Drug – bio-affecting and body treating compositions – Conjugate or complex of monoclonal or polyclonal antibody,...
Reexamination Certificate
1993-12-01
2001-11-20
Housel, James (Department: 1648)
Drug, bio-affecting and body treating compositions
Conjugate or complex of monoclonal or polyclonal antibody,...
C424S179100, C424S009100, C424S184100, C530S351000, C530S387100, C530S391300, C530S391500, C530S391700
Reexamination Certificate
active
06319500
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to reagents and methods for targeting a diagnostic and/or therapeutic agent to a focus of pathogenic infection by using as the targeting vehicle an antibody conjugate that specifically binds to one or more accessible epitopes of the pathogen or of a pathogen-associated antigen.
Drug therapy against pathogens is conventionally effected by means of systemic administration the drug in order to achieve a blood level which toxic to the pathogen wherever it is harbored in the body. Thus, a certain blood level is necessary in order to provide the proper concentration of the drug at the site of infection. This requires high doses and often does not achieve the desired toxicity without resulting in unacceptably adverse side-effects to the patient, since many of these drugs have general cytotoxic properties.
The development and description of murine monoclonal antibodies (MAbs) against infectious organisms has been the subject of a number of reviews (eg., M. C. Harris et al., Indian J. Pediatr., 54:481-488, 1987; S. Cohen, Brit. Med. Bull., 40:291-296, 1984; R. A. Polin, Eur J. Clin. Microbiol., 3:387-398, 1984; R. C. Nowinski et al., Science, 219:637-644, 1983; Part V, Monoclonal Antibodies to Microorganisms, Chapters 17-20, inclusive, In: R. H. Kennett et al., (eds.),
Monoclonal Antibodies. Hybridomas: A New Dimension in Biological Analyses
, New York and London, Plenum Press, 1980, pp. 295-362). These papers, and others in this area, have been concerned with the use of such monoclonal antibody reagents for improved diagnostic tests for the infectious microorganisms, including bacteria, viruses, protozoa and helminths.
It has been proposed that these MAbs can be used as such for both the diagnosis and therapy of certain bacterial diseases, such as group B streptococcal infections (Harris, cited above), but exclusively as diagnostic agents in viral diseases (Harris, cited above). In the case of group B streptococcal infections, MAbs were used in rodents to treat the infection, and it was found in these limited trials that only when the MAbs were infused early after infection was an effect achieved; at 6 hours or later, no survival of the animal occurred (Christensen et al., Pediatric Res., 18:1093-1096, 1984). In the case of malarial parasites, it has been shown that the Fab fragments of a monoclonal antibody directed against the surface coat of malaria sporozoites is active in protecting mice against malarial infection, indicating that it blocks attachment of sporozoites to host receptor cells (P. Potocnjak et al., J. Exp. Med., 151:1504-1513, 1980). This further indicates, since it is achieved by the immunoglobulin molecule lacking the Fc portion, that the protective antibody action is independent of complement or cells.
These animal experiments indicate that early infections can be affected by the use of organism-specific MAbs in well-controlled laboratory experiments involving certain bacteria and parasites. Despite these reports a number of years ago, MAbs have not been shown to have a therapeutic role in infectious diseases in humans. One major reason has been that such MAbs exert a protective action only in specific, usually early stages of infection, being less able to interact with the infectious organisms when they have disseminated into tissue reservoirs that are less accessible to interaction with the injected MAbs. Use of such MAbs to form therapeutic conjugates is not suggested by the references.
A need therefore exists for a method of targeting a diagnostic agent, e.g., an imaging agent, or a therapy agent, e.g., a drug or radioisotope, to a focus of infection with higher efficiency and an enhanced therapeutic index to permit more effective diagnosis and/or treatment of the infection.
OBJECTS OF THE INVENTION
One object of the present invention is to provide an effective and selective method of targeting a focus of infection.
Another object of the invention is to provide diagnostic and therapeutic agents with high specificity for foci of infection.
Another object of the invention is to provide an alternative or adjunct to chemotherapy for treatment of certain microbial and parasitic infections that are not amenable or relatively unresponsive to chemotherapy and which cause debilitating or life-threatening illness.
Another object of the invention is to improve the therapeutic index of a chemotherapeutic agent and/or radiopharmaceutical.
Other objects of the present invention will become more apparent to those of ordinary skill in the art in light of the following discussion.
SUMMARY OF THE INVENTION
These and other objects of the present invention are achieved by providing a method of targeting a diagnostic or therapeutic agent to a focus of infection, which comprises injecting a patient infected with a pathogen parenterally with an antibody conjugate which specifically binds to an accessible epitope of said pathogen or of a pathogen-associated antigen accreted at said focus of infection, said antibody conjugate further comprising a bound diagnostic or therapeutic agent for detecting, imaging or treating said infection.
The invention further provides polyspecific or monospecific antibody conjugates for targeting foci of infection, comprising an immunoreactive component including at least one substantially monospecific antibody or antibody fragment, conjugated to at least one diagnostic or therapeutic agent, wherein the antibody or antibody fragment specifically binds to an accessible epitope of the pathogen or of a pathogen-associated antigen. These can be provided in the form of sterile injectable preparations and kits for use in practicing the foregoing method.
DETAILED DESCRIPTION
Antimicrobial agents are conventionally classified into four main groups, based upon their affecting (1) bacterial cell-wall synthesis, (2) the cytoplasmic membrane, (3) protein synthesis, and (4) nucleic acid synthesis, and often each of these groups can be subdivided into several classes. Reviews of antimicrobial chemotherapy can be found in the chapter by M. P. E. Slack (In: Oxford Textbook of Medicine, Second Ed., Vol. I, edited by D. J. Weatherall, J. G. G. Lidingham, and D. A. Warrell, pp. 5.35-5.53; Oxford University Press, Oxford/Melbourne/New York, 1987) and in Section XII, Chemotherapy of Microbial Diseases (In: Goodman and Gilman's The Pharmacological Basis of Therapeutics, 6th Ed., Goodman et al., Eds., pp. 1080-1248; Macmillan Publishing Co., New York, 1980).
As indicated in these texts, some antimicrobial agents are selective in their toxicity, since they kill or inhibit the microorganism at concentrations that are tolerated by the host (i.e., the drug acts on microbial structures or biosynthetic pathways that differ from those of the host's cells). Other agents are only capable of temporarily inhibiting the growth of the microbe, which may resume growth when the inhibitor is removed. Often, the ability to kill or inhibit a microbe or parasite is a function of the agent's concentration in the body and its fluids.
Whereas these principles and the available antimicrobial drugs have been successful for the treatment of many infections, particularly bacterial infections, other infections have been resistant or relatively unresponsive to systemic chemotherapy, e.g., viral infections and certain fungal, protozoan and parasitic infections.
As used herein, “microbe” denotes virus, bacteria, rickettsia, mycoplasma, protozoa and fungi, while “pathogen” denotes both microbes and infectious multicellular invertebrates, e.g., helminths, spirochetes and the like.
Virus can infect host cells and “hide” from circulating systemic drugs. Even when viral proliferation is active and the virus is released from host cells, systemic agents can be insufficiently potent at levels which are tolerated by the patient.
Similarly, a number of fungal, protozoan and parasitic infections have been resistant to systemic drug therapy, at least in part because an effective antipathogenic dose of a drug has been above the level which is tolerated b
Foley & Lardner
Housel James
Immunomedics Inc.
Nelson Brett
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