Antibody therapeutics: the other race for immunity against SARS-CoV2

Sophie Lutter, OXGENE, looks at the important role antibody therapeutics have to play and how, as the world has looked for Covid-19 treatments in the last year, their significance has been noted.

As the world continues to adjust and respond to the impact of the Covid-19 pandemic, the race to develop a vaccine against the disease has become a race to manufacture and administer recently approved inoculations, and to ensure that these remain effective against newly emerging strains of the virus. But while most of the conversation revolves around preventing (at least) severe disease, hospitalisation and death, another race – that to develop treatments for those who continue to get seriously unwell after catching the virus – is still in progress. In this race, the immune response is again a lead runner, this time in the form of antibody therapeutics.

Introducing antibody therapeutics

The idea behind antibody therapeutics is that rather than waiting for the body to develop its own antibodies against the virus, you can administer externally produced antibodies to confer passive immunity faster than the body can mount its own active defence. The main strength of antibody therapeutics lies in their specificity for the target antigen, which makes them both highly potent and well tolerated, greatly reducing the risk that off-target binding will cause side effects.

The most basic form of antibody therapy is the administration of serum containing polyclonal, pathogen-specific antibodies donated from convalescent donors. In August 2020, the FDA approved this as an emergency treatment for patients hospitalised with Covid-19 in the USA, although the clinical effectiveness of this is still in question. There are over 70 clinical trials assessing the effectiveness of convalescent plasma ongoing worldwide, but none have yet reported conclusive results1. In fact, the UK led RECOVERY trial closed recruitment of patients to the convalescent plasma arm in January 2021, after preliminary analysis showed no significant change in 28-day mortality vs standard care2.

Stopping a virus in its tracks

To be an effective therapeutic, it’s not enough for an antibody to simply bind to the virus, it must also be able to ameliorate its effects. Neutralising antibodies bind to the virus and prevent it from infecting the cell, either by preventing viral attachment to the host cell, or blocking entry post attachment3.

The SARS-CoV2 virus, responsible for Covid-19 disease, contains four structural proteins; the nuclecapsid (N) protein forms the capsid around the genome, which is further surrounded by the membrane (M), envelope (E) and spike (S) proteins4,5. The spike protein consists of two subunits, S1 and S2. The receptor binding domain (RBD) is located on the S1 subunit and binds to angiotensin converting enzyme 2 (ACE2) on the host cell surface. This triggers a conformational change in the spike protein such that the S2 subunit can mediate membrane fusion, allowing viral entry into the host cell6,7.

Mechanisms for blocking viral entry

All the neutralising antibodies against SARS-CoV2 currently in pre-clinical or clinical development target the spike protein, but their mechanisms of action vary (Figure 1). The majority, including Lilly’s etesevimab and bamlanivamab8, Regeneron’s casirivimab and imdevimab9, and AstraZeneca’s AZD744210, bind to the RBD on the S1 subunit, blocking ACE2 binding and attachment to the host cell.

Other novel neutralising antibody candidates still in the discovery stage bind the NTD of the S1 subunit11, which might prevent the conformational change in the spike protein necessary for membrane fusion12.

Another SARS-CoV2 neutralising antibody isolated from memory B cells of a patient infected by SARS-CoV in 2003, also acts without competing for ACE2 binding. Instead, this antibody is thought to act via co-binding to Fcγ receptors, triggering antibody dependent cell mediated cytotoxicity (ADCC) or antibody mediated phagocytosis, aggregation or immune activation13.

Immunogenic epitopes of the S2 subunit, which are conserved between coronaviruses, are also interesting targets for the development of neutralising antibodies, since antibody binding to these epitopes could inhibit membrane fusion, and thus viral entry14, 15. In fact, antibodies against this domain may play a role in pre-existing immunity to SARS-CoV2 infection16.

Overcoming the challenges

Since the first therapeutic antibody was approved by the FDA in 1986, this has become an increasingly important class of drugs. Indeed, therapeutic antibodies are now the predominant treatment for multiple conditions ranging from cancer and metabolic diseases to autoimmune and – increasingly – infectious diseases17. In the latter case, the role of antibody therapeutics is in fact becoming more important with the rise of antimicrobial resistance to traditional small-molecule antibiotics18. But despite huge growth in the field, significant opportunities for further market expansion, and the hope these treatments offer – especially right now – there are still challenges associated with antibody discovery and development.

Antigen specificity: a strength and a flaw

One of the major strengths of antibody therapeutics is their target specificity and affinity. But in situations that emerge and escalate as rapidly as the Covid-19 pandemic, speed is of the essence when it comes to drug development, and this is where antibody specificity can be a drawback. One of the fastest ways to get effective new drugs to patients is to repurpose a treatment that’s already on the market for a different condition, however the specificity of an antibody therapeutic for its target antigen can make this approach challenging. Indeed, several companies, including Alexion with ravilizumab and Novartis with canakinumab, trialled their pre-existing antibody therapeutics, approved for inflammatory or respiratory conditions, in patients with Covid-19, but discontinued the trials when they didn’t meet their efficacy endpoints19,20.

Mitigating for viral escape

The virus itself provides another challenge to antibody specificity. As researchers race to discover new neutralising antibodies against SARS-CoV2, they’re racing not only to develop new treatments that will relieve both patients and the burden on health systems as quickly as possible – but also against the virus itself. One of the biggest risks in developing antibody therapeutics for infectious diseases is antibody escape due to mutations in the antibody-binding epitope on the virus. Several companies developing antibody therapeutics for Covid-19, including Lilly with etesevimab and bamlanivamab and Regeneron with casirivimab and imdevimab, are already mitigating for this. They’re taking a belt and braces approach by trialling antibody cocktails in which each antibody targets a non-overlapping epitope in the spike protein receptor binding domain8,9.

Another strategy to reduce the risk of antibody escape is to target highly conserved viral epitopes. This is the strategy adopted by Vir Biotechnology and GlaxoSmithKline with their VIR-7831/VIR-7832 antibodies21. These antibodies target an epitope on the Spike protein common to both SARS-CoV1 and SARS-CoV2, suggesting that this region may not be prone to mutation.

A final strategy designed to mitigate against antibody escape is the development of bispecific antibodies. These are engineered antibodies that can bind to two separate antigens. A recently pre-published paper suggests that it’s feasible for bispecific antibodies targeting separate epitopes on the SARS-CoV2 spike protein RBD to completely prevent spike protein binding to ACE2 and therefore neutralise SARS-CoV2 infection, while reducing the threat of viral escape mutations22.

Ensuring response duration

A further challenge for passive immunity is the duration of response; the antibody will only be effective for as long as it survives in the body, which is typically around one month23. Antibody catabolism is determined by the interaction between the Fc region of the antibody’s heavy chain with the neonatal Fc receptor (FcRn) on the surface of endothelial cells. Depending on pH and binding affinity, after binding to the FcRN, which prompts internalisation, the antibody is either marked for degradation or recycled back to the cell surface and released into the circulation24. This limitation can be overcome with antibody engineering technologies designed to extend the half-life of therapeutic antibodies and reduce the need for repeat doses. For example, AstraZeneca has utilised their proprietary half-life extension technology in the development of their Long-Acting Antibody (LAAB) combination AZD7442, which is currently in Phase III clinical trials for Covid-19, and is designed to increase treatment durability to six-twelve months following a single dose10.

New opportunities for discovery and beyond

As the antibody therapeutics market has ballooned over the last twenty years, so has investment into antibody discovery and engineering, focussing not just on discovering functional antibodies against a huge number of disease specific antigens, but also on improving the pharmacokinetics of these biologics to maximise their effectiveness. There is huge opportunity in this area; the scale and duration of the Covid pandemic means that the discovery of additional neutralising antibodies against SARS-CoV2 is far from redundant.

Outside of Covid, antibody discovery is still a powerful driver of therapeutics pipelines across numerous diseases, and as our understanding of the molecular mechanisms of disease grows, so does the number of potential targets for antibody-based therapeutics. However, many newly identified targets are difficult-to-access membrane proteins with minimal extra-cellular domains available for antibody binding. Traditional discovery techniques designed to identify antibodies against purified proteins may struggle to identify functional antibodies against these protein targets25. This is where new approaches that retain the target membrane protein within the in its native configuration throughout discovery, may have the advantage26.

Summary and outlook

The Covid pandemic is a global disaster, but the speed, scale and intensity of the international research response has been awe-inspiring. Over the last year, we’ve learned a huge amount about how to discover, develop, test, trial and assess new therapeutic antibodies as quickly as possible, and these are the sorts of lessons that can’t be unlearnt. And nor should they be. In 2014, the World Health Organisation outlined some of the challenges facing the discovery and development of antibody therapeutics for infectious diseases. These included the fact that viral outbreaks are unpredictable, and often associated with high fatality rates in small numbers of patients. Where neutralising antibodies do exist, they are often in short supply, and manufacturing costs are high27.

These challenges require flexibility around trial design and regulatory approval to allow proper testing of novel therapeutics in sub-optimal conditions, fast-tracked approval processes to get drugs to the patients who need them as fast as possible, and innovation and collaboration in manufacturing to produce these therapies at scale and cost. These are all issues that the enormity of the Covid pandemic is forcing the global therapeutics industry to address. But once these mechanisms are in place, the antibody discovery and development market should be stronger, and better prepared to deal with future outbreaks, than ever.

Volume 22, Issue 2 – Spring 2021

Figure 1: A. Schematic of the SARS-CoV2 spike protein, which has two subunits, S1 and S2. The receptor binding domain (RBD) is on the S1 subunit and binds to angiotensin converting enzyme 2 (ACE2) on the host cell surface. Neutralising antibodies against SARS-CoV2 all target the spike protein, but have different mechanisms of action: B. Binding to the RBD on the S1 subunit blocks ACE2 binding. C. Binding elsewhere on the S1 subunit blocks the conformational change needed for the virus to enter the host cell. D. Binding the Spike protein at the same time as an Fcγ receptor triggers antibody dependent cell mediated cytotoxicity (ADCC) or antibody mediated phagocytosis, aggregation or immune activation. E. Binding the S2 subunit may prevent membrane fusion and thus viral entry. Figure created using Biorender

About the author

Dr Sophie Lutter is Scientific Communications and Marketing Manager at OXGENE, a WuXi Advanced Therapies company. OXGENE provides end-to-end research services to cell and gene therapy companies seeking to discover, develop, manufacture and test innovative drug candidates at scale for global commercialization. OXGENE’s proprietary technologies and automation platforms for molecular discovery are seamlessly integrated with a full suite of technologies for cell and gene therapy manufacturing.


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