Unlocking the Potential of SGN-CD70A: Overcoming Drug Resistance in RCC and NHL through Targeted DNA Damage

CD70, a protein from the tumor necrosis factor family, is found in various cancers such as renal cell carcinoma (RCC) and non-Hodgkin lymphoma (NHL), but not typically in normal tissues except for specific immune cells. This makes it a promising target for antibody-drug conjugates (ADCs). The study highlights the effectiveness of SGN-CD70A, a new ADC that uses a CD70-targeting monoclonal antibody linked to a potent DNA cross-linking agent, pyrrolobenzodiazepine (PBD). SGN-CD70A has shown to be more effective than other CD70 ADCs, even in drug-resistant cancers.

The research delves into the mechanism behind SGN-CD70A's potency, revealing that it triggers double-strand DNA breaks (DSBs), which is an early indicator of its cytotoxic effect on cancer cells. The study used several cancer cell lines and monitored DNA damage through immunofluorescence assays with antibodies specific to proteins involved in DNA repair pathways. The treatment with SGN-CD70A resulted in a rapid increase in DNA damage markers, similar to the effects of radiation.

Furthermore, the study observed an activation of the DNA damage response, evidenced by the phosphorylation of proteins ATM and BRCA1, which are key in the cellular response to DSBs. Ongoing work aims to validate these findings in xenograft models and to develop biomarkers for clinical studies, such as pH2A.X, pChk1, and pChk2, which could potentially be used to monitor the effects of SGN-CD70A in future clinical trials.

The findings were presented at the 105th Annual Meeting of the American Association for Cancer Research and published in the Cancer Research journal.