In Search of a Universal Antivenom

Courtesy: World Health Organization 

July 16  happens to be World Snake Day.  A day dedicated to highlighting the role of snakes in maintaining ecological balance and  biodiversity.  Some species of snakes indeed near extinction  which necessitates focused conservation steps.  However  in parallel  is the undeniable  reality of death and deformity inflicted upon  humans by  snakebite.    World Health Organization lists  snakebite as one of the  Neglected Tropical Diseases because antivenoms are not only very species specific but also  in acute short supply.  A  few  monovalent formulations that work against  single snake species  available in market are  grossly inadequate to meet the requirements. Because in  most of the envenomation cases, the exact species  of the snake  responsible for the bite remains  unknown.  Polyvalent formulations  which  can  provide broader coverage against a wide range of venomous snake are  the need of the day.  While the complexity and  diversity of the biology and chemistry  of  venom are indeed the scientific  road blocks in the development of universal  antivenom,  there is an economic  barrier   too.     Snakebite is part of the lifestyle of the poor   in the third world  who can ill afford costly treatments.    Any kind of drug development requires huge  investments in terms of time and money  so  if  profit margins do not  look  attractive  who will venture? 

Typically any snake venom is  a concoction of a variety of short chain neurotoxins (SNX),  long

Courtesy Haggstrom, Wikipedia

chain neurotoxins(LNX), enzymatic toxins such as Phospholipase2 (PLA2) plus a low proportion of other compounds.  LNX  is  the most  lethal component,  SNX less so.  Phospholipase2 breaks down phospholipids, disrupting cell membranes and leading to muscle necrosis, neurotoxicity, and inflammation.  The chemistry , composition  and potency of  venom  vary widely  within  and across snake species. Even geographical variations are seen.  For example  the Indian cobra's venom   primarily contains neurotoxins that disrupt nerve impulses, leading to paralysis. African spitting cobras have a higher proportion of cytotoxins compared to Asiatic cobras.  Some species in addition contain  cardiotoxins too.  Potential respiratory failure is  responsible for a higher number of fatalities.   Thus pathologically  snakebites can cause nerve and muscle dysfunction (neurotoxicity), bleeding and clotting problems (hemotoxicity), and/or localized swelling,  blisters,  tissue death (cytotoxicity) etc. 

Antivenoms are antibodies extracted from horses or camels.  Adhering to  strict protocols these animals are  injected with snake venom below  lethal threshold. Their immune system swings into action and produces antibodies against the venom. Antibodies are extracted from the blood serum,  purified,  processed  and packaged.  Worldwide there are only a handful of antivenom formulations available  in the market  and as mentioned earlier  for effective medication it is important to know which  species  of snake caused the bite. What  if  we could  develop an Universal Antivenom Formulation?  That is the question  Jacob Glanville ,immunoengineer and chief executive of biomedical firm Centivax in South San Francisco, California, asked  and  he found the answer in   Tim Friede. 

Tim Freide an American citizen  has been living  dangerously  for the past almost  two  decades.  A truck mechanic by profession  and a snake collector by hobby, he has been bitten about 200 times by a variety of snakes accidentally and has intentionally  injected himself with snake venoms for about 600 times. Not that he hasn't  had set backs: once he was   knocked  off into a comma for 4 days.   He took it all  because he is a snake lover and want to be immune  to their stings.  A rather bizarre  wish, one would think.   But then  that  exactly is his claim to fame : An individual  hyperimmune  to  envenomation of any kind. 

Glanville saw the videos uploaded by  Freide  in the Youtube  and immediately  contacted   Prof Peter Kwong  at Columbia University. The  duo lost no time  to get  in touch with  Friede  and a research project was born.  They  were literally after  Friede's blood.  Friede agreed. Friede's  blood was subjected  to systematic analysis  by the research teams at Centivax and Columbia University.  As expected  Friede's hyperimmune blood indeed had an  abundance of antibodies against LNX and SNX neurotoxins. 

Over the  years   having encountered  envenomation   from  diverse  species from   black mambas to   king cobras and kraits, Friede's     immune system had  adapted  and evolved  broad spectrum  antibodies that could counter multiple toxins from various species.   The researchers identified  the  gene  that encoded for these antibodies and then   using a technique called  Phage Display  that involves several intricate   steps, generated and harvested    two broad spectrum  antibodies SNX-B03 and LNX-D09 that can neutralize  LNX and SNX neurotoxins from a wide variety of snakes including black mamba, King cobra.   

Next the team  made  a cocktail of SNX-B03 , LNX-D09 and Varespladib  a known phospholipase2 inhibitor. This  formulation was    tested in mice  against 19 diverse  and intense venoms of the elapid group, classified as most lethal by World Health Organization.  The formulation  provided  full protection against 13  and partial protection against the remaining 6.  Glanville is  excited: “That, for me, was a very exciting moment.  A universal antivenom is now tractable, within reach, and we have the tool, and we just need to keep turning the crank to find it.”   

Glanville is hopeful that   philanthropic societies, governments  and  pharmaceutical companies will collectively provide the necerssary financial support.  Thus the  road to designing an universal polyvalent antivenom is clear. However making it available/accessible  to the victim  on the spot  remains a challenge.

REFERENCES:

1. Snakebite envenomation turns again  into a neglected tropical disease.

2.Snake venom protection by a cocktail of varespladib and broadly neutralizing human antibodies.   Glanville et al.,  Cell (188) 3117-3134, 2025.

3.Thoughts, observations and experiments on the action of snake venom on the blood : with an appendix by George B Halford