# US 11,028,170 B2 · Inhibitors of T-cell activation

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- Number: US 11,028,170 B2
- Document ID: US11028170B2
- Status: Granted
- Kind: B2
- Application number: 15/788,433
- Filed: 2017-10-19
- Published: 2018-02-01
- Granted: 2021-06-08
- Earliest claimed: 2011-06-30
- Assignees: Genzyme Corporation
- Applicants: Genzyme Corporation
- Inventors: Yunxiang Zhu; Jozsef Karman; Ronnie Wei; Canwen Jiang; Seng Cheng
- Web page: https://patentgrep.com/patent/US11028170B2

## CPC

- C07K 16/2803: {against the immunoglobulin superfamily}
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 5/14: of the thyroid hormones, e.g. T3, T4
- A61P 7/06: Antianaemics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/08: Vasodilators for multiple indications
- A61P 9/14: Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/12: of the kidneys
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 17/06: Antipsoriatics
- A61P 17/10: Anti-acne agents
- A61P 17/14: for baldness or alopecia
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 21/04: for myasthenia gravis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 27/14: Decongestants or antiallergics
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 14/47: from mammals
- C07K 14/70532: {B7 molecules, e.g. CD80, CD86}
- C07K 14/70539: {MHC-molecules, e.g. HLA-molecules}
- C07K 2319/00: Fusion polypeptide
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention provides a bispecific biologic comprising a ligand specific for CTLA-4 and a ligand specific for a pMHC complex.

## Claims

### Claim 1

A method of tolerizing a T-cell to an antigen, comprising contacting said T-cell with an antigen-presenting cell which is presenting a peptide derived from said antigen complexed to a MHC molecule and a bispecific fusion protein comprising a ligand specific for CTLA-4 and a ligand specific for a peptide-MHC class II (pMHCII) complex, wherein the T-cell expresses a T-cell receptor (TCR) and cell surface CTLA-4, and the ligand specific for CTLA-4 is selected from the group consisting of CD80 (B7-1), CD86 (B7-2), and mutants thereof with greater binding avidity for CTLA-4 than CD28, thereby crosslinking CTLA-4 to the pMHCII complex and the TCR.

### Claim 2 (depends on 1)

The method of claim 1, wherein the method is used to treat an autoimmune disease.

### Claim 3 (depends on 2)

The method according to claim 2, wherein the bispecific fusion protein is administered in combination with a further immune suppressant or modulator.

### Claim 4 (depends on 2)

The method according to claim 2, wherein the autoimmune disease is selected from type 1 diabetes (T1D), Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis RA, inflammatory bowel disease (IBD), ulcerative colitis (UC), Crohn's disease (CD), multiple sclerosis (MS), scleroderma, pemphigus vulgaris (PV), psoriasis, atopic dermatitis, celiac disease, Chronic Obstructive Lung disease, Hashimoto's thyroiditis, Graves' disease (thyroid), Sjogren's syndrome, Guillain-Barré syndrome, Goodpasture's syndrome, Addison's disease, Wegener's granulomatosis, primary biliary sclerosis, sclerosing cholangitis, autoimmune hepatitis, polymyalgia rheumatica, Raynaud's phenomenon, temporal arteritis, giant cell arteritis, autoimmune hemolytic anemia, pernicious anemia, polyarteritis nodosa, Behcet's disease, primary biliary cirrhosis, uveitis, myocarditis, rheumatic fever, ankylosing spondylitis, glomerulonephritis, sarcoidosis, dermatomyositis, myasthenia gravis, polymyositis, alopecia areata, and vitiligo.

### Claim 5 (depends on 2)

The method of claim 2, wherein the ligand specific for the pMHCII complex is selected from an anti-MHC antibody and LAG-3.

### Claim 6 (depends on 2)

The method of claim 2, wherein the ligand specific for CTLA-4 and the ligand specific for the pMHCII complex are spaced apart by a linker.

### Claim 7 (depends on 6)

The method of claim 6, wherein the linker is one or more of a polyamino acid sequence and an antibody Fc domain.

### Claim 8 (depends on 7)

The method of claim 7, wherein the polyamino acid sequence is G9 (Gly-9).

### Claim 9 (depends on 2)

The method of claim 2, wherein the ligand specific for CTLA-4 is CD80.

### Claim 10 (depends on 9)

The method of claim 9, wherein CD80 is mutated to increase binding avidity or specificity for CTLA-4 over CD28.

### Claim 11 (depends on 10)

The method of claim 10, wherein CD80 is human CD80 comprising at least one of mutations W84A, K71G, K71V, S109G, R123S, R123D, G124L, S190A, S201A, R63A, M81A, N97A and E196A.

### Claim 12 (depends on 11)

The method of claim 11, wherein CD80 comprises the mutation W84A or E196A of human CD80.

### Claim 13 (depends on 2)

The method of claim 2, wherein the ligand specific for the pMHCII complex is LAG-3.

### Claim 14 (depends on 13)

The method of claim 13, wherein LAG-3 is mutated to increase specificity for pMHCII.

### Claim 15 (depends on 14)

The method of claim 14, wherein LAG-3 is human LAG-3 comprising at least one of mutations R73E, R75A, R75E and R76E.

### Claim 16 (depends on 14)

The method of claim 14, wherein LAG-3 comprises the mutation R75A or R75E.