Redirection of cellular immunity by receptor chimeras

• US 7,049,136 B2
• Filed: 02/02/1999
• Issued: 05/23/2006
• Est. Priority Date: 03/07/1991
• Status: Expired due to Term

• Current Assignee: The General Hospital Corporation (Mass General Brigham, Inc.)
• Original Assignee: The General Hospital Corporation (Mass General Brigham, Inc.)
• Inventors: Seed, Brian, Kolanus, Waldemar, Romeo, Charles
• Primary Examiner(s): Nolan, Patrick J.
• Application Number:
  US09/243,008
• Publication Number:
  US 20040005334A1
• Time in Patent Office: 2,667 Days
• Field of Search: 435/346, 435/325, 530/350, 424/195.11
• US Class Current: 435/325
• CPC Class Codes: A61K 2039/5156 expressing foreign proteins
• CPC Class Codes: A61K 35/13 Tumour cells, irrespective of tissue of origin tumour vaccines A61K39/00
• CPC Class Codes: A61K 35/15 Cells of the myeloid line, e.g. granulocytes, basophils, eosinophils, neutrophils, leucocytes, monocytes, macrophages or mast cells; Myeloid precursor cells; Antigen-presenting cells, e.g. dendritic cells presenting a specific antigen A61K39/00; therapeutic combinations of antibodies, or fragments thereof, and blood-derived cells A61K39/00
• CPC Class Codes: A61K 35/17 Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes when activated by a specific antigen A61K39/00
• CPC Class Codes: A61K 35/545 Embryonic stem cells; Pluripotent stem cells; Induced pluripotent stem cells; Uncharacterised stem cells
• 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 39/4631 Chimeric Antigen Receptors [CAR]
• CPC Class Codes: A61K 39/464838 Viral antigens
• CPC Class Codes: A61K 47/6901 Conjugates being cells, cell fragments, viruses, ghosts, red blood cells or viral vectors
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: C07K 14/705 Receptors; Cell surface antigens; Cell surface determinants tumour specific antigens C07K14/4748
• CPC Class Codes: C07K 14/70503 Immunoglobulin superfamily
• CPC Class Codes: C07K 14/7051 T-cell receptor (TcR)-CD3 complex
• CPC Class Codes: C07K 14/70514 CD4
• CPC Class Codes: C07K 14/70535 Fc-receptors, e.g. CD16, CD32, CD64 (CD2314/705F)
• CPC Class Codes: C07K 16/28 against receptors, cell surface antigens or cell surface determinants
• CPC Class Codes: C07K 19/00 Hybrid peptides , i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
• CPC Class Codes: C07K 2319/00 Fusion polypeptide
• CPC Class Codes: C12N 2799/023 where the vector is derived from a poxvirus
• CPC Class Codes: C12N 9/1205 : Phosphotransferases with an alcohol group as acceptor (2.7.1), e.g. protein kinases

Abstract

Disclosed is a method of directing a cellular response in a mammal by expressing in a cell of the mammal a chimeric receptor which causes the cells to specifically recognize and destroy an infective agent, a cell infected with an infective agent, a tumor or cancerous cell, or an autoimmune-generated cell. Also disclosed are cells which express the chimeric receptors and DNA encoding the chimeric receptors.

Claims

1. A cell expressing a proteinaceous membrane-bound chimeric receptor,

the first of said receptor comprising (a) an extracellular portion which is capable of specifically recognizing and binding a target cell or a target infective agent, (b) a transmembrane portion derived from a T cell receptor, a B cell receptor, or an Fc receptor protein which, in the absence of an intracellular signalling domain, is capable of signalling said cell to destroy a receptor-bound target cell or a receptor-bound target infective agent, and (c) an intracellular domain that does not signal said cell to destroy a receptor-bound target cell or receptor-bound target infective agent;

and

the second of said receptors comprising (a) an extracellular portion which is capable of specifically recoginizing and binding said target cell or said target infective agent, and (b) an intracellular portion which is derived for CD28.

2. The cell of claim 1, wherein, following binding of said extracellular portion to said cell or agent, said transmembrane portion oligomerizes with a cytolytic signal-transducing protein of said receptor-bearing cell resulting in destruction of said receptor-bound agent or cell.

3. The cell of claim 1, wherein said binding is MHC-independent.

4. The cell of claims 1, wherein said transmembrane portion comprises an oligomerizing portion of a T cell receptor protein, a B cell receptor protein, or an Fc receptor protein, or a functional derivative thereof.

5. The cell of claim 1, wherein said extracellular portion comprises the ligand-binding portion of a receptor, the receptor-binding portion of a ligand, the antigen-binding portion of an antibody, or a functional derivative thereof.

6. The cell of claim 1, wherein said target infective agent is an immunodeficiency virus or said target cell is a host cell infected with an immunodeficiency virus.

7. The cell of claim 6, wherein said extracellular portion comprises an HIV envelope-binding portion of CD4, or a functional derivative thereof.

8. The cell of claim 6, wherein said HIV-envelope binding portion of CD4 comprises the peptide encoded by nucleotides 1–

369 of SEQ ID NO;

1.

10. The cell of claim 1, wherein said cell destroys said receptor-bound target cell or target infective agent by cytolysis.

11. The cell of claim 1, wherein said transmembrane portion of the first of said receptors is derived from a T cell receptor protein.

12. The cell of claim 11, wherein said T cell receptor protein is ζ

.

13. The cell of claim 12, wherein said chimeric receptor comprises amino acids 400–

420 of SEQ ID NO;

6.

9. A cell which expresses at least two proteinaceous membrane-bound chimeric receptors,

the first of said receptors comprising (a) an extracellular portion which is capable of specifically recognizing and binding a target cell or a target infective agent, and (b) a transmembrane portion derived from a T cell receptor CD3, zeta, or eta polypeptide, a B cell receptor, or an Fc receptor, and (c) an intracellular domain that does not signal target cell or target infective agent destruction;

and

the second of said receptors comprising (a) an extracellular portion which is capable of specifically recognizing and binding said target cell or said target infective agent, and (b) an intracellular portion which is derived from CD28.