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Toxins
Special Issues
Immunogenicity of Botulinum Toxin
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Immunogenicity of Botulinum Toxin

A special issue of Toxins (ISSN 2072-6651). This special issue belongs to the section "Bacterial Toxins".

Deadline for manuscript submissions: 30 April 2025 | Viewed by 25731

Special Issue Editors

Dr. Sara Samadzadeh

E-Mail Website
Guest Editor
1. Departments of Neurology, University of Düsseldorf, Moorenstrasse 5, D-40225 Düsseldorf, Germany
2. Experimental and Clinical Research Center, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
3. Department of Regional Health Research and Molecular Medicine, University of Southern Denmark, Odense, Denmark
4. Department of Neurology, Slagelse Hospital, Slagelse, Denmark
Interests: multiple sclerosis; clinical neurology; movement disorders; demyelinating diseases; neuroimmunology; neuro-ophthalmology
Prof. Dr. Harald Hefter

E-Mail Website
Guest Editor
Department of Neurology, University of Dusseldorf, Moorenstr 5, D-40225 Dusseldorf, Germany
Interests: botulinum toxin therapy; pathogenesis of sensorimotor integration disorders; heavy metal intoxication
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is aimed at describing the immunogenicity of botulinum neurotoxins (BoNT). BoNTs are clostridial products and form a family of highly specialized proteins that attack the mechanism of exocytosis in a variety of cells. The clostridial protein complex contains hemagglutinins, non-hemagglutinins, and pure BoNT. These different components all work to induce immune responses. Therefore, the responses to BoNTs are not uniform, and a broad spectrum of responses is observed.

The contact of the human body with BoNTs may occur by chance, during food poisoning, when BoNTs are used as biological weapons, or when BoNTs are clinically applicated. This implies that antibody formation can be life-saving on the one hand, and may be a therapy-limiting factor on the other hand. Several BoNTs have been tried for clinical applications. However, today only BoNT/A is mainly used for clinical applications owing to its long-lasting effect and low antigenicity.

However, even for the development of clinically applicable preparations of botulinum neurotoxin type A (BoNT/A), attempts at purification and improvement in biological function and reduction of immunoresistance are absolutely necessary. Thus far, in all attempts, BoNT/A-treatment can still cause primary, secondary, partial or complete treatment failure.  Furthermore, for a good clinical outcome of this highly effective, symptomatic therapy, tissue, muscle, and dose selection have to be optimized and different guidance techniques should be used. Knowledge of the course of disease before and after BoNT/A-therapy is important. This underlines the relevance of the documentation of injection sites, dose per site, and the use of clinical scores for the careful monitoring of BoNT-therapy and the assessment of the patient´s experience of improvement in quality of life. The side effects of BoNT-therapy are usually mild and sometimes overestimated. Nevertheless, BoNTs should be applied with care, since supersensitive patients exist. Different clinical and laboratory tests have been developed for the early detection of a partial secondary treatment failure.  

This issue would cover the mentioned above aspects in general with a focus on the following points:

  • Issues related to BoNT/A therapy and neutralizing antibodies

a. Laboratory and clinical tests for detecting antibody formation
b. Special cases in Botulinum Toxin Therapy (case reports and literature reviews)

(Cases without BoNT indication approval—therapy-resistant cases, unusual cases -…)

Dr. Sara Samadzadeh
Prof. Dr. Harald Hefter
Guest Editors

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a double-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Toxins is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • botulinum neurotoxin (BoNT)
  • botulinum neurotoxin type A (BoNT/A)
  • neutralizing antibodies
  • immunoresistance
  • primary and secondary treatment failure
  • antigenicity
  • complex protein-free BoNT/A
  • complex protein containing BoNT/A
  • therapy switching

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Published Papers (9 papers)

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Research

Jump to: Review

12 pages, 1247 KiB  
Article
“Pseudo”-Secondary Treatment Failure Explained via Disease Progression and Effective Botulinum Toxin Therapy: A Pilot Simulation Study
by Harald Hefter, Dietmar Rosenthal and Sara Samadzadeh
Toxins 2023, 15(10), 618; https://doi.org/10.3390/toxins15100618 - 18 Oct 2023
Cited by 1 | Viewed by 1833
Abstract
Background: The objective of this study was to provide evidence from a simple simulation. In patients with focal dystonia, an initial good response to botulinum neurotoxin (BoNT) injections followed by a secondary worsening does not necessarily arise from an antibody-induced secondary treatment failure [...] Read more.
Background: The objective of this study was to provide evidence from a simple simulation. In patients with focal dystonia, an initial good response to botulinum neurotoxin (BoNT) injections followed by a secondary worsening does not necessarily arise from an antibody-induced secondary treatment failure (NAB-STF), but may stem from a “pseudo”-secondary treatment failure (PSEUDO-STF). Methods: The simulation of the outcome after BoNT long-term treatment was performed in four steps: 1. The effect of the first single BoNT injection (SI curve) was displayed as a 12-point graph, corresponding to the mean improvement from weeks 1 to 12. 2. The remaining severity of the dystonia during the nth injection cycle was calculated by subtracting the SI curve (weighted by the outcome after n − 1 cycles) from the outcome after week 12 of the (n − 1)th cycle. 3. A graph was chosen (the PRO curve), which represents the progression of the severity of the underlying disease during BoNT therapy. 4. The interaction between the outcome during the nth BoNT cycle and the PRO curve was determined. Results: When the long-term outcome after n cycles of BoNT injections (applied every 3 months) was simulated as an interactive process, subtracting the effect of the first cycle (weighted by the outcome after n − 1 cycles) and adding the progression of the disease, an initial good improvement followed by secondary worsening results. This long-term outcome depends on the steepness of the progression and the duration of action of the first injection cycle. We termed this response behavior a “pseudo”-secondary treatment failure, as it can be compensated via a dose increase. Conclusion: A secondary worsening following an initial good response in BoNT therapy of focal dystonia might not necessarily indicate neutralizing antibody induction but could stem from a “PSEUDO”-STF (a combination of good response behavior and progression of the underlying disease). Thus, an adequate dose adaptation must be conducted before diagnosing a secondary treatment failure in the strict sense. Full article
(This article belongs to the Special Issue Immunogenicity of Botulinum Toxin)
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Figure 1

Figure 1
<p>Daily self-assessment of disease severity using a 21-point Likert scale throughout the initial BoNT injection cycle in two CD patients. The severity of CD at the beginning of BoNT therapy was established at 100%. Patient p1 demonstrated an outstanding response, peaking at an improvement of 65%, and showing a 20% residual improvement after 3 months (<b>A</b>). Conversely, patient p2 had a positive response to the first injection, but with a more modest peak improvement of 45%, along with a 10% residual improvement (<b>B</b>).</p> Full article ">Figure 2
<p>Daily self-assessment of the disease severity (using a 21-point Lickert scale) during the first 4 BoNT injection cycles of two further patients with CD. The severity of CD at the onset of BoNT therapy was set to 100%. Patient p3 (<b>A</b>) experienced an excellent response, with a peak effect of 60% during the first injection cycle, a 20% residual improvement after 3 months, and a residual improvement of 60% after 4 injection cycles. Patient p4 (<b>B</b>) also responded well to the first injection, with a peak effect of 40% and a residual improvement of 10%. After 4 injections, patient p4 had a residual improvement of 40%.</p> Full article ">Figure 3
<p>In part (<b>A</b>) a SI<sub>1,p1</sub>(w) curve, which showcases a peak effect of 55% and a residual improvement of 20%, was used for the simulation of 20 BoNT injections administered every 12 weeks. The residual severity of the disease, RS<sub>m,p1</sub>(w), was depicted based on the SI<sub>1,p1</sub>(w) curve. In part (<b>B</b>), a SI<sub>1,p2</sub>(w) curve, with a peak effect of 27,5% and a residual improvement of 10%, was employed for the simulation of 20 BoNT injections given at 12-week intervals. The residual severity of the disease, RS<sub>m,p2</sub>(w), was illustrated using the SI<sub>1,p2</sub>(w) curve.</p> Full article ">Figure 4
<p>In (<b>A</b>,<b>B</b>), a linear function illustrating a progression of 60% over 4.6 years was applied to the RS<sub>m,p</sub>(w) curves presented in <a href="#toxins-15-00618-f003" class="html-fig">Figure 3</a>A,B. In (<b>C</b>,<b>D</b>), a linear function representing a 40% progression across the same 4.6-year duration was incorporated into the RS<sub>m,p</sub>(w) curves from <a href="#toxins-15-00618-f003" class="html-fig">Figure 3</a>A,B. Notably, part D did not exhibit any secondary worsening, despite all computations being carried out in a manner consistent with (<b>A</b>–<b>C</b>).</p> Full article ">
11 pages, 1659 KiB  
Communication
Addressing the Real-World Challenges of Immunoresistance to Botulinum Neurotoxin A in Aesthetic Practice: Insights and Recommendations from a Panel Discussion in Hong Kong
by Wilson W. S. Ho, Lisa Chan, Niamh Corduff, Wang-Tak Lau, Michael U. Martin, Clifton Ming Tay, Sandy Wang and Raymond Wu
Toxins 2023, 15(7), 456; https://doi.org/10.3390/toxins15070456 - 12 Jul 2023
Cited by 7 | Viewed by 3066
Abstract
With increasing off-label aesthetic indications using higher botulinum neurotoxin A (BoNT-A) doses and individuals starting treatment at a younger age, particularly in Asia, there is a greater risk of developing immunoresistance to BoNT-A. This warrants more in-depth discussions by aesthetic practitioners to inform [...] Read more.
With increasing off-label aesthetic indications using higher botulinum neurotoxin A (BoNT-A) doses and individuals starting treatment at a younger age, particularly in Asia, there is a greater risk of developing immunoresistance to BoNT-A. This warrants more in-depth discussions by aesthetic practitioners to inform patients and guide shared decision-making. A panel comprising international experts and experienced aesthetic practitioners in Hong Kong discussed the implications and impact of immunoresistance to BoNT-A in contemporary aesthetic practice, along with practical strategies for risk management. Following discussions on a clinical case example and the results of an Asia-Pacific consumer study, the panel concurred that it is a priority to raise awareness of the possibility and long-term implications of secondary non-response due to immunoresistance to BoNT-A. Where efficacy and safety are comparable, a formulation with the lowest immunogenicity is preferred. The panel also strongly favored a thorough initial consultation to establish the patient’s treatment history, explain treatment side effects, including the causes and consequences of immunoresistance, and discuss treatment goals. Patients look to aesthetic practitioners for guidance, placing an important responsibility on practitioners to adopt risk-mitigating strategies and adequately communicate important risks to patients to support informed and prudent BoNT-A treatment decisions. Full article
(This article belongs to the Special Issue Immunogenicity of Botulinum Toxin)
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Figure 1
<p>Consumer awareness and experience of diminishing BoNT-A treatment efficacy. (<b>A</b>) Awareness of diminishing efficacy and associated signs/symptoms. (<b>B</b>) Experienced diminishing efficacy.</p> Full article ">Figure 2
<p>Patient’s BoNT-A treatment journey from first injection to positive test for NAb. BoNT-A, botulinum neurotoxin A; ABO, abobotulinumtoxinA; INCO, incobotulinumtoxinA; MHDA, mouse hemi-diaphragm assay; NAb, neutralizing antibody; ONA, onabotulinumtoxinA. <sup>1</sup> Details are based on patient’s recall; <sup>2</sup> The patient visited different clinics/injectors for each treatment; <sup>3</sup> The patient noticed a reduction in treatment efficacy although she was injected with similar doses as previous treatments, and that treatment effects lasted for a shorter time compared with previous treatments; <sup>4</sup> The patient experienced no clinical effect for all treatments, indicating complete non-response to BoNT-A.</p> Full article ">Figure 3
<p>Preferred strategies to mitigate immunogenic risk with BoNT-A treatment. BoNT-A: botulinum neurotoxin A; NAb: neutralizing antibody; SNR: secondary non-response.</p> Full article ">
13 pages, 917 KiB  
Article
No Secondary Treatment Failure during Incobotulinumtoxin—A Long-Term Treatment Demonstrated by the Drawing of Disease Severity
by Harald Hefter, Raphaela Brauns, Beyza Ürer, Dietmar Rosenthal, Philipp Albrecht and Sara Samadzadeh
Toxins 2023, 15(7), 454; https://doi.org/10.3390/toxins15070454 - 12 Jul 2023
Cited by 1 | Viewed by 1474
Abstract
The aim of this study was to detect clinical hints regarding the development of secondary treatment failure (STF) in patients with focal dystonia who were exclusively treated with incobotulinumtoxin/A (incoBoNT/A). In total, 33 outpatients (26 with idiopathic cervical dystonia, 4 with Meige syndrome [...] Read more.
The aim of this study was to detect clinical hints regarding the development of secondary treatment failure (STF) in patients with focal dystonia who were exclusively treated with incobotulinumtoxin/A (incoBoNT/A). In total, 33 outpatients (26 with idiopathic cervical dystonia, 4 with Meige syndrome and 3 with other cranial dystonia) who were treated with repeated injections of incoBoNT/A for a mean period of 6.4 years without interruptions were recruited to draw the course of their disease severity (CoD) from the onset of symptoms to the onset of BoNT therapy (CoDB graph) and from the onset of BoNT therapy to recruitment (CoDA graph). At the time of recruitment, the patients assessed the change in severity as a percentage of the severity at the onset of BoNT therapy. Blood samples were taken to test the presence of neutralizing antibodies (NABs) using the mouse hemidiaphragm assay (MHDA). Patients reported an improvement of about 70% with respect to the mean. None of the patients tested positive for MHDA. Three different types of CoDB and three different types of CoDA graphs could be distinguished. The patients with different CoDB graphs reported different long-term outcomes, but there was no significant difference in long-term outcomes between patients with different CoDA graphs. None of the patients produced a CoDA graph with an initial improvement and a secondary worsening as a hint for the development of STF. A primary non-response was not observed in any of the patients. During long-term treatment with BoNT/A, NABs and/or STF may develop. However, in the present study on patients with incoBoNT/A long-term monotherapy, no hints for the development of NABs or STF could be detected, underlining the low antigenicity of incoBoNT/A. Full article
(This article belongs to the Special Issue Immunogenicity of Botulinum Toxin)
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Figure 1

Figure 1
<p>For each of the three patient subgroups (DO subgroup (<b>upper row</b>), CO subgroup (<b>middle row</b>) and RO subgroup (<b>lower row</b>)) a typical CoDB graph is demonstrated on the left side; all CoDB graphs in the middle part and the average CoDB graph and the corresponding plus/minus 1 standard deviation range across all patients within the subgroup are on the right side.</p> Full article ">Figure 2
<p>For each of the three patient subgroups (DR subgroup (<b>upper row</b>), CR subgroup (<b>middle row</b>) and RR subgroup (<b>lower row</b>)), a typical CoDA graph is demonstrated on the left side; all CoDA graphs in the middle part and the average CoDA graph and the corresponding plus/minus 1 standard deviation range across all patients within the subgroup are on the right side. No patient had a CoDA graph exhibiting initial improvement and secondary worsening, indicating a secondary treatment failure.</p> Full article ">
16 pages, 2107 KiB  
Article
Lessons about Botulinum Toxin A Therapy from Cervical Dystonia Patients Drawing the Course of Disease: A Pilot Study
by Harald Hefter, Isabelle Schomaecker, Max Schomaecker, Beyza Ürer, Raphaela Brauns, Dietmar Rosenthal, Philipp Albrecht and Sara Samadzadeh
Toxins 2023, 15(7), 431; https://doi.org/10.3390/toxins15070431 - 30 Jun 2023
Cited by 5 | Viewed by 1898
Abstract
Aim of the study: To compare the course of severity of cervical dystonia (CD) before and after long-term botulinum toxin (BoNT) therapy to detect indicators for a good or poor clinical outcome. Patients and Methods: A total of 74 outpatients with idiopathic CD [...] Read more.
Aim of the study: To compare the course of severity of cervical dystonia (CD) before and after long-term botulinum toxin (BoNT) therapy to detect indicators for a good or poor clinical outcome. Patients and Methods: A total of 74 outpatients with idiopathic CD who were continuously treated with BoNT and who had received at least three injections were consecutively recruited. Patients had to draw the course of severity of CD from the onset of symptoms until the onset of BoNT therapy (CoDB graph), and from the onset of BoNT therapy until the day of recruitment (CoDA graph) when they received their last BoNT injection. Mean duration of treatment was 9.6 years. Three main types of CoDB and four main types of CoDA graphs could be distinguished. The demographic and treatment-related data of the patients were extracted from the patients’ charts. Results: The best outcome was observed in those patients who had experienced a clear, rapid response in the beginning. These patients had been treated with the lowest doses and with a low number of BoNT preparation switches. The worst outcome was observed in those 17 patients who had drawn a good initial improvement, followed by a secondary worsening. These secondary nonresponders had been treated with the highest initial and actual doses and with frequent BoNT preparation switches. A total of 12 patients were primary nonresponders and did not experience any improvement at all. No relation between the CoDB and CoDA graphs could be detected. Primary and secondary nonresponses were observed for all three CoDB types. The use of initial high doses as a relevant risk factor for the later development of a secondary nonresponse was confirmed. Conclusions: Patients’ drawings of their course of disease severity helps to easily detect “difficult to treat” primary and secondary nonresponders to BoNT on the one hand, but also to detect “golden responders” on the other hand. Full article
(This article belongs to the Special Issue Immunogenicity of Botulinum Toxin)
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Figure 1

Figure 1
<p>(<b>Left side</b>) Average CoDA graphs and the corresponding plus/minus 1 standard deviation ranges across all patients within the rapid response (RR), continuous response (CR), and poor response (PR) subgroups are presented. (<b>Right side</b>) All CoDA graphs of all patients within the RR, CR, and PR subgroups are presented.</p> Full article ">Figure 2
<p>(<b>Left side</b>) Average CoDA graphs and the corresponding plus/minus 1 standard deviation ranges across all patients within the secondary treatment failure I (STFI) and the secondary treatment failure II (STFII) subgroups are presented. (<b>Right side</b>) All CoDA graphs of all patients within the STFI and STFII subgroups are presented.</p> Full article ">Figure 3
<p>The CoDB graph (<b>left side</b>) and the CoDA graph (<b>right side</b>) of one exceptional patient in the other response (OR) subgroup are presented. Before BoNT therapy, as well as after BoNT therapy, this patient had experienced long-lasting relapses, which is a rare phenomenon in CD.</p> Full article ">Figure 4
<p>Treatment-related data were produced on the day of recruitment and were extracted from the charts of the patients. Drawings of the CoDB and CoDA graphs are based on patients’ recall on the day of recruitment.</p> Full article ">Figure 5
<p>Five types of CoDA graphs (RR-, CR-, PR-, STFI-, and STFII-type).</p> Full article ">
16 pages, 1912 KiB  
Article
Neutralizing Antibody Formation with OnabotulinumtoxinA (BOTOX®) Treatment from Global Registration Studies across Multiple Indications: A Meta-Analysis
by Joseph Jankovic, Jean Carruthers, Markus Naumann, Patricia Ogilvie, Terry Boodhoo, Mayssa Attar, Swati Gupta, Ritu Singh, John Soliman, Irina Yushmanova, Mitchell F. Brin and Jie Shen
Toxins 2023, 15(5), 342; https://doi.org/10.3390/toxins15050342 - 17 May 2023
Cited by 16 | Viewed by 5806
Abstract
Though the formation of neutralizing antibodies (NAbs) during treatment with botulinum neurotoxin is rare, their presence may nonetheless affect the biological activity of botulinum toxin and negatively impact clinical response. The goal of this updated meta-analysis was to evaluate and characterize the rate [...] Read more.
Though the formation of neutralizing antibodies (NAbs) during treatment with botulinum neurotoxin is rare, their presence may nonetheless affect the biological activity of botulinum toxin and negatively impact clinical response. The goal of this updated meta-analysis was to evaluate and characterize the rate of NAb formation using an expanded dataset composed of 33 prospective placebo-controlled and open-label clinical trials with nearly 30,000 longitudinal subject records prior to and following onabotulinumtoxinA treatment in 10 therapeutic and aesthetic indications. Total onabotulinumtoxinA doses per treatment ranged from 10 U to 600 U administered in ≤15 treatment cycles. The NAb formation at baseline and post-treatment was tested and examined for impact on clinical safety and efficacy. Overall, 27 of the 5876 evaluable subjects (0.5%) developed NAbs after onabotulinumtoxinA treatment. At study exit, 16 of the 5876 subjects (0.3%) remained NAb positive. Due to the low incidence of NAb formation, no clear relationship was discernable between positive NAb results and gender, indication, dose level, dosing interval, treatment cycles, or the site of injection. Only five subjects who developed NAbs post-treatment were considered secondary nonresponders. Subjects who developed NAbs revealed no other evidence of immunological reactions or clinical disorders. This comprehensive meta-analysis confirms the low NAb formation rate following onabotulinumtoxinA treatment across multiple indications, and its limited clinical impact on treatment safety and efficacy. Full article
(This article belongs to the Special Issue Immunogenicity of Botulinum Toxin)
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Figure 1

Figure 1
<p>Numbers within or above the circles reflect subject records available for neutralizing antibody evaluation at each treatment cycle (95% of subjects received 1–9 cycles) by approved indication, Indications are ordered by year of onabotulinumtoxinA approval, with approval year in parentheses. Circle sizes are proportional to the number of patient records indicated.</p> Full article ">Figure 2
<p>NAb status post-treatment and at study exit of subjects who were seronegative at baseline, by indication. Numbers refer to numbers of subjects. NAb, neutralizing antibody; NDO, neurogenic detrusor overactivity.</p> Full article ">Figure 3
<p>Jitter plot showing subjects who were NAb negative (top) and NAb positive (bottom) by dose and treatment cycle for each approved indication (≈95% of subjects received 1–9 treatment cycles; no subject was positive beyond treatment cycle 9).</p> Full article ">Figure 4
<p>Methodology to determine NAb formation in response to onabotulinumtoxinA treatment based on individual subject scenarios for baseline vs. post-treatment NAb results. Abbreviations—NAb, neutralizing antibody; OnabotA, onabotulinumtoxinA.</p> Full article ">

Review

Jump to: Research

8 pages, 236 KiB  
Review
Onabotulinumtoxin A for the Treatment of Post-Traumatic Headache: Is It Better than Anti-CGRP Antibodies?
by Lanfranco Pellesi, Dilara Onan and Paolo Martelletti
Toxins 2024, 16(10), 427; https://doi.org/10.3390/toxins16100427 - 2 Oct 2024
Viewed by 1588
Abstract
Post-traumatic headache (PTH) is a common and debilitating consequence of traumatic brain injury (TBI), often resembling migraine and tension-type headaches. Despite its prevalence, the optimal treatment for PTH remains unclear, with current strategies largely extrapolated from other headache disorders. This review evaluates the [...] Read more.
Post-traumatic headache (PTH) is a common and debilitating consequence of traumatic brain injury (TBI), often resembling migraine and tension-type headaches. Despite its prevalence, the optimal treatment for PTH remains unclear, with current strategies largely extrapolated from other headache disorders. This review evaluates the use of onabotulinumtoxin A (ONA) and anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) in the treatment of PTH. A comprehensive literature search was conducted on PubMed, including studies published up to September 2024, focusing on the efficacy, safety, and mechanisms of onabotulinumtoxin A and anti-CGRP mAbs in PTH. Both clinical trials and observational studies were reviewed. ONA, widely recognized for its efficacy in chronic migraine, has shown limited benefits in PTH with only one trial involving abobotulinumtoxin A in a cohort of 40 subjects. A phase 2 trial with fremanezumab, an anti-CGRP monoclonal antibody, failed to demonstrate significant efficacy in PTH, raising questions about the utility of targeting CGRP in this condition. ONA may offer advantages over anti-CGRP mAbs, not only in terms of its broader mechanism of action but also in cost-effectiveness and higher patient adherence. Both ONA and anti-CGRP mAbs are potential options for the management of PTH, but the current evidence is insufficient to establish clear guidelines. The negative results from the fremanezumab trial suggest that CGRP inhibition may not be sufficient for treating PTH, whereas onabotulinumtoxin A’s ability to target multiple pain pathways may make it a more promising candidate. Full article
(This article belongs to the Special Issue Immunogenicity of Botulinum Toxin)
25 pages, 3146 KiB  
Review
Continuous Treatment with IncobotulinumtoxinA Despite Presence of BoNT/A Neutralizing Antibodies: Immunological Hypothesis and a Case Report
by Michael Uwe Martin, Clifton Ming Tay and Tuck Wah Siew
Toxins 2024, 16(10), 422; https://doi.org/10.3390/toxins16100422 - 1 Oct 2024
Viewed by 2054
Abstract
Botulinum Neurotoxin A (BoNT/A) is a bacterial protein that has proven to be a valuable pharmaceutical in therapeutic indications and aesthetic medicine. One major concern is the formation of neutralizing antibodies (nAbs) to the core BoNT/A protein. These can interfere with the therapy, [...] Read more.
Botulinum Neurotoxin A (BoNT/A) is a bacterial protein that has proven to be a valuable pharmaceutical in therapeutic indications and aesthetic medicine. One major concern is the formation of neutralizing antibodies (nAbs) to the core BoNT/A protein. These can interfere with the therapy, resulting in partial or complete antibody (Ab)-mediated secondary non-response (SNR) or immunoresistance. If titers of nAbs reach a level high enough that all injected BoNT/A molecules are neutralized, immunoresistance occurs. Studies have shown that continuation of treatment of neurology patients who had developed Ab-mediated partial SNR against complexing protein-containing (CPC-) BoNT/A was in some cases successful if patients were switched to complexing protein-free (CPF-) incobotulinumtoxinA (INCO). This seems to contradict the layperson’s basic immunological understanding that repeated injection with the same antigen BoNT/A should lead to an increase in antigen-specific antibody titers. As such, we strive to explain how immunological memory works in general, and based on this, we propose a working hypothesis for this paradoxical phenomenon observed in some, but not all, neurology patients with immunoresistance. A critical factor is the presence of potentially immune-stimulatory components in CPC-BoNT/A products that can act as immunologic adjuvants and activate not only naïve, but also memory B lymphocyte responses. Furthermore, we propose that continuous injection of a BoN/TA formulation with low immunogenicity, e.g., INCO, may be a viable option for aesthetic patients with existing nAbs. These concepts are supported by a real-world case example of a patient with immunoresistance whose nAb levels declined with corresponding resumption of clinical response despite regular INCO injections. Full article
(This article belongs to the Special Issue Immunogenicity of Botulinum Toxin)
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Figure 1

Figure 1
<p>Summary scheme of the activation of the immune system: The naïve situation. (<b>A</b>) Dendritic cells (DCs) are sentinel cells residing in tissues. Upon encountering a microbial challenge, microbial surface structures, e.g., flagellin, act as immunologic adjuvants (red arrow) to activate pattern-recognition receptors (PRRs) on DCs. Activated DCs phagocytose what they have recognized (antigens) in their vicinity. Phagocytosed proteins are digested in phagosomes to antigenic peptides that are loaded onto MHC II. Upon optimal activation, DC move from the tissue into the next draining lymph node (rolling blue arrow from <b>A</b> to <b>B</b>). (<b>B</b>) In the lymph node, DCs settle as professional antigen presenting cells (APC) presenting peptides on MHC II to antigen-specific naïve T helper lymphocytes (Th0). If a naïve Th0 cell recognizes the presented peptide in MHC II, it interacts with the costimulatory surface molecules on the APC (double arrow) and receives cytokines from the APC (single arrow). The Th0 cell becomes fully activated, starts to proliferate, and clonally expands to a large number of effector Th cells with identical peptide specificity. (<b>C</b>) An antigen-specific naïve B lymphocyte (B) recognizes the same antigen with its B cell antigen receptor (BCR) that is a plasma membrane-anchored immunoglobulin. In the presence of immunologic adjuvants (red arrow) these PRR are engaged, and this B cell becomes optimally activated (left). It internalizes its BCR with the bound antigen, processes it to antigenic peptides (right), and presents these in MHC II on the surface (the same peptide as presented by the DC). One of the offsprings of the clonally expanded antigen-specific Th provides help in form of costimulatory molecules (double-headed arrow) and T helper cell cytokines (single arrow). This allows clonal expansion of this antigen-specific B cell to develop into many B plasma cells with the same antigen specificity. In the naïve immune response, immunologic adjuvants (red arrows) come into action twice: first by facilitating full activation of DC to become APC, and second, by allowing full activation of an antigen-specific B cell.</p> Full article ">Figure 2
<p>Antigen-specific B lymphocytes have several options of contributing antibodies in a naïve and memory situation. (<b>A</b>) The naïve situation. An antigen-specific B lymphocyte that has been optimally stimulated by its antigen plus immunologic adjuvants presents peptides to an antigen-specific T helper lymphocyte in the lymph node and receives T cell help to clonally expand. The clonal offspring have several options. They can develop into IgM-producing antibody factories, or plasma blasts (P) providing the first wave of protective antibodies with a low to moderate affinity (far left). A few of these IgM-positive B cells may develop into resting memory cells (left). In the germinal center (GC), B cells undergo several rounds of proliferation (middle). They can switch antibody classes and contribute with IgG antibodies with a similar affinity for the antigen to the first wave of Abs (middle). Some of these B cells can be rescued to become IgG-positive memory B cells (middle). Others can switch antibody classes and improve the affinity of their BCR by undergoing somatic hypermutation and affinity maturation. A part of these B cells can either become IgG-positive memory B cells (right) or produce higher-affinity IgG Abs in the late stage of an immune response (far right). (<b>B</b>) The recall situation. After encountering the same antigen again, all depicted types of memory B cells can rapidly produce antigen-specific Abs of different isotypes and affinities. Immunologic adjuvants can contribute to optimal B cell activation in the naïve and the recall situation (indicated by the red arrows).</p> Full article ">Figure 3
<p>Trend of nAb titers over time. From July 2019 (VII/19) to January 2024 (I/20), the patient’s serum was analyzed for nAbs to BoNT/A using an ex-vivo mouse hemidiaphragm assay (service performed by toxogen GmbH, since Jan 2023 by toxologics GmbH, Hannover, Germany) at regular intervals. The patient received INCO every 3–4 months, from July 2019 (VI/19)–April 2024 (IV/24), with a dose of 50 units per masseter. Titers of nAbs were progressively on a downward trend from July 2019 (VI/19), eventually reaching below the lower cutoff point of 1.82 mIU/mL and hence regarded as undetectable in January 2023. (International unit (IU)/mL is a measurement of neutralizing BoNT/A activity in serum. One IU neutralizes 10,000 LD<sub>50</sub> BoNT/A. The botulinum neurotoxin serotype A antitoxin standard was trivalent Botulismus Antitoxin Behring (registration no. 31a/78) Batch 080031A from Novartis Vaccines and Diagnostics GmbH &amp; Co. KG, 35006 Marburg, Germany).</p> Full article ">Figure 4
<p>Assessment of clinical responses of patient. (<b>A</b>) Photographic demonstration of masseter reduction. Before incobtulinumtoxinA injection in September 2023 and March 2024; 2 months post-injection with INCO in May 2024. (<b>B</b>) Ultrasonographic measurement of masseter thickness reduction. Following INCO injection in January 2024, mean thickness of masseter decreased from 15.7 mm to 15.0 mm in March 2024, and from 14.7 mm in April 2024 to 13.5 mm in May 2024. (<b>C</b>) Photographic demonstration of clinical response to INCO treatment in the glabella at maximum frown: (left) before; September 2023 (right) after; November 2023).</p> Full article ">
20 pages, 1353 KiB  
Review
Complexing Protein-Free Botulinum Neurotoxin A Formulations: Implications of Excipients for Immunogenicity
by Michael Uwe Martin, Juergen Frevert and Clifton Ming Tay
Toxins 2024, 16(2), 101; https://doi.org/10.3390/toxins16020101 - 10 Feb 2024
Cited by 3 | Viewed by 4968
Abstract
The formation of neutralizing antibodies is a growing concern in the use of botulinum neurotoxin A (BoNT/A) as it may result in secondary treatment failure. Differences in the immunogenicity of BoNT/A formulations have been attributed to the presence of pharmacologically unnecessary bacterial components. [...] Read more.
The formation of neutralizing antibodies is a growing concern in the use of botulinum neurotoxin A (BoNT/A) as it may result in secondary treatment failure. Differences in the immunogenicity of BoNT/A formulations have been attributed to the presence of pharmacologically unnecessary bacterial components. Reportedly, the rate of antibody-mediated secondary non-response is lowest in complexing protein-free (CF) IncobotulinumtoxinA (INCO). Here, the published data and literature on the composition and properties of the three commercially available CF-BoNT/A formulations, namely, INCO, Coretox® (CORE), and DaxibotulinumtoxinA (DAXI), are reviewed to elucidate the implications for their potential immunogenicity. While all three BoNT/A formulations are free of complexing proteins and contain the core BoNT/A molecule as the active pharmaceutical ingredient, they differ in their production protocols and excipients, which may affect their immunogenicity. INCO contains only two immunologically inconspicuous excipients, namely, human serum albumin and sucrose, and has demonstrated low immunogenicity in daily practice and clinical studies for more than ten years. DAXI contains four excipients, namely, L-histidine, trehalosedihydrate, polysorbate 20, and the highly charged RTP004 peptide, of which the latter two may increase the immunogenicity of BoNT/A by introducing neo-epitopes. In early clinical studies with DAXI, antibodies against BoNT/A and RTP004 were found at low frequencies; however, the follow-up period was critically short, with a maximum of three injections. CORE contains four excipients: L-methionine, sucrose, NaCl, and polysorbate 20. Presently, no data are available on the immunogenicity of CORE in human beings. It remains to be seen whether all three CF BoNT/A formulations demonstrate the same low immunogenicity in patients over a long period of time. Full article
(This article belongs to the Special Issue Immunogenicity of Botulinum Toxin)
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Figure 1

Figure 1
<p>Schematical depiction of botulinum neurotoxin A. (<b>a</b>) The 150 kDa neuromodulator BoNT/A consists of one heavy chain of 100 kDa (red circle) and one light chain of 50 kDa (red square) covalently linked by a disulfide bridge (yellow line). (<b>b</b>) The progenitor complex of 900 kDa is composed of the 150 kDa neuromodulator BoNT/A (red), a non-toxic non-hemagglutinin (NTNHA) of 150 kDA (green), and a 12-subunit complex consisting of 3 different hemagglutinins (HAs): 3 times HA70, 3 times HA 17, and 6 times HA33. The schemes were modified from the structures in [<a href="#B3-toxins-16-00101" class="html-bibr">3</a>].</p> Full article ">Figure 2
<p>Schematic depiction of principal differences in purity of selected BoNT/A preparations. (<b>a</b>) BoNT/A formulations without bacterial complexing proteins, containing only the 150 kDa neuromodulator, namely IncobotulinumtoxinA [<a href="#B8-toxins-16-00101" class="html-bibr">8</a>,<a href="#B9-toxins-16-00101" class="html-bibr">9</a>], Coretox<sup>®</sup> [<a href="#B10-toxins-16-00101" class="html-bibr">10</a>] and DaxibotulinumtoxinA [<a href="#B11-toxins-16-00101" class="html-bibr">11</a>,<a href="#B12-toxins-16-00101" class="html-bibr">12</a>]. (<b>b</b>) BoNT/A formulations containing clostridial complexing proteins, such as AbobotulinumtoxinA [<a href="#B13-toxins-16-00101" class="html-bibr">13</a>], OnabotulinumtoxinA [<a href="#B14-toxins-16-00101" class="html-bibr">14</a>], PrabotulinumtoxinA [<a href="#B15-toxins-16-00101" class="html-bibr">15</a>] and LetibotulinumtoxinA [<a href="#B16-toxins-16-00101" class="html-bibr">16</a>]. Some of these also contain bacterial components such as flagellin, bacterial DNA and inactive toxin molecules [<a href="#B17-toxins-16-00101" class="html-bibr">17</a>,<a href="#B18-toxins-16-00101" class="html-bibr">18</a>].</p> Full article ">Figure 3
<p>Simplified model of the activation of the immune system. Two decisions have to be made by the immune system in a strictly hierarchical order before antibodies can be produced. Firstly, sentinel dendritic cells need to be fully activated by “<b>danger signals</b>” to become professional antigen-presenting cells. They present peptides of the antigen (here, BoNT/A) to an antigen-specific T helper lymphocyte, which can recognize the presented peptide as “<b>foreign</b>”. Secondly, if the peptide is foreign, such as in clostridial BoNT/A, this T helper lymphocyte becomes activated and subsequently supports antigen-specific B lymphocytes. These become activated and finally produce and release antigen-specific antibodies to BoNT/A, possibly including neutralizing antibodies.</p> Full article ">
11 pages, 303 KiB  
Review
Deep Brain Stimulation for Focal or Segmental Craniocervical Dystonia in Patients Who Have Failed Botulinum Neurotoxin Therapy—A Narrative Review of the Literature
by Thorsten M. Odorfer and Jens Volkmann
Toxins 2023, 15(10), 606; https://doi.org/10.3390/toxins15100606 - 9 Oct 2023
Cited by 1 | Viewed by 2117
Abstract
(1) Background: The first-line treatment for patients with focal or segmental dystonia with a craniocervical distribution is still the intramuscular injection of botulinum neurotoxin (BoNT). However, some patients experience primary or secondary treatment failure from this potential immunogenic therapy. Deep brain stimulation (DBS) [...] Read more.
(1) Background: The first-line treatment for patients with focal or segmental dystonia with a craniocervical distribution is still the intramuscular injection of botulinum neurotoxin (BoNT). However, some patients experience primary or secondary treatment failure from this potential immunogenic therapy. Deep brain stimulation (DBS) may then be used as a backup strategy in this situation. (2) Methods: Here, we reviewed the current study literature to answer a specific question regarding the efficacy and safety of the use of DBS, particularly for cervical dystonia (CD) and Meige syndrome (MS) in patients with documented treatment failure under BoNT. (3) Results: There are only two studies with the highest level of evidence in this area. Despite this clear limitation, in the context of the narrowly defined research question of this paper, it is possible to report 161 patients with CD or MS who were included in studies that were able to show a statistically significant reduction in dystonic symptoms using DBS. Safety and tolerability data appeared adequate. However, much of the information is based on retrospective observations. (4) Conclusions: The evidence base in this area is in need of further scientific investigation. Most importantly, more randomized, controlled and double-blind trials are needed, possibly including a head-to-head comparison of DBS and BoNT. Full article
(This article belongs to the Special Issue Immunogenicity of Botulinum Toxin)
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