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Writer's pictureMaria McGovern

How Monoclonal Antibodies are Revolutionising Medicine


Monoclonal antibodies (mAbs) are a class of biological immunotherapy treatments that present a new way to target specific mutations and defects in protein structure, allowing for the treatment of a wide range of diseases and conditions, including cancer. Since the first mAb was licensed over 30 years ago, pharmaceutical interest in mAbs has grown considerably. They have become the fastest-growing type of pharmaceutical molecules with dozens of mAbs currently approved by the FDA for clinical use (Monoclonal Antibodies, 2022). In the last five years, sales of mAbs have grown faster than any other type of biopharmaceutical product. The continuing rapid development and licencing of new mABs, along with existing mAbs, are estimated to drive global sales of mAbs to nearly $315 billion by 2025 (Ecker et al., 2020). Along with their lower safety risks compared to other drug modalities, multiple proof-of-concept studies have shown that mAbs provide a rapid route for new therapeutics. This continues to drive the growth of the mAb market and as a result, mAbs have become a go-to drug against new targets (Carrara et al., 2021). 

 

What are mAbs?

The blood contains natural antibodies that are used to fight infection by combating harmful pathogens. mAbs are artificial, specified versions of these natural antibodies. They are developed in labs from just one (monoclonal) cell line with a desired specificity. Much like a natural antibody, mAbs work by recognising and binding to a specific protein on a target cell. mAbs can be specified to target cancer cells or even immune system cells. Depending on the type of cell they bind to. When they bind to cancerous cells, mAbs prompt the immune system to attack and fight those cells (Monoclonal Antibodies (mAbs), 2018). mAbs represent the intersection of traditional immunology and advanced biotechnological methods. Recombinant biotechnology and protein chemistry advances have enabled the development in the field of recombinant mAbs such as chimeric mAbs, mAb fragments, single domain mAbs and multispecific mAbs. These mAb variants could change how mAbs are produced, as they could potentially improve production yields and be more stable. They could also have clinical advantages, such as increased bioavailability, longer half-lives, targeting multiple antigens, enhanced functional activity, or alternative administration routes (Monoclonal Antibodies, 2022).

 

Figure 1: Structure of Monoclonal Antibodies (Dabhadkar et al., 2022).

Discovery and Development

The first mAbs were developed in the 1970s as scientific tools, but have since been shown to be powerful human therapeutics. In 1975, César Milstein and Georges J. F. Köhler developed a method for producing high amounts of specified monoclonal antibodies (Leavy, 2016). This method is called "hybridoma technology", and involves fusing a specific B cell, that produces antibodies, with a myeloma cell. By culturing these fused cells, they created a hybridoma cell line with characteristics of both the B cells (to produce the specific antibodies) and the myeloma cell (immortality). The resulting hybridoma cells were capable of producing identical antibodies with the same specificity, which are known as monoclonal antibodies (Scott et al., 2012). Following further development, Milstein and Köhler used this method to generate several hybridoma cell lines that produced large amounts of identical monoclonal antibodies. This was a breakthrough, and within a few years, the potential for medical uses of mAbs was discovered. Hybridoma technology was soon employed by pharmaceutical companies to develop mAb therapeutics. Milstein and Köhler were awarded a Nobel Prize in Physiology or Medicine in 1984 for their research that led to these promising treatments (Leavy, 2016).

 

In 1986, the first mAb medication, Muromonab CD3, was approved for use in humans. Muromonab CD3 is a murine (from mice) mAb that can be used to prevent kidney, liver, heart and kidney-pancreas organ transplant rejection by blocking all cytotoxic T cell function. When it was discovered, Muromonab CD3 provided a life-saving immunosuppressive therapy approach (Todd & Brogden, 1989). The first chimeric (from multiple animal sources) mAb, Rituximab, was approved in 1997 to treat low-grade B cell lymphoma. Approval and licencing of chimeric mAbs paved the way for humanised and eventually fully human mAbs (Singh et al., 2018).


Figure 2: Hybridoma Technology (Mohta, 2023).

 

How Modern mAbs Are Developed

 

Pharmaceutical development of new mAbs can occur in many ways. There is no one "best" way of approaching mAb development, but the process generally consists of several key stages. First, a suitable antigen target associated with the desired disease is selected. As in the case of mAbs used to treat cancer, identifying antigen targets will include analysing the differences in tumour vs non-tumour cell lines. Next, the target is validated by using antibodies determines differences in the expression of the antigen in tumour vs non-tumour cells, and to demonstrate that the antigen is expressed on the surface of tumorous cells. Then in vitro and in vivo screening occurs to determine any tumour-reducing effects of the antibodies. Following this, antibodies for the target antigen are generated in large amounts. This can be done through hybridoma techniques or newer technology, such as phage display and transgenic mice. Although hybridoma technology has been the most successful so far, large phage libraries may offer a more direct and comprehensive means to identify tumour-binding antibodies going forward. Once large quantities of the mAbs are produced, they are tested for specificity and efficacy (Carter et al., 2004).

 

Therapeutic Applications

mAbs have already been demonstrated to be effective in a wide variety of diseases, including oncological diseases, autoimmune disorders, and infectious diseases. In oncology, trastuzumab and rituximab have shown significant efficacy in targeting cancer cells. In immunology, adalimumab and infliximab can be used to treat autoimmune conditions like rheumatoid arthritis and inflammatory bowel disease (Shim, 2011). There are also mAbs that can combat viral infections, such as palivizumab which is used against the respiratory syncytial virus, and nirsevimab which targets influenza (Langedijk & Bont, 2023).


Figure 3: mAbs Targeting a Cancer Cell (Unknown, 2019).

The COVID-19 pandemic increased awareness of the therapeutic and prophylactic effects of mAbs against viral infections. In the emergency of the pandemic, Emergency-Use Authorisation (EUA) was given by many countries to companies that could provide mAb products for early treatment of COVID-19 at unprecedented speeds. These products were discovered, developed, manufactured, clinically tested, and approved through EUA within 10-24 months of the beginning of the pandemic. This benefited hundreds of thousands of patients and reduced hospitalisation and death, leading to an overall reduction of COVID-19 fatalities (Kelley et al., 2022).


The rapid development and approval of mAb treatments during the COVID-19 pandemic paved the way for the possibility of faster turnaround times for future mAb treatments. The pharmaceutical industry converging their collective focus on mAb processes, coupled with their existing mAb development and production facilities, along with EUA, allowed the process of mAb drug development, which usually takes up to ten years, to occur within just two years. The experience of the pandemic promises to create major changes in the speed at which mAbs go from development to directly benefiting patients (Kelley et al., 2022).


Figure 4: mAb Treatment of COVID-19 (Srakocic, 2022).

Mechanism of Action

mAbs exert their therapeutic effects through several different mechanisms, depending on their design and specific targets. The specificity of these mechanisms enables mAbs to bind with high affinity, with reduced off-target effects and drug-drug interactions. Some of these mechanisms include the neutralisation of pathogens, enhancing immune system activity, and directly modulating cellular functions. Through these mechanisms, mAbs can block pathological processes, facilitate immune recognition, or trigger the immune system's response to malignant cells (Castelli et al., 2019). For example, mAbs used in oncology treatments bind to surface receptors to prompt a signalling cascade that results in a death signal and tumour cell death. These mAbs use mechanisms such as cross-linking of surface antigen-mediated signalling leading to cell death, blocking activation signals to prevent cell growth, antibody-dependent cellular cytotoxicity (ADCC), complement-mediated cytotoxicity (CMC), altering the cytokine environment, or promoting an anti-tumour immune system response (Weiner, 2007). One of the most investigated mAbs, the anti-cancer medication rituximab, has been shown to employ the CMC mechanism. Human antibodies induce CMC, rituximab can use this mechanism as it contains a human IgG1 constant region (Weiner, 2007).


Another mechanism used by mAbs to perform their effects is tumour necrosis factor-alpha (TNF-α) inhibition. TNF is an inflammatory cytokine involved in the expression of proteins and influences cellular behaviours like proliferation and cell death (Levin et al., 2016). Adalimumab is a human, recombinant mAb that targets tumour necrosis factor-alpha (TNF-α) with high affinity. This medication has proven efficacy in the treatment of multiple autoimmune conditions, including rheumatoid arthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, Crohn's disease, and ulcerative colitis (Ellis & Azmat, 2020). Studies have suggested that adalimumab works through two different mechanisms: T-cell apoptosis and by inducing M2-type wound-healing macrophages, which is important in adalimumab’s treatment of inflammatory bowel disease as it facilitates healing of the mucosa of the bowel (Levin et al., 2016).

 

Figure 5: mAb Inhibition of TNF (Rajput & Ware, 2016).

Challenges and Future Prospects

Despite their wide-reaching effects and success, the development and production of mAbs face many challenges and difficulties. Biologic drugs are the most expensive drugs to produce, due to the necessity to use expensive living cells to produce them, their sensitivity to changes in the manufacturing process, and their structural complexity makes them difficult to characterise and determine potential clinical effects, which delays development. The high cost of production results in a higher subsequent price of mAbs to patients. Furthermore, high production costs limit competition from other companies, which normally drives down the costs of drugs (Makurvet, 2021). The high price tag of mAbs, and other biologics, can drastically limit accessibility and raise concerns about equitable healthcare distribution. One way that the price of mAbs can be reduced is through biosimilars. These are generic versions that are highly similar to the reference biological medications in their pharmacological activity, safety, and quality. Biosimilars are cheaper to make as the companies producing them do not have to cover the same development costs as the companies that create new drugs. Although biosimilars provide competition to drive costs down and provide more accessible treatments, this is only possible once the patent of the reference material has lapsed (Rehman et al., 2018).

 

Within production, there are further challenges. For example, variations between batches must be minimised. The heterogeneity of antibody-drug substances may impair the activity, efficacy, safety, and pharmacokinetic properties of the drug. Batch consistency is key to ensure compliance with pharmaceutical regulatory agencies, and quality assurance of drug products (Wohlenberg et al., 2022).

 

Figure 6: Production of mAbs (Weinstein, 2022).

Although there have been significant improvements in the ability of pharmaceutical companies to manufacture, characterize, and stabilize mAbs, there are many remaining challenges, such as analytical and stabilization issues with developing high-concentration mAbs. In order to overcome the limitations in mAb production, several mAb-based modalities are currently in development. These include antibody-drug conjugates (ADCs), fusion proteins, and bispecific antibodies (bsAbs). ADCs use the binding specificity of the antibodies to bring cytotoxic agents to the target cells. This reduces non-specific antibody binding and therefore minimises the side effects of these medications. mAb-based products and mAb derivatives are also part of the future of mAbs and may be key to circumventing some of the issues and challenges facing traditional mAbs (Goswami et al., 2013).

 

The future of monoclonal antibodies appears promising, with ongoing research focused on enhancing their development and ways to maximize their efficacy. Advances in antibody engineering, such as the development of bispecific and multispecific antibodies, aim to broaden their applications and improve treatment outcomes. Additionally, efforts are underway to optimize manufacturing processes, reduce production costs, and enhance the scalability of monoclonal antibody production. Striking a balance between innovation and accessibility remains an important consideration in furthering the field of monoclonal antibodies (Wohlenberg et al., 2022).

 

Conclusion

 

Monoclonal antibodies are undoubtedly a revolutionary medical technology. From the development of the first monoclonal antibodies to the current era of sophisticated antibody engineering, mAb drugs have changed the face of modern medicine by offering effective treatments for multiple diseases. Expanding therapeutic tools through the development of mAb derivatives and mAb-based products is also important to help alleviate issues and maximise therapeutic benefits. While researchers continue to navigate challenges and ethical considerations, the ongoing refinement of mAbs has the potential to unlock even more therapeutic possibilities and treat even more diseases.


Bibliographical References

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Carter, P., Smith, L. M., & Ryan, M. C. (2004). Identification and validation of cell surface antigens for antibody targeting in oncology. Endocrine-related Cancer, 11(4), 659–687. https://doi.org/10.1677/erc.1.00766


Castelli, M., McGonigle, P., & Hornby, P. J. (2019). The pharmacology and therapeutic applications of monoclonal antibodies. Pharmacology Research & Perspectives, 7(6). https://doi.org/10.1002/prp2.535


Ecker, D. M., Crawford, T. J., & Seymour, P. (2020). The therapeutic monoclonal antibody market. Bioprocess International, 9–14. https://bioprocessintl.com/business/economics/the-market-for-therapeutic-mab-products/


Ellis, C. R., & Azmat, C. E. (2020). Adalimumab. Europe PMC. Retrieved February 15, 2024, from https://europepmc.org/article/nbk/nbk557889


Goswami, S., Wang, W., Arakawa, T., & Ohtake, S. (2013). Developments and challenges for MAB-Based Therapeutics. Antibodies, 2(4), 452–500. https://doi.org/10.3390/antib2030452


Kelley, B., De Moor, P., Douglas, K., Renshaw, T., & Traviglia, S. (2022). Monoclonal antibody therapies for COVID-19: lessons learned and implications for the development of future products. Current Opinion in Biotechnology, 78, 102798. https://doi.org/10.1016/j.copbio.2022.102798


Langedijk, A. C., & Bont, L. (2023). Respiratory syncytial virus infection and novel interventions. Nature Reviews Microbiology, 21(11), 734–749. https://doi.org/10.1038/s41579-023-00919-w


Leavy, O. (2016). The birth of monoclonal antibodies. Nature Immunology, 17(S1), S13. https://doi.org/10.1038/ni.3608


Levin, A. D., Wildenberg, M. E., & Van Den Brink, G. R. (2016). Mechanism of action of Anti-TNF therapy in inflammatory bowel Disease. Journal of Crohn’s and Colitis, 10(8), 989–997. https://doi.org/10.1093/ecco-jcc/jjw053


Makurvet, F. D. (2021). Biologics vs. small molecules: Drug costs and patient access. Medicine in Drug Discovery, 9, 100075. https://doi.org/10.1016/j.medidd.2020.100075


Monoclonal antibodies. (2022). World Health Organization. Retrieved February 12, 2024, from https://www.who.int/teams/health-product-policy-and-standards/standards-and-specifications/monoclonal-antibodies#:~:text=Monoclonal%20antibodies%20(mAbs)%20are%20immunoglobulins,depend%20on%20other%20effector%20functions.


Monoclonal antibodies (MABs). (2018). Cancer Research UK. Retrieved February 5, 2024, from https://www.cancerresearchuk.org/about-cancer/treatment/immunotherapy/types/monoclonal-antibodies


Rehman, K., Bukhari, N. I., & Babar, Z. (2018). Equitable Access to Biosimilars: An Overview. In Elsevier eBooks (pp. 129–142). https://doi.org/10.1016/b978-0-12-811945-7.00009-9


Scott, A. M., Wolchok, J. D., & Old, L. J. (2012). Antibody therapy of cancer. Nature Reviews Cancer, 12(4), 278–287. https://doi.org/10.1038/nrc3236


Shim, H. (2011). One target, different effects: a comparison of distinct therapeutic antibodies against the same targets. Experimental & Molecular Medicine, 43(10), 539. https://doi.org/10.3858/emm.2011.43.10.063


Singh, S., Kumar, N., Dwiwedi, P., Charan, J., Kaur, R. J., Sidhu, P., & Chugh, V. K. (2018). Monoclonal Antibodies: a review. Current Clinical Pharmacology, 13(2), 85–99. https://doi.org/10.2174/1574884712666170809124728


Todd, P. A., & Brogden, R. N. (1989). Muromonab CD3. Drugs, 37(6), 871–899. https://doi.org/10.2165/00003495-198937060-00004


Weiner, G. J. (2007). Monoclonal antibody mechanisms of action in cancer. Immunologic Research, 39(1–3), 271–278. https://doi.org/10.1007/s12026-007-0073-4


Wohlenberg, O. J., Kortmann, C., Meyer, K. V., Schellenberg, J., Dahlmann, K., Bahnemann, J., Scheper, T., & Solle, D. (2022). Optimization of a mAb production process with regard to robustness and product quality using quality by design principles. Engineering in Life Sciences, 22(7), 484–494. https://doi.org/10.1002/elsc.202100172

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Medicine is multifaceted and has a profound impact on our lives, providing not only treatment but also support for our overall well-being. To get the best results, it is important to choose incredible professionals who can provide quality care. The article on https://curapaindoctors.com/back-muscle-spasm-strain/ offers useful information on managing muscle spasms and back strains.

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Cancer is one of the major fields in which monoclonal antibodies are used. By specifically targeting cancer cells or obstructing the signals that encourage their proliferation, these antibodies have completely changed the geometry dash way cancer is treated.

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Maria McGovern

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