Targeting cytotoxic cells with chimeric receptors for adoptive immunotherapy

• US 9,745,368 B2
• Filed: 03/15/2014
• Issued: 08/29/2017
• Est. Priority Date: 03/15/2013
• Status: Active Grant

• Current Assignee: Novartis Ag, Trustees Of The University Of Pennsylvania (University of Pennsylvania)
• Original Assignee: Novartis Ag, Trustees Of The University Of Pennsylvania (University of Pennsylvania)
• Inventors: Milone, Michael C., Wang, Enxiu
• Primary Examiner(s): Ouspenski, Ilia
• Application Number:
  US14/214,824
• Publication Number:
  US 20140322183A1
• Time in Patent Office: 1,263 Days
• Field of Search: None
• CPC Class Codes: C07K 14/70503 Immunoglobulin superfamily
• CPC Class Codes: C07K 14/70535 Fc-receptors, e.g. CD16, CD32, CD64 (CD2314/705F)
• CPC Class Codes: C07K 16/18 against material from animals or humans
• CPC Class Codes: C07K 2319/03 containing a transmembrane segment
• CPC Class Codes: C07K 2319/33 fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies
• CPC Class Codes: C07K 2319/70 containing domain for protein-protein interaction

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).

Claims

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.