# US 10,370,428 B2 · Methods of treatment using CTLA4 mutant molecules

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- Number: US 10,370,428 B2
- Document ID: US10370428B2
- Status: Granted
- Kind: B2
- Application number: 15/668,824
- Filed: 2017-08-04
- Published: 2017-12-28
- Granted: 2019-08-06
- Earliest claimed: 2000-05-26
- Assignees: Bristol-Myers Squibb Company
- Applicants: Bristol-Myers Squibb Company
- Inventors: Robert James Peach; Joseph Naemura; Peter S. Linsley; Jurgen Bajorath
- Web page: https://patentgrep.com/patent/US10370428B2

## CPC

- C07K 14/7051: {T-cell receptor (TcR)-CD3 complex}
- A61K 38/1774: {Immunoglobulin superfamily (e.g. CD2, CD4, CD8, ICAM molecules, B7 molecules, Fc-receptors, MHC-molecules)}
- A61K 39/39: characterised by the immunostimulating additives, e.g. chemical adjuvants
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 17/06: Antipsoriatics
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- C07H 21/04: with deoxyribosyl as saccharide radical
- C07K 14/70521: {CD28, CD152}
- C12N 5/0636: {T lymphocytes}
- 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 2039/505: {comprising antibodies}
- C07K 2319/30: Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
- C12N 2501/51: B7 molecules, e.g. CD80, CD86, CD28 (ligand), CD152 (ligand)
- 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)
- 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
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

The present invention provides soluble CTLA4 mutant molecules which bind with greater avidity to the CD80 and/or CD86 antigen than wild type CTLA4 or non-mutated CTLA4Ig. The soluble CTLA4 molecules have a first amino acid sequence comprising the extracellular domain of CTLA4, where certain amino acid residues within the S25-R33 region and M97-G107 region are mutated. The mutant molecules of the invention may also include a second amino acid sequence which increases the solubility of the mutant molecule.

## Claims

### Claim 1

A method for inhibiting graft versus host disease in a subject which comprises administering to the subject a soluble CTLA4 mutant molecule comprising an extracellular domain as shown in SEQ ID NO:6 beginning with alanine at position 26 or methionine at position 27 and ending with aspartic acid at position 150.

### Claim 2 (depends on 1)

The method of claim 1 wherein the soluble CTLA4 mutant molecule further comprising an amino acid sequence which alters the solubility, affinity or valency of the soluble CTLA4 mutant molecule.

### Claim 3 (depends on 2)

The method of claim 2, wherein the soluble CTLA4 mutant molecule comprises a human immunoglobulin constant region.

### Claim 4 (depends on 3)

The method of claim 3 wherein the immunoglobulin constant region is mutated to reduce effector function.

### Claim 5 (depends on 3)

The method of claim 3 wherein the immunoglobulin constant region comprises a hinge, CH2 and CH3 regions of an immunoglobulin molecule.

### Claim 6 (depends on 5)

The method of claim 5, wherein any or all of the cysteine residues within the immunoglobulin hinge are substituted with serine.

### Claim 7 (depends on 6)

The method of claim 6 wherein a cysteine at position 156 is substituted with a serine, a cysteine at position 162 is substituted with a serine, and a cysteine at position 165 is substituted with a serine, as shown in SEQ ID NO:6.

### Claim 8 (depends on 1)

The method of claim 1, wherein the soluble CTLA4 mutant molecule further comprises a junction amino acid residue and an immunoglobulin, where the junction amino acid residue is located between the amino acid sequence which ends with aspartic acid at position +150 and the immunoglobulin.

### Claim 9 (depends on 8)

The method of claim 8, wherein the junction amino acid residue is glutamine.

### Claim 10

A method for inhibiting graft versus host disease in a subject which comprises administering to the subject a soluble CTLA4 mutant molecule comprising the amino acid sequence shown in SEQ ID NO:6 beginning with alanine at position 26 or methionine at position 27 and ending with lysine at position 383.