The European AntibotABE Framework Program and Its Update: Development of Innovative Botulinum Antibodies

Area of Science:

• Immunology
• Microbiology
• Toxicology

Background:

• Botulinum neurotoxins (BoNT) serotypes A, B, and E are lethal and cause most human botulism cases.
• Existing therapies may have limitations, necessitating the development of novel neutralizing agents.
• Targeting heavy and light chains (HC and LC) of BoNT offers a strategy for synergistic neutralization.

Purpose of the Study:

• To develop recombinant antibodies capable of neutralizing botulinum neurotoxins (BoNT) A, B, and E.
• To create an oligoclonal antibody cocktail for enhanced therapeutic efficacy against botulism.
• To assess the in vivo protective potential of these humanized antibodies.

Main Methods:

• Immunization of macaques with recombinant BoNT/A, B, or E HC or LC.
• Generation of immune phage-display libraries and selection of neutralizing antibody fragments.
• Germline humanization of antibody fragments and expression as immunoglobulin G (IgGs).
• In vitro, ex vivo, and in vivo efficacy testing in a standardized protection model.

Main Results:

• Identified protective antibody combinations against BoNT/A and BoNT/B.
• An anti-LC antibody demonstrated high protective efficacy against BoNT/E.
• Developed five humanized antibodies for potential clinical development.
• The antibody cocktail showed high "humanness," predicting good human tolerance.

Conclusions:

• The AntiBotABE Program successfully developed neutralizing recombinant antibodies against BoNT A, B, and E.
• An oligoclonal antibody cocktail targeting multiple BoNT components shows significant therapeutic potential.
• These humanized antibodies are suitable for clinical and regulatory development for treating botulism.