Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Monoclonal antibody or fragment thereof
Reexamination Certificate
1994-11-03
2004-05-18
Chan, Christina Y. (Department: 1644)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Monoclonal antibody or fragment thereof
C424S130100, C424S141100, C424S144100, C424S143100, C424S153100, C424S173100, C435S343000, C435S343100, C435S343200, C530S387100, C530S387300, C530S388100, C530S388200, C530S388220, C530S388700, C530S388730
Reexamination Certificate
active
06737059
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates generally to methods for the alleviation of symptoms associated with inflammatory disease states, and more particularly to the inhibition of inflammatory processes through administration of a pharmaceutically effective amount of an antibody substance immunologically reactive with molecules expressed on the surface of leukocytes.
Inflammation is a body process central to a number of diseases and is the body's primary defense against infection. The inflammatory process involves an orchestrated series of events initiated in response to tissue damage. In all cases, this cellular damage ultimately leads to the influx of white blood cells (leukocytes) to the site of injury. As leukocytes arrive at the site of injury, they become metabolically activated and begin to secrete specific proteins (mediators) that are generally of defensive significance, for example, in the eradication of bacteria.
If unregulated, the inflammatory state may persist as a condition known as chronic inflammation. In this setting, the mediators produced may amplify the inflammatory response and cause damage to otherwise normal tissue. Depending upon the body site, such tissue damage may result in chronic diseases such as arthritis, multiple sclerosis, asthma, emphysema, ulcerative colitis, and various autoimmune diseases.
Multiple sclerosis (MS) is a chronic disease characterized by recurrent if attacks of neurologic dysfunction due to lesions in the central nervous system. These lesions, termed “plaques,” represent areas of iaxonal demyelination which are the hallmark of multiple sclerosis. The lesions contain inflammatory cells such as lymphocytes, macrophages and neutrophils in areas where myelin is being destroyed. The classic clinical features of multiple sclerosis include impaired vision and weakness or paralysis of one or more limbs. After a number of years, patients experience a slow, steady deterioration of neurologic function. The disease course is unpredictable and involves exacerbations and remissions in 75% of patients. Although a few patients die within the first few years of onset, the average duration of disease is greater than 30 years.
There are an estimated 250,000 cases of multiple sclerosis in the United States, with approximately 10,000 new cases occurring each year. The cause is unknown but epidemiology implicates immunologic or infectious factors resulting in a chronic inflammatory brain condition. Multiple sclerosis is a disease of young adults, with 66% of cases occurring at ages 20-40; 60% of the patients are women. Over one million physician visits occur annually for multiple sclerosis in the United States alone; however, there is currently no effective treatment for multiple sclerosis. Therapy is directed toward the reduction of the severity of acute episodes and prevention of relapses. In acute flare-ups, steroids reduce severity and speed recovery. Experimental therapy with other immunosuppressive agents, such as cyclophosphamide, has been tried, but with limited success.
A model for human multiple sclerosis is experimental allergic encephalomyelitis (EAE), an acute inflammatory and demyelinating disease of the central nervous system (CNS). [Rose, et al.,
Clin. Immunol. Immunopathol
., 59:1-15 (1991)]. For both EAE and MS, there is considerable evidence that immunological and inflammatory processes contribute to the pathogenesis of the disease. [Hauser, et al.,
Ann Neurol
13:418-425 (1983); Traugott, et al.,
Cell. Immunol
., 68:261-275 (1982); Rose, et al.,
Clin. Immunol. Immunopathol
., 45:405-423 (1987). This is supported by the presence of perivascular mononuclear cellular infiltrates in lesions and macrophage-dependent phagocytosis of myelin in the CNS white matter. [Prineas, et al.,
Lab. Invest
., 38:409-421 (1978); Alvord, J C Koetsier, editor;
Handbook of Clinical Neurol
, 3(47):467-502, Koetsier (ed.); Amsterdam; Elsevier Science Publishers BV (1985)]. The mechanisms by which these blood cells first recognize the brain as a target organ and then traverse the blood brain barrier are not well understood.
The migration of blood cells into extravascular sites of inflammation involves a complex series of events including: i) recognition of an intravascular chemotactic stimulus, ii) adherence to endothelium, iii) diapedesis across the endothelium, and iv) migration through subendothelial connective tissue. [Snyderman, et al.,
Science
, 213:830-837 (1981)]. Endothelial cells (EC) found on lumenal surfaces of blood vessels are the first cells that leukocytes encounter during migration from the blood to the extravascular space. Molecules expressed by both the leukocytes and by the endothelial cells are important in regulating the adhesive interaction between these two cell types.
One family of leukocyte receptors, variously designated “leukocyte integrins,” “leukointegrins,” and “CD11/CD18 integrins,” are involved in cell-cell and cell-protein interactions of all leukocytes. [Hynes,
Cell
, 48:549-554 (1987); Beatty, et al.,
J. Immunol
., 131:2913-2918 (1983)]. The CD11/CD18 antigen family consists of three heterodimers, each containing a unique &agr;-chain (CD11a, CD11b, or CD11c), and a common &bgr;-chain (CD18). [Sanchez-Madrid, et al.,
J. Exp. Med
., 158:1785-1803 (1983)]. The CD11a/CD18 integrin is referred to as LFA-1; the CD11b/CD18 integrin is referred to as Mac-1; the CD11c/CD18 integrin is referred to as p 150,95.
Numerous murine hybridomas have been generated which produce monoclonal antibodies of varying isotype to the common &bgr; chain (CD18) of the leukocyte integrins. These include: mAb 1B4 [IgG2a; Wright, et al.,
Proc. Nat'l. Acad. Sci. USA
, 80:5699-5703 (1983)]; mAb 60.3 [IgG2a; Beatty, et al.,
J. Immunol
., 131:2913-2918 (1983)]; mAb TS1/18 [IgG1; Sanchez-Madrid, supra]; mAb H52 [Hildreth, et al.,
Science
244:1075-1803 (1989)]; and ATCC T1B 218 [IgG2a Kappa; Springer, et al.,
J. Exp. Med
., 158:586-602 (1983)]. Production of chimeric and humanized monoclonal antibodies against human CD18 is referred to in Law, et al., European Patent Application 440 351 A2, published Aug. 7, 1992.
Monoclonal antibodies directed against the common &bgr;-chain of leukocyte integrins completely inhibit adherence of PMNCs to un-activated endothelial cells and certain matrix proteins in vitro. [Harlan, et al.,
Blood
, 66:167-178 (1985); Zimmerman, et al.,
J. Clin. Invest
., 81:531-537 (1988); Bohnsack, et al.,
J. Exp. Med
., 171:1221-1237 (1990); Luscinskas, et al.,
J. Immunol
., 142:2257-2263 (1989)]. Moreover, the systemic administration of anti-CD11/CD18 antibodies inhibits tissue accumulation of PMNCs. [Springer, et al.,
Nature
, 346:425-434 (1990); Jutila, et al.,
Transplantation
, 48:727-731 (1989); Arfors, et al.,
Blood
, 60:338-340 (1987); Price, et al.,
J. Immunol
., 139:4174-4177 (1987); and, Doerschuk, et al.,
J. Immunol
., 144:2327-2333 (1990)].
Arfors, et al., supra, studied the effect of the anti-CD18 antibody, mAb 60.3, on induced PMN accumulation in vivo and found that both PMN accumulation and PMN-dependent plasma leakage were abolished in the inflammatory skin lesions of rabbits treated with mAb 60.3 prior to intra dermal injection with the chemotactic factors fMLP, leukotriene (LMB
4
) and C5a. These chemotactic agents cause a significant increase in albumin extravasation; extravasation of PMNs at chemotaain-injective sites is followed by plasma leakage. Curiously, histamine-induced PMN-independent plasma leakage was unaffected by pre-treatment with mAb 60.3.
Hernandez, et al.,
Am. J. Physiol
., 253:H699 (1987) investigated whether PMNs mediate the increase in microvascular permeability produced by ischemia-reperfusion (I/R) by treating cats with either saline, anti-neutrophil serum (ANS), or mAb 60.3. The results indicated that both PMN depletion and prevention of PMN adherence significantly attenuated the increase in microvascular permeability ind
Board of Regents of the University Washington
Chan Christina Y.
Gambel Phillip
Marshall & Gerstein & Borun LLP
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