Isolated DNA molecules encoding RANK-L

Details Isolated DNA molecules encoding RANK-L Isolated DNA molecules encoding RANK-L

1997-12-22

2001-06-05

Eyler, Yvonne (Department: 1646)

Chemistry: molecular biology and microbiology

Micro-organism, tissue cell culture or enzyme using process...

Recombinant dna technique included in method of making a...

C435S320100, C435S325000, C435S252300, C435S254110, C536S023500, C530S350000

Reexamination Certificate

active

06242213

ABSTRACT:

TECHNICAL FIELD OF THE INVENTION
The present invention relates generally to the field of cytokines, and more specifically to cytokine receptor/ligand pairs having immunoregulatory activity.
BACKGROUND OF THE INVENTION
Efficient functioning of the immune system requires a fine balance between cell proliferation and differentiation and cell death, to ensure that the immune system is capable of reacting to foreign, but not self antigens. Integral to the process of regulating the immune and inflammatory response are various members of the Tumor Necrosis Factor (TNF) Receptor/Nerve Growth Factor Receptor superfamily (Smith et al.,
Science
248:1019; 1990). This family of receptors includes two different TNF receptors (Type I and Type II; Smith et al.,
supra
; and Schall et al.,
Cell
61:361, 1990), nerve growth factor receptor (Johnson et al.,
Cell
47:545, 1986), B cell antigen CD40 (Stamenkovic et al.,
EMBO J.
8:1403, 1989), CD27 (Camerini et al.,
J. Immunol.
147:3165, 1991), CD30 (Durkop et al.,
Cell
68:421, 1992), T cell antigen OX40 (Mallett et al.,
EMBO J.
9:1063, 1990), human
Fas
antigen (Itoh et al.,
Cell
66:233, 1991), murine 4-1BB receptor (Kwon et al.,
Proc. Natl. Acad. Sci. USA
86:1963, 1989) and a receptor referred to as Apoptosis-Inducing Receptor (AIR; U.S. Ser. No. 08/720,864, filed Oct. 4, 1996).
CD40 is a receptor present on B lymphocytes, epithelial cells and some carcinoma cell lines that interacts with a ligand found on activated T cells, CD40L (U.S. Ser. No. 08/249,189, filed May 24, 1994). The interaction of this ligand/receptor pair is essential for both the cellular and humoral immune response. Signal transduction via CD40 is mediated through the association of the cytoplasmic domain of this molecule with members of the TNF receptor-associated factors (TRAFs; Baker and Reddy,
Oncogene
12:1, 1996). It has recently been found that mice that are defective in TRAF3 expression due to a targeted disruption in the gene encoding TRAF3 appear normal at birth but develop progressive hypoglycemia and depletion of peripheral white cells, and die by about ten days of age (Xu et al.,
Immunity
5:407, 1996). The immune responses of chimeric mice reconstituted with TRAF3
-/-
fetal liver cells resemble those of CD40-deficient mice, although TRAF3
-/-
B cells appear to be functionally normal.
The critical role of TRAF3 in signal transduction may be in its interaction with one of the other members of the TNF receptor superfamily, for example, CD30 or CD27, which are present on T cells. Alternatively, there may be other, as yet unidentified members of this family of receptors that interact with TRAF3 and play an important role in postnatal development as well as in the development of a competent immune system. Identifying additional members of the TNF receptor superfamily would provide an additional means of regulating the immune and inflammatory response, as well as potentially providing further insight into post-natal development in mammals.
SUMMARY OF THE INVENTION
The present invention provides a counterstructure, or ligand, for a novel receptor referred to as RANK (for receptor activator of NF-&khgr;B), that is a member of the TNF superfamily. The ligand, which is referred to as RANKL, is a Type 2 transmembrane protein with an intracellular domain of less than about 50 amino acids, a transmembrane domain and an extracellular domain of from about 240 to 250 amino acids. Similar to other members of the TNF family to which it belongs, RANKL has a ‘spacer’ region between the transmembrane domain and the receptor binding domain that is not necessary for receptor binding. Accordingly, soluble forms of RANKL can comprise the entire extracellular domain or fragments thereof that include the receptor binding region.
RANK is a Type I transmembrane protein having 616 amino acid residues that is a member of the TNFR superfamily, and interacts with TRAF3. Triggering of RANK by over-expression, co-expression of RANK and membrane bound RANKL, or by soluble RANKL or agonistic antibodies to RANK, results in the upregulation of the transcription factor NF-&khgr;B, a ubiquitous transcription factor that is most extensively utilized in cells of the immune system.
These and other aspects of the present invention will become evident upon reference to the following detailed description of the invention.


REFERENCES:
patent: 5763223 (1998-06-01), Wiley
patent: 5843678 (1998-12-01), Boyle
patent: 6017729 (2000-01-01), Anderson et al.
patent: 0816380 A1 (1998-01-01), None
patent: WO 96/34095 (1996-10-01), None
patent: WO 97/23614 (1997-07-01), None
patent: WO 98/25958 (1998-06-01), None
patent: WO 98/46644 (1998-10-01), None
patent: WO 98/46751 (1998-10-01), None
Boyle v. Gorman and Mattson, Board of Patent Appeals and Interferences, Interference No. 104,336, Paper No. 39.
Yasuda et al.,Proc. Natl. Acad. Sci.95:3597; 1998.
Suda et al.,Endocr. Rev.13:66; 1992.
Suda et al.,Bone17:87S; 1995.
Suda et al., inEndocrine Review Monographs. eds. Bikle, D.D. & Negrovilar, A. (Endocrine Soc., Bethesda), vol. 4, pp. 266-270; 1995.
Lacey et al.,Cell93:165; 1998.
Anderson et al.,Nature 390:175-79; 1997.
Wong et al.,J. Biol. Chem. 272(40):25190-94, 1997.
Wiley et al.,Immunity 3(6):673-82, 1995.
Marra et al., The WashU-HHMI Mouse EST project, Accession No. AA170348, Feb. 16, 1997.*
Gray et al., Genetics 144(4):1601-1610, Accession AF012089, Dec. 1996.*
EMBL Database entry HS421358; Accession No. W74421, Jun. 21, 1996; Hillier et al.;Homo sapienscDNA clone 346544 contains Alu repetitive element.

Affiliated with

Also associated with

Rating

Isolated DNA molecules encoding RANK-L does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Isolated DNA molecules encoding RANK-L, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Isolated DNA molecules encoding RANK-L will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2477531