Biotechnological Trends in Spider and
Scorpion Antivenom Development.

Spiders and scorpions are notorious for their fearful dispositions and their ability to inject venom into prey and predators, causing symptoms such as necrosis, paralysis, and excruciating pain. Information on venom composition and the toxins present in these species is growing due to an interest in using bioactive toxins from spiders and scorpions for drug discovery purposes and for solving crystal structures of membrane-embedded receptors. Additionally, the identification and isolation of a myriad of spider and scorpion toxins has allowed research within next generation antivenoms to progress at an increasingly faster pace. In this review, the current knowledge of spider and scorpion venoms is presented, followed by a discussion of all published biotechnological efforts within development of spider and scorpion antitoxins based on small molecules, antibodies and fragments thereof, and next generation immunization strategies. The increasing number of discovery and development efforts within this field may point towards an upcoming transition from serum-based antivenoms towards therapeutic solutions based on modern biotechnology.
Scorpion stings and spider bites are a major public health concern in developing parts of the world, yet envenomation from these creatures still remains a neglected tropical disease . Scorpionism affects people in Northern Africa, the Middle East, Central and South America, and to some extent India . In comparison, spider bites mainly affect people in the Americas, Australia, and Africa , although bites are also known to occur in Europe . In the scorpion order, nearly 2000 species are recognized , which is significantly less than the 44,000 recognized spider species . Fortunately, only a subset of these species are of medical relevance, with the members of the Buthidae family (including bark scorpions and fat-tailed scorpions), Latrodectus genus (widow spiders) and Loxosceles genus (recluse spiders) being the main species with venom that may cause harm to humans .

Scorpions are considered the second most dangerous venomous animals to humans (after snakes), and their stings mainly affect children and adolescents . Effective treatment against envenomings from the most venomous scorpions and spiders consists of parental administration of animal-derived antisera by medically trained personnel. Currently, there are 19 antivenoms for human use and one antivenom for animal use on the market for scorpion stings, whereas only 10 antivenoms are used clinically for the treatment of spider bites . All of these antivenoms are of equine origin, and although they are effective in neutralizing scorpion and spider venoms, such animal-derived antisera suffer from significant drawbacks due to the heterologous nature of the proteins present in the antisera, which may elicit both early and late adverse reactions in human recipients . Additionally, only a subset of the antibodies or antibody fragments present in these antivenoms have a therapeutic value since the presence of non-toxic immunogens in the venoms used for immunization may elicit therapeutically irrelevant antibodies in the immunized animal. This was demonstrated by Pucca et al., who showed that only 1%–2.5% of antibodies in equine scorpion antivenoms were able to neutralize important venom toxins . Since scorpion and spider antivenoms are derived from animal serum, individual differences in the immune responses of the production animals may give rise to batch-to-batch variation . Finally, due to the very minute amounts of venom that can be extracted from scorpions and spiders, production of antisera against scorpion stings and spider bites is dependent on a highly laborious venom collection process, where large numbers of spiders and scorpions need to be milked (under microscope for spiders) in order to procure enough venom for immunization . These challenges warrant technological innovation, not only to obtain safer and more effective antivenoms, but also to establish more sustainable productions processes that are independent of both venoms and animals .
This review presents the different biotechnological trends in the development of next generation scorpion and spider antivenoms. Initially, focus will be directed towards the growing body of data on spider and scorpion toxins and proteomes, which may be harnessed for developing either recombinant or synthetic antivenoms. A comprehensive overview of the use of immunization strategies is beyond the scope of the paper, and can be found elsewhere. However, the use of recombinant and synthetic toxins obtained through the use of biotechnological approaches is discussed, as well as the potential for including small molecules in future spider and scorpion antivenoms.