Engineered botulinum neurotoxin B with improved binding to human receptors has enhanced efficacy in preclinical models

Mark Elliott, Christine Favre-Guilmard, Sai Man Liu, Jacquie Maignel, Geoffrey Masuyer, Matthew Beard, Christopher Boone, Denis Carré, Mikhail Kalinichev, Stephane Lezmi, Imran Mir, Camille Nicoleau, Shilpa Palan, Cindy Perier, Elsa Raban, Sicai Zhang, Min Dong, Pål Stenmark, Johannes Krupp

Research output: Contribution to journalArticlepeer-review

31 Citations (SciVal)

Abstract

Although botulinum neurotoxin serotype A (BoNT/A) products are common treatments for various disorders, there is only one commercial BoNT/B product, whose low potency, likely stemming from low affinity toward its human receptor synaptotagmin 2 (hSyt2), has limited its therapeutic usefulness. We express and characterize two full-length recombinant BoNT/B1 proteins containing designed mutations E1191M/S1199Y (rBoNT/B1 MY ) and E1191Q/S1199W (rBoNT/B1 QW ) that enhance binding to hSyt2. In preclinical models including human-induced pluripotent stem cell neurons and a humanized transgenic mouse, this increased hSyt2 affinity results in high potency, comparable to that of BoNT/A. Last, we solve the cocrystal structure of rBoNT/B1 MY in complex with peptides of hSyt2 and its homolog hSyt1. We demonstrate that neuronal surface receptor binding limits the clinical efficacy of unmodified BoNT/B and that modified BoNT/B proteins have promising clinical potential.

Original languageEnglish
Article numbereaau7196
Pages (from-to)1-13
Number of pages13
JournalScience Advances
Volume5
Issue number1
DOIs
Publication statusPublished - 16 Jan 2019

Funding

We thank J.-L. Blachon (Ipsen) for help with the statistical analysis and M. Norbert (genOway) for help with compiling the husbandry data for the hSyt2 mice. We thank the scientists at stations I02, I03, and I04-1 of Diamond Light Source, Didcot, Oxfordshire (UK) for support during data collection (allocations MX11265 and MX15806). Funding: M.D. acknowledges the grant support from the NIH (NS080833 and AI132387) and holds the Investigator in the Pathogenesis of Infectious Disease award from the Burroughs Wellcome Fund. P.S. acknowledges the support by the Swedish Research Council (2014–5667), the Wenner-Gren Foundation, and the Swedish Cancer Society. This study was supported by an industry-sponsored research grant from Ipsen to M.D. and a grant for a postdoctoral fellow to P.S. sponsored by Ipsen.

ASJC Scopus subject areas

  • General

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