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Immunotoxin (mAB-RICIN) for the treatment of focal movement disorders

a technology of focal movement and immunonotoxin, which is applied in the field of immunonotoxin (mabricin) for the treatment of focal movement disorders, can solve the problems of increasing the risk of side effects, accompanied by repeated exposure to btx, and reducing the effect and duration of benefi

Inactive Publication Date: 2005-12-01
UNITED STATES OF AMERICA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0004] 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.

Problems solved by technology

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.
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.

Method used

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  • Immunotoxin (mAB-RICIN) for the treatment of focal movement disorders
  • Immunotoxin (mAB-RICIN) for the treatment of focal movement disorders

Examples

Experimental program
Comparison scheme
Effect test

example 1

ITX Cytotoxic Activity

[0061] A. Protein Purification

[0062] Ricin was purified from seeds of Ricinus communis by elution from Sepharose columns with N-acetylgalactosamine, as described by Nicolson et al (Biochemistry (1974) 13:196-204). Onconase was purified from the eggs of Rana pipiens, as described previously (Ardelt et al., J. Biol. Chem., (1991) 266:245-251). CRM 107 (a mutated form of diphtheria toxin with an inactivated binding domain) was purified as described previously (Greenfield L, Johnson V G, Youle R J, Science, 1987;238:536-539). The plant lectin, RCA120, was purchased from Sigma (St. Louis,. MO). MoAb 35 (an anti-nicotinic acetylcholine receptor monoclonal antibody) (Tzartos et al., J. Biol. Chem., (1981) 256:8635-8645; Clementi and Sher, Eur. J. Cell Biol., (1985) 37:220-228; Tzartos et al., Proc. Natl. Acad. Sci. USA, 1982;79:188-192) was purified from ascites (mouse) by ammonium sulfate precipitation and DEAE sepharose.

[0063] B. Immunotoxin Synthesis

[0064] Conj...

example 2

Cytotoxic Activity Of Other Protein Toxins

[0077] In an effort to identify the most potent and specific reagent, three other toxins: RCA120, Tfn-CRM 107, and onconase were investigated. RCA120 (MW=120,000) is a tetrameric plant lectin similar to a dimer of ricin (Lin and Li, Eur. J. Biochem. (1980) 105:453-459). Myotubes and myoblasts were nearly equally sensitive to RCA120 (IC50=3.5×10−10 M). Tfn-CRM 107 (MW=150,000) is an immunotoxin (Johnson et al., J. Neurosurg. (1989) 70:240-248) selective for the transferrin receptor and high transferrin receptor numbers on myotube cell cultures and high rates of iron uptake (Sorokin et al., J. Cell Physiol. (1987) 131:342-353) have been observed. Tfn-CRM 107 was nearly as toxic to myotubes (IC50=3×10−7 M) as myoblasts (IC50=2×10−7 M). However, overall myotoxicity was lower than predicted. Onconase (MW=12,000), currently in phase III clinical trials for treatment of pancreatic cancer, was 2.5-fold more toxic to myotubes than myoblasts at the I...

example 3

Rat Muscle Biopsies

[0078] Female Balb / c mice (16-18 g) received 0.3 ml IP injections (30 g needle). For each agent, five serial 2-fold dilutions of toxin were tested. At each dilution three mice were injected and the experiment was repeated twice. The maximum tolerated dose was determined to be the maximum dose / kg where all animals survived. This dose was used as an estimate of the maximum tolerated dose (MTD) in rats. The maximum tolerated dose of ITX was 2 μg / kg in mice. Thus, for 250 g rats 1 / 100 and 1 / 300 of the maximum tolerated dose of ITX was estimated to be 5 ng and 1.7 ng, respectively. These doses of ITX were delivered intramuscularly to the rats in a volume of 30 μl. Hereafter in this example, comparable doses of the toxins refers to doses that are the same fraction of the maximum tolerated dose (or LD50 in the case of BTX). This comparison yields an estimate of the therapeutic window, which may be a useful gauge of the toxins clinical potential.

[0079] Frozen and lyophi...

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Abstract

Compositions and methods for treatment of focal muscle spasms. Immunotoxin conjugates comprise a toxin conjugated to an antibody reactive to a muscle specific antigen.

Description

TECHNICAL FIELD [0001] 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 [0002] 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 clin...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K36/47A61K39/395A61K47/48C07K16/28
CPCA61K47/48446A61K47/48453C07K16/286A61K47/48561A61K2039/505A61K47/48476A61K47/6819A61K47/6821A61K47/6827A61K47/6849
Inventor HOTT, JONATHAN S.YOULE, RICHARD J.HALLETT, MARKDALAKAS, MARINOS C.
Owner UNITED STATES OF AMERICA
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