The science and manufacturing behind botulinum neurotoxin type A-ABO in clinical use.

ABSTRACT

BACKGROUND: Since the first comprehensive description of the physiologic effects of botulism toxicity in the 1820s, specific formulations of botulinum neurotoxin type A (BoNT-A) have been developed. Now, a new botulinum neurotoxin type A formulation (BoNTA-ABO; Dysport [abobotulinumtoxinA]; Medicis Aesthetics, Scottsdale, AZ) has been made available in the United States and these same physiologic effects have become beneficial clinical targets. This formulation has been used successfully for nearly 20 years in Europe and other countries under the trade name Dysport (Clostridium botulinum type A toxin-hemagglutinin complex; Ipsen Biopharm, Wrexham, UK). BoNT-A injections are administered to achieve temporary local flaccid paralysis of targeted muscles. Injection of BoNT-A formulations for aesthetic purposes was by far the most common minimally-invasive (nonsurgical) cosmetic procedure performed in the United States in 2008. OBJECTIVE: The objective of this review is to describe the latest data regarding the mechanism of action of BoNTA-ABO, the potential roles of neurotoxin-associated proteins (NAP), the manufacturing standards for these biologic products, and the specific manufacturing process and characteristics of BoNTA-ABO. METHODS: A systematic search using the US National Library of Medicine PubMed database was performed and the relevant articles were reviewed. Direct input and data from the worldwide manufacturer of Dysport have been included. RESULTS: The four sequential steps in the mechanism of action of BoNTA-ABO are binding, internalization, translocation, and intracellular proteolysis of the target protein. Although all BoNT-A products must meet standards for quality, potency, and safety, they should not be considered equivalent formulations because they have different production strains of the bacterium C botulinum, as well as different isolation and manufacturing processes that result in unique product characteristics. The production steps for Dysport-including a unique proprietary purification process using column chromatography and a unique proprietary finishing process-result in consistent and unique product features. Studies confirm that Dysport has a high degree of long-term batch-to-batch consistency for a range of specified properties, including specific potency, protein composition, toxin complex charge-density properties, and endopeptidase activity. In the native, natural form, NAP protect the endogenous neurotoxin from degradation in the acidic environment of the stomach; in biologic formulations, they may have effects on the structural stability, binding, uptake, and transcytosis of BoNT-A products in other areas of the body. NAP are most likely to stabilize the neurotoxin in a vial of clinical product. CONCLUSIONS: A thorough understanding of the mechanism of action, product characteristics, and effects of NAP is important to ensure appropriate and safe clinical use of BoNT-A products. Now approved in the United States, Dysport is an important addition to the group of available BoNT-A formulations.