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Sci Adv. 2019 Jan 16;5(1):eaau7196. doi: 10.1126/sciadv.aau7196. eCollection 2019 Jan.

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

Author information

1
Ipsen Bioinnovation, 102 Park Drive, Milton Park, Abingdon OX14 4RY, UK.
2
Ipsen Innovation, 5 Avenue du Canada, 91940 Les Ulis, France.
3
Department of Biochemistry and Biophysics, Stockholm University, Stockholm SE-106 91, Sweden.
4
Department of Urology, Boston Children's Hospital, Department of Microbiology and Immunobiology and Department of Surgery, Harvard Medical School, Boston, MA 02115, USA.
5
Department of Experimental Medical Science, Lund University, 221 00 Lund, Sweden.

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/B1MY) and E1191Q/S1199W (rBoNT/B1QW) 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/B1MY 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.

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