Clinical relevance of botulinum toxin immunogenicity

Reiner Benecke, Reiner Benecke

Abstract

Botulinum toxin type A is a 150 kD protein produced by Clostridium botulinum, which exists in a complex with up to six additional proteins. The ability of botulinum toxin to inhibit acetylcholine release at the neuromuscular junction has been exploited for use in medical conditions characterized by muscle hyperactivity. As such, botulinum toxin is widely recommended by international treatment guidelines for movement disorders and it has a plethora of other clinical and cosmetic indications. The chronic nature of these conditions requires repeated injections of botulinum toxin, usually every few months. Multiple injections can lead to secondary treatment failure in some patients that may be associated with the production of neutralizing antibodies directed specifically against the neurotoxin. However, the presence of such antibodies does not always render patients non-responsive. The reported prevalence of immunoresistance varies greatly, depending on factors such as study design and treated indication. This review presents what is currently known about the immunogenicity of botulinum toxin and how this impacts upon patient non-response to treatment. The complexing proteins may act as adjuvants and stimulate the immune response. Their role and that of neutralizing and non-neutralizing antibodies in the response to botulinum toxin is discussed, together with an assessment of current neutralizing antibody measurement techniques. Botulinum toxin preparations with different compositions and excipients have been developed. The major commercially available preparations of botulinum toxin are Botox (onabotulinumtoxin A; Allergan, Inc., Ireland), Dysport (abobotulinumtoxin A; Ipsen Ltd, UK), and Xeomin (incobotulinumtoxin A; botulinum toxin type A [150 kD], free from complexing proteins; NT 201; Merz Pharmaceuticals GmbH, Germany). The new preparations of botulinum toxin aim to minimize the risk of immunoresistance in patients being treated for chronic clinical conditions.

Figures

Fig. 1
Fig. 1
Histogram showing latencies between the initiation of botulinum toxin therapy and the occurrence of complete antibody-induced therapy failure in a study of 27 patients.[9]
Table I
Table I
Laboratory and clinical tests used to measure botulinum toxin antibodies
Table II
Table II
Comparison of botulinum toxin products and formulations
Fig. 2
Fig. 2
Total bacterial protein and neurotoxin content of botulinum toxin type A products. Mean concentrations of botulinum neurotoxin type A in onabotulinumtoxinA, incobotulinumtoxinA, and abobotulinumtoxinA were analyzed by a sensitive sandwich ELISA.[15]

References

    1. Scott A.B. Botulinum toxin injection into extraocular muscles as an alternative to strabismus surgery. J Pediatr Ophthalmol Strabismus. 1980;17:21–5.
    1. Albanese A., Asmus F., Bhatia K.P., et al. EFNS guidelines on diagnosis and treatment of primary dystonias. Eur J Neurol. 2011;18:5–18. doi: 10.1111/j.1468-1331.2010.03042.x.
    1. Novak I., Campbell L., Boyce M., et al. Botulinum toxin assessment, intervention and aftercare for cervical dystonia and other causes of hypertonia of the neck: international consensus statement. Eur J Neurol. 2010;17(Suppl. 2):94–108. doi: 10.1111/j.1468-1331.2010.03130.x.
    1. Simpson D.M., Blitzer A., Brashear A., et al. Assessment: Botulinum neurotoxin for the treatment of movement disorders (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2008;70:1699–706. doi: 10.1212/01.wnl.0000311389.26145.95.
    1. Simpson D.M., Gracies J.M., Graham H.K., et al. Assessment: Botulinum neurotoxin for the treatment of spasticity (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2008;70:1691–8. doi: 10.1212/01.wnl.0000311391.00944.c4.
    1. Dressler D. Clinical presentation and management of antibody-induced failure of botulinum toxin therapy. Mov Disord. 2004;19(Suppl. 8):S92–100. doi: 10.1002/mds.20022.
    1. National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health. Myasthenia gravis fact sheet [online]. Available from URL: [Accessed 2011 Jan 26]
    1. Kromminga A., Schellekens H. Antibodies against erythropoietin and other protein-based therapeutics: an overview. Ann N Y Acad Sci. 2005;1050:257–65. doi: 10.1196/annals.1313.027.
    1. Dressler D. Clinical features of antibody-induced complete secondary failure of botulinum toxin therapy. Eur Neurol. 2002;48:26–9. doi: 10.1159/000064953.
    1. Sharma S.K., Fu F.N., Singh B.R. Molecular properties of a hemagglutinin purified from type A Clostridium botulinum. J Protein Chem. 1999;18:29–38. doi: 10.1023/A:1020691215056.
    1. Eisele K.H., Fink K., Vey M., et al. Studies on the dissociation of botulinum neurotoxin type A complexes. Toxicon. 2011;57:555–65. doi: 10.1016/j.toxicon.2010.12.019.
    1. Lee J.-C., Yokota K., Arimitsu H., et al. Production of anti-neurotoxin antibody is enhanced by two subcomponents, HA1 and HA3b, of Clostridium botulinum type B 16S toxin-haemagglutinin. Microbiology. 2005;151:3739–47. doi: 10.1099/mic.0.28421-0.
    1. Kukreja R., Chang T.-W., Cai S., et al. Immunological characterization of the subunits of type A botulinum neurotoxin and different components of its associated proteins. Toxicon. 2009;53:616–24. doi: 10.1016/j.toxicon.2009.01.017.
    1. Atassi M.Z. On the enhancement of anti-neurotoxin antibody production by subcomponents HA1 and HA3b of Clostridium botulinum type B 16S toxin-haemagglutinin. Microbiology. 2006;152:1891–5. doi: 10.1099/mic.0.28862-0.
    1. 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.
    1. Sun Y, Wang L, Singh BR. Botulinum neurotoxin type A complex proteins bind to neuronal as well as non-neuronal cells [poster]. 14th International Congress of Parkinson’s Disease and Movement Disorders; 2010 Jun 13–17; Buenos Aires, Argentina
    1. Atassi M.Z. Basic immunological aspects of botulinum toxin therapy. Mov Disord. 2004;19(Suppl. 8):S68–84. doi: 10.1002/mds.20020.
    1. Brin M.F., Lew M.F., Adler C.H., et al. Safety and efficacy of NeuroBloc (botulinum toxin type B) in type A-resistant cervical dystonia. Neurology. 1999;53:1431–8. doi: 10.1212/WNL.53.7.1431.
    1. Dressler D., Bigalke H., Benecke R. Botulinum toxin type B in antibody-induced botulinum toxin type A therapy failure. J Neurol. 2003;250:967–9. doi: 10.1007/s00415-003-1129-6.
    1. Jankovic J. Botulinum toxin therapy for cervical dystonia. Neurotox Res. 2006;9:145–8. doi: 10.1007/BF03033933.
    1. Dressler D., Hallett M. Immunological aspects of Botox, Dysport and Myobloc/NeuroBloc. Eur J Neurol. 2006;13(Suppl. 1):11–5. doi: 10.1111/j.1468-1331.2006.01439.x.
    1. Kamm C., Benecke R. Individualized management of cervical dystonia with different serotypes of botulinum toxin: recent therapeutic advances and risk development of neutralizing antibodies. Eur Neurol J. 2010;2:49–54.
    1. Borodic G., Johnson E., Goodnough M., et al. Botulinum toxin therapy, immunologic resistance, and problems with available materials. Neurology. 1996;46:26–9. doi: 10.1212/WNL.46.1.26.
    1. Göschel H., Wohlfarth K., Frevert J., et al. Botulinum A toxin therapy: neutralizing and nonneutralizing antibodies — therapeutic consequences. Exp Neurol. 1997;147:96–102. doi: 10.1006/exnr.1997.6580.
    1. Wenzel R.G. Pharmacology of botulinum neurotoxin serotype A. Am J Health Syst Pharm. 2004;61(Suppl. 6):S5–10.
    1. Jankovic J., Vuong K.D., Ahsan J. Comparison of efficacy and immunogenicity of original versus current botulinum toxin in cervical dystonia. Neurology. 2003;60:1186–8. doi: 10.1212/.
    1. Mejia N.I., Vuong K.D., Jankovic J. Long-term botulinum toxin efficacy, safety, and immunogenicity. Mov Disord. 2005;20:592–7. doi: 10.1002/mds.20376.
    1. Bigalke H., et al. Properties of pharmaceutical products of botulinum neurotoxins. In: Jankovic J., Albanese A., Atassi M.Z., et al., editors. Botulinum toxin: therapeutic clinical practice and science. Philadelphia (PA): Saunders Elsevier; 2009. pp. 389–97.
    1. Frevert J. Xeomin is free from complexing proteins. Toxicon. 2009;54:697–701. doi: 10.1016/j.toxicon.2009.03.010.
    1. Frevert J. Xeomin: an innovative new botulinum toxin type A. Eur J Neurol. 2009;16(Suppl. 2):11–3. doi: 10.1111/j.1468-1331.2009.02879.x.
    1. Eisele KH, Taylor HV, Bluemel lJ. Immunogenicity of NT 201 (Xeomin®) in Cynomolgus monkeys following repeated, high dose injections [poster]. 44th Annual Interagency Botulism Research Coordinating Committee (IBRCC) Meeting; 2007 Oct 14–18; Asilomar (CA)
    1. Jost W.H., Blümel J., Grafe S. Botulinum neurotoxin type A free of complexing proteins (XEOMIN®) in focal dystonia. Drugs. 2007;67:669–83. doi: 10.2165/00003495-200767050-00003.
    1. Frevert J., Dressler D. Complexing proteins in botulinum toxin type A drugs: a help or a hindrance? Biologics. 2010;4:325–32.
    1. Electronic Medicines Compendium (eMC). XEOMIN® 50 U: summary of product characteristics. 2011 [online]. Available from URL: [Accessed 2012 Feb 13]
    1. Brin M.F., Comella C.L., Jankovic J., et al. Long-term treatment with botulinum toxin type A in cervical dystonia has low immunogenicity by mouse protection assay. Mov Disord. 2008;23:1353–60. doi: 10.1002/mds.22157.
    1. Minnasch P. Presence of neutralising antibodies in a patient population with cervical dystonia prior to clinical study entry [poster]. American Academy of Neurology Annual Meeting; 2010 Apr 10–17; Honolulu (HI)
    1. Mohammadi B., Buhr N., Bigalke H., et al. A long-term follow-up of botulinum toxin A in cervical dystonia. Neurol Res. 2009;31:463–6. doi: 10.1179/174313209X405137.
    1. Müller K., Mix E., Adib Saberi F., et al. Prevalence of neutralising antibodies in patients treated with botulinum toxin type A for spasticity. J Neural Transm. 2009;116:579–85. doi: 10.1007/s00702-009-0223-z.
    1. Naumann M., Carruthers A., Carruthers J., et al. Meta-analysis of neutralizing antibody conversion with onabotulinumtoxinA (BOTOX®) across multiple indications. Mov Disord. 2010;25:2211–8. doi: 10.1002/mds.23254.
    1. Truong D., Brodsky M., Lew M., et al. Long-term efficacy and safety of botulinum toxin type A (Dysport) in cervical dystonia. Parkinsonism Relat Disord. 2010;16:316–23. doi: 10.1016/j.parkreldis.2010.03.002.
    1. Greene P., Fahn S., Diamond B. Development of resistance to botulinum toxin type A in patients with torticollis. Mov Disord. 1994;9:213–7. doi: 10.1002/mds.870090216.
    1. Herrmann J., Geth K., Mall V., et al. Clinical impact of antibody formation to botulinum toxin A in children. Ann Neurol. 2004;55:732–5. doi: 10.1002/ana.20098.
    1. Koman L.A., Brashear A., Rosenfeld S., et al. Botulinum toxin type a neuro-muscular blockade in the treatment of equinus foot deformity in cerebral palsy: a multicenter, open-label clinical trial. Pediatrics. 2001;108:1062–71. doi: 10.1542/peds.108.5.1062.
    1. European Medicines Agency (EMA). Guideline on immunogenicity assessment of biotechnology-derived therapeutic proteins [online]. Available from URL: USL} [Accessed 2011 Jan 26]
    1. Schulte-Baukloh H., Bigalke H., Miller K., et al. Botulinum neurotoxin type A in urology: antibodies as a cause of therapy failure. Int J Urol. 2008;15:407–15. doi: 10.1111/j.1442-2042.2008.02016.x.
    1. Kranz G., Sycha T., Voller B., et al. Neutralizing antibodies in dystonic patients who still respond well to botulinum toxin type A. Neurology. 2008;70:133–6. doi: 10.1212/01.wnl.0000287087.99612.e5.
    1. Lange O., Bigalke H., Dengler R., et al. Neutralizing antibodies and secondary therapy failure after treatment with botulinum toxin type A: much ado about nothing? Clin Neuropharmacol. 2009;32:213–8. doi: 10.1097/WNF.0b013e3181914d0a.
    1. Shone C., Wilton-Smith P., Appleton N., et al. Monoclonal antibody-based immunoassay for type A Clostridium botulinum toxin is comparable to the mouse bioassay. Appl Environ Microbiol. 1985;50:63–7.
    1. Dressler D., Dirnberger G. Botulinum toxin antibody testing: comparison between the immunoprecipitation assay and the mouse diaphragm assay. Eur Neurol. 2001;45:257–60. doi: 10.1159/000052139.
    1. Hanna P.A., Jankovic J., Vincent A. Comparison of mouse bioassay and immunoprecipitation assay for botulinum toxin antibodies. J Neurol Neurosurg Psychiatry. 1999;66:612–6. doi: 10.1136/jnnp.66.5.612.
    1. Palace J., Nairne A., Hyman N., et al. A radioimmuno-precipitation assay for antibodies to botulinum A. Neurology. 1998;50:1463–6. doi: 10.1212/WNL.50.5.1463.
    1. Dressler D., Lange M., Bigalke H. Mouse diaphragm assay for detection of antibodies against botulinum toxin type B. Mov Disord. 2005;20:1617–9. doi: 10.1002/mds.20625.
    1. Rasetti-Escargueil C., Lui Y., Rigsby P., et al. Phrenic nerve-hemidiaphragm as a highly sensitive replacement assay for determination of functional botulinum toxin antibodies. Toxicon. 2011;57:1008–16. doi: 10.1016/j.toxicon.2011.04.003.
    1. Hatheway C.H., Dang C. Immunogenicity of the neurotoxins of Clostridium botulinum. In: Jankovic J., Hallett M., editors. Therapy with botulinum toxin. New York (NY): Marcel Dekker; 1994. pp. 93–107.
    1. Hamjian J.A., Walker F.O. Serial neurophysiological studies of intramuscular botulinum-A toxin in humans. Muscle Nerve. 1994;17:1385–92. doi: 10.1002/mus.880171207.
    1. Dressler D., Bigalke H., Rothwell J.C. The sternocleidomastoid test: an in vivo assay to investigate botulinum toxin antibody formation in humans. J Neurol. 2000;247:630–2. doi: 10.1007/s004150070132.
    1. Birklein F., Erbguth F. Sudomotor testing discriminates between subjects with and without antibodies against botulinum toxin A: a preliminary observation. Mov Disord. 2000;15:146–9. doi: 10.1002/1531-8257(200001)15:1<146::AID-MDS1023>;2-X.
    1. US prescribing information. Irvine (CA): Allergan, Inc.; 2010.
    1. US prescribing information. Wrexham: Ipsen Biopharm, Ltd.; 2010.
    1. Prescribing information. Gansu: Lanzhou Institute of Biological Products; 2011.
    1. Xeomin®: US prescribing information. Merz Pharmaceuticals GmbH [online]. Available from URL: [Accessed 2012 Feb 7]
    1. Electronic Medicines Compendium (eMC). XEOMIN® 100 U: summary of product characteristics, 2011 [online]. Available from URL: [Accessed 2012 Feb 13]
    1. US prescribing information. San Francisco (CA): Solstice Neurosciences, Inc.; 2009.
    1. Ranoux D., Gury C., Fondarai J., et al. Respective potencies of Botox and Dysport: a double blind, randomised, crossover study in cervical dystonia. J Neurol Neurosurg Psychiatry. 2002;72:459–62.
    1. Chadda S., Tilden D., Jones D., et al. Cost effectiveness of Xeomin® in the management of cervical dystonia and blepharospasm. Eur J Hosp Pharm. 2009;15:38–46.
    1. Marchetti A., Magar R., Findley L., et al. Retrospective evaluation of the dose of Dysport and BOTOX in the management of cervical dystonia and blepharospasm: the REAL DOSE study. Mov Disord. 2005;20:937–44. doi: 10.1002/mds.20468.
    1. Benecke R., Jost W.H., Kanovsky P., et al. A new botulinum toxin type A free of complexing proteins for treatment of cervical dystonia. Neurology. 2005;64:1949–51. doi: 10.1212/01.WNL.0000163767.99354.C3.
    1. Roggenkämper P., Jost W.H., Bihari K., et al. Efficacy and safety of a new Botulinum Toxin Type A free of complexing proteins in the treatment of blepharospasm. J Neural Transm. 2006;113:303–12. doi: 10.1007/s00702-005-0323-3.
    1. Wohlfarth K., Müller C., Sassin I., et al. Neurophysiological double-blind trial of a botulinum neurotoxin type A free of complexing proteins. Clin Neuropharmacol. 2007;30:86–94. doi: 10.1097/01.WNF.0000240951.18821.50.
    1. Sesardic D. Is it possible to accurately determine content of botulinum neurotoxin type A in drug products? Drugs R D. 2010;10:91–2. doi: 10.2165/11584910-000000000-00000.
    1. Pickett A. Consistent biochemical data are essential for comparability of botulinum toxin type A products. Drugs R D. 2011;11:97–8. doi: 10.2165/11590750-000000000-00000.
    1. Sattler G., Callander M.J., Grablowitz D., et al. Noninferiority of incobotulinumtoxinA, free from complexing proteins, compared with another botulinum toxin type A in the treatment of glabellar frown lines. Dermatol Surg. 2010;36(Suppl. 4):2146–54. doi: 10.1111/j.1524-4725.2010.01706.x.

Source: PubMed

スポンサーと協力者

医学的状態

薬物療法

3
購読する