Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Blood proteins or globulins – e.g. – proteoglycans – platelet...
Reexamination Certificate
1999-03-04
2001-10-16
Bansal, Geetha P. (Department: 1642)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Blood proteins or globulins, e.g., proteoglycans, platelet...
C530S387700, C530S387900, C530S388100, C530S388200, C530S388220, C530S388300, C530S388250, C530S388400, C530S388500, C530S388600, C530S388700, C530S388800, C530S395000, C514S002600, C514S012200
Reexamination Certificate
active
06303755
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 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 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.
SUMMARY OF THE INVENTION
In general, 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, or Fc&agr;R) are found on white blood cells including macrophages, monocytes, neutrophils, eosinophils and lymphocytes. The bispecific and multi specific 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. 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 a receptor for IgA, causing modulation of the receptor such that further binding of IgA to that receptor is decreased.
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 and mucine antigens, which are overexpressed by certain tumor cells.
The bispecific molecules of the invention emcompass 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 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 binds a cancer cell antigen, a pathogen antigen, or an antigen on an infected cell. The invention includes nucleic acid sequences of the V
H
and V
&kgr;
regions of the A77 antibody and the predicted amino acid sequences of these regions, and these sequence are preferably used for humanizing the A77 binding determinants for therapeutic multispecific molecules. Preferably the second binding determinant of the molecules of the invention is at least a functional fragment of antibody 520C9, antibody H425 or antibody CC49. A preferred embodiment carries one binding determinant for Fc&agr;R and one for the HER
eu antigen found for example on tumors of the breast, ovary, and lung.
Several methods of producing bispecific binding molecules are encompassed by the invention, including by chemical linkage of the binding determinants, and by recombinant genetic methods. Recombinant bispecific molecules encoded by nucleic acid sequences carrying genes encoding binding determinants which are thus genetically linked are encompassed by the invention. Further, bispecific binding molecules of the invention are produced by cell fusion of two antibody-producing cell lines carrying the respective nucleic acid sequences encoding the binding determinants, such as hybridoma cell lines, to obtain a progeny cell line producing the bispecific molecule of the invention.
In addition to bispecific binding molecules, the instant invention encompasses multispecific binding molecules which comprise at least a first binding determinant which binds an Fc&agr; receptor and a second binding determinant which binds a target antigen, and at least a third binding determinant. Binding of the first determinant of these multispecific binding molecules to Fc&agr;R is not inhibited by human immunoglobulin A, so there is no competition for binding by endogenous IgA molecules. Multispecific binding molecules encompass bispecific and trispecific compositions, and those with four or more binding determinants. A preferred embodiment of a trispecific binding molecule carries an additional binding determinant that binds to an Fc receptor that is not an Fc&agr; receptor, including for example a binding determinant for CD2, CD3, Fc&ggr; receptor, F&egr; receptor, Fc&dgr; receptor and/or Fc&mgr; receptor, these determinants being in addition to the first binding determinant to Fc&agr; receptor. The most preferred embodiment of an additional binding determinant for an FcR is a determinant for Fc&ggr; receptor. For a multispecific binding molecule of the invention carrying a binding determinant for an Fc&ggr; receptor, binding to Fc&ggr;R is not inhibited by human IgG, since the molecule binds Fc&ggr; at a different epitopic site from IgG binding of Fc&ggr;R. By incorporating at least binding determinant for each of Fc&agr;R and Fc&ggr;R into a single molecule, the therapeutic capability of the molecule is increased to enhance affinity and kinetics of binding of white blood cells to tumor cells or cells of pathogenic organisms or pathogen-infected cells, increasing opportunities for cytolysis and phagocytosis of these targets.
The preferred embodiment of the invented multispecific binding molecules with a determinant for Fc&agr;, is a molecule that carries a third binding determinant that binds to a second target antigen or a second target epitope on a cancer cell, a pathogen, or a pathogen-infected cell. The preferred means of producing these molecules is by chemical linkage of the binding determinants, however the invention encompasses also multispecific binding molecules which are recombinantly produced, or which are produced by cell fusion of two or more cell lines each of which carries the nucleic acid sequences encoding the binding determinants. Preferably at least one binding determinant is an antibody or an antibody fragment, and to improve the success of the outcome during continued treatment of humans, the binding determinant is a humanized antibody, which is engineered to minimize the number of foreign epitopes born by the mol
Deo Yashwant M.
Graziano Robert
Keler Tibor
Bansal Geetha P.
Dini Peter W.
Lahive & Cockfield LLP
Medarex Inc.
Remillard Jane E.
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