Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Blood proteins or globulins – e.g. – proteoglycans – platelet...
Reexamination Certificate
2000-06-08
2002-06-11
Kunz, Gary L. (Department: 1646)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Blood proteins or globulins, e.g., proteoglycans, platelet...
C530S300000, C530S324000, C530S388100, C530S388230, C530S351000, C435S069500, C435S007100
Reexamination Certificate
active
06403770
ABSTRACT:
The present invention relates to a novel cytokine which has been designated Neutrokine-alpha (“Neutrokine-alpha”). In addition, an apparent splicing variant of Neutrokine-alpha has been identified and designated Neutrokine-alphaSV. In specific embodiments, the present invention provides nucleic acid molecules encoding Neutrokine-alpha and Neutrokine-alphaSV polypeptides. In additional embodiments, Neutrokine-alpha and Neutrokine-alphaSV polypeptides are also provided, as are vectors, host cells and recombinant methods for producing the same.
RELATED ART
Human tumor necrosis factors (TNF-alpha) and (TNF-beta, or lymphotoxin) are related members of a broad class of polypeptide mediators, which includes the interferons, interleukins and growth factors, collectively called cytokines (Beutler, B. and Cerami, A.,
Annu. Rev. Immunol
. 7:625-655 (1989)). Sequence analysis of cytokine receptors has defined several subfamilies of membrane proteins (1) the Ig superfamily, (2) the hematopoietin (cytokine receptor superfamily) and (3) the tumor necrosis factor (TNF)
erve growth factor (NGF) receptor superfamily (for review of TNF superfamily see, Gruss and Dower,
Blood
85(12):3378-3404 (1995) and Aggarwal and Natarajan,
Eur. Cytokine Netw
., 7(2):93-124 (1996)). The TNF/NGF receptor superfamily contains at least 10 different proteins. Gruss and Dower, supra. Ligands for these receptors have been identified and belong to at least two cytokine superfamilies. Gruss and Dower, supra.
Tumor necrosis factor (a mixture of TNF-alpha and TNF-beta) was originally discovered as a result of its anti-tumor activity, however, now it is recognized as a pleiotropic cytokine capable of numerous biological activities including apoptosis of some transformed cell lines, mediation of cell activation and proliferation and also as playing important roles in immune regulation and inflammation.
To date, known members of the TNF-ligand superfamily include TNF-alpha, TNF-beta (lymphotoxin-alpha), LT-beta, OX40L, Fas ligand, CD30L, CD27L, CD40L and 4-IBBL. The ligands of the TNF ligand superfamily are acidic, TNF-like molecules with approximately 20% sequence homology in the extracellular domains (range, 12%-36%) and exist mainly as membrane-bound forms with the biologically active form being a trimeric/multimeric complex. Soluble forms of the TNF ligand superfamily have only been identified so far for TNF, LT-beta, and Fas ligand (for a general review, see Gruss, H. and Dower, S. K.,
Blood
, 85(12):3378-3404 (1995)), which is hereby incorporated by reference in its entirety. These proteins are involved in regulation of cell proliferation, activation, and differentiation, including control of cell survival or death by apoptosis or cytotoxicity (Armitage, R. J.,
Curr. Opin. Immunol
. 6:407 (1994) and Smith, C. A.,
Cell
75:959 (1994)).
Tumor necrosis factor-alpha (TNF-alpha; also termed cachectin; hereinafter “TNF”) is secreted primarily by monocytes and macrophages in response to endotoxin or other stimuli as a soluble homotrimer of 17 kDa protein subunits (Smith, R. A. et al.,
J. Biol. Chem
. 262:6951-6954 (1987)). A membrane-bound 26 kD precursor form of TNF has also been described (Kriegler, M. et al.,
Cell
53:45-53 (1988)).
Accumulating evidence indicates that TNF is a regulatory cytokine with pleiotropic biological activities. These activities include: inhibition of lipoprotein lipase synthesis (“cachectin” activity) (Beutler, B. et al.,
Nature
316:552 (1985)), activation of polymorphonuclear leukocytes (Klebanoff, S. J. et al.,
J. Immunol
. 136:4220 (1986); Perussia, B., et al.,
J. Immunol
. 138:765 (1987)), inhibition of cell growth or stimulation of cell growth (Vilcek, J. et al.,
J. Exp. Med
. 163:632 (1986); Sugarman, B. J. et al.,
Science
230:943 (1985); Lachman, L. B. et al.,
J. Immunol
. 138:2913 (1987)), cytotoxic action on certain transformed cell types (Lachman, L. B. et al., supra; Darzynkiewicz, Z. et al.,
Canc. Res
. 44:83 (1984)), antiviral activity (Kohase, M. et al.,
Cell
45:659 (1986); Wong, G. H. W. et al.,
Nature
323:819 (1986)), stimulation of bone resorption (Bertolini, D. R. et al.,
Nature
319:516 (1986); Saklatvala, J.,
Nature
322:547 (1986)), stimulation of collagenase and prostaglandin E2 production (Dayer, J.-M. et al.,
J. Exp. Med
. 162:2163 (1985)); and immunoregulatory actions, including activation of T cells (Yokota, S. et al.,
J. Immunol
. 140:531 (1988)), B cells (Kehrl, J. H. et al.,
J. Exp. Med
. 166:786 (1987)), monocytes (Philip, R. et al.,
Nature
323:86 (1986)), thymocytes (Ranges, G. E. et al.,
J. Exp. Med
. 167:1472 (1988)), and stimulation of the cell-surface expression of major histocompatibility complex (MHC) class I and class II molecules (Collins, T. et al.,
Proc. Natl. Acad. Sci. USA
83:446 (1986); Pujol-Borrel, R. et al.,
Nature
326:304 (1987)).
TNF is noted for its pro-inflammatory actions which result in tissue injury, such as induction of procoagulant activity on vascular endothelial cells (Pober, J. S. et al.,
J. Immunol
. 136:1680 (1986)), increased adherence of neutrophils and lymphocytes (Pober, J. S. et al.,
J. Immunol
. 138:3319 (1987)), and stimulation of the release of platelet activating factor from macrophages, neutrophils and vascular endothelial cells (Camussi, G. et al.,
J. Exp. Med
. 166:1390 (1987)).
Recent evidence implicates TNF in the pathogenesis of many infections (Cerami, A. et al.,
Immunol. Today
9:28 (1988)), immune disorders, neoplastic pathology, e.g., in cachexia accompanying some malignancies (Oliff, A. et al.,
Cell
50:555 (1987)), and in autoimmune pathologies and graft-versus host pathology (Piguet, P.-F. et al.,
J. Exp. Med
. 166:1280 (1987)). The association of TNF with cancer and infectious pathologies is often related to the host's catabolic state. A major problem in cancer patients is weight loss, usually associated with anorexia. The extensive wasting which results is known as “cachexia” (Kern, K. A. et al.
J. Parent. Enter. Nutr
. 12:286-298 (1988)). Cachexia includes progressive weight loss, anorexia, and persistent erosion of body mass in response to a malignant growth. The cachectic state is thus associated with significant morbidity and is responsible for the majority of cancer mortality. A number of studies have suggested that TNF is an important mediator of the cachexia in cancer, infectious pathology, and in other catabolic states.
TNF is thought to play a central role in the pathophysiological consequences of Gram-negative sepsis and endotoxic shock (Michie, H. R. et al.,
Br. J. Surg
. 76:670-671 (1989); Debets, J. M. H. et al.,
Second Vienna Shock Forum
, p.463-466 (1989); Simpson, S. Q. et al.,
Crit. Care Clin
. 5:27-47 (1989)), including fever, malaise, anorexia, and cachexia. Endotoxin is a potent monocyte/macrophage activator which stimulates production and secretion of TNF (Kornbluth, S. K. et al.,
J. Immunol
. 137:2585-2591 (1986)) and other cytokines. Because TNF could mimic many biological effects of endotoxin, it was concluded to be a central mediator responsible for the clinical manifestations of endotoxin-related illness. TNF and other monocyte-derived cytokines mediate the metabolic and neurohormonal responses to endotoxin (Michie, H. R. et al.,
N. Eng. J. Med
. 318:1481-1486 (1988)). Endotoxin administration to human volunteers produces acute illness with flu-like symptoms including fever, tachycardia, increased metabolic rate and stress hormone release (Revhaug, A. et al.,
Arch. Surg
. 123:162-170 (1988)). Elevated levels of circulating TNF have also been found in patients suffering from Gram-negative sepsis (Waage, A. et al.,
Lancet
1:355-357 (1987); Hammerle, A. F. et al.,
Second Vienna Shock Forum
p. 715-718 (1989); Debets, J. M. H. et al.,
Crit. Care Med
. 17:489-497 (1989); Calandra, T. et al.,
J. Infec. Dis
. 161:982-987 (1990)).
Passive immunotherapy directed at neutralizing TNF may have a beneficial effect in Gram-negative sepsis and endotoxemia, based on the increased TNF production and elevated TNF levels in these pathology states,
Ebner Reinhard
Ni Jian
Rosen Craig A.
Yu Guo-Liang
Human Genome Sciences Inc.
Human Genome Sciences Inc.
Kunz Gary L.
Prasad Sarada C
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