PDGF mutants and methods of use thereof

Patent metadata

Field	Value
Publication number	US-12344666-B2
Application number	US-202217836684-A
Country	US
Kind code	B2
Filing date	Jun 9, 2022
Priority date	Jun 9, 2021
Publication date	Jul 1, 2025
Grant date	Jul 1, 2025

Abstract

Isolated polypeptides having enhanced affinity for a PDGF receptor and/or a VEGF receptor are provided. Compositions comprising the polypeptides and methods of use thereof are also provided.

First claim

The invention claimed is:

1. An isolated polypeptide having an amino acid sequence comprising at least about 93% of SEQ ID NO: 1, wherein the polypeptide binds to a PDGF receptor and/or a VEGF receptor and increases PDGF and/or VEGF signaling in the cell, and wherein the polypeptide comprises at least one amino acid substitution resulting in a higher binding affinity to the receptor than a wild-type PDGF or VEGF polypeptide, wherein the at least one amino acid substitution is selected from the group consisting of: M12R, I13E, K17N, E21Y, V22L, E24R, R28N, R32I, N57Y, Q71M, and T101K, and any other amino acid substitutions are conservative amino acid substitutions or selected from the group consisting of 177F and K98R.

2. The isolated polypeptide of claim 1 wherein the polypeptide comprises at least one amino acid substitution at position 13, 17, 21, 22, 24, 28, 32, 57, 71, or 101.

3. The isolated polypeptide of claim 1 wherein the polypeptide has an amino acid sequence comprising at least 95% identity to any one of SEQ ID NOs: 2-9 and 11.

4. A composition for increasing PDGF and/or VEGF signaling in a subject, the composition comprising any polypeptide of claim 1 , and a pharmaceutically acceptable carrier.

5. An isolated nucleic acid that encodes for any polypeptide of claim 1 .

6. A vector comprising the isolated nucleic acid of claim 5 and a heterologous nucleic acid sequence.

7. A host cell expressing the vector of claim 6 .

8. The host cell of claim 7 wherein the host cell comprises a bacterial cell.

9. A method of increasing PDGF and/or VEGF signaling in a cell the method comprising administering the polypeptide of claim 1 to the cell.

10. A method of treating a disease or condition associated with abnormal PDGF and/or VEGF signaling in a subject in need thereof, the method comprising administering the polypeptide of claim 1 to the subject, wherein the disease or condition is associated with insufficient or reduced PDGF and/or VEGF signaling and administering the polypeptide increases PDGF and/or VEGF signaling in the subject.

11. The method of claim 10 wherein the method is for treating wounds and/or enhancing wound healing.

12. The method of claim 11 , further comprising administering becaplermin to the subject.

13. An isolated polypeptide having an amino acid sequence, wherein the polypeptide binds to a PDGF receptor and/or a VEGF receptor and increases PDGF and/or VEGF signaling in the cell, wherein the polypeptide has an amino acid sequence comprising any one of SEQ ID NOs: 2-9 and 11.

14. The isolated polypeptide of claim 13 wherein the polypeptide has an amino acid sequence consisting of any one of SEQ ID NOs: 2-9 and 11.

15. A composition for increasing PDGF and/or VEGF signaling in a subject, the composition comprising any polypeptide of claim 13 , and a pharmaceutically acceptable carrier.

16. An isolated nucleic acid that encodes for any polypeptide of claim 13 .

17. A vector comprising the isolated nucleic acid of claim 16 and a heterologous nucleic acid sequence.

18. A host cell expressing the vector of claim 17 .

19. A method of increasing PDGF and/or VEGF signaling in a cell the method comprising administering the polypeptide of claim 18 to the cell.

20. A method of treating a disease or condition associated with abnormal PDGF and/or VEGF signaling in a subject in need thereof, the method comprising administering the polypeptide of claim 13 to the subject, wherein the disease or condition is associated with insufficient or reduced PDGF and/or VEGF signaling and administering the polypeptide increases PDGF and/or VEGF signaling in the subject.

Assignees

• Washington University St Louis
• Univ Illinois

Inventors

• Imoukhuede Princess
• Procko Erik

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P27/02 Primary

  Ophthalmic agents · CPC title

• C07K2317/76

  Antagonist effect on antigen, e.g. neutralization or inhibition of binding · CPC title

• A61K38/1858

  Platelet-derived growth factor [PDGF] · CPC title

• C07K16/22 Primary

  against growth factors {; against growth regulators} · CPC title