Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,...
Reexamination Certificate
2000-11-28
2003-06-03
Caputa, Anthony C. (Department: 1642)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
C424S133100, C424S136100, C424S138100, C424S141100, C424S143100, C424S152100, C424S174100, C530S391300, C530S391700, C530S387100, C530S387300, C530S387700, C530S388100, C530S388250
Reexamination Certificate
active
06572856
ABSTRACT:
1. INTRODUCTION
The present invention relates to methods of treating and preventing cancer, viral infection, or microbial infection in an animal comprising administrating to said animal antibodies specific for C3b(i). The present invention also relates to methods of treating and preventing cancer, viral infection, or microbial infection in an animal comprising administering to said animal IgG antibodies, IgM antibodies and/or complement components in combination with antibodies immunospecific for C3b(i). The present invention also relates methods of treating and preventing cancer, viral infection or microbial infection in an animal comprising administering to said animal antibodies that immunospecifically bind to one or more cancer cell antigens, viral antigens or microbial antigens, respectively, in combination with antibodies immunospecific for C3b(i). The present invention also relates to pharmaceutical compositions for the treatment and prevention of cancer, viral infection, and microbial infection comprising antibodies immunospecific for C3b(i). Further, the present invention relates to the detection, imaging, and diagnosis of cancer utilizing antibodies immunospecific for C3b(i).
2. BACKGROUND OF THE INVENTION
The complement system which is composed of some 21 plasma proteins plays an important role in the human immune system, both in the resistance to infections and in the pathogenesis of tissue injury. The activated products of the complement system attract phagocytic cells and greatly facilitate the uptake and destruction of foreign particles by opsonization. There are two distinct pathways for activating complement, the classical pathway and the alternate pathway, that result in conversion of C3 to C3b and subsequent responses (e.g., the formation of the membrane attack complex (“MAC”)). Activation of the classical pathway is initiated by antigen-antibody complexes or by antibody bound to cellular or particulate antigens. The alternate pathway is activated independent of antibody by complex polysaccharides in pathogens such as bacterial wall constituents, bacterial lipopolysaccharides (LPS) and cell wall constituents of yeast (zymosan).
The classic complement pathway is initiated by the binding of C1 to immune complexes containing IgG or IgM antibodies. Activated C1 cleaves C2 and C4 into active components, C2a and C4b. The C4b2a complex is an active protease called C3 convertase, and acts to cleave C3 into C3a and C3b. C3b forms a complex with C4b2a to produce C4b2a3b, which cleaves C5 into C5a and C5b. C5b combines with C6, and the C5b6 complex combines with C7 to form the ternary complex C5b67. The C5b67 complex binds C8 to form the C5b678 complex which in turn binds C9 and results in the generation of the C5-C9 MAC. The insertion of the MAC into the cell membrane results the formation of a transmembrane channel that causes cell lysis.
In the alternative pathway, conversion of C3 to C3b (or C3i) produces a product that can combine with factor B, giving C3bB (or C3iB). These complexes are acted upon by factor D to generate C3bBb, which is a C3 convertase capable of cleaving more C3 to C3b, leading to more C3bBb and even more C3 conversion. Under certain circumstances the C3bBb complex is stabilized by association with the positive regulator properdin (P) by association of C3b and Bb. The C3 convertases can associate with an additional C3b subunit to form the C5 convertase, C3bBb C3b, which is active in the production of the C5-C9 MAC.
In both the classical and alternative pathways, the critical step in the activation of complement is the proteolytic conversion of C3 to the fragments C3b and C3a. C3a is an anaphylatoxin that attracts mast cells to the site of challenge, resulting in local release of histamine, vasodilation and other inflammatory effects. The nascent C3b has an ability to bind to surfaces around its site of generation and functions as a ligand for C3 receptors mediating, for example, phagocytosis.
Endogenous cell surfaces normally exposed to complement are protected by membrane-bound regulators such as decay accelerating factor (“DAF”), C59 (“protectin”), MCP, and the soluble C1 inhibitor or C1NH. DAF and MCP are responsible for limiting production of C3b and insure the generation of inactive forms of C3b, C3bi and C3dg from C3b. CD59 prevents attack of the MAC, which would otherwise destroy the cancer cell. C1 inhibitor binds to the active subcomponents of C1, C1r and C1s, and inhibits their activity.
2.1. Cancer Treatment
Despite advances in prevention and early detection, refinements in surgical technique, and improvements in adjuvant radiotherapy and chemotherapy, the ability to cure many patients of cancer remains elusive. This is especially pertinent to prostate cancer, which remains the most prevalent visceral tumor in American men, with approximately 180,000 new cases and nearly 40,000 deaths expected in 1999 (Landis et al., 1999, Cancer J Clin 49: 8-31). The continuing challenge of prostate cancer treatment is the successful management and eradication of recurrent, metastatic, and hormone-refractory disease, which accounts for the vast majority of prostate cancer-specific morbidity and mortality (Small, 1998, Drugs and Aging 13:71-81).
Many treatment modalities currently under investigation for prostate and other cancers depend upon tissue-specific delivery of anti-neoplastic agents. One immunotherapeutic approach involves conjugating cytotoxic agents to monoclonal antibodies (mAbs) specific for a particular cancer cell epitope. In this manner, the therapeutic agents can be delivered at a high therapeutic dose directly, and selectively, to the tumor site, thereby minimizing injury to healthy tissue (Bach et al., 1993, Immunol Today 14:421-5; Reithmuller et al., 1993, Cur. Op. Immunol 5:732-9; and Gruber et al., 1996, Spring Sem Immunopath 18:243-51). This method first requires the identification of specific epitopes for each cancer type. Such candidate epitopes must be expressed at high levels on the cancer cells compared to normal tissue. Second, this method requires the development of high affinity mAbs specific for these epitopes and these mAbs must show minimal cross-reactivity with self tissue. The biological mechanism of killing with mAbs will be variable, depending upon the epitopes identified on the cancer cells, and the effector functions of the specific mAb isotype. However, due to antigenic modulation and/or mutation, the cancer cells may reduce the available levels of the target epitope per cell, or eliminate it from their surface altogether. Thus, the use of mAbs in cancer diagnosis and treatment remains problematic.
A more widely applicable approach to treatment of cancer with mAbs would be to identify a ubiquitous antigenic site, present on virtually all cancer cells, and then to develop a panel of mAbs specific for this antigen. A voluminous literature reveals that cancer cells share certain common characteristics. Many types of human cancer cells are characterized by substantial abnormalities in the glycosylation patterns of their cell-surface proteins and lipids (Hakomori et. al., 1996, Canc Res. 56:5309-18; Castronovo et al., 1989, J Nat Canc Inst 81:212-6; Springer et al., 1984, Science 224:1198-206; and Springer et al., 1997, J Mol Med 75:594-602). These differences have led to the identification of antigenic determinants on cancer cells which are expressed at far lower levels on normal cells. Natural IgM antibodies to these epitopes are present in the circulation, and the interaction of such IgM antibodies with these cancer cell surface antigens leads to activation of complement and covalent coupling of complement activation products (C3b and its fragments, collectively referred to as C3b(i)) to the tumor cells (Okada et al., 1974, Nature 248:521-25; Irie et. al., 1974, Science 186:454-456; Desai et al., 1995, J Immunol Methods 188:175-85; Vetvicka et al., 1996, J Clin Invest 98:50-61; Vetvicka et al., 1997, J Immunol 159:599-605; and Vetvicka et al., 1999, Clin Exp Immunol 115:229-35). Although relatively large amount
Chung Leland
Nardin Alessandra
Sokoloff Mitchell H.
Sutherland William M.
Taylor Ronald
Canella Karen A.
Caputa Anthony C.
Pennie & Edmonds LLP
The University of Virginia Patent Foundation
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