Monoclonal antibodies (mAbs) are antibodies that are all made from the same line of identical B cells. Therefore, they bind to the same epitope on the same antigen, and attract the same component of the immune system, initiating a similar immune response depending on the environment.
Monoclonal Antibodies attacking COVID-19 Virus. Image Credit: MattLphotography/Shutterstock.com
Technology has existed for a relatively long time. The use of myeloma cell lines to form hybridomas with B cells was first discovered in the 1970s, and in 1988 the technology was humanized by Riechmann et al. to eliminate adverse reactions in patients, allowing its use in therapy.
However, there are still major advancements being made in the field, due to the wide-ranging applications of mAbs across different medical fields.
Cancer immunology
A key target for cancer immunotherapy is immune checkpoints. These have a key role in regulating the immune system, and in cancer cells downregulate the immune response. Some important checkpoints for cancer cells include CTLA-4, PD-1, and PD-L1.
The development of new mAbs against different cancers has ensured immunotherapies remain an effective tool against cancer, as resistance to older immunotherapies has been demonstrated. It has also contributed to increased survival rates and allowed others to live for longer.
In 2018 Tasuku Honjo and James Allison were recognized for separately identifying and cloning PD-1 and CTLA-4 respectively by being jointly awarded the Nobel Prize in Physiology and Medicine. This work was key in identifying these cell-surface proteins that are critical to the survival and growth of a tumor.
mAbs have also been a useful tool against HER2-positive breast cancer. Tumors that express the HER2 protein are generally overly aggressive, and patients with this type of cancer often experience recurrence of cancer and lower survival rates.
However, HER2 has also been shown to be an effective target for immunotherapy. For example, one mAb binds to the extracellular component of HER2 and inhibits interactions with receptors that contribute to the blocking of cell growth inhibition.
A new anti-HER2 mAb is currently undergoing phase III clinical trials assessing its clinical efficacy. It binds the same HER2 epitope as the existing mAb immunotherapy, both of which inhibit transmembrane signaling pathways.
It has demonstrated enhanced cytotoxic activity against HER2+ cancer cells compared to the existing mAb, increasing T cell-mediated killing. It has also shown marginal improvements in progression-free survival.
How Monoclonal Antibodies Treat Cancer
Inflammatory disease
The use of immunotherapy against inflammatory bowel disease has proved to be a breakthrough for patients with both Crohn’s disease (CD) and ulcerative colitis (UC).
This has been a result of the identification of some of the mechanisms by which chronic inflammation in the gut occurs. Finding specific antigens involved in molecular pathways allows mAbs to be generated against those antigens.
One example binds α-4 β-7 integrin molecules on lymphocytes specific to the gut. This prevents them from migrating into the gut and contributing to the inflammation of the intestine, and as the antigen is only found on lymphocytes in the gut it does not compromise immune response elsewhere in the body.
It has shown clinical remission rates of 35% and 37% respectively for CD and UC, demonstrating its efficacy for use in clinical practice. Although it should be noted that both cohorts had high rates of prior immunotherapy (90% and 73% respectively), this illustrates the complexity of conducting clinical trials for long-term chronic diseases.
Another example binds the P40 subunit of IL-12 and IL-23, interrupting the activation of different components of the immune response.
IL-12 is important in the activation of natural killer cells and cytotoxic T cells, while IL-23 is an important proinflammatory cytokine. Therefore, Ustekinumab helps to limit the destruction of intestinal cells targeted in chronic inflammatory disease.
Various monoclonal antibodies are currently undergoing clinical trials, with three coming close to approval for clinical use. Other trials are investigating different methods of administering mAbs, for example, subcutaneous delivery of some mAbs may maintain efficacy while reducing costs.
Conclusion
As more discoveries are made about molecular mechanisms of inflammatory disease and different cancers, as well as others such as autoimmune disease, more potential molecules are identified for potential targeting. This allows mAbs to be developed against epitopes on these molecules.
The high specificity of mAbs will ensure they remain useful tools, particularly against chronic disease where effective treatment is lacking, as has been shown in inflammatory bowel disease. Further understanding of the immune response will also contribute to the research of monoclonal antibodies in the future.
References
- Costa, R. L. B. and Czerniecki, B. J. (2020) ‘Clinical development of immunotherapies for HER2+ breast cancer: a review of HER2-directed monoclonal antibodies and beyond’, npj Breast Cancer. doi: 10.1038/s41523-020-0153-3.
- Li, Z. et al. (2018) ‘Recent updates in cancer immunotherapy: A comprehensive review and perspective of the 2018 China Cancer Immunotherapy Workshop in Beijing’, Journal of Hematology and Oncology. doi: 10.1186/s13045-018-0684-3.
- Riechmann, L. et al. (1988) ‘Reshaping human antibodies for therapy’, Nature. Nature, 332(6162) pp. 323–327. doi: 10.1038/332323a0.
- Tamilarasan, A. G. et al. (2019) ‘Recent advances in monoclonal antibody therapy in IBD: Practical issues’, Frontline Gastroenterology. BMJ Publishing Group, 10(4), pp. 409–416. doi: 10.1136/flgastro-2018-101054.
Further Reading