Ocular Tissue Distribution of Ocular Surface Immunoglobulin Following Topical and Subconjunctival Administration: A Novel Strategy for Mitigation of Antibody–Drug Conjugate-Associated Ocular Toxicity
Zeenal Dabre, Emily G. Krupa, Bhuvanachandra Pasupuleti, Marianna Bacellar-Galdino, Lee D. Troughton, Christine Mun, Elias Hernandez, Hyung-Geun Moon, Michael T. Flavin, Simon Kaja, Sandeep JainPurpose:
Antibody–drug conjugate (ADC)-associated ocular toxicity is an emerging, sometimes dose-limiting complication. Macropinocytosis has been implicated in off-target ADC uptake by corneal epithelial cells. This study evaluated whether ocular surface immunoglobulin (OSIG) inhibit macropinocytosis in human corneal epithelial cells (HCE-T) and characterized ocular biodistribution and tolerability following topical and subconjunctival administration.
Methods:
Macropinocytosis was quantified in corneal epithelial cells after exposure to vehicle or increasing concentrations of OSIG. Ocular pharmacokinetics were evaluated in New Zealand White rabbits following single topical instillation or subconjunctival injection of 5% OSIG. OSIG concentrations were quantified in ocular tissues, ocular fluids, tears, serum, and submandibular lymph nodes using enzyme-linked immunosorbent assay (ELISA). Local tolerability was assessed after single and repeated subconjunctival injections using clinical observations, Draize scoring, and ophthalmic examinations.
Results:
OSIG inhibited Dextran Texas Red uptake in a concentration-dependent manner, with near-complete inhibition at 5%. Topical OSIG produced only transient conjunctival exposure and did not achieve sustained corneal concentrations. In contrast, subconjunctival administration resulted in sustained ocular surface exposure, with peak corneal concentration of 11,200.8 ng/g on Day 14 and measurable conjunctival exposure through 28 days. Serum exposure was detectable but lower than ocular surface tissue exposure. Subconjunctival OSIG was generally well tolerated after single and repeated dosing, with findings limited mainly to transient conjunctival redness and chemosis. Two clinical cases of ADC-associated ocular toxicity treated with topical OSIG were also reviewed.
Conclusions:
OSIG inhibits macropinocytosis in HCE-T and achieves sustained corneal and conjunctival exposure following subconjunctival administration. These findings support further evaluation of subconjunctival OSIG as a local strategy to mitigate ADC-associated corneal toxicity.