Millions of people are bit by venomous snakes every year, causing severe harm and fatalities through the diverse and complex toxicities of snake venom. Snakebite envenoming is primarily treated using antivenoms produced from animal-derived antibodies. While antivenoms are effective, they can also trigger allergic reactions and often require high doses in order to work. A team led by bioengineer Andreas Laustsen-Kiel at the Technical University of Denmark has focused on developing more effective human antibodies for antivenoms using advanced monoclonal antibodies.
Antibodies are specialized proteins that allow the immune system to distinguish between “self” and “non-self” proteins or polysaccharides. These molecules are composed of four polypeptide chains: two identical “heavy chains” and two identical “light chains.” The antigen binding sites are located at the ends of the light chains and the unique amino acid sequence in this region allows the antibody to recognize a specific location on an antigen known as an epitope. Antibodies are commonly produced by injecting an animal with an antigen in order to trigger an immune response. The immune response produces antibodies that are specific to the antigen, which are then purified in a serum. The serum will contain a heterogenous mixture of different antibodies that all recognize different epitopes of the same antigen because different immune cells will create different antibodies. This mixture of antibodies is called a polyclonal antibody. Additionally, individual immune cells can be isolated and cultured to create monoclonal antibodies which specifically target a single epitope on an antigen.
Antivenoms are typically prepared as monoclonal antibodies which directly target the snake’s venom. While polyclonal antibodies are used for certain antivenoms, their broader range of targeting tends to increase negative side effects such as allergic immune responses. There are issues with monoclonal antibodies as well. Monoclonal antibodies are still degraded by the human body over time and often require high doses to effectively target and remove all of the venom, which can increase side effects. For an ideal antivenom, researchers would want it to have great target specificity while also being effective at lower doses. This is exactly what Andreas Lausten-Kiel has been investigating in his research of pH-responsive antivenoms.
In the bloodstream, antivenom will bind the target venom and both will get packed into endosomes, storage organelles whose acidic environment causes the antivenom to release the venom. The released venom is subsequently degraded by lysosomes, safely removing the venom from the bloodstream. While some of the antivenom will be degraded by the cell, a certain percentage will be transported out of the cell and recycled to target more venom in the bloodstream. Inside the cell, the unbound antivenom will bind a receptor that transports them outside of the cell where the neutral pH of the extracellular space releases the antivenom back into the bloodstream. By studying an array of antivenoms that have amino acid substitutions making them more acidic or basic, Lautsen-Kiels team optimized antivenoms to leverage this pH-dependent process to enhance recycling. These engineered antibodies demonstrate enhanced stability and therapeutic potential at lower doses, which could lead to more efficient and less allergenic antivenom treatments. Specifically, the team discovered antibody candidates for myotoxin II and alpha-cobratoxin from the Fer-de-Lance pit viper and monocled cobra, respectively.
The ability to engineer antibodies that last longer in the bloodstream, through pH-dependent recycling, could significantly enhance the effectiveness of snakebite antivenoms. While there is still much to explore in terms of optimizing pH sensitivity and understanding the underlying mechanisms, the findings from Laustsen-Kiel’s team open new avenues for the development of more targeted, durable, and effective therapies for snakebite envenoming. This is a great example of how antibodies are used in science and medicine today and we encourage teachers to share this with students! If you are interested in learning more about antigen-antibody systems please check out the kits below:
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