By Audrey Ko
Monoclonal antibodies (mAbs) are laboratory-produced proteins that mimic the action of ordinary antibodies produced by our immune system. Since the first monoclonal antibody, Muromonab, was licensed for clinical use in 1986 (Lu et al., 2020), there has been extensive research in the therapeutic effects of these molecules. As of 2019, 80 therapeutic monoclonal antibodies have been approved by the Food and Drug Administration (FDA) and became available in the market, over 30 of which are used to treat cancer (Lu et al., 2020). While chemotherapy is currently the most common treatment method for cancer patients (Cancer Research UK, (n.d.(b)), it inevitably causes severe side effects due to its non-specific toxicity to healthy tissues. Monoclonal antibodies, however, are more specific in action by targeting only tumour cells. Along with continuous research and numerous ongoing clinical trials, these antibodies have the potential to be widely applied in future cancer therapies.
Therapeutic monoclonal antibodies are categorised into 3 different types, each with diverse working mechanisms. Naked monoclonal antibodies are the most common types for cancer treatment and work in an array of ways. Some eliminate tumours by inducing antibody-dependent cellular cytotoxicity (ADCC) (Zahavi & Weiner, 2020), an immune defense mechanism where an effector immune cell actively lyses a target cell whose surface antigens have been bound by specific antibodies. Trastuzumab is a mAb used in HER2-positive breast cancer. HER2 is a transmembrane receptor that is often overexpressed on breast cancer cells (Valabrega, Montemurro & Aglietta, 2007). Upon binding of its extracellular domain to trastuzumab, the cancer cell is marked for the immune system’s attack through ADCC. Natural killer cells with Fc gamma receptors can bind to the Fc region of the mAb, causing its activation and subsequent release of perforin and granzymes (Zahavi & Weiner, 2020). These molecules collectively induce apoptosis of the cancer cell.
Signaling events in cancer cells are strictly regulated to support their rapid growth and proliferation. Proteins involved could in turn be exploited as targets for some naked monoclonal antibodies, thus disrupting normal biological process and leading to cell death. When a tumor increases in size, some area of the tumor may not be able to obtain enough nutrients and become hypoxic. Tumor cells respond to hypoxia by producing vascular endothelial growth factor (VEGF) to promote the formation of new blood vessels through a process called angiogenesis. Bevacizumab is a mAb with anti-angiogenesis effect. It binds to circulating VEGF and prevents its interaction with VEGF receptors on endothelial cells, thereby preventing blood vessel growth (Ferrara et al., 2004). Consequently, tumour cells will starve to death due to insufficient oxygen and nutrients.
The most well-known function of naked mAbs is acting as immune checkpoint inhibitors to enhance immune responses against tumors. The PD-1/PD-L1 pathway is an immune checkpoint that maintains the immune homeostasis by preventing the immune system from attacking normal body cells. The binding of programmed cell death ligand 1 (PD-L1) to programmed cell death protein 1 (PD-1) on the surface of activated T cells will deactivate their cytotoxic activity. Tumour cells take advantage of this mechanism to evade the immune response by overexpressing PD-L1 on their surface (Akinleye & Rasool, 2019), thus inhibiting T cell activity to allow their continued growth. Monoclonal antibodies reverse this inhibition by binding to either PD-1 or PD-L1, re-initiating the anti-tumour T cell response. An example would be Atezolizumab which targets PD-L1 and is an approved drug for the treatment of bladder cancer and non-small cell lung cancer (Krishnamurthy & Jimeno, 2017).
The second type of mAbs is conjugated monoclonal antibodies. A chemotherapeutic drug or a radioactive particle is attached to the antibody, which serves as a shuttle to deliver the treatment directly to cancer cells. Polatuzumab vedotin is a promising treatment for non-Hodgkin lymphoma with abnormal B lymphocytes. It consists of an anti-CD79b mAb covalently attached to monomethyl auristatin E (MMAE) which is an antimitotic agent that blocks the polymerization of tubulin (Dornan et al., 2009). CD79b is a component of the B cell receptor expressed on the surface of over 90% of B cell malignancies. After binding of this antibody-drug conjugate to CD79b, the complex will be internalized by endocytosis. Once inside the cell, lysosomal proteases will cleave the link between MMAE and the antibody, allowing active MMAE to be released (Zhao et al., 2020). They then bind to microtubules and inhibit cell division, leading to cell cycle arrest, and ultimately apoptosis.
Lastly are the bispecific monoclonal antibodies. As the name suggests, they are able to bind to 2 different antigens simultaneously. Blinatumomab is a treatment option for relapsed or refractory B-cell precursor acute lymphoblastic leukemia (Cancer Research UK, n.d.(a)). Its structure is the combination of the antigen binding region of 2 different antibodies (i.e. anti-CD3 and anti-CD19 antibodies). Blinatumomab binds to CD3 on cytotoxic T cells and CD19 which is expressed nearly ubiquitously in B cell lineage (Smits & Sentman, 2016). In this way, cytotoxic T cell and the cancerous B cell are brought to close proximity, initiating a greater immune response. When bound to the mAb, T cell activation is triggered, it releases cytotoxic granules containing perforin and granzymes, resulting in membrane perforation and lysis of the tumor cells.
There has been rapid development of monoclonal antibody cancer therapies in the past decades, contributing to the wellbeing of cancer patients. While it is evident that these “magic bullets” could effectively eliminate cancer, however just like every other therapy, there are several drawbacks associated. Monoclonal antibodies themselves are foreign molecules, when injected into the blood, an allergic reaction could be triggered resulting in hives or itching. Other common side effects include flu-like symptoms, diarrhea, and tiredness (Cancer Research UK, n.d.(b)). Besides, experiments with monoclonal antibodies carried out in vitro or using animal models showed diverse modes of action – some mAbs remain in blood rather than interacting with target antigens. Whether the same happens in human is yet to be discovered. Nevertheless, monoclonal antibodies are promising alternatives for cancer patients given their high specificity and ability to engage the host immune system to develop long-lasting effector response against tumours (Zahavi & Weiner, 2020).
References:
Akinleye, A. & Rasool, Z. (2019) Immune checkpoint inhibitors of PD-L1 as cancer therapeutics. Journal of Hematology and Oncology. 12 (1), 1–13. Available from: doi:10.1186/s13045-019-0779-5
Cancer Research UK. (n.d.(a)) Blinatumomab (Blincyto). Available from: https://www.cancerresearchuk.org/about-cancer/cancer-in-general/treatment/cancer-drugs/drugs/blinatumomab [Accessed: 22 May 2021].
Cancer Research UK. (n.d.(b)) Cancer treatment statistics. Available from: https://www.cancerresearchuk.org/health-professional/cancer-statistics/treatment#heading-Two [Accessed: 22 May 2021].
Dornan, D., Bennett, F., Chen, Y., Dennis, M., Eaton, D., Elkins, K., French, D., Go, M. A. T., Jack, A., Junutula, J. R., Koeppen, H., Lau, J., McBride, J., Rawstron, A., Shi, X., Yu. N., Yu, S.-F., Yue, P., Zheng, B., Ebens, A. & Polson, A. G. (2009) Therapeutic potential of an anti-CD79b antibody-drug conjugate, anti-CD79b-vc-MMAE, for the treatment of non-Hodgkin lymphoma. Blood. 114 (13), 2721–2729. Available from: doi:10.1182/blood-2009-02-205500
Ferrara, N., Hillan, K.J., Gerber, H.P. & Novotny, W. (2004) Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nature Reviews Drug Discovery. 3 (5), 391–400. Available from: doi:10.1038/nrd1381
Krishnamurthy, A. & Jimeno, A. (2017) Atezolizumab: A novel PD-L1 inhibitor in cancer therapy with a focus in bladder and non-small cell lung cancers. Drugs of Today. 53 (4), 217–237. Available from: doi:10.1358/dot.2017.53.4.2589163
Lu, R.-M., Hwang, Y.-C., Liu, I.-J., Lee, C.-C., Tsai, H.-Z., Li, H.-J. & Wu, H.-C. (2020) Development of therapeutic antibodies for the treatment of diseases. Journal of Biomedical Science. 27 (1), 1–30. Available from: doi:10.1186/s12929-019-0592-z
Mayo Clinic. (n.d.) Monoclonal antibody drugs for cancer: How they work. Available from: https://www.mayoclinic.org/diseases-conditions/cancer/in-depth/monoclonal-antibody/art-20047808 [Accessed: 22 May 2021].
Smits, N.C. & Sentman, C.L. (2016) Bispecific T-cell engagers (BiTES) as treatment of B-cell lymphoma. Journal of Clinical Oncology. 34 (10), 1131–1133. Available from: doi:10.1200/JCO.2015.64.9970
Valabrega, G., Montemurro, F. & Aglietta, M. (2007) Trastuzumab: Mechanism of action, resistance and future perspectives in HER2-overexpressing breast cancer. Annals of Oncology. 18 (6), 977–984. Available from: doi:10.1093/annonc/mdl475.
Zahavi, D. & Weiner, L. (2020) Monoclonal Antibodies in Cancer Therapy. Antibodies. 9 (3), 34. Available from: doi:10.3390/antib9030034
Zhao, P., Zhang, Y., Li, W., Jeanty, C., Xiang, G. & Dong, Y. (2020) Recent advances of antibody drug conjugates for clinical applications. Acta Pharmaceutica Sinica B. 10 (9), 1589–1600. Available from: doi:10.1016/j.apsb.2020.04.012
Imperial Bioscience Review 