Although several small molecules with therapeutic potential made headlines at the start of the pandemic, antibodies targeting the SARS-CoV-2 viral particles have since gained quite a momentum. The idea behind these therapeutic antibodies is that they will simulate the body’s natural immune response to the virus and should help COVID patients recover even faster by helping to recognize the viral intruder more easily. A subset of these antibodies, which have received the “neutralization” label, are engineered such that they possess properties that enable them to inhibit the binding of the SARS-CoV-2 viral particle to human cells, thus in a sense neutralizing the virus as it simply cannot replicate if unable to enter a living cell. Hybridoma-based discoveries have made the antibody industry what it is today and advances in engineering and processing have allowed single B cell technologies to add to the growing collection of therapeutic antibodies that could counterbalance the lack of vaccines in certain parts of the world.

At the start of the year, 21 monoclonal antibodies were undergoing clinical trials, 6 of which had reached a late-stage trial or even received emergency authorization. The strategies and rationales behind the discovery of these antibodies are as diverse as the antibodies themselves. Although this is not an exhaustive list of all of the antibodies currently in development, our only hope is that the global infection rate continues to subside, and that the success of these antibodies will only be measured by the speed and accuracy with which they are developed and not by the number of patients who will receive them.

Regeneron Pharmaceuticals – REGEN-COVTM/REGN-COV2: REGN10933 (casirivimab) and REGN10987 (imdevimab)

REGEN-COVTM consists of a non-competing pair of IgG1 monoclonal antibodies that can bind the SARS-CoV-2 viral particle simultaneously. These antibodies were discovered through the immunization of genetically humanized mice with DNA encoding the spike protein of SARS-CoV-2 and boosted with a recombinant receptor binding domain (RBD) of the spike protein. B cells would then be isolated from the spleens of the mice, sorted into individual wells, and with the magic of modern sequencing technology, the antibody mRNA sequences would then be extrapolated. These mice, which make up the VelocImmune® technology platform, have been the most successful transgenic mouse strain to date and have played a key role in the discovery and development of numerous approved therapeutic antibodies including Praluent® (alirocumab), Dupixent® (dupilumab), Kevzara® (sarilumab), Libtayo® (cemiplimab-rwlc), Evkeeza™ (evinacumab-dgnb) as well as the most recently approved antibody cocktail for the treatment of the Ebola virus, Inmazeb™ (atoltivimab, maftivimab, and odesivimab-ebgn).

After administering the Regen-COVTM antibody combo intravenously, patients began seeing symptom improvement roughly six days later. The National Institutes of Health (NIH) treatment guidelines recommended administering this combination treatment in high-risk outpatients as defined by the Emergency Use Authorization (EUA) criteria. Shortly after, the European Medicine Agency (EMA)’s Committee for Medicinal Products for Human Use (CHMP) issued a positive opinion regarding the antibody cocktail and would begin to be used in Europe.

Unfortunately, casirivimab has shown mixed results, including zero neutralizing activity against certain variants such as the one originating from South Africa. The EUA will remain as long as the two discovered antibodies are used in combination but finding a more favorable and efficacious combination could help Regeneron maintain its superiority.

AbCellera Biologics & Eli Lilly – LY-CoV555, LY3819253 (bamlanivimab)

AbCellera’s bamlanivimab, which also targets the RBD, was discovered via single B cell cloning from convalescent patients. In a process similar to the one described above, peripheral blood mononuclear cells (PBMCs) would be extracted from the plasma of recovering patients, and from there individual B cells would be isolated and sorted. As opposed to using earlier methods of directly administering serum from recovering patients, administering a purified monoclonal antibody has the advantages of not including unrelated and non-SARS-CoV-2 binding antibodies, and should offer a more effective and predictable immune response in newly infected patients.

Both bamlanivimab and Regeneron’s Regen-COVTM had shown a strong decrease in patient hospitalizations and emergency room visits, likely related to the resulting decrease in the number of viral particles detected in an infected person’s blood. Individuals who have received either of these mAb therapies have been recommended to delay receiving any of the approved vaccines for a period of three months as a precaution. It is not yet known whether the antibody treatments can interfere with the body’s own immune response to the vaccines, giving patients a false sense of immunity.

The neutralizing IgG1 mAb could be administered alone or in combination with etesevimab which is concurrently being developed by Junshi Bioscience, also through collaboration with Eli Lilly and discussed later. Unfortunately, the EUA for bamlanivimab as a standalone therapy was revoked earlier this year due to treatment failure against various SAR-CoV-2 variants. The potential benefits of this antibody no longer outweigh its potential risks and coming up with new combination strategies will be instrumental to its future.

In a glimmer of hope, AbCellera’s recent acquisition of Trianni (a San Francisco-based transgenic mouse company) opens the door for further antibody development of SARS-CoV2 antibodies. The success of Regeneron’s VelocImmune mice in effectively mimicking a human immune response allowed it to obtain antibodies comparable to those of patients who had contracted and recovered from the viral infection. A key advantage of using mice over convalescent human plasma is it enables scientists to modify and optimize their immunization in real-time, all the while selecting for highly desired and specific epitopes on the target of interest.

Vir Biotechnology & GlaxoSmithKline (GSK) – VIR-7831, GSK4182136 (sotrovimab)

Vir Biotechnology has embraced the French saying “the best soups are made in old pots” and has made full use of single B cell antibody isolation on previously collected blood samples from an individual who was infected with the original SARS-CoV back in 2003.

Concerns with some of the current vaccines have been the loss of antibody production and humoral immunity over time, thus resulting in the need for a strong and consistent cell-mediated immune activation (shown by the lingering presence of SARS-CoV reactive T-cells in patients today who contracted the original SARS-CoV). The concurrent stimulation of the humoral and cell-mediated immune systems offers patients a thorough defense mechanism especially as we do not know when the next outbreak from the coronavirus family will be upon us.

A lot of research has gone into demonstrating that SARS-CoV therapies can be recycled and used against SARS-CoV-2; with the perfect example being the use of SARS-CoV antibodies incorporated into immunoassays to detect SARS-CoV-2 infections early in the pandemic. Unfortunately, the 2003 outbreak was but a small blip on the global scale compared to the current pandemic and the development of therapeutics and diagnostics lagged as they were no longer needed once the number of cases subsided.

The newly identified IgG1 monoclonal antibody has a high affinity for SARS-CoV-2 and was highly potent in neutralization assays. In a recent collaboration between Eli Lilly, Vir, and GSK, sotrovimab is combined with bamlanivimab in a Phase II BLAZE-4 trial, targeting adult patients with mild to moderate COVID-19 symptoms.

AstraZeneca & Vanderbilt University – AZD7442: AZD8895 (tixagevimab) and AZD1061 (cilgavimab)

Vanderbilt University has gone straight to the source of the outbreak and discovered, through single B cell cloning, two notable antibodies from the plasma of convalescent individuals who had been infected with SARS-CoV-2 in Wuhan, China. Following some early research and development work, Vanderbilt then licensed these assets.

AstraZeneca has played a key role throughout the pandemic, with first acquiring the Oxford University ChAdOx1 adenovirus vaccine platform. As has been discussed in various business forums, licensing and acquiring technology allows one to be competitive in the now as opposed to building everything from scratch in-house and having the possibility of missing out in the long run. Moreover, acquiring a pre-established technology (which in this case is a simple protein) has its advantages in the form of intellectual property and patents. This process not only highlights the importance of early-stage research and development as well as the ongoing need for more industry and academic collaborations, bringing some of the greatest scientific minds together.

The neutralizing and non-competing IgG1 pair has since been optimized by AstraZeneca. Through proprietary technology, which resulted in minimized Fc receptor binding and extended serum half-life, these antibodies are reported to remain detectable in a patient’s serum for 6 and up to 12 months. These Long-Acting Antibodies (LAABs) would thus allow for extended protection from a viral infection and the US government has already secured one hundred thousand doses of the antibody combination, with the possibility of acquiring one million more.

Celltrion – CT-P59 – Regkirona (regdanvimab)

The South Korean Ministry of Food and Drug Safety (MFDS) has granted a conditional marketing authorization (CMA) for Celltrion’s regdanvimab. The CMA allows for emergency use of the neutralizing IgG1 antibody in adult patients with mild symptoms of COVID-19 and at least one underlying medical condition or in patients with moderate symptoms of COVID-19. At the moment, Celltrion is working with the FDA and EMA regulatory agencies on approving its antibody overseas.

Regdanvimab, which also targets the RBD protein, was discovered via an antibody library constructed from PBMCs of a convalescent patient and has shown promising data against the United Kingdom (UK) and South African SARS-CoV-2 variants. Although we cannot predict to what extent and which of the SARS-CoV-2 antibodies will be efficacious against the different variants, this ongoing medical dilemma will allow biopharmaceutical companies to show how far they are willing to go to in order to support patients on a global scale, especially those in third world countries.

At the present time, South Korea has yet to roll out any vaccine, although SK Bioscience has been diligently working on one. The development of regdanvimab has allowed the country to buy extra time to assess whether the newly developed vaccines carry any unknown side effects or prove ineffective. Along with South Korea’s extensive track and trace system, antibody treatment has been expected to curb hospitalization rates.

Shanghai Junshi Biosciences & Eli Lilly – JS016, LY-CoV016, LY3832479 (etesevimab)

Junshi Biosciences, fresh off deals with Coherus BioSciences and AstraZeneca for the further development and marketing of its PD-1 antibody, has partnered with Eli Lilly for the progression of its SARS-CoV-2 antibody.

Etesevimab, which has yet to be approved as a solo therapy, can only currently be used in combination with AbCellera’s bamlanivimab. This neutralizing IgG1 antibody combination will offer a multipronged attack towards the SARS-CoV-2 viral particles during an infection. Single monoclonal antibody treatments have been the norm up until now, but combination treatments have shown to be even more efficacious and are slowly coming about. With time, viral particles evolve (usually through recombination or the integration of random mutations) to become more virulent. Viruses oftentimes evolve faster than their hosts making this a significant concern. In improving their fitness, viruses can increase the ease of transmission from host to host or cause even more drastic symptoms. Identifying new drugs to combat this virus is of utmost importance and in creating a synergistic effect through the combination of different antibody treatments, this hopefully limits the number of evolutionary steps a virus can take.

Whether the bamlanivimab-etesevimab or bamlanivimab-sotrovimab antibody combination offers an improved response is yet to be determined. As all the aforementioned SARS-CoV-2 antibodies bind to distinct sites on the spike protein RBD, numerous combinations can and will be considered. These combinations will hopefully minimize the potential of escape variants arising as well as decreasing the amount of each antibody needed per combination dose, thus allowing more doses to be made within the same time frame.

Antibodies for HumanityTM

Numerous other SARS-CoV-2 antibodies remain in development, with the majority of them coming from US and China-based companies. Several transgenic mouse companies and contract research organizations (CROs) also offer the possibility of partnering and licensing out their assets. Abbvie recently licensed ABBV-47D11, a neutralizing IgG1 SARS-CoV-2 antibody from Harbour BioMed (a transgenic mouse company based in the Netherlands). The biopharmaceutical giant has been relatively quiet since the start of the pandemic, most likely focusing on coming up with new and ingenious ways to sell the backlog of botox from their recent Allergan acquisition.

Throughout this pandemic, LakePharma has been diligently working on maintaining its continued efforts to provide clients with high-quality science and one of the best antibody-discovery platforms on the market. In addition to collaborating and working with numerous clients to cater to their SARS-CoV-2 vaccine and antibody needs, LakePharma has discovered a number of monoclonal antibodies that are available to be licensed. These in-house antibodies have varied binding profiles, from previous coronaviruses (MERS, SARS-CoV, …) to various SARS-CoV-2 variants.

If you would like your own SARS-CoV-2 spike-binding mAbs, contact us today!

 

Guillaume Trusz

Author Guillaume Trusz

Guillaume Trusz received his B.S. in Molecular, Cell, and Developmental Biology from the University of California, Los Angeles (UCLA) in 2015 and his M.S. in Biomedical Imaging from the University of California, San Francisco (UCSF) in 2018. Prior to working as an Associate Scientist in the Discovery Immunology Group at LakePharma, Guillaume contributed to various academic and industry related research projects pertaining to small molecules, nanoparticles, as well as biosimilars.

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