Expression of HER2 in the eye and the potential for on-target side effects with antibody-drug conjugates

The use of antibody-drug conjugates (ADCs) specific to human epidermal growth factor receptor 2 (HER2), such as ado-trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (Enhertu, T-DXd), and trastuzumab duocarmazine (SYD985), to treat breast cancer patients has been associated with a variety of toxicities including corneal epithelial keratitis. The anatomic basis for ocular toxicities has not been established. Using immunohistochemistry, HER2 expression was identified in the human corneal, limbal and conjunctival epithelium of fetal and adult human eyes. We also identified HER2 expression in tissues from the Macaca fascicularis (monkey) to confirm a similar distribution of HER2 expression as found in humans and to support the use of this species as a toxicology model in preclinical testing of anti-HER2 ADCs. As in the human, expression of HER2 in monkey was limited to normal epithelium, as illustrated for the eye, kidney, and uterus. Incubation of normal human corneal epithelial cell lines with trastuzumab or T-DXd demonstrated the capacity for receptor-mediated endocytosis of HER2-targeted therapies by epithelia in the eye. Our findings of HER2 expression in normal human corneal epithelium suggest that the ocular adverse events associated with HER2-targeted ADCs may be driven, at least in part, by an on-target effect.