Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Monoclonal antibody or fragment thereof
Reexamination Certificate
2001-11-07
2004-08-24
Nolan, Patrick J. (Department: 1644)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Monoclonal antibody or fragment thereof
C424S183100
Reexamination Certificate
active
06780413
ABSTRACT:
TECHNICAL FIELD
Compositions comprising a toxin conjugated to an antibody selectively reactive to a muscle specific antigen. Methods of using the immunotoxin conjugates for treatment of focal muscle spasms are also provided.
BACKGROUND OF THE INVENTION
A variety of neurological disorders are characterized by disabling, involuntary muscular spasms. The most successful treatment for focal muscle spasm is intramuscular injection of the botulinum toxin A (BTX), the only pharmaceutical formulation of botulinum toxin currently on the market. Intramuscular injection of BTX weakens the muscles and reduces the symptoms. (Jankovic and Brin,
N. Engl. J. Med
., (1991) 324:1186-1194; Stell and Moore, History and current applications of botulinum toxin treatment. In: Moore P, ed. Handbook of botulinum toxin treatment. Oxford: Blackwell Science, Inc., 1995:3-15; Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Assessment: the clinical usefulness of botulinum toxin-a in treating neurologic disorders.
Neurology
(1990) 40:1332-1336; Coffield et a. The site and mechanism of action of botulinum neurotoxin. In: Jankovic J, Hallett M, eds. Therapy with botulinum toxin. New York: Marcel Dekker, Inc., (1994) 3-14). However, the therapeutic effect of BTX is transient and as the BTX paralytic effects wane, patients usually receive additional injections. For many patients, repeated exposure to BTX has been accompanied with decreasing efficacy and duration of benefit. Collateral sprouts of denervated motor nerve terminals and increasing titers of toxin neutralizing antibodies are two mechanisms of resistance to BTX (Coffield et al., supra, Jankovic and Schwartz,
Neurology
(1995) 45:1743-1746). As a result, larger and more frequent doses of BTX become necessary for relief of the spasm, increasing the risk of side-effects. Eventually, some patients become completely refractory to treatment.
Accordingly, what is needed in the art is a means to treat focal muscle disorders with greater specificity and duration of effect. The present invention provides these and other advantages.
SUMMARY OF THE INVENTION
In one aspect the present invention is directed to a method of treating a focal muscle spasm. The method comprises the steps of administering, by intramuscular injection, a therapeutically effective dose of an immunotoxin conjugate to a muscle of the focal muscle spasm. The immunotoxin conjugate comprises an antibody conjugated to a toxin selected from the group consisting of: ricin and abrin, and the antibody is selectively reactive, under immunologically reactive conditions, to a nicotinic acetylcholine receptor (nAchR). In preferred embodiments the antibody is a monoclonal antibody. Typically, the mammalian acetylcholine receptor is a human acetylcholine receptor. In particularly preferred embodiments the toxin is ricin. Typically the focal muscle spasm is selected from the group consisting of: blepharospasm, cervical dystonia, hand dystonia, limb dystonia, hemifacial spasm, bruxism, strabismus, VI nerve palsy, spasmodic dysphonia, and oromandibular dystonia. In other embodiments a therapeutically effective amount of the immunotoxin conjugate is administered with a therapeutically effective amount of botulinum toxin, as an immunoconjugate or in unconjugated form.
In another aspect the present invention relates to a method of treating a focal muscle spasm. The method comprises the steps of administering, by intramuscular injection, a therapeutically effective dose of an immunotoxin conjugate to a muscle of the focal muscle spasm. The immunotoxin conjugate comprises an antibody conjugated to a galactose binding moiety and a toxin selected from the group consisting of: ricin-A and abrin-A, and the antibody is selectively reactive, under immunologically reactive conditions, to a nicotinic acetylcholine receptor (nAchR). In some embodiments the galactose binding moiety is selected from the group consisting of: ricin-B and abrin-B. In preferred embodiments the antibody is a monoclonal antibody. Typically, the mammalian acetylcholine receptor is a human acetylcholine receptor. In particularly preferred embodiments the toxin is ricin. Typically the focal muscle spasm is selected from the group consisting of: blepharospasm, cervical dystonia, hand dystonia, limb dystonia, hemifacial spasm, bruxism, strabismus, VI nerve palsy, spasmodic dysphonia, and oromandibular dystonia.
In another aspect the present invention relates to an immunotoxin conjugate, comprising an antibody conjugated to a toxin selected from the group consisting of: ricin and abrin, where the antibody is selectively reactive, under immunologically reactive conditions, to a mammalian nicotinic acetylcholine receptor. In preferred embodiments the antibody is a monoclonal antibody. Typically, the mammalian acetylcholine receptor is a human acetylcholine receptor. In particularly preferred embodiments the toxin is ricin.
REFERENCES:
patent: 5183462 (1993-02-01), Borodic
patent: 5239062 (1993-08-01), Blattler et al.
patent: 5562907 (1996-10-01), Arnon
patent: 5721215 (1998-02-01), Aoki et al.
patent: 0 770 395 (1997-02-01), None
Appel, S.H. et al., “Accelerated degradation of acetylcholine receptor from cultured rat myotubes with myasthenia gravis sera and globulins,” Proc Natl Acad Sci U S A. May 1977;74(5):2130-4.
Barbet, J. et al., “Specific Toxicity to Activated T and B Lymphocytes of a Ricin A Immunotoxin Directed Against the Class 1 MHC Antigen H-2 K” Antibody, Immunoconj. Radiopharmaceuticals 1(2):169-180 (1988).
Borodic, G. et al., “Botulinum toxin therapy, immunologic resistance, and problems with available materials,” Neurology. Jan. 1996;46(1):26-9.
Christiansen, S.P. et al., “Acute effects of the skeletal muscle-specific immunotoxin ricin-mAb 35 on extraocular muscles of rabbits,” Invest Ophthalmol Vis Sci. Oct. 2000;41(11):3402-9.
Clementi, F. et al., “Acetylcholine receptor degradation: study of mechanism of action of inhibitory drugs ” Eur J Cell Biol. Jan. 1983;29(2):274-80.
Clementi, F. et al., “Antibody induced internalization of acetylcholine nicotinic receptor: kinetics, mechanism and selectivity,” Eur J Cell Biol. May 1985;37:220-8.
de la Cruz, R.R. et al., “Behavior of cat abducens motoneurons following the injection of toxic ricin into the lateral rectus muscle,” Brain Res. Mar. 29, 1991;544(2):260-8.
de la Cruz, R.R. et al., “Effects of target depletion on adult mammalian central neurons: functional correleates,” Neuroscience. Jan 1994;58(1):81-97.
de la Cruz, R.R. et al., “Neurotoxic lesion of oculomotor neruons: evidence for rearrangement of axon terminals of surviving afferent neurons,” Neurotoxicology. 1994 Fall;15(3):633-6.
de al Cruz, R.R. et al., “Response of adult cat abducens internuclear interneurons to selective removal of their target motoneurons,” Exp Brain Res. 1991;84(1):167-72.
Gardner, J.M. et al., “Acetylcholine receptor degradation measured by density labeling: effects of cholingeric ligands and evidence against recycling,” Cell. Mar. 1979;16(3):661-74.
Goldmacher, V.S. et al., “The specific cytotoxicity of immunoconjugates containing blocked ricin is dependent on the residual binding capacity of blocked ricin: evidence that the membrane binding and A-chain translocation activities of ricin cannot be speparated,” Biochem Biophys Res Commun.Mar. 16, 1992;183(2):758-66.
Greenfield, L. et al., “Mutations in diphtheria toxin separate binding from entry and amplify immunotoxin selectivity,” Science. Oct. 23, 1987;238(4826):536-9.
Griffin, T.W. et al., “Chimeras, Castor Beans and Cancer: Antibody and Ligand-Toxin Conjugates as Therapeutic Agents,” In: Cancer Therapy in the Twenty-First Century: Molecular and Immunologic Approaches, Futura Publishing Co., Inc., Mt. Kisco, NY 1994.
Grossband, M.L. et al., “Correlation between in vivo toxicity and preclinical in vitro parameters for the immunotoxin anti-B4-blocked ricin,” Cancer Res. Aug. 1, 1992;52(15):4200-7.
Holds, John B. et al., “Botulinum A toxin injection. Failures in clinical practice and a biochemica
Dalakas Marinos C.
Hallett Mark
Hott Jonathan S.
Youle Richard J.
Auerbach Jeffrey I.
Liniak, Berenato & White, LLC
Nolan Patrick J.
The United States of America as represented by the Department of
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