Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Structurally-modified antibody – immunoglobulin – or fragment...
Reexamination Certificate
1995-05-30
2001-07-10
Bansal, Geetha P. (Department: 1642)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Structurally-modified antibody, immunoglobulin, or fragment...
C424S134100, C424S135100, C424S178100, C424S192100, C424S193100, C424S277100, C530S387100, C530S387300
Reexamination Certificate
active
06258358
ABSTRACT:
BACKGROUND OF THE INVENTION
Antigen molecules are recognized by the immune system after internal processing by antigen-presenting cells, generally mononuclear phagocytic cells such as macrophages and B lymphocytes. In order to present a proteinaceous antigen, the antigen-presenting cell first internalizes the antigen which is then broken down into small peptidic fragments by enzymes contained in vesicles in the cytoplasm of the antigen-presenting cells. After fragmentation, the peptides are linked to cellular major histocompatibility complex (MHC) molecules and presented on the presenting cell's surface to the immune system. Peptides presented in this way are recognized by the T-cell receptor which engages T-lymphocytes into the immune response against this antigen. This antigen presentation also stimulates the B lymphocytes for specific antibody production.
Complexes of antibody and antigen have been used to stimulate an immune response against the antigen. Antigen uptake through antigen-antibody complexes bound to Fc receptors for IgG (Fc&ggr;R) increases the efficiency of antigen presentation and thereby antigen-specific T-cell activation by human and mouse macrophages, (Celis et al (1984)
Science
2:297-299; Chang (1985)
Immunol. Today
6:245-259; Manca et al. (1988)
Immunol.
140:2893-2898; Schalke et al. (1985)
J. Immunol.
13:3643-3648; and Snider et al (1987)
J. Immunol.
1:1609-1616). The binding of these complexes to Fc&ggr;R is mediated by the Fc region of the antibody. This binding is susceptible to inhibition by physiological concentrations of IgG.
SUMMARY OF THE INVENTION
This invention pertains to a binding agent which binds a surface receptor of an antigen-presenting cell in some instances without being blocked substantially by the natural ligand for the receptor and which binds the antigen.
In one aspect of the invention, the binding agent employed is bispecific agent such as a heteroantibody, bispecific antibody, or other bispecific molecule having a binding specificity for the antigen and a binding specificity for a surface receptor of an antigen-presenting cell, such as a mononuclear phagocyte (e.g., a macrophage).
As used herein, the term “heteroantibody” refers to a conjugate of at least the antibody binding sites of two or more antibody molecules of different specificities.
An “antibody binding site” is that portion of the antibody molecule which binds a particular antigenic site. This antibody binding site includes an immunoglobulin variable domain that comprises three hypervariable regions flanked by four relatively conserved framework regions. The hypervariable regions are believed to be responsible for the binding specificity of individual antibodies.
The term “bispecific antibody” refers to a single, divalent antibody which has two different antigen binding sites (variable regions).
A “bispecific molecule” is one which has two different binding specificities and which can be bound to two different molecules or two different sites on a molecule concurrently.
The bispecific binding agent binds the cellular receptor, such as an Fc receptor, and targets the antigen to the cell. In some embodiments, this bispecific binding agent binds the cellular receptor without substantially being blocked by the natural ligand for the receptor. In a preferred embodiment, the bispecific binding agent specifically binds an Fc receptor of an antigen-presenting cell for immunoglobulin G (IgG) without being blocked by IgG. Preferred binding agents are specific for Fc&ggr;RI, Fc&ggr;RII, and Fc&ggr;RIII. In a particularly preferred embodiment, the agent specifically binds the high affinity Fc receptor for immunoglobulin G (Fc&ggr;RI) on macrophages.
In another aspect of the invention, a preferred binding agent is an antibody or binding fragment thereof which includes one or more complementarity determining regions.
As used herein, “complementarity determining region” includes one hypervariable region of an immunoglobulin molecule and selected amino acids disposed in the framework regions which flank that particular hypervariable region in an immunoglobulin molecule.
In some aspects of the invention, the binding agent includes at least two antibody binding fragments linked together by chemical methods or genetically linked via recombinant DNA techniques. One preferable binding agent is a Fab—Fab conjugate, wherein the first Fab binds the high affinity Fc receptor as described above, and the second Fab binds the antigen.
The binding agent of the invention is used to stimulate in a subject an immune response to an antigen. In this method a binding agent and an antigen are provided and administered in a pharmacologically acceptable medium to the subject. The binding agent targets the antigen to the antigen-presenting cell in the subject.
The antigen to be targeted can be derived from a foreign pathogen such as a viral, bacterial, or parasite antigen, or it can be derived from endogenous diseased host cells such as tumor associated antigens on tumor cells. Preferred binding agents include antibodies specific for antigens derived from hepatitis virus such as the hepatitis surface antigen, or an HIV antigen. Other binding agents bind an epitope on bee venom, pollen, or dust mite antigen.
Generally, the antigen is administered as a preformed, chemically coupled complex with the binding agent. Alternatively the antigen is incorporated into the binding agent through recombinant DNA techniques to create a genetic hybrid that codes for a fusion product including the binding agent and antigen. In some cases, however, the antigen and the bispecific binding agent are administered separately or the binding agent may be administered alone.
In another embodiment of the invention, the antigen is directly bound to a receptor-binding agent to create bispecific molecules (e.g., receptor-specific antigens). For example, the antigen can be covalently coupled to an antibody which binds the Fc receptor without being blocked by IgG.
The binding agent which binds an Fc receptor may also be incorporated into a lipid emulsion or the outer layer of a liposome which contains the antigen. Preferably, the binding agent is an antibody which recognizes the Fc&ggr;RI receptor. An additional aspect of the invention is a vaccine including the molecular complex of the invention in a pharmacologically acceptable medium.
The compositions of this invention can be used to treat or prevent infectious diseases such as hepatitis B, to neutralize the acute phase of an infection by a pathogenic organism, to stimulate the immune system in instances of chronic infection of such an organism, to deplete antigen in the circulation of a subject, and to treat tumors.
This invention also relates to methods and compositions used to induce IgG responses against allergens to effect tolerance in the case of IgE-mediated type I hypersensitivity, and to induce a state of T cell tolerance to allergens which would interfere with the development of IgE mediated responses. In these methods a molecular complex is administered which consists of an allergen which binds to IgE on mast cells and basophils, complexed to a heteroantibody that binds the high affinity Fc receptor without being blocked by IgG binding to the receptor. Enough of the complex is administered to the circulation of a subject such that an immune response is induced, which may include the production of allergen-specific IgG, thereby inhibiting the binding of the allergen to IgE on mast cells and basophils. Alternatively, the administration of the complex induces a state of T cell tolerance to the allergen by binding to naive B cells, thereby interfering with an IgE-mediated type I reaction.
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patent: 4950480 (1990-08-01), Barber et al.
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Farci et al Science vol. 258:135-140, 1992.*
Bukh et al Seminars in Liver Disease vol. 15 No. 1 41-63, 1995.*
Fahey et a
Fanger Michael W.
Gosselin Edmund J.
Guyre Paul M.
Romet-Lemonne Jean Loup
Bansal Geetha P.
Dini Peter W.
Lahive & Cockfield LLP
Medarex Inc.
Remillard Jane E.
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