Generation of venom-neutralising recombinant chimeric antibodies

Grantholders

  • Dr John McCafferty

    IONTAS, United Kingdom

Project summary

The main therapeutic intervention for snakebite envenomation relies on the century-old approach of injecting victims with animal-derived polyclonal antiserum. Animal immunisation generates high affinity antibodies and undoubtedly saves lives, but the use of immune antiserum has a number of limitations around consistency, redundancy and immunogenicity.

Recombinant antibody technology will allow the capture, sequencing and characterisation of the monoclonal antibody repertoire arising from immunisation. The resulting high affinity antibodies will be made more human-like by fusing animal-derived variable domains with human constant domains (chimeric antibodies).

This project will generate phage display libraries from horses and llamas immunised with venoms of four sub-saharan African snakes, represented in the co-applicants antivenom EchiTab-Plus_ICP. We will generate antibody panels by phage selection, screening and sequencing. This resolution of the immune repertoire to a complex venom, into its monoclonal components, essentially transforms the problem into one of deconvolution. Affinity capture-mass spectrometry will be used to identify the target of thousands of individual antibodies based on their distinct mass-defined target. Following triage based on binding profiles, antibodies to individual targets will be expressed as chimeric antibodies and validated using in vitro and in vivo animal models of envenomation to generate life-saving, chimeric antibody cocktails.