Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving hydrolase
Reexamination Certificate
2000-05-02
2003-06-03
Achutamurthy, Ponnathapu (Department: 1652)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving hydrolase
C435S226000, C530S412000, C530S417000
Reexamination Certificate
active
06573062
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the purification and characterization of tumor necrosis factor (TNF) receptor (TNF-R) releasing enzyme (TRRE), compositions derived from the enzyme, 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 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 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.
Human TNF and LT mediate their biological activities, both on cells and tissues, by binding specifically to two distinct, although related, glycoprotein plasma membrane receptors of 55 kDa and 75 kDa (p55 and p75 TNF-R, respectively). Holtmann and Wallach (1987)
J. Immunol.
139:151-153. The two receptors share 28 percent AA sequence homology in their extracellular domains, which are composed of four repeating cysteine-rich regions. Tartaglia and Goeddel (1992)
Immunol. Today
13:151-153. However, the receptors lack significant AA sequence homology in their intracellular domains. Dembic et al. (1990)
Cytokine
2:231-237. Due to this dissimilarity, they may transduce different signals and, in turn, exercise diverse functions.
Recent studies have shown that most of the known cellular TNF responses, including cytotoxicity and induction of several genes, may be attributed to p55 TNF-R activation. Engelmann et al. (1990)
J. Biol. Chem.
265:1531-1536; Shalaby et al. (1990)
J. Exp. Med.
172:1517-1520; and Tartaglia et al. (1991)
Proc. Natl. Acad. Sci. USA
88:9292-9296. In addition, the p55 receptor controls early acute graft-versus-host disease. Speiser et al. (1997)
J. Immun.
158:5185-90. In contrast, information regarding the biological activities of p75 TNF-R is limited. This receptor shares some activities with p55 TNF-R and specifically participates in regulating proliferation of and secretion of cytokines by T cells. Shalaby et al. (1990); and Gehr et al. (1992)
J. Immunol.
149:911-917. Both belong to an ever-increasing family of membrane receptors including low-affinity nerve growth factor receptor (LNGF-R), FAS antigen, CD27, CD30 (Ki-1), CD40 (gp50) and OX 40. Cosman (1994)
Stem Cells
(Dayt.) 12:440-455; Meakin and Shooter (1992)
Trends Neurosci.
15:323-331; Grell et al. (1994)
Euro. J. Immunol.
24:2563-2566; Moller et al. (1994)
Int. J. Cancer
57:371-377; Hintzen et al. (1994)
J. Immunol.
152:1762-1773; Smith et al. (1993)
Cell
73:1349-1360; Corcoran et al. (1994)
Eur. J. Biochem.
223:831-840; and Baum et al. (1994)
EMBO J.
13:3992-4001.
All of these receptors share a repetitive pattern of cysteine-rich domains in their extracellular regions. In accord with the pleiotropic activities of TNF and LT, most human cells express low levels (2,000 to 10,000 receptors/cell) of both TNF-Rs simultaneously. Brockhaus et al. (1990)
Proc. Natl. Acad. Sci.
USA 87:3127-3131. Expression of TNF-R on both lymphoid and non-lymphoid cells may be up and down-regulated by many different agents, such as bacterial lipopolysaccharide (LPS), phorbol myristate acetate (PMA; a protein kinase C activator), interleukin-1 (IL-1), interferon-gamma (IFN-&ggr;) and IL-2. Gatanaga et al. (1991)
Cell Immunol.
138:1-10; Yui et al. (1994)
Placenta
15:819-835; and Dett et al. (1991)
J. Immunol.
146:1522-1526. Although expressed in different proportions, each receptor binds TNF and LT with equally high affinity. Brockhaus et al. (1990); and Loetscher et al. (1990)
J. Biol. Chem.
265:20131-20138. Initial studies showed that the complexes of human TNF and TNF-R are formed on the cell membrane, internalized wholly, and then either degraded or recycled. Armitage (1994)
Curr. Opin. Immunol.
6:407-413; and Fiers (1991)
FEBS Lett.
285:199-212.
TNF binding proteins (TNF-BP) were originally identified in the serum and urine of febrile patients, individuals with renal failure, cancer patients, and even certain healthy individuals. Seckinger et al. (1988)
J. Exp. Med.
167:1511-1516; Engelmann et al. (1989)
J. Biol. Chem.
264:11974-11980; Seckinger et al. (1 989)
J. Biol. Chem.
264:11966-11973; Peetre et al. (1988)
Eur. J. Haematol.
41:414-419; Olsson et al. (1989)
Eur. J. Haematol.
42:270-275; Gatanaga et al. (1990a)
Lymphokine Res.
9:225-229; and Gatanaga et al. (1990b)
Proc. Natl. Acad. Sci USA
87:8781-8784. In fact, human brain and ovarian tumors produced high serum levels of TNF-BP. Gatanaga et al. (1990a); and Gatanaga et al. (1990b). These molecules were subsequently purified, characterized, and cloned by different laboratories. Gatanaga et al. (1990b); Olsson et al. (1989); Schall et al. (1990)
Cell
61:361-370; Nophar et al. (1990)
EMBO J.
9:3269-3278; Himmler et al. (1990)
DNA Cell Biol.
9:705-715; Loetscher et al. (1990)
Cell
61:351-359; and Smith et al. (1990)
Science
248:1019-1023. These proteins have been suggested for use in treating endotoxic shock. Mohler et al. (1993)
J. Immunol.
151:1548-1561; Porat et al. (1995)
Crit. Care Med.
23:1080-1089; Fisher et al. (1996)
N. Engl. J. Med.
334:1697-1702; Fenner (1995)
Z Rheumatol.
54:158-164; and Jin et al. (1994)
J. Infect. Dis.
170:1323-1326.
Human TNF-BP consist of 30 kDa and 40 kDa proteins found to be identical to the N-terminal extracellular domains of p55 and p75 TNF-R, respectively. The 30 kDa and 40 kDa TNF-BP are thus also termed soluble p55 and p75 TNF-R, respectively. Studies of these proteins have been facilitated by the availability of human recombinant 30 kDa and 40 kDa TNF-BP and antibodies which specifically recognize each form and allow quantitation by immunoassay. Helleret al. (1990)
Proc. Natl. Acad. Sci. USA
87:6151-6155; U.S. Pat. No. 5,395,760; EP 418,014; and Grosen et al. (1993)
Gynecol. Oncol.
50:68-77. X-ray structural studies have demonstrated that a TNF trimer binds with three soluble TNF-R (sTNF-R) molecules and the complex can no longer interact with TNF-R. Banner et al. (1993)
Cell
73:431-445. The binding of the trimer and sTNF-R, however, is reversible and thes
Gatanaga Tetsuya
Granger Gale A.
Achutamurthy Ponnathapu
Bozicevic Field & Francis LLP
Francis Carol L.
Moore William W.
The Regents of the University of California
LandOfFree
Method for obtaining modulators of TNF receptor releasing... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Method for obtaining modulators of TNF receptor releasing..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method for obtaining modulators of TNF receptor releasing... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3088534