Chimeric receptor genes and cells transformed therewith

• US 8,211,422 B2
• Filed: 10/24/1995
• Issued: 07/03/2012
• Est. Priority Date: 03/18/1992
• Status: Expired due to Fees

• Current Assignee: Cabaret Biotech, Ltd., The United States of America, as represented by the Secretary, Department of Health and Human Services
• Original Assignee: United States Department Of Health And Human Services (Government of the United States of America), Yeda Research and Development Co. Ltd. (Weizmann Institute of Science)
• Inventors: Eshhar, Zelig, Schindler, Daniel, Waks, Tova, Gross, Gideon, Rosenberg, Steven A., Hwu, Patrick
• Primary Examiner(s): WEHBE, ANNE MARIE SABRINA
• Application Number:
  US08/547,263
• Publication Number:
  US 20020137697A1
• Time in Patent Office: 6,097 Days
• Field of Search: 514/44, 514/44.R, 435/320.1, 435/325, 435/69.1, 435/235, 435/455, 424/277.1, 424/184.1, 424/135.1, 424/93.2, 424/93.21, 424/93.71, 536/23.1, 536/23.5, 536/23.4
• US Class Current: 424/93.21
• CPC Class Codes: A61K 38/00 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 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 39/4644 Cancer antigens
• CPC Class Codes: A61K 39/464406 Her-2/neu/ErbB2, Her-3/ErbB3 or Her 4/ ErbB4
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 14/7051 T-cell receptor (TcR)-CD3 complex
• CPC Class Codes: C07K 14/70535 Fc-receptors, e.g. CD16, CD32, CD64 (CD2314/705F)
• CPC Class Codes: C07K 14/7155 for interleukins [IL]
• CPC Class Codes: C07K 16/1045 Lentiviridae, e.g. HIV, FIV, SIV
• CPC Class Codes: C07K 16/3046 Stomach, Intestines
• CPC Class Codes: C07K 16/32 against translation products of oncogenes
• CPC Class Codes: C07K 16/4291 against IgE
• CPC Class Codes: C07K 16/44 against material not provided for elsewhere , e.g. haptens, metals, DNA, RNA, amino acids
• CPC Class Codes: C07K 2319/00 Fusion polypeptide
• CPC Class Codes: C12N 2799/027 where the vector is derived from a retrovirus

Abstract

Chimeric receptor genes suitable for endowing lymphocytes with antibody-type specificity include a first gene segment encoding a single-chain Fv domain of a specific antibody and a second gene segment encoding all or part of the transmembrane and cytoplasmic domains, and optionally the extracellular domain, of an immune cell-triggering molecule. The chimeric receptor gene, when transfected to immune cells, expresses the antibody-recognition site and the immune cell-triggering moiety into one continuous chain. The transformed lymphocytes are useful in therapeutic treatment methods.

Claims

1. An adoptive immunotherapeutic method of treating a patient having a cancer bearing tumor-specific antigen with cells having immunological specificity to a selected tumor-specific antigen, comprising administering to said patient cells that have been transformed with a chimeric gene, wherein said cells are peripheral blood lymphocytes, said chimeric gene containing a) a first DNA segment encoding a single-chain Fv (scFv) domain of an antibody directed against the selected tumor-specific antigen and b) a second DNA segment encoding a lymphocyte-activating molecule subunit of a Fc receptor to express the scFv domain and the lymphocyte-activating molecule on the surface of the lymphocytes and to provide said antibody-type specificity.

2. The method according to claim 1, wherein the second DNA segment of chimeric gene encodes at least a portion of transmembrane and cytoplasmic domains of a lymphocyte-activating protein.

3. The method according to claim 2, wherein the second DNA segment of the chimeric gene further encodes an extracellular domain of a lymphocyte-activating protein.

4. The method according to claim 1, wherein the cells are circulating lymphocytes.

5. The method according to claim 4, wherein the cells are primary T cells.

6. The method according to claim 1, wherein the subunit is selected from the group consisting of a gamma chain and a CD16α

chain of an Fc receptor.

17. The method according to claim 1, wherein the chimeric gene is scFvRγ

.

18. The method according to claim 1, wherein the chimeric gene is scFvRζ

.

19. The method according to claim 1, wherein the tumor-specific antigen is Neu/HER2.

20. The method according to claim 1, wherein the antibody is an anti-HER2 antibody.

21. The method according to claim 20, wherein the anti-HER2 antibody is mAb N29.

22. The method according to claim 1, wherein the Fc receptor is Fcγ

R.

23. The method according to claim 1, wherein the Fc receptor is Fcε

R.

7. A method of treating a tumor in a patient, wherein said tumor bears immunologically reactive tumor-specific antigens, comprising:

transforming cells of the patient with an expression vector wherein said cells are peripheral blood lymphocytes, said expression vector comprising a chimeric gene comprising a first gene segment encoding a single-chain Fv domain (scFv) of an antibody specific to a selected tumor-specific antigen and a second gene segment encoding a molecule selected from the group consisting of a subunit of a Fc receptor and an IL-2 receptor, to express both said scFv domain and said molecule, so that the transformed cells are activated and/or stimulated to proliferate, and exhibit MHC nonrestricted antibody-type specificity when said expressed scFv domain binds to its antigen, and administering the activated cells to the patient, said cells being targeted to the tumor cells, to provide tumor regression.

8. The method according to claim 7, wherein peripheral blood cells of the patient are transformed.

9. The method according to claim 7, wherein the second DNA segment of the chimeric gene encodes at least a portion of the transmembrane and cytoplasmic domains of the molecule.

10. The method according to claim 9, wherein the second DNA segment of the chimeric gene further encodes an extracellular domain of a lymphocyte-activating protein.

11. The method according to claim 7, wherein the cells are circulating lymphocytes.

12. The method according to claim 11, wherein the cells are primary T cells.

13. The method according to claim 7, wherein the subunit is a gamma chain or CD16α

chain of an Fc receptor.

14. The method according to claim 7 wherein the tumor-specific antigen is a gastric cancer antigen.

15. The method according to claim 7 wherein the tumor-specific antigen is a breast cancer antigen.

16. The method according to claim 7 wherein the tumor-specific antigen is an ovarian cancer antigen.

24. The method according to claim 7, wherein the chimeric gene is scFvRγ

.

25. The method according to claim 7, wherein the chimeric gene is scFvRζ

.

26. The method according to claim 7, wherein the tumor-specific antigen is Neu/HER2.

27. The method according to claim 7, wherein the antibody is an anti-HER2 antibody.

28. The method according to claim 27, wherein the anti-HER2 antibody is mAb N29.

29. The method according to claim 7, wherein the Fc receptor is Fcγ

R.

30. The method according to claim 7, wherein the Fc receptor is Fcε

R.