The Black Box of Anti-COVID-19 Monoclonal Antibodies: An Overview, Definitions, and Terminology

We learned on 25 January 2022 that the U.S. Federal Drug Administration (FDA) halted use of most monoclonal antibodies for COVID treatment because they do not work against the Omicron variant. This was a rather surprising announcement. Or wasn’t it?

Occasionally, we hear a comment or read a piece of news about COVID-19 treatments that seems puzzling. Do we all really understand what we are talking about? Or is it like with anything else COVID-related – words are losing their meaning, facts are not considered facts anymore, and everything today is different from yesterday? Are we deafened by the rumbles of the Tower of Babylon?

About 80 years ago, Isaac Asimov, one of the protagonists of the Golden Age of Science Fiction, made a prescient forecast. People will use scientific discoveries in the gadgets that help them in their practical lives but gradually will lose their understanding of the technology behind them. Things will become black boxes. Nobody will remember how they worked or even the meaning of their names.

Think about it: We switch on the TV with a remote, but who considers the miracle of the controller speaking to the machine and how we can instantly see what is happening at the same moment on the other side of the planet?

Have medicines like monoclonal antibodies become “black boxes” that many of us don’t fully understand? And why are there such divergent points of view relative to the Omicron variant? Let’s explore.

Questions:

What is the difference between immunoglobulins and antibodies?
What is the difference between monoclonal and polyclonal?
What is the difference between anti-viral and immunomodulatory antibodies?

Answers:

Immunoglobulins and antibodies

In fact, these are just different names for the same thing. Immunoglobulins and antibodies are special proteins produced by cells of the immune system, enabling it to see, smell, taste, and touch the immensely variable world of antigens and orient it in the chaotic multi-molecular universe of the body. More precisely: Every molecule of natural immunoglobulin can recognize one antigen for which it is genetically programmed, to bind to it and thus label it for the executive part of the immune system.

Polyclonal vs. monoclonal antibodies

To be prepared for a variety of antigens, the immune system produces practically endless numbers of varieties (or “idiotypes”) of antibodies. Cells producing the same idiotype of immunoglobulins are called clones. Except for some proliferative diseases (e.g., multiple myeloma), there is normally no prevailing clone. Antibodies produced by the body are, therefore, “polyclonal.” Even antibodies produced during infection are aimed against various antigen epitopes of the pathogen; hence, the response is never “monoclonal.” Plasma from donors who have recovered from an infection indeed contains higher amounts of polyclonal antibodies against the relevant agent and may help in the treatment of patients with this infection. But still, it is a cocktail of antibodies. Some of them may be better targeted, and some of them would be less effective. It is intuitive that a “magic bullet,” foreseen by the founders of immunology, would be rather a concentration of the most effective one.

But how can individuals acquire monoclonal antibodies when the body normally produces only a polyclonal mixture? It has to come from the lab, as a medicine.

In 1975, Georges Kohler and Cesar Milstein in the Basel Institute of Immunology made a fusion of a B-cell and a multiple myeloma cell, and created a cell able to produce monoclonal antibodies, the “hybridoma”. A myeloma component gave hybridoma immortality, and the B-cell part brought a specificity against an antigen epitope. The Nobel Prize was awarded for this discovery that substantially changed science and medicine, and since 1990, monoclonal antibodies have been used in medicine (and another Nobel Prize was awarded for that).

Monoclonal antibody treatment targets

Treatment of infections is not the only use of monoclonal antibodies in medicine. They can also be used in diagnostics, thanks to their unique ability to find the corresponding antigen and label it. And they can be used for the purification of their target compound from the mixture. But the most prominent examples of successful therapeutic use are the anticancer and anti-inflammatory ones. In oncology, monoclonal antibodies can find specific cancer markers on malignant cells and help to eliminate them, while in autoimmune diseases, the target molecules are various molecules involved in the immune response (cytokines, their receptors, cell surface proteins…). By binding to them, monoclonal antibodies can modulate the activity of the immune system and suppress inflammation.

Monoclonal antibodies in the treatment of COVID-19

The popularity of monoclonal antibodies rose tremendously after 2 October 2020, when the White House announced that the U.S. president was given an experimental “polyclonal antibody cocktail.” At that time, this cocktail was an unapproved mixture of casirivimab and imdevimab. In November 2020, it was awarded with an FDA Emergency Use Authorization (EUA) for the treatment of high-risk patients with mild to moderate disease. (Both casirivimab and imdevimab are monoclonal antibodies, and their combination does not make them polyclonal.) Their target is epitopes of the spike protein on the surface of the SARS-CoV-2 virus causing COVID-19 disease.

More anti-viral antibodies have been developed and authorized since, in the U.S., the EU., and elsewhere, mostly for treatment of mild COVID to prevent its progression to more severe stages (see table below).

Then why is there an issue with the Omicron variant, which has led to the amendment and limitations of the agreed-upon labels? Monoclonal antibodies target the specific antigen on the surface of the virus. If this antigen gets modified due to the mutation of the virus, an antibody can no longer recognize it, becomes “blind,” and loses its efficacy. This is what happened to bamlanivimab/etesevimab and casirivimab/imdevimab with regard to the Omicron variant and that’s the reason why their EUA has been temporarily halted. It is certainly advantageous when the target epitope is shared between variants including Omicron, as it seems to be the case for the recently authorized combination tixagevimab/cilgavimab. EUA was granted by the FDA for pre-exposure prophylaxis in immunocompromised patients or those with a history of severe allergic reactions to COVID-19 vaccines. Thus, tixagevimab/cilgavimab became the first monoclonal antibody product authorized for the prevention of COVID-19.

Here is an overview of all monoclonal antibodies authorized for the treatment of COVID-19: (See references links at the bottom of the page)

And what about tocilizumab? It is also a monoclonal antibody, but substantially different from the antivirals. Its target is a receptor for a cytokine called interleukin-6. Interleukin-6 is secreted in high amounts as part of the overreaction of the immune system to the viral infection (or also during a similar reaction sometimes accompanying treatment with CAR-T cells). This hyper reaction is also called cytokine release syndrome or a “cytokine storm.” Tocilizumab binds to interleukin-6 receptor and blocks its binding to the cytokine. More monoclonal antibodies targeting cytokines are under development for the treatment of COVID-19. Such immune modulation is, by its nature, not specific and does not depend on the composition of viral antigens or its mutations.

Fortunately, Omicron relatively rarely fires up the immune system to the life-endangering extent of a cytokine storm, compared to previous variants, so in that respect, the anti-cytokine treatment is less frequently needed.

A Great Success, in No Uncertain Terms

Monoclonal antibodies represent a great achievement of medical science allowing targeted treatment of various diseases beyond COVID-19. No, they have not become as obscure as a mysterious black box. But it is wise for us to remember what they are and why they are so named, to prevent more confusion and potential “panic” that might occasionally accompany the necessary regulatory changes.

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References:

Monoclonal antibodies authorized for treatment of COVID-19:

The Black Box of Anti-COVID-19 Monoclonal Antibodies: An Overview, Definitions, and Terminology

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