Novel Strategies to Improve the Efficacy and Safety of Antibody Drug Conjugates for HER2-Positive Breast Cancer

Abstract

Antibody drug conjugates (ADCs) have markedly advanced the treatment of hematological and solid tumors, with eleven therapies currently approved and numerous others under investigation. HER2-targeted ADCs have shown remarkable clinical efficacy, with two approved for treating HER2-positive breast cancer (BC). Despite these successes, challenges such as intrinsic or acquired resistance and therapy-associated toxicities limit their therapeutic efficacy. In addition, there are no appropriate preclinical mouse models to test the potential toxicities related to HER2 targeting. Therefore, there remains a clinical need to improve the efficacy and safety of HER2-targeting ADCs for treating HER2-positive tumors and to generate adequate murine models to predict HER2-targeting-related toxicities. In this thesis, we describe three innovative strategies to improve these limitations. First, we describe a strategy that enhances the efficacy of next-generation HER2-targeting ADCs by integrating cellular senescence-triggering agents, like CDK4/6 inhibitors, to increase their bystander effect in HER2-low tumors. Second, we present the development and preclinical assessment of a novel next-generation ADC targeting p95HER2, a truncated form of HER2 that is a tumor-specific antigen expressed in a subset of HER2-positive tumors, and demonstrate that it selectively targets p95HER2-positive tumors with a potentially improved safety profile. Third, we explain the generation of a novel knock-in mouse model expressing human HER2 under the murine Erbb2 promoter, providing a refined tool for evaluating the toxicities associated with HER2-targeted therapies. Collectively, these contributions advance the field of ADCs for HER2-positive tumors by developing combinatorial treatment strategies that increase their effectivity, introducing novel potentially safer ADCs, and generating innovative murine models to assess therapy-associated toxicity, ultimately aiming to improve patient outcomes in HER2-positive BC and potentially in other malignancies.

Date of Award	9 May 2025
Original language	English
Supervisor	Joaquin Vicente Arribas Lopez (Director)