Therapeutic Antibodies for COVID-19

Anti-virus monoclonal antibodies are currently considered one of the most effective therapeutic strategies to reduce viral replication and prevent mortality. Interestingly, experiments in animal models also show that neutralizing mAb therapies can potentially mitigate onward viral transmission.

 

Introduction

The emergence of the highly transmissible Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in December 2019 has resulted in the unexpected ongoing global pandemic. The situation has led to substantial health and economic burdens, urging a unified international collaboration between scientific communities, pharmaceutical companies, regulatory authorities, healthcare workers, and administrative governments worldwide.

The SARS-CoV-2 virus has been classified as a zoonotic RNA virus of the beta-coronavirus family that causes respiratory disease, officially termed Coronavirus disease-2019 (COVID-19). COVID-19 presents with mild symptoms in the majority of the patients. Still, it can cause pneumonia and severe respiratory symptoms, requiring hospitalization, in vulnerable populations such as the elderly, immune-compromised or those with comorbidities. One of the major pathophysiologies associated with disease severity is the dysregulated inflammatory pathways leading to a “cytokine storm”, which can result in tissue and organ damage.

The current disease management mainly focuses on symptomatic and supportive care. Drugs intended for the prophylactic treatment or the prevention of adverse outcomes is still under development. In this regard, anti-virus monoclonal antibodies are one of the most effective therapeutic strategies to reduce viral replication and prevent mortality. Interestingly, experiments in animal models also show that neutralizing mAb therapies can potentially mitigate onward viral transmission.

Other therapeutic antibodies added to the COVID-19 armamentarium include anti-inflammatory antibody drugs repurposed to suppress the cytokine storm or cytokine release syndrome. Recently, the WHO has approved the use of IL-6 inhibiting drugs, Tocilizumab and Sarilumab, to treat in-patients. Several other cytokine-inhibiting and immunomodulatory biologic drugs are under investigation in clinical trials. These include:

Click here to buy immunomodulatory therapeutic mAbs for COVID-19 research.

 

Targets for neutralizing mAbs

The SARS-CoV-2 virus coat comprises four structural proteins, namely Spike (S), Envelope (E), Membrane (M) and Nucleocapsid (N) proteins. The spike protein is host-specific and is responsible for the attachment and entry into the host cell (epithelial cells lining the airway and lungs in humans). As such, the spike protein has been the major target for drug and vaccine development in COVID-19.

The spike protein consists of two subunits: S1 and S2. The S1 comprises the receptor-binding domain (RBD), which attaches to the angiotensin-converting enzyme 2 (ACE2) receptor on the host cell surface. Subsequently, a conformation change occurs, and S2 facilitates viral membrane fusion and entry into the host cell. Most of the neutralizing antibodies thus target the RBD region to prevent binding, entry and consequent infection of host cells. In addition, other neutralizing epitopes in the spike protein have been identified, including the S1 N-terminal domain and S2 subunit, that can be used to develop cocktail mAb drugs.

Neutralizing mAbs

 

Approved and Phase 3 neutralizing mAbs for therapy

In the scenario of the COVID-19 pandemic, polyclonal, monoclonal, and cocktail neutralizing mAbs are being used for treatment. The use of convalescent plasma is the most traditional therapeutic strategy that involves polyclonal neutralizing mAbs from the sera of recovered patients. Engineered monoclonal antibodies (IgGs and IgAs) and cocktails are also being tested, and few have been approved for therapy. SARS-CoV-2 neutralizing mAbs are mostly humanized or fully human, with modified Fc regions to improve pharmacological properties. For example, extending half-life is advantageous in a prophylaxis setting to minimize dose frequencies. Another approach to target the spike protein is to engineer a fusion protein with a recombinant human ACE2 and mAb-Fc fragment. Cocktail mAbs is the most promising strategy to attain superior neutralization properties. Like polyclonal mAbs, cocktail mAbs target more than one epitope for better clinical efficacy. The different cocktail and monoclonal antibody therapies that are approved and under development are listed below:

Casirivimab and Imdevimab mAb cocktail

This cocktail mAb therapy launched by Regeneron targets the SARS-CoV-2 spike protein and prevents the attachment of the virus and its entry into the human cell. Based on emergency use authorization (EUA) by Food and Drug Administration (FDA), Casirivimab and Imdevimab cocktail had been intravenously administered to treat mild to moderate SARS-CoV-2 positive adults and pediatric patients, 12 years and older and weighing at least 40kilograms (kg). The treatment is applicable for a population 65 years of age or older or individuals suffering from chronic medical conditions. The mAb cocktail is administered to patients at high risk for progressing to severe COVID-19 and is not authorized for patients hospitalized or requiring oxygen therapy due to COVID-19.

Bamlanivimab and Etesevimab mAb cocktail

This cocktail therapy from Eli Lilly also acts against the SARS-CoV-2 spike protein hindering the virus entry.  Bamlanivimab and Etesevimab are administered together by intravenous infusion to patients at high risk of progression to severe COVID-19, including hospitalization or death. The cocktail drug is also recommended for people who are not fully vaccinated, does not exhibit an adequate immune response to complete SARS-CoV-2 vaccination, has come in close contact with infected individuals, or is at high risk of exposure to SARS-CoV-2 infected individuals. FDA  has granted EUA only in the case  of post-exposure prophylaxis for adults and pediatric patients (12 years of age and older weighing at least 40 kg)

Sotrovimab

Sotrovimab, launched by GlaxoSmithKline plc (GSK) and Vir Biotechnology Inc., is a monoclonal antibody therapy on EUA by FDA against mild-to-moderate COVID-19 affected adults and pediatric patients (12 years of age and older weighing at least 40 kilograms), and people vulnerable to severe COVID-19, for example, the population aged 65 and above or detected with chronic medical conditions. This SARS-CoV-2 spike protein targeting mAb therapy is not authorized for COVID-19 patients hospitalized or needing mechanical ventilation.

Regdanvimab

Celltrion group’s Regdanvimab is the first monoclonal antibody COVID-19 therapy to receive approval by South Korea’s Ministry of Food and Drug Safety (MFDS). The conditional marketing authorization was based on the first part of a global phase 2/3 trial which demonstrated relief in mild COVID-19 patients as a part of the early treatment regimen. Patients aged 50 years or older with a minimum of one underlying medical condition and moderate symptoms can undergo this mAb therapy by intravenous fusion at a dosage of 40 mg/kg. Presently, Celltrion is seeking conditional approvals by the European Medicines Agency (EMA) and  US FDA.

Neutralizing mAbs in Phase 3 trials

Currently, AstraZeneca has filed a EUA request to the FDA for its mAb cocktail of AZD7442 for early COVID-19 therapy. It has shown satisfactory results in phase 3 trials. AZD7442 is a combination of Tixagevimab (AZD8895) and Cilgavimab (AZD1061) that binds to two distinct sites on the SARS-CoV-2 spike protein. The mAbs were derived from B-cells donated by convalescent patients after SARS-CoV-2 infection. Recently, Brii Biosciences has also filed a EUA application with the US FDA for its combination therapy, BRII-196/BRII-198, to treat non-hospitalized Covid-19 patients at high risk of clinical progression to severe disease.

 

Experiences acquired in efficient isolation methods, Fc- engineering techniques to tweak effector functions and ameliorate half-life, and recent advances in manufacturing, have contributed to the rapid success and availability of these mAbs therapies against COVID-19. The utilization of these mAb therapies and other accessible therapies has helped reduce COVID-19 morbidity and mortality burden across the globe. However, one of the major concerns in the containment of the COVID-19 pandemic is the rapid emergence of SARS-CoV-2 variants or mutants that can evade vaccine immunity and mAb therapies. The currently approved mAbs have shown different degrees of vulnerability to the prevailing SARS-CoV-2 variants. Hence, continuous SARS-CoV-2 genomic screening and in-vitro neutralization assays to validate mAb therapies against emerging variants are essential to curb the pandemic.

Buy therapeutic mAbs for COVID-19 research!

Evidentic is a company providing original biologics as research consumables for academic research and new drug development. Buy approved SARS-CoV-2 neutralizing mAbs and immuno-modulatory therapeutic mAbs in aliquot formats for analytical, in-vitro and in-vivo research.

References

  • Ning, L., Abagna, H. B., Jiang, Q., Liu, S., & Huang, J. (2021). Development and application of therapeutic antibodies against COVID-19. International journal of biological sciences, 17(6), 1486–1496. https://doi.org/10.7150/ijbs.59149
  • Hurt, A. C., & Wheatley, A. K. (2021). Neutralizing Antibody Therapeutics for COVID-19. Viruses, 13(4), 628. https://doi.org/10.3390/v13040628
  • Li C, Zhao H, Cheng L, Wang B. Anti-Inflammation, Immunomodulation and Therapeutic Repair in Current Clinical Trials for the Management of COVID-19. Drug Des Devel Ther. 2021;15:1345-1356. https://doi.org/10.2147/DDDT.S301173
  • Corti, D., Purcell, L. A., Snell, G., & Veesler, D. (2021). Tackling COVID-19 with neutralizing monoclonal antibodies. Cell, 184(12), 3086–3108. https://doi.org/10.1016/j.cell.2021.05.005
  • FDA NEWS RELEASE Coronavirus (COVID-19) Update: FDA Authorizes Monoclonal Antibodies for Treatment of COVID-19
Publishing Date:
Monday, 1 November, 2021
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