METHOD

• US 20140134720A1
• Filed: 05/17/2012
• Published: 05/15/2014
• Est. Priority Date: 05/17/2011
• Status: Abandoned Application

• Current Assignee: UCL Business PLC (University of London)
• Original Assignee: UCL Business PLC (University of London)
• Inventors: Stauss, Hans, Thomas, Sharyn
• Application Number:
  US14/117,947
• Publication Number:
  US 20140134720A1
• Time in Patent Office: Days
• US Class Current: 435/328
• 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 39/4632 T-cell receptors [TCR]; antibody T-cell receptor constructs
• CPC Class Codes: A61K 39/464838 Viral antigens
• CPC Class Codes: C07K 14/7051 T-cell receptor (TcR)-CD3 complex
• CPC Class Codes: C07K 14/70596 Molecules with a "CD"-designation not provided for elsewhere
• CPC Class Codes: C07K 16/46 Hybrid immunoglobulins hybrids of an immunoglobulin with a peptide not being an immunoglobulin C07K19/00
• CPC Class Codes: C12N 2502/99 genetically modified cells
• CPC Class Codes: C12N 2740/14034 Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
• CPC Class Codes: C12N 5/0636 T lymphocytes

Abstract

The present invention provides a method for increasing the sensitivity of a T cell expressing a cell-surface antibody to a target antigen, which comprises the step of lowering the affinity of the antibody to the target antigen by at least 100-fold. The invention also provides chimeric antigen receptor comprising an antibody domain having an affinity for antigen in the range 100-1 μM, its encoding nucleic acid sequence and uses thereof.

Claims

1. A method for increasing the sensitivity of a T cell expressing a cell-surface antibody to a target antigen, which comprises the step of lowering the affinity of the antibody to the target antigen by at least 100-fold.

2. A method according to claim 1, wherein the affinity of the antibody to the target antigen is lowered by at least 1000-fold.

3. A method according to claim 1, wherein the affinity of the antibody is lowered by mutagenesis of the antibody, followed by in vitro selection for low affinity variants.

4. A method according to claim 1, wherein the affinity of the antibody for the target antigen, following lowering, is in the range of 100-1 μ

M.

5. A method according to claim 1, wherein the antibody, following affinity lowering, has a dissociation half time from the target antigen in the range of 5-60 seconds.

6. A method according to claim 1, wherein the antibody is part of a chimeric antigen receptor (CAR) comprising:

(i) an antibody domain, expressed at the T cell surface; and

(ii) a cytoplasmic signalling domain.

7. (canceled)

12. A T cell which expresses a CAR according to claim 7.

8. A chimeric antigen receptor (CAR) for expression in a T cell, comprising an antibody domain and a signaling domain,

wherein the antibody domain has an affinity for a target antigen in the range of 100-1 μ

M, binds to a target antigen with a dissociation half time in the range of 5-60 seconds, or both.

9-11. -11. (canceled)

13-15. -15. (canceled)