / MHC complexes represent a unique class of cell surface targets for immunotherapy. TCR-like antibody-targeting peptides derived from viral or tumor antigens in the context of human leukocyte antigen (HLA)-A1 or HLA-A2 have been described (see, e.g., Sastry et al., J. Viral. 201185(5):1935-1942; Sergeeva et al., Blood, 2011, 117(6):4262-4272; Verma et al., J. Immunol, 2010, 184(4):2156-2165; Willemsen et al., Gene Ther., 2001, 8(21):1601-1608; Dao et al., Sci Transl Med., 2013, 5(176):176ra33; Tassev et al., Cancer Gene Ther., 2012, 19(2):84-100). For example, TCR-like antibodies can be identified by screening libraries such as human scFv phage display libraries.

[0038] The present disclosure generally provides synthetic immune receptors (SIRs) comprising an antigen-binding site operably linked to a T cell receptor domain. The present disclosure also provides one or more recombinant nucleic acid constructs comprising a sequence encoding the SIR, wherein the SIR has one or more antigen-binding domains (e.g., antibodies, antibody fragments, non-immunoglobulin antigen-binding domains, autoantigens, ligands, or receptors) that bind to an antigen or target molecule (described further herein below) and bind to one or more T cell receptor constant chains (including mutants or variants thereof). The antigen-binding domain(s) of the SIR specifically bind to one or more disease-associated antigens or allogeneic antigens described herein, wherein the coding sequence for each of the antigen-binding domains is operably linked to a nucleic acid sequence encoding each of the T cell receptor constant chains to which it binds, such that the antigen-binding domains are operably expressed with the T cell constant chains. In some embodiments, the SIR may have a single antigen-binding domain that binds to a single T cell receptor constant chain. In some embodiments, the SIR has two antigen-binding domains, each binding to a separate T cell receptor constant chain. For example, antigen-binding domain 1 binds to the constant chain of T cell receptor α (TCRα) to form "functional unit 1," and antigen-binding domain 2 binds to the constant chain of T cell receptor β (TCRβ) to form "functional unit 2." The two functional units of such an SIR are co-expressed in the same cell and functionally activated (e.g., heterodimerized). In some embodiments, an SIR has an antigen-binding domain (functional unit 1) that binds to one T cell receptor constant chain in frame, but it is co-expressed with a second T cell receptor constant chain. The purpose of the second T cell receptor constant chain in such an SIR is to facilitate cell surface expression of functional unit 1 (e.g., antigen-binding domain 1 that binds to the T cell receptor constant chain). Thus, the second T cell receptor constant chain may be expressed by itself, as a fusion protein with an epitope tag (e.g., MYC, V5, AcV5, G4Sx2, StrepTagII, etc.), or with any unrelated protein fragment (e.g., vL or vH fragment) that does not interfere with the assembly and function of functional unit 1.For example, an SIR may have an antigen-binding domain 1 operably linked in-frame to the constant chain of a T cell receptor alpha (TCRα) and an empty (i.e., lacking an antigen-binding domain) constant chain of a T cell receptor beta (TCRβ). Such two functional units of an SIR are co-expressed and functionally activated in the same cell. In some embodiments, the two functional units of an SIR are co-expressed by transduction of a single polynucleotide encoding both functional units, while in other embodiments, they are co-expressed by transduction of two different polynucleotides, each encoding one functional unit. In some embodiments, the two functional units of an SIR are inserted at a single locus, while in other embodiments, the two functional units are inserted at two loci. For example, in some embodiments, both functional units may be inserted into the TCR alpha constant chain (TRAC) and expressed as a single polynucleotide. In other embodiments, functional unit 1 may be inserted into the TCR alpha constant chain (TRAC) and functional unit 2 may be inserted into the TCR constant chain beta 1 (TRBC1). In some embodiments, the two functional units of an SIR are co-expressed by transduction of a single polynucleotide encoding both functional units, while in other embodiments, they are co-expressed by transduction of two different polynucleotides, each encoding one functional unit. In some embodiments, an SIR has an antigen-binding domain (functional unit 1) that binds to one T cell receptor constant chain in frame, but it is co-expressed with a second T cell receptor constant chain. The purpose of the second T cell receptor constant chain in such an SIR is to facilitate cell surface expression of functional unit 1 (e.g., antigen-binding domain 1 that binds to the T cell receptor constant chain). Thus, the second T cell receptor constant chain may be expressed by itself, as a fusion protein with an epitope tag (e.g., MYC, V5, AcV5, G4Sx2, StrepTagII, etc.), or as a fusion protein with any unrelated protein fragment (e.g., a vL or vH fragment) that does not interfere with the assembly and function of functional unit 1.For example, an SIR may have an antigen-binding domain 1 operably linked in-frame to the constant chain of T cell receptor α (TCRα) and an empty (i.e., lacking an antigen-binding domain) constant chain of T cell receptor β (TCRβ). Two such functional units of the SIR are co-expressed and functionally activated in the same cell. In some embodiments, the two functional units of the SIR are co-expressed using a single vector; in other embodiments, the two functional units of the SIR are co-expressed in the same cell using different vectors. In some embodiments, the two functional units of the SIR are co-expressed by transduction of a single polynucleotide encoding both functional units; in other embodiments, the two functional units of the SIR are co-expressed by transduction of two different polynucleotides, each encoding one functional unit. Various configurations of the SIR of the present disclosure are provided in Figures 3-8.

[0039] The present disclosure provides a class of chimeric T cell receptors (synthetic immunoreceptors (SIRs)) that can be used in adoptive cell therapy for the treatment of cancer, infectious diseases, autoimmune diseases, and degenerative diseases. In contrast to chimeric antigen receptors (CARs), the SIRs of the present disclosure fully utilize physiological T cell receptor signaling pathways and are therefore less likely to suffer from CAR-associated complications, such as cytokine release syndrome, neurotoxicity, and lack of in vivo persistence. In contrast to CARs, the SIRs of the present disclosure exhibit a reduced tendency for antigen-binding domain self-aggregation, a reduced likelihood of sustained signaling, and a reduced likelihood of premature T cell exhaustion. The SIRs of the present disclosure comprise one or more antigen-binding domains fused to the constant chain of a TCR alpha (Cα), TCR beta (Cβ), TCR delta (Cδ), TCR gamma (Cγ), or pre-TCR alpha (Cα), including mutants and variants of the foregoing. The antigen-binding domain may comprise an antibody or antibody fragment, a vL and / or vH fragment of an antibody, an scFv fragment derived from an antibody, a single-domain antibody, an affibody, a DARPIN, any antigen-binding ligand or receptor, an autoantigen, or any other non-immunoglobulin antigen-binding fragment. The antigen-binding domain may target a single antigen or multiple antigens (bispecific or multispecific SIRs). While the TCR constant domains of an SIR may be expressed alone, they are typically expressed in pairs (e.g., Cα and Cβ, pre-Cα and Cβ, Cδ and Cγ, etc.) to facilitate optimal cell surface expression. The TCR constant chain fragment is typically codon-optimized to enable optimal cell surface expression. The TCR constant fragment may have additional mutations or substitutions to facilitate optimal expression and pairing with complementary chains and / or reduce pairing with endogenous TCR chains and / or stabilize interactions between the antibody-binding domains. The SIR may express one or more additional domains (eg, Myc, streptag, V5, FLAG, Ritx tag, etc.) as a fusion protein.The SIRs of the present disclosure can be introduced into cells using any number of techniques, including, but not limited to, lentiviral vectors, retroviral vectors, adeno-associated viral vectors, baculoviral vectors, sleeping beauty transposons, piggybac transposons, mRNA transfection, or a combination of the above methods. Optimized vectors for SIR delivery are also disclosed. The SIRs of the present disclosure may be expressed under the control of an endogenous promoter (e.g., a TCRα or TCRβ promoter). In some embodiments, the SIRs of the present disclosure are expressed using an exogenous promoter (e.g., a CMV promoter). Additionally, the SIRs of the present disclosure may co-express additional modules, such as cDNAs encoding molecules that promote SIR expression or function (e.g., CD3z, CD3ε, CD3δ, CD3z-41BB fusion proteins, etc.), molecules that promote T cell proliferation, maintenance, expansion, and activation (e.g., 41BBL, CD40L, IL12f, K13, Tax, Tax2, MC159L, cFLIP, scFVs targeting PD1, shRNAs targeting BRD4, etc.), molecules that reduce toxicity (e.g., scFVs targeting vHH or IL6R, IL6, TNFα, etc.), selection markers (e.g., tEGFR, tEGFRvIII, tBCMA, tCD19, etc.), and / or suicide genes (e.g., icaspase 9, HSV thymidine kinase). The SIRs of the present disclosure may be expressed in immune effector cells (e.g., T cells) or stem cells, including induced pluripotent stem cells (iPSCs) that give rise to immune effector cells. The present disclosure also provides subsets of immune effector cells for SIR expression and methods for activating and expanding SIR-expressing immune effector cells. Additionally, the present disclosure describes agents that improve the activation and maintenance or reduce the toxicity of SIR-expressing immune effector cells. The present disclosure also describes a set of in vitro and in vivo assays that can be used to identify SIRs suitable for various applications.

[0040] The term "about," when referring to a measurable value, such as an amount, time, or the like, includes a + / -20% variation from the particular value, in some cases a + / -10% variation, in some cases a + / -5% variation, in some cases a + / -1% variation, and in some cases a + / -0.1% variation, as appropriate for practicing the methods of the present disclosure or describing the compositions herein. Furthermore, any value or range (e.g., less than 20, or similar terminology) explicitly includes every integer between or up to such value. Thus, for example, "1-5 variants" explicitly includes variants of 1, 2, 3, 4, and / or 5.

[0041] The term "accessory module" refers to 41BBL, CD40L, K13, MC159, cFLIP-L / MRITα, cFLIP-p22, HTLV1 Tax, HTLV2 Tax, HTLV2 Tax-RS mutant, FKBPx2-K13, FKBPx2-HTLV2-Tax, FKBPx2-HTLV2-Tax-RS, IL6R-304-vHH-Alb8-vHH, IL12f, PD1-4H1 scFV, PD1-5C4 "Accessory modules" refers to one or more of the following: scFV, PD1-4H1-Alb8-vHH, PD1-5C4-Alb8-vHH, CTLA4 ipilimumab scFV, CTLA4 ipilimumab Alb8-vHH, IL6-19A-scFV, IL6-19A-scFV-Alb8-vHH, sHVEM, sHVEM-Alb8-vHH, hTERT, Fx06, CD3z, CD3z-GGGS-41BB, CD3-BBz, CD3-CD28z, CD3-CD28-Lck fusion protein, hRNA targeting sBrd4, and combinations thereof that can be co-expressed with SIR. Accessory modules can be co-expressed with SIR using a single vector or two or more different vectors. In one embodiment, the accessory module has the amino acid sequence of SEQ ID NOs: 3087 to 3117 (DNA coding sequence: SEQ ID NOs: 812 to 842), or a sequence 80 to 99% identical thereto. In another embodiment, the nucleic acid sequence encoding the accessory module has the sequence of SEQ ID NOs: 812 to 842, or a sequence 80 to 99% identical thereto.

[0042] "Autoantibody" means an antibody produced by B cells that is specific for a self-antigen.

[0043] As used herein, the term "antibody" refers to a protein or polypeptide sequence derived from immunoglobulin that specifically binds to an antigen. Antibodies may be monoclonal or polyclonal, multi-chain or single-chain, or intact immunoglobulins, and may be derived from natural or recombinant sources. Antibodies may be tetramers of immunoglobulin molecules. Antibodies may be "humanized," "chimeric," or non-human.

[0044] The term "antibody fragment" refers to at least a portion of an antibody that retains the ability to specifically interact with an epitope of an antigen (e.g., by binding, steric hindrance, stabilization / destabilization, spatial distribution, etc.). Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab'h, Fv fragments, scFv antibody fragments, disulfide-linked Fvs (sdFv), Fd fragments consisting of VH and CH1 domains, linear antibodies, single domain antibodies such as sdAb (vL or vH), camelid vHH domains, multispecific antibodies formed from antibody fragments such as bivalent fragments having two Fab fragments linked by a disulfide bridge at the hinge region, isolated CDRs, or other epitope-binding fragments of antibodies. Antigen-binding fragments may be incorporated into single domain antibodies, maxibodies, minibodies, nanobodies, intrabodies, diabodies, triabodies, tetrabodies, v-NARs, and bis-scFvs (see, e.g., Hollinger and Hudson, Nature Biotechnology 23:1126-1136, 2005). Antigen-binding fragments may also be grafted onto scaffolds based on polypeptides such as fibronectin type III (Fn3) (see U.S. Patent No. 6,703,199, which describes fibronectin polypeptide minibodies).

[0045] The term "antibody heavy chain" refers to the larger of the two types of polypeptide chains present in native-sequence antibody molecules, which usually determines the class to which the antibody belongs.

[0046] The term "antibody light chain" refers to the smaller of the two types of polypeptide chains present in native-sequence antibody molecules. Kappa (κ) and lambda (λ) light chains refer to the two major antibody light chain isotypes.

[0047] The term "anti-cancer effect" refers to a biological effect that can be demonstrated by various means, including, but not limited to, a reduction in tumor volume, a reduction in the number of cancer cells, a reduction in the number of metastases, an increase in lifespan, a decrease in cancer cell proliferation, a decrease in cancer cell viability, an improvement in various physiological symptoms associated with cancer conditions, etc. An "anti-cancer effect" can also be demonstrated by the ability of an SIR to prevent the development of cancer.

[0048] "Anticancer agent" means an agent that inhibits abnormal cell division and growth, inhibits tumor cell migration, inhibits invasion, or prevents cancer growth and metastasis. The term can also include chemotherapeutic agents, biologic agents (e.g., siRNA, viral vectors that deliver cytotoxic genes, such as modified MLV, adenovirus, herpes virus), antibodies, and the like.

[0049] The term "antigen" or "Ag" refers to a molecule that elicits an immune response. Such an immune response can be antibody production, activation of specific immunologically competent cells, or both. Those skilled in the art will understand that any macromolecule, including almost any protein or peptide, can function as an antigen. Furthermore, antigens can be derived from recombinant or genomic DNA. Thus, those skilled in the art will understand that any DNA having a nucleotide sequence or partial nucleotide sequence encoding a protein that elicits an immune response will encode an "antigen" as described herein. Furthermore, those skilled in the art will understand that an antigen need not be encoded solely by the full-length nucleotide sequence of a gene. The present disclosure includes, but is not limited to, the use of partial nucleotide sequences of two or more genes, and it will be apparent that such nucleotide sequences may be arranged in various combinations to encode a polypeptide that elicits a desired immune response. Furthermore, those skilled in the art will understand that an antigen need not be encoded by a "gene." It will be apparent that antigens can be synthesized, derived from biological samples, or macromolecules other than polypeptides. Such biological samples include, but are not limited to, tissue samples, tumor samples, cells, or fluids containing other biological components.

[0050] Examples of target antigens include, but are not limited to, CD5, CD19; CD123; CD22; CD30; CD171; CS-1 (CD2 subset 1, also known as CRACC, SLAMF7, CD319, and 19A24); C-type lectin-like molecule 1 (CLL-1 or CLECL1); CD33; epidermal growth factor receptor variant III (EGFRviii); ganglioside G2 (GD2); ganglioside GD3 (aNeu5Ac(2-8)aNeu5Ac(2-3)bDGalp(1-4)bDGlcp(1-1)Cer); TNF receptor family member B cell maturation (BCMA); Tn antigen ((Tn Ag) or (GalNAcα-Ser / Thr); prostate-specific membrane antigen (PSMA); receptor tyrosine kinase-like orphan receptor 1 (ROR1); FMS-like tyrosine kinase 3 (FLT3); tumor-associated glycoprotein 72 (TAG72); CD38; CD44v6; glycosylated CD43 epitope expressed in acute leukemia or lymphoma but not hematopoietic progenitor cells, glycosylated CD43 epitope expressed in non-hematopoietic cancers; carcinoembryonic antigen (CEA); epithelial cell adhesion molecule (EPCAM); B7H3 (CD276); KIT (CD117); interleukin-13 receptor subunit alpha 2 (IL-13Ra2 or CD213A2); mesothelin; interleukin-11 receptor alpha (IL-11Ra); 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-β); stage-specific embryonic antigen 4 (SSEA-4); CD20; folate receptor alpha (FRa or FR1); folate receptor beta (FRb); receptor tyrosine protein kinase ERBB2 (Her2 / neu); mucin 1, cell surface associated (MUC1); epidermal growth factor receptor (EGFR); neural cell adhesion molecule (NCAM); prostase; prostatic acid phosphatase (PAP); elongation factor 2 mutated (ELF2M); ephrin B2; fibroblast activation protein alpha (FAP); insulin-like growth factor 1 receptor (IGF-1 receptor), carbonic anhydrase IX (CAIX); proteasome (prosome, macropain) subunit, beta type 9 (LMP2); glycoprotein 100 (gp100);Oncogene fusion protein (bcr-abl) consisting of a break-prone region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (Abl); tyrosinase; ephrin type A receptor 2 (EphA2); sialyl Lewis adhesion molecule (sLe); ganglioside GM3 (aNeu5Ac(2-3)bClalp(1-4)bDGlcp(1-1)Cer); transglutaminase 5 (TGS5); high-molecular-weight melanoma-associated antigen (HMWMAA); and O-acetyl-GD2 ganglioside (OAcGD2). ; tumor endothelial marker 1 (TEM1 / CD248); tumor endothelial marker 7-related (TEM7R); claudin 6 (CLDN6); thyroid-stimulating hormone receptor (TSHR); G protein-coupled receptor class C group 5 member D (GPRC5D); chromosome X open reading frame 61 (CXORF61); CD97; CD179a; anaplastic lymphoma kinase (ALK); polysialic acid; placenta-specific 1 (PLAC1); hexasaccharide moiety of globo-H glycoceramide (GloboH); mammary differentiation antigen (N Y-BR-1; uroplakin 2 (UPK2); hepatitis A virus cellular receptor 1 (HAVCR1); adrenergic receptor β3 (ADRB3), pannexin 3 (PANX3); G protein-coupled receptor 20 (GPR20), lymphocyte antigen 6 complex locus K9 (LY6K), olfactory receptor 51E2 (OR51E2); TCRγ alternative reading frame protein (TARP); Wilms tumor protein (WT1); cancer / testis antigen 1 (NY-ES0-1); cancer / testis 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); X antigen family member 1A (XAGE1); angiopoietin-binding cell surface receptor 2 (Tie2); melanoma cancer-testis antigen 1 (MAD-CT-1); melanoma cancer-testis antigen 2 (MAD-CT-2); Fos-related antigen 1; tumor protein p53 (p53); p53 mutant; prostein; survivin; telomerase; prostate carcinoma antigen 1 (PCT A-1 or galectin-8), melanoma antigen 1 recognized by T cells (MelanA or MARTI); rat sarcoma (Ras) mutant; human telomerase reverse transcriptase (hTERT); sarcoma translocation breakpoints;Melanoma inhibitor of apoptosis (ML-IAP); ERG (transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene); N-acetylglucosaminyltransferase V (NA17); paired box protein Pax-3 (PAX3); androgen receptor; cyclin B1; neuroblastoma-derived homolog of v-myc avian myelocytomatosis viral oncogene (MYCN); Ras homolog family member C (RhoC); tyrosinase-related protein 2 (TRP-2); cytochrome P4501B1 (CYP1B1); CCCTC-binding factor (zinc finger protein)-like (BORIS or Brother of the Regulator of Imprinted Sites), squamous cell carcinoma antigen 3 recognized by T cells (SART3); paired box protein Pax-5 (PAX5); proacrosin-binding protein sp32 (OY-TES1); lymphocyte-specific protein tyrosine kinase (LCK); A-kinase anchor protein 4 (AKAP-4); synovial sarcoma, X-breakpoint 2 (SSX2); receptor for advanced glycation end products (RAGE-1); renal ubiquitous 1 (RU1); renal ubiquitous 2 (RU2); legumain; human papillomavirus E6 (HPV E6); human papillomavirus E7 (HPV E7); intestinal carboxylesterase; heat shock protein 70-2 mutant (mut hsp 70-2); CD79a; CD79b; CD72; leukocyte-associated immunoglobulin-like receptor 1 (LAIR1): Fc fragment of IgA receptor (FCAR or CD89); leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2); CD300 molecule-like family member f (CD300LF); C-type lectin domain family 12 member A (CLEC12A); bone marrow stromal cell antigen 2 (BST2); EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2); lymphocyte antigen 75 (LY75); glypican 3 (GPC3); Fc receptor-like 5 (FCRL5); and immunoglobulin lambda-like polypeptide 1 (IGLL1), MPL, biotin, c-MYC epitope tag, CD34, LAMP1 TROP2, GFRalpha4, CDH17, CDH6, NYBR1, CDH19, CD200R, Slea (CA19.9;Sialyl Lewis antigen) fucosyl GM1, PTK7, gpNMB, CDH1-CD324, DLL3, CD276 / B7H3, IL11Ra, IL13Ra2, CD179b-IGL11, ALK TCRγδ, NKG2D, CD32 (FCGR2A), Tn ag, Timl- / HVCR1, CSF2RA (GM-CSFRα), TGFβR2, Lewis ag, TCRβ chain, TCRβ2 chain, TCRγ chain, TCRδ chain, FITC, luteinizing hormone receptor (LHR), follicle-stimulating hormone receptor (FSHR), chorionic gonadotropin receptor (CGHR or GR), CCR4, GD3, SLAMF6, SLAMF4, HIV1 envelope glycoprotein, HTLV1-Tax, CMVpp65, EBV-EBNA3 c, KSHV-K8.1, KSHV-gH, influenza A hemagglutinin (HA), GAD, PDL1, guanylyl cyclase C (GCC), autoantibodies to desmoglein 3 (Dsg3), autoantibodies to desmoglein 1 (Dsg1), 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, claudin 18.2 (CLD18A2 or CLDN18A.2), P-glycoprotein, STEAP1, Liv1, NECTIN-4, Cripto, gpA33, BST1 / CD157, small-conductance chloride channel, and TNT antibodies. ;

[0051] The term "antigen-presenting cell" or "APC" refers to a cell of the immune system, such as an accessory cell (e.g., a B cell, a dendritic cell, etc.), that displays a foreign antigen on its surface in a complex with a major histocompatibility complex (MHC). T cells recognize such a complex using the T cell receptor (TCR). APCs process antigen and present it to T cells.

[0052] The term "anti-inflammatory effect" refers to a biological effect that can be demonstrated by various means, including, but not limited to, a reduction in the titer of an infectious agent, a reduction in the colony count of an infectious agent, an improvement in various physiological symptoms associated with an infection, etc. An "anti-inflammatory effect" can also be demonstrated by the ability of peptides, polynucleotides, cells, and antibodies to prevent the onset of infection.

[0053] The term "anti-tumor effect" or "anti-cancer effect" refers to a biological effect that can be demonstrated by various means, including, but not limited to, a reduction in tumor volume, a reduction in tumor cell number, a reduction in tumor cell proliferation, a reduction in tumor cell viability, etc.

[0054] As used herein, "affinity" refers to the degree of binding strength. In some instances, affinity depends on the closeness of the steric and chemical fit between a binder and its target (e.g., between an antibody and an antigen containing an epitope specific to the binding domain), the size of the contact area, the distribution of charged and hydrophobic groups, and the like. Generally, affinity refers to the "ability" of a binder to bind to a target. Numerous methods for measuring "affinity" exist in the art. For example, methods for calculating the affinity of an antibody to an antigen are known in the art, including the use of binding experiments to calculate affinity. Binding affinity may be determined using various techniques known in the art, such as 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 is the use of surface plasmon resonance. Surface plasmon resonance is an optical phenomenon that allows the analysis of biospecific interactions in real time by detecting changes in protein concentration within a biosensor matrix, for example, using the BIAcore system (Pharmacia Biosensor AB, Uppsala, Sweden and Pascataway, NJ).

[0055] "Antigen-binding domain," "antigen-binding module," or "antigen-binding segment" refers to a polypeptide or peptide that binds to an antigen with high specificity due to primary, secondary, or tertiary sequence, and / or post-translational modification, and / or charge. Antigen-binding domains can be derived from different sources, such as antibodies, non-immunoglobulin-binding proteins, ligands, or receptors. The present disclosure provides SIRs having antigen-binding domains that bind to one or more target antigens. The present disclosure also provides SIRs having antigen-binding domains that are not derived from antibodies.

[0056] "Affinity" refers to the strength of interaction between a binding agent and its target (e.g., the strength of interaction between an antibody and its antigen target, receptor, cognate, etc.). Affinity can be weak or strong. Methods for calculating the affinity of an antibody to an antigen are known in the art, including the use of binding experiments to calculate affinity. Antibody activity in functional assays (e.g., flow cytometry assays) also reflects antibody affinity. Antibodies and affinities can be phenotypically characterized and compared using functional assays (e.g., flow cytometry assays).

[0057] The term "association constant (Ka)" is defined as the equilibrium constant for the association of a receptor with a ligand.

[0058] The term "autoantigen" refers to an endogenous antigen that stimulates the development of an autoimmune response (e.g., the production of autoantibodies). Autoantigens include antigens from one's own body or antigens from normal tissues that are targets of cell-mediated or antibody-mediated immune responses and can lead to autoimmune disease. Examples of autoantigens include, but are not limited to, desmoglein 1, desmoglein 3, and fragments thereof.

[0059] As used herein, a "beneficial result" can include, but is not limited to, reducing or alleviating the severity of a condition, preventing a condition from worsening, curing a condition, preventing a condition from progressing, reducing the likelihood of a condition progressing in a patient, or extending or increasing the lifespan of a patient.

[0060] As used herein, the term "binding domain" or "antibody molecule" refers to a protein (e.g., an immunoglobulin chain or fragment thereof) that comprises at least one domain (e.g., an immunoglobulin variable domain sequence that can bind to a target with higher affinity than a nonspecific domain). This term encompasses antibodies and antibody fragments. In another embodiment, the antibody molecule is a multispecific antibody molecule, e.g., having a plurality of immunoglobulin variable domain sequences, wherein a first immunoglobulin variable domain sequence of the plurality has binding specificity for a first epitope and a second immunoglobulin variable domain sequence of the plurality has binding specificity for a second epitope. In another embodiment, the multispecific antibody molecule is a bispecific antibody molecule. A bispecific antibody has specificity for two antigens. A bispecific antibody molecule is characterized by a first immunoglobulin variable domain sequence that has binding specificity for a first epitope and a second immunoglobulin variable domain sequence that has binding specificity for a second epitope.

[0061] The term "binds to the same epitope as" refers to the ability of an antibody, scFv, or other antigen-binding domain to bind to a target antigen with the same epitope as an exemplary antibody, scFv, or other antigen-binding domain. For example, the epitopes of exemplary antibodies, scFvs, or other binding agents and other antibodies can be determined using standard epitope mapping techniques. Epitope mapping techniques well known in the art include *Epitope Mapping Protocols in Methods in Molecular Biology*, Vol. 66 (Glenn E. Morris, Ed. 1996), Humana Press, Totowa, New Jersey. For example, linear epitopes can be determined by simultaneously synthesizing large peptides (where the peptides correspond to portions of a protein molecule) and reacting the peptides with an antibody while the peptides remain support-bound. Such techniques are well known in the art and are described, for example, in U.S. Patent No. 4,708,871; Geysen et al. (1984) Proc. Natl. Acad. Sci. USA 8:3998-4002; Geysen et al. (1985) Proc. Natl. Acad. Sci. USA 82:78-182; Geysen et al. (1986) Mol. Immunol. 23:709-715. The epitope bound by the antigen-binding domain of an SIR may be determined by an epitope binning assay. Epitope binning is a competitive immunoassay used to characterize and sort libraries of monoclonal antibodies against a target protein. Antibodies to similar targets are tested pairwise against all other antibodies in the library to determine whether the antibodies mutually inhibit binding to the antigen epitope. Once each antibody has a profile generated against all other antibodies in the library, a competitive inhibition profile against the other antibodies in the library is generated for each antibody. Closely related binning profiles indicate that the antibodies have the same or cl...

Claims

1. At least one recombinant polynucleotide encoding at least one synthetic immunoreceptor (SIR), The at least one SIR is: (a) a T cell receptor (TCR) constant chain, (i) an amino acid sequence at least 98% identical to SEQ ID NO: 3010 and having one or more mutations at positions 48, 61, 91, 92, 93 and / or 94, which may include an optional accessory module; (ii) an amino acid sequence at least 98% identical to SEQ ID NO: 3024 and having one or more mutations at positions 18, 22, 57, 79, 133, 136 and / or 139, which may include an optional accessory module; (iii) an amino acid sequence at least 98% identical to SEQ ID NO: 3025 and having one or more mutations at positions 18, 22, 57, 79, 133, 136 and / or 139, which may include an optional accessory module; (iv) an amino acid sequence at least 98% identical to SEQ ID NO: 3046, 3047, or 3048, which may include an optional accessory module; (v) an amino acid sequence at least 98% identical to SEQ ID NO: 3049, which may include an optional accessory module; (vi) an amino acid sequence at least 98% identical to SEQ ID NO: 3051 or 3052, which may include an optional accessory module; and (vii) a dimeric combination of two TCR constant chains selected from (i) and (ii), (i) and (iii), (iv) and (ii), (iv) and (iii), and (v) and (vi); a T cell receptor constant chain having an amino acid sequence selected from the group consisting of: (b) an optional linker; and (c) one or more non-native TCR antigen-binding domains linked to (a), (1) Antibodies, (2) antibody fragments (e.g., Fv, Fab, (Fab')2); (3) an antibody heavy chain variable region (vH domain) or a fragment thereof; (4) an antibody light chain variable region (vL domain) or a fragment thereof; (5) a single-chain variable fragment (scFv) or a fragment thereof; (6) a single domain antibody (SDAB) or a fragment thereof; (7) a VHH domain derived from a camelid or a fragment thereof; (8) a monomeric variable region of an antibody; (9) Non-immunoglobulin antigen-binding scaffolds, such as DARPINs, affibodies, affilins, adnectins, affitins, obodies, lipibodies, finomers, alphabodies, avimers, atrimers, centilins, pronectins, anticalins, Kunitz domains, armadillo repeat proteins, or fragments thereof; (10) a receptor or a fragment thereof; (11) a ligand or a fragment thereof; (12) Bispecific antibodies, bispecific antibody fragments, bispecific scFVs, bispecific vHHs, bispecific SDABs, bispecific non-immunoglobulin antigen-binding scaffolds, bispecific receptors, or bispecific ligands; and (13) an autoantigen or a fragment thereof; one or more non-native TCR antigen-binding domains selected from the group consisting of: Including, the variants of (a)(i)-(a)(iii) and the dimers of (a)(vii) confer diverse binding affinities of the antigen binding domains to the target antigen, which affinities are at least 5% greater than the binding affinity of a cTCR having the same binding domain; and the synthetic immunoreceptors, when expressed in lymphocytes, express both the antigen binding domains and the T cell receptor constant chains in one or more contiguous chains on the surface of the lymphocyte, such that, when the expressed antigen binding domains bind to their antigen, the lymphocyte is triggered to activate, proliferate, secrete cytokines and / or modulate (induce or suppress) killing of target cells, and have MHC-restricted and non-MHC-restricted antibody type specificities. Recombinant polynucleotides.

2. 2. The recombinant polynucleotide of claim 1, comprising a TCR constant chain of (a)(vii), wherein the non-native TCR binding domain comprises: - variable regions of antibody heavy and light chains or fragments thereof specific for a predetermined target antigen, wherein, when expressed, one of the antibody heavy and light chains or fragments thereof is attached to one of the two chains of (a)(vii) of the T cell constant region, and the other of the antibody heavy and light chains or fragments thereof is attached to the other of the two chains of the T cell constant region; - two single chain variable fragments (scFv) specific for one or more predetermined target antigens, wherein, when expressed, one of the scFvs is attached to one of the two chains of (a)(vii) of the T cell constant region and the other of the scFvs is attached to the other of the two chains of the T cell constant region; - two antibody fragments specific for one or more predetermined target antigens, wherein when expressed, one of the antibody fragments is attached to one of the two chains of (a)(vii) of the T cell constant region and the other of the antibody fragments is attached to the other of the two chains of the T cell constant region; - two single domain antibody (SDAB) fragments specific for one or more predetermined target antigens, wherein, when expressed, one of the SDAB fragments is attached to one of the two chains of (a)(vii) of the T cell constant region and the other of the SDAB fragments is attached to the other of the two chains of the T cell constant region; - two camelid-derived vHH domains specific for one or more predetermined target antigens, wherein, when expressed, one of the vHH domains is attached to one of the two chains of (a)(vii) of the T-cell constant region and the other of the vHH domains is attached to the other of the two chains of the T-cell constant region; - two non-immunoglobulin antigen-binding scaffolds specific for one or more predetermined target antigens, wherein, when expressed, one of the non-immunoglobulin antigen-binding scaffolds is attached to one of the two chains of (a)(vii) of the T-cell constant region and the other of the non-immunoglobulin antigen-binding scaffold domains is attached to the other of the two chains of the T-cell constant region; - two receptors or fragments thereof specific for one or more predetermined target antigens, wherein, when expressed, one of the receptors or fragments thereof is attached to one of the two chains of (a)(vii) of the T cell constant region and the other of the receptors or fragments thereof is attached to the other of the two chains of the T cell constant region; - two ligands or fragments thereof specific for one or more predetermined target antigens, wherein, when expressed, one of the ligands or fragments thereof is attached to one of the two chains of (a)(vii) of the T cell constant region and the other of the ligands or fragments thereof is attached to the other of the two chains of the T cell constant region; - two structurally distinct antigen-binding fragments specific for one or more predetermined target antigens, wherein, when expressed, one of the antigen-binding fragments is attached to one of the two chains of (a)(vii) of the T-cell constant region and the other of the antigen-binding fragments is attached to the other of the two chains of the T-cell constant region; two binding fragments, either or both of which are bispecific or multispecific, and when expressed, one of the antigen-binding fragments is attached to one of the two chains of (a)(vii) of the T-cell constant region and the other of the antigen-binding fragments is attached to the other of the two chains of the T-cell constant region; two autoantigens or fragments thereof, wherein, when expressed, one of the autoantigens or fragments thereof is attached to one of the two chains of (a)(vii) of the T cell constant region and the other of the autoantigens or fragments thereof is attached to the other of the two chains of the T cell constant region; two vLs or fragments thereof, wherein, when expressed, one of the vLs or fragments thereof is attached to one of the two chains of (a)(vii) of the T cell constant region and another of the vLs or fragments thereof is attached to the other of the two chains of the T cell constant region; two vHs or fragments thereof, wherein, when expressed, one of the vHs or fragments thereof is attached to one of the two chains of (a)(vii) of the T cell constant region and the other of the vHs or fragments thereof is attached to the other of the two chains of the T cell constant region; and A recombinant polynucleotide selected from the group consisting of:

3. 2. The recombinant polynucleotide of claim 1, comprising the TCR constant chain of (a)(iv), wherein the non-native TCR binding domain is: - the variable region of the heavy chain (vH) of an antibody or a fragment thereof specific for a predetermined target antigen; - the variable region of the light chain (vL) of an antibody or a fragment thereof specific for a predetermined target antigen; - a single chain variable fragment (scFv) or a fragment thereof specific for a predetermined target antigen, - antibody fragments (e.g. Fv, Fab, (Fab')2) specific for a given target antigen; - single domain (SDAB) fragments specific for a given target antigen; - a camelid-derived vHH domain specific for a predetermined target antigen; - a non-immunoglobulin antigen-binding scaffold specific for a predetermined target antigen; a receptor or a fragment thereof specific for a predetermined target antigen, - a ligand or a fragment thereof specific for a predetermined target antigen, a bispecific antibody, bispecific antibody fragment, bispecific scFV, bispecific vHH, bispecific SDAB, bispecific non-immunoglobulin antigen-binding scaffold, bispecific receptor, or bispecific ligand specific for one or more predetermined target antigens; - an autoantigen or a fragment thereof, A recombinant polynucleotide selected from the group consisting of:

4. 2. The recombinant polynucleotide of claim 1, comprising a polynucleotide encoding (i), (ii), (iii), (iv), (v) or (vi), wherein the non-native TCR binding domain is: - the variable region of the heavy chain (vH) of an antibody specific for a given target antigen; - the variable region of the light chain (vL) of an antibody specific for a given target antigen; - a single chain variable fragment (scFv) specific for a predetermined target antigen; - antibody fragments (e.g. Fv, Fab, (Fab')2) specific for a given target antigen; - single domain (SDAB) fragments specific for a given target antigen; - a camelid-derived vHH domain specific for a predetermined target antigen; - a non-immunoglobulin antigen-binding scaffold specific for a predetermined target antigen; a receptor or a fragment thereof specific for a predetermined target antigen, - a ligand or a fragment thereof specific for a predetermined target antigen, a bispecific antibody, bispecific antibody fragment, bispecific scFV, bispecific vHH, bispecific SDAB, bispecific non-immunoglobulin antigen-binding scaffold, bispecific receptor, or bispecific ligand specific for one or more predetermined target antigens; - an autoantigen or a fragment thereof, A recombinant polynucleotide selected from the group consisting of:

5. The recombinant polynucleotide of claim 1 , wherein the polynucleotide encoding the TCR constant chain is a codon-optimized sequence.

6. 2. The recombinant polynucleotide of claim 1, wherein the polynucleotide encoding the TCR constant chain of (a) encodes a TCR constant chain(s) comprising a mutation that improves expression and / or pairing of the TCR constant chain and that reduces pairing with an endogenous T cell receptor chain.

7. 2. The recombinant polynucleotide of claim 1, wherein the polynucleotide encoding the TCR constant chain of (a) comprises a nucleic acid sequence that is 1 to 40 modifications of a nucleic acid sequence of SEQ ID NOs: 730 to 743 or a sequence that is at least 70% identical to a nucleic acid sequence of SEQ ID NOs: 730 to 743, and that is capable of dimerizing with a TCR β1 chain or a TCR β2 chain.

8. 2. The recombinant polynucleotide of claim 1, wherein the polynucleotide encoding the TCR constant chain of (b) or (c) comprises a nucleic acid sequence that is 1 to 40 modifications of the nucleic acid sequence of SEQ ID NOs: 744-765 or a sequence that is at least 70% identical to the nucleic acid sequence of SEQ ID NOs: 744-765, and that is capable of dimerizing with the TCR alpha chain.

9. The recombinant polynucleotide of claim 1, wherein the polynucleotide encoding the TCR constant chain of (v) comprises a nucleic acid sequence that is 1 to 40 modifications of the nucleic acid sequence of SEQ ID NOs: 769 to 770 or a sequence that is at least 70% identical to the nucleic acid sequence of SEQ ID NOs: 769 to 770 and that is capable of pairing with a TCR δ chain.

10. The recombinant polynucleotide of claim 1, wherein the polynucleotide encoding the TCR constant chain of (vi) comprises a nucleic acid sequence that is 1 to 40 modifications of the nucleic acid sequence of SEQ ID NOs: 771 to 772 or a sequence that is at least 70% identical to the nucleic acid sequence of SEQ ID NOs: 771 to 772, and that is capable of dimerizing with the TCR gamma chain.

11. The recombinant polynucleotide of claim 1, wherein the polynucleotide encoding the TCR constant chain of (iv) comprises a nucleic acid sequence of 1 to 40 modifications of the nucleic acid sequence of SEQ ID NOs: 766-768 or a sequence at least 70% identical to the nucleic acid sequence of SEQ ID NOs: 766-768, and a sequence capable of dimerizing with the TCR β1 chain or the TCR β2 chain.

12. The one or more non-natural TCR antigen binding domains may be CD19; CD123; CD22; CD30; CD171; CS-1 (also known as CD2 subset 1, CRACC, SLAMF7, CD319, and 19A24); C-type lectin-like molecule 1 (CLL-1 or CLECL1); CD33; epidermal growth factor receptor variant III (EGFRviii); ganglioside G2 (GD2); ganglioside GD3 (aNeu5Ac(2-8)aNeu5Ac(2-3)bDGalp(1-4)bDGlcp(1-1)Cer); TNF receptor family member B cell maturation (BCMA); Tn antigen ((Tn Ag) or (GalNAcα-Ser / Thr); prostate-specific membrane antigen (PSMA); receptor tyrosine kinase-like orphan receptor 1 (ROR1); FMS-like tyrosine kinase 3 (FLT3); tumor-associated glycoprotein 72 (TAG72); CD38; CD44v6; glycosylated CD43 epitope expressed in acute leukemia or lymphoma but not in hematopoietic progenitor cells, expressed in non-hematopoietic cancers glycosylated CD43 epitopes; carcinoembryonic antigen (CEA); epithelial cell adhesion molecule (EPCAM); B7H3 (CD276); KIT (CD117); interleukin-13 receptor subunit alpha 2 (IL-13Ra2 or CD213A2); mesothelin; interleukin-11 receptor alpha (IL-11Ra); prostate stem cell antigen (PSCA); protease serine 21 (testis rRNA or PRSS21); vascular endothelial growth factor receptor 2 (VEGFR2); Lewis (Y) antigen; CD24; platelet-derived growth factor receptor beta (PDGFR-β); stage-specific embryonic antigen 4 (SSEA-4); CD20; folate receptor α; receptor tyrosine protein kinase ERBB2 (Her2 / neu); mucin 1, cell surface associated (MUC1); epidermal growth factor receptor (EGFR); neural cell adhesion molecule (NCAM); prostase; prostatic acid phosphatase (PAP); elongation factor 2 mutated (ELF2M); ephrin B2; fibroblast activation protein α (FAP); insulin-like growth factor 1 receptor (IGF-1 receptor), carbonic anhydrase IX (CAIX); proteasome (prosome, macropain) subunit, beta type 9 (LMP2); glycoprotein 100 (gp100);Oncogene fusion protein (bcr-abl) consisting of a break-prone region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (Abl); tyrosinase; ephrin type A receptor 2 (EphA2); fucosyl GM1; sialyl Lewis adhesion molecule (sLe); ganglioside GM3 (aNeu5Ac(2-3)bClalp(1-4)bDGlcp(1-1)Cer); transglutaminase 5 (TGS5); high molecular weight melanoma-associated antigen (HMWMAA); O-acetyl-GD2 ganglioside (OAc GD2); folate receptor beta; tumor endothelial marker 1 (TEM1 / CD248); tumor endothelial marker 7-related (TEM7R); claudin 6 (CLDN6); thyroid-stimulating hormone receptor (TSHR); G protein-coupled receptor class C group 5 member D (GPRC5D); chromosome X open reading frame 61 (CXORF61); CD97; CD179a; anaplastic lymphoma kinase (ALK); polysialic acid; placenta-specific 1 (PLAC1); hexasaccharide moiety of globo-H glycoceramide (GloboH); breast Glandular differentiation antigen (NY-BR-1); uroplakin 2 (UPK2); hepatitis A virus cell receptor 1 (HAVCR1); adrenergic receptor beta 3 (ADRB3), pannexin 3 (PANX3); G protein-coupled receptor 20 (GPR20), lymphocyte antigen 6 complex locus K9 (LY6K), olfactory receptor 51E2 (OR51E2); TCR gamma alternative reading frame protein (TARP); Wilms tumor protein (WT1); cancer / testis antigen 1 (NY-ES0-1); cancer / testis 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); X antigen family member 1A (XAGE1); angiopoietin-binding cell surface receptor 2 (Tie2); melanoma cancer-testis antigen 1 (MAD-CT-1); melanoma cancer-testis antigen 2 (MAD-CT-2); Fos-related antigen 1; tumor protein p53 (p53); p53 mutant; prostein; survivin; telomerase; prostate carcinoma antigen 1 (PCT A-1 or galectin-8), melanoma antigen 1 recognized by T cells (MelanA or MARTI); rat sarcoma (Ras) mutant; human telomerase reverse transcriptase (hTERT); sarcoma translocation breakpoints;Melanoma inhibitor of apoptosis (ML-IAP); ERG (transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene); N-acetylglucosaminyltransferase V (NA17); paired box protein Pax-3 (PAX3); androgen receptor; cyclin B1; neuroblastoma-derived homolog of v-myc avian myelocytomatosis viral oncogene (MYCN); Ras homolog family member C (RhoC); tyrosinase-related protein 2 (TRP-2); cytochrome P450 1B1 (CYP1B1); CCCTC-binding factor (zinc finger protein)-like (BORIS or Brother of the Regulator of Imprinted Sites), squamous cell carcinoma antigen 3 recognized by T cells (SART3); paired box protein Pax-5 (PAX5); proacrosin-binding protein sp32 (OY-TES1); lymphocyte-specific protein tyrosine kinase (LCK); A-kinase anchor protein 4 (AKAP-4); synovial sarcoma, X-breakpoint 2 (SSX2); receptor for advanced glycation end products (RAGE-1); renal ubiquitous 1 (RU1); renal ubiquitous 2 (RU2); legumain; human papillomavirus E6 (HPV E6); human papillomavirus E7 (HPV E7); intestinal carboxylesterase; heat shock protein 70-2 mutant (mut hsp 70-2); CD79a; CD79b; CD72; leukocyte-associated immunoglobulin-like receptor 1 (LAIR1); Fc fragment of the IgA receptor (FCAR or CD89); leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2); CD300 molecule-like family member f (CD300LF); C-type lectin domain family 12 member A (CLEC12A); bone marrow stromal cell antigen 2 (BST2); EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2); lymphocyte antigen 75 (LY75); glypican 3 (GPC3); Fc receptor-like 5 (FCRL5); and immunoglobulin lambda-like polypeptide 1 (IGLL1), MPL, biotin, c-MYC epitope tag, CD34, LAMP1 TROP2, GFRalpha4, CDH17, CDH6, NYBR1, CDH19, CD200R, Slea (CA19.9;Sialyl Lewis antigen) Fucosyl GM1, PTK7, gpNMB, CDH1-CD324, DLL3, CD276 / B7H3, IL11Ra, IL13Ra2, CD179b-IGL11, ALK TCRγ-δ, NKG2D, CD32 (FCGR2A), Tn ag, CSPG4-HMW-MAA, Timl- / HVCR1, CSF2RA (GM-CSFRα), TGFβR2, VEGFR2 / KDR, Lewis Ag, TCRβ chain, TCRβ2 chain, TCRγ chain, TCRδ chain, FITC, luteinizing hormone receptor (LHR), follicle-stimulating hormone receptor (FSHR), chorionic gonadotropin receptor (CGHR), CCR4, GD3, SLAMF6, SLAMF4, HIV1 envelope glycoprotein, HTLV1-Tax, CMVpp65, EBV- EBNA3c, influenza A hemagglutinin (HA), GAD, PDL1, guanylyl cyclase C (GCC), KSHV-K8.1 protein, KSHV-gH protein, autoantibodies against desmoglein 3 (Dsg3), autoantibodies against desmoglein 1 (Dsg1), 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 2. The recombinant polynucleotide of claim 1, which binds to one or more disease-associated antigens selected from the group consisting of G12V, tissue factor 1 (TF1), AFP, GPRC5D, claudin 18.2 (CLD18A2 or CLDN18A.2), P-glycoprotein, STEAP1, LIV1, NECTIN-4, CRIPTO, GPA33, BST1 / CD157, a small-conductance chloride channel, and an antigen recognized by the TNT antibody.

13. 13. The recombinant polynucleotide of claim 12, wherein the one or more non-natural TCR antigen-binding domains comprise an antibody; an antibody fragment; an scFv; an Fv; an Fab; an (Fab')2; a single domain antibody (SDAB); a vH domain or a vL domain; a camelid-derived vHH domain; a non-immunoglobulin antigen-binding scaffold such as a DARPIN, an affibody, an affilin, an adnectin, an affitin, an obody, a lipibody, a fynomer, an alphabody, an avimer, an atrimer, a centilin, a pronectin, an anticalin, a Kunitz domain, or an armadillo repeat protein; a receptor; or a ligand.

14. the one or more non-natural TCR antigen binding domains (i) a heavy chain variable region (vH) encoded by a polynucleotide having the sequence of any one of SEQ ID NOs: 226-400 or 10203-10321, or a sequence at least 98% identical thereto, wherein the polynucleotide encodes a polypeptide that binds to the antigen; (ii) a light chain variable region (vL) encoded by a polynucleotide having the sequence of any one of SEQ ID NOs: 16-191 or 10085-10202, or a sequence at least 98% identical thereto, wherein the polynucleotide encodes a polypeptide that binds to the antigen; (iii) a single chain variable fragment (scFv) encoded by a polynucleotide having the sequence of any one of SEQ ID NOs: 488-657, 10346-10400, or 18098-18160, or a sequence at least 98% identical thereto, wherein the polynucleotide encodes a polypeptide that binds to the antigen; (iv) a camelid VHH domain encoded by a polynucleotide having the sequence of any one of SEQ ID NOs: 421-445 or 10322-10337, or a sequence at least 98% identical thereto, wherein the polynucleotide encodes a polypeptide that binds to the antigen; (v) a non-immunoglobulin scaffold encoded by a polynucleotide having the sequence of any one of SEQ ID NOs: 439-443, or a sequence at least 98% identical thereto, wherein the polynucleotide encodes a polypeptide that binds to the antigen; (vi) a receptor encoded by a polynucleotide having the sequence of any one of SEQ ID NOs: 456-468 or a sequence at least 98% identical thereto, wherein the polynucleotide encodes a polypeptide that binds to its cognate; (vii) a ligand encoded by a polynucleotide having the sequence of any one of SEQ ID NOs: 476-486 or 10402-10404, or a sequence at least 98% identical thereto, wherein the polynucleotide encodes a polypeptide that binds to its cognate; 13. The recombinant polynucleotide of claim 12, selected from the group consisting of:

15. 2. The recombinant polynucleotide of claim 1, wherein the one or more non-natural TCR antigen binding domains comprise one or more of the light chain complementarity determining regions for a selected target antigen set forth in any of SEQ ID NOs: 13999-14879 or 14880, and / or one or more of the heavy chain complementarity determining regions for a selected target antigen set forth in any of SEQ ID NOs: 14881-15761 or 15762.

16. 2. The recombinant polynucleotide of claim 1, wherein the one or more non-naturally occurring TCR antigen binding domains have a variable light chain (vL) domain having a sequence set forth in any one of SEQ ID NOs: 2307-2482 or 12042-12159 with up to 10 conservative amino acid substitutions, and / or a variable heavy chain (vH) domain having a sequence set forth in any one of SEQ ID NOs: 2506-2680 or 12160-12278 with up to 10 conservative amino acid substitutions.

17. 2. The recombinant polynucleotide of claim 1, wherein the one or more non-natural TCR antigen binding domains comprise one or more camelid vHH complementarity determining regions for a selected antigen as set forth in any one of SEQ ID NOs: 2701-2725 or 12279-12294 with up to 10 conservative amino acid substitutions.

18. 2. The recombinant polynucleotide of claim 1, wherein the one or more non-native TCR antigen binding domains have an amino acid sequence set forth in any one of SEQ ID NOs: 2728-2732 or 12296-12301, and a non-immunoglobulin antigen binding domain comprising up to 10 conservative amino acid substitutions.

19. 2. The polynucleotide of claim 1, wherein the one or more non-natural TCR antigen binding domains comprise an scFv domain comprising one or more light chain complementarity determining regions of a variable light chain (vL) domain having the sequence of any one of SEQ ID NOs: 2307-2482 or 12042-12159 and one or more heavy chain complementarity determining regions of a variable heavy chain (vH) domain having the sequence of any one of SEQ ID NOs: 2506-2680 or 12160-12278.

20. 2. The recombinant polynucleotide of claim 1, wherein the one or more non-native TCR antigen binding domains comprise an scFv fragment comprising a sequence selected from the group consisting of SEQ ID NOs: 2770-2939, 12303-12357, and 18162-18224, each with up to 10 conservative amino acid substitutions.

21. 2. The recombinant polynucleotide of claim 1, wherein the one or more non-natural TCR antigen binding domains comprise one or more receptors consisting of the amino acid sequence of any of SEQ ID NOs: 2736-2748 with up to 10 conservative amino acid substitutions.

22. 2. The recombinant polynucleotide of claim 1, wherein the one or more non-natural TCR antigen binding domains have one or more ligands consisting of the sequence of any of SEQ ID NOs: 2758-2768 or 12359-12361 with up to 10 conservative amino acid substitutions.

23. 2. The recombinant polynucleotide of claim 1, wherein the one or more non-native TCR antigen-binding domains comprise the extracellular domain of CD16A, NKG2D, CD4, PD1, desmoglein 3 (Dsg3), or CD4-DC-SIGN.

24. 2. The recombinant polynucleotide of claim 1, wherein the one or more non-natural TCR antigen binding domains comprise one or more extracellular domains of hTPO, mTPO, CGH α chain, CGH β chain, FH β chain, LH β chain, TSH β chain, APRIL, or a combination thereof.

25. the one or more non-natural TCR antigen binding domains are any single chain variable fragment (scFv) comprising the sequence of any one of SEQ ID NOs: 2770-2939, 12303-12357, or 18162-18224, with up to 10 conservative amino acid substitutions; a) any camelid vHH as set forth in any of SEQ ID NOs: 2701-2725 or 12279-12294, with up to 10 conservative amino acid substitutions; or b) any non-immunoglobulin antigen-binding domain having the sequence as set forth in any of SEQ ID NOs: 2728-2732 or 12296-12301, with up to 10 conservative amino acid substitutions; or c) any extracellular domain of a receptor consisting of the amino acid sequence of any of SEQ ID NOs: 2736-2748, with up to 10 conservative amino acid substitutions; or d) any extracellular domain of a ligand having any of the sequences of SEQ ID NOs: 2758-2768 or 12359-12361, with up to 10 conservative amino acid substitutions; 2. The recombinant polynucleotide of claim 1, comprising:

26. the one or more non-natural TCR antigen binding domains have up to 10 conservative amino acid substitutions and comprise a camelid vHH as set forth in any of SEQ ID NOs: 2701-2725 or 12279-12294; a) any single chain variable fragment (scFv) having the sequence of any of SEQ ID NOs: 2770-2939, 12303-12357, or 18162-18224, and having up to 10 conservative amino acid substitutions; or b) any non-immunoglobulin antigen-binding domain having the sequence set forth in any of SEQ ID NOs: 2728-2732 or 12296-12301 and having up to 10 conservative amino acid substitutions; or c) any extracellular domain of a receptor consisting of the amino acid sequence of any of SEQ ID NOs: 2736-2748, with up to 10 conservative amino acid substitutions; or d) any extracellular domain of a ligand having any of the sequences of SEQ ID NOs: 2758-2768 or 12359-12361, with up to 10 conservative amino acid substitutions; 2. The recombinant polynucleotide of claim 1, comprising:

27. 2. The recombinant polynucleotide of claim 1, wherein the one or more non-native TCR antigen binding domains are optionally connected to each of the TCR constant regions by a linker region, wherein the nucleic acid of the linker region encodes an amino acid sequence selected from the group consisting of SEQ ID NOs: 2981-3003, and any combination thereof, or a sequence at least 98% identical thereto, or the linker is encoded by a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 701-725, or a sequence at least 98% identical thereto.

28. 2. The recombinant polynucleotide of claim 1, wherein the one or more non-natural TCR antigen binding domains have a binding affinity for the target antigen that is at least 5-fold less than the antibody from which they are derived.

29. The recombinant polynucleotide of claim 1, wherein the polynucleotide encoding the SIR further comprises a leader sequence or signal peptide at the N-terminus of each chain and having a sequence selected from the group consisting of SEQ ID NOs: 1-9 and 10.

30. The recombinant polynucleotide of claim 1 , wherein at least one polynucleotide encodes two SIRs.

31. 31. The recombinant polynucleotide of claim 30, wherein the polynucleotide encodes two SIRs linked by a nucleotide sequence encoding a cleavable linker.

32. 32. The recombinant polynucleotide of claim 31, wherein the cleavable linker is a self-cleaving cleavable linker.

33. 32. The recombinant polynucleotide of claim 31 , wherein the cleavable linker is any one or more of a 2A linker, a 2A-like linker, or functional equivalents thereof.

34. 32. The recombinant polynucleotide of claim 31 , wherein the cleavable linker is any one or more of a T2A linker, a P2A, an F2A, an E2A linker, or functional equivalents thereof.

35. 32. The recombinant polynucleotide of claim 31, wherein the cleavable linker has the sequence of any one or more of SEQ ID NOs: 780-785.

36. 32. The recombinant polynucleotide of claim 31 , wherein the polynucleotide sequence encoding the cleavable linker is optionally preceded by a nucleotide sequence encoding a furin cleavage site, a furin-like cleavage site, or a functional equivalent thereof.

37. 37. The recombinant polynucleotide of claim 36, wherein the furin cleavage site preceding the cleavable linker has the sequence of any one or more of SEQ ID NOs: 788-790.

38. 38. The recombinant polynucleotide of any one of claims 31 to 37, wherein the polynucleotide sequence encoding the cleavable linker is preceded by a nucleotide sequence encoding a flexible linker.

39. 39. The recombinant polynucleotide of Claim 38, wherein the flexible linker preceding the cleavable linker encodes one or more of a Ser-Gly linker, a Ser-Gly-Ser-Gly linker, or a functional equivalent thereof.

40. 40. The recombinant polynucleotide of claim 39, wherein the flexible linker preceding the cleavable linker has the sequence of SEQ ID NOs: 786-787.

41. 39. The recombinant polynucleotide of claim 38, wherein the polynucleotide sequence encoding the furin cleavage site is followed by a polynucleotide encoding the flexible linker, which is followed by a polynucleotide encoding the cleavable linker, in the order: furin cleavage site, flexible linker, cleavable linker.

42. 32. The recombinant polynucleotide of claim 31, wherein the polynucleotide encoding the cleavable linker precedes a sequence encoding a leader sequence (signal peptide) encoding a second SIR.

43. The recombinant polynucleotide of claim 1 , wherein the SIR is engineered to have diverse binding affinities for selected antigens.

44. The SIR comprises an accessory module.

45. 45. The recombinant polynucleotide of claim 1, wherein the accessory module comprises a CD3z domain.

46. The TCR constant chain (viii) an amino acid sequence at least 98% identical to SEQ ID NO: 12401, 12402, 12403, 12408, or 12409; and (ix) an amino acid sequence at least 98% identical to SEQ ID NO: 12421, 12422, 12423, 12427, or 12428; (x) a dimeric combination of two TCR constant chains of (viii) and (ix); and 46. ​​The recombinant polynucleotide of claim 45, selected from the group consisting of:

47. The recombinant polynucleotide of claim 12, wherein the one or more non-natural TCR antigen binding domains bind to CD19.

48. the one or more non-natural TCR antigen binding domains a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2318-2324, 12060-12068, 12108, 12127, and 12156, or any complementarity determining region (CDR) contained in any of said polypeptides; a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2517-2523, 12178-12186, 1227, 12246, and 12275, or any complementarity determining region (CDR) contained in any of said polypeptides; a polypeptide having a sequence at least 98% identical to SEQ ID NO: 12288, a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2770-2774, 12325, 12308, 18162-18170, and 12354; 48. The recombinant polynucleotide of claim 47, selected from the group consisting of:

49. 48. The recombinant polynucleotide of claim 47, encoding a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 3135-3235, 3250-3346, 3396, 3401-3403, 3406, 3429-3432, 3435-3439, 3540, 3855-3859, 12431-12489, 12491-12493, 12495-12530, 12534, 13195-13203, 13250, 13267, 13289, 13429-13437, 13483, 13501, and 13523.

50. The recombinant polynucleotide of claim 12, wherein the one or more non-natural TCR antigen binding domains bind to CD20.

51. the one or more non-natural TCR antigen binding domains - a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2325-2326, 12069-12077, and 12078, or any complementarity determining region (CDR) contained in any of said polypeptides; a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2524-2525, 12187-12195, and 12196, or any complementarity determining region (CDR) contained in any of said polypeptides; a polypeptide having a sequence at least 98% identical to SEQ ID NO: 12289 or 12290, a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2787-2788, 18177-18186, and 18187; 51. The recombinant polynucleotide of claim 50, selected from the group consisting of:

52. 51. The recombinant polynucleotide of claim 50, which encodes a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 3263, 3348, 3456-3457, 3876-3877, 12464-12465, 12477-12482, 12492, 12534, 13204-13213, 13438-13446, and 13447.

53. The recombinant polynucleotide of claim 12, wherein the one or more non-natural TCR antigen binding domains bind to CD22.

54. the one or more non-natural TCR antigen binding domains a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2327-2329, 12122-12126, and 12132, or any complementarity determining region (CDR) contained in any of said polypeptides; a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2526-2528, 12241-12245, and 12251, or any complementarity determining region (CDR) contained in any of said polypeptides; a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2789-2791, 12320-12330, and 18188; 54. The recombinant polynucleotide of claim 53, selected from the group consisting of:

55. 54. The recombinant polynucleotide of claim 53, which encodes a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 3332, 3433, 3458-3460, 3878-3880, 12483, 12485, 12488-12490, 13241-13245, 13268, 13475-13479, and 13502.

56. 13. The recombinant polynucleotide of claim 12, wherein the one or more non-natural TCR antigen binding domains bind to BCMA.

57. the one or more non-natural TCR antigen binding domains a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2310-2313, 12046-12048, 12118-12119, 12139-12145, and 12146, or any complementarity determining region (CDR) contained in any of said polypeptides; a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2509-2512, 12164-12166, 12237-12238, 12258-12264, and 12265, or any complementarity determining region (CDR) contained in any of said polypeptides; - a polypeptide having a sequence at least 98% identical to SEQ ID NO: 12279-12281, 12283-12285, 12287, 12291-12292, 12293, or 12294; a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2780-2783, 12237-12344, 18174-18175, and 18176; 57. The recombinant polynucleotide of claim 56, selected from the group consisting of:

58. 57. The recombinant polynucleotide of claim 56, encoding a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 3445-3449, 3866-3869, 12463, 12533, 12535-12536, 13181-13183, 13261-13262, 13277-13284, 13415-13417, 13495-13496, 13511-13517, and 13518.

59. 13. The recombinant polynucleotide of claim 12, wherein the one or more non-natural TCR antigen binding domains bind to MPL.

60. the one or more non-natural TCR antigen binding domains - a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2414-2421, 12120, 12128, and 12129, or any complementarity determining region (CDR) contained in any of said polypeptides; - a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2611-2618, 12239, 12247, and 12248, or any complementarity determining region (CDR) contained in any of said polypeptides; a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2871-2878, 12326-12327, and 12318; 60. The recombinant polynucleotide of claim 59, selected from the group consisting of:

61. 60. The recombinant polynucleotide of claim 59, encoding a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 3347, 3373, 3427-3428, 3495, 3556-3562, 3979-3985, 4025, 12454, 12456, 12458, 12462, 12532, 13259, 13265-13266, 13493, 13499, and 13500.

62. 13. The recombinant polynucleotide of claim 12, wherein the one or more non-natural TCR antigen binding domains bind to CS1.

63. the one or more non-natural TCR antigen binding domains - a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2355-2358, 12090-12094, and 12095, or any complementarity determining region (CDR) contained in any of said polypeptides; - a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2553-2555, 12209-12213, and 12214, or any complementarity determining region (CDR) contained in any of said polypeptides; a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2817-2819, 18211-18215, and 18216; 63. The recombinant polynucleotide of claim 62, selected from the group consisting of:

64. 63. The recombinant polynucleotide of claim 62, encoding a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 3376, 3487, 3489, 3907-3909, 12455, 12457, 12459, 12461, 12476, 13226-13231, 13460-13464, and 13465.

65. The recombinant polynucleotide of claim 12, wherein the one or more non-natural TCR antigen-binding domains bind to CD33.

66. the one or more non-natural TCR antigen binding domains - a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2336-2337, 12079-12084, and 12085, or any complementarity determining region (CDR) contained in any of said polypeptides; a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2535-2536, 12197-12202, and 12203, or any complementarity determining region (CDR) contained in any of said polypeptides; - a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2795-2796, 18189-18193, and 18194; 66. The recombinant polynucleotide of claim 65, selected from the group consisting of:

67. 66. The recombinant polynucleotide of claim 65, encoding a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 3464-3465, 3884-3885, 12460, 12473, 12479, 13214-13220, 13448-13453, and 13454.

68. The recombinant polynucleotide of claim 12, wherein the one or more non-natural TCR antigen-binding domains bind to CD123.

69. the one or more non-natural TCR antigen binding domains a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2315, 2472, 12049-12058, and 12059, or any complementarity determining region (CDR) contained in any of said polypeptides; a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2514, 2670, 12167-12176, and 12177, or any complementarity determining region (CDR) contained in any of said polypeptides; a polypeptide having a sequence at least 98% identical to SEQ ID NO: 2716 or 2717, a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2801, 2929, 18196-18205, and 18206; 69. The recombinant polynucleotide of claim 68, selected from the group consisting of:

70. 69. The recombinant polynucleotide of claim 68, encoding a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 3266-3267, 3366-3368, 3375, 3378, 3405, 3409, 3434, 3470, 3492-3497, 3617, 3890, 3912-3913, 4041, 12480, 13184-13194, 13418-13427, and 13428.

71. 13. The recombinant polynucleotide of claim 12, wherein the one or more non-natural TCR antigen binding domains bind to folate receptor 1.

72. the one or more non-natural TCR antigen binding domains a polypeptide having a sequence at least 98% identical to SEQ ID NO: 2373, or any complementarity determining region (CDR) contained in any of said polypeptides; a polypeptide having a sequence at least 98% identical to SEQ ID NO: 2570, or any complementarity determining region (CDR) contained in any of said polypeptides; a polypeptide having a sequence at least 98% identical to SEQ ID NO: 2833, 72. The recombinant polynucleotide of claim 71, selected from the group consisting of:

73. 72. The recombinant polynucleotide of claim 71, which encodes a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 3511 and 3928.

74. 13. The recombinant polynucleotide of claim 12, wherein the one or more non-natural TCR antigen-binding domains bind mesothelin.

75. the one or more non-natural TCR antigen binding domains a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2413, 12154, and 12155, or any complementarity determining region (CDR) contained in any of said polypeptides; - a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2609-2610, 12273, and 12274, or any complementarity determining region (CDR) contained in any of said polypeptides; - a polypeptide having a sequence at least 98% identical to SEQ ID NO: 2713-2714 or 2725; - a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2870, 2899, 12352, and 12353; 75. The recombinant polynucleotide of claim 74, selected from the group consisting of:

76. 75. The recombinant polynucleotide of claim 74, which encodes a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 3414, 3419, 3554, 3585, 3976, 4008, 13287-13288, 13521, and 13522.

77. 13. The recombinant polynucleotide of claim 12, wherein the one or more non-natural TCR antigen binding domains bind to IL13Ra2.

78. the one or more non-natural TCR antigen binding domains - a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2399 and 2400, or any complementarity determining region (CDR) contained in any of said polypeptides; a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2595 and 2596, or any complementarity determining region (CDR) contained in any of said polypeptides; - a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2858 and 2859; 78. The recombinant polynucleotide of claim 77, selected from the group consisting of:

79. 78. The recombinant polynucleotide of claim 77, which encodes a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 3541-3542, 3963, and 3964.

80. The recombinant polynucleotide of claim 12, wherein the one or more non-natural TCR antigen binding domains bind to CD138.

81. the one or more non-natural TCR antigen binding domains a polypeptide having a sequence at least 98% identical to SEQ ID NO: 2316, or any complementarity determining region (CDR) contained in any of said polypeptides; a polypeptide having a sequence at least 98% identical to SEQ ID NO: 2515, or any complementarity determining region (CDR) contained in any of said polypeptides; a polypeptide having a sequence at least 98% identical to SEQ ID NO: 2802, 81. The recombinant polynucleotide of claim 80, selected from the group consisting of:

82. 81. The recombinant polynucleotide of claim 80, which encodes a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 3268, 3374, 3404, 3471, and 3891.

83. 13. The recombinant polynucleotide of claim 12, wherein the one or more non-natural TCR antigen-binding domains bind to TCRgd.

84. the one or more non-natural TCR antigen binding domains a polypeptide having a sequence at least 98% identical to SEQ ID NO: 2449, or any complementarity determining region (CDR) contained in any of said polypeptides; a polypeptide having a sequence at least 98% identical to SEQ ID NO: 2646, or any complementarity determining region (CDR) contained in any of said polypeptides; a polypeptide having a sequence at least 98% identical to SEQ ID NO: 2907, 84. The recombinant polynucleotide of claim 83, selected from the group consisting of:

85. 84. The recombinant polynucleotide of claim 83, which encodes a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 3594 and 4017.

86. The recombinant polynucleotide of claim 12, wherein the one or more non-natural TCR antigen binding domains bind to TCRB1.

87. the one or more non-natural TCR antigen binding domains a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2445 and 2446, or any complementarity determining region (CDR) contained in any of said polypeptides; - a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2642 and 2643, or any complementarity determining region (CDR) contained in any of said polypeptides; - a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2903 and 2904; 87. The recombinant polynucleotide of claim 86, selected from the group consisting of:

88. 87. The recombinant polynucleotide of claim 86, which encodes a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 3590-3591, 4013, and 4014.

89. 13. The recombinant polynucleotide of claim 12, wherein the one or more non-natural TCR antigen binding domains bind to TCRB2.

90. the one or more non-natural TCR antigen binding domains - a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2447 and 2448, or any complementarity determining region (CDR) contained in any of said polypeptides; - a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2644 and 2645, or any complementarity determining region (CDR) contained in any of said polypeptides; a polypeptide having a sequence at least 98% identical to any one of SEQ ID NOs: 2905 and 2906; 90. The recombinant polynucleotide of claim 89, selected from the group consisting of:

91. 90. The recombinant polynucleotide of claim 89, which encodes a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 3353-3364, 3592-3593, 4015, and 4016.

92. 10. A recombinant expression system comprising the recombinant polynucleotide of claim 1 co-expressed with a therapeutic control, The therapeutic control may be any of the following: truncated epidermal growth factor receptor (tEGFR), truncated epidermal growth factor receptor viii (tEGFRviii), truncated CD30 (tCD30), truncated BCMA (tBCMA), truncated CD19 (tCD19), CD34, thymidine kinase, cytosine deaminase, nitroreductase, xanthine guanine phosphoribosyltransferase, human caspase 8, human caspase 9, inducible caspase 9 (icaspase 9), purine nucleoside phosphorylase , linamarase / linamarin glucose oxidase, deoxynucleoside kinase, horseradish peroxidase (HRP) / indole-3-acetic acid (IAA), gamma glutamylcysteine ​​synthase, CD20 / alpha CD20, CD34 / thymidine kinase chimera, dox-dependent caspase 2, mutant thymidine kinase (HSV-TKSR39), AP1903 / Fas system, chimeric cytokine receptor (CCR), selectable marker, and combinations thereof; Recombinant expression systems.

93. 93. The recombinant expression system of claim 92, wherein the tEGFR and tEGFRviii bind to any one or more of an EGFR-specific siRNA, a small molecule compound, an anti-EGFR antibody or fragment thereof, and combinations thereof.

94. 93. The recombinant expression system of claim 92, wherein the tCD30 binds to any one or more of a CD30-specific siRNA, a small molecule compound, an anti-CD30 antibody or fragment thereof, and combinations thereof.

95. 93. The recombinant expression system of claim 92, wherein the tCD19 binds to any one or more of a CD19-specific siRNA, a small molecule compound, an anti-CD19 antibody or fragment thereof, and combinations thereof.

96. 93. The recombinant expression system of claim 92, wherein the CD34 is bound to any one or more of a CD34-specific siRNA, a small molecule compound, an anti-CD34 antibody or fragment thereof, and combinations thereof.

97. 93. The recombinant expression system of claim 92, wherein the selectable marker binds any one or more of a dihydroxyfolate receptor, a mutant DHFR, a methylated DNA-protein cysteine ​​methyltransferase, inosine monophosphate dehydrogenase II (IMDHP2), puromycin acetyltransferase (PAC), a blasticidin resistance gene, a mutant calcineurin a / b (Can / b), CNa12, CNb30, and combinations thereof.

98. 93. The recombinant expression system of claim 92, wherein the CCR comprises any one or more of: (i) an IL-7 cytokine linker IL7Ra; (ii) an IL-RaIL-7 cytokine linker extracellular domain of an IL-7Ra transmembrane domain of the cytoplasmic domain of an IL2Rβ; (iii) an IL-7 cytokine linker IL2Rβ; and (iv) combinations thereof.

99. 10. A recombinant expression system comprising the recombinant polynucleotide of claim 1 co-expressed with an accessory module, The accessory modules include 41BBL, CD40L, K13, MC159, cFLIP-L / MRITα, cFLIP-p22, HTLV1 Tax, HTLV2 Tax, HTLV2 Tax2-RS mutant, FKBPx-K13, FKBPx-HTLV2-Tax, FKBPx-HTLV2-Tax-RS, IL6R-304-vHH-Alb8-vHH, IL12f, PD1-4H1 scFV, and PD1-5C4. scFV, PD1-4H1-Alb8-vHH, PD1-5C4-Alb8-vHH, CTLA4 ipilimumab scFV, CTLA4 ipilimumab Alb8-vHH, IL6-19A-scFV, IL6-19A-scFV-Alb8-vHH, sHVEM, sHVEM-Alb8-vHH, hTERT, Fx06, CD3z, CD3z-GGGS-41BB, CD3-BBz, CD3-CD28z, CD3-CD28-Lck fusion protein, shRNA targeting Brd4, chimeric antigen receptor (CAR), hTERT, heparinase, CAR, inhibitory CAR, and combinations thereof; Recombinant expression systems.

100. 100. The recombinant expression system of claim 92 or 99, wherein the recombinant polynucleotide encoding the SIR, one or more therapeutic controls, and / or one or more accessory modules are linked by a nucleotide sequence encoding a cleavable linker.

101. 101. The recombinant expression system of claim 100, wherein the cleavable linker is a self-cleaving cleavable linker.

102. 102. The recombinant expression system of claim 101, wherein the polynucleotide sequence encoding the cleavable linker is preceded by a nucleotide sequence encoding a furin cleavage site, a furin-like cleavage site, or a functional equivalent thereof.

103. 101. The recombinant expression system of claim 100, wherein the polynucleotide sequence encoding the cleavable linker is optionally preceded by a nucleotide sequence encoding a flexible linker.

104. At least one vector comprising the recombinant polynucleotide of claim 1, selected from the group consisting of a DNA vector, an RNA vector, a plasmid, a lentiviral vector, an adenoviral vector, a retroviral vector, a baculoviral vector, a sleeping beauty transposon vector, and a piggybac transposon vector; vector.

105. 105. The vector of claim 104, wherein the backbone of the vector has a sequence selected from the group consisting of SEQ ID NOs: 870-875 and 876.

106. The vector of claim 104, having a promoter selected from the group consisting of an EF-1 promoter, a CMV IE gene promoter, an EF-1a promoter, a ubiquitin C promoter, an MSCV LTR promoter, and a phosphoglycerate kinase (PGK) promoter.

107. 107. The vector of claim 106, wherein the EF-1 promoter has the sequence of SEQ ID NO: 877 or a sequence which is 80-99% identical thereto.

108. The vector of claim 104, wherein the vector is an in vitro transcription vector or a vector further comprising a poly(A) tail or a 3'UTR.

109. 10. At least one polypeptide encoded by at least one recombinant polynucleotide of claim 1.

110. A recombinant cell expressing at least one recombinant polynucleotide according to claim 1.

111. 1. An isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer, comprising: (a) a T cell receptor (TCR) constant chain, (i) an amino acid sequence at least 98% identical to SEQ ID NO: 3010, having one or more mutations at positions 48, 61, 91, 92, 93, and / or 94, and optionally having an accessory module; (ii) an amino acid sequence at least 98% identical to SEQ ID NO: 3024, having one or more mutations at positions 18, 22, 57, 79, 133, 136, and / or 139, and optionally having an accessory module; (iii) an amino acid sequence at least 98% identical to SEQ ID NO: 3025, having one or more mutations at positions 18, 22, 57, 79, 133, 136, and / or 139, and optionally having an accessory module; (iv) an amino acid sequence at least 98% identical to SEQ ID NO: 3046, 3047, or 3048, optionally with any accessory modules; (v) an amino acid sequence at least 98% identical to SEQ ID NO: 3049, optionally with any accessory module; (vi) an amino acid sequence at least 98% identical to SEQ ID NO: 3051 or 3052, optionally with any accessory module; (vii) a dimeric combination of two TCR constant chains selected from (i) and (ii), (i) and (iii), (iv) and (ii), (iv) and (iii), (v) and (vi); a T cell receptor constant chain having an amino acid sequence selected from the group consisting of: (b) an optional linker; and (c) one or more non-native TCR antigen-binding domains linked to (a), (1) an antibody; (2) an antibody fragment (e.g., Fv, Fab, (Fab')2); (3) an antibody heavy chain variable region (vH domain) or a fragment thereof; (4) an antibody light chain variable region (vL domain) or a fragment thereof; (5) a single-chain variable fragment (scFv) or a fragment thereof; (6) a single domain antibody (SDAB) or a fragment thereof; (7) a camelid-derived VHH domain or a fragment thereof; (8) a monomeric variable region of an antibody; and (9) A non-immunoglobulin antigen-binding scaffold, such as a DARPIN, an affibody, an affilin, an adnectin, an affitin, an obodies, a lipibody, a fynomer, an alphabody, an avimer, an atrimer, a centilin, a pronectin, an anticalin, a Kunitz domain, an armadillo repeat protein, or a fragment thereof; (10) a receptor or a fragment thereof; (11) a ligand or a fragment thereof; (12) A bispecific antibody, bispecific antibody fragment, bispecific scFV, bispecific vHH, bispecific SDAB, bispecific non-immunoglobulin antigen-binding scaffold, bispecific receptor, or bispecific ligand; (13) an autoantigen or a fragment thereof; and a non-native TCR antigen-binding domain selected from the group consisting of: The variants of (a)(i) to (a)(iii) have diverse binding affinities for the target antigen of the antigen binding domain, and the synthetic immunoreceptors, when expressed in lymphocytes, express both the antigen binding domain and the T cell receptor constant chain in one or more contiguous chains on the surface of the lymphocyte, are triggered to activate, proliferate, and secrete cytokines and / or modulate (induce or suppress) killing of the target cell when the expressed antigen binding domain binds to its antigen, and have MHC-restricted and non-MHC-restricted antibody type specificities. An isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer.

112. (a)(vii), wherein the non-native TCR binding domain comprises: - variable regions of antibody heavy and light chains or fragments thereof specific for a predetermined target antigen, wherein, when expressed, one of the antibody heavy and light chains or fragments thereof is attached to one of the two chains of (a)(vii) of the T cell constant region, and the other of the antibody heavy and light chains or fragments thereof is attached to the other of the two chains of the T cell constant region; - two single chain variable fragments (scFv) specific for one or more predetermined target antigens, wherein, when expressed, one of the scFvs is attached to one of the two chains of (a)(vii) of the T cell constant region and the other of the scFvs is attached to the other of the two chains of the T cell constant region; - two antibody fragments specific for one or more predetermined target antigens, wherein, when expressed, one of the antibody fragments is attached to one of the two chains of (a)(vii) of the T cell constant region and the other of the antibody fragments is attached to the other of the two chains of the T cell constant region; - two single domain antibody (SDAB) fragments specific for one or more predetermined target antigens, wherein, when expressed, one of the SDAB fragments is attached to one of the two chains of (a)(vii) of the T cell constant region and the other of the SDAB fragments is attached to the other of the two chains of the T cell constant region; - two camelid-derived vHH domains specific for one or more predetermined target antigens, wherein, when expressed, one of the vHH domains is attached to one of the two chains of (a)(vii) of the T cell constant region and the other of the vHH domains is attached to the other of the two chains of the T cell constant region; - two non-immunoglobulin antigen-binding scaffolds specific for one or more predetermined target antigens, wherein, when expressed, one of the non-immunoglobulin antigen-binding scaffolds is attached to one of the two chains of (a)(vii) of the T-cell constant region and the other of the non-immunoglobulin antigen-binding scaffold domains is attached to the other of the two chains of the T-cell constant region; - two receptors or fragments thereof specific for one or more predetermined target antigens, wherein, when expressed, one of the receptors or fragments thereof is attached to one of the two chains of (a)(vii) of the T cell constant region and the other of the receptors or fragments thereof is attached to the other of the two chains of the T cell constant region; - two ligands or fragments thereof specific for one or more predetermined target antigens, wherein, when expressed, one of the ligands or fragments thereof is attached to one of the two chains of (a)(vii) of the T cell constant region and the other of the ligands or fragments thereof is attached to the other of the two chains of the T cell constant region; and two structurally distinct antigen-binding fragments specific for one or more predetermined target antigens, wherein, when expressed, one of the antigen-binding fragments is attached to one of the two chains of (a)(vii) of the T cell constant region and the other of the antigen-binding fragments is attached to the other of the two chains of the T cell constant region; two binding fragments, either or both of which are bispecific or multispecific, wherein, when expressed, one of the antigen-binding fragments is attached to one of the two chains of (a)(vii) of the T cell constant region and the other of the antigen-binding fragments is attached to the other of the two chains of the T cell constant region; - two autoantigens or fragments thereof, wherein, when expressed, one of the autoantigens or fragments thereof is attached to one of the two chains of (a)(vii) of the T cell constant region and the other of the autoantigens or fragments thereof is attached to the other of the two chains of the T cell constant region; and - two vLs or fragments thereof, wherein, when expressed, one of the vLs or fragments thereof is attached to one of the two chains of (a)(vii) of the T cell constant region and another of the vLs or fragments thereof is attached to the other of the two chains of the T cell constant region; two vHs or fragments thereof, wherein, when expressed, one of the vHs or fragments thereof is attached to one of the two chains of (a)(vii) of the T-cell constant region and the other of the vHs or fragments thereof is attached to the other of the two chains of the T-cell constant region; and 112. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 111, selected from the group consisting of:

113. (a)(iv) and the non-native TCR binding domain comprises: - the variable region of the heavy chain (vH) of an antibody or a fragment thereof specific for a predetermined target antigen; - the variable region of the light chain (vL) of an antibody or a fragment thereof specific for a predetermined target antigen; - a single chain variable fragment (scFv) or a fragment thereof specific for a predetermined target antigen, - antibody fragments (e.g. Fv, Fab, (Fab')2) specific for a given target antigen; - single domain (SDAB) fragments specific for a given target antigen; - a camelid-derived vHH domain specific for a predetermined target antigen; - a non-immunoglobulin antigen-binding scaffold specific for a predetermined target antigen; a receptor or a fragment thereof specific for a predetermined target antigen, - a ligand or a fragment thereof specific for a predetermined target antigen, a bispecific antibody, bispecific antibody fragment, bispecific scFV, bispecific vHH, bispecific SDAB, bispecific non-immunoglobulin antigen-binding scaffold, bispecific receptor, or bispecific ligand specific for one or more predetermined target antigens; - an autoantigen or a fragment thereof, 112. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 111, selected from the group consisting of:

114. (i), (ii), (iii), (iv), (v), or (vi), wherein the non-native TCR binding domain comprises: - the variable region of the heavy chain (vH) of an antibody specific for a given target antigen; - the variable region of the light chain (vL) of an antibody specific for a given target antigen; - a single chain variable fragment (scFv) specific for a predetermined target antigen; - antibody fragments (e.g. Fv, Fab, (Fab')2) specific for a given target antigen; - single domain (SDAB) fragments specific for a given target antigen; - a camelid-derived vHH domain specific for a predetermined target antigen; - a non-immunoglobulin antigen-binding scaffold specific for a predetermined target antigen; a receptor or a fragment thereof specific for a predetermined target antigen, - a ligand or a fragment thereof specific for a predetermined target antigen, a bispecific antibody, bispecific antibody fragment, bispecific scFV, bispecific vHH, bispecific SDAB, bispecific non-immunoglobulin antigen-binding scaffold, bispecific receptor, or bispecific ligand specific for one or more predetermined target antigens; - an autoantigen or a fragment thereof, 112. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 111, selected from the group consisting of:

115. 112. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 111, wherein the TCR constant chain(s) have a mutation that promotes expression and / or pairing of the TCR constant chain and a mutation that reduces pairing with an endogenous T cell receptor chain.

116. 112. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 111, wherein the constant region of the TCR is a TCR receptor alpha chain (Cα) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 3010-3023, or an amino acid sequence comprising 1 to 40 amino acid substitutions or mutations relative to a sequence at least 98% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 3010-3023.

117. 112. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 111, wherein the constant region of the TCR is a TCR receptor beta chain (Cβ) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 3024-3044, or an amino acid sequence comprising 1 to 40 amino acid substitutions or mutations relative to a sequence at least 98% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 3024-3044.

118. 112. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 111, wherein the constant region of the TCR is a TCR receptor gamma chain (Cγ) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 3049-3050, or an amino acid sequence comprising 1 to 40 amino acid substitutions or mutations relative to a sequence at least 98% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 3049-3050.

119. 112. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 111, wherein the constant region of the TCR is a TCR receptor delta chain (Cδ) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 3051-3052, or an amino acid sequence comprising 1 to 40 amino acid substitutions or mutations relative to a sequence at least 98% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 3051-3052.

120. 112. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 111, wherein the constant region of the TCR is a pre-TCR receptor alpha chain (pre-Cα) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 3046-3048, or an amino acid sequence comprising 1 to 40 amino acid substitutions or mutations relative to a sequence at least 98% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 3046-3048.

121. The one or more non-natural TCR antigen binding domains that bind one or more disease-associated antigens may be selected from the group consisting of CD19; CD123; CD22; CD30; CD171; CS-1 (also known as CD2 subset 1, CRACC, SLAMF7, CD319, and 19A24); C-type lectin-like molecule 1 (CLL-1 or CLECL1); CD33; epidermal growth factor receptor variant III (EGFRviii); ganglioside G2 (GD2); ganglioside GD3 (aNeu5Ac(2-8)aNeu5Ac(2-3)bDGalp(1-4)bDGlcp(1-1)Cer); TNF receptor family member B-cell maturation (BCMA); Tn antigen ((Tn Ag) or (GalNAcα-Ser / Thr); prostate-specific membrane antigen (PSMA); receptor tyrosine kinase-like orphan receptor 1 (ROR1); FMS-like tyrosine kinase 3 (FLT3); tumor-associated glycoprotein 72 (TAG72); CD38; CD44v6; glycosylated CD43 epitope expressed in acute leukemia or lymphoma but not in hematopoietic progenitor cells, expressed in non-hematopoietic cancers glycosylated CD43 epitopes; carcinoembryonic antigen (CEA); epithelial cell adhesion molecule (EPCAM); B7H3 (CD276); KIT (CD117); interleukin-13 receptor subunit alpha 2 (IL-13Ra2 or CD213A2); mesothelin; interleukin-11 receptor alpha (IL-11Ra); prostate stem cell antigen (PSCA); protease serine 21 (testis rRNA or PRSS21); vascular endothelial growth factor receptor 2 (VEGFR2); Lewis (Y) antigen; CD24; platelet-derived growth factor receptor beta (PDGFR-β); stage-specific embryonic antigen 4 (SSEA-4); CD20; folate receptor α; receptor tyrosine protein kinase ERBB2 (Her2 / neu); mucin 1, cell surface associated (MUC1); epidermal growth factor receptor (EGFR); neural cell adhesion molecule (NCAM); prostase; prostatic acid phosphatase (PAP); elongation factor 2 mutated (ELF2M); ephrin B2; fibroblast activation protein α (FAP); insulin-like growth factor 1 receptor (IGF-1 receptor), carbonic anhydrase IX (CAIX); proteasome (prosome, macropain) subunit, beta type 9 (LMP2); glycoprotein 100 (gp100);Oncogene fusion protein consisting of a BCR (bcr-ab1) and Abelson murine leukemia viral oncogene homolog 1 (Ab1) (bcr-ab1); tyrosinase; ephrin type A receptor 2 (EphA2); fucosyl GM1; sialyl Lewis adhesion molecule (sLe); ganglioside GM3 (aNeu5Ac(2-3)bClalp(1-4)bDGlcp(1-1)Cer); transglutaminase 5 (TGS5); high molecular weight melanoma-associated antigen (HMWMAA); O-acetyl-GD2 ganglioside (OAc GD2); folate receptor beta; tumor endothelial marker 1 (TEM1 / CD248); tumor endothelial marker 7-related (TEM7R); claudin 6 (CLDN6); thyroid-stimulating hormone receptor (TSHR); G protein-coupled receptor class C group 5 member D (GPRC5D); chromosome X open reading frame 61 (CXORF61); CD97; CD179a; anaplastic lymphoma kinase (ALK); polysialic acid; placenta-specific 1 (PLAC1); hexasaccharide moiety of globo-H glycoceramide (GloboH); breast Glandular differentiation antigen (NY-BR-1); uroplakin 2 (UPK2); hepatitis A virus cell receptor 1 (HAVCR1); adrenergic receptor beta 3 (ADRB3), pannexin 3 (PANX3); G protein-coupled receptor 20 (GPR20), lymphocyte antigen 6 complex locus K9 (LY6K), olfactory receptor 51E2 (OR51E2); TCR gamma alternative reading frame protein (TARP); Wilms tumor protein (WT1); cancer / testis antigen 1 (NY-ES0-1); cancer / testis 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); X antigen family member 1A (XAGE1); angiopoietin-binding cell surface receptor 2 (Tie2); melanoma cancer-testis antigen 1 (MAD-CT-1); melanoma cancer-testis antigen 2 (MAD-CT-2); Fos-related antigen 1; tumor protein p53 (p53); p53 mutant; prostein; survivin; telomerase; prostate carcinoma antigen 1 (PCT A-1 or galectin-8), melanoma antigen 1 recognized by T cells (MelanA or MARTI); rat sarcoma (Ras) mutant; human telomerase reverse transcriptase (hTERT); sarcoma translocation breakpoints;Melanoma inhibitor of apoptosis (ML-IAP); ERG (transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene); N-acetylglucosaminyltransferase V (NA17); paired box protein Pax-3 (PAX3); androgen receptor; cyclin B1; neuroblastoma-derived homolog of v-myc avian myelocytomatosis viral oncogene (MYCN); Ras homolog family member C (RhoC); tyrosinase-related protein 2 (TRP-2); cytochrome P4501B1 (CYP1B1); CCCTC-binding factor (zinc finger protein)-like (BORIS or Brother of the Regulator of Imprinted Sites), squamous cell carcinoma antigen 3 recognized by T cells (SART3); paired box protein Pax-5 (PAX5); proacrosin-binding protein sp32 (OY-TES1); lymphocyte-specific protein tyrosine kinase (LCK); A-kinase anchor protein 4 (AKAP-4); synovial sarcoma, X-breakpoint 2 (SSX2); receptor for advanced glycation end products (RAGE-1); renal ubiquitous 1 (RU1); renal ubiquitous 2 (RU2); legumain; human papillomavirus E6 (HPV E6); human papillomavirus E7 (HPV E7); intestinal carboxylesterase; heat shock protein 70-2 mutant (mut hsp 70-2); CD79a; CD79b; CD72; leukocyte-associated immunoglobulin-like receptor 1 (LAIR1); Fc fragment of the IgA receptor (FCAR or CD89); leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2); CD300 molecule-like family member f (CD300LF); C-type lectin domain family 12 member A (CLEC12A); bone marrow stromal cell antigen 2 (BST2); EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2); lymphocyte antigen 75 (LY75); glypican 3 (GPC3); Fc receptor-like 5 (FCRL5); and immunoglobulin lambda-like polypeptide 1 (IGLL1), MPL, biotin, c-MYC epitope tag, CD34, LAMP1 TROP2, GFRalpha4, CDH17, CDH6, NYBR1, CDH19, CD200R, Slea (CA19.9;Sialyl Lewis antigen) Fucosyl GM1, PTK7, gpNMB, CDH1-CD324, DLL3, CD276 / B7H3, IL11Ra, IL13Ra2, CD179b-IGL11, ALK TCRγδ, NKG2D, CD32 (FCGR2A), Tn ag, CSPG4-HMW-MAA, Timl- / HVCR1, CSF2RA (GM-CSFRα), TGFβR2, VEGFR2 / KDR, Lewis Ag, TCRβ chain, TCRβ2 chain, TCRγ chain, TCRδ chain, FITC, luteinizing hormone receptor (LHR), follicle-stimulating hormone receptor (FSHR), chorionic gonadotropin receptor (CGHR), CCR4, GD3, SLAMF6, SLAMF4, HIV1 envelope glycoprotein, HTLV1-Tax, CMVpp65, EBV- EBNA3c, influenza A hemagglutinin (HA), GAD, PDL1, guanylyl cyclase C (GCC), KSHV-K8.1 protein, KSHV-gH protein, autoantibodies against desmoglein 3 (Dsg3), autoantibodies against desmoglein 1 (Dsg1), 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 112. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 111, wherein the polypeptide or polypeptide heterodimer is selected from the group consisting of G12V, tissue factor 1 (TF1), AFP, GPRC5D, claudin 18.2 (CLD18A2 or CLDN18A.2), P-glycoprotein, STEAP1, LIV1, NECTIN-4, CRIPTO, GPA33, BST1 / CD157, a small conductance chloride channel, and an antigen recognized by the TNT antibody.

122. 122. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 121, wherein the one or more non-natural TCR antigen binding domains comprise an antibody, antibody fragment, scFv, Fv, Fab, (Fab')2, single domain antibody (SDAB), vH or vL domain, camelid-derived vHH domain, non-immunoglobulin antigen binding scaffold, such as a DARPIN, affibody, affilin, adnectin, affitin, obodies, lipibodies, fynomers, alphabodies, avimers, atrimers, centilins, pronectins, anticalins, Kunitz domains, armadillo repeat proteins, receptors, or ligands.

123. the one or more non-natural TCR antigen binding domains (i) a heavy chain variable region (vH) encoding an antigen-binding polypeptide having a sequence set forth in any one of SEQ ID NOs: 2506-2680 or 12160-12278, or a sequence at least 98% identical thereto; (ii) a light chain variable region (vL) encoding an antigen-binding polypeptide having a sequence set forth in any one of SEQ ID NOs: 2307-2482 or 12042-12159, or a sequence at least 98% identical thereto; (iii) a single chain variable fragment (scFv) encoding an antigen-binding polypeptide having a sequence set forth in any one of SEQ ID NOs: 2770-2939, 12303-12357, or 18162-18224, or a sequence at least 98% identical thereto; (iv) a camelid VHH encoding an antigen-binding polypeptide having a sequence set forth in any one of SEQ ID NOs: 2701-2725 or 12279-12294, or a sequence at least 98% identical thereto; (v) a non-immunoglobulin scaffold encoded by a sequence set forth in any one of SEQ ID NOs: 439-443, or a sequence at least 98% identical thereto, wherein the non-immunoglobulin scaffold encodes a cognate-binding polypeptide; (vi) a receptor encoding a polypeptide that binds to an antigen, the polypeptide having a sequence set forth in any one of SEQ ID NOs: 2736-2748 or a sequence at least 98% identical thereto; and (vii) a ligand encoding a polypeptide that binds to a cognate sequence, the ligand having a sequence set forth in any one of SEQ ID NOs: 2758-2768 or 12359-12361 or a sequence at least 98% identical thereto.

122. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 121, selected from the group consisting of:

124. 112. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 111, wherein the one or more non-natural TCR antigen binding domains have one or more light chain complementarity determining regions for a selected target antigen as set forth in any of SEQ ID NOS: 13999-14879 or 14880, and / or one or more heavy chain complementarity determining regions for a selected target antigen as set forth in any of SEQ ID NOS: 14881-15761 or 15762.

125. 112. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 111, wherein said one or more non-naturally occurring TCR antigen binding domains comprise a variable light (vL) domain comprising the sequence of any one of SEQ ID NOs: 2307-2482 or 12042-12159, with up to ten conservative amino acid substitutions, and / or a variable heavy (vH) domain comprising the sequence of any one of SEQ ID NOs: 2506-2680 or 12160-12278, with up to ten conservative amino acid substitutions.

126. 112. The isolated synthetic immune receptor (SIR) polypeptide or polypeptide heterodimer of claim 111, wherein said one or more non-natural TCR antigen binding domains have up to 10 conservative amino acid substitutions and comprise one or more camelid vHH complementarity determining regions for a selected antigen as set forth in any of SEQ ID NOs: 2701-2725 or 12279-12294.

127. 112. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 111, wherein the one or more non-naturally occurring TCR antigen binding domains have a sequence set forth in any of SEQ ID NOs: 2728-2732 or 12296-12301, and the non-immunoglobulin antigen binding domain comprises up to 10 conservative amino acid substitutions.

128. 112. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 111, wherein the one or more non-natural TCR antigen binding domains comprise an scFv domain comprising one or more light chain complementarity determining regions of a variable light chain (vL) domain having the sequence of any one of SEQ ID NOs: 2307-2482 or 12042-12159 and one or more heavy chain complementarity determining regions of a variable heavy chain (vH) domain having the sequence of any one of SEQ ID NOs: 2506-2680 or 12160-12278.

129. 112. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 111, wherein said one or more non-natural TCR antigen binding domains comprise an scFv fragment comprising a sequence selected from the group consisting of SEQ ID NOs: 2770-2939, 12303-12357, or 18162-18224, each with up to 10 conservative amino acid substitutions.

130. 112. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 111, wherein the one or more non-naturally occurring TCR antigen binding domains comprise one or more receptors consisting of the amino acid sequence of any of SEQ ID NOs: 2736-2748, with up to 10 conservative amino acid substitutions.

131. 112. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 111, wherein said one or more non-naturally occurring TCR antigen binding domains have up to 10 conservative amino acid substitutions and have one or more ligands comprising the sequence of any of SEQ ID NOs: 2758-2768 or 12359-12361.

132. 112. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 111, wherein the one or more non-natural TCR antigen binding domains comprise the extracellular domain of CD16A, NKG2D, CD4, PD1, desmoglein 3 (Dsg3), or CD4-DC-SIGN.

133. 112. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 111, wherein the one or more non-natural TCR antigen binding domains comprise one or more extracellular domains of hTPO, mTPO, CGH alpha chain, CGH beta chain, FH beta chain, TSH beta chain, APRIL, or a combination thereof.

134. the one or more non-natural TCR antigen binding domains any single chain variable fragment (scFv) having the sequence of any of SEQ ID NOs: 2770-2939, 12303-12357, or 18162-18224, and having up to 10 conservative amino acid substitutions; a) a camelid vHH as set forth in any of SEQ ID NOs: 2701-2725 or 12279-12294, having up to 10 conservative amino acid substitutions; or b) any non-immunoglobulin antigen-binding domain having the sequence set forth in any of SEQ ID NOs: 2728-2732 or 12296-12301 and having up to 10 conservative amino acid substitutions; or c) any extracellular domain of a receptor consisting of the amino acid sequence of any of SEQ ID NOs: 2736-2748, with up to 10 conservative amino acid substitutions; or d) any extracellular domain of a ligand having any of the sequences of SEQ ID NOs: 2758-2768 or 12359-12361, with up to 10 conservative amino acid substitutions; 112. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 111, having:

135. the one or more non-natural TCR antigen binding domains a camelid vHH having up to 10 conservative amino acid substitutions and set forth in any of SEQ ID NOs: 2701-2725 or 12279-12294; a) any single chain variable fragment (scFv) having the sequence of any of SEQ ID NOs: 2770-2939, 12303-12357, or 18162-18224, and having up to 10 conservative amino acid substitutions; or b) any non-immunoglobulin antigen-binding domain having the sequence set forth in any of SEQ ID NOs: 2728-2732 or 12296-12301 and having up to 10 conservative amino acid substitutions; or c) any extracellular domain of a receptor consisting of the amino acid sequence of any of SEQ ID NOs: 2736-2748, with up to 10 conservative amino acid substitutions; or d) any extracellular domain of a ligand having any of the sequences of SEQ ID NOs: 2758-2768 or 12359-12361, with up to 10 conservative amino acid substitutions; 112. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 111, having:

136. 112. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 111, wherein the one or more non-natural TCR antigen binding domains are optionally connected to each of the TCR constant regions by a linker region, wherein the nucleic acid of the linker region encodes an amino acid sequence selected from the group consisting of SEQ ID NOs: 2981-3003, and any combination thereof, or a sequence at least 98% identical thereto, or the linker is encoded by a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 701-725, or a sequence at least 98% identical thereto.

137. 112. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 111, wherein said one or more non-natural TCR antigen binding domains have a binding affinity for a target antigen that is at least 5-fold less than the antibody from which it is derived.

138. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 111, wherein the polynucleotide encoding the SIR further comprises a leader sequence or signal peptide at the N-terminus of each chain and having a sequence selected from the group consisting of SEQ ID NOs: 1-9 and 10.

139. 112. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 111, wherein the SIR comprises a SIR heterodimer.

140. 112. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 111, wherein the polypeptide has two SIRs joined by a cleavable linker.

141. 141. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 140, wherein the cleavable linker is a self-cleaving cleavable linker.

142. 141. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 140, wherein the cleavable linker is any one or more of a 2A linker, a 2A-like linker, or functional equivalents thereof.

143. 141. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 140, wherein the cleavable linker is any one or more of a T2A linker, a P2A, an F2A, an E2A linker, or functional equivalents thereof.

144. 141. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 140, wherein said cleavable linker has the sequence of any one or more of SEQ ID NOs: 780-785.

145. 141. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 140, wherein the cleavable linker is optionally preceded by a furin cleavage site, a furin-like cleavage site, or a functional equivalent thereof.

146. 146. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 145, wherein the furin cleavage site preceding the cleavable linker has the sequence of any one or more of SEQ ID NOs: 788-790.

147. 147. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of any one of claims 140 to 146, wherein said cleavable linker is preceded by a flexible linker.

148. 148. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 147, wherein the flexible linker preceding the cleavable linker encodes one or more of a Ser-Gly linker, a Ser-Gly-Ser-Gly linker, or functional equivalents thereof.

149. 148. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 147, wherein the flexible linker preceding the cleavable linker has the sequence of SEQ ID NOs: 786-787.

150. 148. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 147, wherein the furin cleavage site is followed by a flexible linker, which is followed by a cleavable linker, in the order: furin cleavage site, flexible linker, cleavable linker.

151. 112. The isolated synthetic immunoreceptor (SIR) polypeptide or polypeptide heterodimer of claim 111, wherein the SIRs are engineered to have diverse binding affinities for selected antigens.

152. 112. An immune effector cell or stem cell comprising at least one polypeptide or heterodimer according to claim 111.

153. An immune effector cell or stem cell comprising at least one recombinant polynucleotide according to claim 1.

154. 105. An immune effector or stem cell comprising at least one vector according to claim 104.

155. 155. An immune effector or stem cell according to any one of claims 152 to 154, comprising multiple SIR polypeptides.

156. The immune or stem cell of claim 155, wherein at least one SIR polypeptide of the plurality of SIR polypeptides targets a different antigen than at least one other SIR polypeptide.

157. The immune or stem cell of claim 155, wherein at least one SIR polypeptide of the plurality of SIR polypeptides targets the same antigen.

158. The immune or stem cell of claim 157, wherein at least one SIR polypeptide of the plurality of SIR polypeptides has a binding affinity for an antigen that is different from at least one other SIR polypeptide.

159. The immune cell or stem cell of any one of claims 152 to 154, wherein the immune cell further comprises at least one chimeric antigen receptor (CAR) polypeptide.

160. The immune or stem cell of claim 159, wherein the antigen binding domain of the SIR polypeptide targets a different antigen than the antigen binding domain of the CAR polypeptide.

161. The immune or stem cell of claim 159, wherein the CAR polypeptide has an intracellular signaling domain that includes a costimulatory signaling domain but not the first signaling domain, or has an intracellular signaling domain that includes the first signaling domain but not the costimulatory signaling domain.

162. The immune or stem cell of claim 161, wherein the CAR polypeptide has a costimulatory signaling domain comprising a functional signaling domain of a protein selected from the group consisting of 4-1BB, CD28, CD27, or OX-40, or the CAR polypeptide has a first signaling domain comprising a functional signaling domain of CD3ζ.

163. The immune cell or stem cell of claim 159, wherein the CAR polypeptide is an inhibitory CAR polypeptide, which has an antigen-binding domain, a transmembrane domain, and an intracellular domain of an inhibitory molecule, and the inhibitory molecule is selected from the group consisting of PD1, PD-L1, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, TGFRβ, CEACAM-1, CEACAM-3, and CEACAM-5.

164. The immune cell or stem cell of claim 159, wherein the CAR polypeptide further comprises an intracellular signaling domain and / or an intracellular signaling domain comprising a first signaling domain, wherein the intracellular signaling domain comprises a first signaling domain comprising a functional domain of CD3ζ and a costimulatory signaling domain comprising a functional domain of 4-1BB and / or CD28.

165. The immune or stem cell of claim 159, wherein the CAR polypeptide has the amino acid sequence of SEQ ID NO: 3077 to SEQ ID NO: 3083.

166. 155. The immune or stem cell of any one of claims 152 to 154, wherein the immune effector cell is optionally a human T cell, a human NKT cell, or a synthetic T cell capable of generating an immune effector cell, or a stem cell, wherein the T cell is diacylglycerol kinase (DGK) and / or Ikaros deficient and / or Brd4 deficient.

167. 153. A population of immune cells or effector cells according to claim 152, comprising a plurality of different SIR polypeptides.

168. 168. The immune or effector cell population of claim 167, wherein the plurality of different SIR polypeptides have different sequences but bind to the same target antigen.

169. 168. The immune or effector cell population of claim 167, wherein the cell population has SIR polypeptides that target different antigens present in a particular disease type.

170. A method for producing a SIR-expressing immune effector cell, comprising the step of introducing at least one vector described in claim 104 or at least one recombinant polynucleotide described in claim 1 into an immune effector cell, or a hematopoietic stem or progenitor cell capable of developing into an immune effector cell, under conditions in which the SIR polypeptide is expressed.

171. a) providing a population of immune effector cells; b) removing restricted T cells from said population, thereby providing restricted T-depleted cells; and steps a) and b) are performed prior to introducing the vector or a recombinant polynucleotide encoding the SIR into the population; The method of claim 170.

172. 172. The method of claim 171, wherein the restricted T cells are removed from the cell population using an anti-CD25 antibody or an anti-GITR antibody.

173. a) providing a population of immune effector cells; b) enriching P-glycoprotein (P-gp or Pgp, MDR1, ABCB1, CD243) positive cells from said population, thereby providing a population of P-glycoprotein (P-gp or Pgp, MDR1, ABCB1, CD243) enriched cells; and 171. The method of claim 170, wherein steps a) and b) are performed before or after introducing the vector or a recombinant polynucleotide encoding the SIR.

174. P-glycoprotein positive cells i) immunoselection using one or more of a cocktail of steps specific for P-glycoprotein; ii) staining with one or more fluorescent dyes that are substrates of P-glycoprotein, such as tetramethylrhodamine methyl ester (TMRM), adriamycin, and actinomycin D, under conditions in which P-glycoprotein is active as a pump, and enriching for cells that are poorly stained by the dyes; iii) Phototoxic compounds that are substrates of P-glycoprotein, such as TH9402, 2-(4,5-dibromo-6-amino-3-imino-3H-xanthen-9-yl)benzoic acid methyl ester hydrochloride, 2-(4,5-dibromo-6-amino-3-imino-3H-xanthen-9-yl)benzoic acid ethyl ester hydrochloride, 2-(4,5-dibromo-6-amino-3-imino-3H-xanthen-9-yl)benzoic acid ethyl ester hydrochloride, selecting cells resistant to any one or more of 2-(4,5-dibromo-6-amino-3-imino-3H-xanthen-9-yl)benzoic acid n-butyl ester hydrochloride, 2-(6-ethylamino-3-ethylimino-3H-xanthen-9-yl)benzoic acid n-butyl ester hydrochloride, or derivatives thereof, or combinations thereof; iv) selection of cells resistant to cytotoxic compounds that are substrates of P-glycoprotein, such as vincristine, vinblastine, taxol, paclitaxel, mitoxantrone, etoposide, adriamycin, daunorubicin, and actinomycin D; 174. The method of claim 173, wherein the enrichment is performed using any one or more of the methods selected from the group consisting of:

175. 1. A method for generating a population of RNA-modified cells, comprising:

10. A method for producing a recombinant polypeptide comprising introducing in vitro transcribed RNA(s) or synthetic RNA(s) into a cell or a population of cells, wherein the RNA(s) comprise the recombinant polynucleotide(s) of claim 1. method.

176. 1. A method of providing disease-resistant immunity to a subject, comprising: Administering to the subject an effective amount of immune effector cells or stem cells capable of generating the immune effector cells according to any one of claims 152 to 154, wherein the cells are autologous T cells, allogeneic T cells, autologous NKT cells, allogeneic NKT cells, autologous or allogeneic hematopoietic stem cells, or autologous or allogeneic iPSCs capable of generating immune effector cells. method.

177. 177. The method of claim 176, wherein the allogeneic T cells, or allogeneic NKT cells, or hematopoietic stem cells, or iPSCs lack or have low expression of a functional TCR or functional HLA.

178. 1. A composition comprising immune effector cells or stem cells capable of generating immune effector cells having one or more synthetic immune receptors (SIRs) for use in combination with an agent that increases the effectiveness of immune effector cells in treating a subject having a disease associated with expression of a disease-associated antigen or in preventing a disease in a subject at increased risk for the disease associated with expression of a disease-associated antigen, the composition comprising: (i) The SIR molecule comprises one or more T cell receptor constant chains linked, via an optional linker, to one or more antigen-binding domains that bind to disease-associated antigens, including CD5, CD19; CD123; CD22; CD30; CD171; CS-1 (also known as CD2 subset 1, CRACC, SLAMF7, CD319, and 19A24); C-type lectin-like molecule 1 (CLL-1 or CLECL1); CD33; epidermal growth factor receptor variant III (EGFRviii); ganglioside G2 (GD2); ganglioside GD3 (aNeu5Ac(2-8)aNeu5Ac(2-3)bDGalp(1-4)bDGlcp(1-1)Cer); TNF receptor family member B cell maturation (BCMA); Tn antigen ((Tn Ag) or (GalNAcα-Ser / Thr); prostate-specific membrane antigen (PSMA); receptor tyrosine kinase-like orphan receptor 1 (ROR1); FMS-like tyrosine kinase 3 (FLT3); tumor-associated glycoprotein 72 (TAG72); CD38; CD44v6; glycosylated CD43 epitope expressed in acute leukemia or lymphoma but not in hematopoietic progenitor cells, glycosylated CD43 epitope expressed in non-hematopoietic cancers; carcinoembryonic antigen (CEA); epithelial cell adhesion molecule (EPCAM); B7H3 (CD276); KIT (CD117); interleukin-13 receptor subunit alpha 2 (IL-13Ra2 or CD213A2); mesothelin; interleukin-11 receptor alpha (IL-11Ra); prostate stem cell Protease Serine 21 (Testisin or PRSS21); Vascular Endothelial Growth Factor Receptor 2 (VEGFR2); Lewis (Y) antigen; CD24; Platelet-Derived Growth Factor Receptor Beta (PDGFR-β); Stage-Specific Embryonic Antigen 4 (SSEA-4); CD20; Folate Receptor Alpha; Receptor Tyrosine Protein Kinase ERBB2 (Her2 / neu); Mucin 1, Cell Surface Associated (MUC1); Epidermal Growth Factor Receptor (EGFR); Neural Cell Adhesion Molecule (NCAM); Prostase; Prostatic Acid Phosphatase (PAP); Elongation Factor 2 Mutant (ELF2M); Ephrin B2; Fibroblast Activation Protein Alpha (FAP); Insulin-Like Growth Factor 1 Receptor (IGF-1 Receptor), Carbonic Anhydrase IX (CAIX);Proteasome (prosome, macropain) subunit, beta type 9 (LMP2); glycoprotein 100 (gp100); oncogene fusion protein consisting of a cleavage-prone region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (Ab1) (bcr-ab1); tyrosinase; ephrin type A receptor 2 (EphA2); fucosyl GM1; sialyl Lewis adhesion molecule (sLe); ganglioside GM3 (aNeu5Ac(2-3)bClalp(1-4)bDGlcp(1-1)Cer); transglutaminase 5 (T GS5); high molecular weight melanoma-associated antigen (HMWMAA); O-acetyl-GD2 ganglioside (OAcGD2); tumor endothelial marker 1 (TEM1 / CD248); tumor endothelial marker 7-related (TEM7R); claudin 6 (CLDN6); thyroid-stimulating hormone receptor (TSHR); G protein-coupled receptor class C group 5 member D (GPRC5D); chromosome X open reading frame 61 (CXORF61); CD97; CD179a; anaplastic lymphoma kinase (ALK); polysialic acid; placenta-specific 1 (PLA C1); hexasaccharide moiety of Globo H glycoceramide (GloboH); mammary differentiation antigen (NY-BR-1); uroplakin 2 (UPK2); hepatitis A virus cellular receptor 1 (HAVCR1); adrenergic receptor beta 3 (ADRB3), pannexin 3 (PANX3); G protein-coupled receptor 20 (GPR20), lymphocyte antigen 6 complex locus K9 (LY6K), olfactory receptor 51E2 (OR51E2); TCR gamma alternative reading frame protein (TARP); Wilms tumor protein (WT1); cancer / testis antigen 1 (N Y-ES0-1); cancer / testis 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); X antigen family member 1A (XAGE1); angiopoietin-binding cell surface receptor 2 (Tie2); melanoma cancer testis antigen 1 (MAD-CT-1); melanoma cancer testis antigen 2 (MAD-CT-2); Fos-related antigen 1; tumor protein p53 (p53); p53 mutant; prostein; survivin; telomerase;Prostate carcinoma antigen 1 (PCT A-1 or galectin 8), melanoma antigen 1 recognized by T cells (MelanA or MARTI); rat sarcoma (Ras) mutant; human telomerase reverse transcriptase (hTERT); sarcoma translocation breakpoints; melanoma inhibitor of apoptosis (ML-IAP); ERG (transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene); N-acetylglucosaminyltransferase V (NA17); Peirce-Bock androgen receptor; cyclin B1; neuroblastoma-derived homolog of the v-myc avian myelocytomatosis viral oncogene (MYCN); Ras homolog family member C (RhoC); tyrosinase-related protein 2 (TRP-2); cytochrome P4501B1 (CYP1B1); CCCTC-binding factor (zinc finger protein)-like (BORIS or Brother of the Regulator of Imprinted Sites), squamous cell carcinoma antigen 3 recognized by T cells (SART3); paired box protein Pax-5 (PAX5); proacrosin-binding protein sp32 (OY-TES1); lymphocyte-specific protein tyrosine kinase (LCK); A-kinase anchor protein 4 (AKAP-4); synovial sarcoma, X-breakpoint 2 (SSX2); receptor for advanced glycation end products (RAGE-1); renal ubiquitous 1 (RU1); renal ubiquitous 2 (RU2); legumain; human papillomavirus E6 (HPV E6); human papillomavirus E7 (HPV E7); intestinal carboxylesterase; heat shock protein 70-2 mutant (mut hsp 70-2); CD79a; CD79b; CD72; leukocyte-associated immunoglobulin-like receptor 1 (LAIR1); Fc fragment of the IgA receptor (FCAR or CD89); leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2); CD300 molecule-like family member f (CD300LF); C-type lectin domain family 12 member A (CLEC12A); bone marrow stromal cell antigen 2 (BST2); EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2); lymphocyte antigen 75 (LY75); glypican 3 (GPC3); Fc receptor-like 5 (FCRL5);and immunoglobulin lambda-like polypeptide 1 (IGLL1), MPL, biotin, c-MYC epitope tag, CD34, LAMP1 TROP2, GFRalpha4, CDH17, CDH6, NYBR1, CDH19, CD200R, Slea (CA19.9; sialyl Lewis antigen) fucosyl GM1, PTK7, gpNMB, CDH1-CD324, DLL3, CD276 / B7H3, IL11Ra, IL13Ra2, CD179b-IGL11, ALK TCRγδ, NKG2D, CD32 (FCGR2A), CSPG4-HMW-MAA, Timl- / HVCR1, CSF2RA (GM-CSFRα), TGFβR2, VEGFR2 / KDR, Lewis Ag, TCRβ chain, TCRβ2 chain, TCRγ chain, TCRδ chain, FITC, luteinizing hormone receptor (LHR), follicle-stimulating hormone receptor (FSHR), chorionic gonadotropin receptor (CGHR), CCR4, SLAMF6, SLAMF4, HIV 1 envelope glycoprotein, HTLV1-Tax, CMVpp65, EBV-EBNA3c, influenza A hemagglutinin (HA), GAD, PDL1, guanylyl cyclase C (GCC), KSHV-K8.1 protein, KSHV-gH protein, autoantibodies against desmoglein 3 (Dsg3), autoantibodies against desmoglein 1 (Dsg1), HLA, HLA-A, HLA-A2, HLA-B, HLA-C, HLA-DP; selected from the group consisting of HLA-DM, HLA-DOA, HLA-DOB, HLA-DQ, HLA-DR, HLA-G, IGE, CD99, RAS G12V, tissue factor 1 (TF1), AFP, GPRC5D, claudin 18.2 (CLD18A2 or CLDN18A.2), P-glycoprotein, STEAP1, LIV1, NECTIN-4, CRIPTO, GPA33, BST1 / CD157, small conductance chloride channel, and antigens recognized by TNT antibodies; (ii) an agent for increasing the effect of the immune cells, - a protein phosphatase inhibitor, a kinase inhibitor (e.g., a P13K / AKT inhibitor, an mTOR inhibitor, an LCK inhibitor, or a BTK inhibitor); and - Cytokines, - inhibitors of immunosuppressive molecules, -T ＲＥＧ an agent that reduces the level or activity of a cell; - an agent that increases the proliferation and maintenance of SIR-modified cells; - Chemokines and - an agent that increases the expression of SIR; - an agent that allows the modulation of the expression or activity of the SIR; - an agent that allows the control of the survival and / or maintenance of SIR-modified cells; - an agent that controls the side effects of SIR-modified cells; - a Brd4 inhibitor, - an agent that delivers a therapeutic (e.g., sHVEM) or prophylactic agent to the site of disease; - an agent that increases the expression of the antigen targeted by the SIR; - adenosine A2a receptor antagonists, Selected from one or more of composition.

179. 1. A method of treating or preventing a disease associated with expression of a disease-associated antigen in a subject, comprising: administering to the subject an effective amount of immune effector cells having a synthetic immune receptor (SIR) molecule in combination with an agent that increases the effectiveness of the immune cells; (i) The SIR molecule comprises one or more T cell receptor constant chains linked, via an optional linker, to one or more antigen-binding domains that bind to disease-associated antigens, including CD5, CD19; CD123; CD22; CD30; CD171; CS-1 (also known as CD2 subset 1, CRACC, SLAMF7, CD319, and 19A24); C-type lectin-like molecule 1 (CLL-1 or CLECL1); CD33; epidermal growth factor receptor variant III (EGFRviii); ganglioside G2 (GD2); ganglioside GD3 (aNeu5Ac(2-8)aNeu5Ac(2-3)bDGalp(1-4)bDGlcp(1-1)Cer); TNF receptor family member B cell maturation (BCMA); Tn antigen ((Tn Ag) or (GalNAcα-Ser / Thr); prostate-specific membrane antigen (PSMA); receptor tyrosine kinase-like orphan receptor 1 (ROR1); FMS-like tyrosine kinase 3 (FLT3); tumor-associated glycoprotein 72 (TAG72); CD38; CD44v6; glycosylated CD43 epitope expressed in acute leukemia or lymphoma but not in hematopoietic progenitor cells, glycosylated CD43 epitope expressed in non-hematopoietic cancers; carcinoembryonic antigen (CEA); epithelial cell adhesion molecule (EPCAM); B7H3 (CD276); KIT (CD117); interleukin-13 receptor subunit alpha 2 (IL-13Ra2 or CD213A2); mesothelin; interleukin-11 receptor alpha (IL-11Ra); prostate stem cell Protease Serine 21 (Testisin or PRSS21); Vascular Endothelial Growth Factor Receptor 2 (VEGFR2); Lewis (Y) antigen; CD24; Platelet-Derived Growth Factor Receptor Beta (PDGFR-β); Stage-Specific Embryonic Antigen 4 (SSEA-4); CD20; Folate Receptor Alpha; Receptor Tyrosine Protein Kinase ERBB2 (Her2 / neu); Mucin 1, Cell Surface Associated (MUC1); Epidermal Growth Factor Receptor (EGFR); Neural Cell Adhesion Molecule (NCAM); Prostase; Prostatic Acid Phosphatase (PAP); Elongation Factor 2 Mutant (ELF2M); Ephrin B2; Fibroblast Activation Protein Alpha (FAP); Insulin-Like Growth Factor 1 Receptor (IGF-1 Receptor), Carbonic Anhydrase IX (CAIX);Proteasome (prosome, macropain) subunit, beta type 9 (LMP2); glycoprotein 100 (gp100); oncogene fusion protein consisting of a cleavage-prone region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (Ab1) (bcr-ab1); tyrosinase; ephrin type A receptor 2 (EphA2); fucosyl GM1; sialyl Lewis adhesion molecule (sLe); ganglioside GM3 (aNeu5Ac(2-3)bClalp(1-4)bDGlcp(1-1)Cer); transglutaminase 5 (TG S5); high molecular weight melanoma-associated antigen (HMWMAA); O-acetyl-GD2 ganglioside (OAcGD2); folate receptor beta; tumor endothelial marker 1 (TEM1 / CD248); tumor endothelial marker 7-related (TEM7R); claudin 6 (CLDN6); thyroid-stimulating hormone receptor (TSHR); G protein-coupled receptor class C group 5 member D (GPRC5D); chromosome X open reading frame 61 (CXORF61); CD97; CD179a; anaplastic lymphoma kinase (ALK); polysialic acid; placenta-specific 1 (PLAC1); hexasaccharide moiety of Globo H glycoceramide (GloboH); mammary differentiation antigen (NY-BR-1); uroplakin 2 (UPK2); hepatitis A virus cellular receptor 1 (HAVCR1); adrenergic receptor beta 3 (ADRB3), pannexin 3 (PANX3); G protein-coupled receptor 20 (GPR20), lymphocyte antigen 6 complex locus K9 (LY6K), olfactory receptor 51E2 (OR51E2); TCR gamma alternative reading frame protein (TARP); Wilms tumor protein (WT1); cancer / testis antigen 1 (NY-ES0-1); cancer / testis 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); X antigen family member 1A (XAGE1); angiopoietin-binding cell surface receptor 2 (Tie2); melanoma cancer testis antigen 1 (MAD-CT-1); melanoma cancer testis antigen 2 (MAD-CT-2); Fos-related antigen 1; tumor protein p53 (p53); p53 mutant; prostein; survivin; telomerase;Prostate carcinoma antigen 1 (PCT A-1 or galectin 8), melanoma antigen 1 recognized by T cells (MelanA or MARTI); rat sarcoma (Ras) mutant; human telomerase reverse transcriptase (hTERT); sarcoma translocation breakpoints; melanoma inhibitor of apoptosis (ML-IAP); ERG (transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene); N-acetylglucosaminyltransferase V (NA17); Peirce-Bock androgen receptor; cyclin B1; neuroblastoma-derived homolog of the v-myc avian myelocytomatosis viral oncogene (MYCN); Ras homolog family member C (RhoC); tyrosinase-related protein 2 (TRP-2); cytochrome P4501B1 (CYP1B1); CCCTC-binding factor (zinc finger protein)-like (BORIS or Brother of the Regulator of Imprinted Sites), squamous cell carcinoma antigen 3 recognized by T cells (SART3); paired box protein Pax-5 (PAX5); proacrosin-binding protein sp32 (OY-TES1); lymphocyte-specific protein tyrosine kinase (LCK); A-kinase anchor protein 4 (AKAP-4); synovial sarcoma, X-breakpoint 2 (SSX2); receptor for advanced glycation end products (RAGE-1); renal ubiquitous 1 (RU1); renal ubiquitous 2 (RU2); legumain; human papillomavirus E6 (HPV E6); human papillomavirus E7 (HPV E7); intestinal carboxylesterase; heat shock protein 70-2 mutant (mut hsp 70-2); CD79a; CD79b; CD72; leukocyte-associated immunoglobulin-like receptor 1 (LAIR1); Fc fragment of the IgA receptor (FCAR or CD89); leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2); CD300 molecule-like family member f (CD300LF); C-type lectin domain family 12 member A (CLEC12A); bone marrow stromal cell antigen 2 (BST2); EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2); lymphocyte antigen 75 (LY75); glypican 3 (GPC3); Fc receptor-like 5 (FCRL5);and immunoglobulin lambda-like polypeptide 1 (IGLL1), MPL, biotin, c-MYC epitope tag, CD34, LAMP1 TROP2, GFRalpha4, CDH17, CDH6, NYBR1, CDH19, CD200R, Slea (CA19.9; sialyl Lewis antigen) fucosyl GM1, PTK7, gpNMB, CDH1-CD324, DLL3, CD276 / B7H3, IL11Ra, IL13Ra2, CD179b-IGL11, ALK TCRγδ, NKG2D, CD32 (FCGR2A), CSPG4-HMW-MAA, Timl- / HVCR1, CSF2RA (GM-CSFRα), TGFβR2, VEGFR2 / KDR, Lewis Ag, TCRβ chain, TCRβ2 chain, TCRγ chain, TCRδ chain, FITC, luteinizing hormone receptor (LHR), follicle-stimulating hormone receptor (FSHR), chorionic gonadotropin receptor (CGHR), CCR4, SLAMF6, SLAMF4, HIV-1 envelope glycoprotein, HTLV-1-Tax, CMV pp65, EBV-EBNA3c, influenza A hemagglutinin (HA), GAD, PDL1, guanylyl cyclase C (GCC), KSHV-K8.1 protein, KSHV-gH protein, autoantibodies against desmoglein 3 (Dsg3), autoantibodies against desmoglein 1 (Dsg1), 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 selected from the group consisting of G12V, tissue factor 1 (TF1), AFP, GPRC5D, claudin 18.2 (CLD18A2 or CLDN18A.2), P-glycoprotein, STEAP1, LIV1, NECTIN-4, CRIPTO, GPA33, BST1 / CD157, small conductance chloride channel, and antigens recognized by TNT antibodies; (ii) an agent for increasing the effect of the immune cells, - a protein phosphatase inhibitor, a kinase inhibitor (e.g., a P13K / AKT inhibitor, an mTOR inhibitor, an LCK inhibitor, or a BTK inhibitor); and - Cytokines, - inhibitors of immunosuppressive molecules, -T ＲＥＧ an agent that reduces the level or activity of a cell; - an agent that increases the proliferation and maintenance of SIR-modified cells; - Chemokines and - an agent that increases the expression of SIR; - an agent that allows the modulation of the expression or activity of the SIR; - an agent that allows the control of the survival and / or maintenance of SIR-modified cells; - an agent that controls the side effects of SIR-modified cells; - a Brd4 inhibitor, - an agent that delivers a therapeutic (e.g., sHVEM) or prophylactic agent to the site of disease; - an agent that increases the expression of the antigen targeted by the SIR; - adenosine A2a receptor antagonists, thereby treating said subject or preventing disease in said subject; method.

180. 1. A method of treating or preventing a disease associated with expression of a disease-associated antigen in a subject, comprising: administering to the subject an effective amount of immune effector cells comprising a synthetic immune receptor (SIR) molecule; (i) The SIR molecule comprises one or more T cell receptor constant chains linked, via an optional linker, to one or more antigen-binding domains that bind to disease-associated antigens, including CD5, CD19; CD123; CD22; CD23; CD30; CD171; CS-1 (also known as CD2 subset 1, CRACC, SLAMF7, CD319, and 19A24); C-type lectin-like molecule 1 (CLL-1 or CLECL1); CD33; epidermal growth factor receptor variant III (EGFRviii); ganglioside G2 (GD2); ganglioside GD3 (aNeu5Ac(2-8)aNeu5Ac(2-3)bDGalp(1-4)bDGlcp(1-1)Cer); TNF receptor family member B cell maturation (BCMA); Tn antigen ((Tn Ag) or (GalNAcα-Ser / Thr); prostate-specific membrane antigen (PSMA); receptor tyrosine kinase-like orphan receptor 1 (ROR1); FMS-like tyrosine kinase 3 (FLT3); tumor-associated glycoprotein 72 (TAG72); CD38; CD44v6; glycosylated CD43 epitope expressed in acute leukemia or lymphoma but not in hematopoietic progenitor cells, glycosylated CD43 epitope expressed in non-hematopoietic cancers; carcinoembryonic antigen (CEA); epithelial cell adhesion molecule (EPCAM); B7H3 (CD276); KIT (CD117); interleukin-13 receptor subunit alpha 2 (IL-13Ra2 or CD213A2); mesothelin; interleukin-11 receptor alpha (IL-11 Ra); 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-β); stage-specific embryonic antigen 4 (SSEA-4); CD20; folate receptor alpha (FRa or FR1); folate receptor beta (FRb); receptor tyrosine protein kinase ERBB2 (Her2 / neu); mucin 1, cell surface associated (MUC1); epidermal growth factor receptor (EGFR); neural cell adhesion molecule (NCAM); prostase; prostatic acid phosphatase (PAP); elongation factor 2 mutated (ELF2M); ephrin B2; fibroblast activation protein alpha (FAP);Insulin-like growth factor 1 receptor (IGF-1 receptor), carbonic anhydrase IX (CAIX); proteasome (prosome, macropain) subunit, beta type 9 (LMP2); glycoprotein 100 (gp100); oncogene fusion protein consisting of a cleavage-prone region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (Ab1) (bcr-ab1); tyrosinase; ephrin type A receptor 2 (EphA2); fucosyl GM1; sialyl Lewis adhesion molecule (sLe); ganglioside GM3 (aNeu5Ac(2-3) bClalp(1-4) bDGlcp(1-1)Cer); transglutaminase 5 (TGS5); high molecular weight melanoma-associated antigen (HMWMAA); O-acetyl-GD2 ganglioside (OAcGD2); tumor endothelial marker 1 (TEM1 / CD248); tumor endothelial marker 7-related (TEM7R); claudin 6 (CLDN6); thyroid-stimulating hormone receptor (TSHR); G protein-coupled receptor class C group 5 member D (GPRC5D); chromosome X open reading frame 61 (CXORF61); CD97; CD179a; anaplastic lymphoma kinase (ALK) K); polysialic acid; placenta-specific 1 (PLAC1); hexasaccharide moiety of globo-H glycoceramide (GloboH); mammary differentiation antigen (NY-BR-1); uroplakin 2 (UPK2); hepatitis A virus cellular receptor 1 (HAVCR1); adrenergic receptor beta 3 (ADRB3), pannexin 3 (PANX3); G protein-coupled receptor 20 (GPR20), lymphocyte antigen 6 complex locus K9 (LY6K), olfactory receptor 51E2 (OR51E2); TCR gamma alternative reading frame protein (TARP); Wilms' tumor protein (WT1) ; cancer / testis antigen 1 (NY-ES0-1); cancer / testis 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); X antigen family member 1A (XAGE1); angiopoietin-binding cell surface receptor 2 (Tie2); melanoma cancer-testis antigen 1 (MAD-CT-1); melanoma cancer-testis antigen 2 (MAD-CT-2); Fos-related antigen 1; tumor protein p53 (p53); p53 mutant; prostein; survivin; telomerase;Prostate carcinoma antigen 1 (PCT A-1 or galectin 8), melanoma antigen 1 recognized by T cells (MelanA or MARTI); rat sarcoma (Ras) mutant; human telomerase reverse transcriptase (hTERT); sarcoma translocation breakpoints; melanoma inhibitor of apoptosis (ML-IAP); ERG (transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene); N-acetylglucosaminyltransferase V (NA17); Peirce-Bock androgen receptor; cyclin B1; neuroblastoma-derived homolog of the v-myc avian myelocytomatosis viral oncogene (MYCN); Ras homolog family member C (RhoC); tyrosinase-related protein 2 (TRP-2); cytochrome P4501B1 (CYP1B1); CCCTC-binding factor (zinc finger protein)-like (BORIS or Brother of the Regulator of Imprinted Sites), squamous cell carcinoma antigen 3 recognized by T cells (SART3); paired box protein Pax-5 (PAX5); proacrosin-binding protein sp32 (OY-TES1); lymphocyte-specific protein tyrosine kinase (LCK); A-kinase anchor protein 4 (AKAP-4); synovial sarcoma, X-breakpoint 2 (SSX2); receptor for advanced glycation end products (RAGE-1); renal ubiquitous 1 (RU1); renal ubiquitous 2 (RU2); legumain; human papillomavirus E6 (HPV E6); human papillomavirus E7 (HPV E7); intestinal carboxylesterase; heat shock protein 70-2 mutant (mut hsp 70-2); CD79a; CD79b; CD72; leukocyte-associated immunoglobulin-like receptor 1 (LAIR1); Fc fragment of the IgA receptor (FCAR or CD89); leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2); CD300 molecule-like family member f (CD300LF); C-type lectin domain family 12 member A (CLEC12A); bone marrow stromal cell antigen 2 (BST2); EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2); lymphocyte antigen 75 (LY75); glypican 3 (GPC3); Fc receptor-like 5 (FCRL5);and immunoglobulin lambda-like polypeptide 1 (IGLL1), MPL, biotin, c-MYC epitope tag, CD34, LAMP1 TROP2, GFRalpha4, CDH17, CDH6, NYBR1, CDH19, CD200R, Slea (CA19.9; sialyl Lewis antigen) fucosyl GM1, PTK7, gpNMB, CDH1-CD324, DLL3, CD276 / B7H3, IL11Ra, IL13Ra2, CD179b-IGL11, TCRγδ, NKG2D, CD32 (FCGR2A), Timl- / HVCR1, CS F2RA (GM-CSFRα), TGFβR2, Lewis Ag, TCRβ chain, TCRβ2 chain, TCRγ chain, TCRδ chain, FITC, luteinizing hormone receptor (LHR), follicle-stimulating hormone receptor (FSHR), chorionic gonadotropin receptor (CGHR), CCR4, SLAMF6, SLAMF4, HIV1 envelope glycoprotein, HTLV1-Tax, CMVpp65, EBV-EBNA3c, KSHV K8.1, KSHV-gH, influenza A hemagglutinin (HA), GAD, PDL1, guanylyl cyclase C (GCC), KSHV-K8.1 protein, KSHV-gH protein, autoantibodies against desmoglein 3 (Dsg3), autoantibodies against desmoglein 1 (Dsg1), 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 selected from the group consisting of G12V, tissue factor 1 (TF1), AFP, GPRC5D, claudin 18.2 (CLD18A2 or CLDN18A.2), P-glycoprotein, STEAP1, LIV1, NECTIN-4, CRIPTO, GPA33, BST1 / CD157, small conductance chloride channel, and antigens recognized by TNT antibodies; (ii) the antigen-binding domain of the SIR molecule has a binding affinity that is at least 5-fold less than the antibody from which the antigen-binding domain was derived; method.

181. 181. The use or method of any one of claims 178 to 180, wherein the disease associated with expression of said disease associated antigen is selected from the group consisting of hyperplasia, precancerous conditions, cancer, and non-cancer related indications associated with said disease associated expression.

182. The cancers include chronic lymphocytic leukemia (CLL), acute leukemia, acute lymphocytic leukemia (ALL), B-cell acute lymphocytic leukemia (B-ALL), T-cell acute lymphocytic leukemia (T-ALL), chronic myeloid leukemia (CML), B-cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt's lymphoma, diffuse large B-cell lymphoma, primary effusion lymphoma, follicular lymphoma, hairy cell lymphoma, small cell lymphoma, and the like. or a blood cancer selected from one or more of large cell follicular lymphoma, malignant lymphoproliferative conditions, MALT lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndromes, non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom's macroglobulinemia, and preleukemia.

183. The cancers include colon cancer, rectal cancer, renal cell carcinoma, liver cancer, non-small cell lung cancer, small intestine cancer, esophageal cancer, melanoma, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, and urethral cancer. , penile cancer, pediatric solid tumors, bladder cancer, kidney or ureter cancer, renal pelvis cancer, tumors of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, Merkel cell carcinoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancers, combinations of said cancers, and metastases of said cancers.

184. The illnesses are associated with viral infections, including but not limited to HIV1, HIV2, HTLV1, Epstein-Barr virus (EBV), cytomegalovirus, adenovirus, adeno-associated virus, BK virus, human herpesvirus 6, human herpesvirus 8, influenza virus, parainfluenza virus, avian influenza virus, MERS and SARS coronavirus, Crimean-Congo hemorrhagic fever virus, rhinovirus, enterovirus, dengue virus, West Nile virus, Ebola virus, Marburg virus, Lassa fever virus, and the like.

184. The use or method of claim 183, comprising the use or method of any of the following viruses: influenza, Zika virus, RSV, measles virus, mumps virus, rhinovirus, varicella virus types 1 and 2, varicella zoster virus, HIV-1, HTLV1, hepatitis viruses, enteroviruses, hepatitis B virus, hepatitis C virus, Nipah and Rift Valley fever virus, Japanese encephalitis virus, Merkel cell polyomavirus or viruses associated with Mycobacterium tuberculosis infection, atypical mycobacterial species, Pneumocystis jiroveci, toxoplasmosis, rickettsii, Nocardia, Aspergillus, Mucor, and Candida.

185. 184. The use or method of claim 183, wherein the disease is an immune disease or a degenerative disease, including but not limited to diabetes mellitus, multiple sclerosis, rheumatoid arthritis, pemphigus vulgaris, ankylosing spondylitis, Hashimoto's thyroiditis, SLE, sarcoidosis, scleroderma, mixed connective tissue disease, graft-versus-host disease, and Alzheimer's disease.

186. (i) the protein phosphatase inhibitor is an SHP-1 inhibitor and / or an SHP-2 inhibitor; (ii) the kinase inhibitor is selected from one or more of a CDK4 inhibitor, a CDK4 / 6 inhibitor, an mTOR inhibitor, an MNK inhibitor, and an overlapping P13K / mTOR inhibitor; (iii) the agent that inhibits the immunosuppressive factor comprises an antibody or antibody fragment, an inhibitory nucleic acid, a clustered regularly interspaced short palindromic repeats (CRISPR), a TAL effector nuclease (TALEN), or a zinc finger endonuclease (ZFN), which inhibits expression of the inhibitory molecule; (iv) the agent that decreases the level or activity of TREG cells is selected from cyclophosphamide, an anti-GITR antibody, CD25 depletion, or a combination thereof; and / or (v) the Brd4 inhibitor is selected from JQ1, MS417, OTXO15, LY303511, and Brd4 inhibitors described in U.S. Patent No. 20140256706A1, or derivatives thereof; 185. The use or method of any of claims 178-180 or 182-184.

187. 185. The use or method of any of claims 178-180 or 182-184, wherein the immunosuppressant is selected from the group consisting of PD1, PD-L1, CTLA-4, TIM-3, LAG-3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, TGFRβ, CEACAM-1, CEACAM-3, and CEACAM-5.

188. 185. The use or method of any of claims 178-180 or 182-184, wherein the agent that inhibits the inhibitory molecule comprises a first polypeptide comprising the inhibitory molecule or a fragment thereof and a second polypeptide that provides a positive signal to a cell, the first and second polypeptides being expressed on the SIR-containing immune cell, and wherein (i) the first polypeptide is PD1, PD-L1, CTLA-4, TIM-3, LAG-3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, TGFRβ, CEACAM-1, CEACAM-3, and CEACAM-5, or a fragment thereof, and / or the second polypeptide has an intracellular signaling domain comprising a first signaling domain and / or a costimulatory signaling domain.

189. 189. The use or method of Claim 188, wherein said first signaling domain comprises a functional domain of CD3ζ and / or said costimulatory signaling domain comprises a functional domain of a protein selected from 41BB, CD27, and CD28.

190. 185. The use or method of any of claims 178-180 or 182-184, wherein the cytokine is selected from IL-15 and / or IL-21.

191. 185. The use or method of any of claims 178-180 or 182-184, wherein the immune effector cells comprising the SIR molecule(s) and the agent that increases the effectiveness of the immune effector cells are administered substantially simultaneously or sequentially.

192. 192. The use or method of claim 191, wherein the SIR molecule is administered in combination with a molecule that targets GITR and / or modulates GITR function.

193. 193. The use or method of claim 192, wherein the molecule that targets GITR and / or the molecule that modulates GITR function is administered prior to the SIR-expressing cell or cell population or prior to apheresis.

194. 185. The use or method of any of claims 178-180 or 182-184, wherein the subject is a human.

195. 1. A composition comprising: 152-153, comprising at least one polynucleotide according to claim 1, an SIR polypeptide molecule according to claim 111, a vector according to claim 104 or a cell according to any one of claims 152-153, and a pharmaceutically acceptable excipient. composition.

196. A kit comprising: comprising at least one polynucleotide according to claim 1, an SIR polypeptide molecule according to claim 111, a vector according to claim 104 or a cell according to any one of claims 152-153, and / or a composition according to claim 144, kit.

197. A recombinant polynucleotide comprising: or having a sequence selected from the group consisting of SEQ ID NOs:900-2264, SEQ ID NOs:4531-6013, SEQ ID NOs:7519-8160, SEQ ID NOs:8803-9230, SEQ ID NOs:9659-9856, SEQ ID NOs:10474-12041, SEQ ID NOs:15786-16011, SEQ ID NOs:16240-16465, SEQ ID NOs:16694-16926, SEQ ID NOs:17162-17394, SEQ ID NOs:17864-17979, SEQ ID NOs:18321-18322, SEQ ID NOs:18242-18259, SEQ ID NOs:18280-18588, SEQ ID NO:18899, and SEQ ID NOs:18915-18916, and SEQ ID NOs:19248-19246, 15, wherein the nucleotide sequence encoding the synthetic immunoreceptor is at least 75% identical to the nucleotide sequence encoding any one of SEQ ID NOs: 15786-16011, 16240-16465, 16694-16926, 17162-17394, 17864-17979, 18321-18322, 18242-18259, 18280-18588, 18899, and 18915-18916, and 19248-19246. Recombinant polynucleotides.

198. An amino acid sequence comprising: an amino acid sequence encoding a synthetic immunoreceptor polypeptide selected from the group consisting of SEQ ID NOs:3135-4498, SEQ ID NOs:6044-7518, SEQ ID NOs:8161-8802, SEQ ID NOs:9231-9658, SEQ ID NOs:9873-10070, SEQ ID NOs:12431-13998, SEQ ID NOs:16013-16238, SEQ ID NOs:16467-16692, SEQ ID NOs:16928-17160, SEQ ID NOs:17396-17628, SEQ ID NOs:17981-18096, SEQ ID NOs:18239-18240, SEQ ID NOs:18261-18278, SEQ ID NOs:18590-18898, SEQ ID NO:18900, and SEQ ID NOs:18919-18920, and SEQ ID NOs:19248-19246, or SEQ ID NO:31 and a sequence that is at least 75% identical to the amino acid sequence encoding the synthetic immunoreceptor polypeptide set forth in any one of SEQ ID NOs: 35-4498, 6044-7518, 8161-8802, 9231-9658, 9873-10070, 12431-13998, 16013-16238, 16467-16692, 16928-17160, 17396-17628, 17981-18096, 18239-18240, 18261-18278, 18590-18898, 18900, and 18919-18920, and 19248-19246. Amino acid sequence.

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