Venom protection by broadly neutralizing antibody from a snakebite subject

Glanville, Jacob; Andrade, Joel Christian; Bellin, Mark; Kim, Sang Il; Pletnev, Sergei; Tsao, David; Verardi, Raffaello; Bedi, Rishi; Liao, Sindy; Newland, Raymond; Bayless, Nicholas; Youssef, Sawsan; Tully, Ena S.; Zhang, Baoshan; Bylund, Tatsiana; Kim, Sujeong; Liu, Tracy; Kwong, Peter D.

doi:10.1101/2022.09.26.507364

Cited by 7 publications

(9 citation statements)

References 30 publications

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“…There are several reasons for this. Despite promising advances [ 28 , 29 ], the first barrier is the diversity of relevant toxins in snake venoms, which represents a challenge in developing broadly neutralising recombinant antibodies. While advancements have been made, they remain largely focused on inhibition of specific toxin subfamilies and are not yet sufficiently developed to be combined and tested in humans.…”

Section: Discussionmentioning

confidence: 99%

Landscape of toxin-neutralizing therapeutics for snakebite envenoming (2015–2022): Setting the stage for an R&D agenda

Borri,

Gutiérrez,

Knudsen

et al. 2024

PLoS Negl Trop Dis

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Background Progress in snakebite envenoming (SBE) therapeutics has suffered from a critical lack of data on the research and development (R&D) landscape. A database characterising this information would be a powerful tool for coordinating and accelerating SBE R&D. To address this need, we aimed to identify and categorise all active investigational candidates in development for SBE and all available or marketed products. Methodology/Principal findings In this landscape study, publicly available data and literature were reviewed to canvas the state of the SBE therapeutics market and research pipeline by identifying, characterising, and validating all investigational drug and biologic candidates with direct action on snake venom toxins, and all products available or marketed from 2015 to 2022. We identified 127 marketed products and 196 candidates in the pipeline, describing a very homogenous market of similar but geographically bespoke products and a diverse but immature pipeline, as most investigational candidates are at an early stage of development, with only eight candidates in clinical development. Conclusions/Significance Further investment and research is needed to address the shortfalls in products already on the market and to accelerate R&D for new therapeutics. This should be accompanied by efforts to converge on shared priorities and reshape the current SBE R&D ecosystem to ensure translation of innovation and access.

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Section: Discussionmentioning

confidence: 99%

Landscape of toxin-neutralizing therapeutics for snakebite envenoming (2015–2022): Setting the stage for an R&D agenda

Borri,

Gutiérrez,

Knudsen

et al. 2024

PLoS Negl Trop Dis

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“…Additional issues arise due to delayed administration of antivenom treatment 13 . Antibody 14,15,16,17,18,19,20,21,22 and non-antibody-based therapeutics 23,24,25,26,27,28,29,30 have been tested in preclinical studies, but the development of these types of molecules require either immunization of animals or development of large libraries that require extensive selection, screening, and optimization efforts 31 .…”

Section: Mainmentioning

confidence: 99%

“…We chose to target our design efforts against the neurotoxin edge β-strands (previously discovered monoclonal antibodies in contrast mimic the nAChR binding site 14,21,22 ), focusing on binding modes blocking neurotoxin binding to nAChRs through steric hindrance. Secondary structure and block adjacency tensors were provided to the RFdiffusion model to specify desired β-strand interactions between the designed binder and target α-neurotoxins (see Methods).…”

Section: Design Of α-Neurotoxin Binding Proteinsmentioning

confidence: 99%

De novo designed proteins neutralize lethal snake venom toxins

Baker,

Torres,

Valle

et al. 2024

Preprint

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Snakebite envenoming remains a devastating and neglected tropical disease, claiming over 100,000 lives annually and causing severe complications and long-lasting disabilities for many more1,2. Three-finger toxins (3FTx) are highly toxic components of elapid snake venoms that can cause diverse pathologies, including severe tissue damage3 and inhibition of nicotinic acetylcholine receptors (nAChRs) resulting in life-threatening neurotoxicity4. Currently, the only available treatments for snakebite consist of polyclonal antibodies derived from the plasma of immunized animals, which have high cost and limited efficacy against 3FTxs5,6,7. Here, we use deep learning methods to de novo design proteins to bind short- and long-chain α-neurotoxins and cytotoxins from the 3FTx family. With limited experimental screening, we obtain protein designs with remarkable thermal stability, high binding affinity, and near-atomic level agreement with the computational models. The designed proteins effectively neutralize all three 3FTx sub-families in vitro and protect mice from a lethal neurotoxin challenge. Such potent, stable, and readily manufacturable toxin-neutralizing proteins could provide the basis for safer, cost-effective, and widely accessible next-generation antivenom therapeutics. Beyond snakebite, our computational design methodology should help democratize therapeutic discovery, particularly in resource-limited settings, by substantially reducing costs and resource requirements for development of therapies to neglected tropical diseases

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“…However, new treatment modalities are being investigated, including the use of monoclonal antibodies obtained using in vitro display technologies such as phage display, which can potentially deliver therapeutic antibodies that are highly specific, possess high neutralizing capacities, and benefit from improved safety profiles [3,4]. A number of such monoclonal antibodies and single domain nanobodies that can neutralize snake toxins in vivo have already been reported [5][6][7][8][9]. However, all these efforts have relied on toxins from native sources.…”

Section: Introductionmentioning

confidence: 99%