Progressing existing snake venom toxin-specific antibodies into humanised, thermostable monoclonal therapies for preclinical manufacture and clinical trials in Africa and India
Year of award: 2021
Grantholders
Dr Kartik Sunagar
Indian Institute of Science, India
Dr Devin Sok
International AIDS Vaccine Initiative, United States
Dr Nicholas Casewell
Liverpool School of Tropical Medicine, United Kingdom
Project summary
Antivenom treatment of snakebite is failing to reduce the annual 138,000 deaths - predominantly in impoverished tropical communities. With a focus upon the most medically-important African and Indian snake venoms, we are developing toxin-neutralising, recombinant, humanised, thermostable monoclonal antibodies (mAbs) that will be more dose- and polyspecifically-effective, affordable and safer than antivenoms, and possess critical economies of scale and manufacturing incentives to secure sustained production/delivery.
We have collected sera and B cells (producing immunoglobulins of distinct structure and therapeutic/mAb-development promise) from:
- multi-envenomed humans
- cows, camels, baboons, mice immunised with the most pathogenic African and Indian venom toxins
- horses used to manufacture African or Indian antivenoms.
Using High-Throughput platforms, we will rank B cells producing these globally-unique animal and human antibodies by in vitro toxin-binding affinity and toxin-function neutralisation, prioritising cross-generic/continental functionality. Genes from top-ranked B cells will be processed into recombinant mAbs (220-500).
Subsequent rounds of in vitro and in vivo (neutralisation of venom-induced lethality in a mouse model of envenoming) down-selection will output 20-40 mAbs for gene-manipulation to deliver 'humanised' and thermostable mAbs.
A final round of in vitro/in vivo selection will deliver 5-10 mAbs/3 mAb mixtures of proven pan-Africa/India polyspecific efficacy for downstream preclinical manufacture and clinical trials.