Methods and Compositions for Cells Expressing a Chimeric Intracellular Signaling Molecule

Patent metadata

Field	Value
Publication number	US-2018282693-A1
Application number	US-201615756244-A
Country	US
Kind code	A1
Filing date	Aug 25, 2016
Priority date	Aug 28, 2015
Publication date	Oct 4, 2018
Grant date	—

Abstract

The present invention relates to compositions and methods for enhancing T cell metabolism and activity for more effective adoptive T cell therapy. By expressing an intracellular signaling molecule in T cells, the T cells are metabolically enhanced with improved cytotoxicity and resistance to immunosuppression imposed by tumor microenvironments. One aspect includes a modified T cell and pharmaceutical compositions comprising the modified cells for adoptive cell therapy and treating a disease or condition associated with enhanced immunity.

First claim

1 . A metabolically enhanced T cell comprising a chimeric intracellular signaling molecule, wherein the chimeric intracellular signaling molecule comprises an intracellular domain of a co-stimulatory molecule and substantially lacks an extracellular ligand-binding domain, and wherein the metabolically enhanced T cell expresses the chimeric intracellular signaling molecule.

2 . The metabolically enhanced T cell of claim 1 , wherein expression of the chimeric intracellular signaling molecule metabolically enhances the T cell.

3 . The metabolically enhanced T cell of claim 1 , wherein expression of the chimeric intracellular signaling molecule improves cytotoxicity and resistance to immunosuppression when in a tumor microenvironment.

4 . The metabolically enhanced T cell of claim 1 further comprising a bispecific antibody.

5 . The metabolically enhanced T cell of claim 4 , wherein the bispecific antibody comprises a first antigen binding domain that binds to a first antigen and a second antigen binding domain that binds to a second antigen.

6 . The metabolically enhanced T cell of claim 5 , wherein the first antigen binding domain binds to a target cell and the second antigen binding domain binds to an activated T cell.

7 . The metabolically enhanced T cell of claim 5 , wherein the bispecific antibody comprises an antigen binding domain comprising a first and a second single chain variable fragment (scFv) molecule.

8 . A metabolically enhanced T cell comprising a chimeric intracellular signaling molecule, wherein the chimeric intracellular signaling molecule comprises an intracellular domain of a co-stimulatory molecule and a non-antigen binding extracellular domain comprising a Fc of IgD or IgA, and wherein the metabolically enhanced T cell expresses the chimeric intracellular signaling molecule.

9 . A pharmaceutical composition comprising the metabolically enhanced T cell of claim 1 and a pharmaceutically acceptable carrier.

10 . Use of the metabolically enhanced T cell of claim 1 in the manufacture of a medicament for the treatment of an immune response in a subject in need thereof.

11 . A method of treating a disease or condition associated with enhanced immunity in a subject comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising the metabolically enhanced T cell of claim 1 .

12 . A method of treating a condition in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising the metabolically enhanced T cell of claim 1 .

13 . A method for stimulating a T cell-mediated immune response to a target cell or tissue in a subject comprising administering to a subject a therapeutically effective amount of a pharmaceutical composition comprising the metabolically enhanced T cell of claim 1 .

14 . A method for generating a metabolically enhanced T cell comprising:
introducing a nucleic acid sequence encoding a chimeric intracellular signaling molecule into a T cell, wherein the nucleic acid sequence comprises a nucleic acid sequence of an intracellular domain of a co-stimulatory molecule and substantially lacks an extracellular ligand-binding domain; and stimulating at least one co-stimulatory molecule on the T cell, wherein the stimulation activates the chimeric intracellular signaling molecule thereby metabolically enhancing the T cell.

15 . The method of claim 14 , wherein the nucleic acid sequence is selected from the group consisting of a DNA and an mRNA.

16 . The method of claim 15 , wherein introducing the nucleic acid sequence comprises electroporating the mRNA into the T cell.

17 . The method of claim 14 , wherein the nucleic acid sequence is a vector selected from the group consisting of a plasmid vector, a viral vector, a retrotransposon, a site directed insertion vector, and a suicide expression vector.

18 . The method of claim 14 further comprising arming the T cell with a bispecific antibody, wherein the bispecific antibody is displayed on the T cell surface.

19 . The method of claim 18 , wherein arming the T cell comprises contacting the T cell with the bispecific antibody.

20 . The method of claim 19 , wherein the bispecific antibody specifically binds the T cell.

21 . The method of claim 19 , wherein arming the T cell comprises arming the T cell with two or more bispecific antibodies and the T cell displays the two or more bispecific antibodies.

22 . The method of claim 21 , wherein the two or more bispecific antibodies specifically bind the T cell.

23 . The method of claim 21 , wherein the bispecific antibodies comprise a combination of antibodies selected from the group consisting of anti-CD3, anti-IgD Fc, and anti-IgA Fc.

24 . The method of claim 18 , wherein the bispecific antibody is chemically heterconjugated to a polyclonal antibody specific for a tumor-associated antigen (TAA), and the T cell specifically binds the TAA polyclonal antibody.

25 . The method of claim 18 wherein arming the T cell comprises electroporating a nucleic acid sequence encoding a bispecific antibody.

26 . The method of claim 18 , wherein the bispecific antibody comprises a first antigen binding domain that binds to a first antigen and a second antigen binding domain that binds to a second antigen.

27 . The method of claim 18 , wherein the bispecific antibody comprises a first antigen binding domain that binds to a target cell and a second antigen binding domain that binds to an activated T cell.

28 . The method of claim 18 , wherein the bispecific antibody comprises an antigen binding domain comprising a first and a second single chain variable fragment (scFv) molecule.

29 . The method of claim 18 , wherein the bispecific antibody comprises an antigen binding domain comprising a first whole immunoglobulin molecule and a second whole IgG immunoglobulin molecule.

30 . The method of claim 29 wherein at least one of the first or second whole immunoglobulin molecules comprises IgG, IgA, or IgD.

31 . A composition comprising the metabolically enhanced T cell generated according to claim 14 .

32 . A population of metabolically enhanced T cells comprising a chimeric intracellular signaling molecule, wherein the chimeric intracellular signaling molecule comprises an intracellular domain of a co-stimulatory molecule and substantially lacks an extracellular ligand-binding domain.

33 . The population of cells of claim 32 further comprising a bispecific antibody.

Assignees

• Univ Pennsylvania
• Univ Wayne State

Inventors

• June Carl H
• Milone Michael
• Zhao Yangbing
• Lum Lawrence G
• Thakur Archana

Classifications

• C07K16/32

  against translation products of oncogenes · CPC title

• C07K2319/02

  containing a signal sequence · CPC title

• A61K35/17

  Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes (when activated by a specific antigen A61K39/00) · CPC title

• C07K16/2887

  against CD20 · CPC title

• C07K2317/31

  multispecific · CPC title