Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Structurally-modified antibody – immunoglobulin – or fragment...
Reexamination Certificate
1997-07-10
2001-02-27
Bansal, Geetha P. (Department: 1642)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Structurally-modified antibody, immunoglobulin, or fragment...
C424S184100, C424S133100, C424S134100, C424S178100, C424S204100, C424S205100, C424S234100, C424S274100, C514S002600, C514S012200, C530S387300, C530S388100, C530S395000
Reexamination Certificate
active
06193966
ABSTRACT:
BACKGROUND OF THE INVENTION
Receptors for the Fc portions of immunoglobulins are important in triggering many of the protective functions of monocytes, macrophages and polymorphonuclear cells. Receptors for IgG (Fc&ggr; receptors or Fc&ggr;R) on these cells have been extensively investigated and bispecific molecules targeting these receptors have been constructed. (See e.g. European Patent No. 0 255 249 entitled “Monoclonal Antibodies to Fc Receptor for Immunoglobulin G on Human Mononuclear Phagocytes”, which is co-owned by Applicants.) In addition, clinical trials of bispecific molecules (BsAb) which have specificity for the Fc&ggr;R and the HER-2
eu antigen, which is found on breast or ovarian cancers, indicate that these molecules are both safe and efficacious (Valone, Frank H. et al. 1995,
J. of Clin. Oncol.
13(9): 2281-2292).
IgA receptors Fc&agr; receptors (Fc&agr;R or CD89) are also capable of promoting effector cell function. Binding of ligand to Fc&agr;R triggers phagocytosis and antibody mediated cell cytotoxicity in leukocytes and Fc&agr;R-bearing cell lines. Fc&agr; receptors can also cooperate with receptors for IgG on effector cells in enhancing the phagocytosis of target cells. Monoclonal antibodies of the IgM (Shen, L. et al., 1989
J. Immunol.
143: 4117) and IgG (Monteiro, R. C. et al., 1992
J. Immunol,
148: 1764) classes have been developed against Fc&agr;R.
IgA is abundant in the human body (Kerr, M. A. 1990,
Biochem. J.
271:285-296). A single class of IgA Fc receptor, Fc&agr;RI or CD89, which binds to monomeric IgA has been identified and characterized (Albrechtsen, M. et al., 1988
Immunol.
64:201; Monteiro R., et al., 1990
J. Exp. Med.,
171:597). Fc&agr;RI is constitutively expressed primarily on cytotoxic immune effector cells including monocytes, macrophages, neutrophils, and eosinophils (Morton, H. C., et al., 1996
Critical Reviews in Immunology
16:423). Fc&agr;RI expression on a sub-population of lymphocytes (Morton, H. C., et al., 1996
Critical Reviews in Immunology
16:423), and on glomerular mesangial cells has been reported (Gomez-Guerrero, C., et al., 1996
J. Immunol.
156:4369-4376). Its expression on monocytes and PMN can be enhanced by TNF-&agr; (Gesl, A., et al., 1994
Scad. J. Immunol.
39:151-156; Hostoffer, R. W., et al., 1994,
The J. Infectious Diseases
170:82-87), IL-1, GM-CSF, LPS or phorbol esters (Shen L., et al.,
J. Immunol.
152:4080-4086; Schiller, C. A. et al., 1994,
Immunology,
81:598-604), whereas IFN-&ggr; and TGF&bgr;1 decrease Fc&agr;RI expression (Reterink, T. J. F., et al., 1996,
Clin. Exp. Immunol.
103:161-166). The &agr;-chain of human Fc&agr;RI is a heavily glycosylated, type one transmembrane molecule belonging to the Ig super-gene family which also includes receptors for IgG and IgE. One gene located on chromosome 19 encodes several alternatively spliced isoforms of the Fc&agr;RI alpha chain (55-110 kDa; Morton, H. C., et al., 1996
Critical Reviews in Immunology
16:423). Myelocytic Fc&agr;RI has been shown to be associated with the FcR &ggr;-chain which is implicated as playing a role in Fc&agr;RI signal transduction (Morton, H. C. et al. 1995,
J. Biol. Chem.
270:29781; Pfefferkorn, L. C., et al. 1995,
J. Immunol.,
153:3228-3236, Saito, K. et al., 1995,
J. Allergy Clin. Immunol.
96:1152).
Fc&agr;RI binds both antigen-complexed and monomeric IgA1 and IgA2 (Mazangera, R. L. et al., 1990
Biochem. J.
272:159-165), consistent with the receptor being saturated in vivo with monomeric IgA in the same manner as Fc&ggr;R and Fc&egr;RI are saturated with IgG and IgE respectively. Cross-linking Fc&agr;RI on myeloid effector cells, by polymeric IgA, IgA immune complexes, or mAb specific for epitopes within or outside the ligand binding domain, stimulates degranulation, superoxide release, secretion of inflammatory cytokines, endocytosis and phagocytosis (Patty, C., A. Herbelin, A. Lihuen, J. F. Bach, and R. C. Monteiro. 1995
Immunology.
86:1-5; Stewart, W. W., R. L. Maz Yegera, L. Shen, and M. A. Kerr. 1994
J. Leucocyte Biology.
56:481-487; Stewart, W. W., and M. A. Kerr. 1990.
Immunology.
71:328-334; Shen, L. 1992.
J. Leukocyte Biology.
51 :373-378.). These physiological responses triggered via Fc&agr;RI can be important in the first line of humoral defense on mucosal surfaces (Morton, H. C., M. van Egmond, and J. G. J. van de Winkel. 1996
Critical Reviews in Immunology.
16:423).
Thus Fc&agr;RI is a clinically relevant trigger receptor on cytotoxic immune effector cells and its activity can be exploited to develop novel immunotherapies. The cytotoxic potential of Fc&agr;RI has not been carefully explored since almost all monoclonal antibody (mAb) based therapies are being developed with mAbs of IgG class which do not bind to Fc&agr;RI.
SUMMARY OF THE INVENTION
The present invention relates to multispecific therapeutic molecules with binding determinants for immunoglobulin A (IgA) receptors. IgA is the predominant antibody class in fluids on mucosal surfaces, and IgA receptors (Fc&agr; receptors, Fc&agr;R or Fc&agr;RI) are found on white blood cells including macrophages, monocytes, neutrophils, eosinophils and lymphocytes. The bispecific and multispecific molecules of the invention can be used as therapeutic agents to harness the cytolysis and phagocytosis capabilities of these white blood cells, enhancing the attack of these cells against cancer cells, cells of infectious microorganisms, and cells infected with pathogens.
In one aspect, the invention includes bispecific binding molecules, comprising a first binding determinant which binds an Fc&agr; receptor and a second binding determinant which binds one or more target antigens. Preferably, the first determinant binds a site on the Fc&agr;R that is different from the binding site for endogenous IgA, so that binding of the molecules of the invention is not blocked or is not substantially blocked by IgA. In a preferred embodiment, the target antigen bound by the second binding determinant of the bispecific molecules of the invention is a cancer cell antigen. In a more preferred embodiment the cancer cell antigen is an antigen of a cancer of the breast, ovary, testis, lung, colon, rectum, pancreas, liver, central nervous system, head and neck, kidney, bone, blood or lymphatic system. In another preferred embodiment, the target antigen is an infectious disease antigen from a pathogen or pathogen-infected cell. In yet another embodiment, the invention features treatment of an autoimmune disease with a composition that binds and modulates a receptor for IgA, causing modulation of the receptor such that further binding of IgA to that receptor is decreased. In a different embodiment, the invention provides compositions that bind and do not modulate a receptor for IgA, so that the effector cells of a subject are armed with the bispecific and multispecific molecules and can bind an antigen on a pathogen or on a cancer.
A preferred embodiment of bispecific molecules of the subject invention comprise molecules with binding determinants for a receptor of the human EGF-like receptor family, for a carcinoembryonic antigen, for a gastrin releasing peptide receptor antigen, and for a mucine antigen, which are overexpressed by certain tumor cells.
The bispecific molecules of the invention encompass molecules that are comprised in part of binding determinants of antibodies, and the molecules of the invention include those that are engineered to include at least one antibody or an antibody fragment. The bispecific binding molecules of the invention preferably comprise a binding determinant from an IgG antibody or IgG fragment, including an Fab, Fab′, F(ab′)
2
, Fv, and single chain Fv. A binding determinant, including an Fab, Fab′, F(ab′)
2
, Fv, and single chain Fv, can be obtained also from an IgA antibody or an antibody of another isotype. A preferred bispecific binding molecule of the invention comprises a first binding determinant that is at least a functional fragment of antibody A77 and a second binding determinant that bind
Deo Yashwant M.
Graziano Robert
Keler Tibor
Bansal Geetha P.
Lahive & Cockfield LLP
Mederax, Inc.
Remillard, Esq. Jane E.
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