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Type a2 botulinum toxin preparation

a technology of botulinum toxin and preparation, which is applied in the field of type a2 botulinum toxin preparation, can solve the problems of reducing the efficacy of i>botulinum toxin, and achieve the effect of reducing clinical response and inducing antibody production

Inactive Publication Date: 2011-02-10
JURIDICAL FOUND THE CHEMO SERO THERAPEUTIC RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0034]The highly purified botulinum toxin (A2 NTX) according to the present invention from HA-negative Clostridium botulinum isolated from infant botulism pathogen has a therapeutic effect to a patient who has a neutralizing antibody to a type A1 botulinum toxin. Besides, as not comprising HA, A2 NTX is less likely to induce antibody production.
[0035]Furthermore, A2 NTX is useful for use as a pharmaceutical preparation for addressing decrease in clinical response caused by a neutralizing antibody to a type A1 botulinum toxin produced when a patient is treated with a pharmaceutical preparation comprising a type A1 botulinum toxin. Therefore, A2 NTX is useful for use as a medicament for treating a disease with muscle overactivity such as strabismus, blepharospasm, hemifacial spasm, spasmodic torticollis, post-stroke apasticity, cerebral palsy, spasmodic dysphonia, headache such as migraine, chronic pain such as lumbago, the stiffness in the shoulders, paresis occurring at the onset of Parkinson disease or multiple sclerosis, myofascial pain syndrome, spasm of the masticatory muscles, chronic anal fissure, overactive bladder, bruxism, facial myokymia, tic, local dystonia, or wrinkle.

Problems solved by technology

In recent years, a problem has been presented that repetitive administration of botulinum toxin may induce production of an anti-botulinum toxin antibody to diminish efficacy of the botulinum toxin.

Method used

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  • Type a2 botulinum toxin preparation
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  • Type a2 botulinum toxin preparation

Examples

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Effect test

example 1

Purification of NTX from Type A2 Clostridium botulinum

[0057]Using Chiba-H strain, type A Clostridium botulinum isolated from patients suffering from a disease with a muscle overactivity, botulinum type A, M toxin, was purified as described by Sakaguchi G., Biochemical aspects of botulism: Purification and oral toxicities of Clostridium botulinum progenitor toxins, 21-34, Lewis G E., 1981, Academic Press, New York.

[0058]The botulinum M toxin was dialyzed against 10 mM phosphate buffer (pH 7.5), adsorbed to DEAE Sepharose column equilibrated with the same buffer, and eluted with 0 to 0.3 mol / L NaCl gradient of the same buffer to separate the neurotoxin (NTX) from non-toxin proteins (NTNH). The obtained highly purified NTX (A2 NTX) was concentrated with YM-10 membrane (Amicon) to 1 mg / mL, dialyzed against 50 mM phosphate buffer (pH 7.5) and stored at −80° C. till use, which was used as A2 NTX.

example 2

Purification of LL toxin and NTX from Type A1 Clostridium botulinum

[0059]Using 62A strain, HA-negative type A1 Clostridium botulinum, the culture and purification of toxins were performed as described by Sakaguchi G. as in Example 1 to give LL toxin and M toxin. Furthermore, NTX was purified from M toxin and used as A1 NTX.

example 3

Construction of Model Rat with Decreased Response to Botulinum Toxin

[0060]LL toxin from 62A strain was diluted with 0.1 mol / L phosphate buffer (pH 6.4) to 0.3 mg / mL and put in a dialysis apparatus. Dialysis was performed at 30° C. for 7 days with a buffer for conversion into toxoid in an amount 100-fold higher than that of the diluted toxin. After dialysis, the toxoid was stored at 4° C. and proved to be nontoxic by administration to mice.

[0061]The toxoid at 10 μg / head was subcutaneously administered to rats (S / D, 6 weeks old, female) for three times at an interval of 2 weeks. The rats were bled 6 and 10 weeks after the 1st administration. Elevation in a neutralizing antibody titer due to A1 NTX was confirmed. A1 NTX, the same kind as the toxoid, at 2×106 U / head was administered to the gastrocnemius muscle of the left hind leg to confirm that CMAP amplitude was not decreased and the symptoms were not altered a day after the administration. CMAP measurement was done as described in W...

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Abstract

A pharmaceutical preparation for use in a patient who has a neutralizing antibody to a botulinum toxin from type A1 Clostridium botulinum (type A1 botulinum toxin), said preparation comprising as an active ingredient 150 kDa type A neurotoxin from type A2 Clostridium botulinum (A2 NTX); a medicament for treating a disease with muscle overactivity for use in a patient who has a neutralizing antibody to a type A1 botulinum toxin, said medicament comprising as an active ingredient said A2 NTX; a method for treating a patient who has a neutralizing antibody to a type A1 botulinum toxin, said method comprising administering said A2 NTX to the patient; and a method for use of A2 NTX in a patient who has said neutralizing antibody. In accordance with the present invention, a problem can be solved of decrease in clinical response caused by a neutralizing antibody to a type A1 botulinum toxin produced when a patient is treated with a pharmaceutical preparation comprising a type A1 botulinum toxin.

Description

TECHNICAL FIELD[0001]The present invention, for addressing decrease in clinical response due to a neutralizing antibody to a botulinum toxin from type A1 Clostridium botulinum (type A1 botulinum toxin), as occasioned when a patient is treated with a pharmaceutical preparation containing type A1 botulinum toxin, relates to a pharmaceutical preparation for administering to a patient suffering from a disease with a muscle overactivity an effective dosage amount of a type A neurotoxin (A2 NTX) of 150 kDa obtained from hemagglutinin (HA)-negative, type A2 Clostridium botulinum isolated as infant botulism pathogen, and a method for treating a patient having a neutralizing antibody to a type A1 botulinum toxin using said pharmaceutical preparation.BACKGROUND ART[0002]A botulinum toxin produced by Clostridium botulinum, anaerobic Gram-positive bacteria, is the most lethal neurotoxin on earth. It is classified into seven types, A, B, C, D, E, F and G, and the property of each type has been e...

Claims

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Application Information

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IPC IPC(8): A61K35/74A61P21/00C12N1/20C07K14/33A61K38/16
CPCA61K38/164A61K38/4893A61P21/00A61P21/02Y02A50/30
Inventor NAKAHIRA, SHINJITORII, YASUSHIGOTO, YOSHITAKASHINMURA, MIHOMUNECHIKA, SATOMIOKUDA, SACHIOKOZAKI, SHUNJI
Owner JURIDICAL FOUND THE CHEMO SERO THERAPEUTIC RES INST
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