Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Monoclonal antibody or fragment thereof
Reexamination Certificate
1995-06-07
2002-03-12
Gambel, Phillip (Department: 1644)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Monoclonal antibody or fragment thereof
C424S130100, C424S133100, C424S135100, C424S141100, C424S145100, C424S158100, C424S139100, C424S130100, C530S387100, C530S387300, C530S387900, C530S388100, C530S388230, C530S388250, C530S388700, C435S326000, C435S328000, C435S331000, C435S033000, C435S337000, C435S343000, C435S346000
Reexamination Certificate
active
06355245
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the treatment of glomerulonephritis (GN) and other inflammatory diseases, and more generally to therapeutic treatments involving the pharmacologic inhibition of a patient's complement system. In particular, the invention relates to the use of antibodies specific to human complement component C5 to accomplish such therapeutic treatment. The invention also relates to compositions comprising native monoclonal antibodies (mAbs) specific to human complement component C5 that block complement hemolytic activity and C5a generation at concentrations that substantially reach the theoretical one to two stoichiometric limit of antibody to antigen that can be achieved by a bivalent antibody. The invention further provides recombinant mabs that are derivatives (including monovalent derivatives) of these native mAbs that provide substantially the same blocking activities as the native mabs.
BACKGROUND OF THE INVENTION
I. Immune Complex Mediated Disease
The formation of immune complexes is the typical consequence of the interaction of antigens with specific antibodies. The inflammatory response that ensues when such complexes accumulate in a limited area is an important element of normal host defenses, leading to immune complex clearance and antigen destruction by phagocytic cells. In contrast, immune complex diseases are reflections of excess complex formation or retarded clearance, usually under conditions of exceptional antigen challenge or immunologic dysregulation. Under such circumstances, immune complexes are deposited or formed at specific tissue sites and resulting inflammatory responses lead to disease states due to localized or systemic tissue damage. The kidney, and more specifically the kidney structure known as the glomerulus, is a particularly important site of immune complex deposition resulting in the development of serious disease conditions.
Human studies, and studies using animal models of human diseases, have implicated the complement system in the pathologies associated with a number of immune complex associated disorders. The activation of complement that mediates the pathology associated with these disorders may be a consequence of an autoimmune mechanism, or can be non-immunologic in origin.
The hypersensitivity response that occurs when antibodies bind to antigens either in tissues or in the circulation results from the activation of complement and the release of molecules that mediate inflammation. This process is classified as either being mediated by the binding of antibody to fixed tissue or cell bound antigens (Type II hypersensitivity) or to circulating antigens, resulting in the formation of circulating immune complexes and their subsequent pathogenic deposition in tissues (Type III hypersensitivity).
Type II hypersensitivity is mediated through the activation of complement following the binding of antibodies to fixed tissue antigens. The inflammatory response that ensues results from the activation of the proinflammatory and lytic components of the complement system and the subsequent recruitment of stimulated leukocytes to the sites of immune complex formation. The increased vascular permeability that results from the anaphylatoxic activities of C3a and C5a further enhances immune complex deposition and leukocyte recruitment.
The cross-linking of antibody bound cells or tissues to effector cells such as neutrophils, platelets, NK cells, and monocytes via their Fc receptors also plays a proinflammatory role. Such cross-linking activates effector cells, stimulating the release of oxygen radicals, prostaglandins, and leukotrienes, which release is further potentiated by the actions of activated complement components.
Examples of Type II hypersensitivity-mediated conditions include hyperacute rejection of transplanted organs, autoimmune hemolytic and thrombocytopenic states, Goodpasture's syndrome (and associated glomerulonephritis and pulmonary hemorrhage), myasthenia gravis, pathologic sequellae associated with insulin-dependent diabetes melitus, and pemphigus vulgaris.
Type III hypersensitivity reactions involving circulating antigens can also result in the development of numerous pathologic conditions. These include glomerulonephritis (discussed in detail below), vasculitis (a potentially life-threatening inflammatory condition of large and/or small blood vessels), rheumatoid arthritis, dermatitis, and other disorders.
Other diseases associated with type III hypersensitivity reactions include autoimmune diseases such as systemic lupus erythematosis (SLE), many infectious diseases, neoplastic diseases, and a wide variety of other conditions (Dixon, et al.
Immune Complex Injury
, in Samter, (ed.) Immunological Diseases, 4th ed. Little Brown & Co. Boston, 1987).
II. Glomerulonephritis
The glomerulus is a key structural and functional element of the kidney. Each glomerulus is found as part of a larger structure that serves as the main functional unit of the kidney and is called a nephron. About a million nephrons are found in each kidney. Each glomerulus is a network of up to fifty parallel capillaries encased in a structure known as Bowman's capsule. The area inside Bowman's capsule that is not taken up by the glomerular capillaries is known as Bowman's space. The glomerulus functions as a filter, separating water and certain solutes from the proteins and cells of the blood into Bowman's space for further processing in the convoluted tubules, loop of Henle, and collecting duct of the nephron.
Glomerulonephritis (GN) is a disease of the kidney characterized by inflammation and resulting enlargement of the glomeruli that is typically due to immune complex formation. The accumulation of immune complexes in the glomeruli results in inflammatory responses, involving inter alia hypercellularity, that can cause total or partial blockage of the glomerulus through, among other factors, narrowing of capillary lumens. One result of this process is the inhibition of the normal filtration function of the glomerulus. Blockage may occur in large numbers of glomeruli, directly compromising kidney function and often causing the abnormal deposition of proteins in the walls of the capillaries making up the glomerulus. Such deposition can, in turn, cause damage to glomerular basement membranes. Those glomeruli that are not blocked develop increased permeability, allowing large amounts of protein to pass into the urine, a condition referred to as proteinuria.
In many cases of severe GN, pathological structures called crescents are formed within the Bowman's space, further impeding glomerular filtration. These structures can only be seen by microscopic examination of tissue samples obtained by biopsy or necropsy, and are thus not always observed in those patients in which they occur. Crescents are a manifestation of hypercellularity and are thought to arise from the extensive abnormal proliferation of parietal epithelial cells, the cells that form the inner lining of the Bowman's capsule. Clinical research has shown that there is a rough correlation between the percentage of glomeruli with crescents and the clinical severity of the disease, and thus the patient's prognosis. When present in large numbers, crescents are a poor prognostic sign.
Symptoms of GN include: proteinuria; reduced glomerular filtration rate (GFR); serum electrolyte changes including azotemia (uremia, excessive blood urea nitrogen—BUN) and salt retention, leading to water retention resulting in hypertension and edema; hematuria and abnormal urinary sediments including red cell casts; hypoalbuminemia; hyperlipidemia; and lipiduria.
In 1990, over 210,000 patients in the United States required hemodialysis or transplantation for chronic renal failure at an annual cost in excess of 7 billion dollars, according to the United States Renal Data System (USRDS). The USRDS compiles data on kidney disease in the United States in conjunction with the National Institute of Diabetes and Digestive and Kidney Diseases, Divisi
Evans Mark J.
Matis Louis A.
Mueller Eileen Elliott
Nye Steven H.
Rollins Scott
Alexion Pharmaceuticals, Inc.
Gambel Phillip
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