This is a second article in the series on therapy options for COVID-19. We discussed Remdesivir and convalescent plasma in the previous article. In this continuation of the topic, we will discuss monoclonal antibody cocktail(s).  As you may recall, this was the third component of the POTUS Protocol.  As always, my discussion is from the very special perspective of how these drugs may (or may not) help CLL patients.

How Antibodies Work

Antibodies (also known as immunoglobulins) are “Y” shaped molecules that our immune systems produce to fight infections of all sorts.  In very simple terms, when we get infected by a bug of some sort that is circulating in the general community, our immune system fights back by first recognizing the invader – perhaps the virus has a particular little bit on its surface that stands out, looks odd, looks dangerous because the body does not recognize it. 

In case of COVID-19, it is the infamous “spike” protein on the surface of the virus that helps it attach itself to the cells of our body and thereafter gain access to the inside of the cell.  Once the invader is identified, a “mug-shot” of the virus developed as it were, this vital information is widely distributed and the body’s defenses kick in.  B-cells are a fundamental part of that defense process, they start the ball rolling.  In short order, the body produces literally billions of  “Y” shaped molecules that are specifically designed to recognize and latch on to the virus – the tips of the two arms of the “Y” are exactly right for locking on to the offending bit on the surface of the targeted virus.  Once the virus is festooned with hordes of “Y” shaped antibodies, it can no longer carry out its nasty job of penetrating our cells.  Out in the open and targeted with a huge bull’s eye and neon lights saying “kill me”, it can no longer hide from the killer cells of the body and is quickly destroyed.

If you were a strapping young person with robust immune system (you wish!), your body may quickly identify the virus and produce hordes of antibodies, nipping off the infection well before any symptoms develop.  You would then be classified among the asymptomatic infected crowd.  Infected, but no symptoms worth speaking of.  I doubt too many CLL patients would fall into this category.  But your kids and grand kids  may be among the asymptomatic-but-infected group.  They don’t have any symptoms, continue to feel invulnerable and masters of the universe, but for some time after infection, until the virus is completely destroyed in their bodies, they will continue to shed virus – a very dangerous situation for the older and more vulnerable members of their families.  You guys remember those young folks who went out partying during spring break last year, then brought back the virus to their parents and grand parents?  I wonder how many of them feel guilty about that bit of dangerous thoughtlessness now.

What if you are not quite in the prime of your life, a little bit more vulnerable?  Well, it takes a little bit longer for the body to recognize and produce the antibodies (immunoglobulins) necessary to kill the virus.  These folks develop symptoms, may get sick to varying degrees.  But as long as nothing goes seriously wrong, their immune systems eventually kill the invading virus and they recover.  At this point, their blood is teeming with lots of immunoglobulins tailored specifically to identify and target COVID-19 virus.  If these people are also of a altruistic type willing to help their fellow citizens, they would volunteer to donate their blood so hospitals can harvest their blood plasma, with its precious horde of antibodies – this is the convalescent plasma we talked about in our last article.  How many people choose to donate blood after recovering from COVID-19 infection, how many overwhelmed hospitals are ready to jump on the offer and harvest the convalescent plasma, how “rich” the plasma is in terms of the antibody concentration, who gets to the head of the line and gets one or more shots of this precious and limited supply of convalescent plasma – these are all questions that policy experts are dealing with on a daily basis.  

Now we get to the high risk crowd.  What if the infected individual has a compromised immune system?  Especially, what if the patient has a B-cell cancer such as CLL or NHL?  Once infected with COVID-19, these folks have a hard time mustering a response, producing their own home grown  antibodies necessary to fight the virus.  “High Risk” is a broad brush stroke, with a range of not-too-shabby to totally buggered-up immune responses.  Have you had CLL for a long time?  Have you had multiple therapies to control the CLL, especially therapies that target B-cells – all B-cells, not just the cancerous B-cells – over the course of your journey?  Rituxan is a classic example.  This man-made monoclonal antibody targets CD20, a protein on the surface of B-cells. After several rounds of Rituxan therapy (or combination therapies such as FCR), CLL patients have heavily depleted ranks of B-cells.  Their bodies have significantly reduced ability to produce protective antibodies when infected. 

How would you know which end of the risk spectrum you are in?  Look at your recent blood tests.  Most doctors ask for immunoglobulin levels as part of their routine monitoring.  Specifically, look for your IgG levels. These are antibodies your body would have developed against garden variety infections in the past little while.  Do you have very low immunoglobulin levels, low enough that your doctor has prescribed regular infusions of IVIG (intravenous immunoglobulins) to top up your own low and waning reserves?  If the answer is yes to the last two questions, you fall into  a high risk category.  Don’t know your IgG levels?  Well, time to ask your doctor to correct that.  Remember, communication and negotiation – your life may depend on these skills.

If you can’t make the anti-COVID-19 immunoglobulins yourself, and heavy duty convalescent plasma from generous human donors is in short supply, what can you do to protect yourself?  Here is where man-made antibody monoclonals come in.  These drugs mimic the natural antibodies that human immune systems produces when infected with COVID-19.  Unlike general IgG which have a variety of immunoglobulins targeting several pathogens, the man-made monoclonals target just one enemy: COVID-19 in this case.  That is where the “mono” comes from, a single minded focus on just one target, the spike protein of COVID-19 virus.  In addition to their single minded focus, they have the advantage in terms of dosage.  Unlike convalescent plasma, monoclonal antibodies can be at whatever concentration researchers deem safe.  

Eli Lilly’s Bamlanivimab

Bamlanivimab is a monoclonal antibody produced by Eli Lilly to treat COVID-19.  One randomized controlled trial has shown that this monoclonal antibody reduced coronavirus symptoms in patients. It also slightly reduced the number of patients who had to be hospitalized or go to the emergency room.

SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19

Background: Covid-19, which is most frequently mild yet can be severe and life-threatening. Virus-neutralizing monoclonal antibodies are predicted to reduce viral load, ameliorate symptoms, and prevent hospitalization.

Results: At the time of the interim analysis, the observed mean decrease from baseline in the log viral load for the entire population was -3.81, for an elimination of more than 99.97% of viral RNA. For patients who received the 2800-mg dose of LY-CoV555, the difference from placebo in the decrease from baseline was -0.53 (95% confidence interval [CI], -0.98 to -0.08; P = 0.02), for a viral load that was lower by a factor of 3.4. Smaller differences from placebo in the change from baseline were observed among the patients who received the 700-mg dose (-0.20; 95% CI, -0.66 to 0.25; P = 0.38) or the 7000-mg dose (0.09; 95% CI, -0.37 to 0.55; P = 0.70). On days 2 to 6, the patients who received LY-CoV555 had a slightly lower severity of symptoms than those who received placebo. The percentage of patients who had a Covid-19-related hospitalization or visit to an emergency department was 1.6% in the LY-CoV555 group and 6.3% in the placebo group.

That was apparently enough for the FDA to issue an emergency use authorization for bamlanivimab as a treatment for COVID-19 in November.  In keeping with the totally insane level of confusion we are dealing with, the National Institutes of Health later released a statement saying at present, “there are insufficient data to recommend either for or against the use of bamlanivimab for the treatment of outpatients with mild to moderate COVID-19.”

We do indeed live in interesting and confusing times. Don’t you wish the various governmental agencies speak to each other, get their guidance in the same book if not on the same page?  Several other caveats are in order.  FDA has become a lot more proactive and generous with its emergency authorizations recently, a break from tradition. How I wish the response was more robust; but as they say, I suppose it beats a kick in the head.  I am willing to bet dollars to donuts the trial did not include any CLL patients, so we have no specific information on that front.  Also, bear in mind that these folks received the drug after they were already infected with the COVID-19 virus.  

Regeneron’s COVID-19 monoclonal antibody cocktail

Regeneron’s COVID-19 antibody cocktail was part of the POTUS Protocol we discussed in our recent article, one of the three drugs President Trump was given after he was infected with the COVID-19 virus.  It is called a cocktail because it includes two drugs (casirivimab and imdevimab), not just one as in the Eli Lilly drug. It too has now been cleared for emergency use by the FDA.  (Don’t you just love the ever so easy to pronounce names of these drugs?  For what it is worth, the ending of the names “mab” is designated to label them as Monoclonal AntiBodies)

REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with Covid-19

Background: Recent data suggest that complications and death from coronavirus disease 2019 (Covid-19) may be related to high viral loads.

Methods: In this ongoing, double-blind, phase 1-3 trial involving nonhospitalized patients with Covid-19, we investigated two fully human, neutralizing monoclonal antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, used in a combined cocktail (REGN-COV2) to reduce the risk of the emergence of treatment-resistant mutant virus. Patients were randomly assigned (1:1:1) to receive placebo, 2.4 g of REGN-COV2, or 8.0 g of REGN-COV2 and were prospectively characterized at baseline for endogenous immune response against SARS-CoV-2 (serum antibody-positive or serum antibody-negative). Key end points included the time-weighted average change from baseline in viral load from day 1 through day 7 and the percentage of patients with at least one Covid-19-related medically attended visit through day 29. Safety was assessed in all patients.

Results: Data from 275 patients are reported. The least-squares mean difference (combined REGN-COV2 dose groups vs. placebo group) in the time-weighted average change in viral load from day 1 through day 7 was -0.56 log10 copies per milliliter (95% confidence interval [CI], -1.02 to -0.11) among patients who were serum antibody-negative at baseline and -0.41 log10 copies per milliliter (95% CI, -0.71 to -0.10) in the overall trial population. In the overall trial population, 6% of the patients in the placebo group and 3% of the patients in the combined REGN-COV2 dose groups reported at least one medically attended visit; among patients who were serum antibody-negative at baseline, the corresponding percentages were 15% and 6% (difference, -9 percentage points; 95% CI, -29 to 11). The percentages of patients with hypersensitivity reactions, infusion-related reactions, and other adverse events were similar in the combined REGN-COV2 dose groups and the placebo group.

Conclusions: In this interim analysis, the REGN-COV2 antibody cocktail reduced viral load, with a greater effect in patients whose immune response had not yet been initiated or who had a high viral load at baseline. Safety outcomes were similar in the combined REGN-COV2 dose groups and the placebo group. 

Meanwhile, back at the ranch…

Federal officials say monoclonal antibodies are in full supply, but patients and providers are not taking advantage of them to treat COVID-19.

In a briefing Thursday, the Department of Health and Human Services and Operation Warp Speed urged Americans to ask their doctors about the treatment to prevent severe illness and help ease the crushing burden of the pandemic on hospitals.

“We now have all the tools we need to both prevent and fight back against COVID-19,” said U.S. Surgeon General Dr. Jerome Adams. “But tools that never leave the toolbox don’t get the work done.”

The Food and Drug Administration has authorized antibodies from Eli Lilly and Regeneron for emergency use in non-hospitalized patients with mild or moderate COVID-19 who are at high risk of developing severe symptoms.

To increase that awareness and public access, HHS has launched a website that allows patients and providers to find potential locations for treatment with monoclonal antibodies. 

Since the earliest days of the pandemic, health officials have promised monoclonal antibodies would be a game-changer in the fight against COVID-19. However, a host of logistical issues and political decisions have prevented large numbers of Americans from benefiting from them, experts say.

Hospitals have limited staff available to deliver monoclonal antibodies because COVID-19 has filled their beds, and health care workers are busy delivering the first vaccinations.  

Antibodies are hard to deliver, requiring a one-hour infusion followed by one to two hours of observation. And the people who need them are at the most contagious stage of disease, making it tricky to deliver the drugs in facilities like cancer or dialysis centers that commonly deliver medication by infusion.

President Donald Trump, former New Jersey Gov. Chris Christie and former New York City Mayor Rudy Giuliani all were able to receive the treatment when they tested positive for COVID-19. 

“Although these look promising, there’s not enough conclusive evidence to know that these are having a clinical benefit,” said Dr. Rajesh Gandhi, an infectious diseases doctor at Massachusetts General Hospital and Harvard Medical School, who sits on both guideline panels.

In small clinical trials, both the Lilly and Regeneron antibodies seemed to help people stay out of the hospital.

Among a high-risk group of people recently diagnosed with COVID-19, approximately 10% of those who received a placebo ended up needing hospital care to treat their disease, compared with only 3% of those who received Lilly’s monoclonal antibody. Regeneron’s results were similar.

But the studies were so small “that it’s hard to be extremely confident in those results,” Gandhi said.


Clear as mud… you agree?

Let me see if we can bring some clarity to the situation, improve our chances of making the right decisions.  Mind you, I too am looking at a very cloudy crystal ball, at highly politicized drug evaluations from governmental agencies and healthcare experts pushing their own personal and professional agendas.  But we are facing heavy duty existential issues here and a certain amount of uncertainty is baked into the cake I suppose.  Keep that in mind as you read on.

For starters, almost all of the information on how well man-made monoclonals (either the Eli Lilly drug or the one from Regeneron) work has come from treating people who had already tested positive for COVID-19.  Would these drugs have worked better if they had been given as prophylaxis, as a way of preventing the disease in the first place?  Scientists would agree that viral load is critically important in how well a given therapy works.  It is a question of the size of the army on both sides of the battle.  High dose of battle-ready monoclonals is a generally a good thing, especially when facing just a trace amount of virus in the body, or as I would like to see it, before the virus has even entered the body.  Monoclonal antibodies hang around in the body for several months, providing protection if you do happen to get infected.  This is why IVIG infusions are typically scheduled for every 3-6 months.  

High risk CLL patients do not have a good chance of developing their own antibodies if they get infected.  They are also not likely to mount a robust immune response, develop the antibody protection they need in response to vaccines.  They are generally older, have one or more other health conditions.  They often take one or more maintenance drugs to keep their CLL under control.  Based on what I have read so far, the safety profile of either of these monoclonal antibody therapies seems pretty good.  Our guys need all the help they can get.  Has this concept of monoclonal prophylaxis been thoroughly tested and all buttoned up with no little blank spots?  Hell, no.  As I said, it is as clear as mud.  But given the dire need for extra protection for our folks, I went out on a limb and suggested prophylactic use of monoclonal antibody therapy as something worth considering.

So far we have heard from several of the CLL experts.  Some of it is second hand from their patients who asked them to comment on my suggestion. Not one of them has shuddered at my suggestion, not a single one!  There are the usual concerns, FDA approval right now is only an emergency authorization, it is only for patients already infected, we have no clinical trial data to show how these drugs would work in CLL patients.  All very valid comments.  On the bright side, a couple of experts suggested that patients are more likely to get access to these monoclonal antibodies if they touched base with their local oncologists.  Doctors use drugs “off label” all the time, well ahead of their full approval from the FDA.  And your local guy may have an easier time doing it, since he/she wont have to deal with as much red tape.

It seems I was not the only brilliant one looking to use monoclonal antibodies to prevent infection, not try and cure it after the fact.  There is a wonderful new clinical trial announced late last year:

Phase III Double-blind, Placebo-controlled Study of AZD7442 for Pre-exposure Prophylaxis of COVID-19 in Adults (PROVENT)

A Phase III Randomized, Double-blind, Placebo-controlled, Multi-center Study in Adults to Determine the Safety and Efficacy of AZD7442, a Combination Product of Two Monoclonal Antibodies (AZD8895 and AZD1061), for Pre-exposure Prophylaxis of COVID-19.

It opened in November of last year and expects to be completed towards the end of 2022.  Warp speed indeed, compared to how long it used to take to get these clinical trials going.  They plan to recruit 5,000 patients, a very robust sized trial.  It is a phase 3 trial with a placebo controlled format – gold standard for clinical trials.  They would be looking for incidence of COVID-19 infection, severity of infection, need for hospitalization as well as any adverse effects.  The clinical trial is offered at over 100 locations!  If you are interested, I strongly urge you to click on the link above and read all the details, see if you are eligible to participate. If you do become a volunteer in this clinical trial, please do share your experiences with other CLL patients.

Be well,