Abstract
Snakebite envenoming is a neglected tropical disease that affects millions of people across the globe. It has been suggested that recombinant antivenoms based on mixtures of human monoclonal antibodies, which target key toxins of medically important snake venom, could present a promising avenue toward the reduction of morbidity and mortality of envenomated patients. However, since snakebite envenoming is a disease of poverty, it is pivotal that next-generation therapies are affordable to those most in need; this warrants analysis of the cost dynamics of recombinant antivenom manufacture. Therefore, we present, for the first time, a bottom-up analysis of the cost dynamics surrounding the production of future recombinant antivenoms based on available industry data. We unravel the potential impact that venom volume, abundance of medically relevant toxins in a venom, and the molecular weight of these toxins may have on the final product cost. Furthermore, we assess the roles that antibody molar mass, manufacturing and purification strategies, formulation, antibody efficacy, and potential cross-reactivity play in the complex cost dynamics of recombinant antivenom manufacture. Notably, according to our calculations, it appears that such next-generation antivenoms based on cocktails of monoclonal immunoglobulin Gs (IgGs) could be manufacturable at a comparable or lower cost to current plasma-derived antivenoms, which are priced at USD 13-1120 per treatment. We found that monovalent recombinant antivenoms based on IgGs could be manufactured for USD 20-225 per treatment, while more complex polyvalent recombinant antivenoms based on IgGs could be manufactured for USD 48-1354 per treatment. Finally, we investigated the prospective cost of manufacturing for recombinant antivenoms based on alternative protein scaffolds, such as DARPins and nanobodies, and highlight the potential utility of such scaffolds in the context of low-cost manufacturing. In conclusion, the development of recombinant antivenoms not only holds a promise for improving therapeutic parameters, such as safety and efficacy, but could possibly also lead to a more competetive cost of manufacture of antivenom products for patients worldwide.
Highlights
The World Health Organization recently reclassified snakebite envenoming as a Category A Neglected Tropical Disease and developed a strategy for reducing the morbidity and mortality for snakebite victims worldwide (Chippaux, 2017; Williams et al, 2019)
Recombinant antivenoms have been hypothesized to be manufacturable at low cost (Laustsen et al, 2016, 2017), which is an important parameter for therapies against neglected tropical diseases
In the following, we present key variables to consider when assessing potential manufacturing costs for recombinant antivenoms using a bottom-up approach and conclude that they represent a promising solution for next-generation snakebite envenoming therapy
Summary
The World Health Organization recently reclassified snakebite envenoming as a Category A Neglected Tropical Disease and developed a strategy for reducing the morbidity and mortality for snakebite victims worldwide (Chippaux, 2017; Williams et al, 2019). Cost of Next-Generation Antivenoms snakebite envenoming therapies is recommended In this relation, a promising avenue that has gained interest in recent years, is the use of recombinant antivenoms based on carefully designed mixtures of human monoclonal antibodies targeting key toxins of medically important snake venoms (Laustsen, 2016). With recent developments in the field of recombinant antivenom research and reports of monoclonal antibodies being effective at low dose in neutralizing key toxins in different animal venoms (Richard et al, 2013; Knudsen and Laustsen, 2018; Laustsen et al, 2018), it is possible to perform a more fine-grained estimation of the prospective cost of manufacture for recombinant antivenoms. We compare the theoretical cost of manufacture for the active pharmaceutical ingredient (API) with the cost of manufacture for the final drug product (FDP), as well as explore the relation between cost of manufacture and the molecular sizes of different antibody formats with the purpose of highlighting the influence of the number of toxin binding sites per mass unit for different types of antibodies
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