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

Ethan S Lindgren¹, Rongshan Yan¹, Onur Cil², Alan S Verkman³, Matilda F Chan^{1

4}, Gerami D Seitzman^{1

4}, Asim V Farooq⁵, Laura A Huppert⁶, Hope S Rugo⁶, Paula R Pohlmann⁷, Janice Lu⁸, Laura J Esserman^{6

9}, Neel D Pasricha^{1

4}

Affiliations

¹ Department of Ophthalmology, University of California San Francisco, San Francisco, CA, USA.
² Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA.
³ Departments of Medicine and Physiology, University of California San Francisco, San Francisco, CA, USA.
⁴ Francis I. Proctor Foundation, University of California San Francisco, San Francisco, CA, USA.
⁵ Department of Ophthalmology and Visual Science, University of Chicago Medical Center, Chicago, IL, USA.
⁶ Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
⁷ Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁸ Department of Medical Oncology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁹ Department of Surgery, University of California San Francisco, San Francisco, CA, USA.

PMID: 38756824
PMCID: PMC11095972
DOI: 10.1007/s40135-024-00322-5

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

Ethan S Lindgren et al. Curr Ophthalmol Rep. 2024 Jun.

. 2024 Jun;12(2):13-22.

doi: 10.1007/s40135-024-00322-5. Epub 2024 Mar 24.

Authors

Affiliations

¹ Department of Ophthalmology, University of California San Francisco, San Francisco, CA, USA.
² Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA.
³ Departments of Medicine and Physiology, University of California San Francisco, San Francisco, CA, USA.
⁴ Francis I. Proctor Foundation, University of California San Francisco, San Francisco, CA, USA.
⁵ Department of Ophthalmology and Visual Science, University of Chicago Medical Center, Chicago, IL, USA.
⁶ Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
⁷ Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁸ Department of Medical Oncology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁹ Department of Surgery, University of California San Francisco, San Francisco, CA, USA.

PMID: 38756824
PMCID: PMC11095972
DOI: 10.1007/s40135-024-00322-5

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.

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Conflict of interest statement

Conflict of Interest N.D.P. serves on the US Medical Keratopathy Advisory Board for Sanofi.

Figures

**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)

See this image and copyright information in PMC

References

1. Dumontet C, Reichert JM, Senter PD, Lambert JM, Beck A. Antibody-drug conjugates come of age in oncology. Nat Rev Drug Discov. 2023;22(8):641–61. - PubMed
2. Reviews the role of each ADC component in ocular surface toxicity.
1. Jaffry M, Choudhry H, Aftab OM, Dastjerdi MH. Antibody-drug conjugates and ocular toxicity. J Ocul Pharmacol Ther. 2023;39(10):675–91. - PubMed
2. Highlights the potential mechanisms of ADC ocular surface toxicity and preventive therapies for FDA-approved ADCs as well as those in development.
1. Naito K, Takeshita A, Shigeno K, Nakamura S, Fujisawa S, Shinjo K, et al. Calicheamicin-conjugated humanized anti-CD33 monoclonal antibody (gemtuzumab zogamicin, CMA-676) shows cytocidal effect on CD33-positive leukemia cell lines, but is inactive on P-glycoprotein-expressing sublines. Leukemia. 2000;14(8):1436–43. - PubMed
1. Fu Z, Li S, Han S, Shi C, Zhang Y. Antibody drug conjugate: the “biological missile” for targeted cancer therapy. Signal Trans-duct Target Ther. 2022;7(1):93. - PMC - PubMed
1. Gogia P, Ashraf H, Bhasin S, Xu Y. Antibody-drug conjugates: a review of approved drugs and their clinical level of evidence. Cancers (Basel). 2023;15(15)3886. - PMC - PubMed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Grants and funding

LinkOut - more resources

Full Text Sources

Research Materials