IMMUNOMODULATING TUMOR NECROSIS FACTOR RECEPTOR 25 (TNFR25) AGONISTS, ANTAGONISTS, AND IMMUNOTOXINS

• US 20160015779A1
• Filed: 04/27/2015
• Published: 01/21/2016
• Est. Priority Date: 08/30/2005
• Status: Active Grant

• Current Assignee: University of Miami
• Original Assignee: University of Miami
• Inventors: Podack, Eckhard R., Deyev, Vadim, Levy, Robert
• Granted Patent: US 9,839,670 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/5152 Tumor cells
• CPC Class Codes: A61K 35/13 Tumour cells, irrespective of tissue of origin tumour vaccines A61K39/00
• CPC Class Codes: A61K 38/1709 from mammals
• CPC Class Codes: A61K 39/0011 Cancer antigens
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 39/4611 T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
• CPC Class Codes: A61K 39/4613 Natural-killer cells [NK or NK-T]
• CPC Class Codes: A61K 39/4621 immunosuppressive or immunotolerising
• CPC Class Codes: A61K 39/464417 Receptors for tumor necrosis factors [TNF], e.g. lymphotoxin receptor [LTR], CD30
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/241 : Tumor Necrosis Factors
• CPC Class Codes: C07K 16/2875 : against the NGF/TNF superfamily, e.g. CD70, CD95L, CD153, CD154 against NGF C07K16/22, against TNF C07K16/241
• CPC Class Codes: C07K 16/2878 : against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
• CPC Class Codes: C07K 2317/14 : Specific host cells or culture conditions, e.g. components, pH or temperature
• CPC Class Codes: C07K 2317/74 : Inducing cell proliferation
• CPC Class Codes: C07K 2317/75 : Agonist effect on antigen
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Abstract

This document provides novel compositions and methods utilizing immunomodulating agents that can stimulate or indirectly augment the immune system, or can have an immunosuppressive effect. TNFR25 agonists disclosed herein have an anti-inflammatory and healing effect. They can be used, e.g., to treat disease caused by asthma and chronic inflammation, such as inflammatory bowel diseases including ulcerative colitis and Crohn'"'"'s Disease. TNFR25 antagonists disclosed herein can inhibit CD8 T cell-mediated cellular immune responses and can, for example, mitigate organ or tissue rejection following a tissue transplantation. TNFR25 agonists disclosed herein represent biological response modifiers that alter the interaction between the body'"'"'s cellular immune defenses and cancer cells to boost, direct, or restore the body'"'"'s ability to fight the cancer when given with tumor vaccines. TNFR25 specific immunotoxins disclosed herein are also capable of increasing the effectiveness of a chemotherapeutic regimen by depleting a cancer patient of naturally occurring immunosuppressive cells.

Claims

1. A method for enhancing expansion of antigen-specific CD8 T cells in a subject, the method comprising the steps of:

(a) administering to the subject an antigenic composition comprising a cell expressing a gp96-Ig protein engineered to be secreted from the cell, and a cognate antigen of the antigen-specific CD8 T cells, wherein the cognate antigen is a non-self antigen, and wherein administration of the antigenic composition is effective for inducing expansion of the antigen-specific CD8 T cells in the subject; and

(b) administering to the subject a TNFR25 agonist in an amount effective to enhance the expansion of the antigen-specific CD8 T cells induced in step (a).

2. The method of claim 1, wherein the TNFR25 agonist is an agonistic anti-TNFR25 antibody that specifically binds TNFR25.

5. The method of claim 1, wherein the cell is a cancer cell.

6. The method of claim 1, wherein the non-self antigen is derived from a pathogen.

7. The method of claim 1, wherein the non-self antigen is derived from a tumor cell.

8. The method of claim 1, wherein the TNFR25 agonist is a TL1A protein or a fragment or variant thereof that specifically binds TNFR25.

9. The method of claim 1, wherein the method further comprises inhibiting the suppressive effects of T regulatory cells.

3. (canceled)

4. (canceled)

10. An antigenic composition comprising a cell expressing a tumor antigen and an immunostimulatory agent that enhances an immune response to the antigenic composition, wherein the tumor antigen is a cognate antigen for antigen-specific CD8 T cells in a subject, and wherein administration of the antigenic composition to the subject is effective for inducing expansion of the antigen-specific CD8 T cells in the subject.

11. The composition of claim 10, wherein the immunostimulatory agent is a gp96-Ig protein.

12. The composition of claim 10, wherein the cell is a cancer cell.

13. The composition of claim 10, further comprising a TNFR25 agonist in an amount effective to enhance the expansion of the antigen-specific CD8 T cells in the subject.

14. The composition of claim 13, wherein the TNFR25 agonist is an agonistic anti-TNFR25 antibody that specifically binds TNFR25.

15. The composition of claim 13, wherein the TNFR25 agonist is a TL1A protein or a fragment or variant thereof that specifically binds TNFR25.

16. A tumor vaccine comprising a tumor antigen and a TNFR25 agonist.

17. The tumor vaccine of claim 16, wherein said TNFR25 agonist is selected from the group consisting of:

(a) an antibody that binds to TNFR25, wherein said antibody is capable of increasing OT-I CD8 cell expansion when cross-primed by gp96-Ig-ovalbumin relative to a control antibody;

(b) a soluble TL1A; and

(c) an expression vector with an expression cassette capable of driving the transgenic expression of a TNFR25 agonist antibody.

18. The tumor vaccine of claim 17, further comprising an adjuvant.

19. A tumor vaccine comprising a tumor antigen and a polypeptide encoded by a sequence that hybridizes under stringent conditions to SEQ ID NO:

3 and/or SEQ ID NO;

7, wherein said sequence encodes an amino acid sequence capable of binding a TNFR25 receptor protein.

20. An expression vector comprising a nucleic acid sequence that hybridizes under stringent conditions to SEQ ID NO:

3 and/or SEQ ID NO;

7, wherein said sequence encodes an amino acid sequence capable of binding a TNFR25 receptor protein.