Methods for selectively stimulating proliferation of T cells
First Claim
1. A method for inducing a population of T cells to proliferate to sufficient numbers for use in therapy, comprising:
- (a) activating a population of T cells in vitro with an agent which stimulates a TCR/CD3 complex-associated signal in the T cells, wherein the agent is selected from the group consisting of an anti-CD3 antibody or a CD3-binding fragment thereof, an anti-CD2 antibody or a CD2-binding fragment thereof, and an antigen in a form suitable to trigger a primary activation signal in the T cell when complexed with the TCR/CD3 complex, wherein said agent is attached on a surface; and
(b) stimulating a CD28 accessory molecule on the surface of the T cells in vitro with a ligand that binds the CD28 accessory molecule on the surface of the T cells, wherein the ligand is selected from the group consisting of an anti-CD28 antibody or a CD28-binding fragment thereof, B7-1 or a CD28-binding fragment thereof, and B7-2 or a CD28-binding fragment thereof, wherein said ligand is attached on the same surface as said agent;
the activating and stimulating steps thereby inducing proliferation of the T cells to sufficient numbers for use in therapy.
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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.
193 Citations
65 Claims
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1. A method for inducing a population of T cells to proliferate to sufficient numbers for use in therapy, comprising:
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(a) activating a population of T cells in vitro with an agent which stimulates a TCR/CD3 complex-associated signal in the T cells, wherein the agent is selected from the group consisting of an anti-CD3 antibody or a CD3-binding fragment thereof, an anti-CD2 antibody or a CD2-binding fragment thereof, and an antigen in a form suitable to trigger a primary activation signal in the T cell when complexed with the TCR/CD3 complex, wherein said agent is attached on a surface; and (b) stimulating a CD28 accessory molecule on the surface of the T cells in vitro with a ligand that binds the CD28 accessory molecule on the surface of the T cells, wherein the ligand is selected from the group consisting of an anti-CD28 antibody or a CD28-binding fragment thereof, B7-1 or a CD28-binding fragment thereof, and B7-2 or a CD28-binding fragment thereof, wherein said ligand is attached on the same surface as said agent; the activating and stimulating steps thereby inducing proliferation of the T cells to sufficient numbers for use in therapy. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 58, 60, 64)
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31. An ex vivo method for inducing a population of CD4+ T cells to proliferate to sufficient numbers for use in therapy, comprising:
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(a) activating a population of CD4+ T cells with an agent which stimulates a TCR/CD3 complex-associated signal in the CD4+ T cells, wherein the agent is selected from the group consisting of an anti-CD3 antibody or a CD3-binding fragment thereof, an anti-CD2 antibody or a CD2-binding fragment thereof, and an antigen in a form suitable to trigger a primary activation signal in the T cell when complexed with the TCR/CD3 complex, wherein the agent is attached on a surface; and (b) stimulating a CD28 accessory molecule on the surface of the T cells with a ligand that binds the CD28 accessory molecule on the surface of the T cells, wherein the ligand is selected from the group consisting of an anti-CD28 antibody or a CD28-binding fragment thereof, B7-1 or a CD28-binding fragment thereof, and B7-2 or a CD28-binding fragment thereof, wherein the ligand is attached on the same surface as said agent, the activating and stimulating steps thereby inducing proliferation of the CD4+ T cells to sufficient numbers for use in therapy, and resulting in a population of CD4+ T cells that are polyclonal with respect to antigen reactivity. - View Dependent Claims (32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 59, 61, 65)
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62. A method for expanding a population of T cells to sufficient numbers for use in therapy, comprising:
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a) activating the population of T cells by contacting the T cells in vitro with an anti-CD3 antibody or a CD3-binding fragment thereof, which is attached on a surface; and b) stimulating a CD28 accessory molecule on the surface of the T cells in vitro with an anti-CD28 antibody or a CD28-binding fragment thereof, wherein said anti-CD28 antibody or CD28-binding fragment thereof is attached on the same surface as the anti-CD3 antibody or CD3-binding fragment thereof, the activating and stimulating steps thereby expanding the population of the T cells to sufficient numbers for use in therapy.
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63. A method for producing a population of T cells suitable for augmenting or supporting T cell growth in vivo, comprising:
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a) activating the population of T cells by contacting the T cells in vitro with an anti-CD3 antibody or a CD3-binding fragment thereof, which is attached on a surface; and b) stimulating a CD28 accessory molecule on the surface of the T cells in vitro with an anti-CD28 antibody or a CD28-binding fragment thereof, wherein said anti-CD28 antibody or CD28-binding fragment thereof is attached on the same surface as the anti-CD3 antibody or CD3-binding fragment thereof, the activating and stimulating steps thereby producing a population of T cells suitable for augmenting or supporting T cell growth in vivo.
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Specification