COVID-19: Monoclonal Antibodies (mAbs) - the Bridge to a Vaccine

the anticipated winter surge of Covid-19 and possible cases of re-infections indicate that the scenario of Covid-19 could change across the world and India, including Manipur

Today, the number of COVID-19 cases in Manipur amounts to an average of nearly 230 new infections in a single day. The case mortality rate (CFR) in the state is currently about 0.6 per cent, relatively lower than that reported in other parts of India and the world. However, the anticipated winter surge of Covid-19 and possible cases of re-infections indicate that the scenario of Covid-19 could change across the world and India, including Manipur.
 
There is currently no approved drug or vaccine for Covid-19. Several vaccine candidates are in late-stage trials. Besides the promising drugs, dexamethasone and remdesivir, there is currently a novel class of treatments called monoclonal antibodies (mABs). Regeneron, Eli Lilly, Abcellera and other pharmaceutical companies are currently conducting trails for single mAb candidates or mAb cocktails.
 
A safe, effective, and affordable vaccine in wide usage may only be available by the middle of 2021 only. Meanwhile, we have to strictly adhere to standard prevention and control procedures such as use of masks, hand hygiene and physical distancing. A faint glimmer of hope may come in the form of an effective and safe monoclonal antibody, much earlier than the first vaccine. That's why we call the mAb as 'the bridge to a vaccine.' 
 
In today's column, I would like to review the status of monoclonal antibodies (mAbs) for treating Covid-19. Clearly, the frontrunners are candidates made by Eli Lilly and Regeneron, leading pharmaceutical companies. They have already reported promising results of their mAb drug trials. Other significant players in this field are Abcellera, GSK, Roche, Sanofi, AstraZeneca, Vir Biotechnology and Humanigen etc.
 
What are monoclonal antibodies (mAbs)?
 
Most of us have by now heard of convalescent plasma therapy (CPT). In this, plasma (liquid portion of blood) is obtained from people who have recovered from Covid-19 and used to treat Covid-19 patients. Convalescent plasma contains various kinds of antibodies that can bind to specific parts of SARS-CoV-2 coronavirus, e.g. the spike protein and prevents it from infecting human cells and then reproducing (making more copies of the deadly virus). An antibody is a Y-shaped protein that can bind with high affinity to a pathogen. e.g. a virus particle or parts of it such as the spike protein. Plasma of recovered individuals contain various types of anti-SARS-CoV-2 antibodies, each made by a specific kind of B cell (B lymphocyte). So, CPT uses polyclonal antibodies-many kinds of antibodies that bind to SARS-CoV-2 in different ways-to treat Covid-19 patients. Not all these antibodies are effective in eliminating the virus. Those which can are called 'neutralizing antibodies.'
 
Let's now try to understand the monoclonal antibodies. In this, we isolate the most potent neutralizing antibody from convalescent plasma. Then, scientists isolate the specific kind of B cell that produces this antibody. The genetic sequence that codes for the antibody is then integrated into Chinese hamster ovary cells. These cells are then grown in bioreactors in pharmaceutical company's manufacturing plants and used as factories to make a monoclonal antibody (mAb). To produce abundant amounts of the mAb, often the bioreactors are 2-story high. The manufacturing process involves large armies of trained manpower and at every step, care must be taken to ensure adequate supply of oxygen, nutrients, and supplements and avoid any possible contamination; for example, by pathogenic microorganisms. That's why mAbs can only be produced in limited quantities and are often very expensive! There's also another way of making mAbs, injecting SARS-CoV-2 into mice to stimulate its immune system to make anti-SARS-CoV-2 antibodies, isolate the most potent antibody (mAb) and make millions of copies of it in bioreactors. We shall consider details of that process in a future column.
 
Several biotechnology companies are racing to make the first effective mAb drug for COVID-19. The hope is that a mAb drug may arrive before a vaccine. Another attraction is that, while there are now some effective drugs for critical Covid patients, e.g. dexamethasone and remdesivir. there are currently no effective treatments for mild to moderate cases. If an effective mAb arrives soon, it could help reduce viral loads in mild and moderate Covid cases (early phase of infection) and prevent their possible hospitalizations due to critical complications such as lung damage, respiratory difficulties, heart injury, cytokine storm and coagulopathy etc.
 
An mAb drug may help treat millions of mild Covid patients and help reduce the load on the world's hospitals and also potentially save many lives. It's even anticipated that mAbs may help recovery of a fraction of severely ill patients. Some scientists are of the opinion that, mAb drugs may find use even after vaccines arrive; vaccines mayn't work in elderly, immunocompromised, and co-morbid patients whose immune systems are so weak that the vaccine mayn't elicit necessary immune responses, and, for them, the mAb drug may be the only available intervention.
 
Vaccines versus mAbs
 
There are certain key differences between a vaccine and an mAb. A vaccine 'trains' our body's immune system to raise natural antibody molecules that fight the virus, whereas an mAb is a synthetic (man-made) antibody molecule that targets a specific part of the virus in a specific way. A vaccine stimulates the immune system to produce polyclonal antibodies that bind the virus in multiple ways whereas an mAb binds a single target on the virus in a specific way. A vaccine sometimes lasts for a lifetime or years or months (Covid-19 vaccine is likely to last only for some months), whereas an mAb may last just a month or so. An mAb usually costs much more than a vaccine.
 
Let's suppose that a hunter uses darts of various shapes to hunt a wild animal. This is like the polyclonal antibody approach. Let's now pick out the sharpest and most effective dart that targets the head of the animal and use that to hunt that animal. This is the monoclonal antibody (mAb) approach. An mAb is a kind of 'stun gun' to tame (or even kill) the virus!
 
The Leading Players
 
The pharmaceutical frontrunners in the mAb race are the well-known firms, Eli Lilly and Regeneron. Both the giants have been making hectic efforts to release the world's first successful mAb drug to treat Covid-19 for the past about 6 months. 
 
Recently, Lilly reported promising results for its candidate mAb against Covid-19 (Science magazine, Sept. 16, 2020). In June, the company started  a trial of its antibody called, LY-CoV555, involving 452 volunteers, who received either a placebo or one of three different doses of the mAb. All the individuals were Covid patients with mild or moderate symptoms, who tested positive in the preceding 3 days, and who had not been hospitalized.
 
Five (5) of 302 patients who got the drug ended up in the hospital (about 1.7%). Nine of 150 patients given the placebo ended up being hospitalized (6%). That is, there was a 72% reduction in risk for hospitalization for people who received the antibody compared to those who were given the placebo.
 
The company reported that there were no serious adverse events caused by its monoclonal antibody. The Lilly drug seems a promising candidate that can treat moderate patients and prevent them from landing up in hospitals with critical symptoms. However, several keys questions remain unsettled. Whether the mAb work equally effectively in older patients as in younger ones? Would the antibody work in severe cases as in milder ones? Whether the mAb would be effective in patients on ventilators or only in pre-critical cases?
 
Meanwhile, the Lilly trial is continuing and the firm aims to enroll a total of 800 patients; the company is also trialing another candidate called LY-CoV106, which targets another site on the SARS-CoV-2 spike protein. Eli Lilly is considering approaching FDA for grant of an emergency use authorization (EUA) for its mAb drug, so that it reaches the market before the end of 2020. Meanwhile, we must keep our fingers crossed and wait with bated breath for the arrival of an mAb drug for Covid-19.
 
Shortly after Lilly's report, Regeneron also reported equally optimistic results of its mAb drug, REGN-CoV2, on Sep. 30, 2020 (Science magazine, Sept. 30, 2020). The firm's drug is a cocktail of 2 monoclonal antibodies that bind to different targets on the spike protein of the coronavirus causing Covid-19. This strategy is used with the thinking that, even if SARS-Cov-2 mutates in the near-term, one of the two mAbs can still bind and block the virus from infecting human cells.
 
The company reported data from its placebo-controlled trial with 275 asymptomatic or moderate patients. The volunteers were divided into two groups: those who had detectable levels of anti-SARS-CoV-2 antibodies in their blood and those who did not (seronegative group). The Regeneron drug had negligible effect on people who already had antibodies but exerted significant effect on seronegative patients, reducing viral loads in nasopharyngeal swabs, rapidly alleviating symptoms, and possibly helping them avoid hospitalizations.
 
Dr Myron Cohen, University of North Carolina, Chapel Hill, commented that "these are provocative results." He, however, warned that both Lily's as well as Regeneron's results are yet to be published in peer-reviewed journals. He said that more data are needed to understand how-or whether-these experimental drugs can best help Covid-19 patients. The Regeneron trail is ongoing and intends to enroll a total of 2,100 volunteers for trialing its mAb cocktail drug.
 
We can fondly hope that one mAb drug: LY-CoV555, REGN-CoV2, LY-CoV106 or another candidate, gets full approval or, at least, EUA, before the end of this year and acts as the much-needed bridge that help humankind surmount the Covid-19 challenge, before an eventual vaccine(s) arrive(s) on the scene!

The President's Medicine
 
One of the most powerful political leaders in the world, President Donald Trump, tested Covid-19 positive on Oct. 2. It's now learnt that he has since moved to Walter Reed Army Hospital, Bethesda, Maryland. It's a cruel irony that one of the most vocal Covid-deniers had to ultimately succumb to 'the tricky charms' of this wily virus. Another important lesson is that, despite the world-class facilities, control and care systems of the White House, its most prominent resident couldn't escape from the sly virus. A consequent message is that SARS-CoV-2, the coronavirus, and COvid-19, the pandemic it causes cannot still be taken lightly!
 
It is also reported that Trump has been given Regeneron's experimental mAb Cocktail drug-REGN-CoV2-that has shown promising early results but is yet to be peer-reviewed (The Guardian, Oct.2, 2020). He received a single 8 g dose of the cocktail, a combination of 2 anti-SARS-CoV-2 neutralising antibodies. Regeneron has a previous successful track record of making an mAb drug against the Ebola virus. Trump was given the drug in addition to Zn, Vit. D, melatonin, aspirin, and famotidine (a heartburn drug). If REGN-CoV2 successfully treats the US President, it might soon be dubbed "The President's Medicine." In such an eventuality, the likelihood of it getting an EUA from the US FDA will be increased manifold. However, the selective use of an experimental drug while many others are struggling with the virus can become controversial.
 
There is as yet no approved cure or vaccine for COVID-19. Meanwhile, it's likely that the number of morbidities and mortalities would continue to soar across most parts of the world including India (and Manipur). What then should we do meanwhile before the development of an approved cure or vaccine.
 
The government must strictly enforce the standard SOPs for tracing, testing, and treating potential infection cases. Within the limits of the available budget, testing must be scaled up to catch more of potential infections including asymptomatic cases. If feasible, antibody based screening (serosurveillance) may be done in infection hotspots to monitor the spread of the infection and the percentage of the population who has developed immunity against the Covid-19 virus.
 
Three kinds of hospitals or treatment facilities need to be set up: first, to treat critical Covid patients; second, to address non-Covid cases, and third, to manage long Covid 'recovered' individuals.
 
The general public must also religiously abide by the necessary control and prevention measures (use of masks, social distancing & hand hygiene etc.); we need to be a tad altruistic: please remember that you're sacrificing a little bit of your creature comforts not just to save your own life but also others' lives!
 
First Published:Oct. 4, 2020, 12:19 p.m.

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