Design and evaluation of ZD06519, a novel camptothecin payload for antibody drug conjugates.
Mark E PetersenMichael G BrantManuel LasalleSamir DasRenee DuanJodi WongTong DingKaylee J WuDayananda SiddappaChen FangWen ZhangAlex M L WuTruman Hirkala-SchaeferGraham A E GarnettVincent FungLuying YangAndrea Hernandez RojasSamuel O LawnStuart D BarnscherJamie R RichRaffaele ColomboPublished in: Molecular cancer therapeutics (2024)
In recent years, the field of antibody drug conjugates (ADCs) has seen a resurgence, largely driven by the clinical benefit observed in patients treated with ADCs incorporating camptothecin-based topoisomerase I inhibitor payloads. Herein, we present the development of a novel camptothecin ZD06519 (FD1), which has been specifically designed for its application as an ADC payload. A panel of camptothecin analogs with different substituents at the C-7 and C-10 positions of the camptothecin core were prepared and tested in vitro. Selected compounds spanning a range of potency and hydrophilicity were elaborated into drug-linkers, conjugated to trastuzumab, and evaluated in vitro and in vivo. ZD06519 was selected based on its favourable properties as a free molecule and as an antibody conjugate, which include moderate free payload potency (~1 nM), low hydrophobicity, strong bystander activity, robust plasma stability, and high-monomeric ADC content. When conjugated to different antibodies using a clinically validated MC-GGFG-based linker, ZD06519 demonstrated impressive efficacy in multiple CDX models and noteworthy tolerability in healthy mice, rats, and non-human primates.
Keyphrases
- metabolic syndrome
- photodynamic therapy
- cancer therapy
- diffusion weighted imaging
- diffusion weighted
- magnetic resonance imaging
- randomized controlled trial
- epidermal growth factor receptor
- high intensity
- computed tomography
- drug delivery
- open label
- adipose tissue
- induced pluripotent stem cells
- pluripotent stem cells
- metastatic breast cancer
- study protocol
- contrast enhanced