Scientists at Scripps Research have engineered a groundbreaking antibody capable of neutralizing the lethal effects of venomous snake toxins from a diverse range of species across Africa, Asia, and Australia. This antibody, detailed in Science Translational Medicine, demonstrated its efficacy in protecting mice from the venom of notoriously deadly snakes such as black mambas and king cobras. By leveraging laboratory-produced forms of toxins, researchers scoured billions of human antibodies to identify one with the ability to thwart the toxins' deleterious effects. This achievement marks a significant stride towards developing a universal antivenom capable of combating the venom of all snake species.
Lead author Joseph Jardine, Ph.D., an assistant professor of immunology and microbiology at Scripps Research, emphasizes the potential impact of this antibody, particularly in low- and middle-income countries where snakebite envenoming exacts a heavy toll. With over 100,000 annual fatalities, predominantly in Asia and Africa, snakebites surpass many neglected tropical diseases in lethality. Traditional antivenoms, derived from immunizing animals with snake venom, are typically effective against a single snake species, necessitating the production of numerous antivenoms to address regional snakebite challenges.
Drawing on insights from their previous investigations into broadly neutralizing antibodies against HIV, the research team recognized parallels in the quest for a universal antivenom. Just as the rapidly evolving HIV proteins exhibit slight variations, different snake venoms display enough diversity that antibodies binding to one variant may not recognize others. However, similar to HIV, snake toxins harbor conserved regions impervious to mutation, offering potential targets for universal antivenom development.
In their study, researchers scrutinized venom proteins from various elapids, a prominent group of venomous snakes including mambas, cobras, and kraits. They identified three-finger toxins (3FTx), prevalent across elapid snakes, as promising therapeutic targets due to their high toxicity and role in inducing paralysis. Employing an innovative platform, the team expressed 16 different 3FTx genes in mammalian cells to produce toxins for laboratory screening. From a library of over 50 billion human antibodies, they isolated approximately 3,800 candidates that bound to 3FTx proteins, subsequently identifying one antibody, 95Mat5, with robust cross-reactivity against multiple 3FTx variants.
Through rigorous testing on mice injected with toxins from various elapid species, including the many-banded krait, Indian spitting cobra, black mamba, and king cobra, researchers observed that 95Mat5 not only prevented mortality but also paralysis. Further analysis revealed that 95Mat5 mimicked the structure of a human protein typically targeted by 3FTx, underscoring the antibody's mechanism of action.
Remarkably, the synthetic nature of 95Mat5 represents a departure from traditional antivenom production methods, obviating the need for animal immunization or snake-derived components. While effective against elapid venoms, 95Mat5 does not neutralize viper venoms, prompting ongoing efforts to develop antibodies targeting viper toxins. Researchers envision a cocktail of antibodies, including 95Mat5 and others, as a potential universal antivenom against medically relevant snake species worldwide.
Source: The Scripps Research Institute