Neutralizing Antibodies, the “Specific Drugs” against SARS-CoV-2

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has developed into a global pandemic and become a serious public health and socioeconomic burden, and thus there is an urgent need for effective means of control. Antibodies already have good precedents of application in the prevention and treatment of sudden and virulent infectious diseases. Many new effective antiviral therapies with fewer side effects have emerged with the flourishing of human’s biomedicine, and neutralizing antibodies are a dazzling one among them.

What are neutralizing antibodies?

Neutralizing antibodies are antibodies produced by B lymphocytes when pathogenic microorganisms invade the body. When viruses, bacteria and other pathogenic microorganisms invade the body, it activates the body’s immune system and stimulates B lymphocytes to produce a variety of antibodies. However, only some of these antibodies can rapidly recognize the pathogenic microorganisms, bind to the antigens on their surfaces and prevent the pathogenic microorganisms from invading the cells by binding to the receptors on the surfaces of the target cells, thereby protecting the body from infection. This process is called neutralization, and the acting antibodies are called neutralizing antibodies.

Antiviral mechanism of SARS-CoV-2 neutralizing antibodies

The COVID-19 pathogen SARS-CoV-2 binds to the angiotensin-converting enzyme 2 (ACE2) on human cells via the spike protein (S protein) and undergoes a cell membrane infusion process, thereby allowing the virus to enter the cells to replicate through endocytosis and process and infect the body.

For SARS-CoV-2, the blocking neutralizing antibody in the RBD (receptor-binding region) of S protein can prevent the RBD of S protein from binding to ACE2, thereby preventing the virus from invading the host cells and ultimately preventing viral infection. This is an important way for neutralizing antibodies to exert their antiviral effects.

R&D progress of anti-SARS-CoV-2 neutralizing antibodies

Etesevimab（JS016/LY-CoV016）/ Bamlanivimab（LY-CoV555）

Junshi Biosciences announced on Jan. 27, 2021 that the double-antibody therapy of its neutralizing antibody etesevimab, developed in collaboration with Eli Lilly, and Eli Lilly’s bamlanivimab met the primary endpoint in the Phase 3 BLAZE-1 clinical trial, which significantly reduced hospitalizations and deaths in high-risk patients diagnosed with COVID-19. Many other healthcare supply companies also made contributions to helping those patients.

BLAZE-1 (NCT04427501) that met the primary endpoint is a randomized, double-blind, placebo-controlled Phase 2/3 study designed to assess the efficacy and safety of bamlanivimab alone or bamlanivimab and etesevimab together for the treatment of symptomatic COVID-19 in the outpatient setting. To be eligible, patients were required to have mild or moderate symptoms of COVID-19 as well as a positive SARS-CoV-2 test based on a sample collected no more than three days prior to drug infusion.

The primary endpoint measure for the Phase 3 portion of the BLAZE-1 trial was the percentage of participants who experience COVID-related hospitalizations or death from any cause by day 29. The key secondary endpoints were change from baseline to day 7 in SARS-CoV-2 viral load, persistently high SARS-CoV2 viral load on day 7, time to sustained symptom resolution, and COVID-related hospitalization, emergency room visit or death from any cause from baseline by day 29.

According to the results, across 1,035 patients, there were 11 events (2.1 percent) in patients taking the double-antibody therapy and 36 events (7.0 percent) in patients taking placebo, representing a 70 percent risk reduction (p= 0.0004). The double-antibody treatment group also demonstrated statistically significant improvements on all key secondary endpoints, providing strong evidence that the therapy reduced viral load and accelerated symptom resolution. The safety profile was consistent with observations from other Phase 1, Phase 2 and Phase 3 trials. Serious adverse events were reported at a similar frequency with the placebo group.

The FDA issued an emergency use authorization (EUA) on Nov. 10, 2020 for bamlanivimab for the treatment of mild to moderate COVID-19 in adult and pediatric patients, making it the first neutralizing antibody authorized for clinical use.

REGN-COV2

Regeneron announced in Sep. 2020 the first data from a descriptive analysis of a seamless Phase 1/2/3 trial of its investigational antibody cocktail REGN-COV2, showing it reduced viral load, alleviated symptoms in non-hospitalized patients with COVID-19, and also showing positive trends in reducing medical visits.

REGN-COV2 is a combination of two monoclonal antibodies (REGN10933 and REGN10987) and was designed specifically to block the infectivity of SARS-CoV-2.

A total of 275 patients were enrolled in the trial designed to evaluate antiviral activity with REGN-COV2 and identify patients most likely to benefit from treatment.

Patients in the trial were randomized 1:1:1 to receive a one-time infusion of 8 grams of REGN-COV2 (high dose), 2.4 grams of REGN-COV2 (low dose), or placebo. All patients entering the trial had laboratory-confirmed COVID-19 that was being treated in the outpatient setting.

Prior to treatment, patients received serology tests to see if they had already generated antiviral antibodies on their own and were classified as seronegative (no measurable antiviral antibodies) or seropositive (measurable antiviral antibodies). About 45% of patients were seropositive, 41% were seronegative and 14% were categorized as “other” due to unclear or unknown serology status.

According to the trial results, serological status at baseline predicted how rapidly patients had alleviation of their COVID-19 clinical symptoms

1. In the untreated (placebo) patients, seropositive patients had a median time to alleviation of symptoms of 7 days, compared to seronegative patients who had a median time to alleviation of symptoms of 13 days.

2. REGN-COV2 rapidly reduced viral load through Day 7 in seronegative patients to reach the key virologic endpoint.

3. Patients with increasingly higher baseline viral levels had correspondingly greater reductions in viral load at Day 7 with REGN-COV2 treatment.

4. Patients who were seronegative and/or had higher baseline viral levels also had greater benefits in terms of symptom alleviation.

Among seronegative patients, the median time to symptom alleviation (defined as symptoms becoming mild or absent) was 13 days in placebo, 8 days in high dose (p=0.22), and 6 days in low dose (p=0.09). Patients with increasing viral loads at baseline had correspondingly increasing benefits in time to symptom alleviation.

Based on the above results, the FDA approved an EUA for the REGN-COV2 low dose in adults with mild-to-moderate COVID-19 who are at high risk for poor outcomes.

VIR-7831

VIR-7831 is a dual-action monoclonal antibody. In pre-clinical trials, the antibody has shown the ability to neutralize the SARS-CoV-2 by binding to an epitope shared with SARS-CoV-1, indicating that the epitope is highly conserved, which may make it more difficult for escape mutants to develop. Moreover, modification of the Fc end of the antibody not only allows it to block the virus from entering healthy cells but also activates the immune system to have the potential to clear infected cells.

VIR-7831 is being currently investigated in patients with early-stage COVID-19 infection, who are at high risk for hospitalization (i.e., patients ≥55 years old with existing lung or cardiovascular disease). The COMET-ICE trial (NCT04545060) has been designed to enroll 20 patients with early symptomatic COVID-19 in the lead-in phase and about 1,300 patients in the expansion phase worldwide, with the primary endpoint being the proportion of patients with COVID-19 progression at day 29 and secondary endpoints including the occurrence of adverse events and development and titers of anti-drug antibodies (ADA) to VIR-7831. The final report is scheduled for July 2021 but, should expectations be fulfilled, the drug should be available in the first quarter of 2021.

A total of 12 neutralizing antibody projects have entered the clinical stage worldwide, and the above are the neutralizing antibody projects that are progressing rapidly. Neutralizing antibodies are expected to become the “specific drugs” for the COVID-19 and a powerful weapon in the fight against infectious diseases because they have both preventive and therapeutic effects, are more specific and safer, and can be prepared on a large scale. Vaccine prevention combined with antibody drug treatment ultimately becomes the hope for ending the COVID-19 pandemic.

References:

1.Anti-SARS-CoV-2 neutralizing monoclonal antibodies: clinical pipeline. MAbs. Jan-Dec 2020;12(1):1854149.

2.https://www.biospace.com/article/releases/regeneron-s-regn-cov2-antibody-cocktail-reduced-viral-levels-and-improved-symptoms-in-non-hospitalized-covid-19-patients/

3. Zhang Qian, Feng Zhenqing. Antibody strategies against the novel coronavirus pneumonia. J Nanjing Med Univ. 2020, 40(02):155-159.