Chimeric receptors and uses thereof in immune therapy

Patent metadata

Field	Value
Publication number	US-10144770-B2
Application number	US-201414516880-A
Country	US
Kind code	B2
Filing date	Oct 17, 2014
Priority date	Oct 17, 2013
Publication date	Dec 4, 2018
Grant date	Dec 4, 2018

Abstract

Disclosed herein are chimeric receptors comprising an extracellular domain with affinity and specific for the Fc portion of an immunoglobulin molecule (Ig) (e.g., an extracellular ligand-binding domain of F158 FCGR3A or V158 FCGR3A variant); a transmembrane domain (e.g., a transmembrane domain of CD8α); at least one co-stimulatory signaling domain (e.g., a co-stimulatory signaling domain of 4-1BB); and a cytoplasmic signaling domain comprising an immunoreceptor tyrosine-based activation motif (ITAM) (e.g., a cytoplasmic signaling domain of CD3ζ). Also provided herein are nucleic acids encoding such chimeric receptors and immune cells expressing the chimeric receptors. Such immune cells can be used to enhance antibody-dependent cell-mediated cytotoxicity and/or to enhance antibody-based immunotherapy, such as cancer immunotherapy.

First claim

What is claimed is:

1. A chimeric receptor, comprising:
(a) an extracellular ligand-binding domain of an Fc receptor;
(b) a transmembrane domain;
(c) at least one co-stimulatory signaling domain, which is from a co-stimulatory protein involved in immune cell co-stimulation; and
(d) a cytoplasmic signaling domain comprising an immunoreceptor tyrosine-based activation motif (ITAM);
wherein either (c) or (d) is located at the C-terminus of the chimeric receptor; wherein (c) and (d) are different signaling domains; and wherein if (a) is an extracellular ligand-binding domain of CD16A, (d) does not comprise an ITAM domain of an Fc receptor.

2. The chimeric receptor of claim 1 , wherein (d) is located at the C-terminus of the chimeric receptor.

3. The chimeric receptor of claim 1 , further comprising (e) a hinge domain which is located at the C-terminus of (a) and the N-terminus of (b).

4. The chimeric receptor of claim 1 , wherein the chimeric receptor comprises:
(a) an extracellular ligand-binding domain of F158 FCGR3A or V158 FCGR3A variant,
(b) a hinge and transmembrane domain of CD8α,
(c) a co-stimulatory signaling domain of 4-1BB, and
(d) a cytoplasmic signaling domain of CD3ζ.

5. The chimeric receptor of claim 4 , wherein the chimeric receptor further comprises a signal peptide of CD8α.

6. The chimeric receptor of claim 4 , wherein the extracellular domain of F158 FCGR3A and V158 FCGR3A variant consist of the amino acid sequences of SEQ ID NO:70 and SEQ ID NO:57, respectively.

7. The chimeric receptor of claim 4 , wherein the hinge and transmembrane domains of CD8α consist of the amino acid sequence of SEQ ID NO: 58.

8. The chimeric receptor of claim 4 , wherein the co-stimulatory signaling domain of 4-1BB consists of the amino acid sequence of SEQ ID NO: 59.

9. The chimeric receptor of claim 4 , wherein the cytoplasmic signaling domain of CD3ζ consists of the amino acid sequence of SEQ ID NO: 60.

10. The chimeric receptor of claim 5 , wherein the signal peptide of CD8a consists of the amino acid sequence of SEQ ID NO: 61.

11. The chimeric receptor of claim 4 , which comprises the amino acid sequence of residues 22 to 436 of SEQ ID NO: 1, or residues 22 to 436 of SEQ ID NO: 31.

12. The chimeric receptor of claim 5 , which comprises the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO:31.

13. A nucleic acid comprising a nucleotide sequence encoding a chimeric receptor of claim 1 .

14. A host cell comprising the chimeric receptor of claim 1 .

15. The host cell of claim 14 , wherein the chimeric receptor comprises:
(a) an extracellular ligand-binding domain of F158 FCGR3A or V158 FCGR3A variant,
(b) a hinge and transmembrane domain of CD8a,
(c) a co-stimulatory signaling domain of 4-1BB, and
(d) a cytoplasmic signaling domain of CD3ζ.

16. The host cell of claim 14 , which is a T lymphocyte or an NK cell.

17. The host cell of claim 16 , wherein the T lymphocyte or the NK cell is activated and/or expanded ex vivo.

18. The host cell of claim 16 , wherein the T lymphocyte or NK cell is an autologous T lymphocyte or an autologous NK cell isolated from a patient having a cancer.

19. The host cell of claim 16 , wherein the T lymphocyte or NK cell is an allogenic T lymphocyte or an allogenic NK cell.

20. A pharmaceutical composition comprising the host cell of claim 14 and a pharmaceutically acceptable carrier or excipient.

21. A method for enhancing efficacy of an antibody-based immunotherapy of a cancer in a subject being treated with an anti-cancer antibody, the method comprising administering to the subject a therapeutically effective amount of T lymphocytes or NK cells that express the chimeric receptor of claim 1 .

22. The method of claim 21 , wherein the chimeric receptor comprises:
(a) an extracellular ligand-binding domain of F158 FCGR3A or V158 FCGR3A variant,
(b) a hinge and transmembrane domain of CD8a,
(c) a co-stimulatory signaling domain of 4-1BB, and
(d) a cytoplasmic signaling domain of CD3ζ.

23. The method of claim 21 , wherein the antibody has a humanized Fc portion, which bind to human CD16.

24. The method of claim 21 , wherein the antibody is selected from the group consisting of Rituximab, Trastuzumab, hu14.18K322A, Epratuzumab, Cetuximab, and Labetuzumab.

25. The method of claim 21 , wherein the T lymphocytes or NK cells are autologous T lymphocytes or autologous NK cells isolated from the subject, or wherein the T lymphocytes or NK cells are allogenic cells.

26. The method of claim 25 , wherein, prior to the administration step, the autologous T lymphocytes or autologous NK cells are activated and/or expanded ex vivo.

27. The method of claim 25 , wherein the allogeneic T lymphocytes are T lymphocytes, in which the expression of the endogenous T cell receptor has been inhibited or eliminated.

28. The method of claim 21 , wherein the chimeric receptor is introduced into the T lymphocytes or the NK cells by a method selected from the group consisting of retroviral transduction, lentiviral transduction, DNA electroporation, and RNA electroporation.

29. A method of enhancing a T lymphocyte or an NK cell antibody-dependent cell cytotoxicity (ADCC) in a subject, the method comprising administering to the subject a therapeutically effective amount of T lymphocytes or NK cells that express the chimeric receptor of claim 1 .

30. The method of claim 29 , wherein the chimeric receptor comprising:
(a) an extracellular ligand-binding domain of F158 FCGR3A or V158 FCGR3A variant,
(b) the hinge and transmembrane domain of CD8a,
(c) a co-stimulatory signaling domain of 4-1BB, and
(d) a cytoplasmic signaling domain of CD3ζ.

31. A method for preparing immune cells expressing a chimeric receptor, comprising:
(i) providing a population of immune cells;
(ii) introducing into the immune cells a nucleic acid encoding a chimeric receptor of claim 1 ; and

culturing the immune cells under conditions allowing for expression of the chimeric receptor.

Assignees

• Nat Univ Singapore
• St Jude Childrens Res Hospital
• Unum Therapeutics Inc

Inventors

• Campana Dario
• Kudo Ko
• Wilson Charles
• Mcginness Kathleen

Classifications

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• A61K2039/515

  Animal cells · CPC title

• A61K2039/572

  cytotoxic response · CPC title

• C07K14/70578

  NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95 (NGF-receptor C07K14/71, TNF-receptor C07K14/7151) · CPC title

• C07K14/7051

  T-cell receptor (TcR)-CD3 complex · CPC title