Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Monoclonal antibody or fragment thereof
Reexamination Certificate
1996-08-01
2001-08-07
Gambel, Phillip (Department: 1644)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Monoclonal antibody or fragment thereof
C424S130100, C424S133100, C424S152100, C424S158100, C424S172100, C424S184100, C424S192100, C514S002600, C514S008100, C514S253030, C514S885000
Reexamination Certificate
active
06270766
ABSTRACT:
BACKGROUND OF THE INVENTION
Monocytes and macrophages secrete cytokines known as tumor necrosis factor alpha (TNF&agr;) and tumor necrosis factor beta (TNF&bgr;) in response to endotoxin or other stimuli. TNF&agr; is a soluble homotrimer of 17 kD protein subunits (Smith et al.,
J. Biol. Chem.
262:6951-6954 (1987)). A membrane-bound 26 kD precursor form of TNF also exists (Kriegler et al.,
Cell
53:45-53 (1988)). For reviews of TNF, see Beutler et al.,
Nature
320:584 (1986); Old,
Science
230:630 (1986); and Le et al.,
Lab. Invest.
56:234 (1987).
Cells other than monocytes or macrophages also produce TNF&agr;. For example, human non-monocytic tumor cell lines produce tumor necrosis factor (TNF) (Rubin et al.,
J. Exp. Med.
164:1350 (1986); Spriggs et al.,
Proc. Natl. Acad. Sci. USA
84:6563 (1987)). CD4+ and CD8+ peripheral blood T lymphocytes and some cultured T and B cell lines (Cuturi et al.,
J. Exp. Med.
165:1581 (1987); Sung et al.,
J. Exp. Med.
168:1539 (1988); Turner et al.,
Eur. J. Immunol.
17:1807-1814 (1987)) also produce TNF&agr;.
TNF causes pro-inflammatory actions which result in tissue injury, such as degradation of cartilage and bone, induction of adhesion molecules, inducing procoagulant activity on vascular endothelial cells (Pober et al.,
J. Immunol.
136:1680 (1986)), increasing the adherence of neutrophils and lymphocytes (Pober et al.,
J. Immunol.
138:3319 (1987)), and stimulating the release of platelet activating factor from macrophages, neutrophils and vascular endothelial cells (Camussi et al.,
J. Exp. Med.
166:1390 (1987)).
Recent evidence associates TNF with infections (Cerami et al.,
Immunol. Today
9:28 (1988)), immune disorders, neoplastic pathologies (Oliff et al.,
Cell
50:555 (1987)), autoimmune pathologies and graft-versus-host pathologies (Piguet 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. Cancer patients suffer from weight loss, usually associated with anorexia.
The extensive wasting which is associated with cancer, and other diseases, is known as “cachexia” (Kern 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 fundamental physiological derangement can relate to a decline in food intake relative to energy expenditure. The cachectic state causes most cancer morbidity and mortality. TNF can mediate cachexia in cancer, infectious pathology, and other catabolic states.
TNF also plays a central role in gram-negative sepsis and endotoxic shock (Michie et al.,
Br. J. Surg.
76:670-671 (1989); Debets et al.,
Second Vienna Shock Forum, p.
463-466 (1989); Simpson et al.,
Crit. Care Clin.
5:27-47 (1989)), including fever, malaise, anorexia, and cachexia. Endotoxin strongly activates monocytelmacrophage production and secretion of TNF and other cytokines (Kornbluth et al.,
J. Immunol.
137:2585-2591 (1986)). TNF and other monocyte-derived cytokines mediate the metabolic and neurohormonal responses to endotoxin (Michie et al.,
New Engl. 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 et al.,
Arch. Surg.
123:162-170 (1988)). Circulating TNF increases in patients suffering from Gram-negative sepsis (Waage et al.,
Lancet
1:355-357 (1987); Hammerle et al.,
Second Vienna Shock Forum p.
715-718 (1989); Debets et al.,
Crit. Care Med.
17:489-497 (1989); Calandra et al.,
J. Infect. Dis.
161:982-987 (1990)).
Thus, TNF&agr; has been implicated in inflammatory diseases, autoimmune diseases, viral, bacterial and parasitic infections, malignancies, and/or neurogenerative diseases and is a useful target for specific biological therapy in diseases, such as rheumatoid arthritis and Crohn's disease. Beneficial effects in open-label trials with a chimeric monoclonal antibody to TNF&agr; (cA2) have been reported with suppression of inflammation (Elliott et al.,
Arthritis Rheum.
36:1681-1690 (1993); Elliott et al.,
Lancet
344:1125-1127 (1994)). See also, Van Dullemen et al.,
Gastroenterology
109:129-135 (1995). Beneficial results in a randomized, double-blind, placebo-controlled trial with cA2 have also been reported with suppression of inflammation (Elliott et al.,
Lancet
344:1105-1110 (1994)).
SUMMARY OF THE INVENTION
The present invention is based on the discovery that treatment of patients suffering from a TNF-mediated disease with a tumor necrosis factor antagonist, such as an anti-tumor necrosis factor antibody, as adjunctive and/or concomitant therapy to methotrexate therapy produces a rapid and sustained reduction in the clinical signs and symptoms of the disease. The present invention is also based on the unexpected and dramatic discovery that a multiple dose regimen of a tumor necrosis factor antagonist, such as an anti-tumor necrosis factor antibody, when administered adjunctively with methotrexate to an individual suffering from a TNF-mediated disease produces a highly beneficial or synergistic clinical response for a significantly longer duration compared to that obtained with a single or multiple dose regimen of the antagonist administered alone or that obtained with methotrexate administered alone. As a result of Applicants' invention, a method is provided herein for treating and/or preventing a TNF-mediated disease in an individual comprising co-administering an anti-TNF antibody or a fragment thereof and methotrexate to the individual in therapeutically effective amounts. In a particular embodiment, methotrexate is administered in the form of a series of low doses separated by intervals of days or weeks.
A method is also provided herein for treating and/or preventing recurrence of a TNF-mediated disease in an individual comprising co-administering an anti-TNF antibody or a fragment thereof and methotrexate to the individual in therapeutically effective amounts. TNF-mediated diseases include rheumatoid arthritis, Crohn's disease, and acute and chronic immune diseases associated with an allogenic transplantation (e.g., renal, cardiac, bone marrow, liver, pancreatic, small intestine, skin or lung transplantation).
Therefore, in one embodiment, the invention relates to a method of treating and/or preventing rheumatoid arthritis in an individual comprising co-administering an anti-TNF antibody or a fragment thereof and methotrexate to the individual in therapeutically effective amounts. In a second embodiment, the invention relates to a method of treating and/or preventing Crohn's disease in an individual comprising co-administering an anti-TNF antibody or a fragment thereof and methotrexate to the individual in therapeutically effective amounts. In a third embodiment, the invention relates to a method of treating and/or preventing other autoimmune diseases and/or acute or chronic immune disease associated with a transplantation in an individual, comprising co-administering an anti-TNF antibody or a fragment thereof and methotrexate to the individual in therapeutically effective amounts.
A further embodiment of the invention relates to compositions comprising an anti-TNF antibody or a fragment thereof and methotrexate.
In addition to anti-TNF antibodies, TNF antagonists include anti-TNF antibodies and receptor molecules which bind specifically to TNF; compounds which prevent and/or inhibit TNF synthesis, TNF release or its action on target cells, such as thalidomide, tenidap, phosphodiesterase inhibitors (e.g, pentoxifylline and rolipram), A2b adenosine receptor agonists and A2b adenosine receptor enhancers; and compounds which prevent and/or inhibit TNF receptor signalling.
REFERENCES:
patent: 5317019 (1994-05-01), Bender
patent: 5656272 (1997-08-01), Le et al.
patent: 5672347 (1997-09-01), Aggarwal et al.
patent: 5698195 (1997-12-01), Le et al.
patent: 5741488 (1998-04-01), Feldm
Feldman Marc
Maini Ravinder N.
Gambel Phillip
Hamilton Brook Smith & Reynolds P.C.
The Kennedy Institute of Rheumatology
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