Scripps Research scientists have developed a versatile antibody that protects against lethal snake venoms from various species in Africa, Asia, and Australia.
The antibody, effective against venoms such as those from black mambas and king cobras, was identified by screening billions of human antibodies using laboratory-generated toxins. This breakthrough is a step closer to a universal antivenom capable of countering the effects of venoms from all snake species.
Challenges in Snakebite Treatment
According to the World Health Organization (WHO), snake venoms are responsible for an estimated 81,000 to 138,000 global deaths annually, consisting of numerous compounds targeting nerve cells and blood clotting.
The common treatment consists of antivenoms, comprising a blend of antibodies collected from horses or sheep after injecting them with nonlethal venom doses. However, according to Kartik Sunagar, the head of the evolutionary venomics lab at the Indian Institute of Science, antivenoms face numerous challenges.
One significant issue is the considerable variation in snake venoms between species, making treatment dependent on the specific snake responsible, which is not always identifiable. Sunagar's research group found that an antivenom effective against the monocellate cobra in certain regions in India is almost completely ineffective in others.
Additionally, many antivenoms are designed to work against several snake species within the same region, resulting in relative weaknesses against each other. For instance, a widely used African cocktail fails to save about one in seven people bitten by the black mamba (Dendroaspis polylepis), leading to fatalities despite multiple vials administered.
Furthermore, due to antivenoms being derived from animal proteins, they pose the risk of causing adverse immune reactions, including life-threatening anaphylaxis. As a result, physicians often delay antivenom administration until snakebite symptoms appear, despite the critical time sensitivity associated with such incidents.
Toxicologist Andreas Laustsen-Kiel underscores the time sensitivity in snakebites, emphasizing quicker antivenom administration for improved clinical outcomes.
Synthetic Antibody: A Universal Antivenom Breakthrough
To tackle the challenges in snakebite treatment, Sunagar collaborated with Casewell and Joseph Jardine, a protein engineering expert at Scripps Research, within a Wellcome Trust-funded consortium. Their approach involved isolating and comparing venom proteins from various elapids, a major group of venomous snakes such as mambas, cobras, and kraits.
The researchers identified a type of protein, three-finger toxins (3FTx), present in all elapid snakes, as a promising therapeutic target due to small sections showing similarities across species and high toxicity causing whole-body paralysis.
In the quest for an antibody to block 3FTx, the team developed an innovative platform. They inserted genes for 16 different 3FTx into mammalian cells to produce toxins in the lab. Screening over 50 billion human antibodies, they narrowed down to about 3,800 antibodies that bound to the 3FTx protein from the many-banded krait.
Further testing identified an antibody, 95Mat5, showing strong interactions across various toxin variants, protecting mice from death and paralysis induced by toxins from different snake species.
The effectiveness of 95Mat5 stems from its mimicry of the human protein that 3FTx typically binds to. Notably, this synthetic antibody, developed without animal immunization or snake involvement, shares a similarity with broad-acting HIV antibodies studied by Jardine. While 95Mat5 is potent against elapid venoms, it does not block viper venoms.
Jardine's team aims to develop broadly neutralizing antibodies against another elapid toxin and two viper toxins, envisioning a combination of these antibodies as a universal antivenom against medically relevant snake venoms worldwide.
They published the findings of their study, titled "Synthetic development of a broadly neutralizing antibody against snake venom long-chain α-neurotoxins," in Science Translational Medicine.
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