Neuromodulator immunogenicity

Introduction

Botulinum toxin A (BoNT-A) preparations are now included in the therapeutic arsenal for various aesthetic manifestations. Since their inception, a distinguishing feature of BoNT-As has been their proclivity to elicit an immune response against themselves (referred to as immunogenicity), most notably the generation of neutralizing antibodies (NAbs), which can have clinical consequences; In parallel, with the advancement of the manufacturing process over the last decade, which has resulted in improved purification and better knowledge of pharmacokinetics.

The term immunogenicity refers to a protein’s ability to elicit an immune response in a human. Since non-human proteins are present in commercially available BoNT preparations, when injected into a patient, these can act as antigens and induce antibody formation, thereby generating an immune response. Antibodies can be neutralizing or non-neutralizing as a result of an immunogenic response to therapeutic substances. Antibodies that neutralize BoNT-A bind to specific locations in the molecule in such a way that they degrade or abolish biological processes directly. NAb reactions may result in a detrimental effect on clinical outcomes by neutralizing the therapeutic product and lowering its efficacy. In some situations, this diminished efficacy might necessitate dosing patients more frequently to get the required therapeutic benefit. It has been noted that few patients do not respond to BoNT injections for several reasons, including the development of immunoresistance due to the formation of NAbs. Primary non-response (PNR) is when patients fail to respond to the initial treatment with BoNT and any subsequent treatments. Secondary non-response (SNR) occurs when patients have an initial response to therapy with BoNT from at least one injection, but there is a loss of clinical response over time with subsequent treatments. However, immunogenicity caused by NAbs is not the only cause of SNR. Insufficient dosage, improper muscle selection, or incorrect injection technique could be common causes of SNR ( Fig. 29.1 ).

It has been observed that the prevalence of NAbs is found to be higher in older BoNT-A formulations than in newer BoNT-As. Moreover, the overall incidence of NAbs after BoNT-A treatment is minimal and reported to be 1% to 2.1% across different studies. The rate of NAb formation with BoNT-A treatment is also rare across aesthetic indications compared to other therapeutic indications.

Pathogenesis of immunogenicity

Dendritic cells (DCs), the most effective antigen-presenting cells (APCs), are the principal immunogenic route. DCs fall into two categories: conventional and plasmacytoid DCs, both of which can be detected in tissues that are still in the early stages of differentiation. A phase of differentiation called maturation occurs when pathogens or foreign antigens are present, and it involves many phenotypic changes, including the overexpression of major histocompatibility complex (MHC)-I and MHC-II and costimulatory molecules like CD80 and CD86. Immune system cells such as DCs and T cells are activated after migrating to the lymph nodes, where they transmit pathogen-derived peptides to CD8C T cells and or CD4C T cells via MHC-I or MHC-II molecules, respectively. Naive T cells that have been exposed to an antigen effectively can mature into effector T cells, which then divide into cytotoxic CD8+ T cells and regulatory CD4+ T helper (Th) cells. MHC-II molecules are recognized and bound by CD4+ T lymphocytes. They do this by stimulating B cells, which then create specific antibodies in response to antigens. Memory T cells can rapidly divide and expand clones in response to re-exposure to the same antigen. There may be no response, or partial or complete loss of BoNT-A activity, depending on antibody serum levels ( Fig. 29.2 ).

A faster antibody response is achieved by avoiding T cell co-stimulation during the T cell-independent antibody response. Pathogen-expressed antigens can activate specific B cells by cross-linking antigen receptors in a multivalent fashion when expressed on the surface in an organized, highly repetitive form. When a few antigen receptor clusters are formed, the activation is triggered by 10 to 20 membrane-bound Ig (mIg) molecules bound to the antigen. Because of the local membrane association caused by multiple activated Btk (Bruton’s tyrosine kinase) molecules clustering together, intracellular calcium ions are mobilized over the long term. Activation and proliferation of B cells in the absence of T cells can be induced by such persistent calcium fluxes. Toll-like receptor (TLR) engagement can induce B cell proliferation via the first signal of multivalent mIg cross-linking, but it can also selectively induce Ig secretion in B cells activated by the second signal of multivalent but not bivalent, antigen receptor engagement. Lacking affinity maturation, this pathway typically results in a transient, low-titre, and poorly specific IgM-type response.

Genetic predisposition to the immunogenicity

When it comes to infection and autoimmunity, the MHC plays a critical role in adaptive and innate immunity, making it the essential region of the vertebrate genome the human leukocyte antigen (HLA), located on chromosome 6 at position 21.31. In human beings, Class II loci are located at the centromeric end of the region. In contrast, class I loci are located at the telomeric end of the 4 Mb region that encodes the conventional HLA loci. Approximately half of the region’s discovered genes are anticipated to be expressed. The region comprises over 200 genes. Only a small subset of the HLA region’s genes is implicated in the immune response, namely those that code for the classical class I (A, B, and C) and class II (DR, DQ, and DP) antigens. Unfortunately, genome-wide significant association with immunogenicity to BoNT-A has not been well-studied. But it is reported that the carrier of DQB1*06:04 (associated with primary biliary cholangitis and narcolepsy) and DQA1*01:02 (associated with type I diabetes, multiple sclerosis, thyroiditis, and autoimmune hepatitis) has a significant association with immunogenicity to BoNT-A. Unpublished immunogenicity data also matches the highly prevalent allele distribution in north and central Africa; central Europe; north, central Australia, and Queensland; western Asia and the Indochina belt. The prevalence varies by ethnicity in the United States, with non-Hispanic whites having the highest incidence and Native Americans having the lowest frequency.