GL50 nucleic acids and uses therefor

Details GL50 nucleic acids and uses therefor GL50 nucleic acids and uses therefor

2000-09-21

2003-02-18

Gambel, Phillip (Department: 1644)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C536S023100, C536S023400, C435S069100, C435S252300, C435S358000, C435S320100

Reexamination Certificate

active

06521749

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 ligand 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 ligand, termed CTLA4 (CD152) 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 Krurnmel (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).
In the past, reports of the existence of additional members of the B7 costimulatory family have been controversial. The antibody BB-1, appeared to recognize a subset of cells greater than either B7-1 or B7-2 positive cells, arguing for the existence of another B7-family member, B7-3. The identity of B7-3 had been in part thought to be answered by expression cloning of T-cell receptor invariant chain using the BB-1 antibody. Although invariant chain is not related to the B7 family, this molecule facilitated a low degree of costimulation when assessed by T cell proliferation assays.
Very recently, a novel surface receptor termed ICOS was described which had sequence identity with CD28 (24%) and CTLA4 (17%) (Hutloff et al. (1999)
Nature
397:263; WO 98/38216). Unlike CD28, ICOS was shown to be upregulated on stimulated T cells and caused the secretion of a panel of cytokines distinct from those mediated by CD28 costimulation (Hutloff et al. (1999)
Nature
397:263).
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. USA
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 of novel nucleic acid molecules and polypeptides encoded by such nucleic acid molecules, referred to herein as GL50 molecules. Preferred GL50 molecules include antigens on the surface of professional antigen presenting cells (e.g., B lymphocytes, monocytes, dendritic cells, Langerhan cells) and other antigen presenting cells (e.g., keratinocytes, endothelial cells, astrocytes, fibroblasts, oligodendrocytes), which costimulate T cell proliferation, bind to costimulatory receptors ligands on T cells (e.g., CD28, CTLA4, and/or ICOS) and/or are bound by antibodies which recognize B7 family members, e.g., anti-GL50 antibodies.
The GL50 nucleic acid and polypeptide molecules of the present invention are useful, e.g., in modulating the immune response. Accordingly, in one aspect, this invention provides isolated nucleic acid molecules encoding GL50 polypeptides, as well as nucleic acid fragments suitable as primers or hybridization probes for the detection of GL50-encoding nucleic acids.
In one embodiment, a GL50 nucleic acid molecule of the invention is at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98% or more identical to a nucleotide sequence (e.g., to the entire length of the nucleotide sequence) including SEQ ID NO:1, 3, or 5, or a complement thereof.
In a preferred embodiment, the isolated nucleic acid molecule includes the nucleotide sequence shown SEQ ID NO:1, 3, or 5, or a complement thereof. In another preferred embodiment, an isolated nucleic acid molecule of the invention encodes the amino acid sequence of a GL50 polypeptide.
Another embodiment of the invention features nucleic acid molecules, preferably the GL50 nucleic acid molecules, which specifically detect the GL50 nucleic acid molecules relative to nucleic acid molecules encoding non-GL50 polypeptides. For example, in one embodiment, such a nucleic acid molecule is at least 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, or 800 nucleotides in length and hybridizes under stringent conditions to a nucleic acid molecule comprising the nucleotide sequence shown in SEQ ID NO:1, 3, or 5, or a complement thereof.
In other preferred embodiments, nucleic acid molecules of the invention encode naturally occurring allelic variants of a human GL50 polypeptide, wherein the nucleic acid molecules hybridize to a nucleic acid molecule which includes SEQ ID NO:1, 3, or 5 under stringent conditions.
Another embodiment of the invention provides an isolated nucleic acid molecule which is antisense to a GL50 nucleic acid molecule, e.g., the coding strand of a GL50 nucleic acid molecule.
Another as

Affiliated with

Also associated with

Rating

GL50 nucleic acids and uses therefor does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with GL50 nucleic acids and uses therefor, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and GL50 nucleic acids and uses therefor will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3145238