Disadvantages of monoclonal antibodies (mAbs) are oftentimes briefly mentioned in passing. Monoclonal antibodies are truly marvelous biopharmaceuticals and laboratory reagents. Nonetheless we want to paint a balanced picture and dedicate this article to highlighting the limitations of mAbs, since we want to enable our readers to consider their specific needs and restraints and make informed choices about their optimal type of antibody format.
Monoclonal antibodies are highly complex biomolecules and their manufacture on scale at the highest quality can be considered biotechnological high-tech, involving the interplay of several fields of science, engineering and process technology.
Antibody drugs are the peak of such an endeavor, as the dimension of passing clinical trials to gain FDA approval is added to the equation.
Although they show low cross-reactivity, antibody therapy generally involves the administration of pharmaceuticals and hence carries the risk of side effects.
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Synthetic conjugates and especially foreign immunoglobulins (mostly murine, chimeric and humanized IgG) may overstimulate the immune system and trigger strong immune responses such as cytokine release syndrome.
Therapeutic monoclonal antibodies used in oncology may be so effective against their target antigen that the debris of destroyed cancer cells overwhelm the body and cause tumor lysis syndrome.
Traditional monoclonal antibody production is a relatively laborious process and involves the fusion of certain immune cells, namely B lymphocytes (B cells) with myeloma cells to generate immortalized hybridoma cell lines, along the lines of their developers Köhler and Milstein. Hybridoma technology needs isolated B cells that secrete specific antibodies against one single epitope. The B cells are harvested from immunized laboratory animals and growing the hybridoma cells in vivo using the ascites method requires a host laboratory animal, hence it is a relatively involved process.
To give two examples: costs for rituximab (autoimmune diseases) are about 20.000 USD 1 and for trastuzumab about 30.000 USD.2
Several modes of action have been identified for monoclonal antibodies. All of them are centered around their high affinity and high specificity towards their antigen. They may bind their antigen and thus block its interaction with other cells. Their antigen could be the binding site of a receptor or an enzyme of a signaling pathway, which would be inactivated by the mAb (checkpoint inhibitors). Another mode of action is the modulation of the patient’s immune system (immunotherapy) by engineering the glycosylation patterns of the Fc region. Unlike the Fab region, the Fc region is not involved in target protein binding, but acts as the coupling point with other immune system components like T cells.3
Afucosylated antibodies induce a very strong immune reaction towards their bound antigen in vitro (ADCC antibodies, candidates for lymphoma, not leukemia). Unfortunately, assays show that the affinity of the receptors to the Fc region is very heterogeneous among patient populations, and the high variability of responses limits the general usefulness of mAbs in these cases. Additionally, therapeutic mAbs have to compete with the patient’s own antibodies for receptor binding.
Compared to polyclonal Abs, mAbs:
Even though monoclonal antibodies have plenty of downsides, their advantages are so valuable that they outweigh the cons for many applications, especially as therapeutics.
Moreover, recent developments helped to reduce the time and cost factors of antibodies. Recombinant antibodies are manufactured using modern molecular biology methods, thus avoiding the downsides of hybridoma cell generation and their culture: long lead times, high costs and contamination risk. Recombinant antibodies are produced in CHO cell lines that can be modified at the genetic level to express the desired antibody.
Recombinant antibodies are expected to close the gap on the downsides relative to polyclonals, while extending the lead on the advantages. evitria is a leading provider for recombinant antibody production service.
What is a monoclonal antibody?
Monoclonal Antibody production
Application of monoclonal antibodies
1.Wallace ZS, Harkness T, Blumenthal KG, Choi HK, Stone JH, Walensky RP. Increasing Operational Capacity and Reducing Costs of Rituximab Administration: A Costing Analysis. ACR Open Rheuma. Published online April 21, 2020:261-268. doi:10.1002/acr2.11133
2.Drucker A, Skedgel C, Virik K, Rayson D, Sellon M, Younis T. The Cost Burden of Trastuzumab and Bevacizumab Therapy for Solid Tumours in Canada. Current Oncology. Published online June 1, 2008:136-142. doi:10.3747/co.v15i3.249
3.Armour KL, van de Winkel JGJ, Williamson LM, Clark MR. Differential binding to human FcγRIIa and FcγRIIb receptors by human IgG wildtype and mutant antibodies. Molecular Immunology. Published online December 2003:585-593. doi:10.1016/j.molimm.2003.08.004