Antibodies to DcR3 Polypeptide, a TNFR Homolog

Details Antibodies to DcR3 Polypeptide, a TNFR Homolog Antibodies to DcR3 Polypeptide, a TNFR Homolog

2001-06-28

2004-07-20

Spector, Lorraine (Department: 1646)

Drug, bio-affecting and body treating compositions

Immunoglobulin, antiserum, antibody, or antibody fragment,...

C424S133100, C424S138100, C424S141100, C424S143100, C530S387100, C530S387300, C530S387700, C530S387900, C530S388220, C530S389100, C530S389700, C530S350000, C530S388150, C435S069700

Reexamination Certificate

active

06764679

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates generally to the identification and isolation of novel DNA and to the recombinant production of novel polypeptides, designated herein as “DcR3”.
BACKGROUND OF THE INVENTION
Various molecules, such as tumor necrosis factor-&agr; (“TNF-&agr;”), tumor necrosis factor-&bgr; (“TNF-&bgr;” or “lymphotoxin”), CD30 ligand, CD27 ligand, CD40 ligand, OX-40 ligand, 4-1BB ligand, Fas ligand (also referred to as Apo-1 ligand or CD95 ligand), and Apo-2 ligand (also referred to as TRAIL) have been identified as members of the tumor necrosis factor (“TNF”) family of cytokines [See, e.g., Gruss and Dower,
Blood,
85:3378-3404 (1995); Wiley et al.,
Immunity,
3:673-682 (1995); Pitti et al.,
J. Biol. Chem.,
271:12687-12690 (1996)]. Among these molecules, TNF-&agr;, TNF-&bgr;, CD30 ligand, 4-1BB ligand, Fas ligand, and Apo-2 ligand (TRAIL) have been reported to be involved in apoptotic cell death. Both TNF-&agr; and TNF-&bgr; have been reported to induce apoptotic death in susceptible tumor cells [Schmid et al.,
Proc. Natl. Acad. Sci.,
83:1881 (1986); Dealtry et al.,
Eur. J. Immunol.,
17:689 (1987)]. Zheng et al. have reported that TNF-&agr; is involved in post-stimulation apoptosis of CD8-positive T cells [Zheng et al.,
Nature,
377:348-351 (1995)]. Other investigators have reported that CD30 ligand may be involved in deletion of self-reactive T cells in the thymus [Amakawa et al., Cold Spring Harbor Laboratory Symposium on Programmed Cell Death, Abstr. No. 10, (1995)].
Fas ligand appears to regulate primarily three types of apoptosis: (a) activation-induced cell death (AICD) of mature T lymphocytes; (b) elimination of inflammatory cells from immune-privileged sites; and (c) killing of damaged cells by cytotoxic lymphocytes [Nagata,
Cell,
88:355 (1997)]. It has been reported that T cell AICD assists in shutting down the host's immune response once an infection has been cleared. Repeated stimulation of the T cell receptor (TCR) by antigen induced expression of Fas ligand and Fas on the surface of T helper cells; subsequently Fas ligand engages Fas and can trigger apoptosis in the activated lymphocytes, leading to their elimination. Immune-privileged sites include tissues such as the eye, brain or testis, in which inflammatory immune responses can perturb function. Cells in immune privileged sites appear to constitutively express Fas ligand, and eliminate infiltrating leukocytes that express Fas through Fas dependent apoptosis. Certain cancers including melanomas [Hahne et al.,
Science,
274:1363 (1996)] and hepatocellular carcinomas [Strand et al.,
Nature Med.,
2:1361-1366 (1996)] use a similar Fas ligand-dependent mechanism to evade immune survaillance. Natural killer (NK) cells and cytotoxic T lymphocytes have been reported to eliminate cells that have been damaged by viral or bacterial infection or by oncogenic transformation by at least two pathways. One pathway involves release of perforin and granzymes, and an alternative pathway involves expression of Fas ligand and induction of apoptosis by engagement of Fas on target cells [Nagata, supra; Moretta,
Cell,
90:13 (1997)].
Mutations in the mouse Fas/Apo-1 receptor or ligand genes (called 1pr and gld, respectively) have been associated with some autoimmune disorders, indicating that Fas ligand may play a role in regulating the clonal deletion of self-reactive lymphocytes in the periphery [Krammer et al.,
Curr. Op. Immunol.,
6:279-289 (1994); Nagata et al.,
Science,
267:1449-1456 (1995)]. Fas ligand is also reported to induce post-stimulation apoptosis in CD4-positive T lymphocytes and in B lymphocytes, and may be involved in the elimination of activated lymphocytes when their function is no longer needed [Krammer et al., supra; Nagata et al., supra]. Agonist mouse monoclonal antibodies specifically binding to the Fas receptor have been reported to exhibit cell killing activity that is comparable to or similar to that of TNF-&agr; [Yonehara et al.,
J. Exp. Med.,
169:1747-1756 (1989)].
Induction of various cellular responses mediated by such TNF family cytokines is believed to be initiated by their binding to specific cell receptors. Two distinct TNF receptors of approximately 55-kDa (TNFR1) and 75-kDa (TNFR2) have been identified [Hohmann et al.,
J. Biol. Chem.,
264:14927-14934 (1989); Brockhaus et al.,
Proc. Natl. Acad. Sci.,
87:3127-3131 (1990); EP 417,563, published Mar. 20, 1991] and human and mouse cDNAs corresponding to both receptor types have been isolated and characterized [Loetscher et al.,
Cell,
61:351 (1990); Schall et al.,
Cell,
61:361 (1990); Smith et al.,
Science,
248:1019-1023 (1990); Lewis et al.,
Proc. Natl. Acad. Sci.,
88:2830-2834 (1991); Goodwin et al.,
Mol. Cell. Biol.,
11:3020-3026 (1991)]. Extensive polymorphisms have been associated with both TNF receptor genes [see, e.g., Takao et al.,
Immunogenetics,
37:199-203 (1993)]. Both TNFRs share the typical structure of cell surface receptors including extracellular, transmembrane and intracellular regions. The extracellular portions of both receptors are found naturally also as soluble TNF-binding proteins [Nophar, Y. et al.,
EMBO J.,
9:3269 (1990); and Kohno, T. et al.,
Proc. Natl. Acad. Sci. U.S.A.,
87:8331 (1990)]. More recently, the cloning of recombinant soluble TNF receptors was reported by Hale et al. [
J. Cell. Biochem. Supplement
15F, 1991, p. 113 (P424)].
The extracellular portion of type 1 and type 2 TNFRs (TNFR1 and TNFR2) contains a repetitive amino acid sequence pattern of four cysteine-rich domains (CRDs) designated 1 through 4, starting from the NH
2
-terminus. Each CRD is about 40 amino acids long and contains 4 to 6 cysteine residues at positions which are well conserved [Schall et al., supra; Loetscher et al., supra; Smith et al., supra; Nophar et al., supra; Kohno et al., supra]. In TNFR1, the approximate boundaries of the four CRDs are as follows: CRD1-amino acids 14 to about 53; CRD2-amino acids from about 54 to about 97; CRD3-amino acids from about 98 to about 138; CRD4-amino acids from about 139 to about 167. In TNFR2, CRD1 includes amino acids 17 to about 54; CRD2-amino acids from about 55 to about 97; CRD3-amino acids from about 98 to about 140; and CRD4-amino acids from about 141 to about 179 [Banner et al.,
Cell,
73:431-445 (1993)]. The potential role of the CRDs in ligand binding is also described by Banner et al., supra.
A similar repetitive pattern of CRDs exists in several other cell-surface proteins, including the p75 nerve growth factor receptor (NGFR) [Johnson et al.,
Cell,
47:545 (1986); Radeke et al.,
Nature,
325:593 (1987)], the B cell antigen CD40 [Stamenkovic et al.,
EMBO J.,
8:1403 (1989)], the T cell antigen OX40 [Mallett et al.,
EMBO J.,
9:1063 (1990)] and the Fas antigen [Yonehara et al., supra and Itoh et al.,
Cell,
66:233-243 (1991)]. CRDs are also found in the soluble TNFR (sTNFR)-like T2 proteins of the Shope and myxoma poxviruses [Upton et al.,
Virology,
160:20-29 (1987); Smith et al.,
Biochem. Biophys. Res. Commun.,
176:335 (1991); Upton et al.,
Virology,
184:370 (1991)]. Optimal alignment of these sequences indicates that the positions of the cysteine residues are well conserved. These receptors are sometimes collectively referred to as members of the TNF/NGF receptor superfamily. Recent studies on p75NGFR showed that the deletion of CRD1 [Welcher, A. A. et al.,
Proc. Natl. Acad. Sci. USA,
88:159-163 (1991)] or a 5-amino acid insertion in this domain [Yan, H. and Chao, M. V.,
J. Biol. Chem.,
266:12099-12104 (1991)] had little or no effect on NGF binding [Yan, H. and Chao, M. V., supra]. p75 NGFR contains a proline-rich stretch of about 60 amino acids, between its CRD4 and transmembrane region, which is not involved in NGF binding [Peetre, C. et

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