Synthetic immune receptors and methods of using the same

Abstract

The present disclosure provides synthetic immunoreceptors (SIRs), nucleic acids encoding SIRs, methods of making SIRs, and methods of using SIRs, for example, in adoptive cell therapy. [Selected Figure] 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 on December 2, 2016, and U.S. Provisional Application No. 62 / 429,597, filed on December 2, 2016, and the disclosures of these provisional applications are incorporated herein by reference.

[0002] The present invention relates to the use of polypeptides, polynucleotides, expression constructs of synthetic immune receptors (SIRs), and immune effector cells (e.g., T cells, NKT cells) and stem cells engineered to express a synthetic immune receptor (SIR). 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 of Sequence Listing by Reference This application is accompanied by a Sequence Listing entitled "Sequence_ST25.txt" created on December 2, 2017, having 77,085,242 bytes of data in machine format for IBM - PC, MS Windows OS. The entire Sequence Listing is incorporated herein by reference for all purposes.

Background Art

[0004] Strategies to activate immune cells to selectively recognize and destroy tumors, i.e., cancer immunotherapy, provide a powerful approach to cancer treatment. Immunotherapies using adoptive transfer of tumor - specific T cells and chimeric antigen receptor (CAR) - modified T cells (CAR - T cells) mediate durable and complete regression of disease in some 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 immunosuppressive agents and antibodies against cytokines to block cytokine release.

[0006] In addition, one of the most important challenges regarding the success of cancer immunotherapy is that such genetically modified T cells must survive for months or more after transfer. This has been found to be an even greater challenge for T cells modified with the CAR gene.

[0007] Recent molecular designs of CAR constructs incorporating co-stimulatory domains CD28 or 41BB have achieved improved persistence. However, including a co-stimulatory domain in the CAR construct results in non-physiological signaling via the receptor. Some CARs exhibit antigen-independent persistent signaling, resulting in unrestricted cell activation that ultimately leads to apoptosis, antigen-independent excessive cytokine release, 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 has been associated with poor in vivo efficacy) (Frigault et al., 2015). One mechanism that has been found to result in the phenotype of CARs with continuous T cell proliferation was the high density of CARs on the cell surface (Frigault et al., 2015).

[0008] T cell receptors (TCRs) are expressed on the surface of T cells. In humans, such receptors recognize the complex formed between human leukocyte antigen (HLA) molecules and antigenic peptides. Recognition of such peptides leads to the 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 include 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 immune receptor (SIR), wherein the at least one SIR comprises: (a) a T cell receptor (TCR) constant chain, which is (i) an amino acid sequence that is at least 98% identical to SEQ ID NO: 3010, has one or more mutations at positions 48, 61, 91, 92, 93, and / or 94, and may include an optional accessory module; (ii) an amino acid sequence that is at least 98% identical to SEQ ID NO: 3024, has one or more mutations at positions 18, 22, 57, 79, 133, 136, and / or 139, and may include an optional accessory module; (iii) an amino acid sequence that is at least 98% identical to SEQ ID NO: 3025, 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 may include an optional accessory module; (vi) an amino acid sequence that is at least 98% identical to SEQ ID NO: 3051 or 3052, and may include an optional accessory module; and (vii) a combination of dimers of two TCR constant chains selected from the group consisting of (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-natural TCR antigen-binding domains linked to (a), which are (1) an antibody; (2) an antibody fragment (e.g., Fv, Fab, (Fab’)2); (3) the variable heavy chain region (vH domain) of an antibody or a fragment thereof; (4) the variable light chain region (vL domain) of an antibody 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) the monomeric variable region of an antibody; (9) a DARPIN, an affibody, an affilin, an adnectin, an affitin, an obody, a lipobody, a finomer, an alphabody,One or more non-natural TCR antigen-binding domains selected from the group consisting of abimers, atrimers, centyrins, prolectins, anticalins, knotted domains, armadillo repeat proteins, or fragments thereof, (10) receptors or fragments thereof, (11) ligands or fragments 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) autoantigens or fragments thereof, wherein the variants of (a)(i)-(a)(iii) and the dimer of (a)(vii) result in diverse binding affinities for the target antigen of the antigen-binding domain, said affinity being at least 5% greater than the binding affinity of a cTCR having the same binding domain, and the synthetic immune receptor, when expressed in a lymphocyte, expresses both the antigen-binding domain and the T cell receptor constant chain on 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 regulate (induce or suppress) activation, proliferation, cytokine secretion and / or death of target cells and has MHC-restricted and MHC-unrestricted antibody-type specificity. In one embodiment, having the TCR constant chain of (a)(vii), the non-natural TCR binding domain is the variable region of the heavy and light chains or fragments thereof of an antibody specific for a given target antigen, which, when expressed, one of the heavy and light chains of the antibody or a fragment thereof is attached to one of the two chains of (a)(vii) of the T cell constant region, and the other of the heavy and light chains of the antibody or a fragment thereof is attached to the other of the two chains of the T cell constant region, a variable region, two single-chain variable fragments (scFvs) specific for one or more given target antigens, which, 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, single-chain variable fragments, two antibody fragments specific for one or more given target antigens, which, when expressed, one of the antibody fragments isAn antibody fragment that 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, which 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, which 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, which 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, which 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, which 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 different antigen-binding fragments specific for one or more predetermined target antigens, which 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 antigen-binding fragment is attached to the other of the two chains of the T cell constant region; a binding fragment, two self-antigens or fragments thereof, and when expressed, one of the self-antigen or its fragment is attached to one of the two chains of (a)(vii) of the T cell constant region, and the other self-antigen or its fragment is attached to the other of the two chains of the T cell constant region; a receptor or a fragment thereof, two vL or fragments thereof, and when expressed, one of the vL or its fragment is attached to one of the two chains of (a)(vii) of the T cell constant region, and the other vL or its fragment is attached to the other of the two chains of the T cell constant region; a receptor or a fragment thereof, two vH or fragments thereof, and when expressed, one of the vH or its fragment is attached to one of the two chains of (a)(vii) of the T cell constant region, and the other vH or its fragment is attached to the other of the two chains of the T cell constant region; a receptor or a fragment thereof, selected from the group consisting of. In another or further embodiment regarding any of the foregoing, the TCR constant chain of (a)(iv) is the variable region or a fragment thereof of the heavy chain (vH) of an antibody specific for a predetermined target antigen, the variable region or a fragment thereof of the light chain (vL) of an antibody specific for a predetermined target antigen, 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, 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, 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 a self-antigen or a fragment thereof.It has a non-natural TCR binding domain selected from the group consisting of. In yet another embodiment, it has a polynucleotide encoding (i), (ii), (iii), (iv), (v), or (vi), and the non-natural 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 given target antigen, an antibody fragment specific for a given target antigen (e.g., Fv, Fab, (Fab’)2), a single-domain (SDAB) fragment specific for a given target antigen, a camelid-derived vHH domain specific for a given target antigen, a non-immunoglobulin antigen-binding scaffold specific for a given target antigen, a receptor or a fragment thereof specific for a given target antigen, a ligand or a fragment thereof specific for a given 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 given target antigens, and an autoantigen or a fragment thereof, selected from the group consisting of. In another or further embodiment regarding any of the foregoing, the polynucleotide encoding the TCR constant chain is a codon-optimized sequence. In another or further embodiment regarding any of the foregoing, the polynucleotide encoding the TCR constant chain of (a) encodes a TCR constant chain having a mutation that improves the expression and / or pairing of the TCR constant chain and that reduces pairing with the endogenous T cell receptor chain. In another or further embodiment regarding any of the foregoing, the polynucleotide encoding the TCR constant chain of (a) is a nucleic acid sequence modified at positions 1 to 40 of the nucleic acid sequences of SEQ ID NOs: 730 to 743 or a sequence at least 70% identical to the nucleic acid sequences of SEQ ID NOs: 730 to 743 and having a sequence capable of dimerizing with the TCRβ1 or TCRβ2 chain. In another or further embodiment regarding any of the foregoing, the polynucleotide encoding the TCR constant chain of (b) or (c) is a nucleic acid sequence modified at positions 1 to 40 of the nucleic acid sequences of SEQ ID NOs: 744 to 765 or a sequence at least 70% identical to the nucleic acid sequences of SEQ ID NOs: 744 to 765 and having a sequence capable of dimerizing with the TCRβ1 or TCRβ2 chain.It has a TCRα chain and an array capable of dimerization. In another or further embodiment relating to any of the foregoing, the polynucleotide encoding the TCR constant chain of (v) is from SEQ ID NO: 769 to, A nucleic acid sequence that is a 1-40 modification of the nucleic acid sequence of 770 or a sequence that is at least 70% identical to the nucleic acid sequence of SEQ ID NOs: 769-770, and has a sequence capable of dimerizing with the TCRδ chain. In another or further embodiment regarding any of the foregoing, the polynucleotide encoding the TCR constant chain of (vi) is a 1-40 modification of the nucleic acid sequence of SEQ ID NOs: 771-772 or a sequence that is at least 70% identical to the nucleic acid sequence of SEQ ID NOs: 771-772, and has a sequence capable of dimerizing with the TCRγ chain. In another or further embodiment regarding any of the foregoing, the polynucleotide encoding the TCR constant chain of (iv) is a 1-40 modification of the nucleic acid sequence of SEQ ID NOs: 766-768 or a sequence that is at least 70% identical to the nucleic acid sequence of SEQ ID NOs: 766-768, and has a sequence capable of dimerizing with the TCRβ1 or TCRβ2 chain. In another or further embodiment regarding any of the foregoing, the one or more non-natural TCR antigen-binding domains that bind to one or more disease-related antigens are: CD19; CD123; CD22; CD30; CD171; CS-1 (also called 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; a glycosylated CD43 epitope that is 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 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; prostate acid phosphatase (PAP); elongation factor 2 variant (ELF2M); ephrin B2; fibroblast activation protein alpha (FAP); insulin-like growth factor 1 receptor (IGF-1 receptor), carbonic anhydrase IX (CAIX); proteasome (prososome, macropain) subunit,β-type 9 (LMP2); glycoprotein 100 (gp100); cancer gene fusion protein (bcr-abl) consisting of a cleavage region (BCR) and Abelson murine leukemia virus oncogene homolog 1 (Abl); tyrosine kinase; 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 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 portion of globo H glycosphingolipid (GloboH); breast 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-ESO-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 variant; prostain; survivin; telomerase; prostate cancer tumor antigen 1 (PCTA-1 or galectin 8),Melanoma antigen 1 recognized by T cells (MelanA or MART1); Rat sarcoma (Ras) variant; Human telomerase reverse transcriptase (hTERT); Sarcoma translocation breakpoint; Melanoma inhibitor of apoptosis (ML-IAP); ERG (membrane-bound protease, serine 2 (TMPRSS2) ETS fusion gene); N-acetylglucosaminyltransferase V (NA17); Paired box protein Pax-3 (PAX3); Androgen receptor; Cyclin B1; v-myc avian myelocytomatosis viral oncogene homolog from neuroblastoma (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 i.e., 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 variant (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 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), 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 G12V, tissue factor 1 (TF1), AFP, GPRC5D, claudin 18.2 (CLD18A2 or CLDN18A.2), P - glycoprotein, STEAP1, LIV1, NECTIN - 4, CRIPTO, GPA33, BST1 / CD157, low - conductance chloride ion channel, and antigens recognized by TNT antibodies, selected from the group consisting of. In another or further embodiment regarding any of the foregoing, the one or more non - natural TCR antigen - binding domains are 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, e.g., DARPIN, affibody, affilin, adnectin, avimer, obodies, lipibody, finomer,It has an alpha body, an abimer, an atrimer, a centyrin, a pronectin, an anticarin, a knotted domain, an armadillo repeat protein, a receptor, or a ligand. In another or further embodiment related to any of the foregoing, one or more non-natural TCR antigen-binding domains are: (i) a polynucleotide having a sequence of any of SEQ ID NOs: 226 to 400 or 10203 to 10321 or a sequence at least 98% identical thereto, which is encoded by a polynucleotide encoding a polypeptide that binds to an antigen, and a heavy chain variable region (vH); (ii) a polynucleotide having a sequence of any of SEQ ID NOs: 16 to 191 or 10085 to 10202 or a sequence at least 98% identical thereto, which is encoded by a polynucleotide encoding a polypeptide that binds to an antigen, and a light chain variable region (vL); (iii) a polynucleotide having a sequence of any of SEQ ID NOs: 488 to 657, 10346 to 10400, or 18098 to 18160 or a sequence at least 98% identical thereto, which is encoded by a polynucleotide encoding a polypeptide that binds to an antigen, and a single-chain variable fragment (scFv); (iv) a polynucleotide having a sequence of any of SEQ ID NOs: 421 to 445 or 10322 to 10337 or a sequence at least 98% identical thereto, which is encoded by a polynucleotide encoding a polypeptide that binds to an antigen, and a camelid VHH domain; (v) a polynucleotide having a sequence of any of SEQ ID NOs: 439 to 443 or a sequence at least 98% identical thereto, which is encoded by a polynucleotide encoding a polypeptide that binds to an antigen, and a non-immunoglobulin scaffold; (vi) a polynucleotide having a sequence of any of SEQ ID NOs: 456 to 468 or a sequence at least 98% identical thereto, which encodes a polypeptide that binds to an antigen, and a receptor encoded by the polynucleotide encoding the polypeptide; (vii) a polynucleotide having a sequence of any of SEQ ID NOs: 476 to 486 or 10402 to A polynucleotide having any one of the sequences of 10404 or a sequence that is at least 98% identical thereto, and a ligand encoded by a polynucleotide encoding a polypeptide that binds to an antigen, selected from the group consisting of. In another or further embodiment regarding any of the foregoing, the one or more non-natural TCR antigen-binding domains are one or more light chain complementarity-determining regions for a selected target antigen as set forth in any one of SEQ ID NOs: 13999 to 14879 or 14880, and / or one or more light chain complementarity-determining regions for a selected target antigen as set forth in any one of SEQ ID NOs: 14881 to 15761 or 15762. In another or further embodiment regarding any of the foregoing, the one or more non-natural TCR antigen-binding domains have a variable light chain (vL) domain having a sequence as 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 as set forth in any one of SEQ ID NOs: 2506 to 2680 or 12160 to 12278 with up to 10 conservative amino acid substitutions. In another or further embodiment regarding any of the foregoing, the one or more non-natural TCR antigen-binding domains have one or more camelid vHH complementarity-determining regions for a selected antigen as set forth in any one of SEQ ID NOs: 2701 to 2725 or 12279 to 12294 with up to 10 conservative amino acid substitutions. In another or further embodiment regarding any of the foregoing, the one or more non-natural TCR antigen-binding domains have an amino acid as set forth in any one of SEQ ID NOs: 2728 to 2732 or 12296 to 12301 and have a non-immunoglobulin antigen-binding domain containing up to 10 conservative amino acid substitutions. In another or further embodiment regarding any of the foregoing, the one or more non-natural TCR antigen-binding domains have one or more light chain complementarity-determining regions of a variable light chain (vL) domain having a 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 a sequence of any one of SEQ ID NOs: 2506 to 2680 or 12160 to 12278, and have a scFv domain.In another or further embodiment relating to any of the foregoing, the one or more non-natural TCR antigen-binding domains comprise scFv fragments having sequences 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. In another or further embodiment relating to any of the foregoing, the one or more non-natural TCR antigen-binding domains comprise one or more receptors consisting of any of the amino acid sequences of SEQ ID NOs: 2736 to 2748 having up to 10 conservative amino acid substitutions. In another or further embodiment relating to any of the foregoing, the one or more non-natural TCR antigen-binding domains comprise one or more ligands consisting of any of the sequences of SEQ ID NOs: 2758 to 2768 or 12359 to 12361 having up to 10 conservative amino acid substitutions. In another or further embodiment relating to any of the foregoing, the one or more non-natural TCR antigen-binding domains have an extracellular domain of CD16A, NKG2D, CD4, PD1, desmoglein 3 (Dsg3), or CD4-DC-SIGN. In another or further embodiment relating to any of the foregoing, the one or more non-natural TCR antigen-binding domains have an extracellular domain of one or more of hTPO, mTPO, CGHα chain, CGHβ chain, FHβ chain, LHβ chain, TSHβ chain, APRIL, or combinations thereof.In another or further embodiment related to any of the foregoing, the one or more non-natural TCR antigen-binding domains comprise any one of the sequences of SEQ ID NOs: 2770-2939, 12303-12357, or 18162-18224, and any single-chain variable fragment (scFv) having up to 10 conservative amino acid substitutions, and a) any camelid vHH having up to 10 conservative amino acid substitutions and described in any of SEQ ID NOs: 2701-2725 or 12279-12294, or b) any non-immunoglobulin antigen-binding domain having the sequence described 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 any of the amino acid sequences of SEQ ID NOs: 2736-2748 and having 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 and having up to 10 conservative amino acid substitutions. In another or further embodiment related to any of the foregoing, the one or more non-natural TCR antigen-binding domains have up to 10 conservative amino acid substitutions and any camelid vHH described in any of SEQ ID NOs: 2701-2725 or 12279-12294, and a) any single-chain variable fragment (scFv) having any of the sequences 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 described 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 any of the amino acid sequences of SEQ ID NOs: 2736-2748 and having 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 and having up to 10 conservative amino acid substitutions.In another or further embodiment relating to any of the foregoing, each of the one or more non-natural TCR antigen-binding domains is 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: 2981-2992 and any combination thereof or a sequence that is 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 that is at least 98% identical thereto. In another or further embodiment relating to 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 that of the antibody from which it was obtained. In another or further embodiment relating to any of the foregoing, the polynucleotide encoding the SIR further has a leader sequence or signal peptide present at the N-terminus of each strand and having a sequence selected from the group consisting of SEQ ID NOs: 1-9 and 10. In another or further embodiment relating to any of the foregoing, at least one polynucleotide encodes two SIRs. In another or further embodiment relating to any of the foregoing, the polynucleotide encodes two SIRs linked by a nucleotide sequence encoding a cleavable linker. In another or further embodiment relating to any of the foregoing, the cleavable linker is a self-cleaving cleavable linker. In another or further embodiment relating to any of the foregoing, the cleavable linker is any one or more of a 2A linker, a 2A-like linker, or a functional equivalent thereof. In another or further embodiment relating to any of the foregoing, the cleavable linker is any one or more of a T2A linker, a P2A, an F2A, an E2A linker, or a functional equivalent thereof. In another or further embodiment relating to any of the foregoing, the cleavable linker has any one or more of the sequences of SEQ ID NOs: 780-785. In another or further embodiment relating to any of the foregoing, a nucleotide sequence encoding a furin cleavage site, a furin-like cleavage site, or a functional equivalent thereof is optionally located before the polynucleotide sequence encoding the cleavable linker.In another or further embodiment relating to any of the foregoing, the Furin cleavage site preceding the cleavable linker has one or more of the sequences of SEQ ID NOs: 788-790. In another or further embodiment relating to any of the foregoing, a nucleotide sequence encoding a flexible linker is located before the polynucleotide sequence encoding the cleavable linker. In another or further embodiment relating to 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 a functional equivalent thereof. In another or further embodiment relating to any of the foregoing, the flexible linker preceding the cleavable linker has the sequences of SEQ ID NOs: 786-787. In another or further embodiment relating to any of the foregoing, a polynucleotide encoding a flexible linker is located behind the polynucleotide sequence encoding the Furin cleavage site, and then a polynucleotide encoding the cleavable linker is located behind it, such that the order is the Furin cleavage site, the flexible linker, and the cleavable linker. In another or further embodiment relating to any of the foregoing, the polynucleotide encoding the cleavable linker is present before the sequence encoding the leader sequence (signal peptide) encoding the second SIR. In another or further embodiment relating to any of the foregoing, the SIR can be designed to have diverse binding affinities for a selected antigen. In another or further embodiment relating to any of the foregoing, the SIR has an accessory module. In another or further embodiment relating to any of the foregoing, the accessory module has a CD3z domain. In another or further embodiment relating to any of the foregoing, the TCR constant chain is selected from the group consisting of: (viii) an amino acid sequence that is at least 98% identical to SEQ ID NOs: 12401, 12402, 12403, 12408, or 12409; (ix) an amino acid sequence that is at least 98% identical to SEQ ID NOs: 12421, 12422, 12423, 12427, or 12428; and (x) a dimeric combination of the two TCR constant chains of (viii) and (ix).In another or further embodiment relating to any of the foregoing, the one or more non-natural TCR antigen-binding domains bind to CD19. In another or further embodiment relating to any of the foregoing, the one or more non-natural TCR antigen-binding domains are a polypeptide having a sequence that is at least 98% identical to any one of SEQ ID NOs: 2318-2324, 12060-12068, 12108, 12127, and 12156, or a complementarity-determining region (CDR) contained in any polypeptide, a polypeptide having a sequence that is at least 98% identical to any one of SEQ ID NOs: 2517-2523, 12178-12186, 1227, 12246, and 12275, or a complementarity-determining region (CDR) contained in any polypeptide, a polypeptide having a sequence that is at least 98% identical to SEQ ID NO: 12288, and a polypeptide having a sequence that is at least 98% identical to any one of SEQ ID NOs: 2770-2774, 12325, 12308, 18162-18170, and 12354, and is selected from the group consisting of. In another or further embodiment relating to any of the foregoing, the recombinant polynucleotide is 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, It encodes a polypeptide having a sequence selected from the group consisting of 13250, 13267, 13289, 13429 - 13437, 13483, 13501, and 13523. In another or further embodiment regarding any of the foregoing, the one or more non - natural TCR antigen - binding domains bind to CD20. In another or further embodiment regarding any of the foregoing, the one or more non - natural TCR antigen - binding domains have a polypeptide having a sequence that is 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 polypeptide, and a polypeptide having a sequence that is 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 polypeptide, and a polypeptide having a sequence that is at least 98% identical to SEQ ID NO: 12289 or 12290, and a polypeptide having a sequence that is at least 98% identical to any one of SEQ ID NOs: 2787 - 2788, 18177 - 18186, and 18187, and is selected from the group consisting thereof. In another or further embodiment regarding 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 another or further embodiment regarding any of the foregoing, the one or more non - natural TCR antigen - binding domains bind to CD22.In another or further embodiment relating to any of the foregoing, the one or more non-natural TCR antigen-binding domains are a polypeptide having a sequence that is at least 98% identical to any one of SEQ ID NOs: 2327-2329, 12122-12126, and 12132, or any complementary determining region (CDR) contained in any of the polypeptides, a polypeptide having a sequence that is at least 98% identical to any one of SEQ ID NOs: 2526-2528, 12241-12245, and 12251, or any complementary determining region (CDR) contained in any of the polypeptides, a polypeptide having a sequence that is at least 98% identical to any one of SEQ ID NOs: 2789-2791, 12320-12330, and 18188, and is selected from the group consisting of. In another or further embodiment relating to any of the foregoing, in the recombinant polynucleotide, it 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 another or further embodiment relating to any of the foregoing, the one or more non-natural TCR antigen-binding domains bind to BCMA.In another or further embodiment related to any of the foregoing, the one or more non-natural TCR antigen-binding domains are a polypeptide having a sequence that is 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, a polypeptide having a sequence that is 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 polypeptides, a polypeptide having a sequence that is at least 98% identical to SEQ ID NOs: 12279-12281, 12283-12285, 12287, 12291-12292, 12293, or 12294, and a polypeptide having a sequence that is at least 98% identical to any one of SEQ ID NOs: 2780-2783, 12237-12344, 18174-18175, and 18176, and is selected from the group consisting of. In another or further embodiment related to 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 another or further embodiment related to any of the foregoing, the one or more non-natural TCR antigen-binding domains bind to MPL.In another or further embodiment relating to any of the foregoing, the one or more non-natural TCR antigen-binding domains are a polypeptide having a sequence that is 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 that is 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 that is at least 98% identical to any one of SEQ ID NOs: 2871-2878, 12326-12327, and 12318, and is selected from the group consisting of. In another or further embodiment relating to any of the foregoing, it encodes 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 another or further embodiment relating to any of the foregoing, the one or more non-natural TCR antigen-binding domains bind to CS1. In another or further embodiment relating to any of the foregoing, the one or more non-natural TCR antigen-binding domains are a polypeptide having a sequence that is 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 that is 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 that is at least 98% identical to any one of SEQ ID NOs: 2817-2819, 18211-18215, and 18216, and is selected from the group consisting of.In another or further embodiment related to any of the foregoing, in the recombinant polynucleotide, it encodes a polypeptide having a sequence selected from the group consisting of SEQ ID NO: 3376, 3487, 3489, 3907-3909, 12455, 12457, 12459, 12461, 12476, 13226-13231, 13460-13464, and 13465. In another or further embodiment related to any of the foregoing, the one or more non-natural TCR antigen-binding domains bind to CD33. In another or further embodiment related to any of the foregoing, the one or more non-natural TCR antigen-binding domains are a polypeptide having a sequence that is at least 98% identical to any one of SEQ ID NO: 2336-2337, 12079-12084, and 12085, or any complementarity-determining region (CDR) contained in any polypeptide, a polypeptide having a sequence that is at least 98% identical to any one of SEQ ID NO: 2535-2536, 12197-12202, and 12203, or any complementarity-determining region (CDR) contained in any polypeptide, a polypeptide having a sequence that is at least 98% identical to any one of SEQ ID NO: 2795-2796, 18189-18193, and 18194, and is selected from the group consisting of. In another or further embodiment related to any of the foregoing, the recombinant polynucleotide encodes a polypeptide having a sequence selected from the group consisting of SEQ ID NO: 3464-3465, 3884-3885, 12460, 12473, 12479, 13214-13220, 13448-13453, and 13454. In another or further embodiment related to any of the foregoing, the one or more non-natural TCR antigen-binding domains bind to CD123.In another or further embodiment related to any of the foregoing, the one or more non-natural TCR antigen-binding domains are a polypeptide having a sequence that is at least 98% identical to any one of SEQ ID NOs: 2315, 2472, 12049 - 12058, and 12059, or any complementary determining region (CDR) contained in any of the polypeptides, a polypeptide having a sequence that is at least 98% identical to any one of SEQ ID NOs: 2514, 2670, 12167 - 12176, and 12177, or any complementary determining region (CDR) contained in any of the polypeptides, a polypeptide having a sequence that is at least 98% identical to SEQ ID NO: 2716 or 2717, and a polypeptide having a sequence that is at least 98% identical to any one of SEQ ID NOs: 2801, 2929, 18196 - 18205, and 18206, and is selected from the group consisting of. In another or further embodiment related to 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 another or further embodiment related to any of the foregoing, the one or more non-natural TCR antigen-binding domains bind to folate receptor 1. In another or further embodiment related to any of the foregoing, the one or more non-natural TCR antigen-binding domains are a polypeptide having a sequence that is at least 98% identical to SEQ ID NO: 2373, or any complementary determining region (CDR) contained in any of the polypeptides, a polypeptide having a sequence that is at least 98% identical to SEQ ID NO: 2570, or any complementary determining region (CDR) contained in any of the polypeptides, and a polypeptide having a sequence that is at least 98% identical to SEQ ID NO: 2833, and is selected from the group consisting of. In another or further embodiment related to 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 relating to any of the foregoing, the one or more non-natural TCR antigen-binding domains bind to mesothelin. In another or further embodiment relating to any of the foregoing, the one or more non-natural TCR antigen-binding domains are at least any one of SEQ ID NOs: 2413, 12154, and 12155. A polypeptide having a sequence that is 98% identical, or any complementarity-determining region (CDR) contained in any of the polypeptides, and a polypeptide having a sequence that is 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, and a polypeptide having a sequence that is at least 98% identical to SEQ ID NOs: 2713-2714 or 2725, and a polypeptide having a sequence that is at least 98% identical to any one of SEQ ID NOs: 2870, 2899, 12352, and 12353, and is selected from the group consisting of. In another or further embodiment regarding any of the foregoing, in the recombinant polynucleotide, it 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 regarding any of the foregoing, in the one or more non-natural TCR antigen-binding domains, it binds to IL13Ra2. In another or further embodiment regarding any of the foregoing, in the one or more non-natural TCR antigen-binding domains, a polypeptide having a sequence that is 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 that is 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 polypeptide having a sequence that is at least 98% identical to any one of SEQ ID NOs: 2858 and 2859, and is selected from the group consisting of. In another or further embodiment regarding any of the foregoing, in the recombinant polynucleotide, it encodes a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 3541-3542, 3542, 3963, and 3964. In another or further embodiment regarding any of the foregoing, in the one or more non-natural TCR antigen-binding domains, it binds to CD138.In another or further embodiment relating to any of the foregoing, the one or more non-natural TCR antigen-binding domains are a polypeptide having a sequence that is 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 that is 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 that is at least 98% identical to SEQ ID NO: 2802, and are selected from the group consisting of. In another or further embodiment relating to any of the foregoing, in the recombinant polynucleotide, it encodes a polypeptide having a sequence selected from the group consisting of SEQ ID NO: 3268, 3374, 3404, 3471, and 3891. In another or further embodiment relating to any of the foregoing, the one or more non-natural TCR antigen-binding domains bind to TCRγδ. In another or further embodiment relating to any of the foregoing, the one or more non-natural TCR antigen-binding domains are a polypeptide having a sequence that is 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 that is 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 that is at least 98% identical to SEQ ID NO: 2907, and are selected from the group consisting of. The recombinant polynucleotide encodes a polypeptide having a sequence selected from the group consisting of SEQ ID NO: 3594 and 4017. In another or further embodiment relating to any of the foregoing, the one or more non-natural TCR antigen-binding domains bind to TCRβ1.In another or further embodiment relating to any of the foregoing, the one or more non-natural TCR antigen-binding domains are a polypeptide having a sequence that is 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 that is 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 that is at least 98% identical to any one of SEQ ID NOs: 2903 and 2904, and are selected from the group consisting of: The recombinant polynucleotide encodes a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 3590-3591, 4013, and 4014. In another or further embodiment relating to any of the foregoing, the one or more non-natural TCR antigen-binding domains bind to TCRB2. In another or further embodiment relating to any of the foregoing, the one or more non-natural TCR antigen-binding domains are a polypeptide having a sequence that is 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 that is 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 that is at least 98% identical to any one of SEQ ID NOs: 2905 and 2906, and are selected from the group consisting of: 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 the 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 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 (icaspase9), purine nucleoside phosphorylase, linamarase / linamarin glucose oxidase, deoxynucleoside kinase, horseradish peroxidase (HRP) / indole-3-acetic acid (IAA), gamma-glutamylcysteine synthetase, CD20 / αCD20, 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 EGFR-specific siRNA, small molecule compounds, anti-EGFR antibodies or fragments thereof, or combinations thereof. In another embodiment, the tCD30 binds to any one or more of CD30-specific siRNA, small molecule compounds, anti-CD30 antibodies or fragments thereof, and combinations thereof. In another embodiment, the tCD19 binds to any one or more of CD19-specific siRNA, small molecule compounds, anti-CD19 antibodies or fragments thereof, and combinations thereof. In another embodiment, the CD34 binds to any one or more of CD34-specific siRNA, small molecule compounds, anti-CD34 antibodies or fragments thereof, and combinations thereof.In another embodiment, the selection 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 has any one or more of (i) IL-7 cytokine linker IL7Ra, (ii) the extracellular domain of the IL-7Ra cytokine linker of the cytoplasmic domain of IL2Rβ, (iii) IL-7 cytokine linker IL2Rβ, and (iv) combinations thereof. In another embodiment, the recombinant expression system has the recombinant polynucleotide of the present disclosure co-expressed with an accessory module, and 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 target Brd4, chimeric antigen receptor (CAR), hTERT, heparinase, CAR, inhibitory CAR, and combinations thereof selected from the group consisting of.In another or further embodiment relating to 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 relating to any of the foregoing, the cleavable linker is a cleavable linker by self-cleavage. In another or further embodiment relating to any of the foregoing, a nucleotide sequence encoding a Furin cleavage site, a Furin-like cleavage site, or a functional equivalent thereof is located in front of the polynucleotide sequence encoding the cleavable linker. In another or further embodiment relating to any of the foregoing, optionally, a nucleotide sequence encoding a flexible linker is located in front of the polynucleotide sequence encoding the cleavable linker.

[0012] Furthermore, the present disclosure provides at least one vector having the recombinant polynucleotide described herein, and the vector is 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 to 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 to 99% identical thereto. In another or further embodiment relating to any of the foregoing, the vector is an in vitro transcription vector, or the vector further has 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] Furthermore, the present disclosure also provides a recombinant cell that expresses at least one recombinant polynucleotide described herein.

[0015] Furthermore, the present disclosure also provides an isolated synthetic immune receptor (SIR) polypeptide or polypeptide heterodimer, wherein the isolated synthetic immune receptor (SIR) polypeptide or polypeptide heterodimer comprises: (a) a T cell receptor (TCR) constant chain, which is (i) an amino acid sequence that is at least 98% identical to SEQ ID NO: 3010, has one or more mutations at positions 48, 61, 91, 92, 93, and / or 94, and may have any accessory module; (ii) an amino acid sequence that is at least 98% identical to SEQ ID NO: 3024, has one or more mutations at positions 18, 22, 57, 79, 133, 136, and / or 139, and may have any accessory module; (iii) an amino acid sequence that is at least 98% identical to SEQ ID NO: 3025, has one or more mutations at positions 18, 22, 57, 79, 133, 136, and / or 139, and may have any accessory module; (iv) an amino acid sequence that is at least 98% identical to SEQ ID NO: 3046, 3047, or 3048, and may have any accessory module; (v) an amino acid sequence that is at least 98% identical to SEQ ID NO: 3049, and may have any accessory module; (vi) an amino acid sequence that is at least 98% identical to SEQ ID NO: 3051 or 3052, and may have any accessory module; (vii) a dimer combination of two TCR constant chains selected from the group consisting of (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) any linker; (c) one or more non-natural TCR antigen-binding domains bound to (a), which are (1) an antibody; (2) an antibody fragment (e.g., Fv, Fab, (Fab’)2); (3) a heavy chain variable region (vH domain) of an antibody or a fragment thereof; (4) a light chain variable region (vL domain) of an antibody 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) DARPIN, affibody, affilin, adnectin,A non-immunoglobulin antigen-binding scaffold such as affitin, obodies, lipobodies, finomers, alphabodies, abimers, atrimers, centyrins, pronectins, anticalins, knotted 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, 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) a self-antigen or a fragment thereof, and a non-natural TCR antigen-binding domain selected from the group consisting of: (a) (i)-(a) (iii) variants have diverse binding affinities for the target antigen of the antigen-binding domain, and the synthetic immune receptor, when expressed in lymphocytes, expresses both the antigen-binding domain and the T cell receptor constant chain on one or more contiguous chains on the surface of the lymphocyte, and when the expressed antigen-binding domain binds to its antigen, it is triggered to activate, proliferate, and secrete cytokines and / or modulate (induce or suppress) the death of target cells, and has MHC-restricted and MHC-unrestricted antibody-type specificities. In another or further embodiment regarding any of the foregoing, the TCR constant chain of (a) (vii) above has a non-natural TCR binding domain, and the non-natural TCR binding domain is the variable region of the heavy and light chains or fragments thereof of an antibody specific for a predetermined target antigen, and when expressed, one of the heavy and light chains or fragments thereof of the antibody is attached to one of the two chains of (a) (vii) of the T cell constant region, and the other of the heavy and light chains or fragments thereof of the antibody is attached to the other of the two chains of the T cell constant region, a variable region, two single-chain variable fragments (scFvs) specific for one or more predetermined target antigens, and 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, single-chain variable fragments, two antibody fragments specific for one or more predetermined target antigens, and when expressed, one of the antibody fragments is attached to one of the two chains of (a) (vii) of the T cell constant region,Another antibody fragment is an antibody fragment attached to one of the two chains of the T cell constant region, and two single-domain antibody (SDAB) fragments specific for one or more predetermined target antigens, such that 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 SDAB fragment 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, such that 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, such that 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 non-immunoglobulin antigen-binding scaffold domain 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, such that 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 receptor or fragment 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, such that 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 ligand or fragment thereof is attached to the other of the two chains of the T cell constant region; two structurally different antigen-binding fragments specific for one or more predetermined target antigens, such that 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 antigen-binding fragment is attached to the other of the two chains of the T cell constant region; and two binding fragments,Either or both of them 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 antigen-binding fragment is attached to the other of the two chains of the T cell constant region; a binding fragment; two self-antigens or fragments thereof which, when expressed, one of the self-antigens or fragments thereof is attached to one of the two chains of (a)(vii) of the T cell constant region, and the other self-antigen or fragment thereof is attached to the other of the two chains of the T cell constant region; a receptor or fragment thereof; two vL or fragments thereof which, when expressed, one of the vL or fragments thereof is attached to one of the two chains of (a)(vii) of the T cell constant region, and the other vL or fragment thereof is attached to the other of the two chains of the T cell constant region; a receptor or fragment thereof; two vH or fragments thereof which, when expressed, one of the vH or fragments thereof is attached to one of the two chains of (a)(vii) of the T cell constant region, and the other vH or fragment thereof is attached to the other of the two chains of the T cell constant region; a receptor or fragment thereof; and is selected from the group consisting of. In another or further embodiment regarding any of the foregoing, the TCR constant chain of (a)(iv) has a non-natural TCR binding domain, and the non-natural TCR binding domain is the variable region or a fragment thereof of the heavy chain (vH) of an antibody specific for a predetermined target antigen, the variable region or a fragment thereof of the light chain (vL) of an antibody specific for a predetermined target antigen, 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, 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, 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.It is selected from the group consisting of a bispecific ligand and a self-antigen or a fragment thereof. In another or further embodiment regarding any of the above, it has the TCR constant domain of (i), (ii), (iii), (iv), (v), or (vi) above, and the non-natural 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, an antibody fragment specific for a predetermined target antigen (e.g., Fv, Fab, (Fab’)2), a single-domain (SDAB) fragment 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, 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 a self-antigen or a fragment thereof. In another or further embodiment regarding any of the above, the TCR constant chain(s) has a mutation that improves the expression and / or pairing of the TCR constant chain and reduces the pairing with the endogenous T cell receptor chain. In another or further embodiment regarding any of the above, the constant region of the TCR is a sequence selected from the group consisting of SEQ ID NOs: 3010 to 3023, or SEQ ID NOs: 3010 to, It is a TCR receptor α chain (Cα) having an amino acid sequence containing 1 to 40 amino acid substitution variants or mutants with respect to a sequence that is at least 98% identical to an amino acid sequence selected from the group consisting of 3023. In another or further embodiment regarding any of the foregoing, the constant region of the TCR is a sequence selected from the group consisting of SEQ ID NOs: 3024 to 3044, or an amino acid sequence having 1 to 40 amino acid substitution variants or mutants with respect 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, which is a TCR receptor β chain (Cβ). In another or further embodiment regarding any of the foregoing, the constant region of the TCR is a sequence selected from the group consisting of SEQ ID NOs: 3049 to 3050, or an amino acid sequence having 1 to 40 amino acid substitution variants or mutants with respect to a sequence that is at least 98% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 3049 to 3050, which is a TCR receptor γ chain (Cγ). In another or further embodiment regarding any of the foregoing, the constant region of the TCR is a sequence selected from the group consisting of SEQ ID NOs: 3051 to 3052, or an amino acid sequence having 1 to 40 amino acid substitution variants or mutants with respect to a sequence that is at least 98% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 3051 to 3052, which is a TCR receptor δ chain (Cδ). In another or further embodiment regarding any of the foregoing, the constant region of the TCR is a sequence selected from the group consisting of SEQ ID NOs: 3046 to 3048, or an amino acid sequence having 1 to 40 amino acid substitution variants or mutants with respect to a sequence that is at least 98% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 3046 to 3048, which is a pre-TCR receptor α chain (pre-Cα). In another or further embodiment regarding any of the foregoing, the one or more non-natural TCR antigen-binding domains that bind to the one or more disease-related antigens are CD19; CD123; CD22; CD30; CD171; CS-1 (CD2 subset 1, CRACC, SLAMF7, CD319,and also called 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 epitopes expressed in acute leukemia or lymphoma but not in hematopoietic progenitor cells, glycosylated CD43 epitopes expressed in non-hematopoietic organ 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; prostate acid phosphatase (PAP); elongation factor 2 variant (ELF2M); Ephrin B2; fibroblast activation protein alpha (FAP); insulin-like growth factor 1 receptor (IGF-1 receptor), carbonic anhydrase IX (CAIX); proteasome (prososome, macropain) subunit,Beta type 9 (LMP2); glycoprotein 100 (gp100); oncogene fusion protein (bcr-abl) consisting of breakpoint cluster region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (Abl); tyrosine kinase; 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); hexasaccharide moiety of globo H glycosphingolipid (GloboH); breast 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-ESO-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 variant; prostain; survivin; telomerase; prostate cancer tumor antigen 1 (PCTA-1 or galectin 8),Melanoma antigen 1 recognized by T cells (MelanA or MART1); Rat sarcoma (Ras) variant; Human telomerase reverse transcriptase (hTERT); Sarcoma translocation breakpoint; Melanoma inhibitor of apoptosis (ML-IAP); ERG (membrane-bound protease, serine 2 (TMPRSS2) ETS fusion gene); N-acetylglucosaminyltransferase V (NA17); Paired box protein Pax-3 (PAX3); Androgen receptor; Cyclin B1; v-myc avian myelocytomatosis viral oncogene homolog from neuroblastoma (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 i.e., 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 variant (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 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 G12V, tissue factor 1 (TF1), AFP, GPRC5D, claudin 18.2 (CLD18A2 or CLDN18A.2), P - glycoprotein, STEAP1, LIV1, NECTIN - 4, CRIPTO, GPA33, BST1 / CD157, low - conductance chloride ion channel, and antigens recognized by TNT antibodies, selected from the group consisting of. In another or further embodiment regarding any of the foregoing, the one or more non - natural TCR antigen - binding domains are 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, e.g., DARPIN, affibody, affilin, adnectin, avitin, obodies, lipobody, finomer, alphabody, abimer, atrimer, centyrin,It has a pro-nectin, anti-carlin, knitted domain, armadillo repeat protein, receptor, or ligand. In another or further embodiment regarding any of the foregoing, the one or more non-natural TCR antigen-binding domains are (i) a heavy chain variable region (vH) having a sequence described in any of SEQ ID NOs: 2506 to 2680 or 12160 to 12278 or a sequence at least 98% identical thereto and encoding a polypeptide that binds to an antigen, (ii) a light chain variable region (vL) having a sequence described in any one of SEQ ID NOs: 2307 to 2482 or 12042 to 12159 or a sequence at least 98% identical thereto and encoding a polypeptide that binds to an antigen, (iii) a single-chain variable fragment (scFv) having a sequence described 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 encoding a polypeptide that binds to an antigen, (iv) a sequence number, or a sequence described in any one of SEQ ID NOs: 2701 to 2725 or 12279 to 12294 or at least A camelid VHH encoding a polypeptide having a 98% identical sequence and binding to an antigen, (v) a non-immunoglobulin scaffold encoding a polypeptide having a sequence described in any one of SEQ ID NOs: 439 to 443 or a sequence at least 98% identical thereto and binding to the same species, (vi) a receptor having a sequence described in any one of SEQ ID NOs: 2736 to 2748 or a sequence at least 98% identical thereto and encoding a polypeptide binding to an antigen, (vii) a ligand having a sequence described 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 binding to the same species, and is selected from the group consisting of. In another or further embodiment regarding any of the foregoing, the one or more non-natural TCR antigen-binding domains are one or more light chain complementarity determining regions for a selected target antigen as described 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 as described in any of SEQ ID NOs: 14881 to 15761 or 15762. In another or further embodiment regarding any of the foregoing, the one or more non-natural TCR antigen-binding domains have up to 10 conservative amino acid substitutions and have a variable light chain (vL) domain containing any one of the sequences of SEQ ID NOs: 2307 to 2482 or 12042 to 12159, and / or have up to 10 conservative amino acid substitutions and have a variable heavy chain (vH) domain containing any one of the sequences of SEQ ID NOs: 2506 to 2680 or 12160 to 12278. The one or more non-natural TCR antigen-binding domains have up to 10 conservative amino acid substitutions and have one or more camelid vHH complementarity determining regions for a selected antigen as described in any of SEQ ID NOs: 2701 to 2725 or 12279 to 12294. In another or further embodiment regarding any of the foregoing, the one or more non-natural TCR antigen-binding domains have a sequence described in any of SEQ ID NOs: 2728 to 2732 or 12296 to 12301 and have a non-immunoglobulin antigen-binding domain containing up to 10 conservative amino acid substitutions.In another or further embodiment related to any of the foregoing, the one or more non-natural TCR antigen-binding domains have a scFv domain comprising one or more light-chain complementarity-determining regions of a variable light chain (vL) domain having any one of the sequences 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 any one of the sequences of SEQ ID NOs: 2506 to 2680 or 12160 to 12278. In another or further embodiment related to any of the foregoing, the one or more non-natural TCR antigen-binding domains have a 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 having up to 10 conservative amino acid substitutions. In another or further embodiment related to any of the foregoing, the one or more non-natural TCR antigen-binding domains have one or more receptors consisting of any of the amino acid sequences of SEQ ID NOs: 2736 to 2748, each having up to 10 conservative amino acid substitutions. In another or further embodiment related to any of the foregoing, the one or more non-natural TCR antigen-binding domains have one or more ligands comprising any of the sequences of SEQ ID NOs: 2758 to 2768 or 12359 to 12361, each having up to 10 conservative amino acid substitutions. In another or further embodiment related to any of the foregoing, the one or more non-natural TCR antigen-binding domains have an extracellular domain of CD16A, NKG2D, CD4, PD1, desmoglein 3 (Dsg3), or CD4-DC-SIGN. In another or further embodiment related to any of the foregoing, the one or more non-natural TCR antigen-binding domains have an extracellular domain of one or more of hTPO, mTPO, CGHα chain, CGHβ chain, FHβ chain, TSHβ chain, APRIL, or combinations thereof.In another or further embodiment relating to any of the foregoing, the one or more non-natural TCR antigen-binding domains have any of the sequences of SEQ ID NOs: 2770-2939, 12303-12357, or 18162-18224, and any single-chain variable fragment (scFv) having up to 10 conservative amino acid substitutions, and a) a camelid vHH as described 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 any of the sequences described 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 any of the amino acid sequences of SEQ ID NOs: 2736-2748 having 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 and having up to 10 conservative amino acid substitutions. In another or further embodiment relating to any of the foregoing, the one or more non-natural TCR antigen-binding domains have a camelid vHH as described in any of SEQ ID NOs: 2701-2725 or 12279-12294 having up to 10 conservative amino acid substitutions, and a) any single-chain variable fragment (scFv) having any of the sequences 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 any of the sequences described 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 any of the amino acid sequences of SEQ ID NOs: 2736-2748 having 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 and having up to 10 conservative amino acid substitutions.In another or further embodiment relating to any of the foregoing, each of the one or more non-natural TCR antigen-binding domains is 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 that is 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 that is at least 98% identical thereto. In another or further embodiment relating to 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 that of the antibody from which it was obtained. In another or further embodiment relating to any of the foregoing, the polynucleotide encoding the SIR further has a leader sequence or signal peptide present at the N-terminus of each strand and having a sequence selected from the group consisting of SEQ ID NOs: 1 to 9 and 10. In another or further embodiment relating to any of the foregoing, the SIR has an SIR heterodimer. In another or further embodiment relating to any of the foregoing, the polypeptide has two SIRs linked by a cleavable linker. In another or further embodiment relating to any of the foregoing, the cleavable linker is a cleavable linker by self-cleavage. In another or further embodiment relating to any of the foregoing, the cleavable linker is any one or more of a 2A linker, a 2A-like linker, or a functional equivalent thereof. In another or further embodiment relating to any of the foregoing, the cleavable linker is any one or more of a T2A linker, a P2A, an F2A, an E2A linker, or a functional equivalent thereof. In a further embodiment, the cleavable linker has any one or more of the sequences of SEQ ID NOs: 780 to 785. In any of the foregoing embodiments, optionally, a furin cleavage site, a furin-like cleavage site, or a functional equivalent thereof is located in front of the cleavable linker. In a further embodiment, the furin cleavage site preceding the cleavable linker has any one or more of the sequences of SEQ ID NOs: 788 to 790.In a further embodiment, a flexible linker is located before the cleavable linker. In a further embodiment, 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. The flexible linker preceding the cleavable linker has the sequences of SEQ ID NOs: 786-787. In a further embodiment, a flexible linker is located after the Furin cleavage site and a cleavable linker is located after the flexible linker such that the order is Furin cleavage site, flexible linker, cleavable linker. In another or further embodiment regarding any of the foregoing, the SIR is designed to have diverse binding affinities for a selected antigen.

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

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

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

[0019] In another or further embodiment relating to any of the foregoing, the immune effector cells or stem cells have a plurality of SIR polypeptides. In another or further embodiment relating to any of the foregoing, at least one of the plurality of SIR polypeptides targets an antigen different from at least one other SIR polypeptide. In another or further embodiment relating to any of the foregoing, at least one of the plurality of SIR polypeptides targets the same antigen. In another or further embodiment relating to any of the foregoing, at least one of the plurality of SIR polypeptides has a binding affinity for an antigen different from at least one other SIR polypeptide. In another or further embodiment relating to any of the foregoing, the immune cells further have at least one chimeric antigen receptor (CAR) polypeptide. In another or further embodiment relating to any of the foregoing, the antigen-binding domain of the SIR polypeptide targets an antigen different from the antigen-binding domain of the CAR polypeptide. In another or further embodiment relating to any of the foregoing, the CAR polypeptide has an intracellular signaling domain that includes a co-stimulatory signaling domain but does not include a primary signaling domain, or the CAR polypeptide has an intracellular signaling domain that includes a primary signaling domain but does not include a co-stimulatory signaling domain. In another or further embodiment relating to any of the foregoing, the CAR polypeptide has a co-stimulatory signaling domain that includes 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 primary signaling domain that includes a functional signaling domain of CD3ζ.In another or further embodiment relating to any of the foregoing, the CAR polypeptide is an inhibitory CAR polypeptide, the inhibitory CAR polypeptide having an antigen-binding domain, a transmembrane domain, and an 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 relating to any of the foregoing, the CAR polypeptide further has an intracellular signaling domain comprising a first signaling domain and / or an intracellular signaling domain, the intracellular signaling domain having a first signaling domain comprising the functional domain of CD3ζ and a co-stimulatory signaling domain comprising the functional domain of 4-1BB and / or CD28. In another or further embodiment relating to any of the foregoing, the CAR polypeptide has the amino acid sequence of SEQ ID NOs: 3077 to 3083. In another or further embodiment relating to any of the foregoing, 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 deficient in diacylglycerol kinase (DGK) and / or Ikaros and / or Brd4.

[0020] The present disclosure provides a method for producing SIR-expressing immune effector cells, the method comprising introducing into immune effector cells, or hematopoietic stem cells or progenitor cells capable of generating immune effector cells, at least one vector of the present disclosure or at least one recombinant polynucleotide of the present disclosure under conditions in which the SIR polypeptide is expressed. In another or further embodiment relating to any of the foregoing, the method further comprises a) providing a population of immune effector cell progenitors, and b) removing regulatory T cells from the progenitor population, thereby providing regulatory T cell-depleted cells, and steps a) and b) are performed prior to introducing the vector or the recombinant polynucleotide encoding the SIR into the progenitor population. In another or further embodiment relating to any of the foregoing, the regulatory T cells are removed from the cell progenitor population using an anti-CD25 antibody or an anti-GITR antibody. In another or further embodiment relating to any of the foregoing, the method further comprises a) providing a population of immune effector cell progenitors, and b) enriching for P-glycoprotein (P-gp or Pgp, MDR1, ABCB1, CD243) positive cells from the progenitor population, thereby providing a population of P-glycoprotein (P-gp or Pgp, MDR1, ABCB1, CD243) enriched cells, and steps a) and b) are performed either before or after introducing the vector or the recombinant polynucleotide encoding the SIR.In another or further embodiment relating to any of the foregoing, the P-glycoprotein positive cells are concentrated using any one or more of the methods selected from the group consisting of: i) immunoselection using one or more of a cocktail of steps specific for P-glycoprotein; ii) staining with one or more of fluorescent dyes that are substrates of P-glycoprotein, tetramethylrhodamine methyl ester (TMRM), adriamycin, and actinomycin D, under the condition that P-glycoprotein is active as a pump, and concentrating cells that are less stained with the dye; iii) selection of cells resistant to any one or more of phototoxic compounds that are substrates of P-glycoprotein, such as TH9402, methyl 2-(4,5-dibromo-6-amino-3-imino-3H-xanthen-9-yl)benzoate hydrochloride, ethyl 2-(4,5-dibromo-6-amino-3-imino-3H-xanthen-9-yl)benzoate hydrochloride, octyl 2-(4,5-dibromo-6-amino-3-imino-3H-xanthen-9-yl)benzoate hydrochloride, n-butyl 2-(4,5-dibromo-6-amino-3-imino-3H-xanthen-9-yl)benzoate hydrochloride, n-butyl 2-(6-ethylamino-3-ethylimino-3H-xanthen-9-yl)benzoate 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 a method for generating a population of recombinant RNA cells, the method comprising introducing in vitro transcribed RNA(s) or synthetic RNA(s) into a cell or population of cells, wherein the RNA(s) has the recombinant polynucleotide(s) described herein.

[0022] The present disclosure provides a method for providing disease-resistant immunity to a subject, the method comprising administering to the subject an effective amount of immune effector cells or stem cells capable of generating the immune effector cells of the present disclosure, where 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 expression of a functional TCR or functional HLA, or have low expression thereof.

[0023] The present disclosure provides a composition having 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 enhances the effect of immune effector cells in the treatment of a subject having a disease associated with the expression of a disease-related antigen or in the prevention of a disease in a subject having an increased risk of a disease associated with the expression of a disease-related antigen, wherein (i) the SIR molecule has one or more T cell receptor constant chains linked through an optional linker to one or more antigen-binding domains that bind to a disease-related antigen, and the disease-related antigen is CD5, CD19; CD123; CD22; CD30; CD171; CS-1 (also called 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; a glycosylated CD43 epitope expressed in acute leukemia or lymphoma but not in hematopoietic progenitor cells, a glycosylated CD43 epitope expressed in non-hematopoietic organ 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 variant (ELF2M); Ephrin B2; Fibroblast activation protein α (FAP); Insulin-like growth factor 1 receptor (IGF-1 receptor), Carbonic anhydrase IX (CAIX); Proteasome (prososome, macropain) subunit, beta type 9 (LMP2); Glycoprotein 100 (gp100); Cancer gene fusion protein consisting of breakpoint cluster region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (Abl) (bcr-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 glycosphingolipid (GloboH); Breast 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); TCRγ alternative reading frame protein (TARP); Wilms tumor protein (WT1); Cancer / testis antigen 1 (NY-ESO-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 antigen family member 1 (MAD-CT-1); melanoma antigen family member 2 (MAD-CT-2); Fos-related antigen 1; tumor protein p53 (p53); p53 variant; prostain; survivin; telomerase; prostate cancer tumor antigen 1 (PCT A-1 or galectin 8), melanoma antigen recognized by T cells 1 (MelanA or MARTI); rat sarcoma (Ras) variant; human telomerase reverse transcriptase (hTERT); sarcoma translocation breakpoint; melanoma inhibitor of apoptosis (ML-IAP); ERG (membrane-spanning protease, serine 2 (TMPRSS2) ETS fusion gene); N-acetylglucosaminyltransferase V (NA17); paired box protein Pax-3 (PAX3); androgen receptor; cyclin B1; v-myc myelocytomatosis viral oncogene homolog, neuroblastoma-derived (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 recognized by T cells 3 (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 ubiquitin 1 (RU1); renal ubiquitin 2 (RU2); regucalcin; human papillomavirus E6 (HPV E6); human papillomavirus E7 (HPV E7); intestinal carboxylesterase; heat shock protein 70-2 variant (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, 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 G12V, tissue factor 1 (TF1), AFP, GPRC5D, claudin 18.2 (CLD18A2 or CLDN18A.2), P - glycoprotein, STEAP1, LIV1, NECTIN - 4, CRIPTO, GPA33, BST1 / CD157, low - conductance chloride ion channel, and an antigen recognized by a TNT antibody, provided that (ii) the agent for increasing the effect of the immune cells is a protein phosphatase inhibitor, a kinase inhibitor (e.g., P13K / AKT inhibitor, mTOR inhibitor, LCK inhibitor, or BTK inhibitor), a cytokine, an inhibitor of an immunosuppressive molecule, T; REGIt is selected from one or more of an agent that reduces the level or activity of 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 the regulation of the expression or activity of SIR, an agent that enables 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 agent (e.g., sHVEM) or a prophylactic agent to the site of a 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 the expression of a disease-related antigen in a subject, the method 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 enhances the effect of immune cells, wherein (i) the SIR molecule has one or more T cell receptor constant chains linked through an optional linker to one or more antigen-binding domains that bind to a disease-related antigen, and the disease-related antigen is CD5, CD19; CD123; CD22; CD30; CD171; CS-1 (also called 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; a glycosylated CD43 epitope expressed in acute leukemia or lymphoma but not in hematopoietic progenitor cells, a glycosylated CD43 epitope expressed in non-hematopoietic organ 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 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 Mutation (ELF2M); Ephrin B2; Fibroblast Activation Protein α (FAP); Insulin-like Growth Factor 1 Receptor (IGF-1 Receptor), Carbonic Anhydrase IX (CAIX); Proteasome (Prososome, Macropain) Subunit, Beta Type 9 (LMP2); Glycoprotein 100 (gp100); Cancer Gene Fusion Protein consisting of Breakpoint Cluster Region (BCR) and Abelson Murine Leukemia Virus Oncogene Homolog 1 (Abl) (bcr-abl); Tyrosinase; Ephrin 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 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 Portion of Globoh Glycosphingolipid (GloboH); Breast 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-ESO-1); Cancer / Testis Antigen 2 (LAGE-1a); Melanoma Associated Antigen 1 (MAGE-A1); ETS Translocation Variant Gene 6 Located on Chromosome 12p (ETV6-AML); Spermatid Protein 17 (SPA17); X Antigen Family Member 1A (XAGE1); Angiopoietin Binding Cell Surface Receptor 2 (Tie2); Melanoma Cancer Testis Antigen 1 (MAD-CT-1);Malignant melanoma antigen 2 (MAD-CT-2); Fos-related antigen 1; Tumor protein p53 (p53); p53 variant; Prostain; Survivin; Telomerase; Prostate carcinoma tumor antigen 1 (PCT A-1 or galectin 8), Melanoma antigen recognized by T cells 1 (MelanA or MARTI); Rat sarcoma (Ras) variant; Human telomerase reverse transcriptase (hTERT); Sarcoma translocation breakpoint; Melanoma inhibitor of apoptosis (ML-IAP); ERG (membrane-spanning protease, serine 2 (TMPRSS2) ETS fusion gene); N-acetylglucosaminyltransferase V (NA17); Paired box protein Pax-3 (PAX3); Androgen receptor; Cyclin B1; v-myc avian myelocytomatosis viral oncogene homolog, neuroblastoma-derived (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 recognized by T cells 3 (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); Kidney ubiquitin 1 (RU1); Kidney ubiquitin 2 (RU2); Legumain; Human papillomavirus E6 (HPV E6); Human papillomavirus E7 (HPV E7); Intestinal carboxylesterase; Heat shock protein 70-2 variant (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, 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 G12V, tissue factor 1 (TF1), AFP, GPRC5D, claudin 18.2 (CLD18A2 or CLDN18A.2), P-glycoprotein, STEAP1, LIV1, NECTIN-4, CRIPTO, GPA33, BST1 / CD157, low-conductance chloride ion channel, and an antigen recognized by a TNT antibody, (ii) an agent for increasing the effect of the immune cell is 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 a T; REGAn agent that reduces the level or activity of cells, an agent that increases the growth and maintenance of SIR-modified cells, a chemokine, an agent that increases the expression of SIR, an agent that enables the regulation of the expression or activity of SIR, an agent that enables 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 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 one or more selected from adenosine A2a receptor antagonists, thereby treating the subject or preventing the disease of the subject.

[0025] The present disclosure provides a method for treating or preventing a disease associated with the expression of a disease-related 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 has one or more T cell receptor constant chains linked through an optional linker to one or more antigen-binding domains that bind to a disease-related antigen, and the disease-related antigen is CD5, CD19; CD123; CD22; CD23; CD30; CD171; CS-1 (also called 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; a glycosylated CD43 epitope expressed in acute leukemia or lymphoma but not in hematopoietic progenitor cells, a glycosylated CD43 epitope expressed in non-hematopoietic organ 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 mutation (ELF2M); Ephrin B2; Fibroblast activation protein α (FAP); Insulin-like growth factor 1 receptor (IGF-1 receptor), Carbonic anhydrase IX (CAIX); Proteasome (prososome, macropain) subunit, beta type 9 (LMP2); Glycoprotein 100 (gp100); Breakpoint cluster region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (Abl) - derived oncogene fusion protein (bcr-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 glycosphingolipid (GloboH); Breast 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); TCRγ alternative reading frame protein (TARP); Wilms tumor protein (WT1); Cancer / testis antigen 1 (NY-ESO-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 antigen 2 (MAD-CT-2); Fos-related antigen 1; Tumor protein p53 (p53); p53 variant; Prostain; Survivin; Telomerase; Prostate carcinoma tumor antigen 1 (PCT A-1 or galectin 8), Melanoma antigen 1 recognized by T cells (MelanA or MARTI); Rat sarcoma (Ras) variant; Human telomerase reverse transcriptase (hTERT); Sarcoma translocation breakpoint; Melanoma inhibitor of apoptosis (ML-IAP); ERG (membrane-spanning protease, serine 2 (TMPRSS2) ETS fusion gene); N-acetylglucosaminyltransferase V (NA17); Paired box protein Pax-3 (PAX3); Androgen receptor; Cyclin B1; v-myc avian myelocytomatosis viral oncogene homolog from neuroblastoma (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); Kidney ubiquitin 1 (RU1); Kidney ubiquitin 2 (RU2); Legumain; Human papillomavirus E6 (HPV E6); Human papillomavirus E7 (HPV E7); Intestinal carboxylesterase; Heat shock protein 70-2 variant (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, 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), 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 G12V, tissue factor 1 (TF1), AFP, GPRC5D, claudin 18.2 (CLD18A2 or CLDN18A.2), P-glycoprotein, STEAP1, LIV1, NECTIN-4, CRIPTO, GPA33, BST1 / CD157, low-conductance chloride ion channel, and an antigen recognized by a TNT antibody, and (ii) the antigen-binding domain of the SIR molecule has a binding affinity that is at least 5-fold less than that of an antibody that induced the antigen-binding domain.;

[0026] In another or further embodiment relating to any of the foregoing methods or uses, the disease associated with the expression of the disease-related antigen is selected from the group consisting of proliferative diseases, pre-cancerous conditions, cancer, and non-cancer-related indications associated with the expression related to the disease. In another or further embodiment relating to any of the foregoing methods or uses, the cancer is 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 myelogenous leukemia (CML), B-cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt lymphoma, diffuse large B-cell lymphoma, primary effusion lymphoma, follicular lymphoma, hairy cell lymphoma, small cell or large cell follicular lymphoma, malignant lymphoproliferative disorders, MALT lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndromes, non-Hodgkin lymphoma, Hodgkin lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenström macroglobulinemia, and a blood cancer selected from one or more of pre-leukemia. In another or further embodiment relating to any of the foregoing methods or uses, the cancer is colon cancer, rectal cancer, renal cell cancer, 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, gastric cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, cancer of the vulva, Hodgkin disease, non-Hodgkin lymphoma, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, solid tumors in children, bladder cancer, cancer of the kidney or ureter, renal pelvis cancer, tumors of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal cord axis tumors, brainstem glioma, pituitary adenoma, Kaposi sarcoma, Merkel cell carcinoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancer, combinations of the above cancers, and metastases of the above cancers, and is selected from the group consisting of.In another or further embodiment relating to any of the foregoing methods or uses, the disease is associated with a viral infection and includes, but is 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, Zika virus, RSV, measles virus, mumps virus, rhinovirus, varicella virus types 1 and 2, varicella - zoster virus, HIV - 1, HTLV1, hepatitis virus, enterovirus, hepatitis B virus, hepatitis C virus, Nipah and Rift Valley fever virus, Japanese encephalitis virus, Merkel cell polyomavirus or a virus associated with mycobacterium tuberculosis infection, atypical mycobacterial species, Pneumocystis jirovecii, toxoplasmosis, rickettsia, Nocardia, Aspergillus, Mucor, and Candida. In another or further embodiment relating to any of the foregoing methods or uses, the disease is an immune disease or a degenerative disorder and includes, but is not limited to, type 1 diabetes, 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 related to any of the foregoing 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 PI3K / mTOR inhibitor; (iii) the agent that inhibits the immunosuppressive factor is an antibody or antibody fragment, an inhibitory nucleic acid, a clustered regularly interspaced short palindromic repeat (CRISPR) with spacers inserted at equal intervals, a TAL effector nuclease (TALEN), or a zinc finger nuclease (ZFN) that inhibits the expression of the inhibitory molecule; (iv) the agent that reduces the level or activity of the 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, OTX015, LY303511, and the Brd4 inhibitor described in U.S. Patent No. 20140256706A1, or derivatives thereof. In another or further embodiment related to any of the foregoing 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 related to any of the foregoing methods or uses, the agent that inhibits the inhibitory molecule has a first polypeptide containing the inhibitory molecule or a fragment thereof and a second polypeptide that provides a positive signal to the cell, and the first and second polypeptides are expressed on the SIR-containing immune cells. (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 (ii) the second polypeptide has an intracellular signaling domain containing a first signaling domain and / or a costimulatory signaling domain.In another or further embodiment relating to any of the foregoing methods or uses, the first signaling domain has the functional domain of CD3ζ, and / or the co-stimulatory signaling domain has the functional domain of a protein selected from 41BB, CD27, and CD28. In another or further embodiment relating to any of the foregoing methods or uses, the cytokine is selected from IL-15 and / or IL-21. In another or further embodiment relating to any of the foregoing methods or uses, the immune effector cell(s) comprising the SIR molecule(s) and the agent that increases the effect of the immune effector cell are administered substantially simultaneously or sequentially. In another or further embodiment relating to any of the foregoing 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 relating to any of the foregoing methods or uses, the molecule that targets GITR and / or the molecule that modulates GITR function is administered before the SIR-expressing cells or cell population or before apheresis. In another or further embodiment relating to any of the foregoing methods or uses, the subject is human.

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

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

[0029] The present disclosure has a sequence selected from the group consisting of SEQ ID NOs: 900 to 2264, SEQ ID NOs: 4531 to 6013, SEQ ID NOs: 7519 to 8160, SEQ ID NOs: 8803 to 9230, SEQ ID NOs: 9659 to 9856, SEQ ID NOs: 10474 to 12041, SEQ ID NOs: 15786 to 16011, SEQ ID NOs: 16240 to 16465, SEQ ID NOs: 16694 to 16926, SEQ ID NOs: 17162 to SEQ ID NO: 17394, SEQ ID NOs: 17864 to 17979, SEQ ID NOs: 18321 to 18322, SEQ ID NOs: 18242 to 18259, SEQ ID NOs: 18280 to 18588, SEQ ID NO: 18899, SEQ ID NOs: 18915 to 18916, or has a sequence that is at least 75% identical to the nucleotide sequence encoding the synthetic immune receptor set forth in any one of SEQ ID NOs: 900 to 2264, SEQ ID NOs: 4531 to 6013, SEQ ID NOs: 7519 to 8160, SEQ ID NOs: 8803 to 9230, SEQ ID NOs: 9659 to 9856, SEQ ID NOs: 10474 to 12041, SEQ ID NOs: 15786 to 16011, SEQ ID NOs: 16240 to 16465, SEQ ID NOs: 16694 to 16926, SEQ ID NOs: 17162 to SEQ ID NO: 17394, SEQ ID NOs: 17864 to 17979, SEQ ID NOs: 18321 to 18322, SEQ ID NOs: 18242 to 18259, SEQ ID NOs: 18280 to 18588, SEQ ID NO: 18899, SEQ ID NOs: 18915 to 18916, and also provides a recombinant polynucleotide encoding a synthetic immune receptor.

[0030] The present disclosure provides 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, or a sequence that is at least 75% identical to the amino acid sequence encoding the synthetic immunoreceptor polypeptide described in any one 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. The present invention also relates to the following. [Item 1] At least one recombinant polynucleotide encoding at least one synthetic immune receptor (SIR), wherein said at least one SIR is (a) a T cell receptor (TCR) constant chain, (i) an amino acid sequence that is at least 98% identical to SEQ ID NO: 3010 and has one or more mutations at positions 48, 61, 91, 92, 93 and / or 94, and may include an optional accessory module, (ii) an amino acid sequence that is at least 98% identical to SEQ ID NO: 3024 and has one or more mutations at positions 18, 22, 57, 79, 133, 136 and / or 139, and may include an optional accessory module, (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 may include an optional accessory module, (vi) an amino acid sequence that is at least 98% identical to SEQ ID NO: 3051 or 3052, and may include an optional accessory module, as well as (vii) a combination of dimers 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, (c) one or more non-natural TCR antigen-binding domains linked to (a), (1) an antibody, (2) an antibody fragment (e.g., Fv, Fab, (Fab’)2), (3) the variable heavy chain region (vH domain) of an antibody or a fragment thereof, (4) the variable light chain region (vL domain) of an antibody 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) The monomer variable region of an antibody, (9) A non-immunoglobulin antigen-binding scaffold such as a DARPIN, an affibody, an affilin, an adnectin, an affitin, an orbody, a lipobody, a fibronomer, an alphabody, an abimer, an atrimer, a centyrin, a pronectin, an anticalin, a knotted 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, One or more non-natural TCR antigen-binding domains selected from the group consisting of, comprising (a) The variants of (a)(i)-(a)(iii) and the dimer of (a)(vii) provide diverse binding affinities for the target antigen of the antigen-binding domain, the affinity being at least 5% greater than the binding affinity of a cTCR having the same binding domain, and the synthetic immune receptor, when expressed in a lymphocyte, expresses both the antigen-binding domain and the T cell receptor constant chain on 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 modulate (induce or suppress) activation, proliferation, cytokine secretion and / or death of target cells and has MHC-restricted and MHC-unrestricted antibody-type specificity, A recombinant polynucleotide. [Item 2] (a)(vii) The recombinant polynucleotide according to Item 1, comprising a TCR constant chain, wherein the non-natural TCR binding domain is - The variable regions of the heavy and light chains of an antibody specific for a predetermined target antigen or fragments thereof, which, when expressed, one of the heavy and light chains of the antibody 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 heavy and light chains of the antibody or fragments thereof is attached to the other of the two chains of the T cell constant region, a variable 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 scFv 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 antibody fragment 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 SDAB fragment 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 non-immunoglobulin antigen-binding scaffold domain 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 receptor or fragment thereof is attached to the other of the two chains of the T cell constant region. - Two ligands or fragments thereof that are specific for one or more predetermined target antigens, such that 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 ligands or fragments thereof, and - Two structurally different antigen-binding fragments that are specific for one or more predetermined target antigens, such that 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 structurally different antigen-binding fragments, and - Two binding fragments, either or both of which are bispecific or multispecific, such that 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, and - Two self-antigens or fragments thereof, such that when expressed, one of the self-antigens 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 self-antigens or fragments thereof is attached to the other of the two chains of the T cell constant region, two self-antigens or fragments thereof, and - Two vL or fragments thereof, such that when expressed, one of the vL 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 vL or fragments thereof is attached to the other of the two chains of the T cell constant region, two vL or fragments thereof, and - Two vH or fragments thereof, such that when expressed, one of the vH 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 vH or fragments thereof is attached to the other of the two chains of the T cell constant region, two vH or fragments thereof, and A recombinant polynucleotide selected from the group consisting of. [Item 3] The recombinant polynucleotide according to item 1, comprising the TCR constant chain of (a)(iv), wherein the non-natural TCR binding domain is - the variable region or a fragment thereof of the heavy chain (vH) of an antibody specific for a predetermined target antigen, and - the variable region or a fragment thereof of the light chain (vL) of an antibody specific for a predetermined target antigen, and - a single-chain variable fragment (scFv) specific for a predetermined target antigen or a fragment thereof, and - an antibody fragment specific for a predetermined target antigen (e.g., Fv, Fab, (Fab’)2); a single-domain (SDAB) fragment specific for a predetermined target antigen, and - a camelid-derived vHH domain specific for a predetermined target antigen, and - a non-immunoglobulin antigen-binding scaffold specific for a predetermined target antigen, and - a receptor specific for a predetermined target antigen or a fragment thereof, and - a ligand specific for a predetermined target antigen or a fragment thereof, 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 - a self-antigen or a fragment thereof, and is a recombinant polynucleotide selected from the group consisting of. [Item 4] The recombinant polynucleotide according to item 1, comprising a polynucleotide encoding (i), (ii), (iii), (iv), (v) or (vi), 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, and - the variable region of the light chain (vL) of an antibody specific for a predetermined target antigen, and - a single-chain variable fragment (scFv) specific for a predetermined target antigen, and - an antibody fragment specific for a predetermined target antigen (e.g., Fv, Fab, (Fab’)2); a single-domain (SDAB) fragment specific for a predetermined target antigen, and - a camelid-derived vHH domain specific for a predetermined target antigen, and - a non-immunoglobulin antigen-binding scaffold specific for a predetermined target antigen, and - a receptor specific for a predetermined target antigen or a fragment thereof, and - a ligand specific for a predetermined target antigen or a fragment thereof, 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 autoreantigen or a fragment thereof, and A recombinant polynucleotide selected from the group consisting of [Item 5] The recombinant polynucleotide according to Item 1, wherein the polynucleotide encoding the TCR constant chain is a codon-optimized sequence. [Item 6] The recombinant polynucleotide according to Item 1, wherein the polynucleotide encoding the TCR constant chain of (a) comprises a TCR constant chain (s) having a mutation that improves the expression and / or pairing of the TCR constant chain and a mutation that reduces the pairing with the endogenous T cell receptor chain. [Item 7] The recombinant polynucleotide according to Item 1, wherein the polynucleotide encoding the TCR constant chain of (a) is a nucleic acid sequence modified at positions 1 to 40 of the nucleic acid sequence of SEQ ID NOs: 730 to 743 or a sequence having at least 70% identity to the nucleic acid sequence of SEQ ID NOs: 730 to 743 and comprises a sequence capable of dimerizing with the TCRβ1 chain or the TCRβ2 chain. [Item 8] The recombinant polynucleotide according to Item 1, wherein the polynucleotide encoding the TCR constant chain of (b) or (c) is a nucleic acid sequence modified at positions 1 to 40 of the nucleic acid sequence of SEQ ID NOs: 744 to 765 or a sequence having at least 70% identity to the nucleic acid sequence of SEQ ID NOs: 744 to 765 and comprises a sequence capable of dimerizing with the TCRα chain. [Item 9] The recombinant polynucleotide according to Item 1, wherein the polynucleotide encoding the TCR constant chain of (v) is a nucleic acid sequence modified at positions 1 to 40 of the nucleic acid sequence of SEQ ID NOs: 769 to 770 or a sequence having at least 70% identity to the nucleic acid sequence of SEQ ID NOs: 769 to 770 and comprises a sequence capable of pairing with the TCRδ chain. [Item 10] The recombinant polynucleotide according to Item 1, wherein the polynucleotide encoding the TCR constant chain of (vi) is a nucleic acid sequence modified at positions 1 to 40 of the nucleic acid sequence of SEQ ID NOs: 771 to 772 or a sequence having at least 70% identity to the nucleic acid sequence of SEQ ID NOs: 771 to 772 and comprises a sequence capable of dimerizing with the TCRγ chain. [Item 11] The recombinant polynucleotide according to Item 1, wherein the polynucleotide encoding the TCR constant chain of (iv) is a nucleic acid sequence modified at positions 1 to 40 of the nucleic acid sequence of SEQ ID NOs: 766 to 768 or a sequence having at least 70% identity to the nucleic acid sequence of SEQ ID NOs: 766 to 768 and comprises a sequence capable of dimerizing with the TCRβ1 chain or the TCRβ2 chain. [Item 12] The one or more non-natural TCR antigen-binding domains are: 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 epitopes expressed in acute leukemia or lymphoma but not in hematopoietic progenitor cells, glycosylated CD43 epitopes expressed in non-hematopoietic organ 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; prostate acid phosphatase (PAP); elongation factor 2 variant (ELF2M); Ephrin B2; fibroblast activation protein alpha (FAP); insulin-like growth factor 1 receptor (IGF-1 receptor), carbonic anhydrase IX (CAIX); proteasome (prososome, macropain) subunit, beta type 9 (LMP2); glycoprotein 100 (gp100);Cancer gene fusion protein (bcr-abl) consisting of a readily cleavable region (BCR) and Abelson murine leukemia virus oncogene homolog 1 (Abl); tyrosine kinase; 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 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 glycosphingolipid (GloboH); breast 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-ESO-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 variant; prostain; survivin; telomerase; prostate cancer tumor antigen 1 (PCT A-1 or galectin 8), melanoma antigen 1 recognized by T cells (MelanA or MART1); rat sarcoma (Ras) variant; 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; v-myc avian myelocytomatosis viral oncogene homolog from neuroblastoma (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 i.e., Brother of the Regulator of Imprinted Sites), Squamous cell carcinoma antigen 3 recognized by T cells antigen 3 (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 variant (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;Carcinoembryonic antigen (CEA), fucosyl GM1, PTK7, gpNMB, CDH1 - CD324, DLL3, CD276 / B7H3, IL11Ra, IL13Ra2, CD179b - IGL11, ALK TCRγ-δ, NKG2D, CD32 (FCGR2A), Tn antigen, 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, 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 G12V, tissue factor 1 (TF1), AFP, GPRC5D, claudin 18.2 (CLD18A2 or CLDN18A.2), P - glycoprotein, STEAP1, LIV1, NECTIN - 4, CRIPTO, GPA33, BST1 / CD157, low - conductance chloride ion channel, and antigens recognized by TNT antibodies, one or more of the disease - related antigens selected from the group consisting of; [Item 13] The one or more non-natural TCR antigen-binding domains include an antibody; an antibody fragment; scFv; Fv; Fab; (Fab’)2; single domain antibody (SDAB); vH domain or vL domain; camelid-derived vHH domain; a non-immunoglobulin antigen-binding scaffold such as DARPIN, affibody, affilin, adnectin, affitin, avobody, lipobody, fibronomer, alphabody, abimer, atrimer, centyrin, pronectin, anticalin, knotted domain, armadillo repeat protein; a receptor; or a ligand, and the recombinant polynucleotide according to item 12. [Item 14] The one or more non-natural TCR antigen-binding domains are (i) a polynucleotide having any one of the sequences of SEQ ID NOs: 226 to 400 or 10203 to 10321 or a sequence at least 98% identical thereto, which encodes a heavy chain variable region (vH) of a polypeptide that binds to its antigen, (ii) a polynucleotide having any one of the sequences of SEQ ID NOs: 16 to 191 or 10085 to 10202 or a sequence at least 98% identical thereto, which encodes a light chain variable region (vL) of a polypeptide that binds to its antigen, (iii) a polynucleotide having any one of the sequences of SEQ ID NOs: 488 to 657, 10346 to 10400 or 18098 to 18160 or a sequence at least 98% identical thereto, which encodes a single-chain variable fragment (scFv) of a polypeptide that binds to its antigen, (iv) a polynucleotide having any one of the sequences of SEQ ID NOs: 421 to 445 or 10322 to 10337 or a sequence at least 98% identical thereto, which encodes a camelid VHH domain of a polypeptide that binds to its antigen, (v) a polynucleotide having any one of the sequences of SEQ ID NOs: 439 to 443 or a sequence at least 98% identical thereto, which encodes a non-immunoglobulin scaffold of a polypeptide that binds to its antigen, (vi) A polynucleotide having any one of the sequences of SEQ ID NOs: 456 to 468 or a sequence that is at least 98% identical thereto, which encodes a receptor encoded by a polynucleotide that encodes a polypeptide that binds to its cognate, (vii) A polynucleotide having any one of the sequences of SEQ ID NOs: 476 to 486 or 10402 to 10404 or a sequence that is at least 98% identical thereto, which encodes a ligand encoded by a polynucleotide that encodes a polypeptide that binds to its cognate, The recombinant polynucleotide according to item 12, selected from the group consisting of. [Item 15] The one or more non-natural TCR antigen-binding domains are one or more of the light chain complementarity-determining regions for a selected target antigen as set forth in any of SEQ ID NOs: 13999 to 14879 or 14880, and / or one or more of the heavy chain complementarity-determining regions for a selected target antigen as set forth in any of SEQ ID NOs: 14881 to 15761 or 15762, The recombinant polynucleotide according to item 1. [Item 16] The one or more non-natural TCR antigen-binding domains have a variable light chain (vL) domain having a sequence as set forth in any one of SEQ ID NOs: 2307 to 2482 or 12042 to 12159 having up to 10 conservative amino acid substitutions, and / or a variable heavy chain (vH) having a sequence as set forth in any one of SEQ ID NOs: 2506 to 2680 or 12160 to 12278 having up to 10 conservative amino acid substitutions The recombinant polynucleotide according to item 1 having a domain. [Item 17] The one or more non-natural TCR antigen-binding domains have one or more camelid vHH complementarity-determining regions for a selected antigen as set forth in any one of SEQ ID NOs: 2701 to 2725 or 12279 to 12294 having up to 10 conservative amino acid substitutions, The recombinant polynucleotide according to item 1. [Item 18] The one or more non-natural TCR antigen-binding domains have an amino acid as set forth in any one of SEQ ID NOs: 2728 to 2732 or 12296 to 12301 and have a non-immunoglobulin antigen-binding domain containing up to 10 conservative amino acid substitutions, The recombinant polynucleotide according to item 1. [Item 19] 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 any one of the sequences 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 any one of the sequences of SEQ ID NOs: 2506 to 2680 or 12160 to 12278. The polynucleotide according to item 1. [Item 20] The one or more non-natural TCR antigen-binding domains have 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 substitution variants. The recombinant polynucleotide according to item 1. [Item 21] The one or more non-natural TCR antigen-binding domains have one or more receptors consisting of any amino acid sequence of SEQ ID NOs: 2736 to 2748 having up to 10 conservative amino acid substitution variants. The recombinant polynucleotide according to item 1. [Item 22] The one or more non-natural TCR antigen-binding domains have one or more ligands consisting of any sequence of SEQ ID NOs: 2758 to 2768 or 12359 to 12361 having up to 10 conservative amino acid substitution variants. The recombinant polynucleotide according to item 1. [Item 23] The one or more non-natural TCR antigen-binding domains have an extracellular domain of CD16A, NKG2D, CD4, PD1, desmoglein 3 (Dsg3), or CD4-DC-SIGN. The recombinant polynucleotide according to item 1. [Item 24] The one or more non-natural TCR antigen-binding domains have an extracellular domain of one or more of hTPO, mTPO, CGHα chain, CGHβ chain, FHβ chain, LHβ chain, TSHβ chain, APRIL, or a combination thereof. The recombinant polynucleotide according to item 1. [Item 25] The one or more non-natural TCR antigen-binding domains comprise any one of the sequences of SEQ ID NOs: 2770 to 2939, 12303 to 12357, or 18162 to 18224, and any single-chain variable fragment (scFv) having up to 10 conservative amino acid substitution variants, a) having up to 10 conservative amino acid substitutions and any camelid vHH described in any of SEQ ID NOs: 2701 - 2725 or 12279 - 12294, or b) any non - immunoglobulin antigen - binding domain having a sequence described 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 an amino acid sequence from any of SEQ ID NOs: 2736 - 2748 and having up to 10 conservative amino acid substitutions, or d) any extracellular domain of a ligand having a sequence of any of SEQ ID NOs: 2758 - 2768 or 12359 - 12361 and having up to 10 conservative amino acid substitutions, and The recombinant polynucleotide according to item 1. [Item 26] Said one or more non - natural TCR antigen - binding domains have up to 10 conservative amino acid substitutions and are combined with a camelid vHH described in any of SEQ ID NOs: 2701 - 2725 or 12279 - 12294, and a) any single - chain variable fragment (scFv) having a sequence from 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 a sequence described 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 an amino acid sequence from any of SEQ ID NOs: 2736 - 2748 and having up to 10 conservative amino acid substitutions, or d) any extracellular domain of a ligand having a sequence of any of SEQ ID NOs: 2758 - 2768 or 12359 - 12361 and having up to 10 conservative amino acid substitutions, and The recombinant polynucleotide according to item 1. [Item 27] 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 that is 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 that is at least 98% identical thereto. The recombinant polynucleotide according to item 1. [Item 28] 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 that of the antibody from which it was obtained. The recombinant polynucleotide according to item 1. [Item 29] The polynucleotide encoding the SIR further has a leader sequence or signal peptide present at the N-terminus of each strand and having a sequence selected from the group consisting of SEQ ID NOs: 1 to 9 and 10. The recombinant polynucleotide according to item 1. [Item 30] At least one polynucleotide encodes two SIRs. The recombinant polynucleotide according to item 1. [Item 31] The polynucleotide encodes two SIRs linked by a nucleotide sequence encoding a cleavable linker. The recombinant polynucleotide according to item 30. [Item 32] The cleavable linker is a cleavable linker by self-cleavage. The recombinant polynucleotide according to item 31. [Item 33] The cleavable linker is any one or more of a 2A linker, a 2A-like linker, or a functional equivalent thereof. The recombinant polynucleotide according to item 31. [Item 34] The cleavable linker is any one or more of a T2A linker, P2A, F2A, E2A linker, or a functional equivalent thereof. The recombinant polynucleotide according to item 31. [Item 35] The cleavable linker has any one or more of the sequences of SEQ ID NOs: 780 to 785. The recombinant polynucleotide according to item 31. [Item 36] Optionally, a nucleotide sequence encoding a furin cleavage site, a furin-like cleavage site, or a functional equivalent thereof is located in front of the polynucleotide sequence encoding the cleavable linker. The recombinant polynucleotide according to item 31. [Item 37] The polynucleotide according to item 36, wherein the Furin cleavage site preceding the cleavable linker has any one or more sequences among SEQ ID NOs: 788 to 790. [Item 38] The recombinant polynucleotide according to any one of items 31 to 37, wherein a nucleotide sequence encoding a flexible linker is located before the polynucleotide sequence encoding the cleavable linker. [Item 39] The recombinant polynucleotide according to item 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] The recombinant polynucleotide according to item 39, wherein the flexible linker preceding the cleavable linker has a sequence of SEQ ID NOs: 786 to 787. [Item 41] The recombinant polynucleotide according to item 38, wherein the nucleotide sequence encoding the flexible linker is located after the polynucleotide sequence encoding the Furin cleavage site, and the nucleotide sequence encoding the cleavable linker is located after that, such that the order is the Furin cleavage site, the flexible linker, and the cleavable linker. [Item 42] The recombinant polynucleotide according to item 31, wherein the polynucleotide encoding the cleavable linker is present before the sequence encoding the leader sequence (signal peptide) encoding the second SIR. [Item 43] The recombinant polynucleotide according to item 1, wherein the SIR can be designed to have diverse binding affinities for a selected antigen. [Item 44] The recombinant polynucleotide, wherein the SIR has an accessory module. [Item 45] The recombinant polynucleotide according to item 1, wherein in the recombinant polynucleotide according to item 44, the accessory module has a CD3z domain. [Item 46] The TCR constant chain is (viii) an amino acid sequence that is at least 98% identical to SEQ ID NOs: 12401, 12402, 12403, 12408, or 12409, (ix) an amino acid sequence that is at least 98% identical to SEQ ID NOs: 12421, 12422, 12423, 12427, or 12428, (x) a dimeric combination of the two TCR constant chains of (viii) and (ix), The recombinant polynucleotide according to item 45, which is selected from the group consisting of. [Item 47] The one or more non-natural TCR antigen-binding domains are the recombinant polynucleotide according to item 12 that binds to CD19. [Item 48] The one or more non-natural TCR antigen-binding domains are - a polypeptide having a sequence that is at least 98% identical to any one of SEQ ID NOs: 2318 to 2324, 12060 to 12068, 12108, 12127, and 12156, or any complementarity-determining region (CDR) contained in any of the polypeptides, and - a polypeptide having a sequence that is at least 98% identical to any one of SEQ ID NOs: 2517 to 2523, 12178 to 12186, 1227, 12246, and 12275, or any complementarity-determining region (CDR) contained in any of the polypeptides, and - a polypeptide having a sequence that is at least 98% identical to SEQ ID NO: 12288, and - a polypeptide having a sequence that is at least 98% identical to any one of SEQ ID NOs: 2770 to 2774, 12325, 12308, 18162 to 18170, and 12354, The recombinant polynucleotide according to item 47, selected from the group consisting of. [Item 49] The recombinant polynucleotide according to item 47, encoding a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 3135 to 3235, 3250 to 3346, 3396, 3401 to 3403, 3406, 3429 to 3432, 3435 to 3439, 3540, 3855 to 3859, 12431 to 12489, 12491 to 12493, 12495 to 12530, 12534, 13195 to 13203, 13250, 13267, 13289, 13429 to 13437, 13483, 13501, and 13523. [Item 50] The one or more non-natural TCR antigen-binding domains are the recombinant polynucleotide according to item 12 that binds to CD20. [Item 51] The one or more non-natural TCR antigen-binding domains are - a polypeptide having a sequence that is at least 98% identical to any one of SEQ ID NOs: 2325 to 2326, 12069 to 12077, and 12078, or any complementarity-determining region (CDR) contained in any of the polypeptides, - A polypeptide having a sequence that is at least 98% identical to any one of SEQ ID NOs: 2524-2525, 12187-12195, and 12196, or any complementary determining region (CDR) contained in any of said polypeptides, - A polypeptide having a sequence that is at least 98% identical to SEQ ID NO: 12289 or 12290, - A polypeptide having a sequence that is at least 98% identical to any one of SEQ ID NOs: 2787-2788, 18177-18186, and 18187, The recombinant polynucleotide according to item 50, selected from the group consisting of [Item 52] The recombinant polynucleotide according to 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] The recombinant polynucleotide according to item 12, wherein said one or more non-natural TCR antigen-binding domains bind to CD22. [Item 54] Said one or more non-natural TCR antigen-binding domains - A polypeptide having a sequence that is at least 98% identical to any one of SEQ ID NOs: 2327-2329, 12122-12126, and 12132, or any complementary determining region (CDR) contained in any of said polypeptides, - A polypeptide having a sequence that is at least 98% identical to any one of SEQ ID NOs: 2526-2528, 12241-12245, and 12251, or any complementary determining region (CDR) contained in any of said polypeptides, - A polypeptide having a sequence that is at least 98% identical to any one of SEQ ID NOs: 2789-2791, 12320-12330, and 18188, The recombinant polynucleotide according to item 53, selected from the group consisting of [Item 55] The recombinant polynucleotide according to 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] The one or more non-natural TCR antigen-binding domains are the recombinant polynucleotide according to item 12, which binds to BCMA. [Item 57] The one or more non-natural TCR antigen-binding domains are - a polypeptide having a sequence that is at least 98% identical to any one of SEQ ID NOs: 2310 to 2313, 12046 to 12048, 12118 to 12119, 12139 to 12145, and 12146, or any complementarity-determining region (CDR) contained in any of the polypeptides, and - a polypeptide having a sequence that is at least 98% identical to any one of SEQ ID NOs: 2509 to 2512, 12164 to 12166, 12237 to 12238, 12258 to 12264, and 12265, or any complementarity-determining region (CDR) contained in any of the polypeptides, and - a polypeptide having a sequence that is at least 98% identical to any one of SEQ ID NOs: 12279 to 12281, 12283 to 12285, 12287, 12291 to 12292, 12293, or 12294, and - a polypeptide having a sequence that is at least 98% identical to any one of SEQ ID NOs: 2780 to 2783, 12237 to 12344, 18174 to 18175, and 18176, and the recombinant polynucleotide according to item 56, which is selected from the group consisting of. [Item 58] The recombinant polynucleotide according to item 56, which encodes a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 3445 to 3449, 3866 to 3869, 12463, 12533, 12535 to 12536, 13181 to 13183, 13261 to 13262, 13277 to 13284, 13415 to 13417, 13495 to 13496, 13511 to 13517, and 13518. [Item 59] The one or more non-natural TCR antigen-binding domains are the recombinant polynucleotide according to item 12, which binds to MPL. [Item 60] The one or more non-natural TCR antigen-binding domains are - a polypeptide having a sequence that is 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 the polypeptides, and - A polypeptide having a sequence that is 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 that is at least 98% identical to any one of SEQ ID NOs: 2871-2878, 12326-12327, and 12318, and The recombinant polynucleotide according to item 59, selected from the group consisting of. [Item 61] The recombinant polynucleotide according to 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] The recombinant polynucleotide according to item 12, wherein the one or more non-natural TCR antigen-binding domains bind to CS1. [Item 63] The one or more non-natural TCR antigen-binding domains are - A polypeptide having a sequence that is 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, and - A polypeptide having a sequence that is 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 that is at least 98% identical to any one of SEQ ID NOs: 2817-2819, 18211-18215, and 18216, and The recombinant polynucleotide according to item 62, selected from the group consisting of. [Item 64] The recombinant polynucleotide according to 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] The one or more non-natural TCR antigen-binding domains are the recombinant polynucleotide according to item 12, which binds to CD33. [Item 66] The one or more non-natural TCR antigen-binding domains are - a polypeptide having a sequence that is at least 98% identical to any one of SEQ ID NOs: 2336 to 2337, 12079 to 12084, and 12085, or any complementarity-determining region (CDR) contained in any of the polypeptides, and - a polypeptide having a sequence that is at least 98% identical to any one of SEQ ID NOs: 2535 to 2536, 12197 to 12202, and 12203, or any complementarity-determining region (CDR) contained in any of the polypeptides, and - a polypeptide having a sequence that is at least 98% identical to any one of SEQ ID NOs: 2795 to 2796, 18189 to 18193, and 18194, The recombinant polynucleotide according to item 65, which is selected from the group consisting of. [Item 67] The recombinant polynucleotide according to item 65, which encodes a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 3464 to 3465, 3884 to 3885, 12460, 12473, 12479, 13214 to 13220, 13448 to 13453, and 13454. [Item 68] The one or more non-natural TCR antigen-binding domains are the recombinant polynucleotide according to item 12, which binds to CD123. [Item 69] The one or more non-natural TCR antigen-binding domains are - a polypeptide having a sequence that is at least 98% identical to any one of SEQ ID NOs: 2315, 2472, 12049 to 12058, and 12059, or any complementarity-determining region (CDR) contained in any of the polypeptides, and - a polypeptide having a sequence that is at least 98% identical to any one of SEQ ID NOs: 2514, 2670, 12167 to 12176, and 12177, or any complementarity-determining region (CDR) contained in any of the polypeptides, and - a polypeptide having a sequence that is at least 98% identical to SEQ ID NO: 2716 or 2717, - a polypeptide having a sequence that is at least 98% identical to any one of SEQ ID NOs: 2801, 2929, 18196 to 18205, and 18206, The recombinant polynucleotide according to item 68, which is selected from the group consisting of. [Item 70] The recombinant polynucleotide according to item 68, encoding a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 3266 to 3267, 3366 to 3368, 3375, 3378, 3405, 3409, 3434, 3470, 3492 to 3497, 3617, 3890, 3912 to 3913, 4041, 12480, 13184 to 13194, 13418 to 13427, and 13428. [Item 71] The recombinant polynucleotide according to item 12, wherein the one or more non-natural TCR antigen-binding domains bind to folate receptor 1. [Item 72] The one or more non-natural TCR antigen-binding domains are - a polypeptide having a sequence that is at least 98% identical to SEQ ID NO: 2373, or any complementarity-determining region (CDR) contained in any of the polypeptides, and - a polypeptide having a sequence that is 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 that is at least 98% identical to SEQ ID NO: 2833, The recombinant polynucleotide according to item 71, selected from the group consisting of. [Item 73] The recombinant polynucleotide according to item 71, encoding a polypeptide having a sequence selected from the group consisting of SEQ ID NOs: 3511 and 3928. [Item 74] The recombinant polynucleotide according to item 12, wherein the one or more non-natural TCR antigen-binding domains bind to mesothelin. [Item 75] The one or more non-natural TCR antigen-binding domains are - a polypeptide having a sequence that is 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 the polypeptides, and - a polypeptide having a sequence that is at least 98% identical to any one of SEQ ID NOs: 2609 to 2610, 12273, and 12274, or any complementarity-determining region (CDR) contained in any of the polypeptides, and - a polypeptide having a sequence that is at least 98% identical to SEQ ID NOs: 2713 to 2714 or 2725, and - a polypeptide having a sequence that is at least 98% identical to any one of SEQ ID NOs: 2870, 2899, 12352, and 12353, The recombinant polynucleotide according to item 74, selected from the group consisting of [Item 76] The recombinant polynucleotide according to item 74, encoding a polypeptide having a sequence selected from the group consisting of SEQ ID NO: 3414, 3419, 3554, 3585, 3976, 4008, 13287-13288, 13521, and 13522. [Item 77] The recombinant polynucleotide according to item 12, wherein the one or more non-natural TCR antigen-binding domains bind to IL13Ra2. [Item 78] The one or more non-natural TCR antigen-binding domains - a polypeptide having a sequence that is at least 98% identical to any one of SEQ ID NO: 2399 and 2400, or any complementarity-determining region (CDR) contained in any of the polypeptides, and - a polypeptide having a sequence that is at least 98% identical to any one of SEQ ID NO: 2595 and 2596, or any complementarity-determining region (CDR) contained in any of the polypeptides, and - a polypeptide having a sequence that is at least 98% identical to any one of SEQ ID NO: 2858 and 2859 The recombinant polynucleotide according to item 77, selected from the group consisting of [Item 79] The recombinant polynucleotide according to item 77, encoding a polypeptide having a sequence selected from the group consisting of SEQ ID NO: 3541-3542, 3963, and 3964. [Item 80] The recombinant polynucleotide according to item 12, wherein the one or more non-natural TCR antigen-binding domains bind to CD138. [Item 81] The one or more non-natural TCR antigen-binding domains - a polypeptide having a sequence that is at least 98% identical to SEQ ID NO: 2316, or any complementarity-determining region (CDR) contained in any of the polypeptides, and - a polypeptide having a sequence that is 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 that is at least 98% identical to SEQ ID NO: 2802 The recombinant polynucleotide according to item 80, selected from the group consisting of [Item 82] The recombinant polynucleotide according to item 80, encoding a polypeptide having a sequence selected from the group consisting of SEQ ID NO: 3268, 3374, 3404, 3471, and 3891. [Item 83] The one or more non-natural TCR antigen-binding domains are the recombinant polynucleotide according to item 12 that binds to TCRγδ. [Item 84] The one or more non-natural TCR antigen-binding domains are - a polypeptide having a sequence that is at least 98% identical to SEQ ID NO: 2449, or any complementarity-determining region (CDR) contained in any of the polypeptides, and - a polypeptide having a sequence that is 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 that is at least 98% identical to SEQ ID NO: 2907, The recombinant polynucleotide according to item 83, which is selected from the group consisting of. [Item 85] The recombinant polynucleotide according to item 83, which encodes a polypeptide having a sequence selected from the group consisting of SEQ ID NO: 3594 and 4017. [Item 86] The one or more non-natural TCR antigen-binding domains are the recombinant polynucleotide according to item 12 that binds to TCRβ1. [Item 87] The one or more non-natural TCR antigen-binding domains are - a polypeptide having a sequence that is at least 98% identical to any one of SEQ ID NO: 2445 and 2446, or any complementarity-determining region (CDR) contained in any of the polypeptides, and - a polypeptide having a sequence that is at least 98% identical to any one of SEQ ID NO: 2642 and 2643, or any complementarity-determining region (CDR) contained in any of the polypeptides, and - a polypeptide having a sequence that is at least 98% identical to any one of SEQ ID NO: 2903 and 2904, The recombinant polynucleotide according to item 86, which is selected from the group consisting of. [Item 88] The recombinant polynucleotide according to item 86, which encodes a polypeptide having a sequence selected from the group consisting of SEQ ID NO: 3590 to 3591, 4013, and 4014. [Item 89] The one or more non-natural TCR antigen-binding domains are the recombinant polynucleotide according to item 12 that binds to TCRβ2. [Item 90] The one or more non-natural TCR antigen-binding domains are - a polypeptide having a sequence that is at least 98% identical to any one of SEQ ID NO: 2447 and 2448, or any complementarity-determining region (CDR) contained in any of the polypeptides, and - A polypeptide having a sequence that is at least 98% identical to either of SEQ ID NOs: 2644 and 2645, or any complementarity-determining region (CDR) contained in any of said polypeptides, and - A polypeptide having a sequence that is at least 98% identical to either of SEQ ID NOs: 2905 and 2906, The recombinant polynucleotide according to item 89, selected from the group consisting of. [Item 91] The recombinant polynucleotide according to 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 having the recombinant polynucleotide according to item 1 co-expressed with a therapeutic control, wherein the therapeutic control is selected from the group consisting of truncated epidermal growth factor receptor (tEGFR), truncated 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 (icaspase9), purine nucleoside phosphorylase, linamarase / linamarin glucose oxidase, deoxynucleoside kinase, horseradish peroxidase (HRP) / indole-3-acetic acid (IAA), γ-glutamylcysteine synthetase, CD20 / αCD20, 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 system. [Item 93] The recombinant expression system according to item 92, wherein the tEGFR and tEGFRviii bind to any one or more of EGFR-specific siRNA, small molecule compounds, anti-EGFR antibodies or fragments thereof, and combinations thereof. [Item 94] The recombinant expression system according to item 92, wherein the tCD30 binds to any one or more of CD30-specific siRNA, small molecule compounds, anti-CD30 antibodies or fragments thereof, and combinations thereof. [Item 95] The recombinant expression system according to item 92, wherein the tCD19 binds to any one or more of CD19-specific siRNA, a small molecule compound, an anti-CD19 antibody or a fragment thereof, and combinations thereof. [Item 96] The recombinant expression system according to item 92, wherein the CD34 binds to any one or more of CD34-specific siRNA, a small molecule compound, an anti-CD34 antibody or a fragment thereof, and combinations thereof. [Item 97] The recombinant expression system according to item 92, wherein the selection 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. [Item 98] The recombinant expression system according to item 92, wherein the CCR has any one or more of (i) IL-7 cytokine linker IL7Ra, (ii) the extracellular domain of the cytoplasmic domain of IL2Rβ, the IL-RaIL-7 cytokine linker transmembrane domain of IL-7Ra, (iii) IL-7 cytokine linker IL2Rβ, and (iv) combinations thereof. [Item 99] A recombinant expression system having the recombinant polynucleotide according to item 1 co-expressed with an accessory module, The accessory module is selected from the group consisting of 41BBL, CD40L, K13, MC159, cFLIP-L / MRITα, cFLIP-p22, HTLV1 Tax, HTLV2 Tax, HTLV2 Tax2-RS variant, 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 target Brd4, chimeric antigen receptor (CAR), hTERT, heparinase, CAR, inhibitory CAR, and combinations thereof. Recombinant expression system. [Item 100] 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, the recombinant expression system according to item 92 or 99. [Item 101] The cleavable linker is a cleavable linker by self-cleavage, the recombinant expression system according to item 100. [Item 102] Before the nucleotide sequence encoding the cleavable linker, a nucleotide sequence encoding a furin cleavage site, a furin-like cleavage site, or a functional equivalent thereof is located, the recombinant expression system according to item 101. [Item 103] Before the nucleotide sequence encoding the cleavable linker, optionally, a nucleotide sequence encoding a flexible linker is located, the recombinant expression system according to item 100. [Item 104] At least one vector having the recombinant polynucleotide of item 1, A vector 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] 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] The vector according to item 104, having 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. [Item 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 80-99% identical thereto. [Item 108] The vector according to item 104, wherein the vector is an in vitro transcription vector or a vector further having a poly(A) tail or 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] An isolated synthetic immune receptor (SIR) polypeptide or polypeptide heterodimer, (a) A T cell receptor (TCR) constant chain, (i) An amino acid sequence that is at least 98% identical to SEQ ID NO: 3010, has one or more mutations at positions 48, 61, 91, 92, 93, and / or 94, and may have any accessory module. (ii) An amino acid sequence that is at least 98% identical to SEQ ID NO: 3024, has one or more mutations at positions 18, 22, 57, 79, 133, 136, and / or 139, and may have any accessory module. (iii) An amino acid sequence that is at least 98% identical to SEQ ID NO: 3025, has one or more mutations at positions 18, 22, 57, 79, 133, 136, and / or 139, and may have any accessory module. (iv) an amino acid sequence that is at least 98% identical to SEQ ID NO: 3046, 3047, or 3048 and may have any accessory module, (v) an amino acid sequence that is at least 98% identical to SEQ ID NO: 3049 and may have any accessory module, (vi) an amino acid sequence that is at least 98% identical to SEQ ID NO: 3051 or 3052 and may have 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 TCR constant chain having an amino acid sequence selected from the group consisting of (b) any linker, (c) one or more non-natural TCR antigen-binding domains bound to (a), (1) an antibody, (2) an antibody fragment (e.g., Fv, Fab, (Fab’)2), (3) a heavy chain variable region (vH domain) of an antibody or a fragment thereof, (4) a light chain variable region (vL domain) of an antibody 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) a non-immunoglobulin antigen-binding scaffold such as DARPIN, affibody, affilin, adnectin, avidin, obodyz, lipobody, finomer, alphabody, abimer, atrimer, centyrin, pronectin, anticalin, knotted domain, 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-natural TCR antigen-binding domain selected from the group consisting of The variants of (a)(i)-(a)(iii) have diverse binding affinities for the target antigen of the antigen-binding domain, and when the synthetic immune receptor is expressed in lymphocytes, it expresses both the antigen-binding domain and the T cell receptor constant chain on one or more contiguous chains on the surface of the lymphocytes. When the expressed antigen-binding domain binds to its antigen, it is triggered to activate, proliferate, and secrete cytokines and / or regulate (induce or suppress) the death of the target cells, and has MHC-restricted and MHC-unrestricted antibody-type specificities. An isolated synthetic immune receptor (SIR) polypeptide or polypeptide heterodimer. [Item 112] Having the TCR constant chain of (a)(vii), the non-natural TCR binding domain is - The variable regions of the heavy and light chains of an antibody specific for a predetermined target antigen or fragments thereof, where when expressed, one of the heavy and light chains of the antibody or a fragment thereof is attached to one of the two chains of (a)(vii) of the T cell constant region, and the other of the heavy and light chains of the antibody or a fragment thereof is attached to the other of the two chains of the T cell constant region. Variable region, - Two single-chain variable fragments (scFvs) specific for one or more predetermined target antigens, where 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. Single-chain variable fragment, - Two antibody fragments specific for one or more predetermined target antigens, where 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 antibody fragment is attached to the other of the two chains of the T cell constant region. Antibody fragment, - Two single-domain antibody (SDAB) fragments specific for one or more predetermined target antigens, such that 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; and - Two camelid-derived vHH domains specific for one or more predetermined target antigens, such that 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, such that 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, such that 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, such that 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 different antigen-binding fragments specific for one or more predetermined target antigens, which 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 antigen-binding fragment is attached to the other of the two chains of the T cell constant region; and - Two binding fragments, either or both of which are bispecific or multispecific, which 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 antigen-binding fragment is attached to the other of the two chains of the T cell constant region. - Two self-antigens or fragments thereof, which when expressed, one of the self-antigens or fragments thereof is attached to one of the two chains of (a)(vii) of the T cell constant region, and the other self-antigen or fragment thereof is attached to the other of the two chains of the T cell constant region; and - Two vL or fragments thereof, which when expressed, one of the vL or fragments thereof is attached to one of the two chains of (a)(vii) of the T cell constant region, and the other vL or fragment thereof is attached to the other of the two chains of the T cell constant region; and - Two vH or fragments thereof, which when expressed, one of the vH or fragments thereof is attached to one of the two chains of (a)(vii) of the T cell constant region, and the other vH or fragment thereof is attached to the other of the two chains of the T cell constant region; and The isolated synthetic immune receptor (SIR) polypeptide or polypeptide heterodimer according to item 111, selected from the group consisting of. [Item 113] Having the TCR constant chain of (a)(iv), 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) specific for a predetermined target antigen or a fragment thereof; - An antibody fragment specific for a predetermined target antigen (e.g., Fv, Fab, (Fab’)2), - A single domain (SDAB) fragment 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, The isolated synthetic immune receptor (SIR) polypeptide or polypeptide heterodimer according to item 111, selected from the group consisting of. [Item 114] (i), (ii), (iii), (iv), (v), or (vi) having a TCR constant domain, 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, - 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, - An antibody fragment specific for a predetermined target antigen (e.g., Fv, Fab, (Fab’)2), - A single domain (SDAB) fragment 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, The isolated synthetic immune receptor (SIR) polypeptide or polypeptide heterodimer according to item 111, selected from the group consisting of. [Item 115] The TCR constant chain(s), which have mutations that promote the expression and / or pairing of the TCR constant chain and that decrease pairing with the endogenous T cell receptor chain, of the isolated synthetic immune receptor (SIR) polypeptide or polypeptide heterodimer according to item 111. [Item 116] The constant region of the TCR is a TCR receptor α chain (Cα) having an amino acid sequence containing 1 to 40 amino acid substituents or mutants with respect to a sequence selected from the group consisting of SEQ ID NOs: 3010 to 3023, or a sequence having at least 98% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 3010 to 3023, of the isolated synthetic immune receptor (SIR) polypeptide or polypeptide heterodimer according to item 111. [Item 117] The constant region of the TCR is a TCR receptor β chain (Cβ) having an amino acid sequence containing 1 to 40 amino acid substituents or mutants with respect to a sequence selected from the group consisting of SEQ ID NOs: 3024 to 3044, or a sequence having at least 98% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 3024 to 3044, of the isolated synthetic immune receptor (SIR) polypeptide or polypeptide heterodimer according to item 111. [Item 118] The constant region of the TCR is a TCR receptor γ chain (Cγ) having an amino acid sequence containing 1 to 40 amino acid substituents or mutants with respect to a sequence selected from the group consisting of SEQ ID NOs: 3049 to 3050, or a sequence having at least 98% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 3049 to 3050, of the isolated synthetic immune receptor (SIR) polypeptide or polypeptide heterodimer according to item 111. [Item 119] The constant region of the TCR is a TCR receptor δ chain (Cδ) having an amino acid sequence containing 1 to 40 amino acid substituents or mutants with respect to a sequence selected from the group consisting of SEQ ID NOs: 3051 to 3052, or a sequence having at least 98% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 3051 to 3052, of the isolated synthetic immune receptor (SIR) polypeptide or polypeptide heterodimer according to item 111. [Item 120] The constant region of the TCR is a pre-TCR receptor α-chain (pre-Cα) having an amino acid sequence containing 1 to 40 amino acid substituents or variants with respect to a sequence selected from the group consisting of SEQ ID NOs: 3046 to 3048, or a sequence having at least 98% identity to the amino acid sequence selected from the group consisting of SEQ ID NOs: 3046 to 3048, the isolated synthetic immune receptor (SIR) polypeptide or polypeptide heterodimer according to item 111. [Item 121] The one or more non-natural TCR antigen-binding domains that bind to one or more disease-related antigens are CD19; CD123; CD22; CD30; CD171; CS-1 (also called 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; a glycosylated CD43 epitope expressed in acute leukemia or lymphoma but not in hematopoietic progenitor cells, a glycosylated CD43 epitope expressed in non-hematopoietic organ 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; prostate 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 (prososome, macropain) subunit, beta type 9 (LMP2); glycoprotein 100 (gp100);Cancer gene fusion proteins consisting of a readily cleavable region (BCR) and Abelson murine leukemia virus oncogene homolog 1 (Ab1) (bcr-ab1); tyrosine kinase; 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 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 glycosphingolipid (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 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 variant; prostain; survivin; telomerase; prostate cancer tumor antigen 1 (PCT A-1 or galectin 8), melanoma antigen 1 recognized by T cells (MelanA or MARTI); rat sarcoma (Ras) variant; 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; v-myc avian myelocytomatosis viral oncogene homolog, neuroblastoma-derived (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, i.e., Brother of the Regulator of Imprinted Sites), Squamous cell carcinoma antigen recognized by T cells 3 (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 variant (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 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 G12V, tissue factor 1 (TF1), AFP, GPRC5D, claudin 18.2 (CLD18A2 or CLDN18A.2), P - glycoprotein, STEAP1, LIV1, NECTIN - 4, CRIPTO, GPA33, BST1 / CD157, low - conductance chloride ion channel, and an antigen recognized by a TNT antibody, an isolated synthetic immune receptor (SIR) polypeptide or polypeptide heterodimer according to item 111 selected from the group consisting of; [Item 122] The one or more non-natural TCR antigen-binding domains are 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, for example, DARPIN, affibody, affilin, adnectin, avidin, obody, lipobody, finomer, alphabody, avimer, atrimer, centyrin, pronectin, anticalin, knotted domain, armadillo repeat protein, receptor, or ligand, the isolated synthetic immune receptor (SIR) polypeptide or polypeptide heterodimer according to item 121. [Item 123] The one or more non-natural TCR antigen-binding domains are (i) a heavy chain variable region (vH) having a sequence described in any of SEQ ID NOs: 2506 to 2680 or 12160 to 12278 or a sequence having at least 98% identity thereto and encoding a polypeptide that binds to an antigen, (ii) a light chain variable region (vL) having a sequence described in any one of SEQ ID NOs: 2307 to 2482 or 12042 to 12159 or a sequence having at least 98% identity thereto and encoding a polypeptide that binds to an antigen, (iii) a single-chain variable fragment (scFv) having a sequence described in any one of SEQ ID NOs: 2770 to 2939, 12303 to 12357, or 18162 to 18224 or a sequence having at least 98% identity thereto and encoding a polypeptide that binds to an antigen, (iv) a camelid VHH having a sequence described in any one of SEQ ID NOs: 2701 to 2725 or 12279 to 12294 or a sequence having at least 98% identity thereto and encoding a polypeptide that binds to an antigen, (v) A non-immunoglobulin scaffold encoding a polypeptide that is encoded by any one of the sequences set forth in SEQ ID NOs: 439 to 443 or a sequence that is at least 98% identical thereto and binds to the same species, (vi) A receptor having a sequence set forth in any one of SEQ ID NOs: 2736 to 2748 or a sequence that is at least 98% identical thereto and encoding a polypeptide that binds to an antigen, and (vii) A ligand having a sequence set forth in any one of SEQ ID NOs: 2758 to 2768 or 12359 to 12361 or a sequence that is at least 98% identical thereto and encoding a polypeptide that binds to the same species, The isolated synthetic immune receptor (SIR) polypeptide or polypeptide heterodimer according to item 121, selected from the group consisting of [Item 124] The one or more non-natural TCR antigen-binding domains are one or more light chain complementarity determining regions for a selected target antigen as 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 as set forth in any of SEQ ID NOs: 14881 to 15761 or 15762, The isolated synthetic immune receptor (SIR) polypeptide or polypeptide heterodimer according to item 111. [Item 125] The one or more non-natural TCR antigen-binding domains have up to 10 conservative amino acid substitutions and contain a variable light chain (vL) domain having a sequence of any one of SEQ ID NOs: 2307 to 2482 or 12042 to 12159, and / or have up to 10 conservative amino acid substitutions and contain a variable heavy chain (vH) domain having a sequence of any one of SEQ ID NOs: 2506 to 2680 or 12160 to 12278, The isolated synthetic immune receptor (SIR) polypeptide or polypeptide heterodimer according to item 111. [Item 126] The one or more non-natural TCR antigen-binding domains have up to 10 conservative amino acid substitutions and have one or more camelid vHH complementarity determining regions for a selected antigen as set forth in any of SEQ ID NOs: 2701 to 2725 or 12279 to 12294, The isolated synthetic immune receptor (SIR) polypeptide or polypeptide heterodimer according to item 111. [Item 127] The one or more non-natural TCR antigen-binding domains have the sequences set forth in either SEQ ID NOs: 2728-2732 or 12296-12301, and have a non-immunoglobulin antigen-binding domain containing up to 10 conservative amino acid substitutions, the isolated synthetic immune receptor (SIR) polypeptide or polypeptide heterodimer according to item 111. [Item 128] The one or more non-natural TCR antigen-binding domains have one or more light chain complementarity-determining regions of a variable light chain (vL) domain having one of the sequences 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 one of the sequences of SEQ ID NOs: 2506-2680 or 12160-12278, and have a scFv domain, the isolated synthetic immune receptor (SIR) polypeptide or polypeptide heterodimer according to item 111. [Item 129] The one or more non-natural TCR antigen-binding domains each have up to 10 conservative amino acid substitutions and have a scFv fragment containing a sequence selected from the group consisting of SEQ ID NOs: 2770-2939, 12303-12357, or 18162-18224, the isolated synthetic immune receptor (SIR) polypeptide or polypeptide heterodimer according to item 111. [Item 130] The one or more non-natural TCR antigen-binding domains have up to 10 conservative amino acid substitutions and have one or more receptors consisting of any of the amino acid sequences of SEQ ID NOs: 2736-2748, the isolated synthetic immune receptor (SIR) polypeptide or polypeptide heterodimer according to item 111. [Item 131] The one or more non-natural TCR antigen-binding domains have up to 10 conservative amino acid substitutions and have one or more ligands containing any of the sequences of SEQ ID NOs: 2758-2768 or 12359-12361, the isolated synthetic immune receptor (SIR) polypeptide or polypeptide heterodimer according to item 111. [Item 132] The one or more non-natural TCR antigen-binding domains have the extracellular domain of CD16A, NKG2D, CD4, PD1, desmoglein 3 (Dsg3), or CD4-DC-SIGN, the isolated synthetic immune receptor (SIR) polypeptide or polypeptide heterodimer according to item 111. [Item 133] The one or more non-natural TCR antigen-binding domains are the isolated synthetic immune receptor (SIR) polypeptide or polypeptide heterodimer according to item 111, having one or more extracellular domains of hTPO, mTPO, CGHα chain, CGHβ chain, FHβ chain, TSHβ chain, APRIL, or a combination thereof. [Item 134] The one or more non-natural TCR antigen-binding domains are any single-chain variable fragment (scFv) having a sequence of any 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 having up to 10 conservative amino acid substitutions and having a sequence described in any of SEQ ID NOs: 2701-2725 or 12279-12294, or b) any non-immunoglobulin antigen-binding domain having a sequence described 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 an amino acid sequence of any of SEQ ID NOs: 2736-2748 and having up to 10 conservative amino acid substitutions, or d) any extracellular domain of a ligand having a sequence of any of SEQ ID NOs: 2758-2768 or 12359-12361 and having up to 10 conservative amino acid substitutions, and are the isolated synthetic immune receptor (SIR) polypeptide or polypeptide heterodimer according to item 111. [Item 135] The one or more non-natural TCR antigen-binding domains are any camelid vHH having up to 10 conservative amino acid substitutions and having a sequence described in any of SEQ ID NOs: 2701-2725 or 12279-12294, and a) any single-chain variable fragment (scFv) having a 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 a sequence described 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 an amino acid sequence of any of SEQ ID NOs: 2736-2748 and having up to 10 conservative amino acid substitutions, or d) having a conservative amino acid substitution up to 10 and any extracellular domain of a ligand having any sequence of SEQ ID NOs: 2758 to 2768 or 12359 to 12361, An isolated synthetic immune receptor (SIR) polypeptide or polypeptide heterodimer according to item 111, having [Item 136] Each of the one or more non-natural TCR antigen-binding domains is 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 that is 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 that is at least 98% identical thereto. An isolated synthetic immune receptor (SIR) polypeptide or polypeptide heterodimer according to item 111. [Item 137] 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 that of the antibody from which it was obtained. An isolated synthetic immune receptor (SIR) polypeptide or polypeptide heterodimer according to item 111. [Item 138] The polynucleotide encoding the SIR further has a leader sequence or signal peptide present at the N-terminus of each strand and having a sequence selected from the group consisting of SEQ ID NOs: 1 to 9 and 10. An isolated synthetic immune receptor (SIR) polypeptide or polypeptide heterodimer according to item 111. [Item 139] The SIR has an SIR heterodimer. An isolated synthetic immune receptor (SIR) polypeptide or polypeptide heterodimer according to item 111. [Item 140] The polypeptide has two SIRs linked by a cleavable linker. An isolated synthetic immune receptor (SIR) polypeptide or polypeptide heterodimer according to item 111. [Item 141] The cleavable linker is a cleavable linker by self-cleavage. An isolated synthetic immune receptor (SIR) polypeptide or polypeptide heterodimer according to item 140. [Item 142] The cleavable linker of the isolated synthetic immune receptor (SIR) polypeptide or polypeptide heterodimer according to item 140 is any one or more of a 2A linker, a 2A-like linker, or a functional equivalent thereof. [Item 143] The cleavable linker of the isolated synthetic immune receptor (SIR) polypeptide or polypeptide heterodimer according to item 140 is any one or more of a T2A linker, a P2A, an F2A, an E2A linker, or a functional equivalent thereof. [Item 144] The cleavable linker of the isolated synthetic immune receptor (SIR) polypeptide or polypeptide heterodimer according to item 140 has any one or more of the sequences of SEQ ID NOs: 780-785. [Item 145] Optionally, a Furin cleavage site, a Furin-like cleavage site, or a functional equivalent thereof is located in front of the cleavable linker of the isolated synthetic immune receptor (SIR) polypeptide or polypeptide heterodimer according to item 140. [Item 146] The Furin cleavage site preceding the cleavable linker has any one or more of the sequences of SEQ ID NOs: 788-790 in the isolated synthetic immune receptor (SIR) polypeptide or polypeptide heterodimer according to item 145. [Item 147] A flexible linker is located in front of the cleavable linker of the isolated synthetic immune receptor (SIR) polypeptide or polypeptide heterodimer according to any one of items 140-146. [Item 148] 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 in the isolated synthetic immune receptor (SIR) polypeptide or polypeptide heterodimer according to item 147. [Item 149] The flexible linker preceding the cleavable linker has the sequences of SEQ ID NOs: 786-787 in the isolated synthetic immune receptor (SIR) polypeptide or polypeptide heterodimer according to item 147. [Item 150] The isolated synthetic immune receptor (SIR) polypeptide or polypeptide heterodimer according to item 147, wherein the order is a Furin cleavage site, a flexible linker, and a cleavable linker, and the flexible linker is located behind the Furin cleavage site, and the cleavable linker is located behind the flexible linker. [Item 151] The isolated synthetic immune receptor (SIR) polypeptide or polypeptide heterodimer according to item 111, wherein the SIR is designed to have diverse binding affinities for a selected antigen. [Item 152] An immune effector cell or stem cell having at least one polypeptide or heterodimer according to item 111. [Item 153] An immune effector cell or stem cell having at least one recombinant polynucleotide according to item 1. [Item 154] An immune effector cell or stem cell having at least one vector according to item 104. [Item 155] An immune effector cell or stem cell according to any one of items 152 to 154, having a plurality of SIR polypeptides. [Item 156] The immune cell or stem cell according to item 155, wherein at least one SIR polypeptide among the plurality of SIR polypeptides targets an antigen different from at least one other SIR polypeptide. [Item 157] The immune cell or stem cell according to item 155, wherein at least one SIR polypeptide among the plurality of SIR polypeptides targets the same antigen. [Item 158] The immune cell or stem cell according to item 157, wherein at least one SIR polypeptide among the plurality of SIR polypeptides has a binding affinity for an antigen different from at least one other SIR polypeptide. [Item 159] The immune cell or stem cell according to any one of items 152 to 154, wherein the immune cell further has at least one chimeric antigen receptor (CAR) polypeptide. [Item 160] The immune cell or stem cell according to item 159, wherein the antigen-binding domain of the SIR polypeptide targets an antigen different from the antigen-binding domain of the CAR polypeptide. [Item 161] The immune cell or stem cell according to item 159, wherein the CAR polypeptide has an intracellular signaling domain that includes a costimulatory signaling domain but does not include a first signaling domain, or has an intracellular signaling domain that includes a first signaling domain but does not include a costimulatory signaling domain. [Item 162] The immune cell or stem cell according to item 161, wherein the CAR polypeptide has a costimulatory signaling domain that includes 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 includes a functional signaling domain of CD3ζ. [Item 163] The immune cell or stem cell according to item 159, wherein the CAR polypeptide is an inhibitory CAR polypeptide, the inhibitory CAR polypeptide 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] The immune cell or stem cell according to item 159, wherein the CAR polypeptide further has an intracellular signaling domain that includes a first signaling domain and / or an intracellular signaling domain, and the intracellular signaling domain has a first signaling domain that includes a functional domain of CD3ζ and a costimulatory signaling domain that includes a functional domain of 4-1BB and / or CD28. [Item 165] The immune cell or stem cell according to item 159, wherein the CAR polypeptide has an amino acid sequence of SEQ ID NO: 3077 to SEQ ID NO: 3083. [Item 166] The immune effector cell is optionally a human T cell, human NKT cell, or synthetic T cell capable of generating an immune effector cell, or a stem cell, and the T cell has diacylglycerol kinase (DGK) and / or Ikaros deficiency and / or Brd4 deficiency. The immune cell or stem cell according to any one of items 152 to 154. [Item 167] A population of immune cells or effector cells as described in item 152, which is a population of immune cells or effector cells having a plurality of different SIR polypeptides. [Item 168] The population of immune cells or effector cells according to item 167, wherein the plurality of different SIR polypeptides have different sequences but bind to the same target antigen. [Item 169] The population of immune cells or effector cells according to item 167, wherein the population of cells has SIR polypeptides targeting different antigens present in a specific disease type. [Item 170] A method for producing SIR-expressing immune effector cells, comprising the step of introducing at least one vector according to item 104 or at least one recombinant polynucleotide according to item 1 into immune effector cells, or hematopoietic stem cells or progenitor cells capable of generating immune effector cells, under conditions where the SIR polypeptide is expressed. [Item 171] a) providing a population of immune effector cells; b) removing regulatory T cells from the population, thereby providing regulatory T cell-depleted cells; further comprising, wherein steps a) and b) are performed before introducing the vector or the recombinant polynucleotide encoding the SIR into the population, The method according to item 170. [Item 172] The method according to item 171, wherein the regulatory 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 the population, thereby providing a population of P-glycoprotein (P-gp or Pgp, MDR1, ABCB1, CD243)-enriched cells; further comprising, wherein steps a) and b) are performed before or after introducing the vector or the recombinant polynucleotide encoding the SIR, [Item 174] P-glycoprotein-positive cells are i) immunoselected using one or more of a cocktail of steps specific for P-glycoprotein ii) Under the condition that the P-glycoprotein is active as a pump, staining with one or more of the fluorescent dyes that are substrates of the P-glycoprotein, tetramethylrhodamine methyl ester (TMRM), adriamycin, and actinomycin D, and concentrating the cells that are difficult to be stained with the dye; iii) Selection of cells resistant to any one or more of the phototoxic compounds that are substrates of the P-glycoprotein, such as TH9402, methyl 2-(4,5-dibromo-6-amino-3-imino-3H-xanthen-9-yl)benzoate hydrochloride, ethyl 2-(4,5-dibromo-6-amino-3-imino-3H-xanthen-9-yl)benzoate hydrochloride, octyl 2-(4,5-dibromo-6-amino-3-imino-3H-xanthen-9-yl)benzoate hydrochloride, n-butyl 2-(4,5-dibromo-6-amino-3-imino-3H-xanthen-9-yl)benzoate hydrochloride, n-butyl 2-(6-ethylamino-3-ethylimino-3H-xanthen-9-yl)benzoate hydrochloride, or derivatives thereof, or combinations thereof; iv) Selection of cells resistant to cytotoxic compounds that are substrates of the P-glycoprotein, such as vincristine, vinblastine, taxol, paclitaxel, mitoxantrone, etoposide, adriamycin, daunorubicin, and actinomycin D; The method according to item 173, which is concentrated using any one or more of the methods selected from the group consisting of. [Item 175] A method for generating a population of recombinant RNA cells, comprising: introducing in vitro transcribed RNA(s) or synthetic RNA(s) into a cell or a population of cells, wherein the RNA(s) has the recombinant polynucleotide(s) described in item 1; method. [Item 176] A method for 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 described in 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] The method according to item 176, wherein the allogeneic T cells, or allogeneic NKT cells, or hematopoietic stem cells, or iPSCs lack the expression of functional TCR or functional HLA, or have low such expression. [Item 178] A composition comprising an immune effector cell or a stem cell capable of generating an immune effector cell having one or more synthetic immune receptors (SIRs) for use in combination with an agent that increases the effect of the immune effector cell in the treatment of a subject having a disease associated with the expression of a disease-related antigen or in the prevention of a disease in a subject at increased risk of a disease associated with the expression of a disease-related antigen, (i) The SIR molecule has one or more T cell receptor constant chains that bind through an optional linker to one or more antigen-binding domains that bind to a disease-related antigen, and the disease-related antigen is CD5, CD19; CD123; CD22; CD30; CD171; CS-1 (also called 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 organ cancer; 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; prostate acid phosphatase (PAP); elongation factor 2 variant (ELF2M); Ephrin B2; fibroblast activation protein alpha (FAP); insulin-like growth factor 1 receptor (IGF-1 receptor), carbonic anhydrase IX (CAIX);Proteasome (prososome, macropain) subunit, beta type 9 (LMP2); glycoprotein 100 (gp100); oncogene fusion protein consisting of breakpoint cluster region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (Ab1) (bcr - ab1); tyrosine kinase; 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 glycosphingolipid (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); 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 variant; prostain; survivin; telomerase;Prostate cancer antigen 1 (PCT A-1 or galectin 8), melanoma antigen 1 recognized by T cells (MelanA or MARTI); rat sarcoma (Ras) variant; human telomerase reverse transcriptase (hTERT); sarcoma translocation breakpoint; melanoma inhibitor of apoptosis (ML-IAP); ERG (membrane-spanning protease, serine 2 (TMPRSS2) ETS fusion gene); N-acetylglucosaminyltransferase V (NA17); paired box protein Pax-3 (PAX3); androgen receptor; cyclin B1; v-myc avian myelocytomatosis viral oncogene homolog from neuroblastoma (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 i.e., 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); regucalcin; human papillomavirus E6 (HPV E6); human papillomavirus E7 (HPV E7); intestinal carboxylesterase; heat shock protein 70-2 variant (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, 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, low-conductance chloride ion channel, and an antigen recognized by a TNT antibody, (ii) The agent for increasing the effect of the immune cell is - a protein phosphatase inhibitor, and - a kinase inhibitor (e.g., a PI3K / AKT inhibitor, an mTOR inhibitor, an LCK inhibitor, or a BTK inhibitor), and - a cytokine, and - an inhibitor of an immunosuppressive molecule, and -T REG an agent that reduces the level or activity of cells, and - an agent that increases the proliferation and maintenance of SIR-modified cells, and - a chemokine, and - an agent that increases the expression of SIR, and - an agent that enables the regulation of the expression or activity of SIR, and - an agent that enables the control of the survival and / or maintenance of SIR-modified cells, and - an agent that controls the side effects of SIR-modified cells, and - a Brd4 inhibitor, and - an agent that delivers a therapeutic agent (e.g., sHVEM) or a prophylactic agent to the site of the disease, and - an agent that increases the expression of the antigen targeted by SIR, and - an adenosine A2a receptor antagonist, selected from one or more of the composition. [Item 179] A method for treating or preventing a disease associated with the expression of a disease-related antigen in a subject, 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 effect of the immune cells, (i) The SIR molecule has one or more T cell receptor constant chains that are bound through an optional linker to one or more antigen-binding domains that bind to a disease-related antigen, and the disease-related antigen is CD5, CD19; CD123; CD22; CD30; CD171; CS-1 (also called 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; a glycosylated CD43 epitope that is expressed in acute leukemia or lymphoma but not in hematopoietic progenitor cells, a glycosylated CD43 epitope that is expressed in non-hematopoietic organ 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; prostate acid phosphatase (PAP); elongation factor 2 variant (ELF2M); ephrin B2; fibroblast activation protein alpha (FAP); insulin-like growth factor 1 receptor (IGF-1 receptor), carbonic anhydrase IX (CAIX);Proteasome (prososome, macropain) subunit, beta type 9 (LMP2); glycoprotein 100 (gp100); oncogene fusion protein consisting of breakpoint cluster region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (Ab1) (bcr-ab1); tyrosine kinase; 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); hexasaccharide moiety of globo H glycosphingolipid (GloboH); breast 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-ESO-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 variant; prostain; survivin; telomerase;Prostate cancer antigen 1 (PCT A-1 or galectin 8), melanoma antigen 1 recognized by T cells (MelanA or MARTI); rat sarcoma (Ras) variant; human telomerase reverse transcriptase (hTERT); sarcoma translocation breakpoint; melanoma inhibitor of apoptosis (ML-IAP); ERG (membrane-spanning protease, serine 2 (TMPRSS2) ETS fusion gene); N-acetylglucosaminyltransferase V (NA17); paired box protein Pax-3 (PAX3); androgen receptor; cyclin B1; v-myc avian myelocytomatosis viral oncogene homolog from neuroblastoma (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 ubiquitin 1 (RU1); renal ubiquitin 2 (RU2); regucalcin; human papillomavirus E6 (HPV E6); human papillomavirus E7 (HPV E7); intestinal carboxylesterase; heat shock protein 70-2 variant (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, 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 G12V, tissue factor 1 (TF1), AFP, GPRC5D, claudin 18.2 (CLD18A2 or CLDN18A.2), P-glycoprotein, STEAP1, LIV1, NECTIN-4, CRIPTO, GPA33, BST1 / CD157, low-conductance chloride ion channel, and an antigen recognized by a TNT antibody, selected from the group consisting of; (ii) the agent for increasing the effect of the immune cells is - 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, -T REG an agent that reduces the level or activity of 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 the regulation of the expression or activity of SIR, - an agent that enables 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 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, - an adenosine A2a receptor antagonist, selected from one or more of the above, thereby treating the subject or preventing the disease of the subject, method. [Item 180] A method for treating or preventing a disease associated with the expression of a disease-related 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 has one or more T cell receptor constant chains that are bound through an optional linker to one or more antigen-binding domains that bind to a disease-related antigen, and the disease-related antigen is CD5, CD19; CD123; CD22; CD23; CD30; CD171; CS-1 (also called 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; a glycosylated CD43 epitope that is expressed in acute leukemia or lymphoma but not in hematopoietic progenitor cells, a glycosylated CD43 epitope that is expressed in non-hematopoietic organ 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; prostate acid phosphatase (PAP); elongation factor 2 variant (ELF2M); ephrin B2; fibroblast activation protein alpha (FAP);Insulin-like growth factor 1 receptor (IGF-1 receptor), carbonic anhydrase IX (CAIX); proteasome (prososome, macropain) subunit, beta type 9 (LMP2); glycoprotein 100 (gp100); oncogene fusion protein consisting of a cleavage region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (Ab1) (bcr-ab1); tyrosine kinase; 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 glycosphingolipid (GloboH); breast 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); TCRγ alternative reading frame protein (TARP); Wilms tumor protein (WT1); cancer / testis antigen 1 (NY-ESO-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 variant; prostain; survivin; telomerase;Prostate cancer antigen 1 (PCT A-1 or galectin 8), melanoma antigen 1 recognized by T cells (MelanA or MARTI); rat sarcoma (Ras) variant; 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; v-myc avian myelocytomatosis viral oncogene homolog from neuroblastoma (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 i.e., 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); regucalcin; human papillomavirus E6 (HPV E6); human papillomavirus E7 (HPV E7); intestinal carboxylesterase; heat shock protein 70-2 variant (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, 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), 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 G12V, tissue factor 1 (TF1), AFP, GPRC5D, claudin 18.2 (CLD18A2 or CLDN18A.2), P-glycoprotein, STEAP1, LIV1, NECTIN-4, CRIPTO, GPA33, BST1 / CD157, low-conductance chloride ion channel, and an antigen recognized by a TNT antibody, selected from the group consisting of; (ii) the antigen-binding domain of the SIR molecule has a binding affinity that is at least 5-fold less than that of an antibody that induced the antigen-binding domain, method. [Item 181] The disease associated with the expression of the disease-related antigen is selected from the group consisting of proliferative diseases, pre-cancerous conditions, cancers, and non-cancer-related indications associated with the expression related to the disease, the use or method according to any one of Items 178 to 180. [Item 182] The cancer in the use or method according to item 183 is a blood cancer selected from one or more of 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 myelogenous leukemia (CML), B-cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt lymphoma, diffuse large B-cell lymphoma, primary effusion lymphoma, follicular lymphoma, hairy cell lymphoma, small cell or large cell follicular lymphoma, malignant lymphoproliferative disorders, MALT lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndromes, non-Hodgkin lymphoma, Hodgkin lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenström macroglobulinemia, and preleukemia. [Item 183] The cancer in the use or method according to item 183 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, head or neck cancer, cutaneous or uveal malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal area, gastric cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin lymphoma, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, solid tumors in children, bladder cancer, cancer of the kidney or ureter, renal pelvic cancer, tumors of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal cord axis tumors, brainstem glioma, pituitary adenoma, Kaposi sarcoma, Merkel cell carcinoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancer, combinations of the foregoing cancers, and metastatic lesions of the foregoing cancers. [Item 184] The disease is associated with viral infection and includes, but is 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, Zika virus, RSV, measles virus, mumps virus, rhinovirus, varicella virus types 1 and 2, varicella - zoster virus, HIV - 1, HTLV1, hepatitis virus, enterovirus, hepatitis B virus, hepatitis C virus, Nipah and Rift Valley fever virus, Japanese encephalitis virus, Merkel cell polyomavirus or a virus associated with mycobacterial tuberculosis infection, atypical mycobacterial species, Pneumocystis jirovecii, toxoplasmosis, rickettsia, Nocardia, Aspergillus, Mucor, and Candida, the use or method according to item 183. [Item 185] The disease is an immune disease or a degenerative disease and includes, but is not limited to, type 1 diabetes, 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, the use or method according to item 183. [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 dual PI3K / mTOR inhibitor, (iii) The agent that inhibits the immunosuppressive factor includes an antibody or antibody fragment, an inhibitory nucleic acid, a clustered regularly interspaced short palindromic repeat (CRISPR), a TAL effector nuclease (TALEN), or a zinc finger endonuclease (ZFN) that inhibits the expression of the inhibitory molecule. (iv) The agent that reduces the level or activity of the Treg cells is selected from cyclophosphamide, 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 US Patent No. 20140256706A1, or derivatives thereof, The use or method according to any one of items 178 to 180 or 182 to 184. [Item 187] 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, and the use or method according to any one of items 178 to 180 or 182 to 184. [Item 188] The agent that inhibits the inhibitory molecule has a first polypeptide containing the inhibitory molecule or a fragment thereof and a second polypeptide that provides a positive signal to the cell, and the first and second polypeptides are expressed on the SIR-containing immune cells, 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 containing a first signaling domain and / or a costimulatory signaling domain, and the use or method according to any one of items 178 to 180 or 182 to 184. [Item 189] The use or method according to item 188, wherein the first signaling domain has a functional domain of CD3ζ, and / or the costimulatory signaling domain has a functional domain of a protein selected from 41BB, CD27, and CD28. [Item 190] The cytokine is selected from IL-15 and / or IL-21, and the use or method according to any one of items 178 to 180 or 182 to 184. [Item 191] The use or method according to any one of items 178 to 180 or 182 to 184, wherein the immune effector cell(s) comprising the SIR molecule(s) and the agent that increases the effect of the immune effector cell are administered substantially simultaneously or sequentially. [Item 192] The use or method according to item 191, wherein the SIR molecule is administered in combination with a molecule that targets GITR and / or a molecule that regulates GITR function. [Item 193] The use or method according to item 192, wherein the molecule that targets GITR and / or the molecule that regulates GITR function is administered before the SIR-expressing cell or cell population or before apheresis. [Item 194] The use or method according to any one of items 178 to 180 or 182 to 184, wherein the subject is a human. [Item 195] A composition comprising at least one polynucleotide according to item 1, the SIR polypeptide molecule according to item 111, the vector according to item 104 or the cell according to any one of items 152 to 153, and a pharmaceutically acceptable excipient. Composition. [Item 196] A kit comprising at least one polynucleotide according to item 1, the SIR polypeptide molecule according to item 111, the vector according to item 104 or the cell according to any one of items 152 to 153, and / or the composition according to item 144. Kit. [Item 197] A recombinant polynucleotide comprising Having a sequence selected from the group consisting of SEQ ID NOs: 900 to 2264, SEQ ID NOs: 4531 to 6013, SEQ ID NOs: 7519 to 8160, SEQ ID NOs: 8803 to 9230, SEQ ID NOs: 9659 to 9856, SEQ ID NOs: 10474 to 12041, SEQ ID NOs: 15786 to 16011, SEQ ID NOs: 16240 to 16465, SEQ ID NOs: 16694 to 16926, SEQ ID NOs: 17162 to 17394, SEQ ID NOs: 17864 to 17979, SEQ ID NOs: 18321 to 18322, SEQ ID NOs: 18242 to 18259, SEQ ID NOs: 18280 to 18588, SEQ ID NO: 18899, and SEQ ID NOs: 18915 to 18916, and SEQ ID NOs: 19248 to 19246, or having a sequence that is at least 75% identical to the nucleotide sequence encoding the synthetic immunoreceptor set forth in any one of SEQ ID NOs: 900 to 2264, SEQ ID NOs: 4531 to 6013, SEQ ID NOs: 7519 to 8160, SEQ ID NOs: 8803 to 9230, SEQ ID NOs: 9659 to 9856, SEQ ID NOs: 10474 to 12041, SEQ ID NOs: 15786 to 16011, SEQ ID NOs: 16240 to 16465, SEQ ID NOs: 16694 to 16926, SEQ ID NOs: 17162 to 17394, SEQ ID NOs: 17864 to 17979, SEQ ID NOs: 18321 to 18322, SEQ ID NOs: 18242 to 18259, SEQ ID NOs: 18280 to 18588, SEQ ID NO: 18899, and SEQ ID NOs: 18915 to 18916, and SEQ ID NOs: 19248 to 19246, encoding a synthetic immunoreceptor A recombinant polynucleotide. [Item 198] An amino acid sequence 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 the amino acid sequence encoding the synthetic immunoreceptor polypeptide described in any one 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 Amino acid sequence.

Brief Description of the Drawings

[0031] Details of one or more embodiments of the present invention are described below by the accompanying drawings and the description herein. Other features, objects, and advantages of the present invention will be apparent from the description herein, the drawings, and the claims.

[0032]

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BEST MODE FOR CARRYING OUT THE INVENTION

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

[0034] Furthermore, unless otherwise specified, the term "or" means "and / or." Similarly, the terms "having," "have," "including," and "include" are synonymous with each other and have no limiting meaning.

[0035] When the term "have" is used in the description of various embodiments, in certain cases, one of ordinary skill in the art will understand that a particular embodiment may alternatively be described using the terms "consisting essentially of" or "consisting of," and this point should also be further understood.

[0036] Unless otherwise specified, all technical and scientific terms used in this specification 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) provide the skilled artisan with general guidance regarding many of the terms used in this application.For references regarding methods of preparing antibodies, see Greenfield, Antiboides 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 Jul, 6(7):511-9, Queen and Selick, Humanized Immunoglobulins, U.S. Patent No. 5,585,089, and Riechmann et al., Reshaping human antibodies for therapy, Nature 1988 Mar 24, 332(6162):323-7. All of the titles and subtitles provided herein are for ease of reading only and should not be construed as limiting the present 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, the appropriate methods and materials are as described below. All publications, patent applications, patents, and other references described herein are hereby incorporated 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 for illustrative purposes only and have no limiting meaning whatsoever.

[0037] The synthetic immune receptors (SIRs) of the present disclosure have an antigen-binding domain (e.g., an antibody or antibody fragment) capable of binding to an antigen, e.g., in an MHC-dependent or MHC-independent manner. Peptides derived from endogenous proteins typically fill the pockets 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 in immunotherapy. TCR-like antibody target peptides derived from viral or tumor antigens have been described in the context of human leukocyte antigen (HLA)-A1 or HLA-A2 (see, e.g., Sastry et al., J. Viral. 201185(5):1935-1942, Sergeeva et al., Blood, 2011, 117(6):4262-4272, Verma et al., JImmunol, 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 a synthetic immune receptor (SIR) comprising an antigen-binding site operably linked to a T cell receptor domain. Further, 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., an antibody, an antibody fragment, a non-immunoglobulin antigen-binding domain, a self-antigen, a ligand, or a receptor) that bind to an antigen or a target molecule (further described herein below) and bind to one or more T cell receptor constant chains (including variants or modifications thereof). The antigen-binding domain(s) of the SIR specifically bind to one or more disease-related antigens or allogeneics described herein, in which case the coding sequence of each of the antigen-binding domains is operably linked to the nucleic acid sequence encoding each of the T cell receptor constant chains to which it binds, such that the antigen-binding domain is operably expressed with the T cell constant chain. 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 that each bind to a separate T cell receptor constant chain. For example, antigen-binding domain 1 binds to the constant chain of the T cell receptor α (TCRα) to form "functional unit 1", and antigen-binding domain 2 binds to the constant chain of the T cell receptor β (TCRβ) to form "functional unit 2". The two functional units of such SIR are co-expressed in the same cell and functionally activated (e.g., heterodimerized). In some embodiments, the SIR has an antigen-binding domain (functional unit 1) that binds to one T cell receptor constant chain in a frame unit, which is co-expressed with a second T cell receptor constant chain. The purpose of the second T cell receptor constant chain in such 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 having an epitope tag (e.g., MYC, V5, AcV5, G4Sx2, StrepTagII, etc.), or as a fusion protein having any irrelevant protein fragment (e.g., vL or vH fragment) that does not interfere with the assembly and function of functional unit 1.For example, SIR may have an antigen-binding domain 1 that is operably linked in-frame to the constant chain of the T cell receptor α (TCRα), and the empty (i.e., lacking an antigen-binding domain) constant chain of the T cell receptor β (TCRβ). Two functional units of such SIR are co-expressed in the same cell and are functionally activated. In some embodiments, the two functional units of SIR are co-expressed by transduction of a single polynucleotide encoding both functional units, and 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 SIR are inserted into a single locus, and in other embodiments, the two functional units are inserted into two loci. For example, in some embodiments, both functional units may be inserted into the TCRα constant chain (TRAC) and expressed as a single polynucleotide. In other embodiments, functional unit 1 may be inserted into the TCRα constant chain (TRAC), and functional unit 2 may be inserted into the TCR constant chain β1 (TRBC1). In some embodiments, the two functional units of SIR are co-expressed by transduction of a single polynucleotide encoding both functional units, and in other embodiments, they are co-expressed by transduction of two different polynucleotides each encoding one functional unit. In some embodiments, SIR has an antigen-binding domain (functional unit 1) that binds to one T cell receptor constant chain in-frame, which is co-expressed with a second T cell receptor constant chain. The purpose of the second T cell receptor constant chain in such 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, or as a fusion protein having an epitope tag (e.g., MYC, V5, AcV5, G4Sx2, StrepTagII, etc.), or as a fusion protein having any irrelevant protein fragment (e.g., vL or vH fragment) that does not interfere with the assembly and function of functional unit 1.For example, the SIR may have an antigen-binding domain 1 that is operably linked in frame to the constant chain of the T cell receptor α (TCRα), and an empty (i.e., lacking an antigen-binding domain) constant chain of the T cell receptor β (TCRβ). The two functional units of such SIR are co-expressed in the same cell and are functionally activated. In some embodiments, the two functional units of the SIR are co-expressed using a single vector, and 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, and in other embodiments, they 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 FIGS. 3-8.

[0039] The present disclosure provides a class of chimeric T cell receptors (synthetic immune receptors (SIRs)) that can be used in adoptive cell therapies 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 and effectively utilize the physiological T cell receptor signaling pathway and thus are less likely to give rise to complications associated with CARs, 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 self-aggregation of the antigen-binding domain, a reduced likelihood of persistent signaling, and a reduced likelihood of early T cell exhaustion. The SIRs of the present disclosure include one or more antigen-binding domains fused to the constant chain of TCRα (Cα), TCRβ (Cβ), TCRδ (Cδ), TCRγ (Cγ), or pre-TCRα (Cα) (including the aforementioned variants and modifications). The antigen-binding domain may have an antibody or antibody fragment, vL and / or vH fragments of an antibody, scFv fragments derived from an antibody, single-domain antibodies, affibodies, DARPins, any antigen-binding ligand or receptor, autoantigen, or any other non-immunoglobulin antigen-binding fragment. The antigen-binding domain may target a single antigen or multiple antigens (bispecific or multispecific SIR). The TCR constant domain of the SIR may be expressed alone, but is usually expressed in pairs (e.g., Cα and Cβ, pre-Cα and Cβ, Cδ and Cγ, etc.) to promote optimal cell surface expression. The TCR constant chain fragment is usually codon-optimized to allow for optimal cell surface expression. The TCR constant fragment may have additional variants or substituents for promoting optimal expression and pairing with complementary chains, and / or reducing pairing with endogenous TCR chains, and / or stabilizing the interaction between antibody-binding domains. The SIR may express one or more additional domains (e.g., Myc, streptag, V5, FLAG, Ritx tag, etc.) as a fusion protein.The SIR 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 combinations of the above methods. Optimized vectors for SIR delivery are also disclosed. The SIR of the present disclosure may be expressed such that it is under the control of an endogenous promoter (e.g., TCRα or TCRβ promoter). In some embodiments, the SIR of the present disclosure is expressed using an exogenous promoter (e.g., CMV promoter). Further, the SIR 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 protein, etc.), molecules that promote T cell proliferation, maintenance, expansion, and activation (e.g., 41BBL, CD40L, IL12f, K13, Tax, Tax2, MC159L, cFLIP, scFV targeting PD1, shRNA targeting BRD4, etc.), molecules that reduce toxicity (e.g., vHH or scFV targeting IL6R, IL6, TNFα, etc.), selection markers (e.g., tEGFR, tEGFRvIII, tBCMA, tCD19, etc.), and / or suicide genes (e.g., icaspase9, HSV thymidine kinase). The SIR 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 generate immune effector cells. The present disclosure also provides subsets of immune effector cells for SIR expression, and methods for activation and expansion of immune effector cells expressing SIR. Further, the present disclosure describes agents that improve the activation and maintenance of immune effector cells expressing SIR or reduce their toxicity. 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] When referring to measurable values such as amounts and times, the term "about" includes variations of + / - 20%, in some cases + / - 10%, in some cases + / - 5%, in some cases + / - 1%, and in some cases + / - 0.1% from a specific value, when suitable for carrying out the methods of the present disclosure or describing the compositions herein. Further, any value or range (e.g., less than 20, or similar terms) explicitly includes every integer between and up to such values. Thus, for example, "1 to 5 variants" explicitly includes 1, 2, 3, 4, and / or 5 variants.

[0041] The term "accessory module" means one or more of 41BBL, CD40L, K13, MC159, cFLIP-L / MRITα, cFLIP-p22, HTLV1 Tax, HTLV2 Tax, HTLV2 Tax-RS variant, FKBPx2-K13, FKBPx2-HTLV2-Tax, FKBPx2-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, hRNA targeting sBrd4, and combinations thereof co-expressible with SIR. The accessory module can be co-expressed with SIR using a single vector or two or more different vectors. In one embodiment, the accessory module has an 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 other embodiments, 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 are specific for an autoantigen.

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

[0044] The term "antibody fragment" means at least a portion of an antibody that retains the ability to specifically interact (e.g., by binding, steric hindrance, stabilization / destabilization, spatial distribution, etc.) with an epitope of an antigen. Examples of antibody fragments include, but are not limited to, Fab, Fab’, F(ab’)2, 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, bispecific antibodies formed from antibody fragments such as a bivalent fragment having two Fab fragments linked by a disulfide bridge in the hinge region, isolated CDRs, or other epitope-binding fragments of an antibody. The antigen-binding fragment may be incorporated into a single-domain antibody, a maxibody, a minibody, a nanobody, an intrabody, a diabody, a triabody, a tetrabody, v-NAR, and a bis-scFv (see, e.g., Hollinger and Hudson, Nature Biotechnology 23:1126-1136, 2005). The antigen-binding fragment may be grafted onto a scaffold based on a polypeptide 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 an antibody molecule of natural sequence, 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 an antibody molecule of natural sequence. Kappa (κ) and lambda (λ) light chains refer to the two major antibody light chain isotypes.

[0047] The term "anticancer effect" means a biological effect that can be demonstrated by various means including, but not limited to, reduction in tumor volume, reduction in the number of cancer cells, reduction in the number of metastases, extension of lifespan, reduction in cancer cell proliferation, reduction in cancer cell survival rate, and improvement of various physiological symptoms associated with cancer symptoms. The "anticancer effect" can also be demonstrated by the ability of the SIR to prevent the occurrence of cancer.

[0048] "Anticancer agent" means an agent that inhibits abnormal cell division and growth, an agent that inhibits the movement of tumor cells, an agent that inhibits invasion, or an agent that prevents the growth and metastasis of cancer. This term may also include chemotherapeutic agents, biological agents (e.g., siRNA, viral vectors such as modified MLV, adenovirus, herpesvirus that deliver cytotoxic genes), antibodies, etc.

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

[0050] Examples of target antigens include, but are not limited to, 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 epitopes expressed in acute leukemia or lymphoma but not in hematopoietic progenitor cells, glycosylated CD43 epitopes expressed in non-hematopoietic organ 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; prostate acid phosphatase (PAP); elongation factor 2 mutation (ELF2M); Ephrin B2; fibroblast activation protein alpha (FAP); insulin-like growth factor 1 receptor (IGF-1 receptor), carbonic anhydrase IX (CAIX); proteasome (prososome, macropain) subunit, beta type 9 (LMP2); glycoprotein 100 (gp100);Cancer gene fusion protein (bcr-abl) consisting of a readily cleavable region (BCR) and Abelson murine leukemia virus oncogene homolog 1 (Abl); Tyrosine kinase; 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); 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 glycosphingolipid (GloboH); Breast 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-ESO-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 variant; Prostain; Survivin; Telomerase; Prostate cancer tumor antigen 1 (PCTA-1 or galectin 8), Melanoma antigen 1 recognized by T cells (MelanA or MART1); Rat sarcoma (Ras) variant; 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; v-myc avian myelocytomatosis viral oncogene neuroblastoma-derived homolog (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 recognized by T cells 3 (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 variant (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 - EBNA3c, KSHV - K8.1, KSHV - gH, influenza A hemagglutinin (HA), GAD, PDL1, guanylyl cyclase C (GCC), 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 G12V, tissue factor 1 (TF1), AFP, GPRC5D, claudin 18.2 (CLD18A2 or CLDN18A.2), P - glycoprotein, STEAP1, Liv1, NECTIN - 4, Cripto, gpA33, BST1 / CD157, low - conductance chloride ion channel, and TNT antibody are included.;

[0051] The term "antigen - presenting cell" or "APC" means immune system cells such as accessory cells (e.g., B cells, dendritic cells, etc.) that present foreign antigens complexed with the major histocompatibility complex (MHC) on their surface. T cells recognize such complexes using the T - cell receptor (TCR). APCs process antigens and present them to T cells.

[0052] The term "anti-inflammatory effect" means a biological effect that can be demonstrated by various means including, but not limited to, for example, a decrease in the titer of an infectious agent, a decrease in the number of colonies of an infectious agent, and improvement of various physiological symptoms related to infectious symptoms. The "anti-inflammatory effect" can also be demonstrated by the ability of a peptide, polynucleotide, ce...

Claims

1. At least one recombinant polynucleotide encoding at least one synthetic immune receptor (SIR) comprising a heterodimer of T cell receptor constant chains, wherein said at least one SIR comprises (a) a T cell receptor (TCR) constant chain, wherein (i) a T cell receptor alpha constant chain (Cα) or a variant thereof, which may optionally comprise an accessory module, and (ii) a T cell receptor beta 1 or beta 2 constant chain (Cβ1 or Cβ2) or a variant thereof, which may optionally comprise an accessory module a T cell receptor constant chain having an amino acid sequence selected from the group consisting of: and (b) an optional linker; and (c) one or more non-natural TCR antigen-binding domains linked to one or both of the TCR constant chains of (a), wherein (1) an antibody; (2) an antibody fragment (e.g., Fv, Fab, (Fab’)2); (3) a heavy chain variable domain (vH domain) or a fragment thereof and a light chain variable domain (vL domain) or a fragment thereof of an antibody specific for a given target antigen, wherein one of said vH and vL domains or fragments thereof is attached to one of the TCR constant chains of (a), and the other of said vH and vL domains or fragments thereof is attached to the other of the TCR constant chains of (a); a vH domain or a fragment thereof and a vL domain or a fragment thereof; (4) a single-chain variable fragment (scFv) or a fragment thereof; (5) a single-domain antibody (SDAb) or a fragment thereof; (6) a camelid-derived VHH domain or a fragment thereof; (7) a monomeric variable region of an antibody; (8) a non-immunoglobulin antigen-binding scaffold selected from DARPin, affibody, affilin, adnectin, affitin, avobody, lipobody, finomer, alphabody, abimer, atrimer, centyrin, pronectin, anticalin, knotted domain, armadillo repeat protein or fragments thereof; (9) a receptor or a fragment thereof; (10) a ligand or a fragment thereof; (11) a bispecific antibody, bispecific antibody fragment, bispecific scFV, bispecific vHH, bispecific SDAb, bispecific non-immunoglobulin antigen-binding scaffold, bispecific receptor, or bispecific ligand; and (12) an autoantigen or a fragment thereof, one or more non-natural TCR antigen-binding domains selected from the group consisting of: and comprising When expressed in human lymphocytes, the synthetic immunoreceptor is expressed on the surface of lymphocytes by two chains, expressing both the antigen-binding domain and the T cell receptor constant chain. As a result, when the expressed antigen-binding domain binds to its antigen, the lymphocyte is triggered to activate, proliferate, secrete cytokines and / or regulate (induce or suppress) the death of target cells and has MHC-restricted or MHC-unrestricted antibody-type specificity. The at least one SIR is a dimer combination of the following (i) and (ii), or the following (i) and (iii), wherein the T cell receptor (TCR) constant chain is (i) an amino acid sequence that is at least 80% identical to SEQ ID NO: 3010 and optionally has one or more mutations at positions 48, 61, 91, 92, 93 and / or 94, and may include an optional accessory module, and (ii) an amino acid sequence that is at least 80% identical to SEQ ID NO: 3024 and optionally has one or more mutations at positions 18, 22, 57, 79, 133, 136 and / or 139, and may include an optional accessory module, or (iii) an amino acid sequence that is at least 80% identical to SEQ ID NO: 3025 and optionally has one or more mutations at positions 18, 22, 57, 79, 133, 136 and / or 139, and may include an optional accessory module, a dimer combination of (i) and (ii), or (i) and (iii) having an amino acid sequence selected from the group consisting of A recombinant polynucleotide comprising. **Claim 2** The polynucleotide encoding the TCR constant chain of (a) is the recombinant polynucleotide according to claim 1, comprising a mutation that improves the expression and / or pairing of the TCR constant chain and reduces the pairing with the endogenous T cell receptor chain. The mutation is (i) codon optimization, (ii) a nucleic acid sequence having 1 to 40 amino acid substitutions or mutations with respect to the nucleic acid sequences of SEQ ID NOs: 730 to 743 or a sequence that is at least 70% identical to the nucleic acid sequences of SEQ ID NOs: 730 to 743, and is a sequence capable of dimerizing with the TCRβ1 or TCRβ2 chain. (iii) A nucleic acid sequence having 1 to 40 amino acid substitutions or mutations with respect to the nucleic acid sequences of SEQ ID NOs: 744 to 765, or a sequence that is at least 70% identical to the nucleic acid sequences of SEQ ID NOs: 744 to 765, and is dimerizable with the TCRα chain. A recombinant polynucleotide selected from the group consisting of.

3. The one or more non-natural TCR antigen-binding domains are: CD19; CD5; CD123; CD22; CD30; CD171; MPL (TPO-R or thrombopoietin receptor); CS-1 (also called 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; 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 organ 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); 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); carbonic anhydrase IX (CAIX); tyrosinase; fucosyl GM1; sialyl Lewis adhesion molecule (sLe); ganglioside GM3; transglutaminase 5 (TGS5); high molecular weight melanoma-associated antigen (HMWMAA); 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);Breast differentiation antigen (NY-BR-1); Wilms tumor protein (WT1); Cancer / testis antigen 1 (NY-ESO-1); Melanoma-associated antigen 1 (MAGE-A1); Melanoma antigen recognized by T cells 1 (MelanA or MART1); Rat sarcoma (Ras) variant; Human telomerase reverse transcriptase (hTERT); Human papillomavirus E6 (HPV E6); Human papillomavirus E7 (HPV E7); CD79a; CD79b; CD72; Leukocyte-associated immunoglobulin-like receptor 1 (LAIR1); C-type lectin domain family 12 member A (CLEC12A); EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2); Lymphocyte antigen 75 (LY75); Glypican 3 (GPC3); Fc receptor-like 5 (FCRL5); Immunoglobulin lambda-like polypeptide 1 (IGLL1); MPL; Biotin; c-MYC epitope tag; CD34; LAMP1 TROP2; GFRalpha4; CDH17; CDH6; CDH19; CD200R; Slea (CA19.9; Sialyl Lewis antigen) fucosyl GM1; PTK7; CDH1-CD324; DLL3; CD276 / B7H3; IL11Ra; IL13Ra2; CD179b-IGL11; ALK TCRγ-δ; NKG2D; CD32 (FCGR2A); CSPG4-HMW-MAA; Tim1- / HVCR1; CSF2RA (GM-CSFRα); TGFβR2; VEGFR2 / KDR; Lewis Ag; TCRβ1 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; CMV pp65; EBV-EBNA3c; Influenza A hemagglutinin (HA); GAD; PDL1; Guanylyl cyclase C (GCC); KSHV-K8.1 protein; KSHV-gH protein; Autoantibody against desmoglein 3 (Dsg3); Autoantibody against desmoglein 1 (Dsg1); HLA-A2; HLA-B; HLA-C; HLA-DP; HLA-DM; HLA-DOA; HLA-DOB; HLA-DQ; HLA-DR; HLA-G; IgE; CD99; Lym1; Lym2; RAS G12V; Tissue factor 1 (TF1); AFP;The recombinant polynucleotide according to claim 1, which binds to one or more of the disease-related antigens selected from the group consisting of GPRC5D; Claudin 18.2 (CLD18A2 or CLDN18A.2); STEAP1; LIV1; nectin-4; Cripto; GPA33; BST1 / CD157; low-conductance chloride ion channel; and TNT.

4. The one or more non-natural TCR antigen-binding domains are (i) A polynucleotide having any one of the sequences of SEQ ID NOs: 226 to 400 or 10203 to 10321, or a sequence that is at least 98% identical thereto, encoding a polypeptide that binds to its antigen and contains the CDRs as described above, and a heavy chain variable region (vH) encoded by the polynucleotide, and A polynucleotide having any one of the sequences of SEQ ID NOs: 16 to 191 or 10085 to 10202, or a sequence that is at least 98% identical thereto, encoding a polypeptide that binds to its antigen and contains the CDRs as described above, and a light chain variable region (vL) encoded by the polynucleotide, (ii) A polynucleotide having any one of the sequences of SEQ ID NOs: 488 to 657, 10346 to 10400, or 18098 to 18160, or a sequence that is at least 98% identical thereto, encoding a polypeptide that binds to its antigen and contains the CDRs as described above, and a single-chain variable fragment (scFv) encoded by the polynucleotide, (iii) A polynucleotide having any one of the sequences of SEQ ID NOs: 421 to 445 or 10322 to 10337, or a sequence that is at least 98% identical thereto, encoding a polypeptide that binds to its antigen and contains the CDRs as described above, and a VHH domain derived from a camelid encoded by the polynucleotide, (iv) A polynucleotide having any one of the sequences of SEQ ID NOs: 448 to 452 or 10339 to 10344, or a sequence that is at least 98% identical thereto, encoding a polypeptide that binds to its antigen, and a non-immunoglobulin scaffold encoded by the polynucleotide, (v) A receptor encoded by a polynucleotide having any one of the sequences of SEQ ID NOs: 456 to 468, or a sequence that is at least 98 to 100% identical thereto, and (vi)A ligand encoded by a polynucleotide having any one of the sequences of SEQ ID NOs: 476 to 486 or 10402 to 10404, or a sequence that is at least 98-100% identical thereto, The recombinant polynucleotide according to claim 3, selected from the group consisting of.

5. Said one or more non-natural TCR antigen-binding domains are (i) Any one of the sequences of SEQ ID NOs: 2307 to 2482 or 12042 to 12159 having up to 9 conservative amino acid substitutions, or a sequence that is 98-100% identical to the amino acid sequence of SEQ ID NOs: 2307 to 2482 or 12042 to 12159, and comprising the complementarity-determining regions (CDRs) of SEQ ID NOs: 2307 to 2482 or 12042 to 12159 A variable light chain (vL) domain, and any one of the sequences of SEQ ID NOs: 2506 to 2680 or 12160 to 12278 having up to 9 conservative amino acid substitutions, or a sequence that is 98-100% identical to the amino acid sequence of SEQ ID NOs: 2506 to 2680 or 12160 to 12278, and comprising the complementarity-determining regions (CDRs) of SEQ ID NOs: 2506 to 2680 and 12060 to 12278 A variable heavy chain (vH) domain, wherein the SEQ ID NOs of the target antigen, vL and vH domains and their CDRs are those described in Table 5, and the non-natural TCR antigen-binding domain binds to the antigen, vL domain and vH domain, (ii) Any one described in SEQ ID NOs: 2701 to 2725 or 12279 to 12294 having up to 9 conservative amino acid substitutions, or having a sequence that is 98-100% identical to the amino acid sequences of SEQ ID NOs: 2701 to 2725 and 12279 to 12294, and comprising the complementarity-determining regions (CDRs) of SEQ ID NOs: 2701 to 2725 and 12279 to 12294, and one or more camelid-derived vHHs for the selected antigen that bind to the antigen, (iii) A sequence described in any one of SEQ ID NOs: 2728 to 2732 or 12296 to 12301 having up to 9 conservative amino acid substitutions, or having a sequence that is 98-100% identical to the amino acid sequences of SEQ ID NOs: 2728 to 2732 and 12296 to 12301, and a non-immunoglobulin antigen-binding domain that binds to the antigen, (iv)A variable light chain (vL) domain light chain complementarity determining region comprising any one of the sequences of SEQ ID NOs: 2307 to 2482 or 12042 to 12159, and a heavy chain complementarity determining region of a variable heavy chain (vH) domain comprising any one of the sequences of SEQ ID NOs: 2506 to 2680 or 12160 to 12278, an scFv domain (v) A sequence selected from the group consisting of SEQ ID NOs: 2770 to 2939, 12303 to 12357, or 18162 to 18224, each having up to 18 conservative amino acid substitutions, or a sequence having 98 to 100% identity to the amino acid sequences of SEQ ID NOs: 2770 to 2939, 12303 to 12357, and 18162 to 18224, and comprising the complementarity determining regions (CDRs) of SEQ ID NOs: 2770 to 2939, 12303 to 12357, and 18162 to 18224, and an scFv fragment that binds to its antigen (vi) Any amino acid sequence of SEQ ID NOs: 2736 to 2747 having up to 19 conservative amino acid substitutions, or one or more receptors comprising a sequence having 98 to 100% identity to the amino acid sequence of SEQ ID NOs: 2736 to 2747 (vii) Any sequence of SEQ ID NOs: 2758 to 2768, 12359 to 12361, and 18918 having up to 19 conservative amino acid substitutions, or any sequence having 98 to 100% identity to the amino acid sequences of SEQ ID NOs: 2758 to 2768, 12359 to 12361, and 18918, and one or more ligands (viii) The extracellular domain of CD16A, NKG2D, CD4, PD1, desmoglein 3 (Dsg3), or CD4-DC-SIGN, or a variant thereof (ix) The extracellular domain of one or more of hTPO, mTPO, CGHα chain, CGHβ chain, FHβ chain, LHβ chain, TSHβ chain, APRIL, or variants or combinations thereof, and (x) Any combination of (i) to (ix) The recombinant polynucleotide according to claim 1, selected from the group consisting of

6. The one or more non-natural TCR antigen-binding domains bind to CD19 and (i) At least 98% identical to any one of SEQ ID NOs: 2318 to 2324, 12060 to 12068, 12108, 12127, or 12156, and comprising the complementarity determining regions (CDRs) contained in any of the polypeptides, and a vL polypeptide that binds to its antigen, and At least 98% identical to any one of SEQ ID NOs: 2517 - 2523, 12178 - 12186, 1227, 12246, or 12275, and comprising a complementarity-determining region (CDR) contained in any of said polypeptides, and binding to its antigen, a vH polypeptide, (ii) At least 98% identical to SEQ ID NO: 12288, comprising said complementarity-determining region (CDR), and binding to its antigen, a polypeptide, and (iii) At least 98% identical to any one of SEQ ID NOs: 2770 - 2774, 12325, 12308, 18162 - 18170, or 12354, and comprising a complementarity-determining region (CDR) contained in any of said polypeptides, and binding to its antigen, a polypeptide The recombinant polynucleotide according to claim 3, comprising a polypeptide sequence selected from the group consisting of

7. The recombinant polynucleotide according to claim 6, encoding a polypeptide comprising 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.

8. The recombinant polynucleotide according to claim 1, co-expressed with an accessory module, The accessory module is selected from the group consisting of 41BBL, CD40L, K13, MC159, cFLIP-L / MRITα, cFLIP-p22, HTLV1 Tax, HTLV2 Tax, HTLV2 Tax2-RS mutant, FKBPx2-K13, FKBPx2-HTLV2-Tax, FKBPx2-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 target Brd4, chimeric antigen receptor (CAR), hTERT, heparinase, inhibitory CAR, cytokine, chemokine, IL2, IL-7, IL-15, IL12f, IL-21, co-stimulatory substance, soluble receptor, and combinations thereof. Recombinant polynucleotide.

9. At least one vector comprising the recombinant polynucleotide of claim 1, Selected from the group consisting of DNA vector, RNA vector, plasmid, lentiviral vector, adenoviral vector, retroviral vector, baculoviral vector, sleeping beauty transposon vector, and piggybac transposon vector. Vector.

10. An isolated synthetic immune receptor (SIR) polypeptide, (a) a T cell receptor (TCR) constant chain, (i) a T cell receptor alpha constant chain (Cα) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 3010 and optionally having one or more mutations at positions 48, 61, 91, 92, 93, and / or 94 and optionally containing any accessory module, and (ii) a T cell receptor beta 1 or beta 2 constant chain (Cβ1 or Cβ2) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 3024 or 3025 and optionally having one or more mutations at positions 18, 22, 57, 79, 133, 136, and / or 139, and optionally containing any accessory modules, a T cell receptor constant chain having an amino acid sequence selected from the group consisting of, (b) any linker, (c) one or more non-natural TCR antigen-binding domains linked to (a), (1) an antibody, (2) an antibody fragment (e.g., Fv, Fab, (Fab')2), (3) a heavy chain variable domain (vH domain) or a fragment thereof and a light chain variable domain (vL domain) or a fragment thereof of an antibody specific for a given target antigen, wherein one of the vH and vL domains or fragments thereof is attached to one of the two TCR constant chains of (a), and the other of the vH and vL domains or fragments thereof is attached to the other of the two TCR constant chains of (a), the vH domain or fragment thereof and the vL domain or fragment thereof, (4) a single-chain variable fragment (scFv) or a fragment thereof, (5) a single-domain antibody (SdAb) or a fragment thereof, (6) a VHH domain or a fragment thereof derived from a camelid, (7) a monomeric variable region of an antibody, (8) a non-immunoglobulin antigen-binding scaffold selected from DARPIN, affibody, affilin, adnectin, avidin, obody, lipobody, finomer, alphabody, avimer, atrimer, centyrin, pronectin, anticalin, knotted domain, armadillo repeat protein, or fragments thereof, (9) a receptor or a fragment thereof, (10) a ligand or a fragment thereof, (11) a bispecific antibody, bispecific antibody fragment, bispecific scFV, bispecific VHH, bispecific SdAb, bispecific non-immunoglobulin antigen-binding scaffold, bispecific receptor, or bispecific ligand, and (12) an autoantigen or a fragment thereof, a non-natural TCR antigen-binding domain selected from the group consisting of, and comprising a heterodimer of When expressed in human lymphocytes, the synthetic immune receptor is expressed on the surface of lymphocytes by two chains, expressing both the antigen-binding domain and the T cell receptor constant chain. When the expressed antigen-binding domain binds to its antigen, it is triggered to activate, proliferate, secrete cytokines, and / or regulate (induce or suppress) the death of the target cell, and has MHC-restricted or MHC-unrestricted antibody-type specificity. An isolated synthetic immune receptor (SIR) polypeptide. **Claim 11** Comprising the TCR constant domains of (i) and (ii), wherein the non-natural TCR binding domain is - the variable region of the heavy chain (vH) of an antibody specific for a given target antigen, and 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 given target antigen, - an antibody fragment specific for a given target antigen (e.g., Fv, Fab, (Fab')2), - a single-domain antibody (SDAB) fragment specific for a given target antigen, - a camelid-derived vHH domain specific for a given target antigen, - a non-immunoglobulin antigen-binding scaffold specific for a given target antigen, - a receptor specific for a given target antigen or a fragment thereof, - a ligand specific for a given target antigen or a fragment thereof, - 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 given target antigens, and - a self-antigen or a fragment thereof, The isolated synthetic immune receptor (SIR) polypeptide according to claim 10, selected from the group consisting of. **Claim 12** The TCR constant chain comprises a mutation that promotes the expression and / or pairing of the TCR constant chain and reduces the pairing with the endogenous T cell receptor chain. The TCR is (i) an amino acid sequence having 1 to 40 amino acid substitutions or mutations with respect to a sequence selected from the group consisting of SEQ ID NOs: 3010 to 3023, or a TCR receptor α chain (Cα) comprising a sequence at least 80% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 3010 to 3023, and (ii)An amino acid sequence having 1 to 40 amino acid substitutions or mutations with respect to a sequence selected from the group consisting of SEQ ID NOs: 3024 to 3044, or a TCR receptor β chain (Cβ) comprising a sequence that is at least 80% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 3024 to 3044 The isolated synthetic immune receptor (SIR) polypeptide according to claim 10, selected from the group consisting of

13. The one or more non-natural TCR antigen-binding domains are: CD19; CD5; CD123; CD22; CD30; CD171; MPL (TPO-R or thrombopoietin receptor); CS-1 (also called 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; 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; a glycosylated CD43 epitope expressed in acute leukemia or lymphoma but not in hematopoietic progenitor cells; a glycosylated CD43 epitope expressed in non-hematopoietic organ 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); 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); carbonic anhydrase IX (CAIX); tyrosinase; fucosyl GM1; sialyl Lewis adhesion molecule (sLe); ganglioside GM3; transglutaminase 5 (TGS5); high molecular weight melanoma-associated antigen (HMWMAA); 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);Breast differentiation antigen (NY-BR-1); Wilms tumor protein (WT1); Cancer / testis antigen 1 (NY-ESO-1); Melanoma-associated antigen 1 (MAGE-A1); Telomerase; Melanoma antigen recognized by T cells 1 (MelanA or MART1); Rat sarcoma (Ras) variant; Human telomerase reverse transcriptase (hTERT); Human papillomavirus E6 (HPV E6); Human papillomavirus E7 (HPV E7); CD79a; CD79b; CD72; Leukocyte-associated immunoglobulin-like receptor 1 (LAIR1); C-type lectin domain family 12 member A (CLEC12A); EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2); Lymphocyte antigen 75 (LY75); Glypican 3 (GPC3); Fc receptor-like 5 (FCRL5); Immunoglobulin lambda-like polypeptide 1 (IGLL1); MPL; Biotin; c-MYC epitope tag; CD34; LAMP1 Trop2; GFRalpha4; CDH17; CDH6; CDH19; CD200R; Slea (CA19.9; Sialyl Lewis antigen) Fucosyl GM1; PTK7; CDH1-CD324; DLL3; CD276 / B7H3; IL11Ra; IL13Ra2; CD179b-IGL11; ALK TCRγ-δ; NKG2D; CD32 (FcγR2A); CSPG4-HMW-MAA; Tim1- / HVCR1; CSF2RA (GM-CSFRα); TGFβR2; VEGFR2 / KDR; Lewis Ag; TCRβ1 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; CMV pp65; EBV-EBNA3c; Influenza A hemagglutinin (HA); GAD; PDL1; Guanylyl cyclase C (GCC); KSHV-K8.1 protein; KSHV-gH protein; Autoantibody against desmoglein 3 (Dsg3); Autoantibody against desmoglein 1 (Dsg1); HLA-A2; HLA-B; HLA-C; HLA-DP; HLA-DM; HLA-DOA; HLA-DOB; HLA-DQ; HLA-DR; HLA-G; IgE; CD99; Lym1; Lym2; RAS G12V;The isolated synthetic immune receptor (SIR) polypeptide of claim 10 that binds to one or more disease-related antigens selected from the group consisting of tissue factor 1 (TF1); AFP; GPRC5D; claudin 18.2 (CLDN18A2 or CLDN18.2); STEAP1; LIV1; nectin-4; cripto; GPA33; BST1 / CD157; low-conductance chloride ion channel; and TNT.

14. The one or more non-natural TCR antigen-binding domains are (i) a sequence described in any of SEQ ID NOs: 2506 to 2680 or 12160 to 12278, or a sequence having up to 9 conservative amino acid substitutions in the sequence described in any of SEQ ID NOs: 2506 to 2680 or 12160 to 12278, or a sequence that is at least 98 - 100% identical to an amino acid sequence of any of SEQ ID NOs: 2506 to 2680 or 12160 to 12278, comprising the complementarity-determining regions (CDRs) of SEQ ID NOs: 2506 to 2680 or 12160 to 12278 and containing a sequence encoding a polypeptide that binds to its antigen, a heavy chain variable region (vH), and a sequence described in any one of SEQ ID NOs: 2307 to 2482 or 12042 to 12159, or a sequence having up to 9 conservative amino acid substitutions in the sequence described in any of SEQ ID NOs: 2307 to 2482 or 12042 to 12159, or a sequence that is at least 98 - 100% identical to an amino acid sequence of any of SEQ ID NOs: 2307 to 2482 and 12042 to 12159, comprising the complementarity-determining regions (CDRs) of SEQ ID NOs: 2307 to 2482 or 12042 to 12159 and containing a sequence encoding a polypeptide that binds to its antigen, a light chain variable region (vL), (ii) The sequence described in any one of SEQ ID NOs: 2770 to 2939, 12303 to 12357, or 18162 to 18224, or a sequence having up to 18 conservative amino acid substitutions in the sequence described in any of SEQ ID NOs: 2770 to 2939, 12303 to 12357, or 18162 to 18224, or a sequence that is at least 98 to 100% identical to any of the amino acid sequences of SEQ ID NOs: 2770 to 2939, 12303 to 12357, and 18162 to 18224, and includes a complementarity-determining region (CDR) of SEQ ID NOs: 2770 to 2939, 12303 to 12357, and 18162 to 18224, and a single-chain variable fragment (scFv) encoding a polypeptide that binds to its antigen. (iii) The sequence described in any one of SEQ ID NOs: 2701 to 2725 or 12279 to 12294, or a sequence having up to 9 conservative amino acid substitutions in the sequence described in any of SEQ ID NOs: 2701 to 2725 or 12279 to 12294, or a sequence that is at least 98 to 100% identical thereto, and includes a complementarity-determining region (CDR) of SEQ ID NOs: 2701 to 2725 or 12279 to 12294, and a VHH domain derived from a camelid animal encoding a polypeptide that binds to its antigen. (iv) Any one of SEQ ID NOs: 448 to 452, or SEQ ID NOs: 10339 to 10344, or a sequence having up to 9 conservative amino acid substitutions in the sequence described in any of SEQ ID NOs: 448 to 452, or SEQ ID NOs: 10339 to 10344, or a sequence that is at least 98 to 100% identical thereto and encodes a polypeptide that binds to its antigen, and is encoded by any one of the polynucleotides described. A non-immunoglobulin scaffold. (v) A receptor comprising a sequence described in any one of SEQ ID NOs: 2736 to 2748 having up to 19 conservative amino acid substitutions or a sequence that is at least 98 to 100% identical thereto. (vi) A ligand comprising a sequence described in any one of SEQ ID NOs: 2758 to 2768 or 12359 to 12361 having up to 19 conservative amino acid substitutions or a sequence that is at least 98 to 100% identical thereto. (vii) The extracellular domain of CD16A, NKG2D, CD4, PD1, desmoglein 3 (Dsg3), or CD4-DC-SIGN, or a variant thereof. (viii) One or more extracellular domains of hTPO, mTPO, CGHα chain, CGHβ chain, FHβ chain, LHβ chain, TSHβ chain, APRIL, or variants or combinations thereof, and (ix) Any combination of (i) to (viii) The isolated synthetic immune receptor (SIR) polypeptide according to claim 10, selected from the group consisting of. **Claim 15** Said one or more non-natural TCR antigen-binding domains are (i) Containing any one of the sequences of SEQ ID NOs: 2307 to 2482 or 12042 to 12159 having up to 10 conservative amino acid substitutions, a variable light chain (vL) domain containing the complementarity-determining regions (CDRs) of SEQ ID NOs: 2307 to 2482 and 12042 to 12159, and containing any one of the sequences of SEQ ID NOs: 2506 to 2680 or 12160 to 12278 having up to 10 conservative amino acid substitutions, a variable heavy chain (vH) domain containing the complementarity-determining regions (CDRs) of SEQ ID NOs: 2506 to 2680 or 12160 to 12278, wherein the SEQ ID NOs of the target antigen, vL and vH domains and their complementarity-determining regions are as described in Table 5, and a vL domain and a vH domain that bind to said antigen, (ii) Any one described in SEQ ID NOs: 2701 to 2725 or 12279 to 12294 having up to 10 conservative amino acid substitutions, containing the complementarity-determining regions (CDRs) of SEQ ID NOs: 2701 to 2725 or 12279 to 12294, and one or more camelid-derived vHHs for the selected antigen that bind to said antigen, (iii) Having a sequence described in any of SEQ ID NOs: 2728 to 2732 or 12296 to 12301, having up to 10 conservative amino acid substitutions, and a non-immunoglobulin antigen-binding domain that binds to said antigen, (iv) A scFv domain comprising the light chain complementarity-determining region of a variable light chain (vL) domain containing any one of the sequences of SEQ ID NOs: 2307 to 2482 or 12042 to 12159, and the heavy chain complementarity-determining region of a variable heavy chain (vH) domain containing any one of the sequences of SEQ ID NOs: 2506 to 2680 or 12160 to 12278, (v) An scFv fragment having a sequence selected from the group consisting of SEQ ID NOs: 2770-2939, 12303-12357, or 18162-18224, each having up to 10 conservative amino acid substitutions, including the complementarity-determining regions (CDRs) of SEQ ID NOs: 2770-2939, 12303-12357, or 18162-18224, and binding to its antigen. (vi) One or more receptors comprising any amino acid sequence of SEQ ID NOs: 2736-2748 having up to 10 conservative amino acid substitutions. (vii) One or more ligands comprising any sequence of SEQ ID NOs: 2758-2768, 12359-12361, and 18918 having up to 10 conservative amino acid substitutions. (viii) The extracellular domain or a variant thereof of CD16A, NKG2D, CD4, PD1, desmoglein 3 (Dsg3), or CD4-DC-SIGN. (ix) One or more extracellular domains of hTPO, mTPO, CGHα chain, CGHβ chain, FHβ chain, LHβ chain, TSHβ chain, APRIL, or a variant or a combination thereof, and (x) Any combination of (i)-(ix). An isolated synthetic immune receptor (SIR) polypeptide or polypeptide heterodimer according to claim 10, selected from the group consisting of.

16. An immune effector cell or stem cell comprising at least one polypeptide according to claim 10, at least one recombinant polynucleotide according to claim 1, and / or at least one vector according to claim 9.

17. The immune cell or stem cell according to claim 16, wherein the immune cell further comprises at least one chimeric antigen receptor (CAR) polypeptide.

18. A pharmaceutical composition for providing disease-resistant immunity to a subject, comprising an effective amount of immune effector cells or stem cells capable of generating the immune effector cells according to claim 16, 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. Pharmaceutical composition.

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