A new study byKhaleket al.highlights broadly neutralizing human monoclonal antibodies (mAbs) that might be used to develop recombinant antivenoms with superior therapeutic benefits. Keywords:Snakebite envenoming, snake venom toxins, antivenom, recombinant antivenom, monoclonal antibodies, broadly-neutralizing antibodies Snakebite envenomings kill ~100 000 victims each year and leave many more with permanent sequelae. antibodies (or fragments thereof) isolated from the plasma of immunized animals have been used for over 125 years and have saved countless lives [1,2]. Nevertheless, an unmet medical need remains because these Teriflunomide medicines suffer from serious drawbacks relating to their nature and method of manufacture. The key drawbacks include their relatively high cost of production, limited efficacy (especially against non- or poorly immunogenic toxins), and safety concerns relating to their nonhuman origin which imposes a risk of causing serum sickness or even anaphylaxis in severe cases [3]. For over four decades researchers have been exploring the idea of using mAbs as a substitute for plasma-derived polyclonal antibodies of animal origin [2]. Although some work on the discovery of different mAbs was carried out in the 1980s to 2010s, none of these molecules ever joined into clinical trials, and only a few showed promising effects in neutralizing key toxins [2,3]. Part of the explanation is likely that all the IgG antibodies reported were of non-human (mostly murine) origin and Rabbit Polyclonal to OR10J5 that the human single-chain variable fragments (scFvs) discovered displayed limited therapeutic Teriflunomide utility [2,3]. However, in 2013 the first promising camelid mAb fragment (VHH) was discovered which could protect mice against a lethal dose of -cobratoxin from the monocled cobra [4], and in 2018 the first fully human IgG mAbs were reported that neutralized dendrotoxins from the black mamba [5]. From then it took another 4 years before a human IgG mAb could rescue mice from a lethal dose of whole venom from the monocled cobra [6], and Teriflunomide it was not until 2023 that a human IgG mAb showed broadly neutralizing capacity against long-chain -neurotoxins from different elapid venoms (Physique 1A) [7]. These discoveries were all based on phage display technology and deep insights into the composition of snake venoms [2,3,8]. == Physique 1. == Discovery, screening, and optimization approaches for the development of recombinant broadly neutralizing human monoclonal antibodies (mAbs) that can neutralize long-chain -neurotoxins from elapid snakes [7,9]. Whereas Ledsgaardet al.[7] employed phage display selection and affinity maturation by chain shuffling, Khaleket al.[9] utilized yeast display technology combined with affinity maturation by mutagenesis for the discovery of their mAb. Each approach has its own benefits; however, the antibody developed by Khaleket al., 95mat5 [9], seems to better neutralize long-chain -neurotoxins from different snake species than the antibody 2554_01_D11 used by Ledsgaardet al.[7]. Abbreviations: nAChR, nicotinic acetylcholine receptor; VH, immunoglobulin heavy-chain variable region genes; VL, immunoglobulin light-chain variable region genes. A recent report by Khaleket al.now describes the discovery of a new human IgG mAb with superior broadly neutralizing activity against long-chain -neurotoxins from a range of different elapid snake species (e.g., cobras and mambas) [9]. By using a human fragment antigen-binding (Fab) antibody library combined with yeast display technology, as well as further enhancement of the affinity of the antibody for long-chain -neurotoxins by usingin vitromethods and a thorough screening program, the authors identified the human IgG mAb, 95mat5 (Physique 1B). They further exhibited that this antibody blocks the conversation between selected long-chain -neurotoxins and the nicotinic acetylcholine receptor (nAChR)in vitro, and showed that mice were guarded against a lethal venom challenge when the antibody was preincubated with the venom mixture, as well as when the antibody was delivered up to 30 minutes after venom injection. Importantly, this was exhibited using elapid venoms from three different snake genera (Naja,Dendroaspis, andOphiophagus) where long-chain -neurotoxins play an important role in exerting overall toxicity. To appreciate the achievement of Khalek and colleagues, it is important to understand that snake venoms are very complex mixtures of protein-based toxins, that no two snake venoms share the same composition or even the same toxins, and that the venom of each species contains tens to hundreds of different toxins grouped into over a dozen different protein families [2,3]. Consequently, it is seldom sufficient to neutralize only a single specific toxin to protect a mouse or an individual against a whole venom [5,8]. Being.