Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Monoclonal antibody or fragment thereof
Reexamination Certificate
1999-10-22
2003-08-12
Gambel, Phillip (Department: 1644)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Monoclonal antibody or fragment thereof
C424S130100, C424S139100, C424S141100, C424S143100, C424S144100, C424S173100, C530S387100, C530S388100, C530S387300, C530S388200, C530S388220, C530S388700, C530S388730, C435S326000, C435S331000, C435S332000, C435S334000, C435S343000, C435S343100, C435S346000
Reexamination Certificate
active
06605279
ABSTRACT:
BACKGROUND OF THE INVENTION
To induce antigen-specific T cell activation and clonal expansion, two signals provided by antigen-presenting cells (APCs) must be delivered to the surface of 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; Williams, I. R. and Unanue, E. R. (1990)
J. Immunol
. 145, 85-93). The first signal, which confers specificity to the immune response, is mediated 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 (Schwartz, R. H. (1990)
Science
248, 1349-1356). 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).
Considerable evidence suggests that the B7 protein, expressed on APCs, is one such critical costimulatory molecule (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; Koulova, L., et al., (1991)
J. Exp. Med
173, 759-762; Reiser, H;, et al. (1992)
Proc. Natl. Acad Sci. USA
. 89, 271-275; Linsley, P. S. et al. (1990)
Proc. Natl. Acad. Sci. USA
. 87, 5031-5035; Freeman, G. J. et al. (1991)
J. Exp. Med
. 174,625-631.). B7 is the counter-receptor for two ligands expressed on T lymphocytes. The first ligand, termed CD28, is constitutively expressed on resting T cells and increases after activation. After signaling through the T cell receptor, ligation of CD28 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; Thompson, C. B., et al. (1989)
Proc. Natl. Acad. Sci. USA
. 86, 1333-1337; June, C. H., et al. (1990)
Immunol. Today
. 11, 211-6; Harding, F. A., et al. (1992)
Nature
. 356, 607-609.). The second ligand, termed CTLA4 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, 267-15 270). DNA sequences encoding the human and murine CTLA4 protein are described in Dariavach, et al. (1988)
Eur. J. Immunol
. 18(12), 1901-1905; Brunet, J. F., et al. (1987) supra; Brunet, J. F. et al. (1988)
Immunol. Rev
. 103:21-36; and Freeman, G. J., et al. (1992)
J. Immunol
. 149, 3795-3801. Although B7 has a higher affinity for CTLA4 than for CD28 (Linsley, P. S., et al., (1991)
J. Exp. Med
. 174, 561-569), the function of CTLA4 is still unknown.
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 humans 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 B7:CD28/CTLA4 pathway offers great potential to stimulate or suppress immune responses in humans.
SUMMARY OF THE INVENTION
This invention pertains to isolated nucleic acids encoding novel molecules which costimulate T cell activation. Preferred costimulatory molecules include antigens on the surface of B lymphocytes, professional antigen presenting cells (e.g., monocytes, dendritic cells, Langerhan cells) and other cells (e.g., keratinocytes, endothelial cells, astrocytes, fibroblasts, oligodendrocytes) which present antigen to immune cells, and which bind either CTLA4, CD28, both CTLA4 and CD28 or other known or as yet undefined receptors on immune cells. Such costimulatory molecules are referred to herein as CTLA4/CD28 binding counter-receptors or B lymphocyte antigens, and are capable of providing costimulation to activated T cells to thereby induce T cell proliferation and/or cytokine secretion. Preferred B lymphocyte antigens include B7-2 and B7-3 and soluble fragments or derivatives thereof which bind CTLA4 and/or CD28 and have the ability to inhibit or induce costimulation of immune cells. In one embodiment, an isolated nucleic acid which encodes a peptide having the activity of the human B7-2 B lymphocyte antigen is provided. Preferably, the nucleic acid is a cDNA molecule having a nucleotide sequence encoding human B7-2, as shown in
FIG. 8
(SEQ ID. NO:1). In another embodiment, the nucleic acid is a cDNA molecule having a nucleotide sequence encoding murine B7-2, as shown in
FIG. 14
(SEQ ID NO:22).
The invention also features nucleic acids which encode a peptide having B7-2 activity and at least about 50%, more preferably at least about 60% and most preferably at least about 70% homologous with an amino acid sequence shown in
FIG. 8
(SEQ ID NO:2) or an amino acid sequence shown in
FIG. 14
(SEQ ID NO:23). Nucleic acids which encode peptides having B7-2 activity and at least about 80%, more preferably at least about 90%, more preferably at least about 95% and most preferably at least about 98% or at least about 99% homologous with an amino acid sequence shown in
FIG. 8
(SEQ ID NO:2) or an amino acid sequence shown in
FIG. 14
(SEQ ID NO:23) are also within the scope of the invention. In another embodiment, the peptide having B7-2 activity is encoded by a nucleic acid which hybridizes under high or low stringency conditions to a nucleic acid which encodes a peptide having an amino acid sequence of
FIG. 8
(SEQ ID NO:2) or a peptide having an amino acid sequence shown in
FIG. 14
(SEQ ID NO:23).
The invention further pertains to an isolated nucleic acid comprising a nucleotide sequence encoding a peptide having B7-2 activity and having a length of at least 20 amino acid residues. Peptides having B7-2 activity and consisting of at least 40 amino acid residues in length, at least 60 amino acid residues in length, at least 80 amino acid residues in length, at least 100 amino acid residues in length or at least 200 or more amino acid residues in length are also within the scope of this invention. Particularly preferred nucleic acids encode a peptide having B7-2 activity, a length of at least 20 amino acid residues or more and at least 50% or greater homology (preferably at least 70%) with a sequence shown in
FIG. 8
(SEQ ID NO:2).
In one preferred embodiment, the invention features an isolated DNA encoding a peptide having B7-2 activity and an amino acid sequence represented by a formula:
X
n
-Y-Z
m
In the formula, Y consists essentially of amino acid residues 24-245 of the sequence shown in
FIG. 8
(SEQ ID NO:2). X
n
and Z
m
are additional amino acid residue(s) linked to Y by an amide bond. X
n
and Z
m
are amino acid residues selected from amino acid residues contiguous to Y in the amino acid sequence shown in
Freeman Gordon J.
Gray Gary S.
Nadler Lee M.
Gambel Phillip
Genetics Institute Inc.
Lahive & Cockfield LLP
Mandragouras Esq. Amy E.
Williams, Esq. Megan H.
LandOfFree
Therapeutic compositions for inhibiting the interactions of... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Therapeutic compositions for inhibiting the interactions of..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Therapeutic compositions for inhibiting the interactions of... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3084114