The physiochemical properties of an antibody-drug conjugate (ADC) are one key design attribute that can impacts its stability and pharmacokinetics/pharmacodynamics and are one of the key design attributes. Typically, ADCs with better hydrophilicity are less prone to aggregation, and have lower systemic clearance, and greater anti-tumor activities and thus a larger therapeutic index. However, the need to incorporate lipophilic payloads with an enhanced bystander effects has posed significant challenges to ADC and linker design, especially at drug-antibody ratios of 8 and even 16higher. Here we present a novel ADC platform that can greatly improveimproves the hydrophilicity, physiochemical stability, and pharmacokinetics of ADCs conjugated to lipophilic payloads such as exatecan, MMAE, SN38 and EErribulin. All payloads which are allare expect to exhibit strong bystander effects.By introducing PEG, polyhydroxyl and/or polycarboxyl groups, we generated hydrophilic linkers that enable site specific and, highly homogeneous conjugation of payloads to multiple prototypical antibodies at DAR 4, 8 and even 16. Compared. These ADCs were evaluated for their binding affinity, hydrophilicity, physiochemical stability, in vitro and in vivo anti-tumor activities, tolerability, and pharmacokinetics. In addition, comparisons were made with with theirthe corresponding naked unconjugated parent antibodies and conventional vedotin- and deruxtecan-based ADCs., these ADCs were evaluated for their binding affinity, hydrophilicity, physiochemical stability, in vitro and in vivo anti-tumor activities, tolerability, and pharmacokinetics. These novel ADCs were found to be stable at 37℃ for up to 30 days, after for at least 5 cycles of freeze-thaw, and at concentrations as high as 100 mg/mL, as assessed by visual inspection, hydrophobic interaction chromatography and size exclusion chromatography. Binding affinities of these ADCs to target-positive cell lines were similar to their corresponding naked unconjugated parent antibodies. These ADCs demonstrated strong tumor growth inhibition with single or repeated dosing in multiple tumor xenograft mouse models. The pharmacokinetic profiles of these ADCs are similar to those of the naked respective parent unconjugated antibodies. Assessments of ADCs using these new platform linkers in cynomolgus monkeys demonstrated showed better tolerability than ADCs using the traditional drug linkers.In summary, our novel ADC platform enables conjugation of hydrophobic payloads at high DARs as high as 8 or 16 with favorable physiochemical properties, results in robust pharmacokinetics, strong potency in vivo, and better tolerability. Therefore the potential for a meaningful therapeutic window may be realized through this novel ADC platform.

Citation Format: Haidong Liu, Wenke Qi, Lei Wang, Guobao Wang, Xinyue Chen, Julia Gavrilyuk, Tae Han, Baiteng Zhao, Xiao Shang. Novel ADC platform delivers promising in vivo activity and safety [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1405.