Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues
Reexamination Certificate
1998-05-14
2003-07-15
Eyler, Yvonne (Department: 1646)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
C435S069100, C435S007200, C536S023500
Reexamination Certificate
active
06593456
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the purification and characterization of factors that substantially alter tumor necrosis factor (TNF) receptor (TNF-R) releasing enzyme (TRRE) activity, and methods of use thereof. Modulation of TRRE levels indirectly modulates effective levels of TNF. The invention further relates to methods of treatment of pathological conditions caused or exacerbated by altered levels or activity of TNF such as inflammatory conditions including autoimmune diseases, infections, septic shock, obesity, cachexia, and conditions that are associated with decreased effective levels or activity of TNF such as cancer.
BACKGROUND OF THE INVENTION
Tumor necrosis factor (TNF or TNF-&agr;) and lymphotoxin (LT or TNF-&bgr;) are related cytokines that share 40 percent amino acid (AA) sequence homology. Old (1987)
Nature
330:602-603. These cytokines are released mainly by macrophages, monocytes and natural killer (NK) cells in response to broad immune reactions. Gorton and Galli (1990)
Nature
346:274-276; and Dubravec et al. (1990)
Proc. Natl. Acad. Sci. USA
87:6758-6761. Although initially discovered as agents inducing hemorrhagic necrosis of tumors, these cytokines have been shown to have essential roles in both the inductive and effector phases of immune reactions and inflammation. The two cytokines cause a broad spectrum of effects on cells in vitro and tissues in vivo, including: (i) vascular thrombosis and tumor necrosis; (ii) inflammation; (iii) activation of macrophages and neutrophils; (iv) leukocytosis; (v) apoptosis; and (vi) shock. Beretz et al. (1990)
Biorheology
27:455-460; Driscoll (1994)
Exp. Lung Res.
20:473-490; Ferrante (1992)
Immunol. Ser.
57:417-436; Golstein et al. (1991)
Immunol. Rev.
121:29-65; and van der Poll and Lowry (1995)
Shock
3:1-12. For a review of the mechanism of action of TNF, see Massague (1996)
Cell
85:947-950. TNF has been associated with a variety of disease states including various forms of cancer, arthritis, psoriasis, endotoxic shock, sepsis, autoimmune diseases, infections, obesity, and cachexia. Attempts have been made to alter the course of a disease by treating the patient with TNF inhibitors. These attempts have met with varying degrees of success. For example, oxpentifylline did not alter the course of Crohn's disease, a chronic inflammatory bowel disease. Bauditz et al. (1997)
Gut
40:470-4. However, the TNF inhibitor dexanabinol provided protection against TNF following traumatic brain injury. Shohami et al. (1997)
J. Neuroimmun.
72:169-77.
Cachexia is pathological weight loss generally associated with anorexia, weakness, anemia, asthenia, and loss of body lipid stores and skeletal muscle protein. This state often accompanies burns, trauma, infection, and neoplastic diseases. Lawson et al. (1982)
Annu. Rev. Nutr.
2:277-301; Argiles et al. (1988)
Mol. Cell. Biochem.
81:3-17; and Ogiwara et al. (1994)
J. Surg. Oncol.
57:129-133. TNF concentrations are elevated in many patients with cachexia. Scuderi et al. (1986)
Lancet
2:1364-65; Grau et al. (1987)
Science
237:1210-1212; and Waage et al. (1986)
Scand. J Immunol.
24:739-743. TNF inhibits collagen &agr;I gene expression and wound healing in a murine model of cachexia. Buck et al. (1996)
Am. J. Pathol.
149:195-204. In septicemia (the invasion of bacteria into the bloodstream), increased endotoxin concentrations may raise TNF levels, causing cachexia. Beutler et al. (1985)
Science
229:869-871; Tracey et al. (1987)
Nature
330:662-664; and Michie et al. (1988)
New Engl. J. Med
318:1481-1486. During cachexia, the loss of white adipose tissue is caused by the decreased activity of lipoprotein lipase (LPL); TNF lowers the activity of this enzyme. Price et al. (1986)
Arch. Biochem. Biophys.
251:738-746; Cornelius et al. (1988)
Biochem. J.
249:765-769; Fried et al. (1989)
J. Lipid. Res.
30:1917-1923; Semb et al. (1987)
J. Biol. Chem.
262:8390-8394; and Evans et al. (1988)
Biochem. J.
256:1055-1058. Fat tissue loss is also associated with an increase in lipase activity and inhibition of glucose transport; TNF is also linked to both of these changes. Kawakami et al. (1987)
J. Biochem.
331-338; Feingold et al. (1992)
Endocrinology
130:10-16; and Hauner et al. (1995)
Diabetologia
38:764-771. TNF mediates hypertriglyceridaemia associated with cachexia. Dessi et al. (1995)
Br. J Cancer
72:1138-43. TNF also participates in the protein wasting, loss of skeletal muscle and loss of nitrogen associated with cachexia. Costelli et al. (1993)
J. Clin. Invest.
92:2783-2789; Flores et al. (1989)
J. Clin. Invest.
83:1614-1622; Goodman (1991)
Am. J. Physiol.
260:E727-730; Zamir et al. (1992)
Arch. Surg.
127:170-174; Llovera et al. (1993)
J. Natl. Cancer Inst.
USA 85:1334-1339; and Garcia-Martinez et al. (1993)
FEBS Lett.
323:211-214.
Cachexia is also associated with TNF expression in cancer patients. TNF is linked to the three factors contributing to body weight control: intake, expenditure, and storage of energy. Administration of either TNF or IL-1, for example, induces a decrease in food intake. Rothwell (1993)
Int. J. Obesity
17:S98-S101; Arbos et al. (1992)
Mol. Cell. Biochem.
1 12:53-59; Fargeas et al. (1993)
Gastroenterology
104:377-383; Plata-Salaman et al. (1994)
Am. J. Physiol.
266:R1711-1715; Schwartz et al. (1995)
Am. J. Physiol.
269:R949-957; and Oliff et al. (1987)
Cell
50:555-563. Interestingly, TNF may have key roles in both extremes of weight problems. Abnormalities in its activity may lead to obesity; changes in its production result in the opposite effect, cachexia. Argilés et al. (1997)
FASEB J.
11:743-751.
TNF has additional, related roles. It is involved in thermogenesis, particularly nonshivering thermogenesis in brown adipose tissue (BAT), a tissue with an elevated level in cachexia. Nicholls (1983)
Biosci. Rep.
3:431-441; Rothwell (1993)
Int. J. Obesity
17:S98-S101; Bianchi et al. (1989)
Horm. Metab. Res.
21:1 1; and Oudart et al. (1995)
Can. J. Physiol. Pharmacol.
73:1625-1631. TNF has also been implicated in non-insulin-dependent (type II) diabetes. Hotamisligil et al. (1995)
J. Clin. Invest.
95:2409-2415; Arner (1996)
Diabetes Metab.
13:S85-S86; Spiegelman et al. (1993)
Cell
73:625-627; Saghizadeh et al. (1996)
J. Clin. Invest.
97:1111-16; and Hofmann et al. (1994)
Endocrinology
134:264-270.
These data help explain how TNF mediates the opposite effects of obesity and cachexia. TNF has functional similarities to leptin, which has been proposed to be an “adipostat.” Zhang et al. (1994)
Nature
372:425-432; Phillips et al. (1996)
Nature Genet.
13:18-19; and Madej et al. (1995)
FEBS Lett.
373:13-18. Like leptin, TNF is expressed and secreted by adipocytes and can travel to the brain. TNF administration also results in an increase in circulating leptin concentrations. Grunfeld et al. (1996)
J. Clin. Invest.
97:2152-57. It is possible to reconcile the participation of TNF in obesity and cachexia. TNF can be considered one of many signals coming from adipose tissue that participate in the feedback mechanism that informs the hypothalamic center about the state of the adipocyte energy depot. TNF probably counteracts excessive energy intake and is able to stimulate thermogenesis either directly or by increasing sympathetic activity. TNF released by adipose tissue will also stimulate lipolysis, decrease LPL activity, decrease the expression of the glucose transporter GLUT4, and inhibit lipogenesis in the adipocyte, thus contributing to the maintenance (but not increased fat deposition) of the adipose tissue mass. In cachexia, however, the situation is different. A high production of TNF by activated macrophages (as a result of a tumor or an infection) contributes to anorexia, increased thermogenesis, and adipose tissue dissolution. However, a pathological state can be created where there is an excess of TNF informing the brain that adipose tissue needs dissolution. The two situations can thus be reconciled: in cachexia there is a pathological overproduction
Gatanaga Tetsuya
Granger Gale A.
Bozicevic Field & Francis LLP
Eyler Yvonne
Francis Carol L.
Murphy Joseph
The Regents of the University of California
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