Design, synthesis and biological evaluation of camptothecin analogue FL118 as a payload for antibody-drug conjugates in targeted cancer therapy

[Display omitted] •FL118, a potent camptothecin derivative, enhances ADC anti-tumor activity and demonstrates efficacy in Kadcyla®-resistant cell lines.•FL118-derived ADCs showed potent in vitro cytotoxicity in various cancer cell lines and achieved significant TGI in Trop2/HER2 xenograft models.•Sac-CL2A-FL118 (10) exhibited superior pharmacokinetics, higher systemic exposure vs. Trodelvy®, and NOAEL of 10 mg/kg in toxicity studies. FL118, a camptothecin derivative with dual mechanisms of action through topoisomerase I inhibition and proteasome-mediated degradation of anti-apoptotic proteins exhibits potent anti-tumor activity while remaining resistant to drug efflux transporters. This work describes the targeted delivery of FL118 to tumors via antibody-drug conjugates (ADCs) using the pH-sensitive CL2A linker. ADCs targeting Trop2, HER2, and EGFR exhibited potent in vitro cytotoxicity, with IC50 values as low as 0.025 nM in Trop2-positive FaDu cells. In vivo, Sac-CL2A-FL118 showed 130 % tumor growth inhibition (TGI) at 7 mg/kg in Trop2-expressing xenografts surpassing Trodelvy®. Pharmacokinetic evaluations revealed that FL118-ADCs exhibited a 2.6-fold increase in AUC and approximately 1.7-fold higher Cmax compared to Trodelvy®, confirming their favorable profiles and supporting their potential as a promising therapeutic approach.