Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Monoclonal antibody or fragment thereof
Reexamination Certificate
1998-03-18
2001-03-27
Gambel, Phillip (Department: 1644)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Monoclonal antibody or fragment thereof
C424S130100, C424S133100, C424S135100, C424S141100, C424S143100, C424S144100, C424S153100, C424S173100, C435S326000, C435S332000, C435S334000, C435S343000, C435S343100, C435S343200, C435S346000, C530S387100, C530S387300, C530S388100, C530S388200, C530S388220, C530S388700, C530S388730, C530S388750
Reexamination Certificate
active
06207156
ABSTRACT:
FIELD OF THE INVENTION
This invention relates generally to the field of immunology and specifically to peptides which bind to CTLA-4 and stimulate T-cell proliferation.
BACKGROUND OF THE INVENTION
The complex process of T-cell activation and proliferation is based on diverse interactions such as antigen presentation, cell-cell contact and soluble immune mediators e.g., cytokines or lymphokines. Many of these interactions are mediated in T-cells through surface receptors. T helper cells, for example, require for activation both the presentation of an antigen by an antigen presenting cell (APC) in association with major histocompatibility complex (MHC) and a secondary signal. The secondary signal may be a soluble factor or may involve an interaction with another set of receptors on the surface of T-cells. Antigen presentation in the absence of the secondary signal, however, is not sufficient to activate T helper cells.
The CTLA-4/CD28/B7 system is a group of proteins involved in regulating T-cell proliferation through this secondary signaling pathway. The T-cell proliferative response is controlled by the interaction of the B7 family of proteins, which are expressed on the surface of APCs, with CTLA-4 (cytotoxic T lymphocyte antigen #4) and CD28.
The B7 family of proteins is composed of structurally related glycoproteins including B7-1, B7-2, and B7-3 (Galea-Lauri et al.,
Cancer Gene Therapy
, v. 3, p. 202-213 (1996); Boussiotis, et al.,
Proc. Nat. Acad. Sci. USA
, v. 90, p.11059-11063 (1993)). The different B7 proteins appear to have different expression patterns on the surface of antigen presenting cells. For example B7-2 is constitutively expressed on the surface of monocytes, whereas B7-1 is not, although B7-1 expression is induced in these cells when the cells are stimulated with interferon gamma (IFN-&ggr;). The different expression patterns may indicate a different role for each of the B7 family members. The B7 proteins is believed to be involved in the events relating to stimulation of an immune response by its ability to interact with various immune cell surface receptors. It is believed, for example, that B7 plays a role in augmenting T-cell proliferation and cytokine production through its interaction with the CD28 receptor.
CD28, a homodimeric glycoprotein having two disulfide linked 44-kd subunits, is found on 95% of CD4
+
and 50% of CD8
+
cells. Studies using monoclonal antibodies reactive with CD28 have demonstrated that CD28 is involved in a secondary signal pathway in the activation of T-cell proliferation. Antibodies which block the interaction of CD28 with its ligand have been found to inhibit T-cell proliferation in vitro resulting in antigen specific T cell energy. (Harding et al.,
Nature
, v. 356, p. 607 (1991)).
Recently a T-cell surface receptor protein, CTLA-4, having approximately 20% sequence homology to CD28 was identified. Although CTLA-4 is not endogenously expressed on T-cell surfaces, its expression is induced when CD28 interacts with B7 on the surface of an APC. Once CTLA-4 is expressed on the surface of the T-cell it is capable of interacting with B7.
Several groups have hypothesized that CTLA-4 and CD28 might have opposing effects on a T-cell and that CTLA-4 and CD28 might compete for binding of B7. (Krummel et al.,
International Immunology
, v. 8, p.519-523 (1995); Galea-Lauri et al.,
Cancer Gene Therapy
, v. 3, p. 202-213 (1996)). When a T-cell is presented an antigen by APC and B7 interacts with CD28 on the T-cell surface, a secondary signal is created which stimulates the T-cell to proliferate. When, however, B7 interacts with CTLA-4 the secondary signal is not created. It is still unclear whether the interaction of CTLA-4 with B7 initiates an inhibitory signaling pathway to prevent the cell from proliferating or whether the interaction of CTLA-4 with B7 simply acts to reduce the amount of B7 available for binding to CD28. In either case, it appears that CTLA-4, CD28, and B7 each play an important role in the intricate regulation of T-cell proliferation.
SUMMARY OF THE INVENTION
The present invention relates to peptides which bind to CTLA-4 and which co-stimulate T-cell proliferation. The peptides of the invention, which include monoclonal antibodies, functionally active antibody fragments and functionally active polypeptides, specifically interact with human CTLA-4 and prevent the interaction of B7 with human CTLA-4.
These peptides have particular utility as pharmaceuticals for the immunotherapy of T-cell proliferation sensitive disorders because of their ability to co-stimulate T-cell proliferation. The peptides of the invention are particularly effective for immunotherapy of T-cell proliferation sensitive disorders when administered in combination with conventional therapeutics used for the treatment of such disorders. For instance a tumor, which is a T-cell proliferation sensitive disorder, is conventionally treated with a chemotherapeutic agent which functions by killing rapidly dividing cells. The peptides of the invention when administered in conjunction with a chemotherapeutic agent enhance the tumoricidal effect of the chemotherapeutic agent by stimulating T-cell proliferation to enhance the immunological rejection of the tumor cells.
A major advantage of the peptides of the invention derives from the fact that they specifically interact with human CTLA-4. Because the peptides of the invention interact specifically with human CTLA-4 they may be used in vivo in humans to co-stimulate T-cell proliferation. The in vivo enhancement of T-cell proliferation is desirable as an aid in the treatment of many of T-cell proliferation sensitive disorders of the immune system, such as diseases resulting from immunodeficiency, as well as disorders involving unwanted cellular invasion or growth, such as invasion of the body by foreign microorganisms or tumor growth.
In particular, the present invention provides a composition of a peptide that selectively binds to human CTLA-4 and co-stimulates T-cell proliferation. In one embodiment the peptide has a CTLA-4 binding CDR3 region. The CTLA-4 binding CDR3 region may be a CDR3
A3.4H2
or functional variant thereof of a monoclonal antibody produced by hybridoma A3.4H2 deposited under ATCC Accession No. HB-12319. In another embodiment the CTLA-4 binding CDR3 region is a CDR3
A3.6B10
or functional variant thereof of a monoclonal antibody produced by hybridoma A3.6B10 deposited under ATCC Accession No. HB-12318.
The peptide may be an intact soluble monoclonal antibody. According to one embodiment of the invention the peptide is an intact soluble monoclonal antibody
A3.4H2
produced by the hybridoma cell line deposited under ATCC Accession No.HB-12319 or an intact antibody having the binding characteristics of the deposited monoclonal antibody. In another embodiment the peptide is an intact soluble monoclonal antibody
A3.6B10
produced by the hybridoma cell line deposited under ATCC Accession No. HB-12318 or an intact antibody having the binding characteristics of the deposited monoclonal antibody. According to yet another embodiment the peptide is a humanized monoclonal antibody.
The peptide also may be a functionally active monoclonal antibody fragment or a functionally active polypeptide. In one embodiment the peptide is a monoclonal antibody fragment selected from the group consisting of an F(ab′)
2
fragment, an Fd fragment, and an Fab fragment. In another embodiment the peptide has a light chain CDR2 region selected from the group consisting of a CDR2
A3.4H2
or functional variant thereof of a monoclonal antibody produced by hybridoma A3.4H2 deposited under ATCC Accession No. HB-12319 and a CDR2
A3.6B10
or functional variant thereof of a monoclonal antibody produced by hybridoma A3.6B10 deposited under ATCC Accession No. HB-12318. According to another embodiment the peptide has a light chain CDR1 region selected from the group consisting of a CDR1
A3.4H2
or functional variant thereof of a monoclonal antibody produced by hybridoma A3.4H2 deposited under ATCC Accession No.
Greenfield Edward A.
Kuchroo Vijay K.
Brigham and Women's Hospital, Inc.
Gambel Phillip
Wolf Greenfield & Sacks P.C.
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