Apo-2-receptor

Details Apo-2-receptor Apo-2-receptor

1998-05-14

2002-01-29

Spector, Lorraine (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, C435S252300, C435S361000, C435S254200, C435S325000, C536S023500, C530S350000

Reexamination Certificate

active

06342369

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates generally to the identification, isolation, and recombinant production of novel polypeptides, designated herein as Apo-2, and to anti-Apo-2 antibodies.
BACKGROUND OF THE INVENTION
Apoptosis or “Programmed Cell Death”
Control of cell numbers in mammals is believed to be determined, in part, by a balance between cell proliferation and cell death. One form of cell death, sometimes referred to as necrotic cell death, is typically characterized as a pathologic form of cell death resulting from some trauma or cellular injury. In contrast, there is another, “physiologic” form of cell death which usually proceeds in an orderly or controlled manner. This orderly or controlled form of cell death is often referred to as “apoptosis” [see, e.g., Barr et al.,
Bio/Technology
, 12:487-493 (1994); Steller et al.,
Science
, 267:1445-1449 (1995)]. Apoptotic cell death naturally occurs in many physiological processes, including embryonic development and clonal selection in the immune system [Itoh et al.,
Cell
, 66:233-243 (1991)]. Decreased levels of apoptotic cell death have been associated with a variety of pathological conditions, including cancer, lupus, and herpes virus infection [Thompson,
Science
, 267:1456-1462 (1995)]. Increased levels of apoptotic cell death may be associated with a variety of other pathological conditions, including AIDS, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, retinitis pigmentosa, cerebellar degeneration, aplastic anemia, myocardial infarction, stroke, reperfusion injury, and toxin-induced liver disease [see, Thompson, supra].
Apoptotic cell death is typically accompanied by one or more characteristic morphological and biochemical changes in cells, such as condensation of cytoplasm, loss of plasma membrane microvilli, segmentation of the nucleus, degradation of chromosomal DNA or loss of mitochondrial function. A variety of extrinsic and intrinsic signals are believed to trigger or induce such morphological and biochemical cellular changes [Raff,
Nature
, 356:397-400 (1992); Steller, supra; Sachs et al.,
Blood
, 82:15 (1993)]. For instance, they can be triggered by hormonal stimuli, such as glucocorticoid hormones for immature thymocytes, as well as withdrawal of certain growth factors [Watanabe-Fukunaga et al.,
Nature
, 356:314-317 (1992)]. Also, some identified oncogenes such as myc, rel, and E1A, and tumor suppressors, like p53, have been reported to have a role in inducing apoptosis. Certain chemotherapy drugs and some forms of radiation have likewise been observed to have apoptosis-inducing activity [Thompson, supra].
TNF Family of Cytokines
Various molecules, such as tumor necrosis factor-&agr; (“TNF-&agr;”), tumor necrosis factor-&agr; (“TNF-&bgr;” or “lymphotoxin”), CD30 ligand, CD27 ligand, CD40 ligand, OX-40 ligand, 4-1BB ligand, Apo-1 ligand (also referred to as Fas 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); WO 97/01633 published Jan. 16, 1997]. Among these molecules, TNF-&agr;, TNF-&bgr;, CD30 ligand, 4-1BB ligand, Apo-1 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)].
Mutations in the mouse Fas/Apo-1 receptor or ligand genes (called lpr and gld, respectively) have been associated with some autoimmune disorders, indicating that Apo-1 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)]. Apo-1 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 Apo-1 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)].
TNF Family of Receptors
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)]. The cloning of recombinant soluble TNF receptors was reported by Hale et al. [
J. Cell. Biochem. Supplement
15
F
, 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
, 73:431-435 (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 [Mallet et al.,
EMBO J
., 9:1063 (1990)] and the Fas antigen [Yonehara et al., supra and Itoh et al., supra]. CRDs are also found in the soluble TNFR (sTNFR)-like T2 proteins of the S

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