MONOCLONAL ANTIBODIES: What are they? What do they do?

This is a difficult subject to write about. Difficult because to understand it, you must possess basic knowledge of the immune system and of the broader topic, immunology. In the blog, “The Lymphatic System and Lymphomas:…” some basic information was presented, but the subject is still very complex. Monoclonal Antibodies (MAb’s) are protein substances artificially produced in the laboratory, that mimic natural antibodies. Natural antibodies are produced when an antigen (a foreign invader-virus, bacteria, allergen, etc.) attacks the body in an attempt to cause illness or damage normal cells. Natural antibodies remain in the immune system and prevent re-infection upon reexposure. 

What produces natural antibodies? The immune system makes natural antibodies in the  “organs” of the system. The bone marrow, spleen, lymph nodes, thymus gland, and skin are the lymphatic “organs” that produce natural antibodies. Each “organ” contains a type of white blood cells which are components of the body’s defense mechanism. Neutrophils, lymphocytes, and monocytes (or macrophages) are the important WBC’s of the immune system. Lymphocytes, the primary immune cell, are divided into 3 types—T-cells, B-cells, NK cells. 

It’s B-cell lymphocytes that produce Monoclonal antibodies. COVID-19 antigenic protein material (just like the protein that causes disease) is exposed to B-cells grown in tissue culture. The end result is a clone antibody that has the same function as natural antibodies. In their “manufactured form,” MAb’s are then given to the patient through an IV infusion. MAb’s trick the body into believing they are natural antibodies.

MAb’s work by two mechanisms: 

1. MAb’s are specifically designed to recognize COVID-19 virus antigen when it enters the body and attack and destroy it.
2. If not destroyed, the MAb’s will “lock onto” the virus proteins and prevent them from attacking healthy cells. 

The major therapeutic advantage for MAb’s is their specificity. Specificity means MAb’s are produced to attack a specific antigen, in this case, COVID-19.. They only attack that particular invader and spare harm and damage to uninvolved organs and cells. Toxic, harmful effects are thus lessened or eliminated. An analogy would be to shoot a tin can off a fence post with a rifle, not a shotgun. The can has been hit without damaging the fence post.

MAb’s against COVID-19 are used for post-exposure prophylaxis and for the treatment of mild to moderate COVID-19 cases in patients at risk of developing more severe disease. So if you’ve been exposed to someone with COVID-19 and are at high risk of severe disease (obesity, heart disease, diabetes, debilitated state, etc.), you’re a candidate for Monoclonal Antibody infusion. 

The February 1 issue of JAMA, which I just received, has an interesting study on MAb’s. Researchers at 122 sites in the U.S., Romania, and Moldova studied 314 patients who tested positive for COVID-19. 204 of them were asymptomatic and had no COVID-19 serum antibodies. Half were given shots of two MAb’s (casirivimab, imdevimab) and half placebo. The MAb group were “significantly prevented [from] progression to symptomatic disease compared with placebo.” This study demonstrates the profound effect MAb’s have on preventing clinical disease.

Early in their existence, MAb’s were used to treat autoimmune diseases. Rheumatoid Arthritis, Crohn’s disease, and Ulcerative Colitis were the most common entities treated, and very successfully at that. Psoriasis, Psoriatic arthritis, and Ankylosing Spondylitis treatments came later as did treating various cancers. In 2017 (old data), MAb’s had been “approved” for 30 “targets”, most of them cancers, but that number has increased.

Monoclonal Antibodies are now called “magic bullets,” and have been termed “the new backbone of the pharmaceutical industry.” They work because they are a reproduction/replication/clone of natural substances produced within the body. They have excellent “target selectivity” meaning they hit the target straight on with no toxic effects. Inflammatory diseases and cancer are their major uses. 

Monoclonal Antibody technology is the collaboration of Molecular Biology, Immunology, and Protein Engineering scientists who came together to develop a new product that improves outcomes for terribly destructive diseases. Have you ever seen what rheumatoid arthritis can do to a person’s hands and feet? Or how miserable Crohn’s disease patients are? These drugs are a godsend for these folks. 

MAb’s are expensive and require an IV infusion given at regular intervals at an infusion clinic. Regeneron pharmaceuticals makes casirivimab and imdevimab approved for treating COVID-19 symptoms and for post exposure prophylaxis. But Omicron is resistant to this combo!

Eli Lilly makes Bamlanivimab and etesevimab, both of which have had good results for post-exposure prophylaxis and treatment.

GlaxoSmithKline’s sotrovimab is effective “against all Omicron spike protein mutations.” 

Astra-Zeneca’s EVUSHELD was the first MAb given Emergency Use Authorization by the FDA for preexposure prophylaxis. That means, if you’re immunocompromized and do not develop antibodies to a COVID vaccine, for disease prevention, you can receive two shots in the arm (Tixagevimab and Cilgavimab) in lieu of vaccination. Also, if you’re at risk of, or have had a severe reaction to, the COVID vaccine, you’re a candidate. Also, if you have no B-cells, or are on high-dose steroid therapy, you’re eligible. 

“All approved MAb’s are effective against alpha, beta, gamma, and delta variants.” 

Despite this, MAb’s are not a substitute for vaccination nor should they be given to healthy people who don’t want to be vaccinated. MAb’s have an expanding range of clinical applications and changes are occurring rapidly. They are being used as components of diagnostic clinical laboratory tests and are also effective for treating cholesterol and metabolic bone disease. 

The American public doesn’t yet understand the benefits of Monoclonal antibodies and regards this treatment as an alternative to vaccination. It’s not! If it is used in lieu of vaccination, because being obese or having heart disease is not enough to qualify for MAb’s. If, however, you have no natural antibodies after 3 shots of vaccine, MAb’s are your best hope. 

Dr. G’s Opinion: Monoclonal antibodies are the penicillin of today’s generation. Doctors have seen how effective they are in treating RA, Crohn’s, and UC. They are capable of completely relieving symptoms. With time and more development, it’s possible many more indications will be found, and many enigmatic diseases will be eliminated. But for the present, controlling COVID-19 is enough of a task!

Familiar names of MAb’s: Cosentyx, Stelara, Remicade, Humira, Tremfya, Emgality, Repatha, Fasenra, Avastin, Prolia, Dupixent, Taltz, Opdivo, Xolair, Ketruda, Entyvio to name a few seen in TV ads.

References: NEWS AND ANALYSIS. Rubin R. Questions remain about who will get monoclonal antibodies for COVID-19 preexposure prophylaxis. JAMA 2022 Jan 18;327(3):207-208.

Understanding monoclonal antibodies. BMJ 2007;45(7).

Shepard HM, Phillips GL, Thanos CD, Feldman M. Developments in therapy with monoclonal antibodies and related proteins. Clin Med 2017;17(3):220-232.

Nelson PN, Reynolds GM, Waldron EE, Ward E, Giannopoulos K, Murray PG. Monoclonal Antibodies. J Clin Pathol: Mol Pathol 2000;53:111-117.

O’Brien MP, et al. (37 others) Effect of subcutaneous Casirivimab and Imdevimab Antibody combination vs Placebo on development of symptomatic COVID-19 in early asymptomatic SARS-CoV-2 Infection. A randomized clinical trial. JAMA 2022 Feb 1;327(5):432-441. 

Editorial: Li JZ, Gandhi RT. Realizing the potential of Anti-SARS-CoV-2 Monoclonal Antibodies. JAMA 2022 Feb 1;327(5):427-428.