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Chapter 4 - Immunological properties of botulinum neurotoxins

Published online by Cambridge University Press:  05 February 2014

Hans Bigalke
Institute of Toxicology, Hannover Medical School, Hannover, Germany
Dirk Dressler
Movement Disorder Section, Department of Neurology, Hannover Medical School, Hannover, Germany
Jürgen Frevert
Institute of Toxicology, Hannover Medical School, Hannover, Germany
Daniel Truong
The Parkinson’s and Movement Disorders Institute, Fountain Valley, California
Dirk Dressler
Department of Neurology, Hannover University Medical School
Mark Hallett
George Washington University School of Medicine and Health Sciences, Washington, DC
Christopher Zachary
Department of Dermatology, University of California, Irvine
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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 (Göschel 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.

Publisher: Cambridge University Press
Print publication year: 2014

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Aoki, KR (2002). Immunological and other properties of therapeutic botulinum toxin serotypes. In Brin, MF, Jankovic, J, Hallett, M (eds.) Scientific and Therapeutic Aspects of Botulinum Toxin. Philadelphia, PA: Lippincott, Williams & Wilkins, pp. 103–13.Google Scholar
Atassi, MZ (2006). On the enhancement of anti-neurotoxin antibody production by subcomponents HA1 and HA3b of Clostridium botulinum type B 16S toxin-haemagglutinin. Microbiology, 152, 1891–5.CrossRefGoogle ScholarPubMed
Callaway, JE (2004). Botulinum toxin type B (Myobloc®): pharmacology and biochemistry. Clin Dermatol, 22, 23–8.CrossRefGoogle Scholar
Chinnapongse, RB, Lew, MF, Ferreira, JJ et al. (2012). Immunogenicity and long-term efficacy of botulinum toxin type B in the treatment of cervical dystonia: report of 4 prospective, multicenter trials. Clin Neuropharmacol, 35, 215–23.CrossRefGoogle ScholarPubMed
Choi, NW, Estes, MK, Langridge, WH (2006). Ricin toxin B subunit enhancement of rotavirus NSP4 immunogenicity in mice. Viral Immunol, 19, 54–63.CrossRefGoogle ScholarPubMed
Critchfield, J (2002). Considering the immune response to botulinum toxin. Clin J Pain, 18(Suppl), S133–41.CrossRefGoogle ScholarPubMed
Dressler, D (2006). Pharmacological aspects of therapeutic botulinum toxin preparations. Nervenarzt, 77, 912–21.CrossRefGoogle ScholarPubMed
Dressler, D (2012). Five-year experience with incobotulinumtoxinA (Xeomin). The first botulinum toxin drug free of complexing proteins. Eur J Neurol, 19, 385–9.CrossRefGoogle ScholarPubMed
Dressler, D, Bigalke, H (2004). Antibody-induced failure of botulinum toxin type B therapy in de novo patients. Eur Neurol, 52, 132–5.CrossRefGoogle ScholarPubMed
Dressler, D, Hallett, M (2006). Immunological aspects of Botox®, Dysport® and Myobloc®/NeuroBloc®. Eur J Neurol, 13(Suppl 1), 11–15.CrossRefGoogle Scholar
Dressler, D, Lange, M, Bigalke, H (2005). The mouse diaphragm assay for detection of antibodies against botulinum toxin type B. Mov Disord, 20, 1617–19.CrossRefGoogle ScholarPubMed
Frevert, J (2010). Content of botulinum neurotoxin in Botox®/Vistabel®, Dysport®/Azzalure®, and Xeomin®/Bocouture®. Drugs R D, 10, 67–73.CrossRefGoogle Scholar
Fujinaga, Y, Matsumura, T, Jin, Y, Takegahara, Y, Sugawara, Y (2009). A novel function of botulinum toxin-associated proteins: HA proteins disrupt intestinal epithelial barrier to increase toxin absorption. Toxicon, 54, 583–6.CrossRefGoogle ScholarPubMed
Göschel, H, Wohlfarth, K, Frevert, J, Dengler, R, Bigalke, H (1997). Botulinum A toxin therapy: neutralizing and nonneutralizing antibodies: therapeutic consequences. Exp Neurol, 147, 96–102.CrossRefGoogle ScholarPubMed
Hambleton, P (1992). Clostridium botulinum toxins: a general review of involvement in disease, structure, mode of action and preparation for clinical use. J Neurol, 239, 16–20.CrossRefGoogle ScholarPubMed
Herrmann, J, Geth, K, Mall, V et al. (2004). Clinical impact of antibody formation to botulinum toxin in children. Ann Neurol, 55, 732–5.CrossRefGoogle ScholarPubMed
Honko, AN, Sriranganathan, N, Lees, CJ, Mizel, SB (2006). Flagellin is an effective adjuvant for immunization against lethal respiratory challenge with Yersinia pestis. Infect Immun, 74, 1113–20.CrossRefGoogle ScholarPubMed
Hunt, TJ (2007). Botulinum toxin composition. US Patent Application 2007/0025019.
Kessler, KR, Skutta, M, Benecke, R (1999). Long-term treatment of cervical dystonia with botulinum toxin A: efficacy, safety, and antibody frequency. German Dystonia Study Group. J Neurol, 246, 265–74.CrossRefGoogle ScholarPubMed
Kromminga, A, Schellekens, H (2005). Antibodies against erythropoietin and other protein-based therapeutics: an overview. Ann N Y Acad Sci, 1050, 257–65.CrossRefGoogle ScholarPubMed
Lange, O, Bigalke, H, Dengler, R et al. (2009). Neutralizing antibodies and secondary therapy failure after treatment with botulinum toxin type A: much ado about nothing?Clin Neuropharmacol, 32, 213–18.CrossRefGoogle ScholarPubMed
Lee, JC, Yokota, K, Arimitsu, H et al. (2005). Production of anti-neurotoxin antibody is enhanced by two subcomponents, HA1 and HA3b, of Clostridium botulinum type B 16S toxin-haemagglutinin. Microbiology, 151, 3739–47.CrossRefGoogle ScholarPubMed
Lee, SE, Kim, SY, Jeong, BC et al. (2006). A bacterial flagellin, Vibrio vulnificus FlaB, has a strong mucosal adjuvant activity to induce protective immunity. Infect Immun, 74, 694–702.CrossRefGoogle Scholar
Oshima, M, Deitiker, PR, Jankovic, J et al. (2011). Human T-cell responses to botulinum neurotoxin. Proliferative responses in vitro of lymphocytes from botulinum neurotoxin A-treated movement disorder patients. J Neuroimmunol, 237, 66–72.CrossRefGoogle ScholarPubMed
Panjwani, N, O’Keeffe, R, Pickett, A (2008). Biochemical, functional and potency characteristics of type A botulinum toxin in clinical use. Botulinum J, 1, 153–66.CrossRefGoogle Scholar
Paus, S, Bigalke, H, Klockgether, T (2006). Neutralizing antibodies against botulinum toxin A after a wasp sting. Arch Neurol, 63, 1808–9.CrossRefGoogle ScholarPubMed
Pickett, A, Shipley, S, Panjwani, N, O’Keeffe, R, Sing, BR (2005). Characterisation and consistency of botulinum A toxin-hemagglutinin complex used for clinical therapy. In Proceedings of the International Conference on Basic and Therapeutic Aspects of Botulinum and Tetanus Toxins, Denver, 23–25 June 2005.Google Scholar
Shankar, G, Pendley, C, Stein, KE (2007). A risk-based bioanalytical strategy for the assessment of antibody immune responses against biological drugs. Nat Biotechnol, 25, 555–61.CrossRefGoogle ScholarPubMed
Shenyan, G, Rumpel, S, Zhou, J et al. (2012). Botulinum neurotoxin is shielded by NTNHA in an interlocked complex. Science, 335, 977–81.Google Scholar
Siegel, LS (1989). Evaluation of neutralizing antibodies to type A, B, E, and F botulinum toxins in sera from human recipients of botulinum pentavalent (ABCDE) toxoid. J Clin Microbiol, 27, 1906–8.Google Scholar
Strotmeier, J, Willjes, G, Binz, T, Rummel, A (2012). Human synaptotagmin-II is not a high affinity receptor for botulinum neurotoxin B and G: increased therapeutic dosage and immunogenicity. FEBS Lett, 586, 310–13.CrossRefGoogle ScholarPubMed
Wohlfarth, K, Goschel, H, Frevert, J, Dengler, R, Bigalke, H (1997). Botulinum A toxins: units versus units. Naunyn-Schmiedeberg Arch Pharmacol, 355, 335–40.CrossRefGoogle ScholarPubMed

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