Deep virology knowledge, urgency and partnership form the crucible for rapid antibody development to combat respiratory virus infection, explains Paul Kellam.
It is often said that crisis is the mother of invention, and it is hard to imagine a more pressing crisis than a global pandemic of a respiratory virus infection that is new to humankind. Despite best efforts, the WHO estimates that globally, at least 6.7 million lives have been lost so far in the SARS-CoV-2 pandemic.
The pandemic, however, showed many ways in which rapid coordination of public and private research and development can lead to profound advances in treatments for a new disease. RQ Biotechnology emerged in 2022, born from the urgent need to find ways to prevent SARS-CoV-2 infection using monoclonal antibodies (mAbs), especially for vulnerable and high-risk populations [1].
Antibodies prevent infection
Monoclonal antibodies are a well-established drug class, most often used to treat cancers and diseases of immune dysfunction. Despite antibody responses often being the only correlate of immune protection from infection following vaccination, the ability to use monoclonal antibodies as passive immunisation, to provide instant immunity, has not developed as rapidly compared to their other uses. They are, however, the missing part of the jigsaw to protect people from infection and disease.
The establishment of virus genome sequencing at a level never seen before allowed the rapid initiation of vaccine production. It also allowed the genetic tracking of the virus
Crucially, monoclonal antibodies can protect clinically vulnerable people, those who either cannot mount a strong vaccine response or cannot take the vaccine due to their other underlying clinical health conditions. The level of protection afforded by mAbs is equivalent to the most potent vaccines.
MAbs, therefore, complete a robust, threelayered prevention of infectious disease: vaccination for all, monoclonal antibodies for the most vulnerable and treatment with antivirals for those that still end in hospital.
A third way
The playbook for pandemic response worked well in some areas and less so in others. The establishment of virus genome sequencing at a level never seen before allowed the rapid initiation of vaccine production. It also allowed the genetic tracking of the virus, showing quickly how genetically variable SARS-CoV-2 could be, and rapidly identifying variants of concern (VOC).
Such genetic variation can cause problems for vaccines, small molecule drugs and mAbs, rendering them less effective. Intensive study of the SAR-CoV-2 spike protein defined how the virus accumulates mutations in the spike that prevent antibodies from binding which otherwise potently block (neutralise) virus infection. Fusing these data streams together has been crucial for vaccine and mAb development.
The discovery and development of potent mAbs to prevent infection must cope with the evolution of the virus spike target. Two broad strategies arise, the first is to use two (or more) mAbs to target distinct sites (epitopes) on the spike so that virus infection of cells is neutralised, with the mAbs acting as potent cell entry inhibitors.
If mutation occurs at one site leading to loss of potency for one mAb, the overall potency of the product is maintained by the second mAb. The second strategy is to use one mAb to target an epitope in the spike, with lower frequency of mutation. Often mAbs to these epitopes have less neutralising potency, with modifications to the body (the fragment crystallisable (Fc) region) of the mAb necessary to leverage other antibody protective functions in the body.
For the first generation of approved mAbs, spike evolution has led to the loss of activity for both approaches, with mutations rendering products such as Ronapreve (a two mAb combination) and Xevudy (a single mAb with enhanced Fc functions) ineffective. Evusheld, however, maintained its activity for both mAbs against early VOCs, and one mAb in the cocktail has remained active to many of the more recent Omicron variants, although the FDA is currently awaiting additional data to verify how Evusheld works against new Omicron variants such as XBB.1.5 [2]. Together, this suggests a third approach is possible, namely the discovery and development of potent neutralising mAb pairs to epitopes peppered with antibody escape mutations but where the mAbs are nonetheless robust to the common mutations that arise in the virus population. RQ Bio is following this approach, where deep knowledge of virus and antibody evolution aids the discovery of potent neutralising mAbs.
Networks matter
The pandemic showed that rapid development and clinical testing of any product required a partnership between originator laboratories, be they academic or industrial, large pharma, with their ability for product development, and clinical trial networks, often underpinned by national governments and healthcare systems. This remains true now for mAbs, where preclinical, in vitro data on virus neutralisation potency, coupled with established data on the pharmacokinetics of mAbs, allows pharma to de-risk and speed up first into human and efficacy studies. RQ Bio licensed its first SARSCoV- 2 mAbs to AstraZeneca, and their speed allowed the start of clinical trials in less than a year from mAb isolation.
The Covid-19 pandemic has highlighted weakness in healthcare systems throughout the world, but also shown how to rapidly discover and develop mAbs to provide instant, passive immunity to respiratory virus infection. The challenge now is to harness these advances to protect the most vulnerable people, keeping them healthy during periods of intense virus infection, such as the winter, and keep healthcare systems functioning, rather than inundated, having to treat preventable disease.
Paul Kellam is CSO at RQ Biotechnology Ltd and Professor of Virus Genomics, Department of Infectious Disease, Imperial College London
References:
1 https://www.who.int/westernpacific/ emergencies/covid-19/information/high-risk-groups
2 https://www.fda.gov/drugs/drugsafety-and-availability/fda-releasesimportant-informationabout-risk-covid-19-due-certain-variantsnot-neutralizedevusheld
