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

doi:10.1126/sciadv.aau7196

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

Department of Life Sciences

Research output: Contribution to journal › Article › peer-review

25 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 language	English
Article number	eaau7196
Pages (from-to)	1-13
Number of pages	13
Journal	Science Advances
Volume	5
Issue number	1
DOIs	https://doi.org/10.1126/sciadv.aau7196
Publication status	Published - 16 Jan 2019

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Elliott, M., Favre-Guilmard, C., Liu, S. M., Maignel, J., Masuyer, G., Beard, M., Boone, C., Carré, D., Kalinichev, M., Lezmi, S., Mir, I., Nicoleau, C., Palan, S., Perier, C., Raban, E., Zhang, S., Dong, M., Stenmark, P., & Krupp, J. (2019). Engineered botulinum neurotoxin B with improved binding to human receptors has enhanced efficacy in preclinical models. Science Advances, 5(1), 1-13. [eaau7196]. https://doi.org/10.1126/sciadv.aau7196

Elliott, M, Favre-Guilmard, C, Liu, SM, Maignel, J, Masuyer, G, Beard, M, Boone, C, Carré, D, Kalinichev, M, Lezmi, S, Mir, I, Nicoleau, C, Palan, S, Perier, C, Raban, E, Zhang, S, Dong, M, Stenmark, P & Krupp, J 2019, 'Engineered botulinum neurotoxin B with improved binding to human receptors has enhanced efficacy in preclinical models', Science Advances, vol. 5, no. 1, eaau7196, pp. 1-13. https://doi.org/10.1126/sciadv.aau7196

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

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. ",

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AU - Elliott, Mark

AU - Favre-Guilmard, Christine

AU - Liu, Sai Man

AU - Maignel, Jacquie

AU - Masuyer, Geoffrey

AU - Beard, Matthew

AU - Boone, Christopher

AU - Carré, Denis

AU - Kalinichev, Mikhail

AU - Lezmi, Stephane

AU - Mir, Imran

AU - Nicoleau, Camille

AU - Palan, Shilpa

AU - Perier, Cindy

AU - Raban, Elsa

AU - Zhang, Sicai

AU - Dong, Min

AU - Stenmark, Pål

AU - Krupp, Johannes

PY - 2019/1/16

Y1 - 2019/1/16

N2 - 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.

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

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