By Helen Luojia Zhang
Traditional chemotherapy and radiotherapy destroy many types of healthy cells in addition to targeted cancer cells, leading to serious side effects. Antibody-drug conjugates (ADCs) are a class of drug designed as a targeted therapy that specifically deliver the cytotoxic payload to cells that express the target antigen of interest (Khongorzul et al., 2020). ADCs have made great improvements upon tissue specificity and could potentially increase the therapeutic index of antineoplastic agents. To date, nine different ADCs have been approved as cancer treatments and many more are currently in preclinical and clinical trials (Drago, Modi & Chandarlapaty, 2021).
The earliest idea of ADCs can be traced back to 1913 when Paul Ehrlich proposed the concept of targeted delivery of toxic compounds to certain cells (Strebhardt & Ullrich, 2008). After a few decades, scientists manage to link methotrexate, a cytotoxic agent, to an antibody for leukaemia cell targeting (Drago, Modi & Chandarlapaty, 2021). Later, advances in hybridoma technology allowed the large-scale production of monoclonal antibodies (mAb), which had a profound effect on ADC development. The first clinical trial of ADCs for cancer treatment began in the 1980s. But it was not until 2000 that the first ADCs known as gemtuzumab ozogamicin were approved by the FDA.
The key components of modern ADCs include a mAb that binds a specific tumour-associated antigen, a cytotoxic payload that induces target cell death, and a linker. Each of the components require careful optimisation to achieve a desirable therapeutic effect. An ideal mAb target would be cell surface proteins that are highly expressed in cancer cells but absent or have limited expression in normal tissue. This allows ADCs to deliver highly cytotoxic drugs directly to tumour cells without affecting other healthy cells. In addition to tumour specificity, target turnover rates and internalization are other factors that need to be considered when choosing mAb targets (Drago, Modi & Chandarlapaty, 2021). The connecting linker is also crucial for pharmacological and clinical properties of ADCs. It has to be stable enough to ensure the cytotoxic agents remain firmly attached to the mAb when circulating in the plasma to avoid any systemic toxicity due to premature release of the drug (Jain et al., 2015). Meanwhile, it is required to efficiently release the cytotoxic payload once it has been internalised into a cancer cell. Besides, high cytotoxicity of the payload is essential to achieve therapeutic efficacy since only a small fraction of the administered dose of ADCs could reach target cells. The drug-to-antibody ratio (DAR) is the number of cytotoxic payloads attached to the antibodies. It is important to optimise DAR value, as low DAR might reduce potency while high DAR could increase toxicity (Sun et al., 2017). The average DAR of most current clinical stage ADCs is limited to 3-4.
The mechanism of action of ADCs is quite complicated and diverse depending on different types of linkers and payloads used. Following administration, ADCs circulate in the bloodstream and diffuse towards target cells with specific antigen. The antibody binds to target antigen on tumour cells before being internalised into the cell together with the payload via clathrin-mediated endocytosis (Chau, Steeg & Figg, 2019). Then the ADC-antigen complex is transported along the endocytic pathway towards lysosomes where the linker between the antibody and the drug will be cleaved, enabling release of the drug from their mAb carriers. The released cytotoxic agents could diffuse throughout the cell to exert effect on its target substrates, such as tubulin or DNA minor groove, ultimately leading to cell death. Hydrophobic drug molecules could also pass through the plasma membrane and take its effect upon neighbouring cells in a process known as the bystander effect.
ADCs provide promising new options for cancer treatment by integrating the effect of highly potent cytotoxic agents and antibodies. Technological advances allow new generations of ADCs to evolve, which may provide enhanced target specificity and payload potency. Studies have shown that some ADCs have notable activity against treatment-refractory cancer (Drago, Modi & Chandarlapaty, 2021). However, there are still limitations of this type of therapy. These include leaky systemic toxicity or off-target toxicity, potentially due to unstable linker and expression of target antigen on healthy cells. Also, some cells may evolve mechanisms of resistance to ADCs. Further research and clinical development are required to overcome those issues and to enhance the anticancer efficacy of ADCs.
References:
Chau, C. H., Steeg, P. S. & Figg, W. D. (2019) Therapeutics Antibody-drug conjugates for cancer. The Lancet. 394(10200), 793-804. Available from: doi: 10.1016/S0140-6736(19)31774-X
Drago, J. Z., Modi, S. & Chandarlapaty, S. (2021) Unlocking the potential of antibody–drug conjugates for cancer therapy. Nature Reviews Clinical Oncology. 1-18. Available from: doi: 10.1038/s41571-021-00470-8.
Jain, N., Smith, S. W., Ghone, S. & Tomczuk, B. (2015) Current ADC Linker Chemistry. Pharmaceutical Research. 32(11), 3526-3540. Available from: doi: 10.1007/s11095-015-1657-7.
Khongorzul, P., Ling, C. J., Khan, F. U., Ihsan, A. U. & Zhang, J. (2020) Antibody Drug Conjugates: A Comprehensive Review. Molecular Cancer Research. 18(1), 3-19.
Strebhardt, K. & Ullrich, A. (2008) Paul Ehrlich’s magic bullet concept: 100 years of progress. Nature Reviews. Cancer. 8(6), 473-480. Available from: doi: 10.1038/nrc2394.
Sun, X., Ponte, J. F., Yoder, N. C., Laleau, R., Coccia, J., Lanieri, L., Qiu, Q., Wu, R., Hong, E., Bogalhas, M., Wang, L., Dong, L., Setiady, Y., Maloney, E. K., Ab, O., Zhang, X., Pinkas, J., Keating, T. A., Chari, R., Erickson, H. K. & Lambert, J. M. (2017) Effects of Drug-Antibody Ratio on Pharmacokinetics, Biodistribution, Efficacy, and Tolerability of Antibody-Maytansinoid Conjugates. Bioconjugate Chemistry. 28(5), 1371-1381. Available from: doi: 10.1021/acs.bioconjchem.7b00062.
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