Novel development strategies and challenges for anti-Her2 antibody-drug conjugates

Antibody-drug conjugates (ADCs) combining potent cytotoxicity of small-molecule drugs with the selectivity and excellent pharmacokinetic profile of monoclonal antibody (mAb) are promising therapeutic modalities for a diverse range of cancers. Owing to overexpression in a wide range of tumors, human epidermal growth factor receptor 2 (Her2) is one of the most utilized targeting antigens for ADCs to treat Her2-positive cancers. Owing to the high density of Her2 antigens on the tumor cells and high affinity and high internalization capacity of corresponding antibodies, 56 anti-Her2 ADCs which applied >10 different types of novel payloads had entered preclinical or clinical trials. Seven of 12 Food and Drug Administration (FDA)-approved ADCs including Polivy (2019), Padcev (2019), EnHertu (2019), Trodelvy (2020), Blenrep (2020), Zynlonta (2021), and Tivdak) (2021) have been approved by FDA in the past three years alone, indicating that the maturing of ADC technology brings more productive clinical outcomes. This review, focusing on the anti-Her2 ADCs in clinical trials or on the market, discusses the strategies to select antibody formats, the linkages between linker and mAb, and effective payloads with particular release and action mechanisms for a good clinical outcome.