Methods of treating HIV infected subjects

• US 6,905,680 B2
• Filed: 01/26/1996
• Issued: 06/14/2005
• Est. Priority Date: 11/23/1988
• Status: Expired due to Fees

• Current Assignee: Genetics Institute LLC (Pfizer Inc.), the united states of america as represented by the secretary of the navy, Board of Regents of the University of Michigan (University of Michigan)
• Original Assignee: Genetics Institute LLC (Pfizer Inc.), the united states of america as represented by the secretary of the navy, 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:
  US08/592,711
• Publication Number:
  US 20020115214A1
• Time in Patent Office: 3,427 Days
• Field of Search: 424/134.1, 424/143.1, 424/178.1, 514/2, 514/8, 514/12
• US Class Current: 424/93.71
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/507 Comprising a combination of two or more separate antibodies
• CPC Class Codes: A61K 2039/5158 Antigen-pulsed cells, e.g. T-cells
• 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 39/02 Bacterial antigens
• CPC Class Codes: A61K 39/12 Viral antigens
• 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 39/464838 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 2710/00088 : for redistribution
• CPC Class Codes: C12N 2740/16011 : Human Immunodeficiency Virus, HIV
• 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 ex vivo proliferation of a population of T cells from an HIV-infected subject to sufficient numbers for use in therapy, comprising contacting a population of T cells ex vivo with a surface having attached thereto:

an anti-CD3 antibody or CD3-binding fragment thereof, which stimulates a TCR/CD3 complex-associated signal in T cells, and

an anti-CD28 antibody or CD28-binding fragment thereof, which stimulates a CD28-sssociated signal in T cells;

wherein the anti-CD3 antibody or CD3-binding fragment thereof, and the anli-CD28 antibody or CD28-binding fragment thereof, are attached on the same surface,

the anti-CD3 antibody or CD3-binding fragment thereof and the anti-CD28 antibody or CD28-binding fragment thereof thereby, inducing the T cells to proliferate to sufficient numbers for use in therapy; and

whereby the CD28 stimulation by the anti-CD28 antibody or CD28-binding fragment thereof provides a proliferative advantage for HIV-uninfected CD4⁺ T cells over HIV-infected CD4⁺ T cells and a protective effect against HIV infection for uninfected CD4⁺ T cells.

5. The method of any one of claims 1, 2, 3, or 4, wherein the anti-CD3 antibody or CD3-binding fragment thereof is an anti-human CD3 antibody or CD3-binding fragment thereof.

6. The method of any one of claims 1, 2, 3, or 4, wherein the anti-CD28 antibody or CD28-binding fragment thereof is an anti-human CD28 antibody or CD28-binding fragment thereof.

7. The method of any one of claims 1, 2, 3, or 4, further comprising contacting said population of T cells ex vivo with IL-2.

8. The method of any one of claims 1, 5, 7, 2, 3, or 4, wherein the anti-CD3 antibody or CD3-binding fragment thereof, and the anti-CD28 antibody or CD28-binding fragment thereof, are monoclonal antibodies or fragments thereof.

9. The method of any one of claims 1, 2, 3, or 4, further comprising contacting said population of T cells ex vivo with an anti-retroviral agent.

10. The method of any one of claims 1 or 2, further comprising re-administering said population of T cells to said subject.

11. The method of any one of claims 1, 2, 3, or 4, wherein said surface is a bead.

12. The method of any one of claims 1, 2, 3, or 4, wherein said surface is a magnetic immunobead.

13. The method of any one of claims 1, 2, 3, or 4, wherein said surface is a tissue culture dish.

14. The method of any one of claims 1, 2, 3, or 4, wherein said surface is a cell surface.

2. A method for inducing ex vivo proliferation of a population of T cells from an HIV-infected subject to sufficient numbers for use in therapy, comprising contacting a population of T cells ex vivo with a surface having attached thereto:

an anti-CD3 antibody or CD3-binding fragment thereof, which stimulates a TCR/CD3 complex-associated signal in T cells, and

an anti-CD28 antibody or CD28-binding fragment thereof, which stimulates a CD28-sssociated signal in T cells;

wherein the anti-CD3 antibody or CD3-binding fragment thereof, and the anti-CD28 antibody or CD28-binding fragment thereof, are attached on the same surface,

the anti-CD3 antibody or CD3-binding fragment thereof, and the anti-CD28 antibody or CD28-binding fragment thereof, thereby inducing the T cells to proliferate to sufficient numbers for use in therapy; and

whereby the percent CD4⁺ T cells expressing the cell surface marker CD45RO increases.

3. A method of treating an HIV-infected subject, comprising contacting a population of T cells from the subject ex vivo with a surface having attached thereto:

an anti-CD3 antibody or CD3-binding fragment thereof, which stimulates a TCR/CD3 complex-associated signal in T cells, and

an anti-CD28 antibody or CD28-binding fragment thereof, which stimulates a CD28-sssociated signal in T cells;

wherein the anti-CD3 antibody or CD3-binding fragment thereof, and the anti-CD28 antibody or CD28-binding fragment thereof, are attached on the same surface,

the anti-CD3 antibody or CD3-binding fragment thereof, and the anti-CD28 antibody or CD28-binding fragment thereof, thereby inducing the T cells to proliferate to sufficient numbers for use in therapy;

whereby the CD28 stimulation by the anti-CD28 antibody or CD28-binding fragment thereof provides a proliferative advantage for HIV-iminfected CD4⁺ T cells over HIV-infected CD4⁺ T cells and a protective effect against HIV infection for uninfected CD4⁺ T cells, and readministering the T cells to the subject.

4. A method of treating an HIV-infected subject, comprising contacting a population of T cells from the subject ex vivo with a surface having attached thereto:

an anti-CD3 antibody or CD3-binding fragment thereof, which stimulates a TCR/CD3 complex-associated signal in T cells, and

an anti-CD28 antibody or CD28-binding fragment thereof, which stimulates a CD28-sssociated signal in T cells;

wherein the anti-CD3 antibody or CD3-binding fragment thereof, and the anti-CD28 antibody or CD28-binding fragment thereof, are attached on the same surface,

the anti-CD3 antibody or CD3-binding fragment thereof, and the anti-CD28 antibody or CD28-binding fragment thereof, thereby inducing the T cells to proliferate to sufficient numbers for use in therapy;

whereby the percent of CD4⁺ T cells expressing the cell surface marker CD45RO increases, and readministering the T cells to the subject.