Methods and reagents for modulating macrophage phenotype

Patent metadata

Field	Value
Publication number	US-12016881-B2
Application number	US-202117396792-A
Country	US
Kind code	B2
Filing date	Aug 9, 2021
Priority date	Jun 3, 2016
Publication date	Jun 25, 2024
Grant date	Jun 25, 2024

Abstract

The present invention is directed to methods of inducing a phenotypic change in a population of monocytes and/or macrophages. The method includes administering to the population of monocytes and/or macrophages, a macrophage stimulating agent coupled to a carrier molecule, wherein the carrier molecule facilitates macropinocytic uptake of the agent by monocytes and macrophages in the population and is defective in neonatal Fc receptor binding, wherein the administering induces a phenotypic change in the monocytes and macrophages in the population.

First claim

What is claimed is:

1. A method of treating a tumor in a subject comprising:
selecting a subject having a tumor and
administering to the selected subject an anti-tumor agent coupled to a carrier molecule selected from (i) a modified or variant human albumin protein or fragment thereof, and (ii) a modified or variant human immunoglobulin G protein or fragment thereof, wherein the carrier molecule is defective in neonatal Fc receptor (FcRn) binding, wherein said anti-tumor agent and carrier molecule are taken up via macropinocytosis by monocytes and/or macrophages within the tumor microenvironment, thereby activating the monocytes and/or macrophages to have an anti-tumor immune response.

2. The method of claim 1 , wherein the tumor is characterized by tumor cells expressing FcRn.

3. The method of claim 1 , wherein the anti-tumor agent is a chemotherapeutic agent.

4. The method of claim 1 , wherein the chemotherapeutic agent is a taxane.

5. The method of claim 3 , wherein the taxane is paclitaxel.

6. The method of claim 1 , wherein the carrier molecule is a modified or variant human albumin protein or fragment thereof.

7. The method of claim 6 , wherein the modified or variant human albumin protein or fragment thereof comprises one or more amino acid modifications at one or more amino acid positions corresponding to 464, 494, 495, 496, 499, 500, 510, 535, 536, 537, 538, and 573 of SEQ ID NO: 1.

8. The method of claim 7 , wherein the modified or variant human albumin protein or fragment thereof comprises one or more amino acid modifications selected from the group consisting of D494N, D494Q, D494A, E495Q, E495A, T496A, P499A, K536A, P537A, K538A, K500A, K573STOP, H464Q, H510Q, and H535Q.

9. The method of claim 1 , wherein the anti-tumor agent is paclitaxel and the carrier molecule is a modified or variant human albumin protein or fragment thereof.

10. The method of claim 1 , wherein the carrier molecule defective in FcRn binding is a modified or variant immunoglobulin G protein or fragment thereof.

11. A method of treating a tumor in a subject comprising:
selecting a subject having a tumor characterized by tumor cells expressing FcRn; and
administering to the selected subject an anti-tumor agent coupled to a carrier molecule selected from (i) a modified or variant human albumin protein or fragment thereof and (ii) a modified or variant human immunoglobulin G protein or fragment thereof, wherein the carrier molecule is defective in neonatal Fc receptor (FcRn) binding, wherein said anti-tumor agent and carrier molecule are taken up by the tumor cells expressing FcRn to cause tumor cell death.

12. The method of claim 11 , wherein the anti-tumor agent is a chemotherapeutic agent.

13. The method of claim 12 , wherein the chemotherapeutic agent is a taxane.

14. The method of claim 13 , wherein the taxane is paclitaxel.

15. The method of claim 11 , wherein the carrier molecule is a modified or variant human albumin protein or fragment thereof.

16. The method of claim 15 , wherein the modified or variant human albumin protein or fragment thereof comprises one or more amino acid modifications at one or more amino acid positions corresponding to 464, 494, 495, 496, 499, 500, 510, 535, 536, 537, 538, and 573 of SEQ ID NO: 1.

17. The method of claim 16 , wherein the modified or variant human albumin protein or fragment thereof comprises one or more amino acid modifications selected from the group consisting of D494N, D494Q, D494A, E495Q, E495A, T496A, P499A, K536A, P537A, K538A, K500A, K573STOP, H464Q, H510Q, and H535Q.

18. The method of claim 11 , wherein the anti-tumor agent is paclitaxel and the carrier molecule is a modified or variant human albumin protein or fragment thereof.

19. The method of claim 11 , wherein the carrier molecule defective in FcRn binding is a modified or variant immunoglobulin G protein or fragment thereof.

Assignees

• Univ New York

Inventors

• Bar-Sagi Dafna
• Cullis Jane
• Ramirez Craig

Classifications

• C12N5/0645 Primary

  Macrophages, e.g. Kuepfer cells in the liver; Monocytes · CPC title

• A61K35/15 Primary

  Cells of the myeloid line, e.g. granulocytes, basophils, eosinophils, neutrophils, leucocytes, monocytes, macrophages or mast cells; Myeloid precursor cells; Antigen-presenting cells, e.g. dendritic cells (presenting a specific antigen A61K39/00; therapeutic combinations of antibodies, or fragments thereof, and blood-derived cells A61K39/00) · CPC title

• C12N2501/2304

  Interleukin-4 (IL-4) · CPC title

• C12N2501/231

  Interleukin-10 (IL-10) · CPC title

• A61K38/2026

  IL-4 · CPC title