Where do venom antibodies come from and how do they neutralize a “soup” of venom components?
Spencer Greene, MD, MS, FACEP, FACMT, FAACT, FAAEM 12 October 2021
A few years ago, I was watching a TV drama in which a group of geniuses solve all sorts of crises, whether they be cybercrimes, medical emergencies, or engineering catastrophes. In one episode, a character was bitten by a venomous snake. One of his colleagues suggested they go out and catch the snake, so they could create antivenom and minimize the envenomation.
Umm, that's not how it works. Not at all.
Before I address antivenom, let me talk a little bit about venom.
Snake venom has been described as a “soup of antigens.” There are literally dozens of components, many with fancy names like metalloproteinases, serine proteases, phospholipases (PLA2), hyaluronidase, and disintegrins. Most of those words probably mean nothing to you. That’s cool. What's important is that the various components can cause some combination of local tissue injury, hematologic toxicity, muscle damage, neurological toxicity, and cardiovascular collapse.
Some venom components are found in multiple species, genera, and families of snakes. Others are found in just a small number of species. Some “ingredients” are exclusive to single species. The best way to prevent these various toxins from causing toxicity is to neutralize them. And that is what antivenom does. Large volumes of preformed antibody particles are administered to someone following envenomation, and the antibody fragments render the various venom components inactive.
So where do these antibodies come from? They come from a host animal. Over the years, many animal species have been used. Although the horse is most common, CroFab is ovine-derived, meaning it comes from sheep. This has important clinical implications, because sheep serum is less likely to elicit an allergic reaction than horse serum, which contains a highly immunogenic immunoglobulin G subclass. Over several months, different flocks of hearty Australian sheep are exposed to small amounts of venom from multiple US snake species. In response, the sheep produce antibodies, which are then processed, purified, and made into a powder, and that’s how you end up with antivenom!
And CroFab isn’t just one antivenom; it’s four! (However, in 2017 the Society for the Study of Amphibians and Reptiles changed the taxonomic classification so that there are two different cottonmouth species: the northern cottonmouth, Agkistrodon piscivorus, and the Florida cottonmouth, A. conanti. But I digress.) The final antivenom is a blend of antibodies taken from four separate flocks of sheep, each exposed to the venom of a different species.
The World Health Organization (WHO) has stated that an effective antivenom is derived from clinically relevant snakes that are native to the geographic region where the antivenom will be used, and the snakes used in CroFab production hit both targets. Western diamondback rattlesnake venom has specific metalloproteinases. Eastern diamondback rattlesnake venom has a variety of serine proteases. Mojave toxin is found in Mojave rattlesnake venom. Finally, cottonmouth venom has specific PLA2 isoforms that are also found in copperhead venom. Furthermore, the snakes used in CroFab production are collected from across each snake’s range distribution to address geographic venom variation.
Incidentally, the antibodies then undergo an affinity purification step that is unique to CroFab. It removes unnecessary antibodies so that only venom-neutralizing antibodies remain. This increases specificity and minimizes nonspecific foreign proteins that can lead to adverse reactions.
Now that you’ve read a lot of words (roughly 535 prior to the start of this paragraph!), let me summarize and emphasize some points. Snake venom is complex and causes a variety of local and systemic effects. CroFab® consists of purified antibodies that can neutralize medically important venom components from multiple native snake species, and it should be used for clinically significant envenomations.
One final, not especially important point. Both “antivenin” and “antivenom” are acceptable; the Associated Press prefers the former, while the WHO endorses the latter in English-speaking countries. Just don’t put a hyphen in the middle of either word. That drives me crazy!
Dr. Greene is a paid consultant for BTG International Inc.
Spencer Greene, MD, MS, FACEP, FACMT, FAACT, FAAEM is a board-certified medical toxicologist and emergency physician. He currently serves as the Director of Toxicology and an attending emergency physician at HCA Houston Healthcare-Kingwood. He is a Clinical Professor at the University of Houston College of Medicine. Dr. Greene is a recognized expert in the management of snake envenomation in the US. He has treated more than 1000 snakebites at the bedside and has authored more than 50 scholarly articles and book chapters. He has also served as the course director for the Houston Venom Conference since 2013.
CroFab® Crotalidae Polyvalent Immune Fab (Ovine) is a sheep-derived antivenin indicated for the management of adult and pediatric patients with North American crotalid envenomation. The term crotalid is used to describe the Crotalinae subfamily (formerly known as Crotalidae) of venomous snakes which includes rattlesnakes, copperheads and cottonmouths/water moccasins.
IMPORTANT SAFETY INFORMATION
Do not administer CroFab® to patients with a known history of hypersensitivity to any of its components, or to papaya or papain unless the benefits outweigh the risks and appropriate management for anaphylactic reactions is readily available.
WARNINGS AND PRECAUTIONS
Coagulopathy: In clinical trials, recurrent coagulopathy (the return of a coagulation abnormality after it has been successfully treated with antivenin), characterized by decreased fibrinogen, decreased platelets, and elevated prothrombin time, occurred in approximately half of the patients studied; one patient required re-hospitalization and additional antivenin administration. Recurrent coagulopathy may persist for 1 to 2 weeks or more. Patients who experience coagulopathy due to snakebite should be monitored for recurrent coagulopathy for up to 1 week or longer. During this period, the physician should carefully assess the need for re-treatment with CroFab® and use of any type of anticoagulant or anti-platelet drug.
Hypersensitivity Reactions: Severe hypersensitivity reactions may occur with CroFab®. In case of acute hypersensitivity reactions, including anaphylaxis and anaphylactoid reactions, discontinue infusion and institute appropriate emergency treatment. Patients allergic to papain, chymopapain, other papaya extracts, or the pineapple enzyme bromelain may also have an allergic reaction to CroFab®. Follow-up all patients for signs and symptoms of delayed allergic reactions or serum sickness (e.g., rash, fever, myalgia, arthralgia).
The most common adverse reactions (incidence ≥ 5% of subjects) reported in the clinical studies were urticaria, rash, nausea, pruritus and back pain. Adverse reactions involving the skin and appendages (primarily rash, urticaria, and pruritus) were reported in 12 of the 42 patients. Two patients had a severe allergic reaction (severe hives and a severe rash and pruritus) following treatment and one patient discontinued CroFab® due to an allergic reaction. Recurrent coagulopathy due to envenomation and requiring additional treatment may occur.
Please see full Prescribing Information.