Q A &

EUR: What is the role of a linker in an antibody-drug conjugate?

Lorenzo Turelli: A linker is an essential component of an ADC connecting the monoclonal antibody to a cytotoxic drug. Linkers are mainly divided in two categories: cleavable and non-cleavable. We are mostly interested in cleavable linkers: motifs whose cleavage can be operated by enzymes or chemically (acidic pH, reductive conditions, etc.), as this will dictate how and when the drug will be released.

EUR: What are the main challenges in developing linkers?

LT: For cleavable linkers, the main challenge is to design a system whose cleavage takes place in the tumoral cell to avoid toxicity.

EUR: Is this an issue you’re addressing in your research?

LT: I aim to develop new types of acidcleavable linkers responsive in a very narrow pH range: stable in plasma, but rapidly cleaved in the more acidic environment of tumoral cells (pH around 5).

Once such selectivity is proved, we attach to the linker a cytotoxic drug and eventually we put in place the bioconjugation to the monoclonal antibody.

EUR: What results have you gained so far?

LT: We have recently developed a new type of acid cleavable linker which proved to be specifically cleaved in a tumoral cell, but stable in plasma. We then attached to it an highly potent drug called MMAF, prior to connecting it through a mAb by means of a specific reaction (CuAAC). This work has been recently published

EUR: Have you been able to test this?

LT: We tested this novel ADC in vitro, on a cancer cell type. After we got some good results in vitro, we then moved to an in vivo test and compared it with a commercially available ADC called Kadcyla.

We found that our new ADC was highly effective, highly potent, leading to full tumour regression within 23 days.