ADCs Are “Legos,” Customize Cancer Treatment By Target, Safety

Antibody-drug conjugates (ADCs) are transformable, allowing for more targeted treatment across biomarkers and cancer types and changing the safety profiles of each therapy, according to Paolo Tarantino, MD, PhD, a clinical research fellow at Dana-Farber Cancer Institute.

In an interview with Oncology Nursing News at the 2025 International Congress on the Future of Breast Cancer East, hosted by Physicians Education Resource LLC®, Tarantino compared ADCs to Lego blocks in that you can switch out the antibody, linker, and payload to create unique therapies, altering each one’s target and associated adverse events (AEs). According to Tarantino, each part plays a unique role in the composition of ADCs.

The payload may determine cross-resistances, said Tarantino. For that reason, it has a part in determining the sequencing of ADCs. Likewise, the linker largely dictates the safety profile of an ADC. If a linker is unstable, the AEs associated with the ADC will resemble chemotherapy-related AEs; however, if the linker is more stable, the drug’s safety profile will more closely resemble the antibody component of the ADC.

The antibody, Tarantino explained, targets the treatment. For this reason, certain antibody components are better suited for certain cancer types. For instance, an antibody that targets HER2 would be best suited for breast cancer, while a tissue factor pathway inhibitor would be more appropriate for the treatment of patients with ovarian cancer.

Transcript

I consider ADCs like Legos. You can switch or change every piece, and this leads to major differences in clinical profile. Each of the 3 main pieces—antibody, linker, payload—are extremely important in a different way. The payload is important because it’s the one that can lead to cross-resistance. If you use a topoisomerase I inhibitor ADC, after that, if available, you may want to think of something different, like a microtubule inhibitor ADC. In terms of resistance, you may want to switch the payload.

The linker is very important for the stability of the ADC. Very unstable linkers tend to lead to a lot of chemotherapy-related adverse effects [AEs] like alopecia, fatigue, neutropenia, whereas very stable ADCs totally switch the toxicity profile toward the antibody, so you see less of the chemotherapy-related AEs, but more of the antibody-related.

With TROP2 inhibitor ADCs, you may start seeing some stomatitis or rash, and with HER2-targeting ADCs, and some cardiotoxicity. It’s very important to understand that ADCs are placed on a stability continuum, and the linker usually determines the place on this continuum where the ADC is.

Finally, the antibody is critical for the type of disease you’re treating. We know that HER2 ADCs are key for breast cancer, along with TROP2 ADCs. Nectin-4 ADCs treat urothelial cancer, tissue factor ADCs treat cervical cancer, and we are [continuing to learn] more. It’s very hard to tell which one of the 3 pieces is most important, but it’s important to understand that each one of them has important repercussions and to learn the repercussions of each, which is very important in oncology.

This transcript has been edited for clarity and conciseness.