Enhanced Targeted Therapy: The Efficacy of Next-Generation ADC DAN-311 in HER2-Low Breast Cancer

This study explores the development of a novel nanoparticle therapeutic, DAN-311, designed to improve upon traditional antibody-drug conjugates (ADCs) by leveraging biocompatible polymer chemistry. The nanoparticle is constructed by attaching chemotherapy agents to a polymer through linkers that can adjust release rates and pharmacokinetics. DAN-311 specifically targets HER2, a protein found in breast cancer cells, with trastuzumab, and carries the chemotherapy drug camptothecin (CPT), an inhibitor of topoisomerase I.

The research highlights two main benefits of DAN-311 for patients with HER2-low expressing tumors: a higher drug-to-antibody ratio (DAR) that can enhance the bystander effect, where the drug is effective against both targeted and neighboring cells, and the nanoparticle's ability to combat HER2 non-expressing cells through the enhanced permeability and retention (EPR) effect.

The study details the consistency and control of critical characteristics of the DAN-311 nanoparticles, such as particle size, chemotherapy load, and release rate, which are crucial for efficient large-scale manufacturing. It also reports on the enhanced efficacy of DAN-311 in a HER2-low breast cancer xenograft mouse model, comparing its performance to trastuzumab and the non-targeted core nanoparticle.

The results show that the nanoparticles maintained a consistent size and DAR across different conditions and demonstrated linear release kinetics in various media. DAN-311 significantly outperformed the control and core particle in inhibiting tumor growth. The non-targeted core particle also showed significant tumor growth inhibition, which lasted for at least three weeks post-treatment.

The study concludes that DAN-311 is a promising next-generation ADC that can effectively inhibit tumor growth in HER2-low xenograft mouse models. Its targeted delivery and high DAR enhance cell killing capabilities, and the EPR effect allows for additional treatment of non-HER2-expressing areas within tumors. The drug is now moving forward to clinical trials for the treatment of HER2-low metastatic breast cancer patients.

The study's findings were presented at the 2021 San Antonio Breast Cancer Symposium and published in the Cancer Research journal.