Multitude Therapeutics Highlights Breakthrough ADC Platform Featuring Exatecan-Based Linker-Payload Technology in Cancer Discovery

In the “Highlights” section of the April 2023 issue of Cancer Discovery (IF = 38.272), Dr. Avantika Gupta and colleagues from Memorial Sloan Kettering Cancer Center published an article titled “ADCs or: How I Learned to Stop Worrying and Love Chemotherapy,” commenting on a paper by Dr. Meng Xun’s team at Puzhong Biopharma, which was published in the same issue. They stated that the linker technology platform featured in this study may represent a significant milestone in enabling antibody–drug conjugates (ADCs) to overcome chemical resistance and enhance therapeutic efficacy.

The text mentions that more than 80 years ago, scientists rapidly converted warfare-grade poison gas into nitrogen mustard for the treatment of lymphoma, ushering in a new era of medical therapy for advanced cancer. With advances in chemotherapy drugs over the subsequent decades, treatment for conditions such as childhood leukemia and germ cell tumors gradually became feasible. However, due to limitations including transient antitumor efficacy, chemical resistance, and toxicity, it has remained challenging to translate these agents into therapies for the most common malignant tumors.

With the recent advancements in antibody-drug conjugates (ADCs), the field of chemotherapy has been reinvigorated. ADCs enable more precise and targeted delivery of cytotoxic chemotherapy agents to tumor cells, thereby enhancing tumor-killing efficacy while minimizing damage to non-cancerous tissues. As of early 2023, more than ten ADCs had received FDA approval, and hundreds were under development.

With the rapid advancements in antibody-drug conjugate (ADC) technology, a question has arisen: Can these effective delivery mechanisms be leveraged to deploy more potent chemotherapeutic agents against refractory cancers? Dr. Meng Xun’s team at Allpharm is attempting to answer this question in their study published in Cancer Discovery. Advances in linker-payload chemistry are poised to deliver the next qualitative leap in overcoming chemical resistance and achieving improved therapeutic responses.

An antibody-drug conjugate (ADC) consists of three basic components: a cytotoxic payload, a linker, and a biomarker-specific monoclonal antibody (mAb). Unlike conventional chemotherapy, the dose of payload delivered to tumor cells is limited to some extent by the bulky nature of monoclonal antibodies. Even when multiple payloads are attached to each monoclonal antibody, highly potent cytotoxic agents must be used to achieve antitumor effects. All currently approved ADCs utilize highly potent cytotoxic payloads, and ADCs based on TOP1 inhibitors have had a significant clinical impact in recent years.

Dr. Meng Xun’s team improved the tumor-killing potency of the payload by incorporating exatecan, a more potent TOP1 inhibitor that is also a weak substrate for MDR transport proteins, into the ADC design. In this study, the TOP1 inhibitor exatecan was integrated into the ADC architecture to leverage its enhanced antitumor activity, thereby providing a more effective chemotherapy regimen for the treatment of refractory tumors.

Exatecan has been proven to be a more potent TOP1 inhibitor than existing DXd/SN-38, while being less susceptible to efflux by ATP-binding cassette (ABC) transporters. However, its higher hydrophobicity and the formation of aggregates during antibody conjugation have limited the application of exatecan in ADCs.

A potential approach to overcoming this obstacle is the modification of linkers. Dr. Meng Xun’s team investigated how modifications to the maleimidopropyl and para-aminobenzyl (pAB) spacer affect the aggregation of antibody-drug conjugates (ADCs). A better understanding of linker chemistry enables the conjugation of antibodies to safer and more effective drugs targeting various tumor types. They observed that, compared with existing ADCs based on trastuzumab (HER2), patritumab (HER3), sacituzumab, datopotamab (TROP2), or DS-6000 (CDH6), combining modified linkers with an exatecan payload and the aforementioned antibodies generally yielded superior antitumor efficacy relative to the original ADCs.

Furthermore, while the safety of exatecan ADCs was validated in several representative animal models in this study, early-phase clinical trials remain critical for evaluating and determining the true therapeutic window of these agents.

Finally, Dr. Gupta stated that specific advances in linker and payload chemistry are propelling the field of “targeted chemotherapy” into the era of fourth-generation antibody-drug conjugates (ADCs). Continuous exploration and research into mechanisms of drug resistance provide a theoretical foundation for designing superior drugs, which hold promise for broadly improving prognoses in cancer patients. Regarding the modern application of chemotherapy, sometimes cultivating old ground can yield new fruits.