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The role of human serum albumin and neurotoxin associated proteins in the formulation of BoNT/A products.
Toxicon 2019; 168:158-163T

Abstract

Botulinum neurotoxin (BoNT) is synthesized as a progenitor toxin complex (PTC) by Clostridium botulinum. This PTC comprises, in addition to the neurotoxin itself, neurotoxin associated proteins (NAPs) which are composed of three hemagglutinins and one non-toxic, non-hemagglutinin protein. After oral ingestion, these NAPs protect the neurotoxin from the low pH and proteases in the gastrointestinal tract and play a role in the entry via the intestinal barrier. Two of the three therapeutically used botulinum neurotoxin serotype A (BoNT/A) products (onabotulinumtoxinA and abobotulinumtoxinA) contain different amounts of NAPs, while incobotulinumtoxinA, lacks these proteins. In addition, human serum albumin (HSA) that is supposed to stabilize BoNT/A is added at different concentrations. Up to now, the function of the NAPs and HSA after parenteral therapeutic application is not completely understood. To investigate the influence of NAPs and HSA on potency of BoNT/A, we used the ex vivo mouse phrenic nerve hemidiaphragm assay. Increasing doses of HSA resulted dose-dependently in a more pronounced effect of BoNT/A. Though, a plateau was reached with concentrations of 0.8 mg/ml HSA and higher, the accessory addition of NAPs in a relevant amount (4 ng/ml) did not further enhance the effect of BoNT/A. In conclusion, in our ex vivo assay an adequate concentration of HSA prevented BoNT/A from loss of effect and supplementary NAPs did not alter this effect. A confirmation of these data in an in vivo assay is still lacking. However, it might be supposed that even in clinically applied BoNT/A products an increase of HSA accompanied by the avoidance of NAPs could potentially reduce the injected dose and, thus, the risk of unwanted side effects, the treatment costs as well as the risk of a secondary therapy failure due to BoNT/A neutralizing antibodies.

Authors+Show Affiliations

Department of Neurology, Hannover Medical School, Hannover, Germany. Electronic address: Kutschenko.Anna@mh-hannover.de.Institute of Toxicology, Hannover Medical School, Hannover, Germany.Department of Neurology, Hannover Medical School, Hannover, Germany.Department of Neurology, BG Hospital Bergmannstrost, Halle (Saale), Germany.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31323228

Citation

Kutschenko, Anna, et al. "The Role of Human Serum Albumin and Neurotoxin Associated Proteins in the Formulation of BoNT/A Products." Toxicon : Official Journal of the International Society On Toxinology, vol. 168, 2019, pp. 158-163.
Kutschenko A, Bigalke H, Wegner F, et al. The role of human serum albumin and neurotoxin associated proteins in the formulation of BoNT/A products. Toxicon. 2019;168:158-163.
Kutschenko, A., Bigalke, H., Wegner, F., & Wohlfarth, K. (2019). The role of human serum albumin and neurotoxin associated proteins in the formulation of BoNT/A products. Toxicon : Official Journal of the International Society On Toxinology, 168, pp. 158-163. doi:10.1016/j.toxicon.2019.07.005.
Kutschenko A, et al. The Role of Human Serum Albumin and Neurotoxin Associated Proteins in the Formulation of BoNT/A Products. Toxicon. 2019;168:158-163. PubMed PMID: 31323228.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The role of human serum albumin and neurotoxin associated proteins in the formulation of BoNT/A products. AU - Kutschenko,Anna, AU - Bigalke,Hans, AU - Wegner,Florian, AU - Wohlfarth,Kai, Y1 - 2019/07/16/ PY - 2019/03/25/received PY - 2019/07/11/revised PY - 2019/07/16/accepted PY - 2019/7/20/pubmed PY - 2019/7/20/medline PY - 2019/7/20/entrez KW - Botulinum neurotoxin KW - Human serum albumin KW - Mouse hemidiaphragm assay KW - Neurotoxin associated proteins KW - Neutralizing antibodies SP - 158 EP - 163 JF - Toxicon : official journal of the International Society on Toxinology JO - Toxicon VL - 168 N2 - Botulinum neurotoxin (BoNT) is synthesized as a progenitor toxin complex (PTC) by Clostridium botulinum. This PTC comprises, in addition to the neurotoxin itself, neurotoxin associated proteins (NAPs) which are composed of three hemagglutinins and one non-toxic, non-hemagglutinin protein. After oral ingestion, these NAPs protect the neurotoxin from the low pH and proteases in the gastrointestinal tract and play a role in the entry via the intestinal barrier. Two of the three therapeutically used botulinum neurotoxin serotype A (BoNT/A) products (onabotulinumtoxinA and abobotulinumtoxinA) contain different amounts of NAPs, while incobotulinumtoxinA, lacks these proteins. In addition, human serum albumin (HSA) that is supposed to stabilize BoNT/A is added at different concentrations. Up to now, the function of the NAPs and HSA after parenteral therapeutic application is not completely understood. To investigate the influence of NAPs and HSA on potency of BoNT/A, we used the ex vivo mouse phrenic nerve hemidiaphragm assay. Increasing doses of HSA resulted dose-dependently in a more pronounced effect of BoNT/A. Though, a plateau was reached with concentrations of 0.8 mg/ml HSA and higher, the accessory addition of NAPs in a relevant amount (4 ng/ml) did not further enhance the effect of BoNT/A. In conclusion, in our ex vivo assay an adequate concentration of HSA prevented BoNT/A from loss of effect and supplementary NAPs did not alter this effect. A confirmation of these data in an in vivo assay is still lacking. However, it might be supposed that even in clinically applied BoNT/A products an increase of HSA accompanied by the avoidance of NAPs could potentially reduce the injected dose and, thus, the risk of unwanted side effects, the treatment costs as well as the risk of a secondary therapy failure due to BoNT/A neutralizing antibodies. SN - 1879-3150 UR - https://www.unboundmedicine.com/medline/citation/31323228/The_role_of_human_serum_albumin_and_neurotoxin_associated_proteins_in_the_formulation_of_BoNT/A_products L2 - https://linkinghub.elsevier.com/retrieve/pii/S0041-0101(19)30408-8 DB - PRIME DP - Unbound Medicine ER -