Fusion proteins for modulating regulatory and effector t cells

Patent metadata

Field	Value
Publication number	US-2016347846-A1
Application number	US-201414764024-A
Country	US
Kind code	A1
Filing date	Jan 31, 2014
Priority date	Jan 31, 2013
Publication date	Dec 1, 2016
Grant date	—

Abstract

The present invention provides fusion proteins that act on the glucocorticoid-induced TNFR family-related gene (GITR) and OX40 signaling pathway. In certain aspects, the proteins of the invention are useful in modulating both regulatory T (Treg) cells and effector T (Teff) cells.

First claim

What is claimed is:

1 . A fusion protein comprising a first domain and a second domain,
wherein the first domain comprises a binding moiety that binds to a first member from the tumor necrosis family receptor (TNFR) superfamily, and wherein the second domain comprises a binding moiety that binds to a second member from the TNFR superfamily.

2 . The fusion protein of claim 1 , wherein the first member from the TNFR superfamily and the second member from the TNFR superfamily are co-expressed in a single cell.

3 . The fusion protein of claim 1 , wherein the first member from the TNFR superfamily comprises glucocorticoid-induced TNFR family-related gene (GITR).

4 . The fusion protein of claim 1 , wherein the second member from the TNFR superfamily comprises OX40.

5 . The fusion protein of claim 1 , wherein the first member from the TNFR superfamily comprises GITR and the second member from the TNFR superfamily comprises OX40.

6 . The fusion protein of claim 1 , wherein the first domain comprises an antibody, or fragment thereof, that binds GITR.

7 . The fusion protein of claim 1 , wherein the second domain comprises at least a portion of the extracellular domain of OX40 ligand.

8 . The fusion protein of claim 1 , wherein the fusion protein is an antibody-ligand protein comprising the sequence of SEQ ID NO: 5.

9 . The fusion protein of claim 1 , wherein the fusion protein is a type I-II protein fusion wherein the first domain comprises a component of a type I protein and the second domain comprises a component of a type II protein, further wherein the type I protein is a protein having its amino terminus orientated extracellularly in the native protein and the type II is a protein having its carboxyl terminus orientated extracellularly in the native protein.

10 . A method of regulating immune cells, the method comprising contacting a populating of immune cells with a fusion protein comprising a first domain and a second domain,
wherein the first domain comprises a binding moiety that binds to a first member from the TNFR superfamily, and wherein the second domain comprises a binding moiety that binds to a second member from the TNFR superfamily.

11 . The method of claim 10 , wherein the first member from the TNFR superfamily comprises GITR and the second member from the TNFR superfamily comprises OX40.

12 . The method of claim 10 , wherein the population of immune cells comprises regulatory T (Treg) cells and effector T (Teff) cells.

13 . The method of claim 12 , wherein the fusion protein attenuates Treg suppressive function.

14 . The method of claim 12 , wherein the fusion protein inhibits Treg generation.

15 . The method of claim 12 , wherein the fusion protein increases Teff cell proliferation, interleukin-2 production, and NF-κB signaling.

16 . A method of modulating an immune response in a mammal in need thereof, the method comprising administering to the mammal a therapeutically effective amount of a fusion protein comprising a first domain and a second domain,
wherein the first domain comprises a binding moiety that binds to a first member from the TNFR superfamily, and wherein the second domain comprises a binding moiety that binds to a second member from the TNFR superfamily.

17 . The method of claim 16 , wherein the first member from the TNFR superfamily comprises GITR and the second member from the TNFR superfamily comprises OX40.

18 . The method of claim 16 , wherein the fusion protein modulates Treg cells and Teff cells.

19 . The method of claim 16 , wherein the mammal is human.

20 . A method of treating or ameliorating cancer in a mammal in need thereof, the method comprising administering to the mammal a therapeutically effective amount of a fusion protein comprising a first domain and a second domain,
wherein the first domain comprises a binding moiety that binds to a first member from the TNFR superfamily, and wherein the second domain comprises a binding moiety that binds to a second member from the TNFR superfamily.

21 . The method of claim 20 , wherein the first member from the TNFR superfamily comprises GITR and the second member from the TNFR superfamily comprises OX40.

22 . The method of claim 20 , wherein the fusion protein modulates Treg cells and Teff cells.

23 . The method of claim 20 , wherein the mammal is human.

24 . A method of enhancing an immune response in a mammal in need thereof, the method comprising administering to the mammal a therapeutically effective amount of a fusion protein comprising a first domain and a second domain,
wherein the first domain comprises a binding moiety that binds to a first member from the TNFR superfamily, and wherein the second domain comprises a binding moiety that binds to a second member from the TNFR superfamily.

25 . The method of claim 24 , wherein the first member from the TNFR superfamily comprises GITR and the second member from the TNFR superfamily comprises OX40.

26 . The method of claim 24 , wherein the fusion protein modulates Treg cells and Teff cells.

27 . The method of claim 24 , wherein the mammal is human.

Assignees

• Univ Jefferson
• Univ Pennsylvania

Inventors

• Tykocinski Mark L

Classifications

• C07K2319/31

  fusions, other than Fc, for prolonged plasma life, e.g. albumin · CPC title

• C07K2319/00

  Fusion polypeptide · CPC title

• C07K2319/22

  containing a Strep-tag · CPC title

• C07K14/52

  Cytokines; Lymphokines; Interferons · CPC title

• C07K16/2878 Primary

  against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95 · CPC title