# US 2021/0275585 A1 · Compositions and methods of treating a t cell mediated disorder

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- Number: US 2021/0275585 A1
- Document ID: US20210275585A1
- Status: Published application
- Kind: A1
- Application number: 17/190,297
- Filed: 2021-03-02
- Published: 2021-09-09
- Earliest claimed: 2009-11-04
- Assignees: Case Western Reserve University
- Applicants: Case Western Reserve University
- Inventors: M. Edward Medof; Feng Lin; Michael G. Strainic
- Web page: https://patentgrep.com/patent/US20210275585A1

## CPC

- C12N 5/0636: {T lymphocytes}
- A61K 35/17: Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes (when activated by a specific antigen A61K39/00)
- A61K 40/11: T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells
- A61K 40/22: Immunosuppressive or immunotolerising
- A61K 40/416: {Antigens related to auto-immune diseases; Preparations to induce self-tolerance}
- A61K 40/42: Cancer antigens
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- A61K 2035/122: {for inducing tolerance or supression of immune responses}
- A61K 2035/124: {the cells being hematopoietic, bone marrow derived or blood cells}
- A61K 2239/38: characterised by the dose, timing or administration schedule
- C12N 2501/998: Proteins not provided for elsewhere
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

A method of generating a CD4+FoxP3+ Treg cell, the method includes administering at least one complement antagonist to a naive CD4+ T cell at an amount effective to substantially inhibits C3a receptor (C3aR) and/or C5a receptor (C5aR) signal transduction in the CD4+ T cell, induce TGF-β1 expression of the CD4+ T cell, and induce differentiation of the of the naive CD4+ T cell into a CD4+FoxP3+ Treg cell.

## Claims

### Claim 1

A method of treating inflammation in a subject, the method comprising:
administering at least one complement antagonist to a naive CD4+ T cell at an amount effective to substantially inhibits C3a receptor (C3aR) and/or C5a receptor (C5aR) signal transduction in the CD4+ T cell, induce TGF-β1 expression of the CD4+ T cell, and induce differentiation of the of the naive CD4+ T cell into a CD4+FoxP3+ Treg cell; and
administering a therapeutically effective amount of the CD4+FoxP3+ Treg cells to the subject.

### Claim 2 (depends on 1)

The method of claim 1, wherein the at least one complement antagonist substantially inhibits interaction of at least one of C3a or C5a with the C3aR or C5aR of the CD4+ T cell.

### Claim 3 (depends on 2)

The method of claim 2, the at least one complement antagonist being selected from the group consisting of a small molecule, a polypeptide, and a polynucleotide.

### Claim 4 (depends on 3)

The method of claim 3, the polypeptide comprising an antibody directed against at least one of C3, C5, C3 convertase, C5 convertase, C3a, C5a, C3aR, or C5aR.

### Claim 5 (depends on 2)

The method of claim 2, the step of administering the at least one complement antagonist further including administering to the naive CD4+ T cell a C3aR antagonist and an a C5aR antagonist.

### Claim 6 (depends on 2)

The method of claim 2, the step of administering the at least one complement antagonist further including administering to the cell a C3a antagonist and a C5a antagonist.

### Claim 7 (depends on 1)

The method of claim 1, the CD4+FoxP3+ Treg cells being administered systemically to the subject being treated.

### Claim 8 (depends on 1)

The method of claim 1, wherein the complement antagonist substantially induces naive CD4+cell expression of CD25, CTLA-4, FoxP3, DAF and C5L2, downregulates dendritic cell B7/CD40 and CD4+ effector cell CD28/CD40 ligand costimulatory molecule expression, and inhibits dendritic cell C5a/C3a production and CD4+ cell C5aR/C3aR signal transduction in the subject.

### Claim 9 (depends on 1)

The method of claim 1, further comprising the step of isolating the naive CD4+ Tcells from a mammalian subject.

### Claim 10 (depends on 1)

The method of claim 1, further comprising the step of culturing the naive CD4+ T cells in the presence of dendritic cells.

### Claim 11 (depends on 1)

The method of claim 1, further comprising the step of culturing the naive CD4+ T cells with agents which promote the expansion and survival of CD4+FoxP3+ Treg cells.

### Claim 12 (depends on 11)

The method of claim 11, the one or more agents being selected from the group consisting of an anti-CD3/28, IL-2, TGF-β and combinations thereof.

### Claim 13

A method of treating a T cell mediated disease in a subject, the method comprising:
administering to the subject a therapeutically effective amount of at least one complement antagonist and a pharmaceutically acceptable carrier, wherein the at least one complement antagonist substantially inhibits interaction of at least one of C3a or C5a with the C3a receptors (C3aR) and C5a receptors (C5aR) on interacting dendritic cells and CD4+T cells in the subject.

### Claim 14 (depends on 13)

The method of claim 13, wherein the complement antagonist does not substantially systemic complement activation.

### Claim 15 (depends on 13)

The method of claim 13, wherein the T cell mediated disease is selected from the group consisting of achlorhydra autoimmune active chronic hepatitis, acute disseminated encephalomyelitis, acute hemorrhagic leukoencephalitis, Addison's disease, agammaglobulinemia, alopecia areata, Alzheimer's disease, amyotrophic lateral sclerosis, ankylosing spondylitis, anti-gbm/tbm nephritis, antiphospholipid syndrome, antisynthetase syndrome, aplastic anemia, arthritis, atopic allergy, atopic dermatitis, autoimmune cardiomyopathy, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, autoimmune lymphoproliferative syndrome, autoimmune peripheral neuropathy, autoimmune polyendocrine syndrome, autoimmune progesterone dermatitis, autoimmune thrombocytopenia purpura, autoimmune uveitis, balo disease/balo concentric sclerosis, bechets syndrome, Berger's disease, Bickerstaff's encephalitis, blau syndrome, bullous pemphigoid, castleman's disease, chagas disease, chronic fatigue immune dysfunction syndrome, chronic inflammatory demyelinating polyneuropathy, chronic lyme disease, chronic obstructive pulmonary disease, churg-strauss syndrome, cicatricial pemphigoid, coeliac disease, cogan syndrome, cold agglutinin disease, cranial arteritis, crest syndrome, Crohns disease, Cushing's syndrome, Dego's disease, Dercum's disease, dermatitis herpetiformis, dermatomyositis, diabetes mellitus type 1, Dressler's syndrome, discoid lupus erythematosus, eczema, endometriosis, enthesitis-related arthritis, eosinophilic fasciitis, epidermolysis bullosa acquisita, essential mixed cryoglobulinemia, evan's syndrome, fibrodysplasia ossificans progressive, fibromyalgia, fibromyositis, fibrosing aveolitis, gastritis, gastrointestinal pemphigoid, giant cell arteritis, glomerulonephritis, Goodpasture's syndrome, Graves' disease, Guillain-barre syndrome (gbs), Hashimoto's encephalitis, Hashimoto's thyroiditis, henoch-schonlein purpura, hidradenitis suppurativa, Hughes syndrome, inflammatory bowel disease (IBD), idiopathic inflammatory demyelinating diseases, idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura, iga nephropathy, inflammatory demyelinating polyneuopathy, interstitial cystitis, irritable bowel syndrome (ibs), Kawasaki's disease, lichen planus, Lou Gehrig's disease, lupoid hepatitis, lupus erythematosus, meniere's disease, microscopic polyangiitis, mixed connective tissue disease, morphea, multiple myeloma, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neuromyelitis optica, neuromyotonia, occular cicatricial pemphigoid, opsoclonus myoclonus syndrome, ord thyroiditis, Parkinson's disease, pars planitis, pemphigus, pemphigus vulgaris, pernicious anaemia, polymyalgia rheumatic, polymyositis, primary biliary cirrhosis, primary sclerosing cholangitis, progressive inflammatory neuropathy, psoriasis, psoriatic arthritis, raynaud phenomenon, relapsing polychondritis, Reiter's syndrome, rheumatoid arthritis, rheumatoid fever, sarcoidosis, schizophrenia, Schmidt syndrome, Schnitzler syndrome, scleritis, scleroderma, Sjögren's syndrome, spondyloarthropathy, sticky blood syndrome, still's disease, stiff person syndrome, sydenham chorea, sweet syndrome, takayasu's arteritis, temporal arteritis, transverse myelitis, ulcerative colitis, undifferentiated connective tissue disease, undifferentiated spondyloarthropathy, vasculitis, vitiligo, Wegener's granulomatosis, Wilson's syndrome, Wiskott-Aldrich syndrome, hypersensitivity reactions of the skin, atherosclerosis, ischemia-reperfusion injury, myocardial infarction, and restenosis.

### Claim 16 (depends on 13)

The method of claim 13, the at least one complement antagonist being selected from the group consisting of a small molecule, a polypeptide, and a polynucleotide.

### Claim 17 (depends on 16)

The method of claim 16, the polypeptide comprising an antibody directed against at least one of C3, C5, C3 convertase, C5 convertase, C3a, C5a, C3aR, or C5aR.

### Claim 18 (depends on 13)

The method of claim 13, the step of administering the at least one complement antagonist further including administering to the subject an antibody directed against C5aR and an antibody directed against C3aR.

### Claim 19 (depends on 13)

The method of claim 13, the step of administering the at least one complement antagonist further including administering to the subject an antibody directed against C5a and an antibody directed against C3a.

### Claim 20 (depends on 13)

The method of claim 13, the complement antagonist and a pharmaceutically acceptable carrier being administered locally to a site of T cell mediated disease in the subject.