Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Structurally-modified antibody – immunoglobulin – or fragment...
Reexamination Certificate
1997-10-08
2001-02-27
Scheiner, Laurie (Department: 1648)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Structurally-modified antibody, immunoglobulin, or fragment...
C424S143100, C424S145100, C424S158100, C424S178100
Reexamination Certificate
active
06193967
ABSTRACT:
BACKGROUND OF THE INVENTION
Atheromatous lesions consist of numerous cellular and acellular elements. Macrophages are a major constituent of these lesions as they develop into characteristic cholesteryl ester-laden foam cells (Ross, R. (1986)
New England J. Med
. 314:488-500; Munro, J. M. and Cotran, R. S. (1988)
Laboratory Invest
. 58:249-261). For macrophages, foam cell development during atherogenesis is ultimately dependent upon uptake of various forms of low density lipoprotein (LDL) (reviewed in Brown, M. S. and Goldstein, J. L.
Ann. Rev. Biochem
. 52:223-261). Of late, emphasis has been placed on the importance of the interaction of chemically modified or oxidized LDL with macrophage scavenger receptors (reviewed in Steinberg, D., et al. (1988)
New England J. Med
. 320:915-924), which may occur during atherogenesis in vivo (Steinberg, D., et al. (1988)
New England J. Med
. 320:915-924; Haberland, M. E., et al. (1988)
Science
241:215-218; Palinski, W., et al. (1989)
Proc. Natl. Acad. Sci. USA
86:1372-1376; Rosenfeld, M. E., etal. (1990)
Arteriosclerosis
10:336-349; Boyd, H. C., et al. (1990)
Am. J. Path
. 135:815-825).
Foam cell development may also be influenced by the interaction of lipoproteins with pathways other than those associated with scavenger receptors. In particular, recent studies have shown that immune complexes consisting of LDL bound to anti-LDL antibodies (LDL-IC) can cause foam cell development in vitro through interaction with IgG Fc receptors (Fc&ggr;R) when administered to both mouse (Klimov, A. N., et al. (1985)
Atherosclerosis
58:1-15) and human macrophages (Lopes-Virella, M. F., et al. (1991)
Arteriosclerosis and Thrombosis
11:1356-1367; Griffith, R. L., et al. (1988)
J. Exp. Med
. 168:1041-1059). LDL-IC (reviewed in Orekhov, A. N. (1991)
Curr. Opin. Lipidology
2:329-333) consisting of antibodies bound to either native or oxidized LDL exist in numerous situations in vivo (Szondy, E., et al. (1983)
Atherosclerosis
49:69-77; Parums, D. V., et al. (1990)
Arch. Pathol. Lab. Med
. 114:383-387; Beaumont, J. L., et al. (1988)
Atherosclerosis
74:191-201; Kigore, L. L., et al. (1985)
J. Clin. Invest
. 76:225-232), and in several cases have been correlated with abnormalities of lipid metabolism and atherosclerosis (Szondy, E., et al., supra; Parums, D. V., et al., supra; Beaumont, J. L., et al., supra; Kigore, L. L., et al., supra; Cohen, L., et al. (1966)
Am. J. Med
. 40:299-316).
In contrast to the role of LDL in foam cell development, human high density lipoprotein (HDL) may play a role in preventing foam cell development. HDL is known to play a role in cholesterol efflux from extrahepatic tissues, such as vascular tissue, to the liver where it can be metabolized. See, e.g., Badimon, J. J. et al. (1992)
Circulation
(Supp. III) 86(6):III-86-III-94; Castell, W. P. et al (1977)
Circulation
55(5):767-772. Moreover, it has been shown that plasma HDL both inhibits the development of experimental atherosclerosis and induces regression of the lipid infiltration into vessel (e.g., aortic) walls. Badimon, J. J. et al., supra.
Human Fc&ggr; receptors (Fc&ggr;R) (reviewed in Fanger, M. W., et al. (1989)
Immunology Today
10:92-99), of which there are three structurally and functionally distinct types (i.e., Fc&ggr;RI, Fc&ggr;RII and Fc&ggr;RIII), are well-characterized cell surface glycoproteins that mediate phagocytosis or antibody-dependent cell cytotoxicity (ADCC) of immunoglobulin G (IgG) opsonized targets.
Bispecific antibody technology has been used to evaluate the function of specific Fc&ggr;R. Investigators have shown that Fc&ggr;R are the only cell surface molecules on myeloid cells capable of triggering phagocytic or cytotoxic function (Shen, L., et al. (1986)
J. Immunol
. 137:3378-3382; Shen, L. et al. (1987)
J. Immunol
. 139:534-538; Connor, R. I., et al. (1990)
J. Immunol
. 145:1483-1489; Anderson, C. L., et al. (1990)
J. Exp. Med
. 171:1333-1345). However, clear differences in the functional ability of the different Fc&ggr;R could be demonstrated that was dependent not only on the Fc&ggr;R class or isoform but on the state of activation and differentiation of the cell (Fanger, M. W., et al. (1989)
Immunology Today
10:92-99; Van de Winkel, J. G. and Anderson, C. L. (1991)
J. Leukocyte Biol
. 49:511-524).
SUMMARY OF THE INVENTION
This invention pertains to bispecific molecules which can bind human low density lipoprotein (LDL) and/or which can simultaneously target human LDL for ingestion and metabolic degradation by effector cells such as monocytes, macrophages, eosinophils, granulocytes, platelets and neutrophils. The bispecific molecules of this invention have a first binding specificity for human LDL and a second binding specificity for an Fc&ggr; receptor for immunoglobulin G (IgG), such as the human Fc&ggr; receptors Fc&ggr;RI, Fc&ggr;RII and Fc&ggr;RIII. In a preferred embodiment, such bispecific molecules are capable of binding to IgG-occupied Fc&ggr; receptors on effector cells. For specifically targeting Fc&ggr;RI, it is preferred that the bispecific molecule have a binding specificity for an epitope on the receptor which is distinct from the Fc ligand binding domain of the receptor for the Fc region of IgG.
This invention further pertains to bispecific molecules which can bind human high density lipoprotein (HDL) and/or which can simultaneously target HDL to effector cells such as macrophages or macrophage-derived foam cells for HDL uptake of cholesterol from the effector cells. The bispecific molecules of this invention have a first binding specificity for human HDL and a second binding specificity for an Fc&ggr; receptor for immunoglobulin G (IgG), such as the human Fc&ggr; receptors Fc&ggr;RI, Fc&ggr;RII and Fc&ggr; RIII. In a preferred embodiment, such bispecific molecules are capable of binding to IgG-occupied Fc&ggr; receptors on effector cells. For specifically targeting Fc&ggr;RI, it is preferred that the bispecific molecule have a binding specificity for an epitope on the receptor which is distinct from the Fc ligand binding domain of the receptor for the Fc region of IgG.
A bispecific molecule of the invention can be a bispecific antibody (i.e., a single antibody or antibody fragment with a dual binding specificity), a heteroantibody (i.e., an aggregate of two or more antibodies or antibody fragments, each having a different binding specificity) or a single chain bispecific polypeptide. In general, a bispecific antibody, heteroantibody or single chain bispecific polypeptide comprises: at least one antigen binding region derived from an anti-Fc receptor antibody whose binding to human Fc receptor is not blocked by human IgG; and at least one antigen binding region specific for a human lipoprotein, such as human LDL or human HDL.
The binding of a bispecific molecule of the present invention, e.g., a bispecific molecule having a binding specificity for human LDL, to an appropriate effector cell results in a targeted effector cell, i.e., an effector cell to which is bound a bispecific antibody or heteroantibody containing antigen binding regions specific for human LDL. The targeted effector cells can be used to bring about phagocytosis of LDL by the effector cells. The binding of another bispecific molecule of the present invention, e.g., a bispecific molecule having a binding specificity for human HDL, to an appropriate effector cell, e.g., a macrophage-derived foam cell, results in a targeted effector cell, i.e., an effector cell to which is bound a bispecific antibody or heteroantibody containing antigen binding regions specific for human HDL. The targeted effector cells can be used to bind HDL, thereby allowing uptake and/or removal of cholesterol from the effector cells.
The bispecific molecules of this invention have therapeutic as well as diagnostic applications. As therapeutic agents, the bispecific molecules can be administered to an individual alone, or pre-bound to effector cells having the appropriate Fc receptor prior to administration. In either form, the bispecific molecules of the pr
DiGiorgio, Esq. Jeanne M.
Lahive & Cockfield LLP
Remillard, Esq. Jane E.
Scheiner Laurie
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