Methods for inducing a population of T cells to proliferate using agents which recognize TCR/CD3 and ligands which stimulate an accessory molecule on the surface of the T cells

• US 6,352,694 B1
• Filed: 03/10/1995
• Issued: 03/05/2002
• Est. Priority Date: 06/03/1994
• Status: Expired due to Term

• Current Assignee: Genetics Institute LLC (Pfizer Inc.), the united states of america as represented by the secretary of the navy, University of Alabama (University of Alabama System), Board of Regents of the University of Michigan (University of Michigan)
• Original Assignee: Genetics Institute LLC (Pfizer Inc.), Board of Regents of the University of Michigan (University of Michigan)
• Inventors: Nabel, Gary J., June, Carl H., Thompson, Craig B., Gray, Gary S., Rennert, Paul D.
• Primary Examiner(s): Gambel, Phillip
• Application Number:
  US08/403,253
• Time in Patent Office: 2,552 Days
• Field of Search: 424/93.1, 424/93.7, 424/457, 424/480, 424/130.1, 424/141.1, 424/153.1, 424/154.1, 424/93.71, 424/577, 424/578, 435/7.1, 435/2, 435/7.2, 435/7.21, 435/7.24, 435/375, 435/377, 530/387.1, 530/388.1, 530/388.2, 530/388.22, 530/388.7, 530/388.73, 530/388.75
• US Class Current: 424/93.71
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/5158 Antigen-pulsed cells, e.g. T-cells
• CPC Class Codes: A61K 2239/38 characterised by the dose, timing or administration schedule
• 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 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 39/464411 Immunoglobulin superfamily
• CPC Class Codes: A61K 39/464838 Viral antigens
• 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 14/70521 CD28, CD152
• CPC Class Codes: C07K 14/70532 B7 molecules, e.g. CD80, CD86
• CPC Class Codes: C07K 16/00 Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies antibodies with enzymatic activity, e.g. abzymes C12N9/0002
• CPC Class Codes: C07K 16/2806 against CD2
• CPC Class Codes: C07K 16/2809 against the T-cell receptor (TcR)-CD3 complex
• CPC Class Codes: C07K 16/2812 against CD4
• CPC Class Codes: C07K 16/2815 against CD8
• CPC Class Codes: C07K 16/2818 against CD28 or CD152
• CPC Class Codes: C07K 16/2833 against MHC-molecules, e.g. HLA-molecules
• CPC Class Codes: C07K 16/2866 against receptors for cytokines, lymphokines, interferons
• CPC Class Codes: C07K 16/289 : against CD45
• CPC Class Codes: C07K 16/2896 : against molecules with a "CD"-designation, not provided for elsewhere
• CPC Class Codes: C07K 2317/24 : containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/34 : Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• CPC Class Codes: C07K 2317/54 : F(ab')2
• CPC Class Codes: C07K 2317/55 : Fab or Fab'
• CPC Class Codes: C07K 2317/73 : Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• CPC Class Codes: C07K 2317/74 : Inducing cell proliferation
• CPC Class Codes: C07K 2319/00 : Fusion polypeptide
• CPC Class Codes: C07K 2319/30 : Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
• CPC Class Codes: C12N 2501/51 : B7 molecules, e.g. CD80, CD86, CD28 (ligand), CD152 (ligand)
• CPC Class Codes: C12N 2501/515 : CD3, T-cell receptor complex
• CPC Class Codes: C12N 2501/599 : with CD designations not provided for elsewhere
• CPC Class Codes: C12N 2740/16011 : Human Immunodeficiency Virus, HIV
• CPC Class Codes: C12N 2795/00011 : Details
• CPC Class Codes: C12N 5/0636 : T lymphocytes

Abstract

Methods for inducing a population of T cells to proliferate by activating the population of T cells and stimulating an accessory molecule on the surface of the T cells with a ligand which binds the accessory molecule are described. T cell proliferation occurs in the absence of exogenous growth factors or accessory cells. T cell activation is accomplished by stimulating the T cell receptor (TCR)/CD3 complex or the CD2 surface protein. To induce proliferation of an activated population T cells, an accessory molecule on the surface of the T cells, such as CD28, is stimulated with a ligand which binds the accessory molecule. The T cell population expanded by the method of the invention can be genetically transduced and used for immunotherapy or can be used in methods of diagnosis.

Claims

1. A method for inducing a population of T cells to proliferate to sufficient numbers for use in therapy;

comprising;

a) activating the population of T cells by contacting the T cells in vitro with an anti-CD3 antibody which is immobilized on a solid phase surface; and

b) stimulating an accessory molecule on the surface of the T cells in vitro with an anti-CD28 antibody, wherein said anti-CD28 antibody is immobilized on the same solid phase surface as the anti-CD3 antibody, the activating and stimulating steps thereby inducing proliferation of the T cells to sufficient numbers for use in therapy.

2. The method of claim 1, wherein the anti-CD3 antibody is an anti-human CD3 monoclonal antibody.

3. The method of claim 1, wherein the anti-CD28 antibody is an anti-human CD28 monoclonal antibody.

4. The method of claim 1, wherein said solid phase surface is a bead.

5. The method of claim 4, wherein the bead is a magnetic immunobead.

6. The method of claim 1, wherein said solid phase surface is a tissue culture dish.

7. The method of claim 1, wherein the anti-CD3 antibody and the anti-CD28 antibody are immobilized on the solid phase surface via a covalent modification.

8. The method of claim 1, wherein the anti-CD3 antibody and the anti-CD28 antibody are immobilized on the solid phase surface via an avidin-biotin complex.

9. The method of claim 1, wherein the anti-CD3 antibody and the anti-CD28 antibody are directly immobilized on the solid phase surface.

10. The method of claim 1, wherein the T cells are induced to proliferate for at least 3 days.

11. The method of claim 2, wherein the T cells are induced to proliferate for at least 7 days.

12. The method of claim 1, wherein the T cells are induced to proliferate to about 100-fold the original T cell population.

13. The method of claim 1, wherein the T cells are induced to proliferate to about 100,000-fold the original T cell population.

14. The method of claim 1, wherein said anti-CD3 antibody and said anti-CD28 antibody are whole antibodies.

15. The method of claim 1, wherein the population of T cells is induced to proliferate to sufficient numbers for use in treating an infectious disease.

16. The method of claim 1, wherein the population of T cells is induced to proliferate to sufficient numbers for use in treating cancer.

17. A method for inducing a population of T cells to proliferate to sufficient numbers for use in therapy, comprising:

a) activating the population of T cells by contacting the T cells in vitro with an anti-CD3 antibody which is immobilized on a solid phase surface; and

b) stimulating an accessory molecule on the surface of the T cells in vitro with a stimulatory form of a natural ligand for CD28 selected from the group consisting of B7-1 and B7-2, wherein said stimulatory forrn of a natural ligand for CD28 is immobilized on the same solid phase surface as the anti-CD3 antibody, the activating and stimulating steps thereby inducing proliferation of the T cells to sufficient numbers for use in therapy.

18. The method of claim 17, wherein the stimulatory form of a natural ligand for CD28 is B7-1.

19. The method of claim 17, wherein the stimulatory form of a natural ligand for CD28 is B7-2.

20. The method of claim 17, wherein said solid phase surface is a bead.

21. The method of claim 20, wherein the bead is a magnetic immunobead.

22. The method of claim 17, wherein said solid phase surface is a tissue culture dish.

23. The method of claim 17, wherein the anti-CD3 antibody and the stimulatory form of a natural ligand for anti-CD28 are immobilized on the solid phase surface via a covalent modification.

24. The method of claim 17, wherein the anti-CD3 antibody and the stimulatory form of a natural ligand for anti-CD28 are immobilized on the solid phase surface via an avidin-biotin complex.

25. The method of claim 17, wherein the anti-CD3 antibody and the stimulatory form of a natural ligand for anti-CD28 are directly immobilized on the solid phase surface.

26. The method of claim 17, wherein The T cells are induced to proliferate for at least 3 days.

27. The method of claim 17, wherein the T cells are induced to proliferate for at least 7 days.

28. The method of claim 17, wherein the T cells are induced to proliferate to about 100-fold the original T cell population.

29. The method of claim 17, wherein the T cells are induced to proliferate to about 100,000-fold the original T cell population.

30. The method of claim 17, wherein said anti-CD3 antibody is a whole antibody.

31. The method of claim 17, wherein the population of T cells is induced to proliferate to sufficient numbers for use in treating an infectious disease.

32. The method of claim 17, wherein the population of T cells is induced to proliferate to sufficient numbers for use in treating cancer.