Abstract
Antivenoms developed from the plasma of hyperimmunized animals are the only effective treatment available against snakebite envenomation but shortage of supply contributes to the high morbidity and mortality toll of this tropical disease. We describe a synthetic biology approach to affordable and cost‐effective antivenom production based on plant‐made recombinant polyclonal antibodies (termed pluribodies). The strategy takes advantage of virus superinfection exclusion to induce the formation of somatic expression mosaics in agroinfiltrated plants, which enables the expression of complex antibody repertoires in a highly reproducible manner. Pluribodies developed using toxin‐binding genetic information captured from peripheral blood lymphocytes of hyperimmunized camels recapitulated the overall binding activity of the immune response. Furthermore, an improved plant‐made antivenom (plantivenom) was formulated using an in vitro selected pluribody against Bothrops asper snake venom toxins and has been shown to neutralize a wide range of toxin activities and provide protection against lethal venom doses in mice.
Highlights
Passive immunization (PI) with polyclonal antibodies purified from animal serum was first adopted to treat diphtheria in the 19th century (Graham and Ambrosino, 2015)
The spatio-temporal dynamics of the mosaic-like expression patterns were monitored in Nicotiana benthamiana leaves after agroinfiltration of three virus-based infective clones encoding GFP, BFP and DsRed fluorescent proteins (Figure 1a)
Based on the computer simulations, we anticipated that, for a given set of initial parameters, mosaic composition would be a highly reproducible outcome (Figure 1c) and that reproducibility would increase with the number of initial infection foci
Summary
Passive immunization (PI) with polyclonal antibodies (pAbs) purified from animal serum was first adopted to treat diphtheria in the 19th century (Graham and Ambrosino, 2015). PAbs-based antivenoms remain the only available treatment against complex toxin mixtures such as those present in snake venoms. Antivenom supply is at constant risk due to high manufacturing costs and the low income level of target populations (Arnold, 2016; Harrison et al, 2009). Manufacturing costs for complex antibody cocktails are still high because to ensure consistency they often require parallel production lines for each component of the cocktail. It is difficult to reconcile moves towards cocktail simplification with a major trend in antivenom formulation, namely to widen the spectrum of snake venoms covered by a single treatment (Lavonas, 2012; Stock et al, 2007)
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