Novel chemical linkers for next-generation antibody-drug conjugates(ADCs)

Abstract

Antibody-drug conjugates (ADCs), monoclonal antibodies conjugated with highly potent drugs (payloads) through chemical linkers, are an emerging class of therapeutic agents for cancer chemotherapy. Their clinical success has been demonstrated by the 4 ADCs already approved by the U.S. Food and Drug Administration (FDA), and more than 60 promising ADCs now in clinical trials. Further advancement of this novel molecular platform could potentially revolutionize current strategies and regimens for treating cancers. The linker structure and antibody-linker conjugation modality critically contribute to ADC homogeneity, circulation stability, pharmacokinetic profiles, tolerability, and overall treatment efficacy. Despite extensive eŠorts to improve these parameters, most ADC linkers used to date possess linear structures, and therefore accommodate only single payloads. The clinical potential of branched ADC linkers, enabling the installation of two payload molecules, remains unexplored because of the lack of efficient conjugation methods. In addition, according to a recent report, the stability of enzymatically cleavable linkers in mouse circulation is another crucial factor for the successful evaluation of ADCs in preclinical studies. In this review, I present my research group's eŠort to develop both branched linkers and efficient conjugation methods for constructing dual-loading ADCs with high homogeneity and enhanced potency. I also present a novel tripeptide ADC linker with enhanced stability in mouse circulation. Multidisciplinary experience, approaches, and collaboration are key to successfully advancing our ADC research programs. I herein describe how my experience in the U.S. has helped to develop and manage complex biomedical research projects in a small academic laboratory setting.