Trastuzumab deruxtecan ( T-DXd , DS-8201 ) has a clinical incidence of interstitial lung disease (ILD) of approximately 10-15%. The mechanism of occurrence is not due to a single factor, but rather an interaction between target-dependent and non-target-dependent pathways. Firstly, the target-dependent mechanism arises from the low expression levels of HER2 in alveolar epithelial cells and lung stromal cells, leading to ADC uptake into lung tissue via receptor-mediated endocytosis. DXd, being a lipophilic topoisomerase I inhibitor, directly induces cytotoxic damage to lung cells. Secondly, the non-target-dependent mechanism mainly involves: alveolar macrophages phagocytosing ADC through Fcγ receptors, and the high expression of lysosomal enzyme cathepsin B in lung tissue, which further accelerates the release of DXd, thereby amplifying the risk of lung damage.

Dato-DXd (Datopotamab deruxtecan) also carries DXd as its payload, but the target shifts from HER2 to TROP-2. Based on the aforementioned ILD mechanism analysis, Dato-DXd can avoid the target-dependent pathway since TROP-2 is expressed at very low or negligible levels in normal adult alveolar epithelial cells, primarily limited to airway epithelium or fetal lung development stages, and is almost absent in the core regions of alveoli, contrasting sharply with the relatively higher expression of HER2 in alveoli. However, the non-target-dependent mechanism involving alveolar macrophage phagocytosis and lysosomal enzyme activation remains unavoidable, leading to Dato-DXd still being able to induce ILD, with reported incidence as low as about 5%. The alveoli seem to be spared by Dato-DXd, but due to the high expression of TROP2 in the cornea and conjunctiva, ocular toxicity has become a focal point, such as dry eye (24%), keratitis (11%), and conjunctivitis (6%), with overall incidence rates ranging from 22% to 40%. The lipophilicity of DXd enhances penetration into the ocular surface, releasing it in ocular cells through targeted endocytosis, interfering with microtubule function, causing corneal damage and lacrimal gland dysfunction. Symptoms include dryness, foreign body sensation, and blurred vision, which are mostly low-grade according to CTCAE grading but can affect quality of life.

Both TROP-2 targeting sacituzumab govitecan (SG) and trastuzumab deruxtecan have payloads of govitecan (SN-38) and tirumotecan (an analogue of belotecan, a topo I inhibitor), respectively, both utilizing pH-sensitive unstable linkers (such as CL2A or similar hydrolyzable linkers), leading to partial premature release of the payload in the bloodstream, thereby limiting non-target exposure and accumulation of the drug in the eyes, avoiding the common ocular toxicity issues seen with Dato-DXd. The hydrophilic payloads of SG and trastuzumab deruxtecan further reduce the risk of non-target ocular damage.