Monoclonal antibodies explained: the first treatment for COVID-19
During the first few months of the pandemic, I often googled the phrase “covid-19 treatments” hoping that something had finally been approved for those at risk from the super-exponential outbreak. Although the quarantine successfully slowed down the spread of the virus, it’s easy to forget that almost 28,000 people were dying each week as early as July 1, 2020.
In order to find a life-saving treatment, the first question to ask is how the virus actually kills patients. In many cases, COVID-19 amplifies pre-existing conditions affecting their lungs or kidneys, resulting in organ failure. In other cases, the virus causes the patient’s immune system to malfunction and attack the body, similar to a severe allergic reaction.
This means that in most cases, survival depends on whether one’s immune system can adapt fast enough to safely counteract the virus.
So how does this work? You might have noticed the strange triangular knobs poking out of most representations of the virus:
These are called spike proteins. Their main purpose is to clamp onto cells, specifically parts called ACE2 receptors. By doing this, the virus can inject genetic material and replicate itself inside of the cell. Eventually, the cloned viruses will burst out, 1979 Alien-style.
In order to avoid this, our immune system manufactures tiny Y-shaped proteins called antibodies, which are essentially designed to swarm the spike proteins so that they can’t attach to the ACE2 receptor. As such, antibodies are designed to target only one antigen (in our case, the spike protein) so that they don’t accidentally damage your body.
Most of our bodies are decent at creating these antibodies without any outside help. However, those with compromised immune systems or other medical conditions might not be able to produce these quickly enough to avoid a fatal outcome.
This is where monoclonal antibodies (mAbs) step into the picture. When a patient’s immune system is unable to fend off a disease, it is sometimes possible to use artificial or donated antibodies to jump-start the immune system’s response to a virus or other antigen.
Over the past few decades, mAbs have been used to treat a surprisingly wide range of diseases such as cancers, multiple sclerosis, Alzheimer’s, and even the Ebola virus.
Below is an approachable video which delves further into this topic:
During the SARS coronavirus outbreak in 2002–2004, several monoclonal antibodies were extracted from patients who developed an immunity. Interestingly, many of these antibodies also work against the current virus, meaning that some people were immune to COVID-19 long before the pandemic.
In contrast, a recent study found that convalescent plasma (blood donation) does not work as well as previously thought, meaning that the SARS monoclonal antibodies are indeed the first known effective treatments for COVID-19.
Biotech companies are scrambling to create mAb therapeutics for COVID-19, since they are likely to be approved before a vaccine becomes available to the public, especially for emergency treatment of high-risk patients.
While human safety trials have begun for these antibody treatments, there are several hurdles to overcome in order to ensure that the selected mAbs are safe and effective.
The most important requirement for an antibody treatment is that it both binds to and neutralizes the antigen in as many patients as possible.
Some antibodies will bind to (grab) the correct spike proteins, but in some cases the antibodies cannot neutralize the virus (prevent from attacking cells) due to having insufficient binding affinity (grip on the antigen).
Likewise, it is absolutely critical for therapeutic antibodies to maximize binding specificity (specialization toward a specific antigen). In other words, an antibody with low binding specificity can interfere with unrelated bodily functions, potentially causing even more damage than before.
Because antibodies need very high binding affinity and specificity to operate correctly in other people’s bodies, lab tests are extremely important to finding safe and effective treatments. Unfortunately, this process is highly expensive and sometimes requires hundreds of tests before finding a suitable candidate.
It’s sometimes possible to use computers to speed up this process. Tools such as docking simulators and modeling frameworks are helpful for guessing the binding affinity between a given antibody and antigen, but these are notoriously hit-or-miss solutions. Predicting binding specificity is even more challenging; antibodies can theoretically bind to almost anything (even inorganic materials).
Every computational advancement in this field has an enormous impact on the time and cost of creating effective mAb treatments.
Due to the plethora of free antibody data and software across the internet, anyone can learn about and contribute to this field of research. Below are some great starting points to explore the world’s knowledge base of antibodies and antigens:
- RCSB PDB: interactive 3D models of molecular structures.
- BioPython: an excellent library for working with molecular data in Python.
- Thera-SAbDab: hundreds of existing therapeutic antibodies.
- CoV-AbDab: hundreds of monoclonal antibodies related to COVID-19.
- Hex: a popular molecular docking simulator.
If you are interested in joining the ongoing research effort, I am running a volunteer-driven team which is ranking the binding specificity of antibodies targeting SARS-CoV-2 (the virus which causes the COVID-19 disease). We would love to work with anyone who knows a monoclonal antibody lab researcher, or has dabbled in deep learning and large-scale data analysis.
Thanks for reading! I hope that this has successfully piqued your interest in monoclonal antibodies and their potential for treating COVID-19.
