Abstract 6369: Perivascular niche-resident alveolar macrophages confer interstitial pneumonitis related to trastuzumab deruxtecan

Abstract Background: T-DXd, a HER2-targeting antibody-drug conjugate (ADC), has shown transformative potential in cancer therapy but is implicated in causing fatal interstitial lung disease (ILD) in clinical trials. The mechanistic basis for these ADC-induced adverse effects remains unclear. This study aimed to investigate whether T-DXd-induced ILD represents an off-target adverse event (AE) and to explore the underlying cellular and molecular mechanisms. Methods: We analyzed HER2 antigen expression in a panel of 98 normal human lung tissues to determine whether T-DXd-induced ILD is on-target or off-target. To study the mechanisms of ILD, we developed an immunocompetent murine model that replicates T-DXd-induced lung toxicity. Using single-cell RNA sequencing, we identified alveolar macrophages (AMs) as the primary cell type affected by T-DXd in the lung microenvironment. Intravital microscopy was employed to visualize how perivascular AMs engulf T-DXd via Fc-FcγR engagement. To mitigate T-DXd-induced toxicity, a pre-conditioning strategy using IgG1 or the parental antibody of T-DXd was tested in the murine model. Results: Analysis of HER2 expression in normal lung tissues revealed minimal expression, confirming that T-DXd-induced ILD is an off-target AE. Single-cell RNA sequencing and intravital microscopy identified perivascular AMs as the key mediators of lung toxicity, driven by Fc-FcγR engagement with T-DXd. This interaction triggered a phenotypic shift in AMs toward an inflammatory, pro-ILD state, characterized by activation of the SPP1 pathway. Pre-conditioning AMs with IgG1 or the parental antibody of T-DXd effectively reduced ADC uptake, alleviating lung inflammation and immune activation in the murine model. Conclusion: T-DXd-induced ILD is an off-target AE mediated by Fc-FcγR-driven phagocytosis of T-DXd by perivascular alveolar macrophages. This interaction promotes an inflammatory SPP1high phenotype in AMs, leading to lung inflammation and immune activation. Pre-conditioning strategies targeting AMs offer a potential clinical approach to reduce nonspecific ADC uptake and mitigate lung toxicity. These findings provide significant insights into the mechanisms of ADC-induced toxicities and potential intervention strategies. Citation Format: Qing Wei, Teng Yang, Ziwen Zhang, Jiayu Zhu, Xiru Xue, Jieer Ying, Peng Guo, Xiangdong Cheng. Perivascular niche-resident alveolar macrophages confer interstitial pneumonitis related to trastuzumab deruxtecan [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6369.