Structural Insights into Rational Design of Single-Domain Antibody-Based Antitoxins against Botulinum Neurotoxins

Journal Article · Sat Feb 01 00:00:00 EST 2020 · Cell Reports

DOI:https://doi.org/10.1016/j.celrep.2020.01.107· OSTI ID:1601520

Lam, Kwok-ho; Tremblay, Jacqueline M.; Vazquez-Cintron, Edwin; Perry, Kay; Ondeck, Celinia; Webb, Robert P.; McNutt, Patrick M.; Shoemaker, Charles B.; Jin, Rongsheng

Botulinum neurotoxin (BoNT) is one of the most acutely lethal toxins known to humans, and effective treatment for BoNT intoxication is urgently needed. Single-domain antibodies (VHH) have been examined as a countermeasure for BoNT because of their high stability and ease of production. Here, we investigate the structures and the neutralization mechanisms for six unique VHHs targeting BoNT/A1 or BoNT/B1. These studies reveal diverse neutralizing mechanisms by which VHHs prevent host receptor binding or block transmembrane delivery of the BoNT protease domain. Guided by this knowledge, we design heterodimeric VHHs by connecting two neutralizing VHHs via a flexible spacer so they can bind simultaneously to the toxin. These bifunctional VHHs display much greater potency in a mouse co-intoxication model than similar heterodimers unable to bind simultaneously. Taken together, our studies offer insight into antibody neutralization of BoNTs and advance our ability to design multivalent anti-pathogen VHHs with improved therapeutic properties.

• Research Organization: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
• Sponsoring Organization: USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institute of Allergy and Infectious Diseases (NIAID)
• Grant/Contract Number: AC02-06CH11357; AC02-76SF00515; P41GM103393; R01AI139087; R21AI139690; R21AI123920; R01AI125704
• OSTI ID: 1601520
• Alternate ID(s): OSTI ID: 1606432
• Journal Information: Cell Reports, Journal Name: Cell Reports Vol. 30 Journal Issue: 8; ISSN 2211-1247
• Publisher: Elsevier
• Country of Publication: Netherlands
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
botulinum neurotoxin
single-domain antibody
VHH
neutralizing epitope
bifunctional antibody
antitoxin
structure-based design