Date: 23rd February 2021
As we find ourselves in the second year of a global pandemic, and for many of us still under harsh restrictions and lockdown, it is becoming clear that the emergence of SARS-CoV-2 variant strains may alter the strategic exit path that balances on the delivery of safe and effective vaccines. Now, Adagio Therapeutics has announced the dosing of the first patients in a Phase 1 trial of their COVID-19 vaccine, ADG20, which is uniquely positioned to protect against the currently common circulating SARS-CoV-2 variants and future SARS-related viruses with pandemic potential.
Adagio Therapeutics, Inc., based in Waltham, US, is a biotechnology company founded in 2020 to develop best-in-class antibodies to broadly neutralise coronaviruses. They have announced the initiation of a Phase 1 clinical trial to evaluate the safety, tolerability and pharmacokinetics of ADG20, their lead monoclonal antibody candidate. The trial will commence in the US, and will then be extended globally. The antibody was designed to have broad neutralising activity, such that is could maximise its potential to avoid viral escape that is predicted from the emergence of resistant or more potent mutated strains.
The Spike (S) protein of SARS-CoV and SARS-CoV-2 share 76% identity however, only limited numbers of cross-neutralising antibodies have so far been identified. These rare broadly neutralising antibodies (bnAbs) offer an attractive proposition for therapeutic drug stockpiling to tackle and prevent future pandemics from SARS-related coronavirus. However, they often translate with suboptimal efficacy or impractical dosing regimes, which hinder their consideration as a viable strategy.
The Adagio team along with researchers from The University of North Carolina at Chapel Hill, The Ragon Institute of Massachusetts General Hospital and The Scripps Research Institute, US, have addressed this unmet clinical need, employing a directed evolution approach to engineer three SARS-CoV-2 antibodies (isolated from 2003 SARS survivors) for enhanced neutralisation breadth and potency. The scientific data on ADG2 – the precursor to ADG20- was published in Science journal at the same time as Adagio’s announcement on the commencement of the clinical trials.
One of the 3 engineered antibody variant, ADG-2, showed the most promise, with strong binding activity to a large panel of receptor binding domains (RBD) from closely related species (Sarbecovirus subgenus) and neutralised representative epidemic SARS-related viruses with high potency. Furthermore, ADG-2 was able to bind to 30 of the most frequently encountered SARS-CoV-2 RBD variants, as well as to 6 naturally circulating SARS-CoV-2 variants which are reportedly resistance to neutralising Abs.
ADG-2 was able to neutralise SARS-CoV-2 with a similar or increased potency of rival Abs, and triggered robust and diverse Fc-mediated effector activity – such as Ab-induced phagocytosis and hallmarks of natural killer cell activation.
Finally, the team showed that ADG-2 was able to provide broad protection against SARS and COVID-19 in murine models.
Conclusions and future applications
ADG20 binds to a highly conserved region of the spike protein – an area not targeted by other antibodies. This facilitated potent neutralisation to all known SARS-CoV-2 variants and several pre-emergent coronavirus threats. It represents a promising candidate for the prevention and treatment of COVID-19, and the Adagio team will aggressively advance the clinical trials globally.
With several vaccines showing high efficacy and already approved for use such as the Oxford/AstraZeneca, Pfizer/BioNTech and Moderna vaccines, this new vaccine is uniquely placed to preempt future pandemics from evolving mutated versions of SARS-CoV-2 that are likely to appear over the coming months and years. As this is unfortunately not the last pandemic we are likely to face, it may also address the potential risk of other SARS-related viruses. With MERS first emerging in 2012, and SARS-CoV in 2003, both spreading to 27 or 26 countries respectively, the precedent has been set that a newly emerging SARS-related coronaviruses is a plausible cause of future pandemics. Tools to mitigate such events will be highly valuable to limit the spread and devastation of these diseases.
For more information please see the press release from Adagio Therapeutics
Rappazzo, C. G., L. V. Tse, C. I. Kaku, D. Wrapp, M. Sakharkar, D. Huang, L. M. Deveau, T. J. Yockachonis, A. S. Herbert, M. B. Battles, C. M. O’Brien, M. E. Brown, J. C. Geoghegan, J. Belk, L. Peng, L. Yang, Y. Hou, T. D. Scobey, D. R. Burton, D. Nemazee, J. M. Dye, J. E. Voss, B. M. Gunn, J. S. McLellan, R. S. Baric, L. E. Gralinski and L. M. Walker (2021). “Broad and potent activity against SARS-like viruses by an engineered human monoclonal antibody.” Science 371(6531): 823-829.
https://doi.org/10.1126/science.abf4830
