The development of anti-HER2 agents has been one of the most meaningful advancements in the management of metastatic breast cancer, significantly improving survival outcomes. Despite the efficacy of anti-HER2 monoclonal antibodies, concurrent chemotherapy is still needed to maximize response. Antibody-drug conjugates (ADCs) are a class of therapeutics that combines an antigen-specific antibody backbone with a potent cytotoxic payload, resulting in an improved therapeutic index. Two anti-HER2 ADCs have been approved by the FDA with different indications in HER2-positive breast cancer. Ado-trastuzumab emtansine (T-DM1) was the first-in-class HER2-targeting ADC, initially approved in 2013 for metastatic patients who previously received trastuzumab and a taxane, and the label was expanded in 2019 to include adjuvant treatment of high-risk patients with residual disease after neoadjuvant taxane and trastuzumab-based therapy. In 2020, trastuzumab deruxtecan (T-DXd) was the second approved ADC for patients who had received at least 2 lines of anti-HER2-based therapy in the metastatic setting. The success of these two agents has transformed the treatment of HER2-positive breast cancer and has re-energized the field of ADC development. Given their advanced pharmaceutical properties, next-generation HER2-targeted ADCs have the potential to be active beyond traditional HER2-positive breast cancer and may be effective in cells with low expression of HER2 or ERBB2 mutations, opening a spectrum of new possible clinical applications. Ongoing challenges include improving target-specificity, optimizing the toxicity profile, and identifying biomarkers for patient selection. The aim of this review is to summarize the principal molecular, clinical, and safety characteristics of approved and experimental anti-HER2 ADCs, contextualizing the current and future landscape of drug development.

中文翻译：

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在 HER2 阳性乳腺癌中实施抗体药物偶联物 (ADC)：最新技术和未来方向

抗 HER2 药物的开发是转移性乳腺癌治疗中最有意义的进步之一，显着改善了生存结果。尽管抗 HER2 单克隆抗体有效，但仍需要同步化疗以最大限度地提高反应。抗体-药物偶联物 (ADC) 是一类将抗原特异性抗体骨架与有效的细胞毒性有效载荷相结合的治疗方法，从而提高治疗指数。两种抗 HER2 ADC 已获得 FDA 批准，在 HER2 阳性乳腺癌中具有不同的适应症。Ado-trastuzumab emtansine (T-DM1) 是一流的 HER2 靶向 ADC，最初于 2013 年获批用于先前接受曲妥珠单抗和紫杉烷治疗的转移性患者，该标签于 2019 年扩大，包括对新辅助紫杉烷和基于曲妥珠单抗的治疗后残留疾病的高风险患者的辅助治疗。2020 年，曲妥珠单抗 deruxtecan (T-DXd) 是第二个获批的 ADC，用于在转移性环境中接受至少 2 线抗 HER2 治疗的患者。这两种药物的成功改变了 HER2 阳性乳腺癌的治疗方法，并为 ADC 开发领域重新注入了活力。鉴于其先进的药学特性，下一代 HER2 靶向 ADC 具有超越传统 HER2 阳性乳腺癌的潜力，并且可能对 HER2 或 ERBB2 突变低表达的细胞有效，从而开辟了一系列可能的新临床应用。持续的挑战包括提高目标特异性，优化毒性概况，并确定用于患者选择的生物标志物。本综述的目的是总结已批准和实验性抗 HER2 ADC 的主要分子、临床和安全特征，并结合当前和未来的药物开发前景。