Discovery research and translation science of trastuzumab deruxtecan, from non-clinical study to clinical trial

Abstract

An antibody-drug conjugate (ADC) is a biological drug that binds a drug to a monoclonal antibody via an appropriate linker. ADCs use antibodies to selectively deliver a potent cytotoxic agent to tumor cells, thus drastically improving the therapeutic index of chemotherapeutic agents. We discovered trastuzumab deruxtecan (T-DXd) via study of ADC linker-payload technology that combined a DNA topoisomerase I inhibitor with an anti-human epidermal growth factor receptor 2 (HER2) antibody. T-DXd achieves a high drug-to-antibody ratio with homogeneous conjugation and is highly potent against heterogeneous tumors via the bystander antitumor effect. It is also considered to mitigate safety concerns in systemic circulation due to the linker-payload stability. The non-clinical profile of T-DXd was assessed and its pharmacological advantages were evaluated by in vivo xenograft studies. T-DXd was confirmed to be a valuable therapeutic tool with strong potential to treat breast cancer and other HER2-expressing cancers in a clinical setting. Indeed, T-DXd was recently approved for the treatment of patients with HER2-positive unresectable or recurrent breast cancers in the US, Japan, EU, UK, and Canada and those with HER2-positive unresectable or recurrent gastric cancers in the US and Japan. Highlights 1. The key features of trastuzumab deruxtecan (T-DXd) are its high potency of payload, high drug loading, linker-payload stability, tumor-selectively cleavable, and bystander antitumor effect. 2. The non-clinical profile of T-DXd indicated its pharmacological advantages in xenograft mouse models with a wide range of HER2 expression levels and in a xenograft mouse model grafted with heterogeneous tumor tissues. 3. Safety, tolerability, pharmacokinetic profile, and efficacy of T-DXd were assessed in a clinical trial. In the DESTINY-Breast01 study, overall response rate of 60.9% and median progression-free survival of 16.4 months were achieved (cut-off date: August 1, 2019).