ADC, full name is antibody-drug conjugates. It is a class of biopharmaceutical drugs designed as a targeted therapy for treating cancer. To date, a total of ten ADCs have been approved by the FDA, and more than 100 clinical trials are underway studying their effectiveness in the treatment of blood, lung, breast, brain and other cancers.
ADC technology, has become the focus of intense interest as well as pre-clinical and clinical research since it is being considered as a complex delivery system that combines the benefit of the highly specific tumor targeting of antibodies with the powerful efficacy of a small molecule cytotoxic payload. This approach, in turn, reduces the likelihood of systemic exposure and off-target toxicity.
Conventional chemotherapy targets both proliferating cancer cells and normal cells. The lack of tumor specificity results in severe off-target toxicity and limited efficacy. To order to overcome the limitations of chemotherapeutic agents, appreciable advances have been made in targeted cancer therapies.
Although many antibody therapies have been approved for the treatment of various types of cancer and have shown good clinical benefits, in most cases, they have moderate anti-tumor efficacy as a single drug. Therefore, there is a need for alternative therapies, including ADCs.
Among the several approved drugs, ADCs has demonstrated to be more beneficial to patients than standard intensive chemotherapy.
Over the past few decades, researchers have developed new methods to optimize antibody affinity, selectivity, and pharmacokinetics to improve tumor delivery.They have also searched for unique targets. However, many cancer targets are also expressed by normal cells. To improve targeting of cancer cells rather than normal cells, the researchers developed affinity attenuated binders to improve specific targeting of cancer cells and reduce toxicity on normal cells.
In addition, the so-called bispecific ADCs are being developed as a feasible way to increase tumor selectivity while maintaining a high degree of anti-tumor efficacy. This includes bispecific ADCs against c-MET and EGFR showed effective killing of cancer cells overexpressing EGFR and c-MET, and at the same time reduced toxicity on normal cells expressing EGFR.
In addition to the antibody part of the ADC, new payloads are also being evaluated. While strategies with cytotoxic payloads with lower efficacy and alternative mechanisms of activity exist or are being developed for targets expressed on normal cells, traditionally, payloads used in ADCs have been extremely effective. One reason is that because intracellular targets limit antibody penetration into the tumor, low-to moderate target expression and inefficient internalization may result in very low intracellular toxin concentrations.
Since many targets are expressed on both cancer and normal tissues, cytotoxic drugs with lower efficacy, such as topoisomerase inhibitors, have been successfully applied. For example, one of the FDA approved ADCs drug is trastuzumab deruxtecan (Daiichi Sankyo and AstraZeneca) for the treatment of breast and gastric cancer. Another drug, sacituzumab govitecan (Immunomedics), is designed to target TROP2 and was granted fast diagnosis for patients with triple-negative breast cancer, small-cell lung cancer or non-small-cell lung cancer.
Stability of ADCs
One of the complexities of ADC is that as a targeted delivery system, it must pass many obstacles, including blood circulation, antigen binding, and internalization. Therefore, binding stability is critical for drug delivery to the site of action, especially in the development of very highly potent payloads.
In the development of the next generation of ADCs, researchers are developing more stable conjugation technologies, such as ring-opened maleimides, and the introduction of non-natural amino acids containing azide handles for drug attachment. This includes the development of vinyl pyridine-based PermaLink® technology (Iksuda) which is highly selective for cysteine residues and does not undergo the retro-Michael reaction, providing stability to ADCs.
With decades of research and clinical trials, ADCs have indeed become unique targeted agents. And ongoing research aim to identify new strategies for ADC improvement and deepen the understanding of the complexity of ADC design. It is expected that more and more ADCs drugs will be approved for difficult-to-treat cancers to meet the unmet medical needs of patients .
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 Mysliwy J. Advancements in antibody-drug conjugate technology for cancer treatment. Future Drug Discovery 13 Mar 2020 https://doi.org/10.4155/fdd-2020-0007
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