Immunogenicity Associated with Botulinum Toxin Treatment

Abstract

Botulinum toxin (BoNT) has been used for the treatment of a variety of neurologic, medical and cosmetic conditions. Two serotypes, type A (BoNT-A) and type B (BoNT-B), are currently in clinical use. While considered safe and effective, their use has been rarely complicated by the development of antibodies that reduce or negate their therapeutic effect. The presence of antibodies has been attributed to shorter dosing intervals (and booster injections), higher doses per injection cycle, and higher amounts of antigenic protein. Other factors contributing to the immunogenicity of BoNT include properties of each serotype, such as formulation, manufacturing, and storage of the toxin. Some newer formulations with purified core neurotoxin devoid of accessory proteins may have lower overall immunogenicity. Several assays are available for the detection of antibodies, including both structural assays such as ELISA and mouse-based bioassays, but there is no consistent correlation between these antibodies and clinical response. Prevention and treatment of antibody-associated non-responsiveness is challenging and primarily involves the use of less immunogenic formulations of BoNT, waiting for the spontaneous disappearance of the neutralizing antibody, and switching to an immunologically alternate type of BoNT.

Reply to Comment on Re-Visiting Immunogenicity Associated with Botulinum Toxin Treatment. Toxins 2019, 11, 491

“…Many of the points raised in the commentary by Foster and Beard are echoed in our review [1]. Immunoresistance is a rare phenomenon and accounts for a small minority of patients found to be unresponsive to BoNT.…”

“…examined NAb prevalence in patients treated with BoNT for spasticity. This indication, as discussed in our review [1], appears to have a very low rate of NAbs formation and, therefore, is not suitable for addressing immunogenicity. Likewise, the review by Lacroix-Desmazes et al [6] is not appropriate for citation as the investigators excluded data from studies on patients with SNR.…”

“…In our review we noted that some patients desire shorter injection cycles, based on a survey which found that 45% of patients expressed preference for a treatment cycle of less than 10 weeks [11]. Although this view is frequently expressed by patients treated with BoNT, we certainly do not endorse or advocate for "booster" injections, which in the past have been associated with high frequency of immunoresistance [1]. Most studies examining the effects and safety of shorter inter-dose intervals used incobotulinumtoxinA [12][13][14], but more comparative data are needed before concluding that one product or another is associated with less immunogenicity or longer duration of action [15].…”

Antibody‐induced botulinum toxin treatment failure: A review and novel management approach

“…Many investigative methods to confirm diagnosis of BTF were developed. These methods described elsewhere 4,26,27 . They can be categorized as in vitro tests and in vivo tests as summarized in Table 2.…”

Characterization of a membrane binding loop leads to engineering botulinum neurotoxin B with improved therapeutic efficacy

“…Enhancing toxin binding to nerve terminals facilitates their absorption into local neurons, thus reducing both diffusion from the injection site, which can lead to severe adverse effects [55], and the chance of triggering antibody responses, which renders future treatment ineffective [56]. For instance, BoNT/B shows lower efficacy in humans than BoNT/A, as a single residue change in human Syt II from the mouse version reduced binding affinity of BoNT/B to human Syt II [8,48].…”