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Abstract #82538 Published in IGR 20-4
Rapid Development of Glaucoma Via ITV Nonselective ANGPT 1/2 Antibody: A Potential Role for ANGPT/TIE2 Signaling in Primate Aqueous Humor Outflow
Thackaberry EA; Zhou Y; Zuch de Zafra CL; Fuh G; Lee CV; Sanowar S; Ridgway JB; Kusi AM; Farman C; Booler H; Sheinson D; Rasmussen CA; Miller PE; Wakshull E; Yan M; Bantseev VInvestigative Ophthalmology and Visual Science 2019; 60: 4097-4108
PURPOSE: Investigate a significant, dose-related increase in IOP, leading to glaucomatous damage to the neuroretina and optic nerve following intravitreal (ITV) administration of a bispecific F(ab')2 [anti-VEGF/Angiopoietins [ANGPT]F(ab')2] molecule in adult monkeys. METHODS: ITV ocular tolerability and investigation of anti-VEGF/ANGPT F(ab')2 (blocking both ANGPT1 and ANGPT2) was done in monkeys; mechanistic studies were done in neonatal mice. RESULTS: Following the second ITV dose of anti-VEGF/ANGPT F(ab')2, all 1.5- and 4-mg/eye treated monkeys developed elevated IOP, which eventually was associated with optic disc cupping and thinning of the neuroretinal rim. Histopathologic examination showed nonreversible axonal degeneration in the optic nerves of animals administered 1.5 mg/eye and higher that was considered secondary to high IOP. Anti-ANGPT Fab also caused elevated IOP in monkeys, but anti-VEGF Fab did not contribute to the IOP increase. In addition, an anti-ANGPT2-selective antibody did not change IOP. In mice simultaneous blockade of ANGPT1 and ANGPT2 impaired the expansion and formation of Schlemm's canal (SC) vessels, similar to genetic ablation of Angpt1/Angpt2 and their receptor TIE2. As previously reported, blocking ANGPT2 alone did not affect SC formation in mice. CONCLUSIONS: Dual inhibition of ANGPT1/ANGPT2, but not ANGPT2 alone, leads to increased IOP and glaucomatous damage in monkeys. This confirms a role for TIE2/ANGPT signaling in the control of IOP in adults, a finding initially identified in transgenic mice. Dual pharmacologic inhibition of ANGPT1/ANGPT2 may affect aqueous drainage and homeostasis in adult monkeys and may be useful in developing novel models of glaucoma.
Full article
Classification:
3.8 Pharmacology (Part of: 3 Laboratory methods)
5.2 Primates (Part of: 5 Experimental glaucoma; animal models)
6.1.3 Factors affecting IOP (Part of: 6 Clinical examination methods > 6.1 Intraocular pressure measurement; factors affecting IOP)
3.9 Pathophysiology (Part of: 3 Laboratory methods)
