A Pharmacodynamic Analysis of Choroidal Neovascularization in a Porcine Model Using Three Targeted Drugs

Abstract

PurposeTo compare the efficacy of microneedle-delivered suprachoroidal (SC) pazopanib to intravitreal (Ivit) delivery of pazopanib, bevacizumab, or a fusion protein hI-con1 versus vehicle controls on choroidal neovascularization (CNV) growth in a pig model.MethodsForty-one pigs were injected on the day of CNV induction (hI-con1 on postinduction day 14) with either 2.5 mg Ivit bevacizumab (n = 9), 1 mg Ivit pazopanib (n = 9), 300 Ivit μg hI-con1 (n = 4), or 1 mg SC pazopanib (n = 9), vs. 10 vehicle controls (3 SC + 7 Ivit = 10). Pigs were euthanized at week 2 (11), 3 (8), 4 (11), and 8 (11), and eyes were fixed for histology. The size of the CNV was determined from histology, and CNV height was the primary outcome measure. Immunostaining for cytotoxic T-cells was performed in the hI-con1 study.ResultsIn 39 of 41 (95%) eyes, type 2 CNV lesions were identified. One CNV lesion was lost during dissection. One animal was euthanized due to surgical complications. For mean CNV size comparisons, Ivit pazopanib had smaller mean height measurements (90 ± 20 μm) versus controls (180 ± 20 μm; P = 0.009), and Ivit pazopanib had smaller maximum CNV height (173 ± 43 μm) compared to SC pazopanib (478 ± 105 μm; P = 0.018). The mean lesion size in hI-con1–treated animals trended smaller than in controls (P = 0.11). Immunostaining did not detect cytotoxic T-cells.ConclusionsIntravitreal pazopanib and to a lesser extent hI-con1 reduced the size of CNV lesions. The pig model has nearly a 100% rate of type 2 CNV induction and is a reliable preclinical model with pharmacodynamics similar to humans.

Correlation of spectral domain optical coherence tomography with histology and electron microscopy in the porcine retina

“…The rapid development of OCT technology since its inception in 1991 has provided exquisite methods to identify and evaluate multiple layers of the eye wall and eye tissue, including the vitreoretinal interface, retina, RPE, Bruch membrane, and choroid (Huang et al, 1991). The pig is being employed increasingly as a large animal model for experimental and preclinical studies for human diseases, including retinal vascular (Hein et al, 2012; Hein et al, 2010; Hein et al, 2016) and degenerative diseases (Mones et al, 2016; Scott et al, 2014), and choroidal neovascularization (Tran et al, 2017). Despite the widespread adoption of SD-OCT instrumentation in research laboratories, histologic correlation of the porcine retina with SD-OCT data remains limited.…”

Treating Tissue Factor–Positive Cancers with Antibody–Drug Conjugates That Do Not Affect Blood Clotting

“…Finally, the antibodies described herein could also be prioritized for the treatment of other diseases associated with upregulation of membranous TF expression, such as macular degeneration (49). A FVII-Fc fusion protein that binds TF reduces the size of choroid neovascular (CNV) lesions in various animal models (50,51). With the binding affinities of a subset of the anti-TF antibodies below the affinity of FVII for TF (52), some of the antibodies could be more efficacious than the FVII-Fc fusion protein.…”

The suprachoroidal space as a route of administration to the posterior segment of the eye

“…SCS delivery can result in high bioavailability in the sclera, choroid, and RPE[28, 32, 36, 59, 61, 66, 68–70, 88, 89]. For example, a small molecule HIF-1 inhibitor injected into the SCS of rats distributed throughout the choroid and retina, and prevented choroidal neovascularization in an animal model with selective destruction of Bruch’s membrane[69].…”

“…No studies have yet used SCS delivery for therapeutic effect on the RPE. Studies have shown that choroidal neovascularization is more effectively treated with intravitreal injections of a receptor tyrosine kinase inhibitor than SCS injections, although the authors noted incomplete delivery with the SCS injection[89]. …”