Antibody-drug conjugates (ADCs) are anticancer drugs consisting of a tumor-specific monoclonal antibody linked to a cytotoxic drug (payload) via a linker. The antibody binds to a target antigen on the cancer cell surface, the entire ADC is internalized via endocytosis, and the payload is released by lysosomal enzymes, inducing cell death.
Ocular surface toxicity is one of the most common adverse events of ADCs, with reported prevalence ranging from 20% to 90% depending on the drug and dosing regimen 1). At least three FDA-approved ADCs have been confirmed to cause corneal pseudomicrocysts, with frequencies reaching 41–100% depending on the drug and dosing conditions 2). Two pathways have been proposed for the damage mechanism:
The corneal epithelium expresses EGFR (epidermal growth factor receptor) and HER2, and antibodies/ADCs targeting these are prone to cause corneal epithelial damage. Representative drugs include cetuximab (anti-EGFR antibody), trastuzumab (anti-HER2 antibody), and trastuzumab emtansine.
Major FDA-approved ADCs and representative drugs reported to affect the ocular surface are shown below.
| Drug | Target | Main Indications |
|---|---|---|
| Belantamab mafodotin | BCMA | Multiple myeloma |
| Mirvetuximab soravtansine | FRα | Ovarian cancer |
| Tisotumab vedotin | TF | Cervical cancer |
In addition, ocular surface adverse events have also been reported with enfortumab vedotin (Nectin4-targeted, urothelial carcinoma) and trastuzumab deruxtecan (HER2-targeted, breast cancer).
ADC-related ocular surface changes are often asymptomatic and are frequently discovered for the first time during ophthalmic examination. When subjective symptoms are present:
Pseudomicrocysts
Microcystic epithelial changes (MECs): Inclusion body-like changes within the corneal epithelium. They start near the limbus and spread centrally depending on dose and treatment duration. Bilateral.
IVCM findings: Round hyperreflective structures in the basal to wing cell layers. The superficial epithelium is relatively preserved.
Retroillumination: Best observed with slit-lamp retroillumination.
Conjunctivitis
Bilateral hyperemia: Redness of the bulbar and palpebral conjunctiva. Accompanied by burning sensation, itching, and epiphora.
Subepithelial fibrosis: Reported with tisotumab vedotin. Fibrosis occurs in the palpebral conjunctiva.
Blepharitis: May occur concurrently.
Limbal Lesions
Limbal stem cell dysfunction: Worsening of dry eye symptoms. Vortex pattern on fluorescein staining.
Superior limbic keratoconjunctivitis (SLK): Reported with mirvetuximab soravtansine.
MECs are inclusion body-like changes formed by the uptake of ADC into corneal epithelial cells. Unlike true microcysts, they are thought to result from internalization of ADC into epithelial cells. They spread from the limbus toward the center and often disappear after drug discontinuation. For details, see the Pathophysiology section.
Ocular surface adverse events caused by ADC depend on the type of payload, expression of the target antigen on corneal and conjunctival epithelium, and linker stability.
Anti-EGFR antibodies (e.g., cetuximab) can cause corneal epithelial damage as well as eyelash elongation, trichiasis, and blepharitis. EGFR inhibitors (e.g., erlotinib, gefitinib, osimertinib) also cause corneal epithelial damage through a similar mechanism.
Belantamab mafodotin (BCMA-targeted), mirvetuximab soravtansine (FRα-targeted), and tisotumab vedotin (TF-targeted) have a particularly high frequency of ocular surface adverse events. These are prone to affect the corneal epithelium due to the characteristics of their payloads and targets.
Before starting ADC treatment, perform a baseline examination including visual acuity, refraction, slit-lamp examination, and tear film evaluation. Thereafter, monitor at each cycle, and examine more frequently if symptoms worsen.
The severity of keratopathy is evaluated using the Keratopathy Visual Acuity (KVA) scale. Severity is classified based on corneal findings and changes in best-corrected visual acuity (BCVA), and is used to guide dose adjustments.
IVCM is useful for detailed evaluation of MECs. They appear as round, highly reflective structures in the wing cell layer and basal cell layer, while the superficial epithelium is relatively preserved. No abnormalities are observed in the stroma or endothelium.
Fluorescein staining is important for evaluating limbal stem cell dysfunction. A whorl pattern of staining is characteristic of limbal stem cell deficiency.
Management of ADC-related ocular surface adverse events is based on three pillars: regular monitoring, supportive therapy, and dose adjustment.
Decisions to delay, reduce, or discontinue dosing are made based on the severity of ocular surface adverse events.
In most cases, dose adjustment (delay or reduction) is possible rather than discontinuation. Ocular surface changes are often reversible within weeks to months after drug interruption. However, discontinuation may be considered if severe findings such as ulceration or scarring are present. Collaboration between oncology and ophthalmology is important for decision-making.
When ADC is taken up by corneal epithelial cells, the cytotoxic payload is released intracellularly, inducing apoptosis. Histological examination reveals epithelial cells with vacuolated and granular appearances at various stages of apoptosis. Immunohistochemical staining shows IgG positivity in basal epithelial cells, confirming intracellular uptake of ADC.
MECs begin near the limbus and spread to the central cornea with increasing dose or continued treatment. This peripheral-to-central migration pattern suggests that ADC enters the cornea through the vascular-rich limbus. It is thought that as corneal epithelial cells undergo ADC-induced cell death and new epithelial cells regenerate from the limbus toward the center, damaged cells are pushed toward the center.
For belantamab mafodotin (BCMA-targeted) and mirvetuximab (FRα-targeted), the target antigen is not expressed on corneal or conjunctival epithelium. Therefore, off-target pathways (Fc receptor-mediated uptake, macropinocytosis, passive diffusion of payload) are presumed to be the main toxicity mechanisms.
On the other hand, for ADCs targeting HER2 or EGFR (e.g., trastuzumab emtansine), these receptors are expressed on corneal epithelium, so on-target toxicity may be involved.
Domínguez-Llamas S, Caro-Magdaleno M, Mataix-Albert B, et al. Adverse events of antibody-drug conjugates on the ocular surface in cancer therapy. Clin Transl Oncol. 2023;25(11):3086-3100. PMID: 37454027.
Lindgren ES, Yan R, Cil O, et al. Incidence and Mitigation of Corneal Pseudomicrocysts Induced by Antibody-Drug Conjugates (ADCs). Curr Ophthalmol Rep. 2024;12(2):13-22. PMID: 38756824.
Lonial S, Lee HC, Badros A, et al. Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomised, open-label, phase 2 study. Lancet Oncol. 2020;21(2):207-221. PMID: 31859245.
Lonial S, Nooka AK, Thulasi P, et al. Management of belantamab mafodotin-associated corneal events in patients with relapsed or refractory multiple myeloma (RRMM). Blood Cancer J. 2021;11(5):103. PMID: 34039952.
Kim SK, Ursell P, Coleman RL, Monk BJ, Vergote I. Mitigation and management strategies for ocular events associated with tisotumab vedotin. Gynecol Oncol. 2022;165(2):385-392. PMID: 35277279.
Matulonis UA, Birrer MJ, O’Malley DM, et al. Evaluation of Prophylactic Corticosteroid Eye Drop Use in the Management of Corneal Abnormalities Induced by the Antibody-Drug Conjugate Mirvetuximab Soravtansine. Clin Cancer Res. 2019;25(6):1727-1736. doi:10.1158/1078-0432.CCR-18-2474. PMID:30413525.
