Despite the complexity and diversity of snake venoms, the existing snakebite antivenom, based on Calmette’s research, has been saving lives for more than 125 years. But when compared to other disease and research areas that have been carried lightyears forward by biotechnological advances, is the current antivenom really as good as it could be? The short answer is no.

Unfortunately, the current production method (immunization of horses) is so expensive that many of the people who need the antivenom cannot afford it (see section on snakebite antivenom). Worst of all, the antivenom can cause serious side effects that can be worse than the snake bite itself, and in some cases, the side effects can even be fatal. This is because the antibodies extracted from a horse’s blood, it not only the ones that recognize and neutralize the snake toxins. Numerous other antibodies are also extracted that have no therapeutic effect on the snakebite, as these antibodies recognize bacteria, viruses, hay, dust, and other things the horse has been exposed to. In worst-case scenarios, antivenoms with a therapeutic content as low as 5-15% have been seen (the percentage of antibodies in the antivenom, which bind to the venom components)

It is these problems that researchers from the Center for Antibody Technology (CAT) at the Technical University of Denmark (DTU) have been working to tackle since 2012. It is these problems that researchers from the Center for Antibody Technology (CAT) at the Technical University of Denmark (DTU) have been working to tackle since 2012.

Figure 22. Overview of recombinant antivenom production

The reason why human antibodies have not yet been tried in current antivenom production as it is not acceptable to suggest continuous immunization of humans with subsequent blood sampling. Instead, the Center for Antibody Technology uses modern antibody techniques, including phage display (see section on phage display). Phage display enables a ‘simulation’ of the immunization process that normally takes place in the body, but in vitro (“in glass” in Latin, i.e. outside the body in a container in the lab) using large libraries of antibodies.

The Center for Antibody Technology at DTU is currently working on grouping and characterizing key toxins in the most deadly snake venoms in the world. By grouping the toxins and looking at sequence similarities and where antibodies can bind to the toxins, it is possible to design broad-spectrum antibodies that can bind and neutralize toxins from several different snakes (Figure 23).

Figure 23. Illustration of narrow-spectrum and broad-spectrum antibodies. The illustration shows that using narrow-spectrum antibodies (left) requires a larger number of unique antibodies to neutralize a group of toxins than using broad-spectrum antibodies (right)

In addition, the Center for Antibody Technology is trying to make the antibodies pH-sensitive so that the body’s own mechanism for recycling antibodies into the bloodstream can be utilized (Figure 24). This would mean that one antibody could bind toxins and send them for degradation by the endosomal degradation process (Figure 24), after which the antibody could return to the bloodstream and bind more toxins and repeat the process. A non-pH-sensitive antibody would remain bound to the toxins and will not be reused.

Figure 24. Overview of antibody recycling in the bloodstream and endosome

 

Once a sufficient number of different antibodies have been found that can neutralize a wide range of snake toxins (and thus entire venoms, which consist of many toxins), the next step is to develop the production process for the antibody mixture. In short, this process will be a cultivation process (fermentation process) using mammalian cells that can produce human antibodies. Such cells are already being used in industry to produce antibodies for both cancer and autoimmune diseases.

Using phage display and mammalian cells, it is expected that relevant antibodies can be produced quickly on demand. This might reduce the cost of the antivenom. At best, it will mean being able to produce antivenoms that are both cheap and safe, so more people will have access to antivenoms and physicians will be less worried about the side effects of administering the antivenom. If successful, the world will hopefully see far fewer snakebite-related deaths, disfigurements and disabilities.

 

List the advantages and disadvantages of traditional and recombinant antivenom. Discuss the drawbacks of using antibodies from a horse for treatment and how a recombinant antivenom could change this.

A: In addition to the low therapeutic content, a less potent antivenom will require more doses of antivenom to be used per treatment. It’s quite unfortunate if the victim can barely afford a single dose. In terms of treatment, the biggest problem with antivenom from immunized animals is that the antibodies come from an animal and not a human. This means that in the worst case scenario, the antivenom can cause hyperallergic reactions such as serum sickness, kidney failure and anaphylactic shock.