Towards better antivenoms: navigating the road to new types of snakebite envenoming therapies.

Snakebite envenoming is a significant global health challenge, and for over a century, traditional plasma-derived antivenoms from hyperimmunized animals have been the primary treatment against this infliction. However, these antivenoms have several inherent limitations, including the risk of causing adverse reactions when administered to patients, batch-to-batch variation, and high production costs. To address these issues and improve treatment outcomes, the development of new types of antivenoms is crucial. During this development, key aspects such as improved clinical efficacy, enhanced safety profiles, and greater affordability should be in focus. To achieve these goals, modern biotechnological methods can be applied to the discovery and development of therapeutic agents that can neutralize medically important toxins from multiple snake species. This review highlights some of these agents, including monoclonal antibodies, nanobodies, and selected small molecules, that can achieve broad toxin neutralization, have favorable safety profiles, and can be produced on a large scale with standardized manufacturing processes. Considering the inherent strengths and limitations related to the pharmacokinetics of these different agents, a combination of them might be beneficial in the development of new types of antivenom products with improved therapeutic properties. While the implementation of new therapies requires time, it is foreseeable that the application of biotechnological advancements represents a promising trajectory toward the development of improved therapies for snakebite envenoming. As research and development continue to advance, these new products could emerge as the mainstay treatment in the future.

Towards better antivenoms: navigating the road to new types of snakebite envenoming therapies

Abstract Snakebite envenoming is a significant global health challenge, and for over a century, traditional plasma-derived antivenoms from hyperimmunized animals have been the primary treatment against this infliction. However, these antivenoms have several inherent limitations, including the risk of causing adverse reactions when administered to patients, batch-to-batch variation, and high production costs. To address these issues and improve treatment outcomes, the development of new types of antivenoms is crucial. During this development, key aspects such as improved clinical efficacy, enhanced safety profiles, and greater affordability should be in focus. To achieve these goals, modern biotechnological methods can be applied to the discovery and development of therapeutic agents that can neutralize medically important toxins from multiple snake species. This review highlights some of these agents, including monoclonal antibodies, nanobodies, and selected small molecules, that can achieve broad toxin neutralization, have favorable safety profiles, and can be produced on a large scale with standardized manufacturing processes. Considering the inherent strengths and limitations related to the pharmacokinetics of these different agents, a combination of them might be beneficial in the development of new types of antivenom products with improved therapeutic properties. While the implementation of new therapies requires time, it is foreseeable that the application of biotechnological advancements represents a promising trajectory toward the development of improved therapies for snakebite envenoming. As research and development continue to advance, these new products could emerge as the mainstay treatment in the future.

Engineering and design considerations for next-generation snakebite antivenoms.

Snakebite envenoming is a devastating Neglected Tropical Disease, the treatment of which has seen relatively little innovation since the invention of antivenom serotherapy in 1894. Current antivenoms have been and continue to be invaluable in saving thousands of lives. However, these medicines are associated with a number of drawbacks pertaining to availability, safety, and efficacy. Fortunately, with the advent of novel methodologies, such as antibody discovery technologies, high-throughput drug discovery approaches, and improved methods for protein engineering, we are starting to see scientific advances in the field. This review presents relevant engineering and design considerations for exploiting these methodologies to develop next-generation antivenoms with improved safety, efficacy, and affordability. The pros and cons of different treatment modalities are discussed with regards to immunogenicity, the suitability of preclinical efficacy assays, availability of discovery methods, economic viability of production schemes, and possible regulatory approval paths.

Innovative Immunization Strategies for Antivenom Development.

Snakes, scorpions, and spiders are venomous animals that pose a threat to human health, and severe envenomings from the bites or stings of these animals must be treated with antivenom. Current antivenoms are based on plasma-derived immunoglobulins or immunoglobulin fragments from hyper-immunized animals. Although these medicines have been life-saving for more than 120 years, opportunities to improve envenoming therapy exist. In the later decades, new biotechnological tools have been applied with the aim of improving the efficacy, safety, and affordability of antivenoms. Within the avenues explored, novel immunization strategies using synthetic peptide epitopes, recombinant toxins (or toxoids), or DNA strings as immunogens have demonstrated potential for generating antivenoms with high therapeutic antibody titers and broad neutralizing capacity. Furthermore, these approaches circumvent the need for venom in the production process of antivenoms, thereby limiting some of the complications associated with animal captivity and venom collection. Finally, an important benefit of innovative immunization approaches is that they are often compatible with existing antivenom manufacturing setups. In this review, we compile all reported studies examining venom-independent innovative immunization strategies for antivenom development. In addition, a brief description of toxin families of medical relevance found in snake, scorpion, and spider venoms is presented, as well as how biochemical, bioinformatic, and omics tools could aid the development of next-generation antivenoms.

Integrating Engineering, Manufacturing, and Regulatory Considerations in the Development of Novel Antivenoms.

Snakebite envenoming is a neglected tropical disease that requires immediate attention. Conventional plasma-derived snakebite antivenoms have existed for more than 120 years and have been instrumental in saving thousands of lives. However, both a need and an opportunity exist for harnessing biotechnology and modern drug development approaches to develop novel snakebite antivenoms with better efficacy, safety, and affordability. For this to be realized, though, development approaches, clinical testing, and manufacturing must be feasible for any novel treatment modality to be brought to the clinic. Here, we present engineering, manufacturing, and regulatory considerations that need to be taken into account for any development process for a novel antivenom product, with a particular emphasis on novel antivenoms based on mixtures of monoclonal antibodies. We highlight key drug development challenges that must be addressed, and we attempt to outline some of the important shifts that may have to occur in the ways snakebite antivenoms are designed and evaluated.

Synergistic strategies of predominant toxins in snake venoms.

Synergism is a significant phenomenon present in snake venoms that may be an evolving strategy to potentiate toxicities. Synergism exists between different toxins or toxin complexes in various snake venoms, with phospholipaseA2s (PLA2s) (toxins or subunits) the main enablers. The predominant toxins, snake venom PLA2s, metalloproteases (SVMPs), serine proteases (SVSPs) and three-finger toxins (3FTxs), play essential roles in synergistic processes. The hypothetical mechanisms of synergistic effect can be generalized under the effects of amplification and chaperoning. The Toxicity Score is among the few quantitative methods to assess synergism. Selection of toxins involved in synergistically enhanced toxicity as the targets are important for development of novel antivenoms or inhibitors.