Monoclonal antibodies have revolutionized modern medicine, allowing the treatment of aggressive clinical conditions, and minimizing the risks to patients. Side effects to this class of drugs are well-established, making it simpler to manage risks and helping clinicians match each patient with a suitable antibody treatment while minimizing adverse reactions. Check our frequently asked questions (FAQs) page about monoclonal antibodies for a complete overview of all steps of this robust process for antibody generation.

Essential properties contributing to the safety of antibody therapeutics

Monoclonal antibodies are considered one of the safest classes of pharmaceutical compounds. Consequently, immunotherapy has revolutionized the treatment of many complex conditions such as cancer and autoimmune diseases.

As of December 2020, over 100 monoclonal antibodies have been approved by the FDA and EMA for the treatment of multiple diseases, reflecting the high approval rate of these compounds and their established clinical efficiency. Most of these biopharmaceuticals are produced in mammalian cells (Chinese hamster ovary cells are the most common expression system), while a minority is produced in microbial systems.

This preference towards mammalian systems despite their inherent complexity can be explained by their ability to perform human-like glycosylation. Glycans present on the Fc region of monoclonal antibodies are an important component of full-length monoclonal antibodies and are responsible for modulating important antibody functions including its immunogenicity.

The properties that make antibodies one of the safest classes of biopharmaceuticals include:

  • High selectivity – unlike small molecules, antibodies have very well-defined targets, which reduces off-target toxicity and restricts the therapeutical effect to single regions or cell types within the organism
  • Reduced immunogenicity – since therapeutic antibodies mimic molecules that are naturally produced by the organism, the chances of the immune system recognizing these molecules as foreign (and thus develop resistance) are slim. However, this property is more prevalent in humanized and fully human antibodies. Their chimeric (human-mouse) and murine counterparts are known to cause allergic reactions more frequently.
  • Long half-lives – antibodies can circulate in the patient’s system for several days allowing more infrequent dosing in comparison to other pharmaceuticals
  • Reduced risk of causing resistance – small molecules like antibiotics or antiviral drugs are notorious due to the high risk of inducing resistance (selection/mutation) in their targets. In contrast, the development of resistance to monoclonal antibodies is a rarer occurrence, making these molecules therapeutically more efficient than their smaller counterparts.

Side effects of monoclonal antibody therapy and how to minimize them

Despite being rare, therapeutic antibodies may cause side effects related to immunomodulation and infection.

Immunogenicity of monoclonal antibodies

Monoclonal antibodies, composed of a Fab (antigen-binding) and Fc region (constant domain), operate through various and often independent mechanisms in the human organism. The Fab region is responsible for binding the antigen and blocking its interaction with a ligand. In contrast, the Fc region exerts a more complex response including antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, and antibody-dependent cellular phagocytosis.

Moreover, the Fc affects the transport of monoclonal antibodies across tissues and cell walls and further regulates the circulating levels of these biopharmaceuticals. For this reason, many antibody engineering efforts have been directed to the modulation of glycans covering the Fc region to extend even more the already long half-life of these drugs.

Plus, glycosylation patterns are important for modulating important effector functions and they are often the cause behind many adverse reactions caused by the administration of these drugs.

The main adverse reactions against monoclonal antibodies often manifest in the form of acute anaphylactic (IgE-mediated) or anaphylactoid reactions (not IgE-mediated) such as serum sickness, tumor lysis syndrome, and cytokine release syndrome. These reactions can manifest locally at the site of injection or systemically which could have devastating consequences.

Due to the gravity of some of these reactions, researchers and clinicians are urging a more effective recognition and management of risk factors. Moreover, it is well-established that these reactions can be minimized by ensuring proper hydration, diuresis, premedication, and opting for slow increments in the rate of infusion/dosage of the monoclonal antibody.

Moreover, to minimize these adverse immunogenic reactions, the EMA has issued a concept paper and tentative guidelines for the assessment of immunogenicity of monoclonal antibodies (Reference for the effective version: EMA/CHMP/BMWP/86289/2010).

Exacerbation of infections by monoclonal antibodies

Monoclonal antibody therapy may exacerbate or reactivate infectious diseases due to their immunosuppressive properties.

One of the most well-known and understood reactions to monoclonal antibodies is the reactivation of tuberculosis (TB). TB is a leading cause of death among infectious diseases and it is known that monoclonal antibodies targeting the TNFα factor are prone to reactivating latent TB. For this reason, patients that will receive anti-TNF antibodies should be screened for TB before receiving the therapy.

Other infectious diseases may arise after frequent dosages of monoclonal antibodies. To counter these adverse effects, it is important to carefully consider the medical history of patients to select the patients that are less likely to experience a resurgence of latent infections.

Concluding remarks

Monoclonal antibodies are still among the safest class of pharmaceuticals due to their low toxicity, high therapeutic efficiency, and high selectivity.

Experts agree that the known adverse reactions will be increasingly better managed by the medical community as the system is bound to evolve to precision and personalized medicine approaches.

In this context, knowing the patient’s medical history and identifying risk factors will ensure each patient receives the most efficient drug with the lowest chances of causing side reactions.

  1. Hansel, T. T. et al. The safety and side effects of monoclonal antibodies. Nat Rev Drug Discov. 2010; 9(4):325-338. doi: 10.1038/nrd3003
  2. Ecker, D. M. et al. The Therapeutic Monoclonal Antibody Product Market. BioProcess International. October 30, 2020. Retrieved from: