BACKGROUND: For many indications, BoNT/A is repetitively injected with the risk of developing neutralizing antibodies (NABs). Therefore, it is important to analyze whether there is a difference in antigenicity between the different licensed BoNT/A preparations. METHODS: In this cross-sectional study, the prevalence of NABs was tested by means of the sensitive mouse hemidiaphragm assay (MHDA) in 645 patients. Patients were split into those having exclusively been treated with the complex protein-free incoBoNT/A preparation (CF-MON group) and those having started BoNT/A therapy with a complex protein-containing BoNT/A preparation (CC-I group). This CC-I group was split into those patients who remained either on abo- or onaBoNT/A (CC-MON group) and those who had been treated with at least two BoNT/A preparations (CC-SWI group). To balance treatment duration, only CC-MON patients who did not start their BoNT/A therapy more than 10 years before recruitment (CC-MON-10 group) were further analyzed. The log-rank test was used to compare the prevalence of NABs in the CF-MON and CC-MON-10 group. RESULTS: In the CF-MON subgroup, no patient developed NABs. In the CC-I group, 84 patients were NAB-positive. NABs were found in 33.3% of those who switched preparations (CC-SWI) and in 5.9% of the CC-MON-10 group. Kaplan-Meier curves for remaining NAB-negative under continuous BoNT/A therapy were significantly different (p < 0.035) between the CF-MON and CC-MON-10 group. CONCLUSION: Frequent injections of a complex protein-containing BoNT/A preparation are associated with significantly higher risks of developing NABs than injections with the same frequency using the complex protein-free incoBoNT/A preparation.

Brain and Mind Center University of Sydney Sydney Australia

Department of Neurology Medical Faculty Heinrich Heine University Moorenstrasse 5 40225 Düsseldorf Germany

Department of Neurology Medical University of Vienna Vienna Austria

Department of Neurology Palacky University Olomouc Olomouc Czech Republic

Experimental and Clinical Research Center Charité Universitätsmedizin Berlin Freie Universität Berlin and Humboldt Universität zu Berlin Berlin Germany

Institute of Toxicology Medical School Hannover Hannover Germany

Zobrazit více v PubMed

Frevert J. Pharmaceutical, biological, and clinical properties of botulinum neurotoxin type A products. Drugs R D. 2015;15:1–9. doi: 10.1007/s40268-014-0077-1. PubMed DOI PMC

International Society of Aesthetic Plastic Surgeons. ISAPS international survey on aesthetic/cosmetic procedures performed in 2013. http://www.isaps.org/news/isaps-global-statistics

Jost WH, Friedman A, Michel O, et al. SIAXI: placebo-controlled, randomized, double-blind study of incobotulinumtoxinA for sialorrhea. Neurology. 2019;92:e1982–e1991. doi: 10.1212/WNL.0000000000007368. PubMed DOI PMC

Bellows S, Jankovic J. Immunogenicity associated with botulinum toxin treatment. Toxins. 2019;11:491. doi: 10.3390/toxins11090491. PubMed DOI PMC

Aoki KR, Guyer B. Botulinum toxin type A and other botulinum toxin serotypes: a comparative review of biochemical and pharmacological actions. Eur J Neurol. 2001;8:21–29. doi: 10.1046/j.1468-1331.2001.00035.x. PubMed DOI

Atassi MZ, Dolimbek BZ, Jankovic J, Steward LE, Aoki KR. Regions of botulinum neurotoxin A light chain recognized by human anti-toxin antibodies from cervical dystonia patients immunoresistant to toxin treatment. The antigenic structure of the active toxin recognized by human antibodies. Immunobiology. 2011;216:782–792. doi: 10.1016/j.imbio.2010.12.009. PubMed DOI

Dressler D. Clinical presentation and management of antibody-induced failure of botulinum toxin therapy. Mov Disord. 2004;19:S92–100. doi: 10.1002/mds.20022. PubMed DOI

Hefter H, Rosenthal D, Bigalke H, Moll M. Clinical relevance of neutralizing antibodies in botulinum toxin long-term treated still-responding patients with cervical dystonia. Ther Adv Neurol Disord. 2019;12:1756286419892078. doi: 10.1177/1756286419892078. PubMed DOI PMC

Simpson DM, Hallett M, Ashman EJ, Comella CL, Green MW, Gronseth GS, Armstrong MJ, Gloss D, Potrebic S, Jankovic J, et al. Practice guideline update summary: botulinum neurotoxin for the treatment of blepharospasm, cervical dystonia, adult spasticity, and headache: report of the guideline development subcommittee of the American Academy of Neurology. Neurology. 2016;86:1818–1826. doi: 10.1212/WNL.0000000000002560. PubMed DOI PMC

Greene P, Fahn S, Diamond B. Development of resistance to botulinum toxin type A in patients with torticollis. Mov Disord. 1994;9:213–217. doi: 10.1002/mds.870090216. PubMed DOI

Albrecht P, Jansen A, Lee JI, et al. High prevalence of neutralizing antibodies after long-term botulinum neurotoxin therapy. Neurology. 2019;92:e48–54. doi: 10.1212/WNL.0000000000006688. PubMed DOI

Frevert J. Content of botulinum neurotoxin in Botox®/Vistabel®, Dysport®/Azzalure®, and Xeomin®/Bocouture®. Drugs R D. 2010;10:67–73. doi: 10.2165/11584780-000000000-00000. PubMed DOI PMC

Gu S, Rumpel S, Zhou J, et al. Botulinum neurotoxin is shielded by NTNHA in an interlocked complex. Science. 2012;335:977–981. doi: 10.1126/science.1214270. PubMed DOI PMC

Frevert J, Dressler D. Complexing proteins in botulinum toxin type A drugs: a help or a hindrance? Biologics. 2010;4:325–332. PubMed PMC

Tsui JK, Eisen A, Stoessl AJ, Calne S, Calne DB. Double-blind study of botulinum toxin in spasmodic torticollis. Lancet. 1986;2:245–247. doi: 10.1016/S0140-6736(86)92070-2. PubMed DOI

Jankovic J, Vuong KD, Ahsan J. Comparison of efficacy and immunogenicity of original versus current botulinum toxin in cervical dystonia. Neurology. 2003;60:1186–1188. doi: 10.1212/01.WNL.0000055087.96356.BB. PubMed DOI

Brin MF, Comella CL, Jankovic J, Lai F, Naumann M. Long-term treatment with botulinum toxin type A in cervical dystonia has low immunogenicity by mouse protection assay. Mov Disord. 2008;23:1353–1360. doi: 10.1002/mds.22157. PubMed DOI

Panjwani N, O'Keeffe R, Pickett A. Biochemical, functional and potency characteristics of type A botulinum toxin in clinical use. Botulinum J. 2008;1:153–166. doi: 10.1504/TBJ.2008.018956. DOI

Blümel J, Frevert J, Schwaier A. Comparative antigenicity of three preparations of botulinum neurotoxin type A in the rabbit. Neurotox Res. 2006;9:238.

Hefter H, Rosenthal D, Moll M. High botulinum toxin-neutralizing antibody prevalence under long-term cervical dystonia treatment. Mov Disord Clin Pract. 2016;3:500–506. doi: 10.1002/mdc3.12322. PubMed DOI PMC

Hefter H, Jansen A, Moll M, Ringelstein M, Albrecht P. High prevalence of neutralizing antibodies in BoNT/A long-term–treated patients with focal dystonia and spasticity. Toxicon. 2016;123:S38–S39.

Contarino MF, Van Den Dool J, Balash Y, et al. Clinical practice: evidence-based recommendations for the treatment of cervical dystonia with botulinum toxin. Front Neurol. 2017;8:35. doi: 10.3389/fneur.2017.00035. PubMed DOI PMC

Göschel H, Wohlfarth K, Frevert J, Dengler R, Bigalke H. Botulinum A toxin therapy: neutralizing and nonneutralizing antibodies-therapeutic consequences. Exp Neurol. 1997;147:96–102. doi: 10.1006/exnr.1997.6580. PubMed DOI

Fabbri M, Leodori G, Fernandes RM, et al. Neutralizing antibody and botulinum toxin therapy: a systematic review and meta-analysis. Neurotox Res. 2016;29:105–117. doi: 10.1007/s12640-015-9565-5. PubMed DOI

Lange O, Bigalke H, Dengler R, Wegner F, deGroot M, Wohlfarth K. Neutralizing antibodies and secondary therapy failure after treatment with botulinum toxin type A: much ado about nothing? Clin Neuropharmacol. 2009;32:213–218. doi: 10.1097/WNF.0b013e3181914d0a. PubMed DOI

Hefter H, Brauns R, Ürer B, Rosenthal D, Albrecht P. Effective long-term treatment with incobotulinumtoxin (Xeomin®) without neutralizing antibody induction: a monocentric, cross-sectional study. J Neurol. 2020;267:1340–1347. doi: 10.1007/s00415-019-09681-7. PubMed DOI PMC

Hefter H, Hartmann C, Kahlen U, Moll M, Bigalke H. Prospective analysis of neutralizing antibody titres in secondary non-responders under continuous treatment with a botulinumtoxin type A preparation free of complexing proteins–a single cohort 4-year follow-up study. BMJ Open. 2012;2:e000646. doi: 10.1136/bmjopen-2011-000646. PubMed DOI PMC

Hefter H, Spiess C, Rosenthal D. Very early reduction in efficacy of botulinum toxin therapy for cervical dystonia in patients with subsequent secondary treatment failure: a retrospective analysis. J Neural Transm (Vienna) 2014;121:513–519. doi: 10.1007/s00702-013-1127-5. PubMed DOI PMC

Hefter H, Ürer B, Brauns R, Rosenthal D, Meuth SG, Lee JI, Albrecht P, Samadzadeh S. The complex relationship between antibody titers and clinical outcome in botulinum toxin type A long-term treated patients with cervical dystonia. J Neurol. 2022 doi: 10.1007/s00415-022-11235-3. PubMed DOI PMC

Samadzadeh S, Ürer B, Brauns R, et al. Clinical implications of difference in antigenicity of different botulinum neurotoxin type A preparations: clinical take-home messages from our research pool and literature. Toxins. 2020;12(8):499. doi: 10.3390/toxins12080499. PubMed DOI PMC

Ferreira JJ, Colosimo C, Bhidayasiri R, Marti MJ, Maisonobe P, Om S. Factors influencing secondary non-response to botulinum toxin type A injections in cervical dystonia. Parkinsonism Relat Disord. 2015;21(2):111–115. doi: 10.1016/j.parkreldis.2014.09.034. PubMed DOI

Wissel J, Bensmail D, Ferreira JJ, et al. Safety and efficacy of incobotulinumtoxinA doses up to 800 U in limb spasticity: the TOWER study. Neurology. 2017;88:1321–1328. doi: 10.1212/WNL.0000000000003789. PubMed DOI PMC

Sethi KD, Rodriguez R, Olayinka B. Satisfaction with botulinum toxin treatment: a cross-sectional survey of patients with cervical dystonia. J Med Econ. 2012;15:419–423. doi: 10.3111/13696998.2011.653726. PubMed DOI

Pooled Safety Analysis of IncobotulinumtoxinA in the Treatment of Neurological Disorders in Adults