Antibody Therapeutic Development in Response to COVID-19

By Silvia Hnatova

INTRODUCTION

COVID-19 is a virus of zoonotic origin with 96% homology with is the closest relative in bat, Rhinolophus affinis (Andersen et al., 2020). It has a transmission rate higher than SARS and MERS, with R0 estimate 3.02 (Majumder and Mandl, 2020). Case to fatality ratio estimate is 1.38% although the totalnumbe]r of patients is likely to be underestimated (Verity et al., 2020).

Multiple traditional and off-the-shelf approaches are being clinically tested and validated for COVID-19 treatment: antibody-based therapies, existing drugs re-purposed for COVID-19, mRNA therapies and convalescent plasma from COVID-19 survivors. Here, we will evaluate the antibody therapies for COVID-19 currently in clinical trials and preclinical development.

ANTIBODY THERAPEUTIC DEVELOPMENT IN RESPONSE TO COVID-19

The structural basis of COVID-19 bears 80% identity with SARS-CoV (Yan et al., 2020). The virus is an enveloped, single-stranded RNA virus
(Kuiken et al., 2003). The receptor-binding domain of COVID-19 (RBD) binds to angiotensin-converting enzyme (ACE2) upon entering human cells (Yan et al., 2020). Spikes, the main structural proteins, of COVID-19 are formed of S protein trimers that bear similarity with HIV glycoprotein 160 and Ebola virus glycoprotein (Weissenhorn et al., 1999). The vast majority of novel therapeutics strategies are focused on targeting the RBD domain and S proteins of COVID-19. Another class of antibody therapeutics re-purposes antibodies previously approved for use in autoimmune diseases.

Clinical trials repurposing antibodies approved for autoimmune diseases

A major therapeutics strategy for COVID-19 is re-purposing existing drugs. Critical COVID-19 patients display cytokine storm, due to the abnormal release of interleukin 6 (IL-6), tumour necrosis factors alpha (TNF-alpha) and IL-12 (Xu et al., 2020). The cytokine storm is suspected to contribute to the eventual respiratory failure leading to death. Antibodies against factors involved in cytokine storm are being repurposed for COVID-19. These therapeutics have an added advantage: they are approved for use in autoimmune conditions and their
safety profiles are known.Regeneron Pharmaceuticals together with Sanofi are re-purposing their drug sarilumab (Kevzara ®), for use in COVID-19. Currently, there is a global trial program enrolling patients in multiple countries, and a phase II/phase III clinical trial. Sarilumab, IL-6 receptor antagonist, is currently licensed for use in rheumatoid arthritis patients.Tocilizumab (Actemra) is IL-6 inhibitor owned by Roche. Ten clinical trials using tocilizumab, a rheumatoid arthritis drug, in COVID-19 patients are being carried out by numerous hospitals across the world: Spain, Italy, Switzerland, US and China. Hubei Xinhua Hospital and Wuhan hospitals estimate completion date is 20th June 2020. In a retrospective study of tocilizumab, 90.5% patients displayed absorption of lung lesions on CT scans (Zhang et al., 2020). Peking University First Hospital is carrying Tocilizumab combined with favapiravir is also in clinical trials for COVID-19 patients, expected to be completed in May 2020.Papa Giovani XXIII Hospital together with support from Ergomed plc are reporting positive results from observational case-control studies using siltuximab, a therapeutic for neoplastic diseases. One-third of 21 patients reported improvement in clinical state in previous case studies. I-Mab Biopharma is developing TJM2 antibody to neutralize GM-CSF in COVID-19 patients. TJM2 neutralization of GM-CSF resulted in a reduction of myeloid and T-cell infiltration in the nervous system and prevention of cytokine release syndrome in human xenografts (Sterner et al., 2019). I-Mab’s Company’s Investigational New Drug application has been approved by FDA, enabling clinical trials using TJM2.Gimsilumab, a monoclonal antibody against GM-CSF, is in clinical trials by Roivant Sciences. Phase 1 of gimsilumab has already been carried out using patients with lung disease. The company is now awaiting clearance for the Phase II clinical trials going ahead. Humanigen is also planning a Phase III trial with lenzilumab or Humaneered ® anti-GM-CSF monoclonal antibody. Phase I and II trials have previously been carried out. The current Phase III trial is for use in COVID-19 patients.

Antibodies ready to enter clinical testing

Regeneron Pharmaceuticals announced the discovery of hundreds of fully human antibodies against COVID-19, using the VelocImmune mice and blood from recovered COVID-19 patients. Regeneron previously used a multi-antibody approach for Ebola treatment, currently under review by the FDA. Regeneron is using VelociMab technology to scale up the manufacturing of two selected antibodies that will target the spike protein to neutralize the virus. The aim is to develop prophylactic doses by later this year. Clinical trials are yet to be announced. Regeneron partnered with Health & Human Services’ Biomedical Advanced Research and Defense Authority, to support scaling up and meet demand as soon as the antibody is validated.Distributed Bio uses a similar strategy to Regeneron, by optimizing anti-SARS protective antibodies for COVID-19 using the DBio’s Tumbler technology. The antibodies block the ability of COVID-19 to bind ACE2 receptor, its main point of infection in human cells (Yan et al., 2020). Besides, Distributed Bio developed fully human antibodies against COVID-19 using the SuperHuman 2.0 technology. Clinical trials with human participants are yet to be announced.GSK bought Vir Biotechnology and together they explore VIR-7831 and VIR-7832, monoclonal antibodies developed originally against SARS, for use in COVID-19. Clinical trials are yet to be announced. Vir has also secured rights to Xencor’s Xtend Fc technology aimed at extending the half-life of antibodies that could be used for COVID-19.Vanderbilt University Medical Center is using convalescent plasma from COVID-19 survivors to isolate monoclonal antibodies. Clinical trials have not yet been announced, whilst Vanderbilt is undertaking clinical trials examining nonantibody approaches remdesivir, hydroxychloroquinone and DAS191 in COVID-19.

Antibodies in pre-clinical development

Due to homology between COVID-19 and SARSCoV, monoclonal antibodies against SARS-CoV that bind with COVID-19 may be re-purposed for use in COVID-19 patients (Zhai et al., 2020). However, not all anti-SARS antibodies are successful in binding COVID-19 receptor-binding domain (RBD, Tian et al., 2020).CR3022 is an example of an antibody that was developed against SARS-CoV (ter Meulen et al., 2006). CR3022 was discovered in the phage library derived from the blood of convalescent SARS patients. CR3022 recognises and binds to SARS-CoV (ter Meulen et al., 2006). CR3022 was found to potentially bind COVID-19, via recognising an epitope that does not overlap with ACE2-binding site for COVID-19 RBD (Tian et al., 2020). Crystal structure of CR3022 was described by The Scripps Research Institute in the US and it described that CR3022 binds a highly conserved epitope on both SARS and COVID-19 (Yuan et al., 2020). The knowledge of the conserved epitope vulnerable to binding by antibodies may enable the design of antibodies that could serve for COVID-19 treatment, by providing in vivo protection. However, CR3022 does not neutralize COVID-19 in vitro, possibly due to its lower affinity to COVID-19 than SARS (Yuan et al., 2020). The Wilson lab at Scripps research previously pioneered antibodies for influenza and HIV treatment. It is currently doing more research for antibody-oriented vaccine, inspired by CR3022 design. Antibody design previously used to target SARS and MERS is now being re-purposed for COVID-19. Previously, inhibitors of spike heptad repeat 1 and 2 were found to be efficient for SARS-H2RP and MERS-H2RP (Xia et al., 2020). In vitro assay using ACE2-expressing 293T cells demonstrated inhibition of COVID-19 by SARSCoV-H2RP inhibitor and pan-CoV fusion inhibitor EK1 epitopes of COVID-19 (Xia et al., 2020). The pan-CoV fusion inhibitor targeting HR1 domains of HCoV S proteins was shown to inhibit infection of five coronaviruses, including COVID-19, in mice (Xia et al., 2020). The antibody was delivered as an intranasal suspension to mice, showing potential both as a treatment and as a prophylactic measure (Xia et al., 2020). The authors suggest that this drug, EK1C4 can be used as treatment and prevention in COVID-19 patients. The group is located at Fudan University in China.

Junshi Bioscience together with Institute of Microbiology of the Chinese Academy of Sciences are developing neutralizing antibodies for COVID-19, after preliminary in vitro and in vivo studies. However, no studies have been published yet.Mabpharm Limited is developing ACE-MAB fusion protein to target the spike protein of COVID-19. If successful, the company could be ready for a quick scaling up using its cGMP cell line.AbCellera and Lilly are developing antibodies by screening immune cells from COVID-19 survivors, identifying 500 fully human antibodies. If successful, Lilly would be responsible for scaling up the drug. Another company using the blood of COVID-19 survivors in Korea, Celltrion Group. Besides, Celltrion is hoping to develop a ‘super antibody’, not only against COVID-19, but also against other similar viruses. The company has completed initial screening processes and is planning clinical trials, with candidate screening to be completed by mid-April.Wang et al. (2020) also identified a monoclonal antibody against COVID-19, 47D1, using SARS-S hybridomas derived from immunized mice. However, the mechanism of action of the antibody is yet unknown, unlike the RBD or spike protein-binding antibodies. Harbour Biomed (Shanghai) together with Mount Sinai Health System would be responsible for scaling up. Last Wrapp et al. (2020) identified singledomain antibody, that was capable of neutralizing COVID-19 S pseudotyped viruses.Additional anti-COVID-19 antibodies currently in preclinical development are shown in the table on the following page.

Additional anti-COVID-19 antibodies currently in preclinical development

Company	Antibody Type	Target
Amgen, Adaptie Biotechnologies	Virus-neutralizing
Aqualung Therapeutics	Monoclonal	ALT-100
Beijing Degengrei Biotechnology Co.	Monoclonal	BDB-1
Bioduro LLC	Human synthetic antibodies	Targeting both ACE2 and spike protein
Carterra Inc., Coronavirus Immunotherapy Consortium
Dyadic International Inc	Monoclonal antibodies
Emergent Biosolutions	Antibodies from convalescent plasma
Eusa Pharma	Monoclonal	IL-6
Flanders Institute for Biotechnology	Single-domain
Gigagen	Polyclonal	Recombinant anti-coronavirus 19 hyperimmune gammaglobin
GT Biopharma, Cytovance Biologics	Tri-specific recombinant fusion protein conjugate	Anti-CD16, anti-CDC33, IL-15
Harbour Biomed, Mount Sinai Health System	Monoclonal
Immunoprecise Antibodies	Monoclonal
Inflarx		Anti-C5a
Kiniksa Pharmaceuticals	Monoclonal	Anti GM CSF (mavrilimumab)
Mateon Therapeutics	Monoclonal	OT-101
Medicago
Nascent Biotech	Monoclonal	Vimentin
Ostrich Pharma USA
Proteona	Broadly neutralizing
Sab Biotherapeutics, US Department of Defense	Polyclonal
Tiziana Life Sciences	Monoclonal	IL-6
Xavier Saelens	Single-domain

Conclusion and Future Perspectives

Hundreds of researchers are racing to find the treatment for COVID-19. They are using different approaches: monoclonal antibodies against COVID-19, convalescent plasma and repurposing existing drugs. The industry is working in tandem with researchers to facilitate rapid scaling up and to resolve any logistics issues. Fortunately, antibodies previously developed for SARS patients can be trialled in a record time, and FDA is facilitating the process. Monoclonal antibodies have shown promising results and so have antibody approaches using convalescent plasma from COVID-19 survivors. Approaches inhibiting the cytokine storm associated with respiratory failure in COVID-19 patients are also optimistic. Re-purposing existing drugs with a known safety profile would naturally be faster, safer and more efficient.There are currently 366 clinical trials from all over the world and partnerships between the industry and academia have been formed at a rapid pace. Next few months will shed light on the next promising therapeutics for COVID-19.

About the Author

Silvia Hnatova is a Ph.D. candidate in biochemistry at the University of Cambridge, working on Alzheimer's disease. Her research experience includes cell and molecular biology, biochemistry and genetics, and her main domain of interest is bioinformatics and neurodegenerative diseases.

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