Immunological properties of botulinum neurotoxins

Introduction Botulinum neurotoxins (BoNTs) are used to treat a large number of muscle hyperactivity disorders including dystonia, spasticity, tremor and autonomic disorders (e.g. hyperhidrosis and hypersalivation), as well as facial wrinkles. Commercially available products differ with respect to serotype, formulation and purity. Not all products are approved in all countries. Serotype A-containing products are Botox (onabotulinumtoxinA), Dysport (abobotulinumtoxinA) and Xeomin (incobotulinumtoxinA), whereas NeuroBloc/MyoBloc (rimabotulinumtoxinB) contains serotype B. The active ingredient in all products is BoNT, a two-chain protein with a molecular weight of 150 kDa. BoNT type A (BoNT-A) inhibits release of the neurotransmitter acetylcholine by cleaving synaptosomal associated protein-25, a SNARE protein, while BoNT type B (BoNT-B) cleaves synaptobrevin (vesicle-associated membrane protein-2). Since BoNTs are foreign proteins, the human immune system may respond to them with the production of specific anti-BoNT antibodies. The probability of developing such antibodies increases with the BoNT doses applied (Goschel et al ., 1997; Lange et al ., 2009). Whether other drug-related factors might contribute to immune responses is discussed below. Patient-related factors may also be involved in triggering antibody formation to BoNT. Recently, a patient was reported who was treated with abobotulinumtoxinA for several years with good results until he developed anti-BoNT-induced therapy failure after he received BoNT following a wasp sting (Paus et al ., 2006). Since components of wasp poison are effective immunostimulants, a preactivation of lymphocytes may have triggered antibody formation against BoNT-A. In the following, a method is presented for the quantification of anti-BoNT in sera; the immune cell reactions to antigens are described and drug-related immune responses are discussed.