Claims for Patent: 10,189,903

Summary for Patent: 10,189,903

Title:	Bispecific chimeric antigen receptors and methods of use thereof to treat cancer
Abstract:	The invention is directed to a bispecific chimeric antigen receptor, comprising: (a) at least two antigen-specific targeting regions; (b) an extracellular spacer domain; (c) a transmembrane domain; (d) at least one co-stimulatory domain; and (e) an intracellular signaling domain, wherein each antigen-specific targeting region comprises an antigen-specific single chain Fv (scFv) fragment, and binds a different antigen, and wherein the bispecific chimeric antigen receptor is co-expressed with a therapeutic control. The invention also provides methods and uses of the bispecific chimeric antigen receptors.
Inventor(s):	Jensen; Michael (Bainbridge, WA)
Assignee:	Seattle Children\'s Hospital (Seattle, WA)
Application Number:	15/233,140
Patent Claims:	1. A bispecific chimeric antigen receptor, comprising: a. at least two antigen-specific targeting regions; b. an extracellular spacer domain; c. a transmembrane domain; d. at least one co-stimulatory domain; and e. an intracellular signaling domain, wherein each antigen-specific targeting region comprises a single-domain antibody. 2. The bispecific chimeric antigen receptor of claim 1, wherein the bispecific chimeric antigen receptor is co-expressed with a therapeutic control. 3. The bispecific chimeric antigen receptor of claim 2, wherein the therapeutic control comprises any one or more of truncated epidermal growth factor receptor (EGFRt), thymidine kinase, cytosine deaminase, nitroreductase, xanthine-guanine phosphoribosyl transferase, human caspase 8, human caspase 9, purine nucleoside phosphorylase, linamarase/linamarin/glucose oxidase, deoxyribonucleoside kinase, horseradish peroxidase (HRP)/indole-3-acetic (IAA), gamma-glutamylcy steine synthetase, cluster of differentiation (CD)20/alphaCD20, CD34/thymidine kinase chimera, dox-depedent caspase-2, mutant thymidine kinase (HSV-TKSR39), AP1903/Fas system, a chimeric cytokine receptor (CCR), a selection marker, and combinations thereof. 4. The bispecific chimeric antigen receptor of claim 3, wherein the EGFR t binds any one or more of an EGFR-specific siRNA, a small molecule, an anti-EGFR antibody or a fragment thereof, and a combination thereof. 5. The bispecific chimeric antigen receptor of claim 3, wherein the selection marker comprises any one or more of dihydroxyfolate receptor (DHFR), mutant DHFR, methylated-DNA-protein-cysteine methyltransferase, inosine monophosphate dehydrogenase II (IMDHP2) and combinations thereof. 6. The bispecific chimeric antigen receptor of claim 3, wherein the CCR comprises any one or more of (i) interleukin (IL)-7 cytokine-linker-IL7R.alpha., (ii) IL-7 cytokine-linker-extracellular domain of IL-7R.alpha.-transmembrane domain of IL-7R.alpha.-cytoplasmic domain of IL-2R.beta., (iii) IL-7 cytokine-linker-IL2R.beta., and (iv) combinations thereof. 7. The bispecific chimeric antigen receptor of claim 2, wherein the bispecific chimeric antigen receptor and the therapeutic control are linked via a cleavable linker. 8. The bispecific chimeric antigen receptor of claim 7, wherein the cleavable linker is a self-cleaving cleavable linker. 9. The bispecific chimeric antigen receptor of claim 8, wherein the cleavable linker is a 2A linker or a 2A-like linker. 10. The bispecific chimeric antigen receptor of claim 1, wherein the extracellular spacer domain comprises any one or more of an Fc fragment of an antibody, a hinge region of an antibody, a constant domain of heavy chain (CH)2 region of an antibody, a CH3 region of an antibody, and combinations thereof. 11. The bispecific chimeric antigen receptor of claim 10, wherein the extracellular spacer domain comprises any one or more of (i) a hinge, CH2 and CH3 region of immunoglobulin G4 (IgG4), (ii) a hinge region of IgG4, (iii) a hinge and CH2 region of IgG4, (iv) a hinge region of CD8.alpha., (v) a hinge, CH2 and CH3 region of IgG1, (vi) a hinge region of IgG1, (vii) a hinge and CH2 region of IgG1, and (viii) combinations thereof. 12. The bispecific chimeric antigen receptor of claim 1, wherein the transmembrane domain comprises a transmembrane region of a Type I transmembrane protein. 13. The bispecific chimeric antigen receptor of claim 12, wherein the transmembrane domain comprises any one or more of a transmembrane domain of a zeta chain of a T cell receptor complex, CD28, CD8.alpha., and combinations thereof. 14. The bispecific chimeric antigen receptor of claim 1, wherein the co-stimulatory domain comprises a signaling domain from any one or more of CD28, CD137 (4-1BB), CD134 (OX40), Dap10, CD27, CD2, CD5, intercellular adhesion molecule 1 (ICAM-1), lymphocyte function-associated antigen 1 (LFA-1), Lck, tumor necrosis factor receptor type I (TNFR-I), TNFR-II, Fas, CD30, CD40 and combinations thereof. 15. The bispecific chimeric antigen receptor of claim 1, wherein the intracellular signaling domain comprises a signaling domain of one or more of a human CD3 zeta chain, Fc.gamma.RIII, Fc.epsilon.RI, a cytoplasmic tail of a Fc receptor, an immunoreceptor tyrosine-based activation motif (ITAM) bearing cytoplasmic receptors, and combinations thereof. 16. The bispecific chimeric antigen receptor of claim 1, wherein each of the at least two antigen-specific targeting domains, independently, targets an antigen selected from the group consisting of antigens specific for cancer, an inflammatory disease, a neuronal disorder, diabetes, a cardiovascular disease, an infectious disease, and an autoimmune disease. 17. The bispecific chimeric antigen receptor of claim 16,wherein the antigens specific for cancer comprise any one or more of 4-1BB, 5T4, adenocarcinoma antigen, alpha-fetoprotein, B-cell activating factor (BAFF), B-lymphoma cell, C242 antigen, CA-125, carbonic anhydrase 9 (CA-IX), C-mesenchymal to epithelial transition (MET), C-C chemokine receptor type 4 (CCR4), CD152, CD19, CD20, CD200, CD22, CD221, CD23 (IgE receptor), CD28, CD30 (TNFRSF8), CD33, CD4, CD40, CD44 v6, CD51, CD52, CD56, CD74, CD80, carcinoembryonic antigen (CEA), carlumab (CNTO0888), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), death receptor 5 (DR5), EGFR, epithelial cell adhesion molecule (EpCAM), CD3, fibroblast activation protein (FAP), fibronectin extra domain-B, folate receptor 1, disialoganglioside (GD)2, GD3ganglioside, glycoprotein 75, glycoprotein non-metastatic b (GPNMB), human epidermal growth factor receptor2(HER2)/neu, hepatocyte growth factor (HGF), human scatter factor receptor kinase, insulin-like growth factor 1(IGF-1) receptor, IGF-I, IgG1, L1 cell adhesion molecule (L1-CAM), IL-13, IL-6, integrin .alpha.5.beta.1, integrin .alpha.v.beta.3, amatuximab (MORAb-009), membrane spanning 4-domains A1 (MS4A1), mucin 1 (MUC1), mucin CanAg, N-glycolylneuraminic acid, NPC-1C, platelet-derived growth factor receptor .alpha. (PDGF-R .alpha.), enavatuzumab (PDL192), phosphatidylserine, prostatic carcinoma cells, receptor activator of nuclear factor kappa-B ligand (RANKL), recepteur d'origine nantais (RON), receptor tyrosine kinase-like orphan receptor (ROR1), SCH 900105, syndecan-1 (SDC1), signaling lymphocytic activation molecule (SLAM) F7, tumor-associated glycoprotein 72 (TAG-72), tenascin C, transforming growth factor (TGF) beta 2, TGF-.beta., TNF-related apoptosis inducing ligand receptor 1 (TRAIL-R1), TRAIL-R2, tumor antigen CTAA16.88, vascular endothelial growth factor (VEGF)-A, VEGFR-1, VEGFR2, vimentin, and combinations thereof. 18. The bispecific chimeric antigen receptor of claim 1, wherein each antigen-specific targeting region binds a different antigen. 19. The bispecific chimeric antigen receptor of claim 18, wherein the at least two antigen-specific targeting regions bind (i) CD19and CD20, (ii) CD20 and L1-CAM, (iii) L1-CAM and GD2, (iv) EGFR and L1-CAM, (v) CD19 and CD22, (vi) EGFR and C-MET, (vii) EGFR and HER2, (viii) C-MET and HER2, or (ix) EGFR and ROR1. 20. The bispecific chimeric antigen receptor of claim 18, wherein the at least two antigen-specific targeting regions bind CD19 and CD20. 21. The bispecific chimeric antigen receptor of claim 16, wherein the antigen specific for an inflammatory disease comprises any one or more of amine oxidase copper containing 3 (AOC3) (VAP-1), mavrilimumab (CAM-3001), C-C motif chemokine (CCL)11(eotaxin-1), CD125, CD147 (basigin), CD154 (CD40L), CD2, CD20, CD23 (IgE receptor), CD25 (.alpha. chain of IL-2 receptor), CD3, CD4, CD5, interferon (IFN)-.alpha., IFN-.gamma., IgE, IgE Fc region, IL-1, IL-12, IL-23, IL-13, IL-17, IL-17A, IL-22, IL-4, IL-5, IL-5, IL-6, IL-6 receptor, integrin .alpha.4, integrin .alpha.4.beta.7,LFA-1(CD11a), MEDI-528, myostatin, OX-40 (CD134), rhuMAb .beta.7, scleroscin, sclerostin (SOST), TGF beta 1, TNF-.alpha., VEGF-A, and combinations thereof. 22. The bispecific chimeric antigen receptor of claim 16, wherein the antigen specific for a neuronal disorder comprises beta amyloid, crenezumab (MABT5102A), or a combination thereof. 23. The bispecific chimeric antigen receptor of claim 16, wherein the antigen specific for diabetes comprises IL-1.beta., CD3, or a combination thereof. 24. The bispecific chimeric antigen receptor of claim 16, wherein the antigen-specific for a cardiovascular disease comprises any one or more of fifth component of complement (C5), cardiac myosin, CD41 (integrin alpha-IIb), fibrin II, beta chain, integrin beta 2 (ITGB2) (CD18), sphingosine-1- phosphate, and combinations thereof. 25. The bispecific chimeric antigen receptor of claim 16, wherein the antigen specific for an infectious disease comprises any one or more of anthrax toxin, CCR5, CD4, clumping factor A, cytomegalovirus, cytomegalovirus glycoprotein B, endotoxin, Escherichia coli, hepatitis B surface antigen, hepatitis B virus, HIV-1, Hsp90, Influenza A hemagglutinin, lipoteichoic acid, Pseudomonas aeruginosa, rabies virus glycoprotein, respiratory syncytial virus, TNF-.alpha., and combinations thereof. 26. A composition comprising the bispecific chimeric antigen receptor of claim 1 and a therapeutic control. 27. The combination of claim 26, wherein the therapeutic control comprises any one or more of truncated epidermal growth factor receptor (EGFRt), thymidine kinase, cytosine deaminase, nitroreductase, xanthine-guanine phosphoribosyl transferase, human caspase 8, human caspase 9, purine nucleoside phosphorylase, linamarase/linamarin/glucose oxidase, deoxyribonucleoside kinase, horseradish peroxidase (HRP)/indole-3-acetic (IAA), gamma-glutamylcysteine synthetase, CD20/alphaCD20, CD34/thymidine kinase chimera, dox-depedent caspase-2, mutant thymidine kinase (HSV-TKSR39), AP1903/Fas system, a chimeric cytokine receptor (CCR), a selection marker, and combinations thereof. 28. The combination of claim 27, wherein the EGFRt binds any one or more of an EGFR-specific siRNA, a small molecule, an anti-EGFR antibody or a fragment thereof, or a combination thereof. 29. The combination of claim 27, wherein the selection marker comprises any one or more of dihydroxyfolate receptor (DHFR), mutant DHFR, methylated-DNA-protein-cysteine methyltransferase, inosine monophosphate dehydrogenase II (IMDHP2) and combinations thereof. 30. The combination of claim 27, wherein the CCR comprises any one or more of (i) IL-7 cytokine-linker-IL7R.alpha., (ii) IL-7 cytokine-linker-extracellular domain of IL-7R.alpha.-transmembrane domain of IL-7R.alpha.-cytoplasmic domain of IL-2R.beta., (iii) IL-7 cytokine-linker-IL2R.beta., and (iv) combinations thereof. 31. The combination of claim 26, wherein the bispecific chimeric antigen receptor and the therapeutic control are linked via a cleavable linker. 32. The combination of claim 31 , wherein the cleavable linker is a self-cleaving cleavable linker. 33. The combination of claim 31, wherein the cleavable linker is a 2A linker or a 2A-like linker. 34. A polypeptide encoded by a polynucleotide encoding the bispecific chimeric antigen receptor of claim 1 or the combination of claim 26. 35. A pharmaceutical composition, comprising: a. the bispecific chimeric antigen receptor of claim 1, the combination of claim 26, the polypeptide of claim 34, or a combination thereof; and b. a pharmaceutically acceptable carrier. 36. In combination, the pharmaceutical composition of claim 35 and a composition adapted to biochemically interact with the therapeutic control to inhibit proliferation of a cell expressing the therapeutic control. 37. The combination of claim 36, wherein the composition adapted to biochemically interact with the therapeutic control is any one or more of trastuzumab, methotrexate, cetuximab, ganciclovir, (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU), 5-flurocytosine (5-FC), 5-(azaridin-l-yl)-2, 4-dinitrobenzamide (CB1954), 6-thioguanine, AP1903, fludarabine phosphate, linamarin (lin), difluorodeoxycytidine (dFdC), 1-.beta.-D-arabinofuranosylthymine (ara-T)), indole-3-acetic (IAA), 1-buthionine-S,R-sulfoximine (BSO), rituximab (RTX), doxycycline, tyrosine kinase inhibitors and combinations thereof. 38. A bispecific chimeric antigen receptor, comprising: a. at least two antigen-specific targeting regions; b. an extracellular spacer domain; c. a transmembrane domain; d. at least one co-stimulatory domain; and e. an intracellular signaling domain, wherein each antigen-specific targeting region comprises a single-domain antibody, and wherein each antigen-specific targeting region binds a different antigen. 39. The bispecific chimeric antigen receptor of claim 38, wherein the bispecific chimeric antigen receptor is co-expressed with a therapeutic control, the therapeutic control comprising any one or more of EGFRt, thymidine kinase, cytosine deaminase, nitroreductase, xanthine-guanine phosphoribosyl transferase, human caspase 8, human caspase 9, purine nucleoside phosphorylase, linamarase/linamarin/glucose oxidase, deoxyribonucleoside kinase, horseradish peroxidase (HRP)/indole-3-acetic (IAA), gamma-glutamylcysteine synthetase, CD20/alphaCD20, CD34/thymidine kinase chimera, dox-depedent caspase-2, mutant thymidine kinase (HSV-TKSR39), AP1903/Fas system, a chimeric cytokine receptor (CCR), a selection marker, and combinations thereof. 40. The bispecific chimeric antigen receptor of claim 39, wherein the therapeutic control comprises EGFRt. 41. The bispecific chimeric antigen receptor of claim 40, wherein the EGFRt binds any one or more of an EGFR-specific siRNA, a small molecule, an anti-EGFR antibody or a fragment thereof, and a combination thereof. 42. The bispecific chimeric antigen receptor of claim 39, wherein the selection marker comprises any one or more of dihydroxyfolate receptor (DHFR), mutant DHFR, methylated-DNA-protein-cysteine methyltransferase, inosine monophosphate dehydrogenase II (IMDHP2) and combinations thereof. 43. The bispecific chimeric antigen receptor of claim 39, wherein the CCR comprises any one or more of (i) IL-7cytokine-linker-IL7R.alpha., (ii) IL-7 cytokine-linker-extracellular domain of IL-7R.alpha.-transmembrane domain of IL-7R.alpha.-cytoplasmic domain of IL-2R.beta., (iii) IL-7 cytokine-linker-IL2R.beta., and (iv) combinations thereof. 44. The bispecific chimeric antigen receptor of claim 39, wherein the bispecific chimeric antigen receptor and the therapeutic control are linked via a cleavable linker. 45. The bispecific chimeric antigen receptor of claim 44, wherein the cleavable linker is a self-cleaving cleavable linker. 46. The bispecific chimeric antigen receptor of claim44, wherein the cleavable linker is a 2A linker or a 2A-like linker. 47. The bispecific chimeric antigen receptor of claim 38, wherein the extracellular spacer domain comprises any one or more of an Fc fragment of an antibody, a hinge region of an antibody, a CH2 region of an antibody, a CH3 region of an antibody, and combinations thereof. 48. The bispecific chimeric antigen receptor of claim 47, wherein the extracellular spacer domain comprises any one or more of (i) a hinge, CH2 and CH3 region of IgG4, (ii) a hinge region of IgG4, (iii) a hinge and CH2 region of IgG4, (iv) a hinge region of CD8.alpha.(v) a hinge, CH2 and CH3 region of IgG1, (vi) a hinge region of IgG1, (vii) a hinge and CH2 region of IgG1, and (viii) combinations thereof. 49. The bispecific chimeric antigen receptor of claim 38, wherein the transmembrane domain comprises a transmembrane region of a Type I transmembrane protein, an artificial hydrophobic sequence, or a combination thereof. 50. The bispecific chimeric antigen receptor of claim 49, wherein the transmembrane domain comprises any one or more of a transmembrane domain of a zeta chain of a T cell receptor complex, CD28, CD8.alpha., and combinations thereof. 51. The bispecific chimeric antigen receptor of claim 38, wherein the co-stimulatory domain comprises a signaling domain from any one or more of CD28, CD137 (4-1BB), CD134 (OX40), Dap10, CD27, CD2, CD5, ICAM-1, LFA-1, Lck, TNFR-I, TNFR-II, Fas, CD30, CD40 and combinations thereof. 52. The bispecific chimeric antigen receptor of claim 38, wherein the intracellular signaling domain comprises a signaling domain of one or more of a human CD3 zeta chain, Fc.gamma.RIII, Fc.epsilon.RI, a cytoplasmic tail of a Fc receptor, an immunoreceptor tyrosine-based activation motif (ITAM) bearing cytoplasmic receptors, and combinations thereof. 53. The bispecific chimeric antigen receptor of claim 38, wherein each of the at least two antigen-specific targeting domains, independently, targets an antigen selected from the group consisting of antigens specific for cancer, an inflammatory disease, a neuronal disorder, diabetes, a cardiovascular disease, an infectious disease, and an autoimmune disease. 54. The bispecific chimeric antigen receptor of claim 53, wherein the antigens specific for cancer comprise any one or more of 4-1BB, 5T4, adenocarcinoma antigen, alpha-fetoprotein, BAFF, B-lymphoma cell, C242antigen, CA-125, carbonic anhydrase 9 (CA-IX), C-MET, CCR4, CD152, CD19, CD20, CD200, CD22, CD221, CD23 (IgE receptor), CD28, CD30(TNFRSF8), CD33, CD4, CD40, CD44 v6, CD51, CD52, CD56, CD74, CD80, CEA, CNTO888, CTLA-4, DR5, EGFR, EpCAM, CD3, FAP, fibronectin extra domain-B, folate receptor 1, GD2, GD3 ganglioside, glycoprotein 75, GPNMB, HER2/neu, HGF, human scatter factor receptor kinase, IGF-1 receptor, IGF-I, IgG1, L1-CAM, IL-13, IL-6, insulin-like growth factor I receptor, integrin .alpha.5.beta.1, integrin .alpha.v.beta.3, MORAb-009, MS4A1, MUC1, mucin CanAg, N-glycolylneuraminic acid, NPC-1C, PDGF-R .alpha., PDL192, phosphatidylserine, prostatic carcinoma cells, RANKL, RON, ROR1, SCH 900105, SDC1, SLAMF7, TAG-72, tenascin C, TGF beta 2, TGF-.beta., TRAIL-R1, TRAIL-R2, tumor antigen CTAA16.88, VEGF-A, VEGFR-1, VEGFR2, vimentin, and combinations thereof. 55. The bispecific chimeric antigen receptor of claim 38, wherein the at least two antigen-specific targeting regions bind (i) CD19and CD20, (ii) CD20 and L1-CAM, (iii) L1-CAM and GD2, (iv) EGFR and L1-CAM, (v) CD19 and CD22, (vi) EGFR and C-MET, (vii) EGFR and HER2, (viii) C-MET and HER2, or (ix) EGFR and ROR1. 56. The bispecific chimeric antigen receptor of claim 38, wherein the at least two antigen-specific targeting regions bind CD19 and CD20. 57. The bispecific chimeric antigen receptor of claim 53, wherein the antigen specific for an inflammatory disease comprises any one or more of AOC3 (VAP-1), CAM-3001, CCL11 (eotaxin-1), CD125, CD147 (basigin), CD154 (CD40L), CD2, CD20, CD23 (IgE receptor), CD25 (.alpha. chain of IL-2 receptor), CD3, CD4, CD5, IFN-.alpha., IFN-.gamma., IgE, IgE Fc region, IL-1, IL-12, IL-23, IL-13, IL-17, IL-17A, IL-22, IL-4, IL-5, IL-5, IL-6, IL-6 receptor, integrin .alpha.4, integrin .alpha.4.beta.7, LFA-1 (CD11a), MEDI-528, myostatin, OX-40, rhuMAb .beta.7, scleroscin, SOST, TGF beta 1, TNF-.alpha., VEGF-A, and combinations thereof. 58. The bispecific chimeric antigen receptor of claim 53, wherein the antigen specific for a neuronal disorder comprises beta amyloid, MABT5102A, or a combination thereof. 59. The bispecific chimeric antigen receptor of claim 53, wherein the antigen specific for diabetes comprises L-1.beta., CD3, or a combination thereof. 60. The bispecific chimeric antigen receptor of claim 53, wherein the antigen-specific for a cardiovascular disease comprises any one or more of C5, cardiac myosin, CD41 (integrin alpha-IIb), fibrin II, beta chain, ITGB2 (CD18), sphingosine-1-phosphate, and combinations thereof. 61. The bispecific chimeric antigen receptor of claim 53, wherein the antigen specific for an infectious disease comprises any one or more of anthrax toxin, CCR5, CD4, clumping factor A, cytomegalovirus, cytomegalovirus glycoprotein B, endotoxin, Escherichia coli, hepatitis B surface antigen, hepatitis B virus, HIV-1, Hsp90, Influenza A hemagglutinin, lipoteichoic acid, Pseudomonas aeruginosa, rabies virus glycoprotein, respiratory syncytial virus, TNF-.alpha., and combinations thereof. 62. In combination, the bispecific chimeric antigen receptor of claim 40 and the EGFRt. 63. The combination of claim 62, wherein the EGFRt binds any one or more of an EGFR-specific siRNA, a small molecule, an anti-EGFR antibody or a fragment thereof, or a combination thereof. 64. The combination of claim 62, wherein the bispecific chimeric antigen receptor and the EGFRt are linked via a cleavable linker. 65. The combination of claim 64, wherein the cleavable linker is a self-cleaving cleavable linker. 66. The combination of claim 64, wherein the cleavable linker is a 2A linker or a 2A-like linker. 67. A polypeptide encoded by a polynucleotide encoding the bispecific chimeric antigen receptor of claim 38 or the combination of claim 62. 68. A pharmaceutical composition, comprising: a. any one or more of the bispecific chimeric antigen receptor of claim 38, the combination of claim 62, the polypeptide of claim 67, and combinations thereof; and b. a pharmaceutically acceptable carrier. 69. In combination, the pharmaceutical composition of claim 68 and a composition adapted to biochemically interact with the therapeutic control to inhibit proliferation of a cell expressing the EGFRt. 70. A method for treating cancer in a subject in need thereof, comprising: administering a therapeutically effective amount of the composition of claim 68 to the subject so as to treat the cancer, wherein the at least two antigen-specific targeting regions target at least one antigen associated with the cancer. 71. A bispecific chimeric antigen receptor comprising the sequence set forth in SEQ ID NO: 2, 8 or 11. 72. A bispecific chimeric antigen receptor, comprising: a. at least two antigen-specific targeting regions; b. a CD8.alpha. hinge extracellular spacer domain; c. a CD8.alpha. transmembrane domain; d. a 4-1BB co-stimulatory domain; and e. a CD3 zeta intracellular signaling domain, wherein each antigen-specific targeting region comprises a single-domain antibody. 73. The bispecific chimeric antigen receptor of claim 72, wherein the bispecific chimeric antigen receptor is co-expressed with a therapeutic control, the therapeutic control comprising any one or more of EGFRt, thymidine kinase, cytosine deaminase, nitroreductase, xanthine-guanine phosphoribosyl transferase, human caspase 8, human caspase 9, purine nucleoside phosphorylase, linamarase/linamarin/glucose oxidase, deoxyribonucleoside kinase, horseradish peroxidase (HRP)/indole-3-acetic (IAA), gamma-glutamylcysteine synthetase, CD20/alphaCD20, CD34/thymidine kinase chimera, dox-depedent caspase-2, mutant thymidine kinase (HSV-TKSR39), AP1903/Fas system, a chimeric cytokine receptor (CCR), a selection marker, and combinations thereof. 74. The bispecific chimeric antigen receptor of claim 73, wherein the EGFRt binds any one or more of an EGFR-specific siRNA, a small molecule, an anti EGFR antibody or a fragment thereof, and a combination thereof. 75. The bispecific chimeric antigen receptor of claim 73, wherein the selection marker comprises any one or more of dihydroxyfolate receptor (DHFR), mutant DHFR, methylated-DNA-protein-cysteine methyltransferase, inosine monophosphate dehydrogenase II (IMDHP2) and combinations thereof. 76. The bispecific chimeric antigen receptor of claim73, wherein the CCR comprises any one or more of (i) IL-7 cytokine-linker- IL7R.alpha., (ii) IL-7 cytokine-linker-extracellular domain of IL-7R.alpha.-transmembrane domain of IL-7R.alpha.cytoplasmic domain of IL-2R.beta., (iii) IL-7cytokine-linker-IL2R.beta., and (iv) combinations thereof. 77. The bispecific chimeric antigen receptor of claim 72, wherein each of the at least two antigen-specific targeting domains, independently, targets an antigen selected from the group consisting of antigens specific for cancer, an inflammatory disease, a neuronal disorder, diabetes, a cardiovascular disease, an infectious disease, and an autoimmune disease. 78. The bispecific chimeric antigen receptor of claim 77, wherein the antigen specific for cancer comprises any one or more of 4-1BB, 5T4, adenocarcinoma antigen, alpha-fetoprotein, BAFF, B-lymphoma cell, C242 antigen, CA-125, carbonic anhydrase 9 (CA-IX), C-MET, CCR4, CD152, CD19, CD20, CD200, CD22, CD221, CD23 (IgE receptor), CD28, CD30 (TNFRSF8), CD33, CD4, CD40, CD4 v6, CD51, CD52, CD56, CD74, CD80, CEA, CNTO888, CTLA-4, DR5, EGFR, EpCAM, CD3, FAP, fibronectin extra domain-B, folate receptor 1, GD2, GD3 ganglioside, glycoprotein 75, GPNMB, HER2/neu, HGF, human scatter factor receptor kinase, IGF-1 receptor, IGF-I, IgG1, L1-CAM, IL-13, IL-6, insulin-like growth factor I receptor, integrin .alpha.5.beta.1, integrin .alpha.v.beta.3, MORAb-009, MS4A1, MUC1, mucin CanAg, N-glycolylneuraminic acid, NPC-1C, PDGF-R .alpha., PDL192, phosphatidylserine, prostatic carcinoma cells, RANKL, RON, ROR1, SCH 900105, SDC1, SLAMF7, TAG-72, tenascin C, TGF beta 2, TGF-.beta., TRAIL-R1, TRAIL-R2, tumor antigen CTAA16.88, VEGF-A, VEGFR-1, VEGFR2, vimentin, and combinations thereof. 79. The bispecific chimeric antigen receptor of claim 77, wherein the at least two antigen-specific targeting regions bind (i) CD19 and CD20, (ii) CD20 and L1-CAM, (iii) L1-CAM and GD2, (iv) EGFR and L1-CAM, (v) CD19 and CD22, (vi) EGFR and C-MET, (vii) EGFR and HER2, (viii) C-MET and HER2, or (ix) EGFR and ROR1. 80. The bispecific chimeric antigen receptor of claim 79, wherein the at least two antigen-specific targeting regions bind CD19 and CD20. 81. The bispecific chimeric antigen receptor of claim 77, wherein the antigen specific for an inflammatory disease comprises any one or more of AOC3 (VAP-1), CAM-3001, CCL11 (eotaxin-1), CD125, CD147 (basigin), CD154 (CD40L), CD2, CD20, CD23 (IgE receptor), CD25 (.alpha. chain of IL-2 receptor), CD3, CD4, CD5, IFN-.alpha.IFN-.gamma.IgE, IgE Fc region, IL-1, IL-12, IL-23, IL-13, IL-17, IL-17A, IL-22, IL-4, IL-5, IL-5, IL-6, IL-6 receptor, integrin .alpha.4, integrin .alpha.4.beta.7, LFA-1 (CD11a), MEDI-528, myostatin, OX-40, rhuMAb .beta.7, scleroscin, SOST, TGF beta 1, TNF-.alpha., VEGF-A, and combinations thereof. 82. The bispecific chimeric antigen receptor of claim 77, wherein the antigen specific for a neuronal disorder comprises beta amyloid, MABT5102A, or a combination thereof. 83. The bispecific chimeric antigen receptor of claim77, wherein the antigen specific for diabetes comprises L-1.beta., CD3, or a combination thereof. 84. The bispecific chimeric antigen receptor of claim 77, wherein the antigen-specific for a cardiovascular disease comprises any one or more of C5, cardiac myosin, CD41 (integrin alpha-IIb), fibrin II, beta chain, ITGB2 (CD18) , sphingosine-1-phosphate, and combinations thereof. 85. The bispecific chimeric antigen receptor of claim 77, wherein the antigen specific for an infectious disease comprises any one or more of anthrax toxin, CCR5, CD4, clumping factor A, cytomegalovirus, cytomegalovirus glycoprotein B, endotoxin, Escherichia coli, hepatitis B surface antigen, hepatitis B virus, HIV-1, Hsp90, Influenza A hemagglutinin, lipoteichoic acid, Pseudomonas aeruginosa, rabies virus glycoprotein, respiratory syncytial virus, TNF-a, and combinations thereof. 86. A method for treating cancer in a subject in need thereof, comprising: administering a therapeutically effective amount of the composition of claim 35 to the subject so as to treat the cancer, wherein the at least two antigen-specific targeting regions target at least one antigen that is associated with the cancer. 87. The combination of claim 69, wherein the composition adapted to biochemically interact with the therapeutic control is any one or more of trastuzumab, methotrexate, cetuximab, ganciclovir, (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU), 5-flurocytosine (5-FC), 5-(azaridin-l-yl)-2, 4-dinitrobenzamide (CB1954), 6-thioguanine, AP1903, fludarabine phosphate, linamarin (lin), difluorodeoxycytidine (dFdC), 1-.beta.-D-arabinofuranosylthymine (ara-T)), indole-3-acetic (IAA), 1-buthionine-S,R-sulfoximine (BSO), rituximab (RTX), doxycycline, tyrosine kinase inhibitors or combinations thereof.

Details for Patent 10,189,903

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2032-02-13
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2032-02-13
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2032-02-13
Eli Lilly And Company	ERBITUX	cetuximab	Injection	125084	02/12/2004		2032-02-13
Eli Lilly And Company	ERBITUX	cetuximab	Injection	125084	03/28/2007		2032-02-13
Genentech, Inc.	RITUXAN HYCELA	rituximab and hyaluronidase human	Injection	761064	06/22/2017		2032-02-13