Incidence and Mitigation of Corneal Pseudomicrocysts Induced by Antibody-Drug Conjugates (ADCs)

Abstract

Purpose of review: This study is to highlight the incidence of corneal pseudomicrocysts in FDA-approved antibody-drug conjugates (ADCs), and success of preventive therapies for pseudomicrocysts and related ocular surface adverse events (AEs).

Recent findings: ADCs are an emerging class of selective cancer therapies that consist of a potent cytotoxin connected to a monoclonal antibody (mAb) that targets antigens expressed on malignant cells. Currently, there are 11 FDA-approved ADCs with over 164 in clinical trials. Various AEs have been attributed to ADCs, including ocular surface AEs (keratitis/keratopathy, dry eye, conjunctivitis, blurred vision, corneal pseudomicrocysts). While the severity and prevalence of ADC-induced ocular surface AEs are well reported, the reporting of corneal pseudomicrocysts is limited, complicating the development of therapies to prevent or treat ADC-related ocular surface toxicity.

Summary: Three of 11 FDA-approved ADCs have been implicated with corneal pseudomicrocysts, with incidence ranging from 41 to 100% of patients. Of the six ADCs that reported ocular surface AEs, only three had ocular substudies to investigate the benefit of preventive therapies including topical steroids, vasoconstrictors, and preservative-free lubricants. Current preventive therapies demonstrate limited efficacy at mitigating pseudomicrocysts and other ocular surface AEs.

Keywords: Antibody–drug conjugates; Conjunctiva; Cornea; Corneal pseudomicrocysts; Microcyst-like epithelial changes; Ocular surface adverse events; Ocular surface epithelium.

Fig. 1

Structure of ADCs. There are three well-defined components: antibody, chemical linker, and cytotoxic payload. Of the current FDA-approved ADCs, all have IgG1 or IgG4 mAbs. Payloads, which either damage DNA or disrupt microtubule formation during mitosis, are linked to the mAb via a chemical linker, which are defined as cleavable or non-cleavable. Created with BioRender.com

Fig. 2

Manifestation of corneal pseudomicrocysts. A Examination of the ocular surface with diffuse illumination appears normal. B High magnification sclerotic scatter show numerous peripheral corneal pseudomicrocysts. C Corneal topography demonstrates peripheral ring-like steepening corresponding to the area of corneal pseudomicrocysts

Fig. 3

Potential mechanisms for ADC-induced ocular surface toxicity (reprinted with permission from Elsevier, originally published in Mahalingaiah et al. Potential mechanisms of target-independent uptake and toxicity of antibody–drug conjugates. Pharmacol Ther. 2019)