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Expression of HER2 in the eye and the potential for on-target side effects with antibody-drug conjugates
Simon Davenport1, Bin Xie2, Kevin Hamblett3,4
1Department of Pathology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA. Simon.Davenport@med.usc.edu.
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.
Insights
Human epidermal growth factor receptor 2 (HER2) is expressed in the cornea, suggesting it may cause eye toxicity in patients receiving HER2-targeted antibody-drug conjugates (ADCs) for cancer treatment.
Area of Science:
- Ophthalmology
- Oncology
- Molecular Biology
Background:
- Antibody-drug conjugates (ADCs) targeting human epidermal growth factor receptor 2 (HER2) are used for breast cancer treatment.
- Ocular toxicities, such as corneal epithelial keratitis, are associated with these HER2-targeted ADCs.
- The anatomical basis for these ocular toxicities remains unclear.
Purpose of the Study:
- To investigate the expression of HER2 in ocular tissues.
- To determine if HER2 expression in the eye could explain the ocular toxicities observed with HER2-targeted ADCs.
- To validate the Macaca fascicularis (monkey) as a preclinical toxicology model for anti-HER2 ADCs.
Main Methods:
- Immunohistochemistry was used to detect HER2 expression in human fetal and adult ocular tissues (cornea, limbus, conjunctiva).
- HER2 expression was also assessed in Macaca fascicularis ocular, kidney, and uterine tissues.
- Normal human corneal epithelial cell lines were incubated with trastuzumab or trastuzumab deruxtecan (T-DXd) to assess receptor-mediated endocytosis.
Main Results:
- HER2 expression was identified in the corneal, limbal, and conjunctival epithelium of human eyes.
- Similar HER2 expression patterns were observed in Macaca fascicularis tissues, supporting its use as a model.
- HER2-targeted therapies demonstrated receptor-mediated endocytosis by corneal epithelial cells in vitro.
Conclusions:
- HER2 is expressed in normal human corneal epithelium.
- This expression suggests that ocular adverse events from HER2-targeted ADCs may be an on-target effect.
- The findings support the use of Macaca fascicularis as a preclinical model for evaluating anti-HER2 ADCs.
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