Poster Presentation Royal Australian Chemical Institute National Congress 2026

An SN38 antibody prodrug conjugate strategy for cancer therapy   (#413)

Thi My Hanh Tran 1 , Shane Hickey 1 , Kirsten Bremmel 1 , Clive Prestidge 1
  1. Adelaide University , Adelaide, SA, Australia

Cancer is a global health challenge, accounting for 9.7 million deaths and almost 20 million new cases in 2022.1 Although there are many chemotherapy options clinically available, they all have limitations including adverse effects and drug resistance.2 The 10-hydroxy-7-ethylcamptothecin (SN38) anticancer drug is a potent member of the camptothecin family of topoisomerase inhibitors.3 Unfortunately clinical use of SN38 is hindered due to cytotoxic effects, poor water solubility, and the lability of the lactone ring at physiological conditions.4 To circumvent these limitations, irinotecan (a prodrug of SN38) was developed that offers improved toxicity and metabolic availability compared to SN38. Irinotecan is currently used for the treatment of metastatic colorectal and other gastro-intestinal cancers, however patients respond inconsistently, with patient genetic variability identified as a likely cause.5, 6 Our group has recently disclosed the synthesis and formulation of a novel SN38 lipid prodrug,7 that exhibits significantly improved aqueous solubility, transmembrane permeability, and cellular uptake compared to SN38. Moreover, antitumour studies showcased enhanced tumour growth inhibition properties compared to irinotecan and SN38. In the past two decades, antibody-drug conjugates (ADCs) have become a popular chemotherapy modality, as evidenced by 15 currently FDA approved ADCs and more than 200 in clinical trials.8 In April 2021, the first SN38 ADC - sacituzumab govitecan (commercialised as Trodelvy®) - was approved for use in breast cancer,9 however patients report severe side effects such as delayed-onset diarrhea. In this project, we aim to improve the safety and efficacy of SN38 therapy by incorporating our novel lipid prodrug compound into an ADC scaffold to establish a new ADC prodrug technology that offers improved potency, toxicity, and metabolic availability compared to the clinically available options irinotecan and Trodelvy.

 

 

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