2. Academic Validation
  3. Expression of HER2 in the eye and the potential for on-target side effects with antibody-drug conjugates

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

  • Sci Rep. 2026 May 7. doi: 10.1038/s41598-026-51353-w.
Simon Davenport 1,  Bin Xie 2,  Kevin Hamblett 3 4,  Diana Hausman 3 5,  Ivonne Villalobos 2,  Hardeep P Singh 6 7,  David Cobrinik 6,  David S B Hoon 8,  Jian-Yuan Zhou 2,  Maria Sibug-Saber 2,  Yanling Ma 2,  Gottfried E Konecny 9,  Martin Heur 10,  Dennis J Slamon 9,  Michael F Press 2 11
Affiliations

Affiliations

  • 1 Department of Pathology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA. [email protected].
  • 2 Department of Pathology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.
  • 3 Zymeworks Inc, Seattle, WA, USA.
  • 4 Pfizer, Inc., Bothell, WA, USA.
  • 5 Link Immunotherapeutics, Inc., Seattle, WA, USA.
  • 6 Department of Ophthalmology, Roski Eye Institute, and Norris Comprehensive Cancer Center, The Vision Center and Saban Research Institute, University of Southern California, Children's Hospital of Los Angeles, University of Southern California, Los Angeles, CA, USA.
  • 7 Epic Bio, South San Francisco, CA, USA.
  • 8 Saint John's Cancer Institute, Saint John's Health Center PHS, Santa Monica, CA, USA.
  • 9 Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
  • 10 Department of Ophthalmology, Keck Medicine of USC, University of Southern California, Los Angeles, CA, USA.
  • 11 Ellison Institute of Technology, Los Angeles, CA, USA.
PMID: 42098228 DOI: 10.1038/s41598-026-51353-w
Abstract

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.

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