A narrative review of the current landscape and future perspectives of HER2-targeting antibody drug conjugates for advanced breast cancer

Abstract

Objective: To (I) provide an update of approved antibody drug conjugates (ADCs) and those registered with NMPA, (II) give an overview of HER2-targeting ADCs as a mono-or combination therapy in clinical development for breast cancer and the molecular mechanism of payloads of these molecules, (III) describe the pharmacokinetic profiles of ADCs using mostly exploited vcMMAE platform as an example, (IV) discuss future development strategies for ADC therapeutics in addressing substantially unmet medical needs, such as brain metastasis (BM) and drug resistance in patients with HER2-expressing advanced breast cancer. Background: As the most common type of cancer in women, breast cancer remains a significant challenge for drug discovery and development due to its heterogenous nature and complex molecular subtypes and pathologies. The advent of tyrosine kinase inhibitors (TKIs) and targeted therapies has significantly improved overall survival (OS) for breast cancer patients with early diagnosis, however, those who have experienced metastasis are still facing limited treatment options. ADCs are an emerging class of drugs used in targeted therapies for hematologic malignancies and solid tumors, known for their highly selective binding moiety of monoclonal antibody (mAb) to differentially expressed tumor antigens and highly cytotoxic warheads with defined mechanisms of action. Eleven ADCs have been approved by the FDA, three of which are for breast cancer indication namely HER2-targeting Kadcyla® and ENHERTU®, and TROP2-targeting Trodelvy®, highlighting the clinical potential of this therapeutic modality for breast cancer treatment. Methods: We searched relevant studies published in English in the PubMed, Informa PharmaProjects, ClinicalTrials.gov, FDA and EPO databases, google.com, and in Chinese in NMPA website up to Aug 9, 2021, using search strategies with search terms “HER2 ADC”, “breast cancer”, “antibody drug conjugate” (ADC), “PK/PD”, “linker”, “payload”, “drug resistance”, and/or “brain metastasis”. Conclusions: In this review, we provide an update of HER2-targeting ADCs for breast cancer treatment, the types of payload used in these molecules, and the structures and mechanism of action of these payloads. We describe PK profile using vcMMAE platform and discuss future development strategies in addressing unmet medical needs such as CNS metastasis, HER2-low expression, and acquired drug resistance.