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

T-DXd, a transformative HER2-targeting antibody-drug conjugate (ADC), has been implicated in causing fatal interstitial lung disease (ILD) in multiple clinical trials. However, consensus regarding the mechanistic basis of these ADC-induced adverse effects remains elusive. In this study, we determined that T-DXd-induced ILD represents an off-target adverse event (AE) rather than an on-target off-tumor AE by assessing HER2 antigen expression in a panel of 98 normal human lung tissues. Next, we developed a robust immunocompetent murine model that recapitulates T-DXd-induced ILD events, facilitating in-depth mechanistic studies. Using single-cell RNA sequencing in this model, we identified alveolar macrophages (AMs) as the primary cell type impacted by T-DXd in the lung microenvironment. Intravital microscopy further visualized that AMs resident in perivascular niches directly engulf blood-circulating T-DXd via Fc-Fc gamma R engagement. This interaction with T-DXd triggers a phenotypic shift in AMs from an immunosuppressive to a pro-ILD state, characterized by inflammation and immune activation, mediated through the SPP1 pathways. Furthermore, we explored a clinically applicable strategy to mitigate nonspecific T-DXd uptake in the lung by pre-conditioning perivascular AMs with IgG1 or the parental antibody of T-DXd, which significantly reduced unintended ADC absorption. These findings elucidate a novel mechanism by which T-DXd ignites the lung immune microenvironment and underscore the importance of off-target phagocytosis by innate immune cells in the development of ADC-related toxicities.