HER2-Targeted ADCs: At the Forefront of ADC Technology Development

Abstract

Ado-trastuzumab emtansine, referred to as trastuzumab-MCC-DM1 or T-DM1, was the first antibody drug conjugate (ADC) approved for HER2 positive metastatic breast cancer. This chapter reviews the development of trastuzumab-MCC-DM1, summarizes novel anti-HER2 antibody drug conjugate technologies in clinical trials, and discusses future directions of these technologies beyond targeting HER2. In an effort to improve the efficacy of trastuzumab a panel of drug linkers were conjugated to the anti-HER2 antibody and compared in preclinical experiments. In the hallmark phase III EMILIA trial treatment with trastuzumab-MCC-DM1 led to significantly longer median survival compared to the standard of care lapatinib and capecitabine in patients with 2nd line HER2 positive metastatic breast cancer. Subsequently, multiple anti-HER2 ADCs were generated with different ADC platforms allowing a comparison of different drug linkers, drug to antibody ratios, site-specific antibody drug conjugates, and biparatopic antibody drug conjugates. Anti-HER2 antibody drug conjugates currently in clinical testing are described. Promising early clinical data are emerging from some of the ADCs employing novel technologies. Future directions including bispecific antibody drug conjugates directed against HER2 and another target are discussed. Ultimately the goal is to generate clinical candidate ADCs that can improve patient outcomes. Comparison of anti-HER2 ADCs will inform how novel ADC technologies can be applied beyond HER2 to other cancer associated antigens.