SN-38 is an antineoplastic drug. It is the active metabolite of irinotecan (an analog of camptothecin - a topoisomerase I inhibitor) but has 1000 times more activity than irinotecan itself. In vitro cytotoxicity assays show that the potency of SN-38 relative to irinotecan varies from 2- to 2000-fold.
SN38 is formed via hydrolysis of irinotecan by carboxylesterases and metabolized via glucuronidation by UGT1A1.
The variant of UGT1A1 in ~10% of Caucasians which leads to poor metabolism of SN-38 predicts irinotecan toxicity, as it is then less easily excreted from the body in its SN-38 glucuronide form.
SN-38 and its glucuronide are lost into the bile and intestines. It can cause the symptoms of diarrhoea and myelosuppression experienced by ~25% of the patients administered irinotecan.
SN-38 has been utilized as the cytotoxic payload in the antibody-drug conjugate (ADC) sacituzumab govitecan. Unlike ADCs that employ ultra-toxic payloads with picomolar IC50 values, SN-38 is considered a moderately toxic agent with IC50 in the nanomolar range, potentially allowing for a lower off-target toxicity profile.
In sacituzumab govitecan, SN-38 is conjugated to an anti-Trop2 antibody via a cleavable CL2A linker, achieving a high drug-to-antibody ratio (DAR) of approximately 7.6. This high DAR allows for efficient delivery of the chemotherapeutic agent to tumor cells. The cleavable linker also facilitates the release of SN-38 in both the extracellular space and the cytoplasm. Once released, SN-38's membrane permeability enables it to diffuse out of target cancer cells and exert cytotoxic effects on neighboring cells regardless of their Trop2 expression status, a phenomenon known as the "bystander killing effect".