Methods and reagents for modulating macrophage phenotype

Patent metadata

Field	Value
Publication number	US-11110122-B2
Application number	US-201716306636-A
Country	US
Kind code	B2
Filing date	Jun 5, 2017
Priority date	Jun 3, 2016
Publication date	Sep 7, 2021
Grant date	Sep 7, 2021

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 inducing a phenotypic change in a population of monocytes and/or macrophages, said method comprising:
administering to the population of monocytes and/or macrophages, a macrophage stimulating agent coupled to a carrier molecule, wherein said carrier molecule is 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, and wherein said carrier molecule and agent are taken up via macropinocytosis by monocytes and/or macrophages of the population, thereby inducing a phenotypic change in said monocytes and/or macrophages.

2. The method of claim 1 , wherein the macrophage stimulating agent is a macrophage type-1 stimulating agent selected from the group consisting of paclitaxel, a colony stimulating factor -1 (CSF-1) receptor antagonist, an IL-10 receptor antagonist, a Toll-like receptor (TLR)-2 agonist, a TLR-3 agonist, a TLR-4 agonist, a TLR-7 agonist, a TLR-8 agonist, and a TLR-9 agonist.

3. The method of claim 2 , wherein said administering the carrier molecule and agent to said population induces the expression of one or more macrophage type-1 phenotypic markers selected from the group consisting of IL-1α, IL-1β, IL-6, iNOS, IFNγ, and TNFα in the monocytes and/macrophages of the population.

4. The method of claim 2 , wherein said population of monocytes and/or macrophages comprises type-2 macrophages.

5. The method of claim 2 , wherein the population of monocytes and/or macrophages comprises tumor-associated macrophages.

6. The method of claim 2 , wherein said administering the carrier molecule and agent to said population is carried out in vivo to a subject having pancreatic cancer, breast cancer, or non-small cell lung carcinoma.

7. The method of claim 2 , wherein the macrophage type-1 stimulating agent is paclitaxel and the carrier molecule is a variant human albumin protein or fragment thereof.

8. The method of claim 1 , wherein the macrophage stimulating agent is a macrophage type-2 stimulating agent selected from the group consisting of IL-33, an IL-4 receptor agonist, a glucocorticoid, an IL-10 receptor agonist, and an IL-1 receptor agonist.

9. The method of claim 8 , wherein said administering the carrier molecule and agent to said population induces the expression of one or more macrophage type-2 phenotypic markers selected from the group consisting of IL-10, TGF-β, MRC1, TGM2, CD23, and CCL22 in the macrophages and/or monocytes.

10. The method of claim 8 , wherein the population of monocytes and/or macrophages comprises type-1 macrophages.

11. The method of claim 8 , wherein said administering the carrier molecule and agent to said population is carried out in vivo to a subject having an inflammatory or autoimmune condition.

12. The method of claim 8 , wherein said administering the carrier molecule and agent to said population is carried out in vivo to a subject having Alzheimer's disease.

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

14. The method of claim 13 , wherein the 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.

15. The method of claim 14 , wherein the 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.

16. The method of claim 1 , wherein the carrier molecule defective in FcRn binding is a 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

• C12N2501/2301

  Interleukin-1 (IL-1) · CPC title

• C12N2501/231

  Interleukin-10 (IL-10) · CPC title

• A61K38/2026

  IL-4 · CPC title