Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Anti-idiotypic
Reexamination Certificate
1992-01-02
2002-08-27
Devi, S. (Department: 1645)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Anti-idiotypic
C424S138100, C424S148100, C424S160100, C424S164100, C424S151100, C530S387200, C530S387700, C530S388300, C530S388200, C530S388400, C530S388500, C530S388600
Reexamination Certificate
active
06440416
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a method of stimulating an immune response against malignant cells, pathogenic microorganisms, parasites or viruses in a patient using a primate “pseudoantigen” anti-idiotype antibody that acts as an immunogenic mimic of an antigen produced by or associated with a malignant cell, pathogenic microorganism, parasite or virus. A vaccine using such an anti-idiotype antibody is used in the foregoing method.
One of the major research goals in cancer, microbial or parasite therapy is to trigger the patient's immune system to actively respond to proliferation of the tumor or infectious agent. Certain pathologies, especially cancer and virus infections, appear to be resistant to the immune system because they exhibit characteristics that result in tolerance by the host or that disable the capability of the host's immune system to combat them.
The administration of anti-idiotype antibodies represents one of the most promising approaches to break the self-tolerance to tumor antigens. Anti-idiotype antibodies (termed Ab2) are antibodies directed against the variable region (antigen-binding site) of another antibody (Ab1), the idiotype, and some of these Ab2's (termed Ab2&bgr;) can mimic the three-dimensional structure of the antigen recognized by the Ab1. In turn, immunization with Ab2&bgr; antibodies can induce Ab3 antibodies with specificities similar to the original Ab1 antibodies (such Ab3 antibodies are called Ab1′).
In a variety of experimental systems, Ab2&bgr;'s have been able to induce specific immune responses in lieu of the original antigen. See, e.g., Nepom et al., Proc. Natl. Acad. Sci. USA, 81:2864-2867, 1984; Kennedy et al., Science (Wash., D.C.), 223:930-931, 1984; McNamara et al., Science (Wash., D.C.), 226:1325-1326, 1984; Grzych et al., Nature (Lond.), 316:74-76, 1985; Raychaudhuri et al., J. Immunol., 139:271-278, 1987; Dunn et al., Immunology, 60:181-186, 1987; Bhattacharya-Chatterjee et al., J. Immunol., 139:1354-1360, 1987; Viale et al., J. Immunol., 139:4250-4255, 1987; Smorodinsky et al., Eur. J. Immunol., 18:1713-1718; Kresina et al., J. Clin. Invest., 83:912-920, 1989; and Powell et al., J. Immunol., 142:1318-1324, 1989.
Various approaches using polyclonal or monoclonal Ab2 antibodies have been proposed for human therapy, but they all utilize immunoglobulins from foreign species, e.g., a mouse or goat, as immunogens. See, e.g., Herlyn et al., Proc. Natl. Acad. Sci. USA, 84:8055-8059, 1987; and Ferrone et al., 7th International Congress of Immunology (Abstract 117-9), Berlin, 1989.
Administration of such Ab2 molecules is likely to induce a strong immune response directed against the constant regions of the Ab2 molecule which would have no therapeutic value. Moreover, repeated immunization with foreign proteins can exert deleterious effects. Alternatively, administration of Ab2&bgr; molecules whose constant regions are identical or very similar to those of human immunoglobulins will induce an immune response restricted to idiotypic determinants. Antibodies obtained from animals such as monkeys, which are phylogenetically close to humans, can represent such an alternative. Indeed, baboon antibodies administered in cancer patients are less immunogenic than immunoglobulins from other animals.
In a variety of experimental systems, anti-idiotype antibodies have been shown to functionally mimic the antigen recognized by the Ab1 and to elicit a specific immune response in lieu of this original antigen. See, e.g., Bona et al., Ann. Immunol. (Paris), 136C:299-312, 1985. Furthermore, in two such systems, where the original antigens were the reovirus type 3 hemagglutinin and the random polymer GAT (glutamic acid, alanine and tyrosine), sequence analyses have shown homologies between these antigens and the complementary determining regions of the Ab2 molecules. See, Bruck et al., Proc. Notl. Acad. Sci. USA, 83:6578-6582, 1986; Ollier et al., EMBO J., 4:3681-3688, 1985.
Immunization with Ab2 antibodies mimicking microbial agents protected against challenges with the pathogenic agent in animal models and Ab2&bgr; antibodies would therefore represent valuable surrogate antigens when the original antigen (microbial or parasite) is not available for vaccination. The administration of a functional image antigen present on a foreign immunoglobulin molecule induced an immune response against a tolerized antigen in mice. Tumor antigens generally do not elicit a spontaneous immune response by the host. In a variety of animal models, immunization with Ab2 has been shown to prevent subsequent tumor growth. See, e.g., Raychaudhuri et al., supra; Dunn et al., supra; Powell et al., supra. In humans, clinical trials have shown that administration of murine Ab2 to cancer patients can induce tumor-binding Ab3 antibodies. It is necessary that the induced antibodies be therapeutically effective, but the beneficial effect of antibodies induced by murine Ab2 has not yet been shown. See Herlyn et al., supra; Ferrone et al., supra.
A need continues to exist for solutions to the problems noted above.
OBJECTS OF THE INVENTION
One object of the present invention is to provide a vaccine that will stimulate production of antibodies against normally tolerated tumor and viral antigens in human cancer patients and patients with normally intractable viral infections.
Another object of the invention is to provide a vaccine against pathogenic microorganisms and parasites.
Another object of the invention is to provide a method of treating cancer and infection by pathogenic microorganisms or parasites that uses a non-tumor and non-infectious agent to evoke an immune response specific to tumor or infectious agent antigens.
Another object of the invention is to induce immunity against the development of tumors and against the successful invasion of pathogenic microorganisms and parasites in healthy humans and animals.
Other objects of the invention will be apparent to those of ordinary skill in the art upon careful study of the following discussion and illustrative examples.
SUMMARY OF THE INVENTION
The foregoing objects are achieved by providing a method of stimulating an immune response in a human against malignant cells or an infectious agent, which comprises the step of administering to said human an immunogenic amount of a primate anti-idiotype antibody or antibody fragment that acts as an immunogenic functional mimic of an antigen produced by or associated with a malignant cell or an infectious agent. A method for preparing anti-idiotype antibodies and antibody fragments that mimic tumor or infectious agent antigens is provided, for use in the foregoing method and for preparing a vaccine therefor.
DETAILED DISCUSSION
Anti-idiotype antibodies that mimic tumor or infectious agent antigens are a safe and effective component of vaccines that can induce an immune response against cancers, pathogenic microorganisms, parasites and viruses, either as a therapy for patients suffering from malignancies or infections or as a preventive measure to repress the development of cancer or to ward off an invading microorganism, parasite or virus.
As used herein, “microbe” denotes virus, bacteria, rickettsia, mycoplasma, protozoa, fungi and like microorganisms, “parasite” denotes infectious, generally microsopic or very small multicellular invertebrates, or ova or juvenile forms thereof, which are susceptible to antibody-induced clearance or lytic or phagocytic destruction, e.g., malarial parasites, spirochetes and the like, while “infectious agent” or “pathogen” denotes both microbes and parasites.
Use of the term “antibody” herein will be understood to embrace whole antibodies, antibody fragments and subfragments and thus to be equivalent to the term “antibody/fragment” which is used interchangeably therefor in this discussion, unless otherwise noted. Antibodies can be whole immunoglobulin (IgG) of any class, e.g., IgG, IgM, IgA, IgD, IgE, chimeric antibodies or hybrid antibodies with dual or multiple antigen or epitope specifities, or fr
Goldenberg David M.
Hansen Hans J.
Devi S.
Foley & Lardner
Immunomedics Inc.
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