Abc and gate car-t cell therapy for autoimmune disease

Abstract

Provided herein is a CAR-T receptor, T cells comprising the CAR-T receptor, compositions comprising the T cells, and nucleic acids encoding the T-cell receptor, for use in treating diseases involving B cells.

Description

ABC AND GATE CAR-T CELL THERAPY FOR AUTOIMMUNE DISEASECROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to United States Provisional Patent Application No. 63 / 652,326 filed May 28, 2024, the disclosure of which is hereby incorporated by reference in its entirety.REFERENCE TO A SEQUENCE LISTING

[0002] The Sequence Listing associated with this application is filed in electronic format via Patent Center and is hereby incorporated by reference into the specification in its entirety. The name of the file containing the Sequence Listing is 2500475. xml. The size of the file is 34,876 bytes, and the file was created on May 27, 2025.BACKGROUND

[0003] Age-associated B Cells (ABC), or DN2 B cells have been associated with a variety of autoimmune diseases, including Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis (RA), Ankylosing Spondylitis, Multiple Sclerosis and Atherosclerosis. They are also associated with severe infections such as with malaria and SARS-CoV19. In lupus, ABCs’ frequencies in blood are positively associated with more severe disease and subsets of patients with more severe disease phenotypes have notably more ABCs. We recently showed in a genetic model system that also utilized bone marrow chimera generation in mice, that depletion of ABCs led to less severe disease.

[0004] ABCs are a target, but to date there is no therapeutic way to selectively deplete or inactivate them in either an animal model or a human.

[0005] CAR19 T cells (CAR-T cells targeting cells bearing the CD19 antigen) are currently an FDA-approved autologous engineered T cell product in active clinical use, in which a DNA construct is introduced into normal T cells that encodes a chimeric antigen receptor in which the external portion contains immunoglobulin (Ig) V regions from an antibody that recognizes CD19, a B cell-specific surface protein. This recognition domain is linked to engineered intracytoplasm ic "tail" regions that transduce TCR-like signaling if the ligand-binding (e.g., CD19-binding) domain is triggered. There are several variations on how this is implemented. The result of recognition of a CD19+ B cell by the CAR19 T cell in vivo is the killing of the cell. This was originally developed to treat B lineage neoplasms, such as leukemia and lymphoma, for which it is very effective. More recently, CAR19 T cells have beenrepurposed to treat a variety of autoimmune diseases, for which it is also very effective. However, targeting of all CD19+ cells is not desirable, resulting in undesirable immunosuppression. Methods of selectively targeting specific B-cell subgroups, as well as diseases associated with specific B-cell subgroups, such as ABC cells, memory B cells, and / or activated B cells, are desirable.SUMMARY

[0006] Provided herein is a type of Chimeric Antigen Receptor (CAR) T cell that uses synthetic signaling or “balanced signaling” to target only a certain type of B cell that is associated with immunopathogenesis. This B cell type is variously referred to in the literature as Age-associated B Cells (ABC), or DN2 B cells. These cells have been associated with a variety of autoimmune diseases, including Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis (RA), Ankylosing Spondylitis, Multiple Sclerosis and Atherosclerosis. They are also associated with severe infections such as with malaria and SARS-CoV19. In lupus, ABCs frequencies in blood are positively associated with more severe disease and subsets of patients with more severe disease phenotypes have notably more ABCs. We recently showed in a genetic model system that also utilized bone marrow chimera generation in mice, that depletion of ABCs led to less severe disease.

[0007] Also provided herein is a pair of CAR-T receptors that individually recognize two different surface antigens on a target B cell, optionally a human B cell.

[0008] Also provided herein is a CAR-T cell expressing a pair of CAR-T receptors as described herein.

[0009] Also provided herein is a composition including a CAR-T cell as described herein and a pharmaceutically-acceptable excipient or carrier, such as water, PBS, or serum-free cell culture media.

[0010] Also provided herein is a composition including one or more nucleic acid(s), e.g., a plasmid or plasmid pair, comprising genes for expressing a pair of CAR-T receptors as described herein, optionally in a viral vector genome, such as a recombinant lentiviral vector genome.

[0011] Also provided herein is a method of treating an autoimmune disease in a patient, e.g., a human patient, including administering a composition including a CAR- T cell as described herein to the patient in an amount effective to treat the autoimmune disease in the patient, e.g., from 102to 1012of the CAR-T cells, inclusive, including any increment therebetween, in one or more doses.

[0012] Also provided herein is a method of reducing a population of B cells in a patient, e.g., a human patient, including administering a composition including a CAR-T cell as described herein to the patient in an amount effective to a population of a B cells in the patient, e.g., from 102to 1012of the CAR-T cell cells, inclusive, including any increment therebetween, in one or more doses.

[0013] Also provided herein is a method of treating atherosclerosis in a patient, e.g., a human patient, including administering a composition including a CAR-T cell as described herein to the patient in an amount effective to treat atherosclerosis in the patient, e.g., from 102to 1012of the CAR-T cell cells, inclusive, including any increment therebetween, in one or more doses.

[0014] Also provided herein is a CAR-T cell having a first synthetic receptor for binding a first antigen of a target B cell, and a second receptor for binding a second antigen of a target B cell, the first synthetic receptor having a CD19 recognition domain and the second synthetic receptor having a CD11 c recognition domain.

[0015] Also provided herein is a CAR-T cell having a first synthetic receptor for binding a first antigen of a target B cell, and a second receptor for binding a second antigen of a target B cell, the first synthetic receptor having a sequence of SEQ ID NO: 1 , SEQ ID NO: 3, SEQ ID NO: 6, SEQ ID NO: 8, and / or SEQ ID NO: 11 and the second synthetic receptor having a sequence of SEQ ID NO: 2, SEQ ID NO: 14, SEQ ID NO: 17, and / or SEQ ID NO: 18.

[0016] Also provided herein is use of a CAR-T cell as described herein for the treatment of Addison’s disease; Adult Still’s disease; Agammaglobulinemia; Alopecia areata; Amyloidosis; Ankylosing spondylitis; Anti-GBM / Anti-TBM nephritis; Antiphospholipid syndrome; Autoimmune angioedema; Autoimmune dysautonomia; Autoimmune encephalitis; Autoimmune hepatitis; Autoimmune inner ear disease (AIED); Autoimmune myocarditis; Autoimmune oophoritis; Autoimmune orchitis; Autoimmune pancreatitis; Autoimmune retinopathy; Autoimmune urticaria; Axial spondyloarthritis; Axonal & neuronal neuropathy (AMAN); Balo disease; Behcet’s disease; Benign mucosal pemphigoid (Mucous membrane pemphigoid); Bullous pemphigoid; Castleman disease (CD); Celiac disease; Chagas disease; Chronic inflammatory demyelinating polyneuropathy (CIDP); Chronic recurrent multifocal osteomyelitis (CRMO); Churg-Strauss syndrome (CSS) or Eosinophilic granulomatosis (EGPA); Cicatricial pemphigoid; Cogan’s syndrome; Cold agglutinin disease; Common variable immunodeficiency (CVID) with autoimmune complications;Complex regional pain syndrome (formerly known as reflex sympathetic dystrophy); Congenital heart block; Coxsackie myocarditis; CREST syndrome; Crohn’s disease; Dermatitis herpetiformis; Dermatomyositis; Devic’s disease (neuromyelitis optica); Discoid lupus; Dressier’s syndrome; Endometriosis; Eosinophilic esophagitis (EoE); Eosinophilic fasciitis; Erythema nodosum; Essential mixed cryoglobulinemia; Evans syndrome; Fibromyalgia; Fibrosing alveolitis; Giant cell arteritis (temporal arteritis); Giant cell myocarditis; Glomerulonephritis; Goodpasture’s syndrome; Granulomatosis with polyangiitis; Graves’ disease; Guillain-Barre syndrome; Hashimoto’s thyroiditis; Hemolytic anemia; Henoch-Schonlein purpura (HSP); Herpes gestationis or pemphigoid gestationis (PG); Hidradenitis suppurativa (HS) (Acne inversa); IgA nephropathy; lgG4-related sclerosing disease; Immune thrombocytopenic purpura (ITP); Inclusion body myositis (IBM); Interstitial cystitis (IC); Juvenile arthritis; Juvenile diabetes (Type 1 diabetes); Juvenile myositis (JM); Kawasaki disease; Lambert-Eaton syndrome; Lichen planus; Lichen sclerosus; Ligneous conjunctivitis; Linear IgA disease (LAD); Lyme disease chronic; Malarial autoimmune anemia; Meniere’s disease; Microscopic polyangiitis (MPA); Mixed connective tissue disease (MCTD); Mucha-Habermann disease; Multifocal motor neuropathy (MMN) or MMNCB; MS; Myasthenia gravis; Myelin oligodendrocyte glycoprotein antibody disorder; Myositis; Narcolepsy; Neonatal lupus; Neuromyelitis optica / devic disease; Neutropenia; Ocular cicatricial pemphigoid; Optic neuritis; Palindromic rheumatism (PR); PANDAS (Pediatric autoimmune neuropsychiatric disorders associated with streptococcus infections); Paraneoplastic cerebellar degeneration (PCD); Paroxysmal nocturnal hemoglobinuria (PNH); Pars planitis (peripheral uveitis); Parsonage-Turner syndrome; Pemphigus; Peripheral neuropathy; Perivenous encephalomyelitis; Pernicious anemia (PA); POEMS syndrome; Polyarteritis nodosa; Polyglandular syndromes type I, II, III; Polymyalgia rheumatica; Polymyositis; Postmyocardial infarction syndrome; Postpericardiotomy syndrome; Primary biliary cholangitis; Primary sclerosing cholangitis; Progesterone dermatitis; Progressive hemifacial atrophy (PHA) Parry romberg syndrome; Psoriasis; Psoriatic arthritis; Pulmonary Alveolar Proteinosis (PAP); Pure red cell aplasia (PRCA); Pyoderma gangrenosum; Raynaud’s phenomenon; Reactive arthritis; Relapsing polychondritis; Restless legs syndrome (RLS); Retroperitoneal fibrosis; Rheumatic fever; RA; Sarcoidosis; Schmidt syndrome or Autoimmune polyendocrine syndrome type II; Scleritis; Scleroderma; SLE; SS; Stiff person syndrome (SPS); Susac’s syndrome; Sympathetic ophthalmia (SO);Takayasu’s arteritis; Temporal arteritis / giant cell arteritis; Thrombocytopenic purpura (TTP); Thrombotic thrombocytopenic purpura (Ttp); Thyroid Eye Disease (TED); Tolosa-Hunt syndrome (THS); Transverse myelitis; Type 1 diabetes; Ulcerative colitis (UC); Undifferentiated connective tissue disease (UCTD); Uveitis; Vasculitis; Vitiligo; Vogt-Koyanagi-Harada disease; or Warm autoimmune hemolytic anemia.

[0017] Also provided herein is a method of treating a condition in a patient, including administering a composition comprising from 102to 1012a CAR-T cell as described herein, in one or more doses, to the patient.

[0018] The following numbered clauses illustrate various aspects or embodiments of the present invention.

[0019] 1. A pair of CAR-T receptors that individually recognize two different surface antigens on a target B cell, optionally a human B cell.

[0020] 2. The pair of CAR-T receptors of clause 1 , that are activated only on binding the two different surface proteins on the B cell.

[0021] 3. The pair of CAR-T receptors of clause 1 or clause 2, comprising a first synthetic receptor for binding a first antigen of the B cell, and a second receptor for binding a second antigen of the B cell, and wherein the first synthetic receptor and the second synthetic receptor each comprises amino acid chain comprising a signaling moiety and an antigen binding moiety and wherein the signaling moieties activate the CAR-T cell only when the antigen binding moieties of the first synthetic receptor and the second synthetic receptor bind the first antigen and the second antigen on the B cell.

[0022] 4. The pair of CAR-T receptors of any of clauses 1 -3, wherein the first antigen is a CD19 or CD20.

[0023] 5. The pair of CAR-T receptors of any of clauses 1 -4, wherein the second antigen is CD11c, CD11 b, CD27 or CD80.

[0024] 6. The pair of CAR-T receptors of any of clauses 1 -5, wherein the second antigen is a memory B cell surface antigen.

[0025] 7. The pair of CAR-T receptors of any of clauses 1 -6, wherein the first antigen is CD19, and the second antigen is CD11 c.

[0026] 8. The pair of CAR-T receptors of any of clauses 1 -7, wherein the first synthetic receptor and the second synthetic receptors are CARs that activate the T- cell only when the CARs are bound to both the first antigen and the second antigen.

[0027] 9. The pair of CAR-T receptors of any of clauses 1 -8, wherein the signaling moiety of the first synthetic receptor is LAT, and the signaling moiety of the second synthetic receptor is SLP.

[0028] 10. The pair of CAR-T receptors of any of clauses 1 -9, wherein the signaling moiety of the first synthetic receptor is that, when included in the first synthetic receptor with an antigen binding moiety in a CAR-T cell, is unable to activate the CAR-T cell on binding to a cell having a surface antigen that binds to the antigen binding moiety of the first synthetic receptor without binding of a surface antigen of the cell to the antigen binding moiety of the second synthetic receptor, and the signaling moiety of the second synthetic receptor is a 4-1 BB signaling moiety that is unable to activate the CAR-T cell on binding to a cell having a surface antigen that binds to the antigen binding moiety of the second synthetic receptor without binding of a surface antigen of the cell to the antigen binding moiety of the first synthetic receptor, such that when both of the antigen binding moieties of the first and second synthetic receptors bind surface antigens on a cell, the CAR-T cell is activated.

[0029] 11. The pair of CAR-T receptors of any of clauses 1 -10, wherein the first synthetic receptor comprises an antigen binding moiety linked to a transcription activator that activates a gene encoding the second synthetic receptor comprising an antigen binding moiety linked to a T-cell activator such that a CAR-T cell comprising the first and second synthetic receptors are only activated on antigen binding of both the first and second synthetic receptors.

[0030] 12. The pair of CAR-T receptors of any of clauses 1-11 , wherein the transcription activator is a synNotch activator.

[0031] 13. The pair of CAR-T receptors of any of clauses 1 -12, wherein the second antigen is an activated B cell surface antigen.

[0032] 14. The pair of CAR-T receptors of any of clauses 1 -13, wherein the first antigen binding moiety and the second antigen binding moiety are scFv fragments.

[0033] 15. The pair of CAR-T receptors of any of clauses 1 -14, wherein the B-cell is an ABC cell.

[0034] 16. The pair of CAR-T receptors of any of clauses 1 -15, wherein the B-cell is a memory B cell or an activated B cell.

[0035] 17. A CAR-T cell expressing the pair of CAR-T receptors of any of clauses 1 -16.

[0036] 18. The CAR-T cell of clause 17, able to kill, in vitro, an ABC cell, a memory B cell, and / or an activated B cell expressing the two surface antigens.

[0037] 19. A composition comprising the CAR-T cell of clause 17 or clause 18, and a pharmaceutically-acceptable excipient or carrier, such as water, PBS, or serum-free cell culture media.

[0038] 20. A composition comprising one or more nucleic acid(s), e.g., a plasmid or plasmid pair, comprising genes for expressing the pair of CAR-T receptors of any of clauses 1 -16, optionally in a viral vector genome, such as a recombinant lentiviral vector genome.

[0039] 21 . A method of treating an autoimmune disease in a patient, e.g., a human patient, comprising administering the composition of clause 19 or clause 20 to the patient in an amount effective to treat the autoimmune disease in the patient, e.g., from 102to 1012of the CAR-T cells, inclusive, including any increment therebetween, in one or more doses.

[0040] 22. The method of clause 21 , wherein the B cells are ABC cells.

[0041] 23. The method of clause 21 or clause 22, wherein the patient has: Systemic lupus erythematosus (SLE), Multiple sclerosis (MS), Rheumatoid arthritis (RA), Sjogren’s syndrome (SS), Ankylosing Spondylitis, Axial spondyloarthritis, Scleroderma, Malarial autoimmune anemia, Common variable immunodeficiency (CVID) with autoimmune complications, Crohn’s disease, ulcerative colitis, or dermatomyositis.

[0042] 24. The method of any of clauses 21 -23, wherein the B cells are memory B cells or activated B cells.

[0043] 25. The method of any of clauses 21 -24, wherein the patient has: Addison’s disease; Adult Still’s disease; Agammaglobulinemia; Alopecia areata; Amyloidosis; Ankylosing spondylitis; Anti-GBM / Anti-TBM nephritis; Antiphospholipid syndrome; Autoimmune angioedema; Autoimmune dysautonomia; Autoimmune encephalitis; Autoimmune hepatitis; Autoimmune inner ear disease (AIED); Autoimmune myocarditis; Autoimmune oophoritis; Autoimmune orchitis; Autoimmune pancreatitis; Autoimmune retinopathy; Autoimmune urticaria; Axial spondyloarthritis; Axonal & neuronal neuropathy (AMAN); Balo disease; Behcet’s disease; Benign mucosal pemphigoid (Mucous membrane pemphigoid); Bullous pemphigoid; Castleman disease (CD); Celiac disease; Chagas disease; Chronic inflammatory demyelinating polyneuropathy (CIDP); Chronic recurrent multifocal osteomyelitis (CRMO); Churg-Strauss syndrome (CSS) or Eosinophilic granulomatosis (EGPA); Cicatricial pemphigoid; Cogan’s syndrome; Cold agglutinin disease; Common variable immunodeficiency (CVID) with autoimmune complications; Complex regional pain syndrome (formerly known as reflex sympathetic dystrophy); Congenital heart block; Coxsackie myocarditis; CREST syndrome; Crohn’s disease; Dermatitis herpetiformis; Dermatomyositis; Devic’s disease (neuromyelitis optica); Discoid lupus; Dressier’s syndrome; Endometriosis; Eosinophilic esophagitis (EoE); Eosinophilic fasciitis; Erythema nodosum; Essential mixed cryoglobulinemia; Evans syndrome; Fibromyalgia; Fibrosing alveolitis; Giant cell arteritis (temporal arteritis); Giant cell myocarditis; Glomerulonephritis; Goodpasture’s syndrome; Granulomatosis with polyangiitis; Graves’ disease; Guillain-Barre syndrome; Hashimoto’s thyroiditis; Hemolytic anemia; Henoch-Schonlein purpura (HSP); Herpes gestationis or pemphigoid gestationis (PG); Hidradenitis suppurativa (HS) (Acne inversa); IgA nephropathy; lgG4-related sclerosing disease; Immune thrombocytopenic purpura (ITP); Inclusion body myositis (IBM); Interstitial cystitis (IC); Juvenile arthritis; Juvenile diabetes (Type 1 diabetes); Juvenile myositis (JM); Kawasaki disease; Lambert-Eaton syndrome; Lichen planus; Lichen sclerosus; Ligneous conjunctivitis; Linear IgA disease (LAD); Lyme disease chronic; Malarial autoimmune anemia; Meniere’s disease; Microscopic polyangiitis (MPA); Mixed connective tissue disease (MCTD); Mucha-Habermann disease; Multifocal motor neuropathy (MMN) or MMNCB; MS; Myasthenia gravis; Myelin oligodendrocyte glycoprotein antibody disorder; Myositis; Narcolepsy; Neonatal lupus; Neuromyelitis optica / devic disease; Neutropenia; Ocular cicatricial pemphigoid; Optic neuritis; Palindromic rheumatism (PR); PANDAS (Pediatric autoimmune neuropsychiatric disorders associated with streptococcus infections); Paraneoplastic cerebellar degeneration (PCD); Paroxysmal nocturnal hemoglobinuria (PNH); Pars planitis (peripheral uveitis); Parsonage-Turner syndrome; Pemphigus; Peripheral neuropathy; Perivenous encephalomyelitis; Pernicious anemia (PA); POEMS syndrome; Polyarteritis nodosa; Polyglandular syndromes type I, II, III; Polymyalgia rheumatica; Polymyositis; Postmyocardial infarction syndrome; Postpericardiotomy syndrome; Primary biliary cholangitis; Primary sclerosing cholangitis; Progesterone dermatitis; Progressive hemifacial atrophy (PHA) Parry romberg syndrome; Psoriasis; Psoriatic arthritis; Pulmonary Alveolar Proteinosis (PAP); Pure red cell aplasia (PRCA); Pyoderma gangrenosum; Raynaud’s phenomenon; Reactive arthritis; Relapsing polychondritis; Restless legs syndrome(RLS); Retroperitoneal fibrosis; Rheumatic fever; RA; Sarcoidosis; Schmidt syndrome or Autoimmune polyendocrine syndrome type II; Scleritis; Scleroderma; SLE; SS; Stiff person syndrome (SPS); Susac’s syndrome; Sympathetic ophthalmia (SO); Takayasu’s arteritis; Temporal arteritis / giant cell arteritis; Thrombocytopenic purpura (TTP); Thrombotic thrombocytopenic purpura (Ttp); Thyroid Eye Disease (TED); Tolosa-Hunt syndrome (THS); Transverse myelitis; Type 1 diabetes; Ulcerative colitis (UC); Undifferentiated connective tissue disease (UCTD); Uveitis; Vasculitis; Vitiligo; Vogt-Koyanagi-Harada disease; or Warm autoimmune hemolytic anemia.

[0044] 26. A method of reducing a population of B cells in a patient, e.g., a human patient, comprising administering the composition of clause 19 or clause 20 to the patient in an amount effective to a population of a B cells in the patient, e.g., from 102to 1012of the CAR-T cell cells, inclusive, including any increment therebetween, in one or more doses.

[0045] 27. The method of clause 26, wherein the patient has: Addison’s disease; Adult Still’s disease; Agammaglobulinemia; Alopecia areata; Amyloidosis; Ankylosing spondylitis; Anti-GBM / Anti-TBM nephritis; Antiphospholipid syndrome; Autoimmune angioedema; Autoimmune dysautonomia; Autoimmune encephalitis; Autoimmune hepatitis; Autoimmune inner ear disease (AIED); Autoimmune myocarditis; Autoimmune oophoritis; Autoimmune orchitis; Autoimmune pancreatitis; Autoimmune retinopathy; Autoimmune urticaria; Axial spondyloarthritis; Axonal & neuronal neuropathy (AMAN); Balo disease; Behcet’s disease; Benign mucosal pemphigoid (Mucous membrane pemphigoid); Bullous pemphigoid; Castleman disease (CD); Celiac disease; Chagas disease; Chronic inflammatory demyelinating polyneuropathy (CIDP); Chronic recurrent multifocal osteomyelitis (CRMO); Churg-Strauss syndrome (CSS) or Eosinophilic granulomatosis (EGPA); Cicatricial pemphigoid; Cogan’s syndrome; Cold agglutinin disease; Common variable immunodeficiency (CVID) with autoimmune complications; Complex regional pain syndrome (formerly known as reflex sympathetic dystrophy); Congenital heart block; Coxsackie myocarditis; CREST syndrome; Crohn’s disease; Dermatitis herpetiformis; Dermatomyositis; Devic’s disease (neuromyelitis optica); Discoid lupus; Dressier’s syndrome; Endometriosis; Eosinophilic esophagitis (EoE); Eosinophilic fasciitis; Erythema nodosum; Essential mixed cryoglobulinemia; Evans syndrome; Fibromyalgia; Fibrosing alveolitis; Giant cell arteritis (temporal arteritis); Giant cell myocarditis; Glomerulonephritis; Goodpasture’s syndrome; Granulomatosis with polyangiitis; Graves’ disease; Guillain-Barre syndrome; Hashimoto’s thyroiditis; Hemolytic anemia; Henoch-Schonlein purpura (HSP); Herpes gestationis or pemphigoid gestationis (PG); Hidradenitis suppurativa (HS) (Acne inversa); IgA nephropathy; lgG4-related sclerosing disease; Immune thrombocytopenic purpura (ITP); Inclusion body myositis (IBM); Interstitial cystitis (IC); Juvenile arthritis; Juvenile diabetes (Type 1 diabetes); Juvenile myositis (JM); Kawasaki disease; Lambert-Eaton syndrome; Lichen planus; Lichen sclerosus; Ligneous conjunctivitis; Linear IgA disease (LAD); Lyme disease chronic; Malarial autoimmune anemia; Meniere’s disease; Microscopic polyangiitis (MPA); Mixed connective tissue disease (MCTD); Mucha-Habermann disease; Multifocal motor neuropathy (MMN) or MMNCB; MS; Myasthenia gravis; Myelin oligodendrocyte glycoprotein antibody disorder; Myositis; Narcolepsy; Neonatal lupus; Neuromyelitis optica I devic disease; Neutropenia; Ocular cicatricial pemphigoid; Optic neuritis; Palindromic rheumatism (PR); PANDAS (Pediatric autoimmune neuropsychiatric disorders associated with streptococcus infections); Paraneoplastic cerebellar degeneration (PCD); Paroxysmal nocturnal hemoglobinuria (PNH); Pars planitis (peripheral uveitis); Parsonage-Turner syndrome; Pemphigus; Peripheral neuropathy; Perivenous encephalomyelitis; Pernicious anemia (PA); POEMS syndrome; Polyarteritis nodosa; Polyglandular syndromes type I, II, III; Polymyalgia rheumatica; Polymyositis; Postmyocardial infarction syndrome; Postpericardiotomy syndrome; Primary biliary cholangitis; Primary sclerosing cholangitis; Progesterone dermatitis; Progressive hemifacial atrophy (PHA) Parry romberg syndrome; Psoriasis; Psoriatic arthritis; Pulmonary Alveolar Proteinosis (PAP); Pure red cell aplasia (PRCA); Pyoderma gangrenosum; Raynaud’s phenomenon; Reactive arthritis; Relapsing polychondritis; Restless legs syndrome (RLS); Retroperitoneal fibrosis; Rheumatic fever; RA; Sarcoidosis; Schmidt syndrome or Autoimmune polyendocrine syndrome type II; Scleritis; Scleroderma; SLE; SS; Stiff person syndrome (SPS); Susac’s syndrome; Sympathetic ophthalmia (SO); Takayasu’s arteritis; Temporal arteritis / giant cell arteritis; Thrombocytopenic purpura (TTP); Thrombotic thrombocytopenic purpura (Ttp); Thyroid Eye Disease (TED); Tolosa-Hunt syndrome (THS); Transverse myelitis; Type 1 diabetes; Ulcerative colitis (UC); Undifferentiated connective tissue disease (UCTD); Uveitis; Vasculitis; Vitiligo; Vogt-Koyanagi-Harada disease; or Warm autoimmune hemolytic anemia.

[0046] 28. The method of clause 26 or clause 27, wherein the B cells are ABC cells.

[0047] 29. The method of any of clauses 26-28, wherein the patient has: Systemic lupus erythematosus (SLE), Multiple sclerosis (MS), Rheumatoid arthritis (RA), Sjogren’s syndrome (SS), Ankylosing Spondylitis, Axial spondyloarthritis, Scleroderma, Malarial autoimmune anemia, Common variable immunodeficiency (CVID) with autoimmune complications, Crohn’s disease, ulcerative colitis, or dermatomyositis.

[0048] 30. The method of any of clauses 26-29, wherein the B cells are memory B cells or activated B cells.

[0049] 31 . A method of treating atherosclerosis in a patient, e.g., a human patient, comprising administering the composition of clause 19 or clause 20 to the patient in an amount effective to treat atherosclerosis in the patient, e.g., from 102to 1012of the CAR-T cell cells, inclusive, including any increment therebetween, in one or more doses.

[0050] 32. A CAR-T cell comprising a first synthetic receptor for binding a first antigen of a target B cell, and a second receptor for binding a second antigen of a target B cell, the first synthetic receptor comprising a CD19 recognition domain and the second synthetic receptor comprising a CD11 c recognition domain.

[0051] 33. The CAR-T cell of clause 32, wherein, in the presence of a B cell comprising only one of CD19 or CD11 c, the CAR-T cell is incapable of killing the B cell.

[0052] 34. The CAR-T cell of clause 32 or clause 33, wherein the CD19 recognition domain comprises an anti-CD19 scFv.

[0053] 35. The CAR-T cell of any of clauses 32-34, wherein the first receptor further comprises a CD28 hinge and transmembrane domain comprising at least two cysteine to alanine mutations.

[0054] 36. The CAR-T cell of any of clauses 32-35, wherein the first receptor further comprises a LAT protein cytoplasmic domain modified by deletion of amino acids 171 - 233.

[0055] 37. The CAR-T cell of any of clauses 32-36, wherein the CD11 c recognition domain comprises a CD11 c scFv.

[0056] 38. The CAR-T cell of any of clauses 32-37, wherein the second receptor further comprises a CD8 alpha protein hinge and transmembrane domain.

[0057] 39. The CAR-T cell of any of clauses 32-38, wherein the second receptor further comprises an SLP-76 cytoplasmic domain modified by deletion of amino acids 224-244.

[0058] 40. A CAR-T cell comprising a first synthetic receptor for binding a first antigen of a target B cell, and a second receptor for binding a second antigen of a target B cell, the first synthetic receptor comprising SEQ ID NO: 1 , SEQ ID NO: 3, SEQ ID NO: 6, SEQ ID NO: 8, and / or SEQ ID NO: 11 and the second synthetic receptor comprising SEQ ID NO: 2, SEQ ID NO: 14, SEQ ID NO: 17, and / or SEQ ID NO: 18.

[0059] 41. The CAR-T cell of clause 40, wherein the first synthetic receptor comprises SEQ ID NO: 1.

[0060] 42. The CAR-T cell of clause 40 or clause 41 , wherein the first synthetic receptor comprises SEQ ID NO: 3.

[0061] 43. The CAR-T cell of any of clauses 40-42, wherein the first synthetic receptor comprises SEQ ID NO: 6.

[0062] 44. The CAR-T cell of any of clauses 40-43, wherein the first synthetic receptor comprises SEQ ID NO: 8.

[0063] 45. The CAR-T cell of any of clauses 40-44, wherein the first synthetic receptor comprises SEQ ID NO: 11 .

[0064] 46. The CAR-T cell of any of clauses 40-45, wherein the second synthetic receptor comprises SEQ ID NO: 2.

[0065] 47. The CAR-T cell of any of clauses 40-46, wherein the second synthetic receptor comprises SEQ ID NO: 14.

[0066] 48. The CAR-T cell of any of clauses 40-47, wherein the second synthetic receptor comprises SEQ ID NO: 17.

[0067] 49. The CAR-T cell of any of clauses 40-48, wherein the second synthetic receptor comprises SEQ ID NO: 18.

[0068] 50. Use of the CAR-T cell of any of any of clauses 32-49 for the treatment of Addison’s disease; Adult Still’s disease; Agammaglobulinemia; Alopecia areata; Amyloidosis; Ankylosing spondylitis; Anti-GBM / Anti-TBM nephritis; Antiphospholipid syndrome; Autoimmune angioedema; Autoimmune dysautonomia; Autoimmune encephalitis; Autoimmune hepatitis; Autoimmune inner ear disease (AIED); Autoimmune myocarditis; Autoimmune oophoritis; Autoimmune orchitis; Autoimmune pancreatitis; Autoimmune retinopathy; Autoimmune urticaria; Axial spondyloarthritis;Axonal & neuronal neuropathy (AMAN); Balo disease; Behcet’s disease; Benign mucosal pemphigoid (Mucous membrane pemphigoid); Bullous pemphigoid; Castleman disease (CD); Celiac disease; Chagas disease; Chronic inflammatory demyelinating polyneuropathy (CIDP); Chronic recurrent multifocal osteomyelitis (CRMO); Churg-Strauss syndrome (CSS) or Eosinophilic granulomatosis (EGPA); Cicatricial pemphigoid; Cogan’s syndrome; Cold agglutinin disease; Common variable immunodeficiency (CVID) with autoimmune complications; Complex regional pain syndrome (formerly known as reflex sympathetic dystrophy); Congenital heart block; Coxsackie myocarditis; CREST syndrome; Crohn’s disease; Dermatitis herpetiformis; Dermatomyositis; Devic’s disease (neuromyelitis optica); Discoid lupus; Dressier’s syndrome; Endometriosis; Eosinophilic esophagitis (EoE); Eosinophilic fasciitis; Erythema nodosum; Essential mixed cryoglobulinemia; Evans syndrome; Fibromyalgia; Fibrosing alveolitis; Giant cell arteritis (temporal arteritis); Giant cell myocarditis; Glomerulonephritis; Goodpasture’s syndrome; Granulomatosis with polyangiitis; Graves’ disease; Guillain-Barre syndrome; Hashimoto’s thyroiditis; Hemolytic anemia; Henoch-Schonlein purpura (HSP); Herpes gestationis or pemphigoid gestationis (PG); Hidradenitis suppurativa (HS) (Acne inversa); IgA nephropathy; lgG4-related sclerosing disease; Immune thrombocytopenic purpura (ITP); Inclusion body myositis (IBM); Interstitial cystitis (IC); Juvenile arthritis; Juvenile diabetes (Type 1 diabetes); Juvenile myositis (JM); Kawasaki disease; Lambert-Eaton syndrome; Lichen planus; Lichen sclerosus; Ligneous conjunctivitis; Linear IgA disease (LAD); Lyme disease chronic; Malarial autoimmune anemia; Meniere’s disease; Microscopic polyangiitis (MPA); Mixed connective tissue disease (MCTD); Mucha-Habermann disease; Multifocal motor neuropathy (MMN) or MMNCB; MS; Myasthenia gravis; Myelin oligodendrocyte glycoprotein antibody disorder; Myositis; Narcolepsy; Neonatal lupus; Neuromyelitis optica / devic disease; Neutropenia; Ocular cicatricial pemphigoid; Optic neuritis; Palindromic rheumatism (PR); PANDAS (Pediatric autoimmune neuropsychiatric disorders associated with streptococcus infections); Paraneoplastic cerebellar degeneration (PCD); Paroxysmal nocturnal hemoglobinuria (PNH); Pars planitis (peripheral uveitis); Parsonage-Turner syndrome; Pemphigus; Peripheral neuropathy; Perivenous encephalomyelitis; Pernicious anemia (PA); POEMS syndrome; Polyarteritis nodosa; Polyglandular syndromes type I, II, III; Polymyalgia rheumatica; Polymyositis; Postmyocardial infarction syndrome; Postpericardiotomy syndrome; Primary biliary cholangitis; Primary sclerosingcholangitis; Progesterone dermatitis; Progressive hemifacial atrophy (PHA) Parry romberg syndrome; Psoriasis; Psoriatic arthritis; Pulmonary Alveolar Proteinosis (PAP); Pure red cell aplasia (PRCA); Pyoderma gangrenosum; Raynaud’s phenomenon; Reactive arthritis; Relapsing polychondritis; Restless legs syndrome (RLS); Retroperitoneal fibrosis; Rheumatic fever; RA; Sarcoidosis; Schmidt syndrome or Autoimmune polyendocrine syndrome type II; Scleritis; Scleroderma; SLE; SS; Stiff person syndrome (SPS); Susac’s syndrome; Sympathetic ophthalmia (SO); Takayasu’s arteritis; Temporal arteritis / giant cell arteritis; Thrombocytopenic purpura (TTP); Thrombotic thrombocytopenic purpura (Ttp); Thyroid Eye Disease (TED); Tolosa-Hunt syndrome (THS); Transverse myelitis; Type 1 diabetes; Ulcerative colitis (UC); Undifferentiated connective tissue disease (UCTD); Uveitis; Vasculitis; Vitiligo; Vogt-Koyanagi-Harada disease; or Warm autoimmune hemolytic anemia.

[0069] 51 . A method of treating a condition in a patient, comprising administering a composition comprising from 102to 1012of the CAR-T cell of any of clauses 32-49, in one or more doses, to the patient.

[0070] 52. The method of clause 51 , wherein the condition is Addison’s disease; Adult Still’s disease; Agammaglobulinemia; Alopecia areata; Amyloidosis; Ankylosing spondylitis; Anti-GBM / Anti-TBM nephritis; Antiphospholipid syndrome; Autoimmune angioedema; Autoimmune dysautonomia; Autoimmune encephalitis; Autoimmune hepatitis; Autoimmune inner ear disease (AIED); Autoimmune myocarditis; Autoimmune oophoritis; Autoimmune orchitis; Autoimmune pancreatitis; Autoimmune retinopathy; Autoimmune urticaria; Axial spondyloarthritis; Axonal & neuronal neuropathy (AMAN); Balo disease; Behcet’s disease; Benign mucosal pemphigoid (Mucous membrane pemphigoid); Bullous pemphigoid; Castleman disease (CD); Celiac disease; Chagas disease; Chronic inflammatory demyelinating polyneuropathy (CIDP); Chronic recurrent multifocal osteomyelitis (CRMO); Churg-Strauss syndrome (CSS) or Eosinophilic granulomatosis (EGPA); Cicatricial pemphigoid; Cogan’s syndrome; Cold agglutinin disease; Common variable immunodeficiency (CVID) with autoimmune complications; Complex regional pain syndrome (formerly known as reflex sympathetic dystrophy); Congenital heart block; Coxsackie myocarditis; CREST syndrome; Crohn’s disease; Dermatitis herpetiformis; Dermatomyositis; Devic’s disease (neuromyelitis optica); Discoid lupus; Dressier’s syndrome; Endometriosis; Eosinophilic esophagitis (EoE); Eosinophilic fasciitis; Erythema nodosum; Essential mixed cryoglobulinemia; Evans syndrome; Fibromyalgia; Fibrosing alveolitis; Giantcell arteritis (temporal arteritis); Giant cell myocarditis; Glomerulonephritis; Goodpasture’s syndrome; Granulomatosis with polyangiitis; Graves’ disease; Guillain- Barre syndrome; Hashimoto’s thyroiditis; Hemolytic anemia; Henoch-Schonlein purpura (HSP); Herpes gestationis or pemphigoid gestationis (PG); Hidradenitis suppurativa (HS) (Acne inversa); IgA nephropathy; lgG4-related sclerosing disease; Immune thrombocytopenic purpura (ITP); Inclusion body myositis (IBM); Interstitial cystitis (IC); Juvenile arthritis; Juvenile diabetes (Type 1 diabetes); Juvenile myositis (JM); Kawasaki disease; Lambert-Eaton syndrome; Lichen planus; Lichen sclerosus; Ligneous conjunctivitis; Linear IgA disease (LAD); Lyme disease chronic; Malarial autoimmune anemia; Meniere’s disease; Microscopic polyangiitis (MPA); Mixed connective tissue disease (MCTD); Mucha-Habermann disease; Multifocal motor neuropathy (MMN) or MMNCB; MS; Myasthenia gravis; Myelin oligodendrocyte glycoprotein antibody disorder; Myositis; Narcolepsy; Neonatal lupus; Neuromyelitis optica I devic disease; Neutropenia; Ocular cicatricial pemphigoid; Optic neuritis; Palindromic rheumatism (PR); PANDAS (Pediatric autoimmune neuropsychiatric disorders associated with streptococcus infections); Paraneoplastic cerebellar degeneration (PCD); Paroxysmal nocturnal hemoglobinuria (PNH); Pars planitis (peripheral uveitis); Parsonage-Turner syndrome; Pemphigus; Peripheral neuropathy; Perivenous encephalomyelitis; Pernicious anemia (PA); POEMS syndrome; Polyarteritis nodosa; Polyglandular syndromes type I, II, III; Polymyalgia rheumatica; Polymyositis; Postmyocardial infarction syndrome; Postpericardiotomy syndrome; Primary biliary cholangitis; Primary sclerosing cholangitis; Progesterone dermatitis; Progressive hemifacial atrophy (PHA) Parry romberg syndrome; Psoriasis; Psoriatic arthritis; Pulmonary Alveolar Proteinosis (PAP); Pure red cell aplasia (PRCA); Pyoderma gangrenosum; Raynaud’s phenomenon; Reactive arthritis; Relapsing polychondritis; Restless legs syndrome (RLS); Retroperitoneal fibrosis; Rheumatic fever; RA; Sarcoidosis; Schmidt syndrome or Autoimmune polyendocrine syndrome type II; Scleritis; Scleroderma; SLE; SS; Stiff person syndrome (SPS); Susac’s syndrome; Sympathetic ophthalmia (SO); Takayasu’s arteritis; Temporal arteritis / giant cell arteritis; Thrombocytopenic purpura (TTP); Thrombotic thrombocytopenic purpura (Ttp); Thyroid Eye Disease (TED); Tolosa-Hunt syndrome (THS); Transverse myelitis; Type 1 diabetes; Ulcerative colitis (UC); Undifferentiated connective tissue disease (UCTD); Uveitis; Vasculitis; Vitiligo; Vogt-Koyanagi-Harada disease; or Warm autoimmune hemolytic anemia..BRIEF DESCRIPTION OF THE DRAWINGS

[0071] FIG. 1 (from Mouat et al.) depicts reflex sympathetic dystrophy the role of Age- associated B cells in health vs. autoimmune disease.

[0072] FIGS. 2A AND 2B (reproduced from Nickerson KM, et al. Age-associated B cells are heterogeneous and dynamic drivers of autoimmunity in mice. J Exp Med. 2023 May 1 ;220(5):e20221346). Constitutive genetic depletion of CD11 c+ B cells improves renal disease and reduces T cell activation (A) Mixed bone marrow chimeras were generated in JH - / - MRL / lpr recipients with indicated bone marrow. Data are pooled from three independently generated cohorts of chimeras. (B-S) Recipients were assessed at 24 wk after chimerism for (B) spleen weight; (C) spleen cell number; proportion of (D) CD11 c+MHCII+ conventional dendritic cells of live, (E) CD317+ SiglecH+ plasmacytoid dendritic cells of live, (F) TCR[3+ T cells of live, (G) CD19+ B cells of live, (H) CD11 c- CD11 b+ ABCs among B cells, (I) CD11 c+CD11 b+ ABCs among B cells, (J) CD11 c+CD11 b- ABCs among B cells, (K) CD44+ CD138+ PBs among B cells. (L-M) H&E-stained kidney sections were assessed for (L) interstitial infiltrates and (M) glomerulonephritis. (N) Urine was assessed for proteinuria by albustix. (O and P) Frequency of CD44lowCD62L+ (naive) cells among (O) CD4 T cells or (P) CD8 T cells. (Q) anti-nucleosome IgG, (R) anti-nucleosome lgG2a, and (S) anti-RNA IgG were measured by ELISA. Statistical comparisons by one-tailed Mann- Whitney; *P < 0.05; **P < 0.01 ; ***P < 0.001 ; ****P < 0.0001 .

[0073] FIG. 3. Goal - specific depletion of ABC B cells through AND gate CAR system. CD19+ and CD11 c+ dual positivity is unique to ABCs. AND gate CAR-T cells recognizing CD19 AND CD11 c will deplete ABCs without affecting normal B cells (CD19+,CD11 c-) or dendritic cells / monocytes (CD19- CD11 c+). Binding of single receptors induces no T cell activity, providing a potential safe therapy for treatment of various auto-immune diseases.

[0074] FIG. 4 is a schematic diagram illustrating an exemplary AND gate dual CAR design according to the present invention.

[0075] FIG. 5 provides plasmid maps of exemplary MSGV1 lentivirus constructs, MSGV1 -1 D3-CD28-LATdelGADS and MSGV1 -aCD11 c-CD8h,TM-SLP76delGADS, encoding exemplary CARs.

[0076] FIGS. 6A-L provide exemplary CAR-T receptor sequences (labeled 1 -13). 1. Amino acid sequence of 1 D3-CD28-LAT (SEQ ID NO: 1 ); 2. Amino acid sequence of N418-CD8-SLP76 (SEQ ID NO: 2); 3. Amino acid sequence of anti-CD19scFv-CD28(2CA)H,TM-LATcyto(del171 -233) (SEQ ID NO: 3); 4. Amino acid sequence of antiCD80-CD8-SLP76 (SEQ ID NO: 4); 5. Amino acid sequence of antiCD27-CD8- SLP76 (SEQ ID NO: 5); 6. Amino acid sequence of 1 D3-Notchcore-Gal4-VP64 (SEQ ID NO: 6); 7. DNA sequence of pGal4-N418-CD28-CD3z(SEQ ID NO: 7); 8. Amino acid sequence of FMC63-Notchcore-Gal4-VP64 (SEQ ID NO: 8); 9. DNA sequence of pGal4-antiCD80-CD28-CD3z(SEQ ID NO: 9); 10. DNA sequence of pGal4-antiCD27- CD28-CD3z(SEQ ID NO: 10); 11. Amino acid sequence of FMC63mut(Y261A)-CD8- CD3z (SEQ ID NO: 11 ); 12. Amino acid sequence of antiCD27-CD28-41 BB (SEQ ID NO: 12); 13. Amino acid sequence of antiCD80-CD28-41 BB (SEQ ID NO: 13); 14. Amino acid sequence of N418-CD28-CD3z (SEQ ID NO: 14); 15. Amino acid sequence of antiCD80-CD28-CD3z (SEQ ID NO: 15); 16. Amino acid sequence of antiCD27-CD28-CD3z (SEQ ID NO: 16); 17. Amino acid sequence of anti-huCD11c- CD8-SLP76 (SEQ ID NO: 17); 18. DNA sequence of pGal4-antu-huCD11 c-CD28- CD3z (SEQ ID NO: 18); Amino acid sequence of anti-huCD11 c-CD28-CD3z (SEQ ID NO: 19); and Amino acid sequence of anti-huCD11 C-CD28-41 BB (SEQ ID NO: 20).DETAILED DESCRIPTION

[0077] Other than in the operating examples, or where otherwise indicated, the use of numerical values in the various ranges specified in this application are stated as approximations as though the minimum and maximum values within the stated ranges are both preceded by the word “about”. In this manner, slight variations above and below the stated ranges can be used to achieve substantially the same results as values within the ranges. Also, unless indicated otherwise, the disclosure of ranges is intended as a continuous range including every value between the minimum and maximum values. Further, as used herein, all numbers expressing dimensions, physical characteristics, processing parameters, quantities of ingredients, reaction conditions, and the like, used in the specification and claims are to be understood as being modified in all instances by the term “about”. Moreover, unless otherwise specified, all ranges disclosed herein are to be understood to encompass the beginning and ending range values and any and all subranges subsumed therein. For example, a stated range of “1 to 10” should be considered to include any and all subranges between (and inclusive of) the minimum value of 1 and the maximum value of 10; that is, all subranges beginning with a minimum value of 1 or more and ending with a maximum value of 10 or less, e.g., 1 to 3.3, 4.7 to 7.5, 5.5 to 10, and the like.

[0078] As used herein “a” and “an” refer to one or more. The term “comprising” is open- ended and may be synonymous with “including”, “containing”, or “characterized by”. The term “consisting essentially of” limits the scope of a claim to the specified materials or steps and those that do not materially affect the basic and novel characteristic(s) of the claimed invention.

[0079] As used herein, spatial or directional terms, such as “left”, “right”, “inner”, “outer”, “above”, “below”, “over”, “under”, and the like, relate to the invention as it is shown in the drawing figures are provided solely for ease of description and illustration, and do not imply directionality, unless specifically required for operation of the described aspect of the invention. It is to be understood that the invention can assume various alternative orientations and, accordingly, such terms are not to be considered as limiting.

[0080] As used herein, a “patient” or “subject” is an animal, such as a mammal, including a primate (such as a human, a non-human primate, e.g., a monkey, and a chimpanzee), a non-primate (such as a cow, a pig, a camel, a llama, a horse, a goat, a rabbit, a sheep, a hamster, a guinea pig, a cat, a dog, a rat, a mouse, a horse, and a whale), or a bird (e.g., a duck or a goose).

[0081] As used herein, the terms “treating”, or “treatment” refer to a beneficial or desired result, such as improving one of more, or symptoms of a disease. The terms “treating” or “treatment” also include, but are not limited to, alleviation or amelioration of one or more symptoms of a disease described herein. “Treatment” can also mean prolonging survival as compared to expected survival in the absence of treatment.

[0082] By “lower” in the context of a disease marker or symptom is meant a clinically- relevant and / or a statistically significant decrease in such level. The decrease can be, for example, at least 10%, at least 20%, at least 30%, at least 40%, or more, down to a level accepted as within the range of normal for an individual without such a disorder. In certain aspects, the decrease is down to a level accepted as within the range of normal for an individual without such disorder which can also be referred to as a normalization of a level. In certain aspects, the reduction is the normalization of the level of a sign or symptom of a disease, a reduction in the difference between the subject level of a sign of the disease and the normal level of the sign for the disease (e.g., to the upper level of normal when the value for the subject must be decreased to reach a normal value, and to the lower level of normal when the value for the subject must be increased to reach a normal level).

[0083] “Therapeutically effective amount” or an “amount effective” as used herein, is intended to include the amount of a therapeutic agent as described herein that, when administered to a subject having a disease, is sufficient to effect treatment of the disease (e.g., by diminishing, ameliorating, or maintaining the existing disease or one or more symptoms of disease). The “therapeutically effective amount” may vary depending on the nature of the injury and its causes, how the therapeutic agent is administered, the disease and its severity and the history, age, weight, family history, genetic makeup, the types of preceding or concomitant treatments, if any, and other individual characteristics of the subject to be treated. A “therapeutically-effective amount” also includes an amount of a therapeutic agent that produces some desired local or systemic effect at a reasonable benefit / risk ratio applicable to any treatment.

[0084] A "therapeutically effective amount" refers to an amount of a drug product or active agent effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. An “amount effective” for treatment of a condition is an amount of an active agent or dosage form, such as a single dose or multiple doses, effective to achieve a determinable end-point. The “amount effective” is preferably safe - at least to the extent the benefits of treatment outweighs the detriments, and / or the detriments are acceptable to one of ordinary skill and / or to an appropriate regulatory agency, such as the U.S. Food and Drug Administration. A therapeutically effective amount of an active agent may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the active agent to elicit a desired response in the individual. A "prophylactically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount may be less than the therapeutically effective amount.

[0085] Dosage regimens may be adjusted to provide the optimum desired response (e.g., a therapeutic or prophylactic response). For example, a single bolus may be administered, several divided doses may be administered over time, or the composition may be administered continuously or in a pulsed fashion with doses or partial doses being administered at regular intervals, for example, every 10, 15, 20, 30, 45, 60, 90, or 120 minutes, every 2 through 12 hours daily, or every other day, etc., be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. In some instances, it may be especially advantageous toformulate compositions, such as parenteral or inhaled compositions, in dosage unit form for ease of administration and uniformity of dosage. The specification for the dosage unit forms are dictated by and directly dependent on (a) the unique characteristics of the active compound and the particular therapeutic or prophylactic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals.

[0086] An “effective amount” or “amount effective” to achieve a desirable therapeutic, pharmacological, medicinal, or physiological effect is any amount that achieves the stated purpose, for example, an amount of an active agent described herein effective to reduce symptoms of an autoimmune disease in a patient. Based on the teachings provided herein, one of ordinary skill can readily ascertain effective amounts of the elements of the described dosage form and produce a safe and effective dosage form and drug product. A person of ordinary skill would know much about the therapeutic window of the described therapies, understanding bioavailability, toxic levels, effective targeting levels, etc. and can readily ascertain efficacy of any given dose by monitoring symptoms of a disease, e.g., by monitoring suitable clinical biomarkers in the patient. Examples of an effective amount of an active agent compounded in a delivery vehicle includes from 100 CAR-T cells per kilogram of body weight to 1X108CAR-T cells per kilogram of body weight, including any increment therebetween, 1X104CAR-T cells per kilogram of body weight to 1X107CAR-T cells per kilogram of body weight, such as ranging from 103, from 104, or from 105CAR-T cells to 106, to 107, to 108, to 109, to 101°, to 1011, or to 1012CAR-T cells per dose, including any increment therebetween, such as approximately 103, 104, 105, 105, 106, 107, 108, 109, 101°, or 1011CAR-T cells per dose.

[0087] A nucleic acid molecule (a nucleic acid) refers to a polymeric form of nucleotides, which may include, for example and without limitation, RNA or DNA in any form, including synthetic forms and mixed polymers of the above. A nucleotide may be a ribonucleotide, deoxynucleotide, or a modified form of either type of nucleotide. The term “nucleic acid molecule” as used herein is synonymous with “nucleic acid” and “polynucleotide.” The term includes single- and double-stranded forms of DNA. A polynucleotide may include either or both naturally occurring and modified nucleotides linked together by naturally occurring and / or non-naturally occurring nucleotide linkages.

[0088] A recombinant nucleic acid refers to a nucleic acid molecule (or protein or virus) that is not naturally occurring or has a sequence that is made by an artificial combination of two otherwise separated segments of sequence. This artificial combination is accomplished by chemical synthesis or, more commonly, by the artificial manipulation of isolated segments of nucleic acids, e.g., by broadly-known genetic engineering techniques (see, e.g., Lanigan TM, et al. Principles of Genetic Engineering. Genes (Basel). 2020 Mar 10; 11 (3):291 . , van der Oost J, Patinios C. The genome editing revolution. Trends Biotechnol. 2023 Mar;41 (3):396-409., and Khalil AM. The genome editing revolution: review. J Genet Eng Biotechnol. 2020 Oct 29;18(1 ):68.). The term “recombinant” includes nucleic acids and proteins that have been altered solely by addition, substitution, or deletion of a portion of a natural nucleic acid molecule or protein.

[0089] By "expression" or “gene expression,” it is meant the overall flow of information from a gene or functional / structural RNA, to produce a gene product. The gene product may be a protein that is optionally post-translationally modified, or a functional / structural RNA. A “gene” refers to a functional genetic unit for producing a gene product, such as RNA or a protein in a cell, or other expression system encoded on a nucleic acid and comprising: a transcriptional control sequence, such as a promoter and other c / s-acting elements, such as transcriptional response elements (TREs) and / or enhancers; an expressed sequence that may encode a protein (referred to as an open-reading frame or ORF), and a polyadenylation sequence. By "expression of genes under transcriptional control of," or alternately "subject to control by," a designated sequence such as a promoter or a TRE, it is meant gene expression from a gene containing the designated sequence operably linked (functionally attached, typically in cis) to the gene. A "gene for expression of" a stated gene product is a gene capable of expressing that stated gene product when placed in a suitable environment--that is, for example, when transformed, transfected, transduced, etc. into a cell, and subjected to suitable conditions for expression of the gene to produce the gene product.

[0090] A promoter may comprise one or more c / s-acting nucleic acid control sequences, such as TREs, which direct transcription of a nucleic acid. A promoter may include necessary nucleic acid sequences near the start site of transcription and optionally includes distal enhancer or repressor elements. A “constitutive promoter” is a promoter that is continuously active and is not subject to regulation by externalsignals or molecules in a cell, tissue, or organism. In the case of a constitutive promoter "suitable conditions" for expression of a gene product means that the gene typically need only be introduced into an appropriate host cell. In contrast, the activity of an “inducible promoter” is regulated by an external signal or molecule (for example, a transcription factor) in a cell, tissue, or organism. In the case of an inducible promoter, "suitable conditions" for expression of a gene product means when factors that regulate transcription, such as DNA-binding proteins, are present or absent - for example an amount of the respective inducer is available to the expression system (e.g., cell), or factors causing suppression of a gene are unavailable or displaced - effective to cause expression of the gene.

[0091] Therapeutic compositions, including those containing the cells and compositions, e.g., receptors, disclosed herein, may comprise a pharmaceutically acceptable carrier, or excipient. An excipient is an inactive substance used as a carrier for the active ingredients of a medication. Although "inactive," excipients may facilitate and aid in increasing the delivery or bioavailability of an active ingredient in a drug product. Non-limiting examples of useful excipients include: adjuvants, antiadherents, binders, rheology modifiers, carriers, coatings, disintegrants, emulsifiers, oils, buffers, salts, acids, bases, fillers, diluents, solvents, flavors, colorants, glidants, lubricants, preservatives, antioxidants, sorbents, vitamins, sweeteners, etc., as are available in the pharmaceutical / compounding arts.

[0092] Useful dosage forms for the compositions, e.g., cells, disclosed herein include, for example and without limitation: parenteral, intravenous, intramuscular, intraocular, or intraperitoneal solutions, oral tablets or liquids, topical drops, ointments, or creams, and transdermal devices (e.g., patches). The compound may be a sterile solution comprising the active ingredient (e.g., cell(s)), and a solvent, such as water, saline, lactated Ringer's solution, or phosphate-buffered saline (PBS). Additional excipients, such as polyethylene glycol, emulsifiers, salts, and buffers may be included in the solution. Suitable dosage forms may include single-dose, or multiple-dose vials or other containers, such as medical syringes or droppers, e.g., eye droppers. Pharmaceutical formulations adapted for administration include aqueous and nonaqueous sterile solutions which may contain, in addition to the active pharmaceutical ingredient or drug, for example and without limitation, adjuvants, anti-oxidants, buffers, bacteriostats, lipids, liposomes, lipid nanoparticles, emulsifiers, suspending agents, and rheology modifiers. The formulations may be presented in unit-dose or multi-dosecontainers, for example, sealed ampoules and vials, and may be stored in a freeze- dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water for injections, immediately prior to use. Extemporaneous solutions and suspensions may be prepared.

[0093] Therapeutic / pharmaceutical compositions as described herein may be prepared in accordance with acceptable pharmaceutical procedures, such as described in Remington: The Science and Practice of Pharmacy, 21 st edition, ed. Paul Beringer et al., Lippincott, Williams & Wilkins, Baltimore, MD Easton, Pa. (2005) (see, e.g., Chapters 39, 41 , and 42 for examples of liquid, parenteral, and intravenous formulations and methods of making such formulations).

[0094] Therapeutic compositions typically must be sterile and stable under the conditions of manufacture and storage, other than where live cells are required. For example, sterile injectable solutions can be prepared by incorporating the active agent, e.g., cells or a nucleic acid, in the required amount in an appropriate solvent with one or a combination of ingredients enumerated herein, as required. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, typical methods of preparation are vacuum drying and freeze- drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. The proper fluidity of a solution can be maintained, for example, by the use of a rheology modifier. Prolonged absorption of injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, monostearate salts, gelatin or a hydrogel. Cells may be handled, propagated, passaged, transformed / transfected / transduced, and formulated using sterile technique as is broadly-accepted in the biomedical arts relating to cell-based therapies.

[0095] The phrase "pharmaceutically-acceptable carrier" as used herein means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), solvent, or encapsulating material, involved in carrying or transporting a cell or compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the subjectbeing treated. Some examples of materials which can serve as pharmaceutically- acceptable carriers include: (1 ) sugars, such as lactose, glucose and sucrose; (2) starches, such as com starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) lubricating agents, such as magnesium state, sodium lauryl sulfate and talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; (10) glycols, such as propylene glycol; (11 ) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) pH buffered solutions; (21 ) polyesters, polycarbonates and / or polyanhydrides; (22) bulking agents, such as polypeptides and amino acids (23) serum component, such as serum albumin, HDL and LDL; and (22) other non-toxic compatible substances employed in pharmaceutical formulations. Remington: The Science and Practice of Pharmacy, The University of the Sciences in Philadelphia, Editor, Lippincott, Williams, & Wilkins, Philadelphia, Pa., 21 st Edition (2005) (see above), describes compositions and formulations suitable for pharmaceutical delivery of one or more therapeutic compositions, such as a cell, and additional pharmaceutical agents.

[0096] In general, the nature of the carrier will depend on the particular mode of administration being employed. For instance, parenteral formulations usually comprise injectable fluids that include pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle. For solid compositions (for example, powder, pill, tablet, or capsule forms), conventional non-toxic solid carriers can include, for example, pharmaceutical grades of mannitol, lactose, starch, or magnesium stearate. In addition to biologically-neutral carriers, pharmaceutical compositions to be administered can contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, preservatives, and pH buffering agents and the like, for example sodium acetate or sorbitan monolaurate.

[0097] A B cell (e.g., a B lymphocyte) is a type of blood cell that acts as a center for a population of cells that express clonally diverse cell surface immunoglobulin (Ig) receptors recognizing specific antigenic epitopes (see, e.g., LeBien TW, Tedder TF. Blymphocytes: how they develop and function. Blood. 2008 Sep 1 ;112(5):1570-80). “B cells” include mature B cells, including subtypes thereof, such as, for example and without limitation, transitional B cells, naive B cells, activated B cells, plasma B cells and memory B cells and, in the context of the present invention, precursors thereof, so long as such precursors comprise suitable surface antigens and / or other phenotypic or genotypic characteristics such that they may be subject to regulation as described herein. Activated B cells result from the binding of an antigen to a B cell receptor, such as the binding of an antigen to a B cell receptor of a naive B cell. B cell activation may be done independent of T cells or through T cell dependent pathways. Memory B cells are a long-lived subset of B cells that, after initial activation, circulate throughout the body until they encounter an antigen that binds a B cell receptor on the memory B cell. After the B cell receptor is bound, a memory B cell may differentiate into a plasma cell. All genes and surface markers, as described herein, are broadly- known and do not require further explanation, such as B-cell markers, including, but not limited to CD19, 20, 21 , 22, 23, 24, 25, 40, 72, CD79a,b, CD80, and / orCD86 (see, e.g. LeBien TW, et al. Blood. 2008 Sep 1 ;112(5):1570-80). A “CD11 c+ B cell” refers to a heterogenous population of B cells that express the CD11 c surface antigen. They comprise mainly memory B cells, but may comprise other B cell types (see, e.g., Golinski ML, et al. CD11 c+ B Cells Are Mainly Memory Cells, Precursors of Antibody Secreting Cells in Healthy Donors. Front Immunol. 2020 Feb 25; 11 :32). Age associated B cells (ABCs or ABC cells), may be expanded in the elderly, and also can be associated with various autoimmune diseases, and therefore provide therapeutic targets of the therapies and therapeutic compositions provided herein. ABC cells may be defined as a B cell subset characterized by the CD19+(see, e.g., Wang K, et al. CD19: a biomarker for B cell development, lymphoma diagnosis and therapy. Exp Hematol Oncol. 2012 Nov 29; 1 (1 ):36), CD21 ” (see, e.g., Suryani S, et al. Differential expression of CD21 identifies developmentally and functionally distinct subsets of human transitional B cells. Blood. 2010 Jan 21 ;115(3):519-29), CD11 c+(see, e.g., Golinski ML, et al. Front Immunol. 2020 Feb 25; 11 :32), T-bet+(see, e.g., Knox JJ, et al. T-bet+ memory B cells: Generation, function, and fate. Immunol Rev. 2019 Mar;288(1 ): 149-160) phenotype.

[0098] In the Examples below, CD11 c is targeted. Other surface antigens useful for targeting using the methods and compositions described herein include CD11 b (see, e.g., Schmid MC, et al. Integrin CD11 b activation drives anti-tumor innate immunity.Nat Commun. 2018 Dec 19;9(1 ):5379), CD27 (see, e.g., Grimsholm 0. CD27 on human memory B cells-more than just a surface marker. Clin Exp Immunol. 2023 Jul 21 ;213(2): 164-172), and CD80 (see, e.g., Li L, et al. Research progress of CD80 in the development of immunotherapy drugs. Front Immunol. 2024 Nov 7; 15: 1496992)

[0099] Mouat et al. (Mouat IC, et al. Age-associated B cells in autoimmune diseases. Cell Mol Life Sci. 2022 Jul 7;79(8):402) describe the role of ABCs in autoimmunity (FIG. 1). Age associated B cells (ABCs) are expanded in autoimmune disease patients and may play active roles in pathology. They produce auto-antibodies and inflammatory cytokines and are found at disease sites. They also are proposed to activate T cells at disease sites. As described in Mouat et al., ABCs are associated with a variety of autoimmune diseases. As such, methods and compositions provided herein may be useful in treating, for example and without limitation: Systemic lupus erythematosus (SLE), Multiple sclerosis (MS), Rheumatoid arthritis (RA), Sjogren’s syndrome (SS), Ankylosing Spondylitis, Axial spondyloarthritis, Scleroderma, Malarial autoimmune anemia, Common variable immunodeficiency (CVID) with autoimmune complications, Crohn’s disease, ulcerative colitis, and dermatomyositis. A fuller list of conditions treatable by the methods and compositions provided herein include, without limitation: Addison’s disease; Adult Still’s disease; Agammaglobulinemia; Alopecia areata; Amyloidosis; Ankylosing spondylitis; Anti-GBM / Anti-TBM nephritis; Antiphospholipid syndrome; Autoimmune angioedema; Autoimmune dysautonomia; Autoimmune encephalitis; Autoimmune hepatitis; Autoimmune inner ear disease (AIED); Autoimmune myocarditis; Autoimmune oophoritis; Autoimmune orchitis; Autoimmune pancreatitis; Autoimmune retinopathy; Autoimmune urticaria; Axial spondyloarthritis; Axonal & neuronal neuropathy (AMAN); Balo disease; Behcet’s disease; Benign mucosal pemphigoid (Mucous membrane pemphigoid); Bullous pemphigoid; Castleman disease (CD); Celiac disease; Chagas disease; Chronic inflammatory demyelinating polyneuropathy (CIDP); Chronic recurrent multifocal osteomyelitis (CRMO); Churg-Strauss syndrome (CSS) or Eosinophilic granulomatosis (EGPA); Cicatricial pemphigoid; Cogan’s syndrome; Cold agglutinin disease; CVID with autoimmune complications;

[0100] Complex regional pain syndrome (formerly known as reflex sympathetic dystrophy); Congenital heart block; Coxsackie myocarditis; CREST syndrome; Crohn’s disease; Dermatitis herpetiformis; Dermatomyositis; Devic’s disease (neuromyelitis optica); Discoid lupus; Dressier’s syndrome; Endometriosis;Eosinophilic esophagitis (EoE); Eosinophilic fasciitis; Erythema nodosum; Essential mixed cryoglobulinemia; Evans syndrome; Fibromyalgia; Fibrosing alveolitis; Giant cell arteritis (temporal arteritis); Giant cell myocarditis; Glomerulonephritis; Goodpasture’s syndrome; Granulomatosis with polyangiitis; Graves’ disease; Guillain- Barre syndrome; Hashimoto’s thyroiditis; Hemolytic anemia; Henoch-Schonlein purpura (HSP); Herpes gestationis or pemphigoid gestationis (PG); Hidradenitis suppurativa (HS) (Acne inversa); IgA nephropathy; lgG4-related sclerosing disease; Immune thrombocytopenic purpura (ITP); Inclusion body myositis (IBM); Interstitial cystitis (IC); Juvenile arthritis; Juvenile diabetes (Type 1 diabetes); Juvenile myositis (JM); Kawasaki disease; Lambert-Eaton syndrome; Lichen planus; Lichen sclerosus; Ligneous conjunctivitis; Linear IgA disease (LAD); Lupus; Lyme disease chronic; Malarial autoimmune anemia; Meniere’s disease; Microscopic polyangiitis (MPA); Mixed connective tissue disease (MCTD); Mucha-Habermann disease; Multifocal motor neuropathy (MMN) or MMNCB; Multiple sclerosis; Myasthenia gravis; Myelin oligodendrocyte glycoprotein antibody disorder; Myositis; Narcolepsy; Neonatal lupus; Neuromyelitis optica / devic disease; Neutropenia; Ocular cicatricial pemphigoid; Optic neuritis; Palindromic rheumatism (PR); PANDAS (Pediatric autoimmune neuropsychiatric disorders associated with streptococcus infections); Paraneoplastic cerebellar degeneration (PCD); Paroxysmal nocturnal hemoglobinuria (PNH); Pars planitis (peripheral uveitis); Parsonage-Turner syndrome; Pemphigus; Peripheral neuropathy; Perivenous encephalomyelitis; Pernicious anemia (PA); POEMS syndrome; Polyarteritis nodosa; Polyglandular syndromes type I, II, III; Polymyalgia rheumatica; Polymyositis; Postmyocardial infarction syndrome; Postpericardiotomy syndrome; Primary biliary cholangitis; Primary sclerosing cholangitis; Progesterone dermatitis; Progressive hemifacial atrophy (PHA) Parry romberg syndrome; Psoriasis; Psoriatic arthritis; Pulmonary Alveolar Proteinosis (PAP); Pure red cell aplasia (PRCA); Pyoderma gangrenosum; Raynaud’s phenomenon; Reactive arthritis; Relapsing polychondritis; Restless legs syndrome (RLS); Retroperitoneal fibrosis; Rheumatic fever; Rheumatoid arthritis; Sarcoidosis; Schmidt syndrome or Autoimmune polyendocrine syndrome type II; Scleritis; Scleroderma; Sjogren’s; Stiff person syndrome (SPS); Susac’s syndrome; Sympathetic ophthalmia (SO); Takayasu’s arteritis; Temporal arteritis / giant cell arteritis; Thrombocytopenic purpura (TTP); Thrombotic thrombocytopenic purpura (Ttp); Thyroid Eye Disease (TED); Tolosa-Hunt syndrome (THS); Transverse myelitis; Type 1 diabetes; Ulcerative colitis(UC); Undifferentiated connective tissue disease (UCTD); Uveitis; Vasculitis; Vitiligo; Vogt-Koyanagi-Harada disease; or Warm autoimmune hemolytic anemia.

[0101] ABCs are thus a prime therapeutic target, but to date there is no therapeutic way to selectively deplete or inactivate them in either an animal model or a human. Nickerson et al. (Nickerson KM, et al. J Exp Med. 2023 May 1 ;220(5):e20221346), describes, in a mouse renal disease model, that constitutive genetic depletion of CD1 1 c+ B cells improves renal disease and reduces T cell activation.

[0102] CAR19 T cells are currently an FDA-approved autologous engineered T cell product in which a DNA construct is introduced into normal T cells that encodes a chimeric antigen receptor in which the external portion contains immunoglobulin (Ig) V regions from an antibody that recognizes CD19, a B cell-specific surface protein. This recognition domain is linked to engineered intracytoplasm ic "tail" regions that transduce TCR-like signaling if the ligand-binding (e.g., CD19-binding) domain is triggered. There are several variations on how this is implemented. The result of recognition of a CD19+ B cell by the CAR19 T cell in vivo is the killing of the cell. This was originally developed to treat B lineage neoplasms, such as leukemia and lymphoma, for which it is very effective.

[0103] Genetic deletion of B cells blocked lupus-like disease; and depletion of B cells with an anti-CD20 antibody also could treat established disease. However, B cell depletion with a standard antibody is difficult to achieve in the context of autoimmunity and thus while anti-CD20 antibodies, such as Rituximab, are effective in some autoimmune diseases in some patients, they have failed in other diseases such as lupus, scleroderma and Sjogren’s disease. Therefore, other approaches are still needed.

[0104] More recently, both in mice and in humans, CAR19 T cells have been used to deplete B cells in the context of lupus (mice and humans), scleroderma, vasculitis, and other autoimmune diseases, with a very striking degree of success, albeit not yet in controlled trials. This has ignited great interest in how to better target B cells in the context of autoimmunity. On the one hand, less cumbersome ways of deploying CAR19 T cells — or of substituting reagent-based depletion for their effect — are being sought. On the other hand, it would be most ideal not to deplete ALL B cells in an autoimmune person, as this could be highly immunosuppressive, but rather to deplete just the pathogenic B cells.

[0105] In accordance with the present invention, a method and related compositions are provided to deplete just ABCs using a novel approach to CART cell generation. ABCs in both mice and humans express the surface integrin molecule termed CD11c. CD1 1 c is also expressed on essentially all dendritic cells (DCs) in the body and these DCs are thought to be critical for immune defense. Hence, it is not desirable to target or eliminate all CD11c-expressing cells in the body.

[0106] Instead, as depicted in FIG. 3, provided herein is a synthetic CAR-T cell that carries both a CD19 and a CD11 c recognition domain, each encoded in a different protein. Each one is linked to a partially defective signaling domain such that recognition of either CD19 or CD11c alone will not cause signaling and will not cause killing-type effector function. However, dual recognition of both CD19 and CD11c by the CART cell will lead to complementation and vigorous activating type signaling that will enable the CART cell to kill the target. Via this 'AND" type gating we expect to produce a CAR-T cell that will selectively eliminate ABC-like (CD19+CD11c+) B cells while sparing both naive B cells and DCs. This selective depletion should be effective in treating autoimmune diseases.

[0107] Logic (e.g., AND gate) control of CAR-T cells may be achieved by any useful mechanism, employing two different synthetic receptors, that activate a CAR-T cell only with binding of both synthetic receptors (AND logic gate). In a non-limiting example, a pair of CAR-T receptors using AND gate control may include a first synthetic receptor for binding a first antigen of the B cell, and a second receptor for binding a second antigen of the B cell. In non-limiting embodiments, the first synthetic receptor and the second synthetic receptor may each include an amino acid chain, and the amino acid chain may include a signaling moiety and / or an antigen binding moiety. In non-limiting embodiments, the signaling moiety may activate the CAR-T cell only when the antigen binding moiety of the first synthetic receptor and / or the second synthetic receptor bind the first antigen and the second antigen on a B cell. In non-limiting embodiments, the signaling moiety may activate the CAR-T cell only when both the first and second synthetic receptor bind the first and second antigen on a B cell. For example, Tousley et al. (Co-opting signaling molecules enables logic-gated control of CAR-T cells. Nature. 2023 Mar;615(7952):507-516) describe a CAR-T receptor formed from two synthetic receptors, one comprising a first scFv antibody fragment linked to a LAT-based signaling moiety, and the other comprising a second scFv antibody fragment linked to a SLP-based signaling moiety, where the signalingmoieties only activate their CAR-T cell when both antigen-binding moieties of the combination receptor are bound.

[0108] Other useful signaling moieties, and an exemplary AND logic CAR-T cell strategy are described in Kloss et al. (Combinatorial antigen recognition with balanced signaling promotes selective tumor eradication by engineered T cells. Nat Biotechnol. 2013 Jan;31 (1 ):71 -5). Kloss et al. describe a system and a CAR-T cell including a first CAR, referred to as an inefficient CAR receptor and a second CAR, referred to therein as a chimeric costimulatory receptor (CCR), for detecting CD19 + PSMA prostate cancer tumor cells. The system includes a CAR including an inefficient CD3 moiety linked to a CD19 scFv moiety and a second CAR, referred to as a CCR that includes a PSMA scFv linked to a 4-1 BB signaling moiety, where the inefficient CD3 signaling moiety and the 4-1 BB signaling moiety in the CAR and CCR are unable to activate their T cell unless both the CAR and CCR bind their target antigens on a cell.

[0109] FIG. 4 illustrates an exemplary AND gate dual CAR design according to nonlimiting embodiments of the present invention. FIG. 5 provides plasmid maps of exemplary MSGV1 lentivirus constructs encoding the CARs of FIG. 4.

[0110] As an alternative to the dual CAR approach of Kloss et al. and Tousley et al., Roybal et al. (Roybal KT, et al. Precision Tumor Recognition by T Cells With Combinatorial Antigen-Sensing Circuits. Cell. 2016 Feb 11 ;164(4):770-9) describe an approach in which binding of a T cell to a first cell surface antigen by a first receptor activates transcription and expression of a CAR-That recognizes a second cell surface antigen. More specifically, they describe engineered T cells with transcriptionactivating (synNotch) receptors that sense tumor antigens and upregulate expression of a CAR-To a second antigen. Thus, the synNotch AND-gate T cells only activate in response to combinatorial antigen recognition in the tumor microenvironment, preventing off-target toxicity mediated by single antigen recognition.

[0111] It should be noted that the present disclosure provides exemplary amino acid sequences and nucleic acid sequences encoding amino acid sequences with specific sequences. A person of ordinary skill may readily modify those sequences without functionally affecting the described receptors, and providing a multitude of possible sequences that would adequately function as described is not practically feasible. As such, the provided sequences should be thought of as proof of concept, as opposed to limiting. Monoclonal antibodies and antibody fragments that specifically bind a stated cell surface antigen (e.g., marker or protein) as described herein including thosebinding CD19, CD20, CD11 c, CD11 b, CD27, or CD80 are broadly-available commercially, and can be described as an antibody or antibody fragment (e.g. scFv or nanobody, as are broadly-known) that binds a stated cell surface antigen, such as, for example a CD19-binding scFv, with the understanding that such antibody fragments, while potentially comprising significant variation in variable region amino acid sequences within an antibody framework, would be generally be expected to be useful for integration into the synthetic receptors described herein. As such, due to the broad availability of suitable antibody products and availability of amino acid sequences thereof, the provided sequences may be effectively described in a functional manner as an antibody fragment that binds a stated cell surface antigen. Likewise, receptor signaling moieties may include the exemplary moieties and functionally-equivalent amino acid sequence variants thereof. As with antibodies, a person of ordinary skill may modify the exemplary signaling moiety sequences described herein or in the referenced publications, yet achieve equivalent results as compared to the exemplary sequences.

[0112] A chimeric antigen receptor (CAR) comprises a targeting moiety (also known as an antigen binding moiety) for binding a surface antigen of another cell, and a signaling moiety for generating a signal when the targeting moiety binds a surface antigen on another cell. The CAR-T cells described herein comprise a pair of CARs directed to two different surface antigens (target antigens) of a target, for example and without limitation, a B cell such as an ABC cell, that only activate the CAR-T-cell on which they are expressed if both CARs are bound to their target antigen. The CARs may be expressed on the surface of an engineered T cell, e.g., a CAR-T cell, therefore providing a CAR-T receptor that recognizes two surface antigens on a B-cell and is only activated when both antigens are present on a target (ABC) cell. A first target antigen may be CD19 or CD20 proteins, while a second target antigen may be CD11 c, CD11 b, CD27 or CD80. For example, and without limitation, the first target antigen may be CD19, and the second target antigen may be CD11 c. Examples of useful signal moieties for the CARs include LAT, SLP, an inefficient CD3 moiety, and a 4- 1 BB signaling moiety, as described below. In further detail, for example and without limitation, the signaling moiety of the first synthetic receptor when included in the first synthetic receptor with an antigen binding moiety in a CAR-T cell, is unable to activate the CAR-T cell on binding to a cell having a surface antigen that binds to the antigen binding moiety of the first synthetic receptor without binding of a surface antigen of thecell to the antigen binding moiety of the second synthetic receptor, and the signaling moiety of the second synthetic receptor is a 4-1 BB signaling moiety that is unable to activate the CAR-T cell on binding to a cell having a surface antigen that binds to the antigen binding moiety of the second synthetic receptor without binding of a surface antigen of the cell to the antigen binding moiety of the first synthetic receptor, such that when both of the antigen binding moieties of the first and second synthetic receptors bind surface antigens on a cell, the CAR-T cell is activated. In another nonlimiting example, the first synthetic receptor comprises an antigen binding moiety linked to a transcription activator, such as a synNotch activator, that activates a gene encoding the second synthetic receptor comprising an antigen binding moiety linked to a T-cell activator such that a CAR-T cell comprising the first and second synthetic receptors are only activated on antigen binding of both the first and second synthetic receptors.

[0113] LAT (Linker for activation of T cells, NCBI Reference Sequence: NP_055202.1 ) is a transmembrane molecule critical for the coordination of signals for T cell activation, as further described in Balagopalan et al. (Balagopalan L, et al. Enhanced T-cell signaling in cells bearing linker for activation of T-cell (LAT) molecules resistant to ubiquitylation. Proc Natl Acad Sci U S A. 2011 Feb 15;108(7):2885-90) and Kunii et al. (Kunii N, et al . Enhanced function of redirected human T cells expressing linker for activation of T cells that is resistant to ubiquitylation. Hum Gene Then 2013 Jan;24(1 ):27-37). SLP (H2 domain containing leukocyte protein of 76kDa, NCBI Reference Sequence: NP_005556.1 ) is a signal transducing protein that plays a key role in, among other things, FcyR and integrin signaling, as further described in Newbrough et al. (Newbrough SA, et al. SLP-76 regulates Fcgamma receptor and integrin signaling in neutrophils. Immunity. 2003 Nov;19(5):761 -9). Because LAT and SLP are both heavily involved in signaling within T cells, synthetic receptors may benefit from comprising the intracellular portions of either LAT or SLP. In non-limiting examples, LAT, a portion of LAT, SLP, or a portion of SLP may be the signaling moiety of a synthetic receptor. In a non-limiting example, LAT or a portion of LAT may be the signaling moiety of a first synthetic receptor, SLP or a portion of SLP may be the signaling moiety of a second synthetic receptor.

[0114] 4-1 BB (also known as CD137 or TNF receptor superfamily member 9 (TNFRSF9) or induced by lymphocyte activation (ILA)) is a transmembrane protein expressed on the surface of multiple cell types, including activated T cells. Theintracellular signaling region of 4-1 BB may be used, in non-limiting examples, as a signaling moiety for a synthetic receptor on a CAR-T cell. In some non-limiting examples, 4-1 BB may be a signaling moiety for a second synthetic receptor that is unable to activate a CAR-T cell without the binding of a first receptor as well. Examples of this can be seen in, among other places, Singh et al (Singh, R., et al. 4-1 BB immunotherapy: advances and hurdles. Exp Mol Med 56, 32-39 (2024)).

[0115] An antigen binding moiety, molecule, or complexes thereof may be, for example and without limitation, a monoclonal antibody, including fragments, derivatives, or analogs thereof, or complexes thereof, including without limitation: Fab, Fab', Fv fragments, single chain Fv (scFv) fragments, dsFv, Fab1 fragments, F(ab')2 fragments, single domain antibodies, camelized (camelid) antibodies and antibody fragments, humanized antibodies and antibody fragments, and multivalent versions of the foregoing; multivalent binding reagents including without limitation: monospecific or bispecific antibodies, such as disulfide stabilized Fv fragments, scFv tandems ((ScFv)2 fragments), diabodies, triabodies, tetrabodies, which typically are covalently linked or otherwise stabilized (e.g., leucine zipper or helix stabilized) scFv fragments, bi-specific T-cell engager (BiTE, e.g., a DbTE), di-scFv (dimeric single-chain variable fragment), single-domain antibody (sdAb), or antibody binding domain fragments. Antibody fragments also include miniaturized antibodies or other engineered binding reagents that exploit the modular nature of antibody structure, comprising, often as a single chain, one or more antigen-binding or epitope-binding sequences (e.g., paratope) and, at a minimum, any other amino acid sequences needed to ensure appropriate specificity, delivery, and stability of the composition.

[0116] scFv molecules may be manufactured using any suitable technology. Typically, recombinant cells comprising genes for expressing scFv-containing polypeptides are engineered, e.g., according to decades-old methods using any of a variety of publicly- and commercially-available expression systems. Huston J. S., et al., “Protein engineering of single-chain Fv analogs and fusion proteins, ’’Methods in Enzymology, vol. 203, pp. 46-88, 1991 ; Ahmad ZA, et al. scFv antibody: principles and clinical application. Clin Dev Immunol. 2012;2012:980250; Gqciarz A, Ruddock LW. Complementarity determining regions and frameworks contribute to the disulfide bond independent folding of intrinsically stable scFv. PLoS One. 2017 Dec 18;12(12):e0189964; Sandomenico A, et al. Evolution of Escherichia coli Expression System in Producing Antibody Recombinant Fragments. Int J Mol Sci. 2020 Aug31 ;21 (17):6324; Petrus MLC, et al. A microbial expression system for high-level production of scFv HIV-neutralizing antibody fragments in Escherichia coli. Appl Microbiol Biotechnol. 2019 Nov; 103(21 -22):8875-8888; and Toleikis L, Frenzel A. Cloning single-chain antibody fragments (ScFv) from hybridoma cells. Methods Mol Biol. 2012;907:59-71 ; see, also, w Tbdna TOm / clonin^scfy. In non-limiting embodiments, a CAR-T receptor may comprise an antigen binding moiety, for example an scFv fragment. In some examples, a pair of CAR-T receptors may comprise a first CAR-T receptor wherein the first antigen binding moiety is a scFv fragment and a second CAR-T receptor wherein the second antigen binding moiety is a scFv fragment.

[0117] Using CAR-T cells to kill B cells or a subset of B cells and / or reducing the population of B cells or a subset of B cells, such as memory B cells, activated B cells, or ABC cells, may be useful in treating a variety of conditions. Relevant conditions are described above. As such, CAR-T receptors, constructed as earlier described may be designed to target surface antigens from B cells or a subset of B cells. For example, and without limitation, the surface antigens may be for a memory B cell, the surface antigens may be for an activated B cell, or the surface antigens may be for an ABC cell.

[0118] CAR-T cells expressing the above-described CAR-T receptors may also be constructed or produced. CAR-T cells may be constructed or produced, in nonlimiting examples, by introducing genes for expressing CAR-T receptors into T cells. These T cells may be autologous or allogenic or xenogeneic. In non-limiting embodiments, the T cells are autologous or allogenic to a patient. In a non-limiting example, T cells may be collected and isolated from blood. In non-limiting examples, isolated T cells may be expanded ex vivo to increase the total number of T cells, such as by those methods described in Watanabe et al. (Watanabe N, et al. Impact of Manufacturing Procedures on CAR-T Cell Functionality. Front Immunol. 2022 Apr 13; 13:876339). Genes for expressing CAR-T receptors may be introduced into the T cells ex vivo. Genes for expressing CAR-T receptors may be introduced into the T cells by a number of methods. For example and without limitation, T cells may be transfected or transduced with a nucleic acid or nucleic acids comprising a gene or genes for expressing CAR-T receptors. Transfection may be achieved by, for example and without limitation, physical means such as by electroporation, sonoporation, or other methods as are known in the art. Transfection may be achieved by, for example, by chemical meanssuch as by using cationic lipids, cationic polymers, calcium phosphate, DAED-dextran, peptides, nanoparticles, or other methods as are known in the art. Transfection may be of a nucleic acid or nucleic acids comprising a gene or genes for expressing CAR- T receptors, for example as a plasmid or plasmids or with a gene editing system such as a CRISPR Cas9 system. Transduction may be achieved by, for example, lentiviral transduction, wherein a lentivirus inserts a nucleic acid or nucleic acids comprising a gene or genes for expressing CAR-T receptors into the genome of the host cell, such as a T cell. Other recombinant viral-mediated transfection vectors, such as AAV, HSV, or Ad vectors, as are broadly-known and available, may be employed for delivery of a nucleic acid comprising a gene for expression in a cell according to the methods described herein. Once constructed or produced, CAR-T cells may be expanded ex vivo to quantities sufficient for delivery into a patient in a dose effective, for example and without limitation, treat an autoimmune disease or reduce the population of B cells or subsets of B cells.

[0119] For example and without limitation, a CAR-T cell may express a pair of CAR-T receptors of as previously described. CAR-T cells expressing a pair of CAR-T receptors may, for example, be able to kill, in vitro or in vivo, a B cell or a subset of B cells, such as a memory B cells, activated B cells, or ABC cells. CAR-T cells may comprise a greater composition. A composition comprising CAR-T cells may include a pharmaceutically-acceptable excipient or carrier, such as water, PBS, or serum-free cell culture media.

[0120] A composition may include one or more nucleic acids comprising a gene or genes for expressing a pair of CAR-T receptors. In non-limiting examples, a composition may include a plasmid or plasmids comprising a gene or genes for expressing a pair of CAR-T receptors. A nucleic acid or nucleic acids, such as a plasmid or plasmids, may comprise a gene or genes for expressing a pair of CAR-T receptors comprising, for example a targeting moiety for binding a surface antigen of another cell, and a signaling moiety for generating a signal when the targeting moiety binds a surface antigen on another cell. Non-limiting examples of targeting moieties and signaling moieties for CAR-T receptors are previously described in this application, and any nucleic acid or nucleic acids comprising a gene or genes for expression a pair of CAR-T receptors may comprise, but are not limited to, any of the previously described moieties or those included in other examples found in this application.

[0121] Any of the mentioned compositions may be useful in in vitro applications or in vivo applications. Examples of in vivo applications include, without limitation, reducing the population of B cells or subsets of B cells in a patient and / or treating patients. Such patients may include, but are not limited to, those with an autoimmune disease. For example and without limitation, one may treat an autoimmune disease in a patient with a previously described composition comprising CAR-T cells. CAR-T cells may be administered in one or more doses and may be administered in an amount effective to treat the autoimmune disease. Such amounts may range from, without limitation and inclusive of any increment therebetween, 102to 1012CAR-T cells. In another example, one may reduce the population of B cells or subsets of B cells in a patient with a previously described composition comprising CAR-T cells. CAR-T cells may be administered in one or more doses and may be administered in an amount effective to reduce the population of B cells or subsets of B cells in a patient. Such amounts may range from, without limitation and inclusive of any increment therebetween, 102to 1012CAR-T cells. In non-limiting examples, CAR-T cells may be delivered regionally or systemically such as through arterial infusion, intraventricular infusion, intratumoral infusion, intraperitoneal infusion, intrapleural infusion, or intravenous infusion. Other methods of delivery may include via a hydrogel or microneedle array. Non-limiting examples of methods of delivery may be found in Gu et al. (Gu, X., et al. Infusion and delivery strategies to maximize the efficacy of CAR-T cell immunotherapy for cancers. Exp Hematol Oncol 13, 70 (2024).).

[0122] Examples of subsets of B cells that may be targeted to treat autoimmune diseases and / or to reduce B cell or B cell subsets by such compositions comprising CAR-T cells as described include, without limitation, ABC cells, memory B cells, and activated B cells. Patients to whom are administer these compositions to treat autoimmune diseases and / or to reduce B cell or B cell subsets may have conditions that include, but are not limited to, Systemic lupus erythematosus (SLE), Multiple sclerosis (MS), Rheumatoid arthritis (RA), Sjogren’s syndrome (SS), Ankylosing Spondylitis, Axial spondyloarthritis, Scleroderma, Malarial autoimmune anemia, Common variable immunodeficiency (CVID) with autoimmune complications, Crohn’s disease, ulcerative colitis, or dermatomyositis. Other, non-limiting, examples of conditions that patients who are administered this compositions to treat autoimmune diseases and / or to reduce B cell or B cell subsets may have include Addison’s disease; Adult Still’s disease; Agammaglobulinemia; Alopecia areata; Amyloidosis; Ankylosingspondylitis; Anti-GBM / Anti-TBM nephritis; Antiphospholipid syndrome; Autoimmune angioedema; Autoimmune dysautonomia; Autoimmune encephalitis; Autoimmune hepatitis; Autoimmune inner ear disease (AIED); Autoimmune myocarditis; Autoimmune oophoritis; Autoimmune orchitis; Autoimmune pancreatitis; Autoimmune retinopathy; Autoimmune urticaria; Axial spondyloarthritis; Axonal & neuronal neuropathy (AMAN); Balo disease; Behcet’s disease; Benign mucosal pemphigoid (Mucous membrane pemphigoid); Bullous pemphigoid; Castleman disease (CD); Celiac disease; Chagas disease; Chronic inflammatory demyelinating polyneuropathy (CIDP); Chronic recurrent multifocal osteomyelitis (CRMO); Churg-Strauss syndrome (CSS) or Eosinophilic granulomatosis (EGPA); Cicatricial pemphigoid; Cogan’s syndrome; Cold agglutinin disease; Common variable immunodeficiency (CVID) with autoimmune complications; Complex regional pain syndrome (formerly known as reflex sympathetic dystrophy); Congenital heart block; Coxsackie myocarditis; CREST syndrome; Crohn’s disease; Dermatitis herpetiformis; Dermatomyositis; Devic’s disease (neuromyelitis optica); Discoid lupus; Dressier’s syndrome; Endometriosis; Eosinophilic esophagitis (EoE); Eosinophilic fasciitis; Erythema nodosum; Essential mixed cryoglobulinemia; Evans syndrome; Fibromyalgia; Fibrosing alveolitis; Giant cell arteritis (temporal arteritis); Giant cell myocarditis; Glomerulonephritis; Goodpasture’s syndrome; Granulomatosis with polyangiitis; Graves’ disease; Guillain- Barre syndrome; Hashimoto’s thyroiditis; Hemolytic anemia; Henoch-Schonlein purpura (HSP); Herpes gestationis or pemphigoid gestationis (PG); Hidradenitis suppurativa (HS) (Acne inversa); IgA nephropathy; lgG4-related sclerosing disease; Immune thrombocytopenic purpura (ITP); Inclusion body myositis (IBM); Interstitial cystitis (IC); Juvenile arthritis; Juvenile diabetes (Type 1 diabetes); Juvenile myositis (JM); Kawasaki disease; Lambert-Eaton syndrome; Lichen planus; Lichen sclerosus; Ligneous conjunctivitis; Linear IgA disease (LAD); Lyme disease chronic; Malarial autoimmune anemia; Meniere’s disease; Microscopic polyangiitis (MPA); Mixed connective tissue disease (MCTD); Mucha-Habermann disease; Multifocal motor neuropathy (MMN) or MMNCB; MS; Myasthenia gravis; Myelin oligodendrocyte glycoprotein antibody disorder; Myositis; Narcolepsy; Neonatal lupus; Neuromyelitis optica I devic disease; Neutropenia; Ocular cicatricial pemphigoid; Optic neuritis; Palindromic rheumatism (PR); PANDAS (Pediatric autoimmune neuropsychiatric disorders associated with streptococcus infections); Paraneoplastic cerebellar degeneration (PCD); Paroxysmal nocturnal hemoglobinuria (PNH); Pars planitis(peripheral uveitis); Parsonage-Turner syndrome; Pemphigus; Peripheral neuropathy; Perivenous encephalomyelitis; Pernicious anemia (PA); POEMS syndrome; Polyarteritis nodosa; Polyglandular syndromes type I, II, III; Polymyalgia rheumatica; Polymyositis; Postmyocardial infarction syndrome; Postpericardiotomy syndrome; Primary biliary cholangitis; Primary sclerosing cholangitis; Progesterone dermatitis; Progressive hemifacial atrophy (PHA) Parry romberg syndrome; Psoriasis; Psoriatic arthritis; Pulmonary Alveolar Proteinosis (PAP); Pure red cell aplasia (PRCA); Pyoderma gangrenosum; Raynaud’s phenomenon; Reactive arthritis; Relapsing polychondritis; Restless legs syndrome (RLS); Retroperitoneal fibrosis; Rheumatic fever; RA; Sarcoidosis; Schmidt syndrome or Autoimmune polyendocrine syndrome type II; Scleritis; Scleroderma; SLE; SS; Stiff person syndrome (SPS); Susac’s syndrome; Sympathetic ophthalmia (SO); Takayasu’s arteritis; Temporal arteritis / giant cell arteritis; Thrombocytopenic purpura (TTP); Thrombotic thrombocytopenic purpura (Ttp); Thyroid Eye Disease (TED); Tolosa-Hunt syndrome (THS); Transverse myelitis; Type 1 diabetes; Ulcerative colitis (UC); Undifferentiated connective tissue disease (UCTD); Uveitis; Vasculitis; Vitiligo; Vogt-Koyanagi-Harada disease; or Warm autoimmune hemolytic anemia.

[0123] The following examples illustrate various aspects or embodiments of the present invention, and are intended to be exemplary.Example 1 - Design of a synthetic CAR-T:

[0124] Receptor 1 recognizing CD19 includes the following protein domains: anti- CD19scFv-CD28(2CA)H,TM-LATcyto(del171-233) where CD28-(2CA)H,TM corresponds to the hinge and transmembrane domains of CD28 with 2 cysteine to alanine mutations, and LATcyto(del171-233) refers to the cytoplasmic domain of the LAT protein truncated to lack amino acids 171 -233.

[0125] Receptor 2, recognizing CD11 c includes the following protein domains: anti- CD1 1 cscFv-CD8H,TM SLP-76cyto(del224-244) where CD8)H,TM corresponds to the hinge and transmembrane domains of the CD8alpha protein, and SLP-76cyto(del224- 244) refers to the cytoplasmic domain of the SLP-76 protein truncated to lack amino acids 224-244.

[0126] Another non-limiting embodiment of the invention may include swapping the scFv’s of the receptors: Receptor 1 recognizing CD11 c (anti-CD1 I cscFv- CD28(2CA)H,TMLATcyto( del171 -233)) and Receptor 2 recognizing CD19 (anti- CD19scFv-CD8H,TM SLP-76cyto(del224-244). See, Tousley et al. for additionalinformation on the use of logic-gated intracellular networks (LINK) to design synthetic CAR for T cells and their successful use (Tousley AM, et al. Co-opting signaling molecules enables logic-gated control of CAR-T cells. Nature. 2023 Mar;615(7952):507-516.). Kang et al provides how a CD19 scFv antigen binding moiety may be constructed (Kang CH, et al. Identification of Potent CD19 scFv for CAR-T Cells through scFv Screening with NK / T-Cell Line. Int J Mol Sci. 2020 Dec 1 ;21 (23):9163.) and Ejaz et al. provides how a CD11 c scFv antigen binding moiety may be constructed (Ejaz A, et al. Targeting viral antigens to CD11 c on dendritic cells induces retrovirus-specific T cell responses. PLoS One. 2012;7(9):e45102).

[0127] In non-limiting embodiments, Receptor 1 has a sequence of SEQ ID NO: 17 or SEQ ID NO: 18 and Receptor 2 has a sequence of SEQ ID NO: 3.Example 2 - Receptor design LINK-CAR format

[0128] In one non-limiting embodiment the AND gate receptors targeting pathogenic B cells are generated to sense the antigen combination CD19 and CD11 c using the LINK-CAR format (Tousley et al. 2023). One receptor targeting CD19 includes a single chain variable fragment (scFv) from an anti-CD19 antibody fused to a spacer and transmembrane region such as that from CD28, with 2 cysteines mutated to alanine, and to the LAT cytoplasmic signaling domain with a truncation of residues 171 -233 (LATcyto(del171 -233)). A second receptor, recognizing CD11c includes an anti- CD1 1 c scFv-fused via a hinge and transmembrane region such as that of CD8alpha and the SLP-76 cytoplasmic signaling domain with a truncation of residues 224-244 (SLP-76cyto(del224-244)). Receptors are co-expressed from a constitutive promoter from a retroviral expression construct. Upon binding to CD19 and CD11 c antigens these receptors activate TCR pathway signaling starting at SLP-76 and LAT, leading to T cell activation, and effector functions, while the binding of either single antigen does not lead to a productive signaling response. In another embodiment, the CD11 c scFv is replaced by an anti-CD80 scFv or anti-CD27 scFv recognizing CD19 AND CD80 or CD19 AND CD27. In addition to the embodiment in which the binding regions recognize human antigens and signaling receptor components are derived from human receptors, another embodiment includes the production of a proof-of-concept system targeting murine CD19 AND murine CD11 c using receptors including murine signaling components.Example 3 - Receptor design synNotch format

[0129] In another non-limiting embodiment, AND gate receptors targeting pathogenic B cells are generated to sense the antigen combination of CD19 and CD11 c using the synNotch CAR or SNIPR CAR format (Roybal et a / 2016, Zhu et a / 2022). One receptor recognizing CD19 includes an anti-CD19 scFv such as fused to the Notch core or SNIPR core protein including hinge, transmembrane and cleavage domains. This is fused to a transcriptional activator (TA) such as Gal4-VP64 or p65 which is tethered to the membrane. The second receptor, a CAR targeting CD11 c is expressed from a TA-responsive promoter such as the Gal4 response promoter including TA binding sites (response element) such as GAL4 binding sites upstream of a minimal core promoter such as CMVmin or TAmin. This CAR includes an anti-CD11 c scFv fused via a hinge and transmembrane region such as that of CD8alpha and the cytoplasmic domains of 4-1 BB and CD3zeta to provide co-stimulation and TCR signaling, respectively. Upon recognition of CD19, the CD19-targeting receptor undergoes proteolytic cleavage leading to release of the TA and temporary expression of the CD11 c targeting CAR, allowing for recognition of the CD11c antigen. In another embodiment, the CD11 c scFv is replaced by an anti-CD80 scFv or anti-CD27 scFv recognizing CD19 AND CD80 or CD19 AND CD27. In addition to the embodiment in which the binding regions recognize human antigens and signaling receptor components are derived from human receptors, another embodiment includes the production of a proof-of-concept system targeting murine CD19 AND murine CD11 c using receptors includes murine signaling components.Example 4 - Receptor design balanced signaling format

[0130] In another non-limiting embodiment, AND gate receptors targeting pathogenic B cells is generated to sense the antigen combination CD19 and CD11 c using the balanced signaling CAR format (Kloss et al 2013). One receptor recognizing CD19 includes a mutated anti-CD19 scFv such as FMC63 containing a Y260A mutation, fused via a hinge and transmembrane region such as that of CD8alpha to the CD3zeta cytoplasmic domain. A second receptor, recognizing CD11c includes an anti-CD11 c scFv-fused via a hinge and transmembrane region such as that of CD28 with the CD28 and / or 4-1 BB cytoplasmic co-stimulatory domains. Upon recognition of single antigens receptor signaling is not efficiently activated, but upon binding to both antigens productive TCR and co-stimulatory signaling occur leading to target cell elimination and CAR-T cell effector function. In another embodiment, the CD11c scFv is replacedby an anti-CD80 scFv or anti-CD27 scFv recognizing CD19 AND CD80 or CD19 AND CD27. In addition to the embodiment in which the binding regions recognize human antigens and signaling receptor components are derived from human receptors, another embodiment includes the production of a proof-of-concept system targeting murine CD19 AND murine CD11c using receptors including murine signaling components.Example 5 - AND gate CAR viral vector construction and virus production

[0131] In another non-limiting embodiment, coding regions for these receptors may be cloned using standard molecular biology techniques into the MSGV1 retroviral backbone. They are then packaged into retrovirus using standard techniques. Briefly the expression construct is transfected along with the RD114 packaging plasmid into HEK293-gp cells via liposomal transfection. After 24 hours cells are changed into new media, and after 24 hours viral supernatant is collected new media is added. Viral supernatant is then collected again at 48 hours.Example 6 - AND gate CAR-T cell production (retroviral transduction and T cell expansion)

[0132] Human T cells expressing receptors to target pathogenic B cells are generated by first isolating PBMCs from leukopaks from healthy human donors and undergoing Ficoll gradient centrifugation. Human T cells are obtained by magnetic sorting using the Human Pan T cell isolation kit (Miltenyi Biotec). Once isolated, T cells are cultured in RPMI supplemented with 10% human AB serum (Gemini Bio Products) and 100 U / mL human IL-2 IS (Miltenyi Biotec), 1 ng / mL IL-15 (Miltenyi Biotec), and 4 mM i_- arginine (Sigma-Aldrich). T cells are activated via CD3 and CD28 receptors using the TransAct Human T cell activation reagent (Miltenyi Biotec). After 48 hours, T cells are transduced with a retrovirus encoding the AND gate receptors. Briefly, retrovirus is spun onto retronectin-coated plates (Takara Bio.) at 2000g for 2 h at 32 °C. After removing excess viral supernatant, primary human T cells are then added to the coated plate and spun with the virus and returned to the cell culture incubator. There they are maintained by splitting into new plates every 2-3 days at a concentration of 1 M cells / mL in RPMI cell culture media supplemented with human AB serum and IL- 2 and IL-15 cytokines.Example 7 - Assay to evaluate AND gate specific targeting of T cell activation and target cell lysis

[0133] Dual antigen positive, single antigen positive, and antigen negative target cells are stained with Cell Trace Yellow dye following the manufacturer’s recommended protocol (ThermoFisher). 10,000 target cells per well were then cocultured with 50,000 AND gate CAR-T cells (effector / target = 5:1 ) in a 96-well V-bottom plate. Cells are then incubated at 37 °C for 24 hours and evaluated for T cell activation and target cell lysis by flow cytometry. T cell activation is assessed via staining with fluorescently labeled antibodies recognizing T cell activation markers CD69-BV711 (BD Biosciences) and CD107a-APC (BD Biosciences) Marker expression is specifically evaluated on AND gate CAR-T cells by gating the CellTrace(-) population. Target cell lysis is evaluated by staining with Ghost Dye Red Viability Dye (Tonbo Biosciences), and gating on the CellTrace+ population. Target cells are identified by Cell Trace Yellow, and lysed target cells are identified by positive Ghost Dye staining. Percent- specific cytotoxicity of target cells can be calculated by the equation: 100 x (% experimental lysis - % target-only lysis) / (100 - % target-only lysis). To determine specificity, we can compare the lysis and T cell activation functions in co-incubations with dual antigen positive cells vs. single antigen and antigen negative target cells.Example 8 - Construction of CART products that kill ABC

[0134] T cells are isolated from PBL of a normal healthy donor or a patient with an autoimmune disease; or from a lymphoid organ of a normal mouse or a mouse with an autoimmune disease. The T cells can be isolated by either magnetic bead-based or flow cytometric cell sorting. These T cells are then stimulated in culture for 2 days in the presence of microbeads that are coated with anti-CD3 and anti-CD28, along with IL-2. Following stimulation, the T cells are infected with a lentivirus or retrovirus that encodes the two chains of the bi-functional chimeric Ag receptor, with one chain recognizing CD19 and the other recognizing either CD11 c, CD80, CD27 or another memory B cell-specific surface marker. After three further days of culture and expansion, the cells are washed and recultured for two further days in a lower concentration of IL-2. After washing, the cells are then co-cultured with B cells that express the target of the specific CART, i.e. CD11 c, CD80, or CD27 as follows:

[0135] CAR19 AND gate T cells are manufactured as described above. The cells are then labeled with Cell Trace Yellow dye as described above and cultured with mixtures of B cells containing CD11c+ B cell targets (isolated as below) at graded ratios ofCART cells to target total B cells of 10:1 , 3: 1 , 1 :1 and 0.3:1 , respectively at a total cell count of 1 x 106cells / ml in B cell culture media. Target cells for mouse and human are described below. At 24, 48, and 72 hours cultures are sampled and target T and B cells are enumerated by flow cytometry using counting beads (CountBright, ThermoFisher), staining for CD19, CD11 c, CD4, CD8, and Cell Trace Yellow. In some experiments, B cells are labeled with Cell Trace Violet. Dead cells are further enumerated by using Ghost Dye far red staining. Selective loss of CD11 c+ target B cells compared to total B cells are calculated compared to the starting sample and expressed as a ratio of percentages in the final culture population divided by the percentage in the starting population.

[0136] Murine target cells include splenic B cells isolated from lupus-prone MRL / lpr mice, which are enriched for B cells that naturally express CD11 c. As an additional control, B cells are isolated from MRL / lpr mice that are genetically deficient in T cells, and hence lack CD11 c+ B cells.

[0137] Human target cells can be B cell lymphoma lines, such as NALM-6, that have been transduced to express CD11 c by use of a lentivirus that expresses the Itgax gene.Example 9 - Construction of CD11 c CART products for the treatment of a patient with lupus.

[0138] A patient with lupus diagnosed according to ACR criteria can be treated with a CAR19 AND T cell product. Patients are candidates if they demonstrate a percentage of CD11c+ B cells as a proportion of total B cells in their peripheral blood of 8% or greater. Peripheral blood lymphocytes (PBL) from the patient are collected by apheresis. T cells are isolated from these PBL using a magnetic bead-based negative selection procedure, essentially as described by Mougiakakos et al. (Mougiakakos, D., et al. 2021. CD19-Targeted CAR-T Cells in Refractory Systemic Lupus Erythematosus. N Engl J Med. 385:567-9.). CART cells are then prepared from these cells as described above and by Mougiakakos et al.

[0139] The patient is also treated according to the protocol described by Mougiakakos et al . CD19 AND CD11 c CAR-T cells are produced by lentiviral transduction of autologous fresh leukapheresis product prepared as above in the closed automated CliniMACS Prodigy system. After preparatory lymphodepletion with fludarabine at a dose of 25 mg per square meter of body-surface area per day on days -5, -4, and -3 and cyclophosphamide at a dose of 1000 mg per square meter on day -3, the patientis given an infusion of between 0.5 and 1.5 x106CD19 CAR-T cells per kilogram of body weight. CAR-T cell expansion and depletion of B cells, and ABCs in particular, are monitored in the blood of the patient.Example 10 - Exemplary sequences

[0140] Exemplary sequences of CAR-T receptors can be seen in FIGS. 6A-6L, which provide an amino acid sequence of 1 D3-CD28-LAT (SEQ ID NO: 1 ); an amino acid sequence of N418-CD8-SLP76 (SEQ ID NO: 2); an amino acid sequence of anti- CD19scFv-CD28(2CA)H,TM-LATcyto(del171-233) (SEQ ID NO: 3); an amino acid sequence of antiCD80-CD8-SLP76 (SEQ ID NO: 4); an amino acid sequence of antiCD27-CD8-SLP76 (SEQ ID NO: 5); an amino acid sequence of 1 D3-Notchcore- Gal4-VP64 (SEQ ID NO: 6); a DNA sequence of pGal4-N418-CD28-CD3z(SEQ ID NO: 7); an amino acid sequence of FMC63-Notchcore-Gal4-VP64 (SEQ ID NO: 8); a DNA sequence of pGal4-antiCD80-CD28-CD3z(SEQ ID NO: 9); a DNA sequence of pGal4-antiCD27-CD28-CD3z(DNA, SEQ ID NO: 10); an amino acid sequence of FMC63mut(Y261A)-CD8-CD3z (SEQ ID NO: 11 ); an amino acid sequence of antiCD27-CD28-41 BB (SEQ ID NO: 12); and an amino acid sequence of antiCD80- CD28-41 BB (SEQ ID NO: 13); 14. Amino acid sequence of N418-CD28-CD3z (SEQ ID NO: 14); 15. Amino acid sequence of antiCD80-CD28-CD3z (SEQ ID NO: 15); 16. Amino acid sequence of antiCD27-CD28-CD3z (SEQ ID NO: 16); 17. Amino acid sequence of anti-huCD11 c-CD8-SLP76 (SEQ ID NO: 17); 18. DNA sequence of pGal4-antu-huCD11 c-CD28-CD3z (SEQ ID NO: 18); Amino acid sequence of anti- huCD11c-CD28-CD3z (SEQ ID NO: 19); and Amino acid sequence of anti-huCD11 c- CD28-41 BB (SEQ ID NO: 20). Those of skill in the art will understand that these are merely exemplary sequences and that others may be used, including modified, substituted, and / or mutated sequences based on those listed herein, including those having 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more and / or 99% or more sequence identity to any of SEQ ID NOS: 1-16, all values and subranges therebetween inclusive.

[0141] The present invention has been described with reference to certain exemplary embodiments, dispersible compositions and uses thereof. However, it will be recognized by those of ordinary skill in the art that various substitutions, modifications, or combinations of any of the exemplary embodiments may be made without departing from the spirit and scope of the invention. Thus, the invention is not limited by thedescription of the exemplary embodiments, but rather by the appended claims as originally filed.

Claims

We claim:1 . A pair of CAR-T receptors that individually recognize two different surface antigens on a target B cell, optionally a human B cell.

2. The pair of CAR-T receptors of claim 1 , that are activated only on binding the two different surface proteins on the B cell.

3. The pair of CAR-T receptors of claim 1 , comprising a first synthetic receptor for binding a first antigen of the B cell, and a second receptor for binding a second antigen of the B cell, and wherein the first synthetic receptor and the second synthetic receptor each comprises amino acid chain comprising a signaling moiety and an antigen binding moiety and wherein the signaling moieties activate the CAR-T cell only when the antigen binding moieties of the first synthetic receptor and the second synthetic receptor bind the first antigen and the second antigen on the B cell.

4. The pair of CAR-T receptors of claim 3, wherein the first antigen is a CD19 or CD20.

5. The pair of CAR-T receptors of claim 3, wherein the second antigen is CD11c, CD11 b, CD27 or CD80.

6. The pair of CAR-T receptors of claim 3, wherein the second antigen is a memory B cell surface antigen.

7. The pair of CAR-T receptors of claim 3, wherein the first antigen is CD19, and the second antigen is CD11 c.

8. The pair of CAR-T receptors of claim 3, wherein the first synthetic receptor and the second synthetic receptors are CARs that activate the T-cell only when the CARs are bound to both the first antigen and the second antigen.

9. The pair of CAR-T receptors of claim 8, wherein the signaling moiety of the first synthetic receptor is LAT, and the signaling moiety of the second synthetic receptor is SLP.

10. The pair of CAR-T receptors of claim 8, wherein the signaling moiety of the first synthetic receptor is that, when included in the first synthetic receptor with an antigen binding moiety in a CAR-T cell, is unable to activate the CAR-T cell on binding to a cell having a surface antigen that binds to the antigen binding moiety of the first synthetic receptor without binding of a surface antigen of the cell to the antigen binding moiety of the second synthetic receptor, and the signaling moiety of the second synthetic receptor is a 4-1 BB signaling moiety that is unable to activate the CAR-T cell on binding to a cell having a surface antigen that binds to the antigen binding moiety of the second synthetic receptor without binding of a surface antigen of the cell to the antigen binding moiety of the first synthetic receptor, such that when both of the antigen binding moieties of the first and second synthetic receptors bind surface antigens on a cell, the CAR-T cell is activated.11 . The pair of CAR-T receptors of claim 3, wherein the first synthetic receptor comprises an antigen binding moiety linked to a transcription activator that activates a gene encoding the second synthetic receptor comprising an antigen binding moiety linked to a T-cell activator such that a CAR-T cell comprising the first and second synthetic receptors are only activated on antigen binding of both the first and second synthetic receptors.

12. The pair of CAR-T receptors of claim 11 , wherein the transcription activator is a synNotch activator.

13. The pair of CAR-T receptors of claim 3, wherein the second antigen is an activated B cell surface antigen.

14. The pair of CAR-T receptors of claim 3, wherein the first antigen binding moiety and the second antigen binding moiety are scFv fragments.

15. The pair of CAR-T receptors of claim 1 , wherein the B-cell is anABC cell.

16. The pair of CAR-T receptors of claim 1 , wherein the B-cell is a memory B cell or an activated B cell.

17. A CAR-T cell expressing the pair of CAR-T receptors of claim 1.

18. The CAR-T cell of claim 17, able to kill, in vitro, an ABC cell, a memory B cell, and / or an activated B cell expressing the two surface antigens.

19. A composition comprising the CAR-T cell of claim 17, and a pharmaceutically-acceptable excipient or carrier, such as water, PBS, or serum-free cell culture media.

20. A composition comprising one or more nucleic acid(s), e.g., a plasmid or plasmid pair, comprising genes for expressing the pair of CAR-T receptors of claim 1 , optionally in a viral vector genome, such as a recombinant lentiviral vector genome.21 . A method of treating an autoimmune disease in a patient, e.g., a human patient, comprising administering the composition of claim 19 to the patient in an amount effective to treat the autoimmune disease in the patient, e.g., from 102to 1012of the CAR-T cells, inclusive, including any increment therebetween, in one or more doses.

22. The method of claim 21 , wherein the B cells are ABC cells.

23. The method of claim 22, wherein the patient has: Systemic lupus erythematosus (SLE), Multiple sclerosis (MS), Rheumatoid arthritis (RA), Sjogren’s syndrome (SS), Ankylosing Spondylitis, Axial spondyloarthritis, Scleroderma, Malarial autoimmune anemia, Common variable immunodeficiency (CVID) with autoimmune complications, Crohn’s disease, ulcerative colitis, or dermatomyositis.

24. The method of claim 21 , wherein the B cells are memory B cells or activated B cells.

25. The method of claim 21 , wherein the patient has: Addison’s disease; Adult Still’s disease; Agammaglobulinemia; Alopecia areata; Amyloidosis; Ankylosing spondylitis; Anti-GBM / Anti-TBM nephritis; Antiphospholipid syndrome; Autoimmune angioedema; Autoimmune dysautonomia; Autoimmune encephalitis; Autoimmune hepatitis; Autoimmune inner ear disease (AIED); Autoimmune myocarditis; Autoimmune oophoritis; Autoimmune orchitis; Autoimmune pancreatitis; Autoimmune retinopathy; Autoimmune urticaria; Axial spondyloarthritis; Axonal & neuronal neuropathy (AMAN); Balo disease; Behcet’s disease; Benign mucosal pemphigoid (Mucous membrane pemphigoid); Bullous pemphigoid; Castleman disease (CD); Celiac disease; Chagas disease; Chronic inflammatory demyelinating polyneuropathy (CIDP); Chronic recurrent multifocal osteomyelitis (CRMO); Churg- Strauss syndrome (CSS) or Eosinophilic granulomatosis (EGPA); Cicatricial pemphigoid; Cogan’s syndrome; Cold agglutinin disease; Common variable immunodeficiency (CVID) with autoimmune complications; Complex regional pain syndrome (formerly known as reflex sympathetic dystrophy); Congenital heart block; Coxsackie myocarditis; CREST syndrome; Crohn’s disease; Dermatitis herpetiformis; Dermatomyositis; Devic’s disease (neuromyelitis optica); Discoid lupus; Dressier’s syndrome; Endometriosis; Eosinophilic esophagitis (EoE); Eosinophilic fasciitis; Erythema nodosum; Essential mixed cryoglobulinemia; Evans syndrome; Fibromyalgia; Fibrosing alveolitis; Giant cell arteritis (temporal arteritis); Giant cell myocarditis; Glomerulonephritis; Goodpasture’s syndrome; Granulomatosis with polyangiitis; Graves’ disease; Guillain-Barre syndrome; Hashimoto’s thyroiditis; Hemolytic anemia; Henoch-Schonlein purpura (HSP); Herpes gestationis or pemphigoid gestationis (PG); Hidradenitis suppurativa (HS) (Acne inversa); IgA nephropathy; lgG4-related sclerosing disease; Immune thrombocytopenic purpura (ITP); Inclusion body myositis (IBM); Interstitial cystitis (IC); Juvenile arthritis; Juvenile diabetes (Type 1 diabetes); Juvenile myositis (JM); Kawasaki disease; Lambert-Eaton syndrome; Lichen planus; Lichen sclerosus; Ligneous conjunctivitis; Linear IgA disease (LAD); Lyme disease chronic; Malarial autoimmune anemia; Meniere’s disease; Microscopic polyangiitis (MPA); Mixed connective tissue disease (MCTD); Mucha-Habermann disease; Multifocal motor neuropathy (MMN) or MMNCB; MS;Myasthenia gravis; Myelin oligodendrocyte glycoprotein antibody disorder; Myositis; Narcolepsy; Neonatal lupus; Neuromyelitis optica / devic disease; Neutropenia; Ocular cicatricial pemphigoid; Optic neuritis; Palindromic rheumatism (PR); PANDAS (Pediatric autoimmune neuropsychiatric disorders associated with streptococcus infections); Paraneoplastic cerebellar degeneration (PCD); Paroxysmal nocturnal hemoglobinuria (PNH); Pars planitis (peripheral uveitis); Parsonage-Turner syndrome; Pemphigus; Peripheral neuropathy; Perivenous encephalomyelitis; Pernicious anemia (PA); POEMS syndrome; Polyarteritis nodosa; Polyglandular syndromes type I, II, III; Polymyalgia rheumatica; Polymyositis; Postmyocardial infarction syndrome; Postpericardiotomy syndrome; Primary biliary cholangitis; Primary sclerosing cholangitis; Progesterone dermatitis; Progressive hemifacial atrophy (PHA) Parry romberg syndrome; Psoriasis; Psoriatic arthritis; Pulmonary Alveolar Proteinosis (PAP); Pure red cell aplasia (PRCA); Pyoderma gangrenosum; Raynaud’s phenomenon; Reactive arthritis; Relapsing polychondritis; Restless legs syndrome (RLS); Retroperitoneal fibrosis; Rheumatic fever; RA; Sarcoidosis; Schmidt syndrome or Autoimmune polyendocrine syndrome type II; Scleritis; Scleroderma; SLE; SS; Stiff person syndrome (SPS); Susac’s syndrome; Sympathetic ophthalmia (SO); Takayasu’s arteritis; Temporal arteritis / giant cell arteritis; Thrombocytopenic purpura (TTP); Thrombotic thrombocytopenic purpura (Ttp); Thyroid Eye Disease (TED); Tolosa-Hunt syndrome (THS); Transverse myelitis; Type 1 diabetes; Ulcerative colitis (UC); Undifferentiated connective tissue disease (UCTD); Uveitis; Vasculitis; Vitiligo; Vogt-Koyanagi-Harada disease; or Warm autoimmune hemolytic anemia.

26. A method of reducing a population of B cells in a patient, e.g., a human patient, comprising administering the composition of claim 19 to the patient in an amount effective to a population of a B cells in the patient, e.g., from 102to 1012of the CAR-T cell cells, inclusive, including any increment therebetween, in one or more doses.

27. The method of claim 26, wherein the patient has: Addison’s disease; Adult Still’s disease; Agammaglobulinemia; Alopecia areata; Amyloidosis; Ankylosing spondylitis; Anti-GBM / Anti-TBM nephritis; Antiphospholipid syndrome; Autoimmune angioedema; Autoimmune dysautonomia; Autoimmune encephalitis; Autoimmune hepatitis; Autoimmune inner ear disease (AIED); Autoimmunemyocarditis; Autoimmune oophoritis; Autoimmune orchitis; Autoimmune pancreatitis; Autoimmune retinopathy; Autoimmune urticaria; Axial spondyloarthritis; Axonal & neuronal neuropathy (AMAN); Balo disease; Behcet’s disease; Benign mucosal pemphigoid (Mucous membrane pemphigoid); Bullous pemphigoid; Castleman disease (CD); Celiac disease; Chagas disease; Chronic inflammatory demyelinating polyneuropathy (CIDP); Chronic recurrent multifocal osteomyelitis (CRMO); Churg- Strauss syndrome (CSS) or Eosinophilic granulomatosis (EGPA); Cicatricial pemphigoid; Cogan’s syndrome; Cold agglutinin disease; Common variable immunodeficiency (CVID) with autoimmune complications; Complex regional pain syndrome (formerly known as reflex sympathetic dystrophy); Congenital heart block; Coxsackie myocarditis; CREST syndrome; Crohn’s disease; Dermatitis herpetiformis; Dermatomyositis; Devic’s disease (neuromyelitis optica); Discoid lupus; Dressier’s syndrome; Endometriosis; Eosinophilic esophagitis (EoE); Eosinophilic fasciitis; Erythema nodosum; Essential mixed cryoglobulinemia; Evans syndrome; Fibromyalgia; Fibrosing alveolitis; Giant cell arteritis (temporal arteritis); Giant cell myocarditis; Glomerulonephritis; Goodpasture’s syndrome; Granulomatosis with polyangiitis; Graves’ disease; Guillain-Barre syndrome; Hashimoto’s thyroiditis; Hemolytic anemia; Henoch-Schonlein purpura (HSP); Herpes gestationis or pemphigoid gestationis (PG); Hidradenitis suppurativa (HS) (Acne inversa); IgA nephropathy; lgG4-related sclerosing disease; Immune thrombocytopenic purpura (ITP); Inclusion body myositis (IBM); Interstitial cystitis (IC); Juvenile arthritis; Juvenile diabetes (Type 1 diabetes); Juvenile myositis (JM); Kawasaki disease; Lambert-Eaton syndrome; Lichen planus; Lichen sclerosus; Ligneous conjunctivitis; Linear IgA disease (LAD); Lyme disease chronic; Malarial autoimmune anemia; Meniere’s disease; Microscopic polyangiitis (MPA); Mixed connective tissue disease (MCTD); Mucha-Habermann disease; Multifocal motor neuropathy (MMN) or MMNCB; MS; Myasthenia gravis; Myelin oligodendrocyte glycoprotein antibody disorder; Myositis; Narcolepsy; Neonatal lupus; Neuromyelitis optica / devic disease; Neutropenia; Ocular cicatricial pemphigoid; Optic neuritis; Palindromic rheumatism (PR); PANDAS (Pediatric autoimmune neuropsychiatric disorders associated with streptococcus infections); Paraneoplastic cerebellar degeneration (PCD); Paroxysmal nocturnal hemoglobinuria (PNH); Pars planitis (peripheral uveitis); Parsonage-Turner syndrome; Pemphigus; Peripheral neuropathy; Perivenous encephalomyelitis; Pernicious anemia (PA); POEMS syndrome; Polyarteritis nodosa; Polyglandular syndromes type I, II, III;Polymyalgia rheumatica; Polymyositis; Postmyocardial infarction syndrome; Postpericardiotomy syndrome; Primary biliary cholangitis; Primary sclerosing cholangitis; Progesterone dermatitis; Progressive hemifacial atrophy (PHA) Parry romberg syndrome; Psoriasis; Psoriatic arthritis; Pulmonary Alveolar Proteinosis (PAP); Pure red cell aplasia (PRCA); Pyoderma gangrenosum; Raynaud’s phenomenon; Reactive arthritis; Relapsing polychondritis; Restless legs syndrome (RLS); Retroperitoneal fibrosis; Rheumatic fever; RA; Sarcoidosis; Schmidt syndrome or Autoimmune polyendocrine syndrome type II; Scleritis; Scleroderma; SLE; SS; Stiff person syndrome (SPS); Susac’s syndrome; Sympathetic ophthalmia (SO); Takayasu’s arteritis; Temporal arteritis / giant cell arteritis; Thrombocytopenic purpura (TTP); Thrombotic thrombocytopenic purpura (Ttp); Thyroid Eye Disease (TED); Tolosa-Hunt syndrome (THS); Transverse myelitis; Type 1 diabetes; Ulcerative colitis (UC); Undifferentiated connective tissue disease (UCTD); Uveitis; Vasculitis; Vitiligo; Vogt-Koyanagi-Harada disease; or Warm autoimmune hemolytic anemia.

28. The method of claim 26, wherein the B cells are ABC cells.

29. The method of claim 28, wherein the patient has: Systemic lupus erythematosus (SLE), Multiple sclerosis (MS), Rheumatoid arthritis (RA), Sjogren’s syndrome (SS), Ankylosing Spondylitis, Axial spondyloarthritis, Scleroderma, Malarial autoimmune anemia, Common variable immunodeficiency (CVID) with autoimmune complications, Crohn’s disease, ulcerative colitis, or dermatomyositis.

30. The method of claim 26, wherein the B cells are memory B cells or activated B cells.

31. A method of treating atherosclerosis in a patient, e.g., a human patient, comprising administering the composition of claim 19 to the patient in an amount effective to treat atherosclerosis in the patient, e.g., from 102to 1012of the CAR-T cell cells, inclusive, including any increment therebetween, in one or more doses.

32. A CAR-T cell comprising a first synthetic receptor for binding a first antigen of a target B cell, and a second receptor for binding a second antigen ofa target B cell, the first synthetic receptor comprising a CD19 recognition domain and the second synthetic receptor comprising a CD11 c recognition domain.

33. The CAR-T cell of claim 32, wherein, in the presence of a B cell comprising only one of CD19 or CD11 c, the CAR-T cell is incapable of killing the B cell.

34. The CAR-T cell of claim 32, wherein the CD19 recognition domain comprises an anti-CD19 scFv.

35. The CAR-T cell of claim 34, wherein the first receptor further comprises a CD28 hinge and transmembrane domain comprising at least two cysteine to alanine mutations.

36. The CAR-T cell of claim 34, wherein the first receptor further comprises a LAT protein cytoplasmic domain modified by deletion of amino acids 171 - 233.

37. The CAR-T cell of claim 32, wherein the CD11 c recognition domain comprises a CD11 c scFv.

38. The CAR-T cell of claim 37, wherein the second receptor further comprises a CD8 alpha protein hinge and transmembrane domain.

39. The CAR-T cell of claim 37, wherein the second receptor further comprises an SLP-76 cytoplasmic domain modified by deletion of amino acids 224- 244.

40. A CAR-T cell comprising a first synthetic receptor for binding a first antigen of a target B cell, and a second receptor for binding a second antigen of a target B cell, the first synthetic receptor comprising SEQ ID NO: 1 , SEQ ID NO: 3, SEQ ID NO: 6, SEQ ID NO: 8, and / or SEQ ID NO: 11 and the second synthetic receptor comprising SEQ ID NO: 2, SEQ ID NO: 14, SEQ ID NO: 17, and / or SEQ ID NO: 18.

41. The CAR-T cell of claim 40, wherein the first synthetic receptor comprises SEQ ID NO: 1.

42. The CAR-T cell of claim 40, wherein the first synthetic receptor comprises SEQ ID NO: 3.

43. The CAR-T cell of claim 40, wherein the first synthetic receptor comprises SEQ ID NO: 6.

44. The CAR-T cell of claim 40, wherein the first synthetic receptor comprises SEQ ID NO: 8.

45. The CAR-T cell of claim 40, wherein the first synthetic receptor comprises SEQ ID NO: 11 .

46. The CAR-T cell of claim 40, wherein the second synthetic receptor comprises SEQ ID NO: 2.

47. The CAR-T cell of claim 40, wherein the second synthetic receptor comprises SEQ ID NO: 14.

48. The CAR-T cell of claim 40, wherein the second synthetic receptor comprises SEQ ID NO: 17.

49. The CAR-T cell of claim 40, wherein the second synthetic receptor comprises SEQ ID NO: 18.

50. Use of the CAR-T cell of claim 32 or claim 40 for the treatment of Addison’s disease; Adult Still’s disease; Agammaglobulinemia; Alopecia areata; Amyloidosis; Ankylosing spondylitis; Anti-GBM / Anti-TBM nephritis; Antiphospholipid syndrome; Autoimmune angioedema; Autoimmune dysautonomia; Autoimmune encephalitis; Autoimmune hepatitis; Autoimmune inner ear disease (AIED); Autoimmune myocarditis; Autoimmune oophoritis; Autoimmune orchitis; Autoimmune pancreatitis; Autoimmune retinopathy; Autoimmune urticaria; Axial spondyloarthritis; Axonal & neuronal neuropathy (AMAN); Balo disease; Behcet’s disease; Benignmucosal pemphigoid (Mucous membrane pemphigoid); Bullous pemphigoid; Castleman disease (CD); Celiac disease; Chagas disease; Chronic inflammatory demyelinating polyneuropathy (CIDP); Chronic recurrent multifocal osteomyelitis (CRMO); Churg-Strauss syndrome (CSS) or Eosinophilic granulomatosis (EGPA); Cicatricial pemphigoid; Cogan’s syndrome; Cold agglutinin disease; Common variable immunodeficiency (CVID) with autoimmune complications; Complex regional pain syndrome (formerly known as reflex sympathetic dystrophy); Congenital heart block; Coxsackie myocarditis; CREST syndrome; Crohn’s disease; Dermatitis herpetiformis; Dermatomyositis; Devic’s disease (neuromyelitis optica); Discoid lupus; Dressier’s syndrome; Endometriosis; Eosinophilic esophagitis (EoE); Eosinophilic fasciitis; Erythema nodosum; Essential mixed cryoglobulinemia; Evans syndrome; Fibromyalgia; Fibrosing alveolitis; Giant cell arteritis (temporal arteritis); Giant cell myocarditis; Glomerulonephritis; Goodpasture’s syndrome; Granulomatosis with polyangiitis; Graves’ disease; Guillain-Barre syndrome; Hashimoto’s thyroiditis; Hemolytic anemia; Henoch-Schonlein purpura (HSP); Herpes gestationis or pemphigoid gestationis (PG); Hidradenitis suppurativa (HS) (Acne inversa); IgA nephropathy; lgG4-related sclerosing disease; Immune thrombocytopenic purpura (ITP); Inclusion body myositis (IBM); Interstitial cystitis (IC); Juvenile arthritis; Juvenile diabetes (Type 1 diabetes); Juvenile myositis (JM); Kawasaki disease; Lambert-Eaton syndrome; Lichen planus; Lichen sclerosus; Ligneous conjunctivitis; Linear IgA disease (LAD); Lyme disease chronic; Malarial autoimmune anemia; Meniere’s disease; Microscopic polyangiitis (MPA); Mixed connective tissue disease (MCTD); Mucha-Habermann disease; Multifocal motor neuropathy (MMN) or MMNCB; MS; Myasthenia gravis; Myelin oligodendrocyte glycoprotein antibody disorder; Myositis; Narcolepsy; Neonatal lupus; Neuromyelitis optica / devic disease; Neutropenia; Ocular cicatricial pemphigoid; Optic neuritis; Palindromic rheumatism (PR); PANDAS (Pediatric autoimmune neuropsychiatric disorders associated with streptococcus infections); Paraneoplastic cerebellar degeneration (PCD); Paroxysmal nocturnal hemoglobinuria (PNH); Pars planitis (peripheral uveitis); Parsonage-Turner syndrome; Pemphigus; Peripheral neuropathy; Perivenous encephalomyelitis; Pernicious anemia (PA); POEMS syndrome; Polyarteritis nodosa; Polyglandular syndromes type I, II, III; Polymyalgia rheumatica; Polymyositis; Postmyocardial infarction syndrome; Postpericardiotomy syndrome; Primary biliary cholangitis; Primary sclerosing cholangitis; Progesterone dermatitis; Progressive hemifacial atrophy (PHA) Parryromberg syndrome; Psoriasis; Psoriatic arthritis; Pulmonary Alveolar Proteinosis (PAP); Pure red cell aplasia (PRCA); Pyoderma gangrenosum; Raynaud’s phenomenon; Reactive arthritis; Relapsing polychondritis; Restless legs syndrome (RLS); Retroperitoneal fibrosis; Rheumatic fever; RA; Sarcoidosis; Schmidt syndrome or Autoimmune polyendocrine syndrome type II; Scleritis; Scleroderma; SLE; SS; Stiff person syndrome (SPS); Susac’s syndrome; Sympathetic ophthalmia (SO); Takayasu’s arteritis; Temporal arteritis / giant cell arteritis; Thrombocytopenic purpura (TTP); Thrombotic thrombocytopenic purpura (Ttp); Thyroid Eye Disease (TED); Tolosa-Hunt syndrome (THS); Transverse myelitis; Type 1 diabetes; Ulcerative colitis (UC); Undifferentiated connective tissue disease (UCTD); Uveitis; Vasculitis; Vitiligo; Vogt-Koyanagi-Harada disease; or Warm autoimmune hemolytic anemia.

51. A method of treating a condition in a patient, comprising administering a composition comprising from 102to 1012of the CAR-T cell of claim 32 or claim 40, in one or more doses, to the patient.

52. The method of claim 51 , wherein the condition is Addison’s disease; Adult Still’s disease; Agammaglobulinemia; Alopecia areata; Amyloidosis; Ankylosing spondylitis; Anti-GBM / Anti-TBM nephritis; Antiphospholipid syndrome; Autoimmune angioedema; Autoimmune dysautonomia; Autoimmune encephalitis; Autoimmune hepatitis; Autoimmune inner ear disease (AIED); Autoimmune myocarditis; Autoimmune oophoritis; Autoimmune orchitis; Autoimmune pancreatitis; Autoimmune retinopathy; Autoimmune urticaria; Axial spondyloarthritis; Axonal & neuronal neuropathy (AMAN); Balo disease; Behcet’s disease; Benign mucosal pemphigoid (Mucous membrane pemphigoid); Bullous pemphigoid; Castleman disease (CD); Celiac disease; Chagas disease; Chronic inflammatory demyelinating polyneuropathy (CIDP); Chronic recurrent multifocal osteomyelitis (CRMO); Churg- Strauss syndrome (CSS) or Eosinophilic granulomatosis (EGPA); Cicatricial pemphigoid; Cogan’s syndrome; Cold agglutinin disease; Common variable immunodeficiency (CVID) with autoimmune complications; Complex regional pain syndrome (formerly known as reflex sympathetic dystrophy); Congenital heart block; Coxsackie myocarditis; CREST syndrome; Crohn’s disease; Dermatitis herpetiformis; Dermatomyositis; Devic’s disease (neuromyelitis optica); Discoid lupus; Dressier’s syndrome; Endometriosis; Eosinophilic esophagitis (EoE); Eosinophilic fasciitis;Erythema nodosum; Essential mixed cryoglobulinemia; Evans syndrome; Fibromyalgia; Fibrosing alveolitis; Giant cell arteritis (temporal arteritis); Giant cell myocarditis; Glomerulonephritis; Goodpasture’s syndrome; Granulomatosis with polyangiitis; Graves’ disease; Guillain-Barre syndrome; Hashimoto’s thyroiditis; Hemolytic anemia; Henoch-Schonlein purpura (HSP); Herpes gestationis or pemphigoid gestationis (PG); Hidradenitis suppurativa (HS) (Acne inversa); IgA nephropathy; lgG4-related sclerosing disease; Immune thrombocytopenic purpura (ITP); Inclusion body myositis (IBM); Interstitial cystitis (IC); Juvenile arthritis; Juvenile diabetes (Type 1 diabetes); Juvenile myositis (JM); Kawasaki disease; Lambert-Eaton syndrome; Lichen planus; Lichen sclerosus; Ligneous conjunctivitis; Linear IgA disease (LAD); Lyme disease chronic; Malarial autoimmune anemia; Meniere’s disease; Microscopic polyangiitis (MPA); Mixed connective tissue disease (MCTD); Mucha-Habermann disease; Multifocal motor neuropathy (MMN) or MMNCB; MS; Myasthenia gravis; Myelin oligodendrocyte glycoprotein antibody disorder; Myositis; Narcolepsy; Neonatal lupus; Neuromyelitis optica / devic disease; Neutropenia; Ocular cicatricial pemphigoid; Optic neuritis; Palindromic rheumatism (PR); PANDAS (Pediatric autoimmune neuropsychiatric disorders associated with streptococcus infections); Paraneoplastic cerebellar degeneration (PCD); Paroxysmal nocturnal hemoglobinuria (PNH); Pars planitis (peripheral uveitis); Parsonage-Turner syndrome; Pemphigus; Peripheral neuropathy; Perivenous encephalomyelitis; Pernicious anemia (PA); POEMS syndrome; Polyarteritis nodosa; Polyglandular syndromes type I, II, III; Polymyalgia rheumatica; Polymyositis; Postmyocardial infarction syndrome; Postpericardiotomy syndrome; Primary biliary cholangitis; Primary sclerosing cholangitis; Progesterone dermatitis; Progressive hemifacial atrophy (PHA) Parry romberg syndrome; Psoriasis; Psoriatic arthritis; Pulmonary Alveolar Proteinosis (PAP); Pure red cell aplasia (PRCA); Pyoderma gangrenosum; Raynaud’s phenomenon; Reactive arthritis; Relapsing polychondritis; Restless legs syndrome (RLS); Retroperitoneal fibrosis; Rheumatic fever; RA; Sarcoidosis; Schmidt syndrome or Autoimmune polyendocrine syndrome type II; Scleritis; Scleroderma; SLE; SS; Stiff person syndrome (SPS); Susac’s syndrome; Sympathetic ophthalmia (SO); Takayasu’s arteritis; Temporal arteritis / giant cell arteritis; Thrombocytopenic purpura (TTP); Thrombotic thrombocytopenic purpura (Ttp); Thyroid Eye Disease (TED); Tolosa-Hunt syndrome (THS); Transverse myelitis; Type 1 diabetes; Ulcerative colitis(UC); Undifferentiated connective tissue disease (UCTD); Uveitis; Vasculitis; Vitiligo;Vogt-Koyanagi-Harada disease; or Warm autoimmune hemolytic anemia.

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