Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Monoclonal antibody or fragment thereof
Reexamination Certificate
2000-08-23
2004-10-26
Gambel, Phillip (Department: 1644)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Monoclonal antibody or fragment thereof
C424S130100, C424S137100, C424S139100, C424S141100, C424S143100, C424S152100, C424S153100, C424S154100, C424S172100, C424S173100, C424S184100, C530S387100, C530S387500, C530S387900, C530S388100, C530S388200, C530S388220, C530S388700, C530S388730, C530S388750
Reexamination Certificate
active
06808710
ABSTRACT:
BACKGROUND OF THE INVENTION
In order for T cells to respond to foreign proteins, two signals must be provided by antigen-presenting cells (APCs) to resting T lymphocytes (Jenkins, M. and Schwartz, R. (1987)
J. Exp. Med
. 165:302-319; Mueller, D. L. et al. (1990)
J. Immunol
. 144:3701-3709). The first signal, which confers specificity to the immune response, is transduced via the T cell receptor (TCR) following recognition of foreign antigenic peptide presented in the context of the major histocompatibility complex (MHC). The second signal, termed costimulation, induces T cells to proliferate and become functional (Lenschow et al. (1996)
Annu. Rev. Immunol
. 14:233). Costimulation is neither antigen-specific, nor MHC restricted and is thought to be provided by one or more distinct cell surface molecules expressed by APCs (Jenkins, M. K. et al. (1988)
J. Immunol
. 140:3324-3330; Linsley, P. S. et al. (1991)
J. Exp. Med
. 173:721-730; Gimmi, C. D., et al. 1991
Proc. Natl. Acad. Sci. USA
88:6575-6579; Young, J. W. et al. (1992)
J. Clin. Invest
. 90:229-237; Koulova, L. et al. (1991)
J. Exp. Med
. 173:759-762; Reiser, H. et al. (1992)
Proc. Natl. Acad. Sci. USA
89:271-275; van-Seventer, G. A. et al. (1990)
J. Immunol
. 144:4579-4586; LaSalle, J. M. et al. (1991)
J. Immunol
. 147:774-80; Dustin, M. I. et al. (1989)
J. Exp. Med
. 169:503; Armitage, R. J. et al. (1992)
Nature
357:80-82; Liu, Y. et al. (1992)
J. Exp. Med
. 175:437-445).
The CD80 (B7-1) and CD86 (B7-2) proteins, expressed on APCs, are critical costimulatory molecules (Freeman et al. (1991)
J. Exp. Med
. 174:625; Freeman et al. (1989)
J. Immunol
. 143:2714; Azuma et al. (1993)
Nature
366:76; Freeman et al. (1993)
Science
262:909). B7-2 appears to play a predominant role during primary immune responses, while B7-1, which is upregulated later in the course of an immune response, may be important in prolonging primary T cell responses or costimulating secondary T cell responses (Bluestone (1995)
Immunity
2:555).
One receptor to which B7-1 and B7-2 bind, CD28, is constitutively expressed on resting T cells and increases in expression after activation. After signaling through the T cell receptor, ligation of CD28 and transduction of a costimulatory signal induces T cells to proliferate and secrete IL-2 (Linsley, P. S. et al. (1991)
J. Exp. Med
. 173:721-730; Gimmi, C. D. et al. (1991)
Proc. Natl. Acad Sci. USA
88:6575-6579; June, C. H. et al. (1990)
Immunol. Today
. 11:211-6; Harding, F. A. et al. (1992)
Nature
356:607-609). A second receptor, termed CTLA4 (CD 152) is homologous to CD28 but is not expressed on resting T cells and appears following T cell activation (Brunet, J. F. et al. (1987)
Nature
328:267-270). CTLA4 appears to be critical in negative regulation of T cell responses (Waterhouse et al. (1995)
Science
270:985). Blockade of CTLA4 has been found to remove inhibitory signals, while aggregation of CTLA4 has been found to provide inhibitory signals that downregulate T cell responses (Allison and Krummel (1995)
Science
270:932). The B7 molecules have a higher affinity for CTLA4 than for CD28 (Linsley, P. S. et al. (1991)
J. Exp. Med
. 174:561-569) and B7-1 and B7-2 have been found to bind to distinct regions of the CTLA4 molecule and have different kinetics of binding to CTLA4 (Linsley et al. (1994)
Immunity
1:793). A new molecule related to CD28 and CTLA4, ICOS, has been identified and seems to be important in IL-10 production (Hutloff et al. (1999)
Nature
397:263; WO 98/38216), as has its ligand, which is a new B7 family member (Aicher A. et al. (2000)
J. Immunol
. 164:4689-96; Mages H. W. et al. (2000)
Eur. J. Immunol
. 30:1040-7; Brodie D. et al. (2000)
Curr. Biol
. 10:333-6; Ling V. et al. (2000)
J. Immunol
. 164:1653-7; Yoshinaga S. K. et al. (1999)
Nature
402:827-32). If T cells are only stimulated through the T cell receptor, without receiving an additional costimulatory signal, they become nonresponsive, anergic, or die, resulting in downmodulation of the immune response.
The importance of the B7:CD28/CTLA4 costimulatory pathway has been demonstrated in vitro and in several in vivo model systems. Blockade of this costimulatory pathway results in the development of antigen specific tolerance in murine and human systems (Harding, F. A. et al. (1992)
Nature
356:607-609; Lenschow, D. J. et al. (1992)
Science
257:789-792; Turka, L. A. et al. (1992)
Proc. Natl. Acad. Sci. USA
89:11102-11105; Gimmi, C. D. et al. (1993)
Proc. Natl. Acad. Sci. USA
90:6586-6590; Boussiotis, V. et al. (1993)
J. Exp. Med
. 178:1753-1763). Conversely, expression of B7 by B7 negative murine tumor cells induces T-cell mediated specific immunity accompanied by tumor rejection and long lasting protection to tumor challenge (Chen, L. et al. (1992)
Cell
71:1093-1102; Townsend, S. E. and Allison, J. P. (1993)
Science
259:368-370; Baskar, S. et al. (1993)
Proc. Natl. Acad. Sci
. 90:5687-5690.). Therefore, manipulation of the costimulatory pathways offers great potential to stimulate or suppress immune responses in humans.
SUMMARY OF THE INVENTION
The present invention is based, at least in part, on the discovery that PD-1 is a receptor for B7-4 molecules expressed on antigen presenting cells. PD-1 transmits a negative signal to immune cells, similar to CTLA4. B7-4 molecules are expressed on the surface of antigen presenting cells and provide a costimulatory signal to immune cells and can transmit downmodulatory signals to immune cells, depending upon the molecule to which they bind. Thus, modulation of PD-1, B7-4, and/or the interaction between B7-4 and PD-1 results in modulation of the immune response.
Accordingly, in one aspect, the invention provides a method for modulating an immune response comprising contacting an immune cell with an agent that modulates signaling via PD-1 to thereby modulate the immune response.
In one embodiment, the immune response is downregulated.
In another embodiment, signaling via PD-1 is stimulated using an agent selected from the group consisting of: an activating antibody that recognizes PD-1, a form of B7-4 that binds to an inhibitory receptor, and a small molecule that binds to PD-1.
In one embodiment, the immune cell is selected from the group consisting of: a T cell, a B cell, and a myeloid cell.
In one embodiment, anergy is induced in the immune cell.
In one embodiment, the method further comprising contacting the immune cell with an additional agent that downregulates an immune response.
In one embodiment, the immune response is upregulated.
In one embodiment, the signaling via PD-1 is inhibited using an agent selected from the group consisting of: a blocking antibody that recognizes PD-1, a non-activating form of B7-4, an antibody that recognizes B7-4, and a soluble form of PD-1.
In one embodiment, the step of contacting occurs in vivo. In another embodiment, the step of contacting occurs in vitro.
In another aspect, the invention pertains to a method for modulating the interaction of B7-4 with an inhibitory receptor on an immune cell comprising contacting an antigen presenting cell which expresses B7-4 with an agent selected from the group consisting of: a form of B7-4, a form of PD-1, or an agent that modulates the interaction of B7-4 and PD-1 such that the interaction of B7-4 with an inhibitory receptor on an immune cell is modulated.
In one embodiment, the method further comprises contacting the immune cell or the antigen presenting cell with an additional agent that modulates an immune response.
In one embodiment, the step of contacting is performed in vitro. In another embodiment, the step of contacting is performed in vivo.
In one embodiment, the immune cell is selected from the group consisting of: a T cell, a B cell, and a myeloid cell.
In another aspect, the invention pertains to a method for inhibiting activation in an immune cell via a non-apoptotic mechanism comprising increasing the activity or expression of PD-1 in a immune cell such that immune cell activation is inhibited.
In another aspect, the invention pertains to vaccine
Freeman Gordon J.
Wood Clive
Gambel Phillip
Genetics Institute Inc.
Lahive & Cockfield LLP
Mandragouras Esq. Amy E.
Roark Jessica H.
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