Cost of Manufacturing for Recombinant Snakebite Antivenoms

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.

In vitro discovery and optimization of a human monoclonal antibody that neutralizes neurotoxicity and lethality of cobra snake venom

“…Recently, recombinant antivenoms based on oligoclonal mixtures of human antibodies have been proposed as a cost-competitive alternative to current antivenoms (19–22) . Such recombinant antivenoms may offer safer and more efficacious snakebite envenoming therapy due to their compatibility with the human immune system and the possibility of only including efficacious antibodies, targeting medically relevant snake toxins, in the antivenom mixture (18) .…”

“…Recently, recombinant antivenoms based on oligoclonal mixtures of human antibodies have been proposed as a cost-competitive alternative to current antivenoms (19)(20)(21)(22).…”

Development of Nanobodies Targeting Peste des Petits Ruminants Virus: The Prospect in Disease Diagnosis and Therapy

“…Compared with other biologics, classical monoclonal antibodies produced with long-stablished hybridoma technology are acceptable as the gold standard in immunotherapy and diagnostics [ 78 , 79 , 80 ]. However, these classical monoclonal antibodies need more support costs and they are difficult for massive production compared to their counterpart nanobodies [ 81 , 82 , 83 ]. The high production cost of classical monoclonal antibodies, limited tissue penetration, and less favourable pharmacokinetic stability have stimulated the use of smaller alternative antibody formats, such as the antigen binding fragments, single-chain variable fragments, and nanobodies [ 84 , 85 ].…”

Clinical management of snakebite envenoming: Future perspectives

“…Combined, these studies have demonstrated the feasibility of using phage display technology for the discovery of such molecules, as well as the potential utility of formulating these into so-called ‘recombinant antivenoms’ ( Laustsen, 2016a ). One of the challenges for these types of endeavors is, however, to develop sufficiently broadly-neutralizing monoclonal antibodies, which is a necessity for feasible recombinant antivenom manufacture, as the inclusion of antibodies that are able to cross-neutralize multiple toxins allow the manufacturer to limit the number of antibodies needed in a recombinant antivenom formulation ( Jenkins and Laustsen, 2020 ; Ledsgaard et al, 2018 ). Therefore, recent studies have focused on devising simple, rational methods that allow for facile discovery of antibodies with such properties.…”

“…In contrast to many other disease areas, such as oncology and autoimmune diseases, where antibodies have successfully entered the clinic, SBE is fundamentally different in nature: It is acute, a very large number of targets of great molecular complexity must be neutralized, therapy only needs to be administered over a short period of time, and the majority of patients come from impoverished regions of the tropics ( Laustsen, 2019 ). This puts certain constraints on what antibody formats are likely to be useful for treating this pathology, as well as feasible to develop and cost-competitive to manufacture ( Jenkins and Laustsen, 2020 ; Knudsen et al, 2019 ; Laustsen et al, 2017 ; Laustsen and Dorrestijn, 2018 ). Generally, different antibody formats have different advantages and disadvantages ( Table 2 ), but it is important that the antibody format of choice is compatible with the human immune system and therefore safe, that the format is versatile and allows for facile development of antibodies that can neutralize different toxin families, that the format is easy and low-cost to manufacture, and that the format can be engineered to bind toxins with very high affinity ( Knudsen et al, 2019 ; Laustsen et al, 2018a ).…”