# US 8,785,398 B2 · Methods of treatment using CTLA4 mutant molecules

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- Number: US 8,785,398 B2
- Document ID: US8785398B2
- Status: Granted
- Kind: B2
- Application number: 13/277,425
- Filed: 2011-10-20
- Published: 2012-03-01
- Granted: 2014-07-22
- Earliest claimed: 2000-05-26
- Assignees: Bristol-Myers Squibb Company
- Applicants: Robert James Peach; Joseph Naemura; Peter S. Linsley; Jurgen Bajorath
- Inventors: Robert James Peach; Joseph Naemura; Peter S. Linsley; Jurgen Bajorath
- Web page: https://patentgrep.com/patent/US8785398B2

## 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 treating graft versus host disease in a subject comprising administering to the subject a CTLA4 mutant molecule, wherein the CTLA4 mutant molecule binds CD80 and/or CD86 and comprises an extracellular domain of CTLA4 as shown in SEQ ID NO:8 beginning with alanine at position 26 or methionine at position 27 and ending with aspartic acid at position 150, wherein in the extracellular domain, an alanine at position 55 is substituted with a tyrosine, and a leucine at position 130 is substituted with a glutamic acid.

### Claim 2

A method for treating graft versus host disease in a subject comprising administering to the subject a CTLA4 mutant molecule, wherein the CTLA4 mutant molecule comprises:
(a) an amino acid sequence beginning with methionine at position 27 and ending with aspartic acid at position 150 of SEQ ID NO:4, or
(b) an amino acid sequence beginning with alanine at position 26 and ending with aspartic acid at position 150 of SEQ ID NO:4.

### Claim 3

A method for treating graft versus host disease in a subject comprising administering to the subject a CTLA4 mutant molecule, wherein the CTLA4 mutant molecule comprises:
(a) an amino acid sequence beginning with methionine at position 27 and ending with aspartic acid at position 150 of SEQ ID NO:4 or a portion thereof that binds CD80 and/or CD86, or
(b) an amino acid sequence beginning with alanine at position 26 and ending with aspartic acid at position 150 of SEQ ID NO:4 or a portion thereof that binds CD80 and/or CD86.

### Claim 4 (depends on 2)

The method of claim 2 further comprising an amino acid sequence which alters the solubility or affinity of the CTLA4 mutant molecule.

### Claim 5 (depends on 4)

The method of claim 4, wherein the amino acid sequence which alters the solubility or affinity comprises an immunoglobulin.

### Claim 6 (depends on 5)

The method of claim 5, wherein the immunoglobulin is an immunoglobulin constant region or portion thereof.

### Claim 7 (depends on 6)

The method of claim 6, wherein the immunoglobulin constant region or portion thereof is mutated to reduce effector function.

### Claim 8 (depends on 6)

The method of claim 6, wherein the immunoglobulin constant region or portion thereof comprises a hinge, CH2 and CH3 regions of a human or monkey immunoglobulin molecule.

### Claim 9 (depends on 7)

The method of claim 7, wherein the immunoglobulin constant region or portion thereof comprises a hinge, CH2 and CH3 regions of a human or monkey immunoglobulin molecule.

### Claim 10

A method for treating graft versus host disease in a subject comprising administering to the subject a CTLA4 mutant molecule, wherein the CTLA4 mutant molecule comprises:
(a) an amino acid sequence beginning with methionine at position 27 and ending with lysine at position 383 of SEQ ID NO:4, or
(b) an amino acid sequence beginning with alanine at position 26 and ending with lysine at position 383 of SEQ ID NO:4.

### Claim 11

A method for treating graft versus host disease in a subject comprising administering to the subject a CTLA4 mutant molecule encoded by the nucleic acid molecule designated ATCC No. PTA-2104.