In an article published in Future Drug Discovery, Justyna Mysliwy, Bioconjugation Team Leader at Iksuda Therapeutics, writes about the de developments in the technology of antibody-drug conjugates (ADC).[1]

ADC technology, Mysliwy writes, has been the focus of intense interest as well as pre-clinical and clinical research since it is being viewed as a sophisticated delivery system that combines the benefit of the highly specific tumor targeting of antibodies with the strong potency of a small molecule cytotoxic payload. Such an approach, in turn, reduces the likelihood of systemic exposure and off-target toxicity.

Conventional chemotherapy targets both proliferating cancer cells and normal cells and the lack of tumor specificity leads to severe off-target toxicity and limited efficacy. To overcome the limitations of chemotherapeutic agents, appreciable advances have been made in targeted cancer therapies.

Targeting cancer
While a number of antibodies therapies have been approved for the treatment of various types of cancer, and have demonstrated promising clinical benefits, in most cases, they possess modest antitumor efficacy as a single agent. Hence, the need for alternative therapies, including ADCs

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With seven approved agents, ADCs have demonstrated clear benefits for patients over standard intensive chemotherapy.[2]

Over the decades, researchers have investigated novel ways 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 cancer cells rather than normal cells, affinity-attenuated binders have been developed to improve specific targeting of cancer cells and decrease toxicities on normal cells.

In addition, so-called bispecific ADCs are being developed as a viable route to increase tumor selectivity while retaining highly potent antitumor efficacy. This includes bispecific ADCs directed against c-MET and EGFR displayed efficacious killing of EGFR and c-MET overexpressing cancer cells with reduced toxicity in normal cells expressing EGFR.

In her article, Mysliwy writes that in addition to the antibody part of the ADC, new payloads are also being evaluated. She noted that while strategies with cytotoxic payloads with lower potency and alternative mechanisms of activity exist or are being developed for targets expressed on normal cells, traditionally, payloads used in ADCs have been extremely potent. One reason is that for intracellular targets limited tumor penetration of antibodies, low-to-moderate target expression, and inefficient internalization may result in very low toxin concentrations in the cell.

Because many targets are expressed on both cancer and normal tissues, cytotoxic drugs with lower potencies, such as topoisomerase inhibitors, have been successfully applied. For example, one of the Food and Drug Administration (FDA) recently approved ADCs 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-track designation for patients with triple-negative breast cancer, small-cell lung cancer or non-small-cell lung cancer.

Other promising compounds being evaluated in pre-clinical development includes α-amanitin, which disrupts DNA transcription and causes cell death by binding to RNA polymerase II. One company, Iksuda Therapeutics, is currently working on the development of a payload with a novel protein alkylating mechanism of action.

Stability of ADCs
One of the complexities of ADC is that as a targeted delivery system, it must pass many hurdles, including blood circulation, antigen binding, and internalization. Hence, Mysliwy writes, conjugate stability is critical for drug delivery to the site of action, particularly with the development of very highly potent payloads.

In the creation of the next-generation ADCs, researchers are developing new conjugation technologies with improved stability 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.

This novel technology was used in the development of IKS01, an ADC-targeting folate receptor being developed by Iksuda that is highly effective in causing tumor regression in FRA-expressing xenograft models at doses that are well tolerated. This investigational agent was found to be significantly more active than a benchmark ADC and caused complete regressions in low/moderate FRA-expressing models.[3]

With decades of researcher and clinical trials, ADCs have really become unique calls of targeted agents. And ongoing research to identify new strategies for ADC improvement and increased the understanding of the intricacies of ADC design, are expected to lead to a rapidly growing number of approved ADC for hard to treat cancers – meeting the unmet medical needs of patients.

Justyna Mysliwy’s article is a must-read.

[1] Mysliwy J. Advancements in antibody-drug conjugate technology for cancer treatment. Future Drug Discovery 13 Mar 2020
[2] ADC Drug Map, ADC Review | Journal of Antibody-drug Conjugates. Online. Last accessed March 24, 2020.
[3]Thirlway J, Lodge A, Pelava A et al. Abstract C023: IKS01, a next-generation antibody-drug conjugate, shows target-dependent efficacy in a platinum-resistant tumor model with low levels of folate receptor α expression. Mol. Cancer Ther. 18(Suppl. 12), C023 (2019).

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