# US 12,006,351 B2 · Compositions and methods for modifying activity of extracellular MMP-2

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- Number: US 12,006,351 B2
- Document ID: US12006351B2
- Status: Granted
- Kind: B2
- Application number: 16/314,227
- Filed: 2017-06-30
- Published: 2019-10-24
- Granted: 2024-06-11
- Earliest claimed: 2016-06-30
- Assignees: The Research Foundation for The State University of New York
- Applicants: The Research Foundation for the State University of New York
- Inventors: Dimitra Bourboulia; Mehdi Mollapour; Gennady Bratslavsky
- Web page: https://patentgrep.com/patent/US12006351B2

## CPC

- C07K 14/8146: {Metalloprotease (E.C. 3.4.24) inhibitors, e.g. tissue inhibitor of metallo proteinase, TIMP}
- A61K 38/57: from animals; from humans {(A61K38/553, A61K38/556 take precedence)}
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- C07K 16/32: against translation products of oncogenes
- C07K 16/40: against enzymes
- 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)
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- 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)

## Abstract

Provided are compositions and methods for inhibiting extracellular matrix metalloproteinase-2 (MMP-2) activity. Inhibition of extracellular MMP-2 activity can be useful for restricting extracellular matrix remodeling, tumor cell migration, cell invasion, and/or metastasis. The compositions comprise mutants of Tissue Inhibitor of Metalloproteinase-2 (TIMP-2), where the tyrosine at position 62, 90 and/or 165 has been substituted with a non-phosphorylatable amino acid or with a phosphomimetic of phosphorylated tyrosine, and/or anti-Src antibodies. The method comprises delivering to an extracellular region of a tissue, a composition comprising a TIMP-2 mutant and/or an anti-Src antibody.

## Claims

### Claim 1

An isolated, mutated TIMP-2 molecule of SEQ ID NO: 1, or having at least 95% homology thereto, wherein the Tyr (Y) corresponding to amino acid position 62 is substituted by Glu (E), the Tyr (Y) corresponding to amino acid position 90 is substituted by Glu (E) or Phe (F), and/or the Tyr (Y) corresponding to amino acid position 165 is substituted by Glu (E) or Phe (F).

### Claim 2 (depends on 1)

The isolated, mutated TIMP-2 molecule of claim 1, wherein the Y corresponding to amino acid position 62 is substituted by E.

### Claim 3 (depends on 1)

The isolated, mutated TIMP-2 molecule of claim 1, wherein the Y corresponding to amino acid position 165 is substituted by E.

### Claim 4 (depends on 1)

The isolated, mutated TIMP-2 molecule of claim 1, wherein the Y corresponding to amino acid position 165 is substituted by F.

### Claim 5 (depends on 1)

The isolated, mutated TIMP-2 molecule of claim 1, wherein the Y corresponding to amino acid position 90 is substituted by E.

### Claim 6 (depends on 1)

The isolated, mutated TIMP-2 molecule of claim 1, wherein the Y corresponding to amino acid position 90 is substituted by F.

### Claim 7 (depends on 1)

The isolated, mutated TIMP-2 molecule of claim 1, wherein the Y corresponding to amino acid positions 62, 90, and 165 are each substituted by E.

### Claim 8 (depends on 1)

The isolated, mutated TIMP-2 molecule of claim 1, wherein the Y corresponding to amino acid positions 62, 90, and 165 are each substituted by F.