Single-Cell Transcriptomics Reveals a Multi-Compartmental Cellular Cascade Underlying Elahere-Induced Ocular Toxicity...

Area of Science:

• Oncology
• Ophthalmology
• Immunology

Background:

• Antibody-drug conjugates (ADCs) offer targeted cancer therapy but can cause dose-limiting ocular toxicities.
• Elahere (mirvetuximab soravtansine), an ADC targeting folate receptor alpha (FRα), is effective for ovarian cancer but linked to keratitis.
• FRα is absent in corneal epithelium, necessitating investigation into Elahere's ocular toxicity mechanisms.

Purpose of the Study:

• To identify cell-type-specific molecular mechanisms of Elahere-induced ocular toxicity.
• To elucidate how Elahere affects corneal cell populations and signaling pathways.

Main Methods:

• Sprague-Dawley rats received weekly intravenous Elahere (20 mg/kg) or vehicle for five weeks.
• Ocular toxicity assessed via clinical examination and histopathology.
• Corneal single-cell RNA sequencing (scRNA-seq) analyzed cell populations, gene expression, and signaling pathways.

Main Results:

• Elahere induced significant ocular surface and corneal epithelial damage.
• Myeloid immune cells were depleted, with suppressed homeostatic gene expression in macrophages.
• Corneal progenitor cells expanded (~2.6-fold limbal stem cells), while differentiated cells decreased, indicating differentiation blockade.
• Endothelial cells showed injury and inflammation; FRα was found in endothelial and stromal cells, potentially promoting fibrosis.
• Fc receptor genes in myeloid cells suggest a depletion mechanism.

Conclusions:

• Elahere triggers multi-compartmental ocular toxicity involving vascular endothelial and immune cells.
• The toxicity cascade includes epithelial differentiation arrest and stromal remodeling.
• Findings provide mechanistic insights for mitigating Elahere-associated ocular side effects.