Evaluation of a therapeutic anti-TNF-α drug delivery system for ocular alkali burns

Abstract

Purpose : Ocular burns cause corneal inflammation, neovascularization (CNV) and scarring. We have shown that tumor necrosis factor alpha (TNF-α) is upregulated after burn and that prompt TNF-α inhibition improves corneal wound healing. However, systemic administration of TNF-α inhibitors can cause significant adverse events, while topical administration is limited by poor corneal bioavailability and the need for frequent drug application. This study was designed to test a novel drug delivery system (DDS) for sustained-release of TNF-α inhibitor to the ocular surface. We used a rabbit ocular alkali burn model to assess the efficacy of the DDS in terms of reduction of corneal CNV, opacity and improvement of corneal wound healing.

Methods : DDS was prepared using porous PDMS/PVA composite fabrication that was loaded with 80μg infliximab. Evaluation was performed in 6 Dutch-belted pigmented rabbits that received ocular alkali burn with 2N NaOH. Three rabbits received subconjunctival implantation of anti-TNF-α DDS and 3 sham DDS immediately after the burn. Rabbits were followed with photography for 3 months and analyzed for CNV, opacity and re-epithelialization. Inflammation was assessed using CD45 antibody in tissue sections.

Results : Rabbits treated with anti-TNF-α DDS achieved complete corneal re-epithelialization within 63.6 ± 7.5 days of burn, reduced CNV (0.13 ± 0.05 % of cornea area) and corneal opacity (central score = 2.17 ± 0.85; peripheral score = 0.33 ± 0.41 in a 0-4 scale), while sham DDS treated rabbits exhibited persistent epithelial defect until the end of the study (92 days), increased CNV (0.31 ± 0.14 % of cornea area, p<0.05) and corneal opacity (central score = 3.5 ± 0.57, p>0.05; peripheral score = 2.44 ± 1.41, p<0.05). Anti-TNF-α DDS was well tolerated. The number of CD45+ cells in anti-TNF-α DDS treated eyes was significantly lower (mean=4322 cells/ cornea) compared to sham DDS eyes (mean=17049 cells/ cornea, p<0.05). Infliximab was still present in the DDS 3 months after implantation, evident by anti-human IgG immunolocalization.

Conclusions : Sustained topical delivery of anti-TNF-α for the treatment of ocular alkali burn is feasible using the described DDS. Local anti-TNF-α therapy suppresses corneal inflammation and CNV, and improves wound healing. The described DDS may be beneficial to a variety of ocular surface diseases amenable to biologic therapy.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.