Mitigating HER2-targeted antibody‒drug conjugate-induced interstitial lung disease through Fc-region glycosylation engineering

The clinical application of trastuzumab deruxtecan (T-DXd), a transformative HER2-targeted antibody‒drug conjugate (ADC), is limited by interstitial lung disease (ILD), a severe adverse event associated with alveolar macrophage (AM)-mediated uptake and Fc γ receptor (Fc γ R) engagement. To mitigate this toxicity while preserving anti-tumor efficacy, we explored Fc-engineering strategies aimed at reducing Fc γ R binding and immune activation. Using enzymatic deglycosylation and site-specific mutations (N297A and LALAPG), we generated Fc-engineered trastuzumab variants and incorporated them into T-DXd. Our findings demonstrate that these Fc-engineered ADCs significantly reduce macrophage internalization and lung accumulation without compromising HER2 antigen recognition or tumor cell uptake. In preclinical models, Fc-engineered ADCs reduced ILD incidence, attenuated neutrophil infiltration, and decreased activation of inflammatory pathways. Importantly, they maintain anti-tumor potency. Transcriptomic analysis further reveals that Fc-engineered ADCs suppress antigen processing and presentation pathways implicated in ILD pathogenesis. These results suggest that Fc engineering represents a promising strategy for mitigating ADC-induced pulmonary toxicity, offering a safer alternative for HER2-targeted therapies. Fc-engineered trastuzumab ADCs with reduced Fc γ R affinity decrease macrophage uptake and ILD incidence while preserving HER2 binding and antitumor efficacy. Download: Download high-res image (250KB) Download: Download full-size image