An exatecan derivative based linker-payload platform leads to ADC products with promising anti-tumor efficacy and potential low interstitial lung disease (ILD) risk

Background: Camptothecins-based payload ADCs are attracting attentions as a promising anti-tumor modality. One of the most advanced linker-payload combinations approved and in development is Deruxtecan, which was used in a series of ADCs, including DS-8201, DS-1062. U3-1402, etc. These Dxd ADCs have shown clinical benefits in multiple solid tumors. However, life-threatening ILD can occur in 10–13% of patients treated with DS-8201. There is an interest to develop camptothecin-based ADCs that pose lower ILD risk. Material and Methods: A novel linker-payload combination L101P1003 was developed, that consists of an exatecan derivative payload P1003, a tetrapeptide linker and a maleimide moiety. DB-1303 is a HER2 ADC composed of trastuzumab biosimilar conjugated with L101P1003. The in vitro activity of P1003 was evaluated in multiple cancer cell lines. The pharmacokinetics of P1003 was assessed in vitro and in vivo. The safety profile of P1003 was assessed in rats and monkeys. The in vitro and in vivo activity, pharmacokinetics as well as toxicity of DB-1303 in monkey were evaluated. Results: P1003 showed comparable cellular activity as Dxd, 2–3-fold less potent in EC50. Unlike Dxd, P1003 is neither a substrate of cytochrome P450 enzymes, nor a substrate of BCRP or P-gP. DB-1303 showed comparable anti-proliferation activity to DS-8201 in HER2 high and medium cell lines (NCI-N87 and JIMT-1). In HER2 low PDX models, DB-1303 showed comparable efficacy to DS-8201 at the same doses. P1003 is well tolerated in animals. DB-1303 confirmed a highest non-severely toxic dose (HNSTD) of 80 mg/kg without any observation of ILD related features in pulmonary tissues in cynomolgus. Literature reports indicated that the pulmonary observations in toxicology study in cynomolgus were highly correlated with the ILD in clinic and were suspected to be related with the non-specific internalization and Dxd release in macrophages infiltrated into pulmonary tissues. To explain if the differences in toxicological findings between DB-1303 and DS-8201 are due to the difference in payload release profile, a tumor cell culture assay was developed. After incubation of the ADCs with tumor cells or monocytes at the same concentration for 48 hours, the free payload level in the culture media was detected by LC-MS/MS In a HER2 high expressing NCI-N87 cell line, the payload level of DB-1303 was comparable to DS-8201, while in a monocyte cell line, THP-1, much lower payload release was observed for DB-1303 than DS-8201. In addition, compared to DS-8201, DB-1303 was much more stable in human plasma in a 14-day experiment. Conclusions: The differences in ADC plasma stability and payload release profile from non-specific tissue may partially explain the improved safety of ADCs with linker-payload L101P1003. Currently, DB-1303 is under clinical evaluation (ClinicalTrials.gov Identifier: NCT05150691). No conflict of interest.