Sir Gregory Winter succeeded in developing technologies for making human and human-like antibodies, which have since been used to treat a range of autoimmune conditions and cancer. The resulting new class of drug has revolutionised the pharmaceutical industry and transformed the lives of millions of patients. Here the former Master of Trinity College and Nobel Laureate explains how antibody-based drugs could help in the fight against coronavirus.
For the last two months I have been wondering how antibodies could be developed as pharmaceutical drugs for treatment of coronavirus infections. There are potentially multiple points for intervention in the disease.
In brief, we know that the spike protein of the virus latches onto the ACE2 receptor, which is present on the surface of cells lining the nose, throat, lungs, heart, gut and walls of the blood vessels. Once attached to a cell, the virus gains entry and multiplies, damaging and killing the cell. The infected cells do not die quietly, but secrete small proteins (cytokines) to activate the anti-viral defences of neighbouring cells, and to summon the immune system. The immune system attacks both the virus and infected cells, and in most cases clears the virus. But sometimes, for reasons that are not yet clear, the immune system can over-react, leading to serious inflammation and collateral damage to healthy tissues, particularly the lung, including leakage of blood vessels and formation of blood clots, and a downward spiral to death. This is sometimes referred to as a ‘cytokine storm’.
One potential solution is to block the infection early, for example by development of an antibody to neutralise the virus by blocking its binding to the ACE2 receptor. Such antibodies might be given prophylactically to vulnerable people, and to those in the early stages of infection. The problem with this approach is that the virus, originally from bats, continues to mutate and evolve, and we should expect it to evolve further as it adjusts to its life in humans, and also responds to our attempts to isolate ourselves. For example, the virus may evolve to survive longer on surfaces, or for longer term and continued shedding of the virus after recovery from an infection. A neutralising antibody made to current strains of coronavirus may therefore not neutralise future strains, given a development timeline of one to two years. Ideally the neutralising antibodies should be directed to the most conserved (and presumably least mutable) regions of the spike. Currently several companies, including the Cambridge-based AstraZeneca, are trying to discover antibodies that would neutralise a wide range of strains, and I have been working on a proposal to do so with an academic colleague.
A more immediate solution is to focus on those infected patients who appear to be developing a serious inflammatory reaction. There are already antibodies used for treatment of other diseases, that would be expected to dampen the inflammatory response and/or limit the damage caused by coronavirus. Two of these antibodies, tocilizumab (anti-IL6 receptor) and eculizumab (anti-complement C5) , which were developed by drug companies based on my research, have been reported to help such patients, and clinical trials are underway abroad.
With colleagues, I have made a more detailed case for trials of antibodies against the inflammatory cytokine TNF (DOI: https://doi.org/10.1016/S0140-6736(20)30858-8); anti-TNF antibodies are already widely used to dampen the inflammation in rheumatoid arthritis, Crohn’s disease and psoriasis. The problem is that such interventions to dampen the inflammatory response, may if given too early, compromise the patients’ ability to fight the viral infection. Furthermore, the long half-life of the antibody in the blood may render patients prone to later infections with other viruses or bacteria. However, it is all too easy to be cautious – we need to find out, and to run these and similar medicines in clinical trials as soon as possible. We cannot assume that we will have a vaccine anytime soon.
The entire series of Reflections by Trinity Fellows can be viewed here.