Targeting cytotoxic cells with chimeric receptors for adoptive immunotherapy

Patent metadata

Field	Value
Publication number	US-9745368-B2
Application number	US-201414214824-A
Country	US
Kind code	B2
Filing date	Mar 15, 2014
Priority date	Mar 15, 2013
Publication date	Aug 29, 2017
Grant date	Aug 29, 2017

Abstract

The present invention provides compositions and methods for regulating the specificity and activity of T cells. In one embodiment, the invention provides a type of chimeric antigen receptor (CAR) wherein the CAR is termed a “KIR-CAR” which is a CAR design comprising a component of a receptor naturally found on natural killer (NK) cells. In one embodiment, the NK receptor includes but is not limited to a naturally occurring activating and inhibitory receptor of NK cells known as a killer cell immunoglobulin-like receptor (KIR).

First claim

What is claimed is:

1. A purified, or non-naturally occurring, activating killer cell immunoglobulin-like receptor chimeric antigen receptor (actKIR-CAR) comprising:
an extra-cellular antigen binding domain from an antibody molecule or a non-antibody scaffold;
an activating killer cell immunoglobulin-like receptor (actKIR) transmembrane domain; and
a cytoplasmic domain.

2. The actKIR-CAR of claim 1 , wherein said actKIR transmembrane domain can interact with the transmembrane domain of a DAP12 polypeptide.

3. The actKIR-CAR of claim 2 , wherein said actKIR transmembrane domain comprises a positively charged moiety.

4. The actKIR-CAR of claim 1 , wherein said cytoplasmic domain is a KIR-cytoplasmic domain.

5. The actKIR-CAR of claim 1 , wherein said antigen binding domain from an antibody molecule comprises a scFv.

6. The actKIR-CAR of claim 1 , further comprising an extracellular hinge domain.

7. The actKIR-CAR of claim 1 , comprising an extracellular hinge domain that:
(i) is other than a KIR hinge domain;
(ii) is derived from a natural molecule;
(iii) comprises a non-naturally occurring polypeptide sequence;
(iv) is from human CD8-alpha subunit;
(v) is of less than 50, 20, or 10 amino acids in length, or
(vi) has fewer amino acids than a KIR2DS2 hinge domain.

8. The actKIR-CAR of claim 1 , wherein said actKIR-CAR comprises an actKIR cytoplasmic domain.

9. The actKIR-CAR of claim 1 , wherein said actKIR-CAR can interact with and promote signaling from an Immunoreceptor Tyrosine-based Activation Motif (ITAM)-containing polypeptide.

10. The actKIR-CAR of claim 1 , wherein said actKIR-CAR comprises a KIR D domain.

11. The actKIR-CAR of claim 1 , wherein said actKIR-CAR comprises a KIR D1 domain or a KIR D2 domain.

12. The actKIR-CAR of claim 1 , wherein said actKIR-CAR does not comprise a KIR D domain.

13. The actKIR-CAR of claim 1 , wherein said KIR-CAR comprises a KIR2DS2 transmembrane domain or comprises a KIR2DS2 cytoplasmic domain.

14. The actKIR-CAR of claim 1 , wherein said antigen binding domain from an antibody molecule binds an antigen present on a cancer cell.

15. The actKIR-CAR of claim 1 , wherein said actKIR-CAR can interact with and promote signaling from a DAP12 or DAP10 polypeptide.

16. The actKIR-CAR of claim 1 , wherein said actKIR-CAR can interact with and promote signaling from a DAP12 polypeptide.

17. The actKIR-CAR of claim 1 , wherein said antigen binding domain from an antibody molecule comprises an immunoglobulin single domain antibody (sdAb).

18. The actKIR-CAR of claim 1 , wherein said antigen binding domain from an antibody molecule comprises a single light chain variable domain (VL).

19. The actKIR-CAR of claim 1 , wherein said antigen binding domain from an antibody molecule comprises a single heavy chain variable domain (VH).

20. The actKIR-CAR of claim 1 , wherein said antigen binding domain from an antibody molecule comprises a nanobody.

21. The actKIR-CAR of claim 1 , wherein said antigen binding domain from an antibody molecule binds an antigen present on a solid tumor cell.

22. The actKIR-CAR of claim 1 , wherein said antigen binding domain from an antibody molecule binds an antigen present on a hematological tumor cell.

23. The actKIR-CAR of claim 1 , wherein said antigen binding domain from an antibody molecule binds CD19, mesothelin, CD123, or BCMA.

Assignees

• Novartis Ag
• Univ Pennsylvania

Inventors

• Milone Michael C
• Wang Enxiu

Classifications

• C07K14/70503

  Immunoglobulin superfamily · CPC title

• C07K2319/03

  containing a transmembrane segment · CPC title

• C07K16/18 Primary

  against material from animals or humans · CPC title

• C07K14/70535

  Fc-receptors, e.g. CD16, CD32, CD64 (CD2314/705F) · CPC title

• C07K2319/70

  containing domain for protein-protein interaction · CPC title