Monoclonal antibodies: Will they help end COVID-19?

Trump, who recovered from COVID-19, had famously declared the treatment a “cure”. Drug regulators have since moved to allow its greater use. Here’s a look into mAb therapies:

How many monoclonal antibody drugs are approved against COVID-19?

There are at least five monoclonal antibody drugs, Sotrovimab is the most recent one.

What are antibodies?

Antibodies are protein molecules. Our body makes antibodies to target and help eliminate specific foreign molecules — such as viruses, bacteria or microbes.

What is a monoclonal antibody (mAb)?

Monoclonal antibodies are molecules produced in laboratories. They are engineered to serve as “substitute” antibodies that can immediately restore, enhance or mimic the immune system’s attack on specific antigens — or even cancer cells.

The monoclonal antibodies are concentrated versions of ones that proved to have the ability to do zap antigens.

Why are monoclonal antibodies important?

They enhance passive immunity. In the current pandemic, monoclonal antibody treatments are proven most effective within a few days of receiving a COVID-19 diagnosis. For example, sotrovimab (approved on May 26, 2021) has proven to greatly reduce severity and hospitalisation/death — 85% efficacy.

Monoclonal antibody technology could accelerate existing and identify new anti-viral antibodies that could be used as preventive options to help address the current COVID-19 pandemic and future outbreaks. mAbs belong to a new class of therapies designed to function in different ways. They work at the “epitope” level of an antigen (disease-causing molecule).

Now, it is possible to produce monoclonal antibodies that specifically bind to virtually any suitable molecule/substance; they can then serve to detect or purify it. This capability has become an important tool in biochemistry, molecular biology, and medicine.

What’s the difference between antibodies and monoclonal antibodies?

With natural antibodies, it can take weeks for the best ones to form after an infection occurs. Monoclonal antibodies are designed to shorten this process. In theory, they help the body start to fight the virus right away.

Why are they called "monoclonal”?

Monoclonal antibodies are cells derived by cell division from a single ancestral cell. Monoclonals are a class of antibodies with identical offspring of a hybridoma — and are very specific for a particular location in the body derived from a single clone. They can be grown indefinitely.

Monoclonal antibodies recognise and bind to antigens in order to discriminate between specific epitopes (sub-units of an antigen molecule to which an antibody attaches itself) which provides protection against organisms that cause diseases. In short, those antibodies are named monoclonal because they come from only 1 type of cell, which is the hybridoma cell.

How does the immune system fight COVID-19?

The immune system is like a football squad — each team member has a different function. This team detect and destroy disease-causing agents, such as bacteria and viruses.

Antibodies form a key factor in our immune system. Monoclonal antibodies are identical copies of an antibody that targets one specific antigen (most approved monoclonal antibodies against SARS-CoV-2 target the virus’ spike protein molecules) in order to trigger an immune response.

How do scientists make monoclonal antibodies?

Scientists can make monoclonal antibodies by exposing white blood cells to a particular antigen. Scientists can also produce these antibodies in a laboratory setting to be infused into the blood.

What explains its efficacy against different variants?

It targets the virus at the epitope level.

The antibody binds to an epitope on SARS-CoV-2 (cause of COVID-19) that is shared with SARS-CoV-1 (the virus that causes SARS). This indicates that the epitope is highly conserved, which may make it more difficult for resistance to develop.

Sotrovimab also has been designed to achieve high concentration in the lungs — to ensure optimal penetration into airway tissues affected by SARS-CoV-2 and to have an extended half-life.

Preclinical data for GSK’s sotrovimab suggest it has the potential to both block viral entry into healthy cells and clear infected cells.

Monoclonal, polyclonal, bispecific monoclonal antibodies: What’s the difference?

In general, monoclonal antibody is an antibody made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell.

Monoclonal antibodies can have monovalent affinity, binding only to the same epitope (the part of an antigen that is recognized by the antibody).

On the other hand, polyclonal antibodies bind to multiple epitopes and are usually made by several different antibody secreting plasma cell lineages.

Bispecific monoclonal antibodies can also be engineered, by increasing the therapeutic targets of one monoclonal antibody to two epitopes.

How are monoclonal antibody drugs administered?

At the moment, Phase 3 studies on mAb such as the one done for sotrovimab was done through a vein (intravenously). There are earlier studies for intramuscular injections (IM) of mAbs.

What is the major benefit of this class of anti-COVID drug?

Dr. Howard J. Huang, medical director of the Houston Methodist Lung Transplant Center, explained the use of monoclonal antibodies: as a new class of drug against COVID, Mabs give doctors a way to reduce severity for certain patients at increased risk for developing severe disease.

For the first several months of the pandemic, there was very little that clinicians could do for those who tested positive for COVID-19 but did not require hospitalisation — beyond taking a wait-and-see approach. “If a person's symptoms became severe, we could at that point manage and treat the resulting complications via oxygen therapy and other methods,” said Dr Huang. But, the ideal scenario is to prevent severe symptoms from ever developing in the first place.

How much will monoclonal antibody treatment cost?

In a research note, Mayo Clinic states monoclonal antibody drugs can cost “thousands of dollars” for each treatment. We'll update this article as soon as we confirm the amount.

What supports the FDA approval for sotrovimab?

The data supporting sotrovimab emergency-use authorisation are based on an “interim analysis” from a phase 1/2/3 randomised, double-blind, placebo-controlled clinical trial in 583 non-hospitalised adults with mild-to-moderate COVID-19 symptoms. All participants had positive SARS-CoV-2 test result.

Of these patients, 291 received sotrovimab and 292 received a placebo within five days of onset of COVID-19 symptoms. The primary endpoint was progression of COVID-19 (defined as hospitalisation for greater than 24 hours for acute management of any illness or death from any cause) through day 29.

What is the efficacy of sotrovimab?

According to data reviewed by the FDA, hospitalisation or death occurred in 21 (7%) patients who received placebo compared to 3 (1%) patients treated with sotrovimab — an 85% reduction.

How is their efficacy against new SARS-CoV-2 variants monitored?

The FDA is carefully monitoring circulating viral variants and their sensitivity to monoclonal antibodies authorised to treat COVID-19, including sotrovimab. “Laboratory testing showed that sotrovimab retains activity against the current circulating variants first reported in the United Kingdom, South Africa, Brazil, California, New York and India,” FDA said in a statement

How long do antibodies against SARS-CoV-2 last?

Scientists have found that these antibodies persist for at least 4 months after the infection. For SARS-CoV 1, one study shows the antibodies are still present after 17 years.

What does “investigational therapy” mean?

Sotrovimab is considered an investigational therapy. It is approved for the treatment of mild-to-moderate COVID-19 in adults and paediatric patients (12 years of age and older weighing at least 40 kg) with positive results of direct SARS-CoV-2 viral testing and who are at high risk for progression to severe COVID-19, including hospitalisation or death. This also includes individuals who are 65 years of age and older or individuals who have certain medical conditions.

Is the sotrovimab approval final?

No. The approval type for sotrovimab is called “emergency use authorisation”, the same authorisation FDA gave to casirivimab and imdevimab (administered together) on November 21, 2021. The issuance of an EUA is different than full approval. Drug regulators will continue to investigate the safety and effectiveness against COVID-19.

Is it authorised for patients hospitalised for COVID-19?

No. Sotrovimab is not authorised for patients who are hospitalised due to COVID-19 or require oxygen therapy due to COVID-19. This treatment has not shown benefit in patients hospitalised due to COVID-19. FDA stated that monoclonal antibodies may be associated with worse clinical outcomes when administered to hospitalised patients requiring high-flow oxygen or mechanical ventilation.

Has it been approved in other countries?

Yes. It has been approved in the US (May 26, 2021) and the UAE (May 29, 2021).

India

In India, it’s been reported that Drugs Controller General of India (DCGI), the head of department of the Central Drugs Standard Control Organisation, is reportedly on a “fast-track” mode to give regulatory clearance for the drug, based on data submitted by GSK-Vir or with limited trials, rather than insisting on time-consuming Indian trials to approve the drug.

Canada

In April, Health Canada initiated a review of sotrovimab under the expedited Interim Order application pathway for COVID-19 drugs.

Europe

On May 21, 2021, the European Medicines Agency’s (EMA) Committee for Human Medicinal Products (CHMP) issued a “positive scientific opinion” of sotrovimab. The EMA has also started a “rolling review” of data on sotrovimab. This will continue until enough evidence is available to support the filing of a formal marketing authorisation application.


GSK and Vir stated they are continuing discussions with other global regulators on the regulatory pathways available so that sotrovimab can be made available to patients with COVID-19 as soon as possible.

What is the research code for sotrovimab?

Vir-7831.

Are monoclonal antibodies used to fight cancer?

Yes. Certain monoclonal antibody drugs are now being investigated for use against cancer. They work by enlisting natural immune system functions. These drugs may be used in combination with other cancer treatments. Monoclonal antibodies are being investigated to help eliminate damaged or abnormal cells, such as cancer cells.

What cancers may be treated with monoclonal antibody drugs?

mAb treatments have been developed for some, but not all cancers. Certain types of cancer cells are more vulnerable than others to monoclonal antibody interventions. Treatments have been approved for a number of cancers, including the following: Brain cancer, breast cancer, chronic lymphocytic leukemia, colorectal cancer, head and neck cancers, Hodgkin’s lymphoma, lung cancer, melanoma, non-Hodgkin’s lymphoma, prostate cancer and stomach cancer.

What is the FDA definition of 'high risk' for COVID-19?

The FDA Fact Sheet for Healthcare Providers defines “high risk” to include additional medical conditions and factors associated with increased risk for progression to severe disease.

Will mAb clinical trials continue?

Yes. Sotrovimab is continuing to be studied in ongoing clinical trials. An analysis of safety and efficacy data at day 29 for the full population from the COMET-ICE trial is expected as early as the first half of 2021.

What is the COMET-ICE study?

It is acronym for COVID-19 Monoclonal antibody Efficacy Trial – Intent to Care Early trial in high-risk adult outpatients. It is a multi-center, double-blind, placebo-controlled, Phase 3 trial. The trial is ongoing.

Why was Phase 3 study for sotromivab stopped early?

In March 2021, the Phase 3 study for sotrovimab was “stopped early” by an independent data monitoring committee due to evidence of “profound clinical efficacy".

How many patients were included in the study?

The safety of sotrovimab is primarily based on an interim analysis from 868 patients (430 patients in the treatment arm and 438 in the placebo arm) through day 15.

What is the dosage of sotrovimab?

It is a single intravenous infusion of sotrovimab (500 mg).

What’s the composition of trial participants?

Among those studied, 63% were Hispanic or Latino and 7% were Black or African American. According to the CDC, these populations are approximately three times more likely to be hospitalised and approximately two times more likely to die of COVID.

How was efficacy measured? What was the primary efficacy measurement (or endpoint)?

It was based on was the proportion of patients who have progression of COVID-19 as defined by the need for hospitalisation for greater than 24 hours — for acute management of illness or death.

RESULTS: Interim study results demonstrated an 85% reduction in hospitalisation for more than 24 hours or death in those receiving sotrovimab — compared to placebo.

What are the most common side effects of monoclonal antibody therapy?

According to Mayo Clinic, the more common side effects caused by monoclonal antibody drugs include:

Any adverse effects?

The most common adverse events observed in the sotrovimab treatment group in COMET-ICE were rash (2%) and diarrhoea (1%), all of which were Grade 1 (mild) or Grade 2 (moderate). No other treatment-emergent adverse events were reported at a higher rate with sotrovimab compared to placebo.

The EUA includes a warning for hypersensitivity including anaphylaxis and infusion-related reactions.

In Vitro Data Indicate Sotrovimab Maintains Activity

Does it work against “variants of concern”?

Yes. The drug was found to act against all known variants of concern, including the variant from India.

GSK/Vir explained that because sotrovimab targets a conserved epitope of the spike protein that is less likely to mutate over time, it maintains activity against all known circulating variants of concern — including the variants from Brazil (P.1), California (B.1.427/B.1.429), India (B.1.617), New York (B.1.526), South Africa (B.1.351) and the UK (B.1.1.7).

GSK and Vir will continue to evaluate the ability of sotrovimab to maintain activity against new and emerging variants. The clinical impact of these in vitro variant data is not yet known. Data collection and analysis is still ongoing.

In March 2021, an Independent Data Monitoring Committee recommended that the COMET-ICE trial be stopped for enrolment due to evidence of profound efficacy.

Why is it only administered intravenously, instead of intramuscularly?

There’s an ongoing Phase 2 trial under COMET-PEAK which has two parts: to compare the safety and viral kinetics of 500 mg intramuscularly (IM) administered sotrovimab to 500 mg intravenously administered sotrovimab among low-risk adults with mild to moderate COVID-19 and to evaluate the similarity in efficacy and safety between sotrovimab manufactured by different processes.

There’s also another Phase 3 trial (under COMET-TAIL) set to kick off from June (Q2 2021) as an early treatment for COVID-19 in high-risk adults, to assess whether intramuscularly-administered sotrovimab can reduce hospitalisation or death due to COVID-19

Another Phase 3 trial (under COMET-STAR) is expected to begin in H2 2021 in uninfected adults at high risk to determine whether IM-administered sotrovimab can prevent symptomatic infection.

Sotrovimab was also evaluated in the outpatient setting in BLAZE-4, a Phase 2 trial sponsored by Eli Lilly and Company, designed to assess the safety and efficacy of bamlanivimab (LY-CoV555) alone and bamlanivimab with other neutralising antibodies, including sotrovimab, versus placebo in low-risk adults with mild to moderate COVID-19.

Was Sotrovimab administered alongside another monoclonal antibodies?

Yes. It's part of another investigation, of which there are so so many right now. An interim analysis in trial called BLAZE-4 found that 700 mg of bamlanivimab (code: LY-CoV555) made by Lilly co-administered with GSK/Vir’s sotrovimab (500 mg) demonstrated a 70% relative reduction in patients with persistently high viral load at day 7 compared to placebo.

Additionally, sotrovimab, along with VIR-7832 is being evaluated in the Phase 1b/2a National Health Service-supported AGILE trial in adults with mild to moderate COVID-19.

As a follow-up to Sotrovimab (previously VIR-7831), GSK is also pushing VIR-7832, its the second monoclonal antibody from the Vir-GSK collaboration, to be investigated as a potential COVID-19 treatment.

Note: * On April 16, 2021: Lilly requested Bamlanivimab’s single-use authorisation in the USA to be withdrawn, now only to be used with Etesevimab.