Biosynthetic Oligoclonal Antivenom (BOA) for Snakebite and Next-Generation Treatments for Snakebite Victims †
2. Current Treatment for Snakebite Victims
- Inability to abrogate local tissue damage: Snakebites from several snake species cause severe local tissue damage, leading to disfigurement, amputation, and permanent disability. The administration of antivenoms in most cases fails to neutralize this catastrophic pathology, as the heterologous antibodies or antibody fragments in antivenoms have insufficient pharmacokinetics to reach and neutralize toxins in deep tissue before these have started exerting their toxic functions .
- Allergic reactions and anaphylactic shock: The administration of antivenoms, which are foreign horse-derived antibodies, may lead to acute anaphylactic shock in snakebite victims, which has been demonstrated to be the case for >40% for certain antivenoms [7,8,9,10]. These life-threatening adverse reactions must be managed by attending clinicians.
- Serum sickness: Serum sickness is a delayed response to antivenom administration that occurs for 5–56% of treated victims for certain antivenoms [11,12,13]. The incidence of serum sickness is poorly defined, mostly because patients rarely return to health centers or they are not adequately followed after hospital discharge. Despite best efforts, typical antivenoms contain only 5–36% snake venom toxin-binding antibodies [14,15,16]. The ability of these antibodies to neutralize snakebite pathologies depends on the proportion of toxin-neutralizing antibodies and their pharmacokinetics. Hence, a significant number of antivenom vials are administered to each snakebite victim, with extreme cases requiring as much as 15 g of heterologous antibody protein . Such a high dose administration increases the probability of serum sickness.
- Inability to neutralize snake venoms from different regions: Snake venoms exhibit significant geographic variations in their toxin composition [18,19,20,21,22,23,24,25,26,27,28,29]. These variations are due to local adaptation, differences in diet, and ontogeny . In a large country, like India, it would be ideal to pool venoms from various regions when designing immunization mixtures to overcome this drawback.
- Complex manufacturing processes: Antivenom manufacture is complicated by the dependence of polyclonal antibodies on two biological systems, namely representative snake venoms and individual horse immune systems.
3. Next-Generation Snakebite Therapy
3.1. Biosynthetic Oligoclonal Antibodies (BOA) for Snakebite
- Compatibility with human victims: BOA will contain only human antibodies and will thus be compatible with treatment of human patients .
- Enriched for toxin-neutralizing antibodies: Horse-derived antivenoms contain both toxin-neutralizing and toxin-binding antibodies, but only toxin-neutralizing antibodies are useful for abrogating the pathophysiology of envenomation . Antibody production in animals occurs due to the natural immune response, and there is no control over the antibody clones that expand and produce antibodies . Therefore, horse antibodies show significant differences in their neutralizing capacities. In addition, these antivenoms may also contain antibodies raised against irrelevant infections, to which horses used for antivenom manufacture may have been exposed. Consequently, horse-derived antivenoms contain a small percentage of toxin-neutralizing antibodies . In contrast, recombinant antibodies can be selected precisely for toxin-neutralizing ability. Therefore, the BOA will be enriched for toxin-neutralizing antibodies.
- Consistent and reproducible production: The production of polyclonal antibodies in horses is highly variable, and there will always be inherent batch-to-batch variations. The quality of BOAs will provide excellent consistency and reproducibility, and thus, batch-to-batch variation will be obviated [39,50].
- Tailor-made antibodies with optimal pharmacokinetics (PK) and pharmacodynamics (PD): Different toxins in snake venoms exhibit distinct biodistribution, PK, and PD, which often contributes to multi-organ failure in snakebite victims. Neutralization of such varied properties of toxins requires antibodies with appropriate biodistribution, PK, and PD. This can be achieved by utilizing full-length immunoglobulin G (IgG) antibodies, antibody fragments, or alternative non-antibody-based binding proteins [35,50]. In the preparation of BOAs, it is possible to include a mixture of full-length antibodies and/or fragments based on the properties of each toxin (toxicokinetics). Tailor-made mixtures of antibodies cannot be produced from horse-derived polyclonal antibodies, but are possible in BOA technology.
- Better safety profile: Highly compatible, toxin-neutralizing antibodies with suitable PK and PD are expected to have better safety profiles compared to horse-derived antivenoms . Thus, intravenous administration of a BOA should not cause acute (allergic and anaphylactic) or delayed (serum sickness) reactions.
- Rapid administration of antivenoms: Because of inherent acute allergic and anaphylactic reactions, horse-derived antivenoms are administered to snakebite victims only after the victim develops symptoms and has reached a hospital setting. Such delays lead to poor treatment outcomes. The better safety profile of the BOA will allow quicker administration, for example, during transportation to the hospital, thus likely allowing for improved treatment outcomes.
- Acceptance among clinicians: Poor efficacy compounded with acute (allergic and anaphylactic) and delayed (serum sickness) reactions has kept many clinicians from venturing to treat snakebite victims with antivenom. With better efficacy and safety profiles, BOA will help in the acceptance of treatment of snakebite victims.
- Geographic variation of venoms: Most of the geographic variation in venom composition is due to differences in the abundance of specific toxins in venoms from snake specimens obtained from different regions. Such variations, at times, will make horse-derived antivenoms raised against venoms from one region ineffective against venoms from the same species in another region. Additionally, venoms from the same snake species from different regions may have one or more distinct/unique toxins. In both these cases, the problems can be overcome with BOA by simply including more antibodies or additional antibodies against all offending toxin(s). Such additions will not affect the safety profile of the BOA due to the compatibility of human monoclonal antibodies with the human immune system.
- Cross-reactivity with other snake venom toxins: Some toxin-neutralizing antibodies neutralize related toxins not only from the same species, but also from different species . If such cross-reactivity is intelligently engineered into the monoclonal antibodies during development, it may help in preparing polyvalent BOAs from a stock of a limited number of human antibodies .
- Abrogation of local tissue damage: In most cases, horse-derived antivenoms fail to abrogate local tissue damage induced by snake venom toxins . This inability could be either due to a lack of antibodies that neutralize the offending toxin(s) or to the toxin(s) initiating local tissue damaging processes before being neutralized by antibodies . It may be possible to find suitable human antibodies that could neutralize offending toxins. Alternatively, enzymatic processes leading to local tissue damage could be neutralized using small molecule enzyme inhibitors [55,56] (see below). Finally, by having an improved safety profile, it might be possible to administer BOA during transportation en route to the hospital, thereby minimizing the time that the locally-acting snake toxins can exert their toxic actions around the bite wound.
- Potential prophylactic use of BOA: The better safety profile of BOA could be of prophylactic use for people who will be exposed to snakebite hazards. The longer PK of full-length antibodies (IgGs), which typically have half-lives of several weeks , could provide excellent prophylactic protection, which could reduce mortality, morbidity, and intensity of pathophysiological impact of snakebite.
3.2. Small Molecule Enzyme Inhibitors
- Increased treatment window: Treatment for envenomation should ideally start within a short time period following snakebite, as mortality and morbidity increase significantly beyond this window. Small molecule enzyme inhibitors may substantially increase this time window, if they can be administered in the field setting (i.e., if they are stable at elevated temperatures and orally available), and could thus provide more time to reach hospital care.
- Validated safety in humans: As many of these small molecule inhibitors have been evaluated for their toxicity in human recipients, they have already been proven sufficiently safe for use in the treatment of snakebite envenoming.
Conflicts of Interest
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Kini, R.M.; Sidhu, S.S.; Laustsen, A.H. Biosynthetic Oligoclonal Antivenom (BOA) for Snakebite and Next-Generation Treatments for Snakebite Victims. Toxins 2018, 10, 534. https://doi.org/10.3390/toxins10120534
Kini RM, Sidhu SS, Laustsen AH. Biosynthetic Oligoclonal Antivenom (BOA) for Snakebite and Next-Generation Treatments for Snakebite Victims. Toxins. 2018; 10(12):534. https://doi.org/10.3390/toxins10120534Chicago/Turabian Style
Kini, R. Manjunatha, Sachdev S. Sidhu, and Andreas Hougaard Laustsen. 2018. "Biosynthetic Oligoclonal Antivenom (BOA) for Snakebite and Next-Generation Treatments for Snakebite Victims" Toxins 10, no. 12: 534. https://doi.org/10.3390/toxins10120534