Integrin α5β1 inhibitor JSM6427 combats CNV in animal study Intravitreal JSM6427, a potent and selective inhibitor of integrin α5β1, provided dose-dependent inhibition of choroidal neovascularization (CNV) in monkey and rabbit experimental models; suggesting that JSM6427 may provide a new approach for the treatment of ocular neovascular diseases such as age-related macular degeneration (AMD) in humans.

Integrins, which are transmembrane receptors composed of α and β subunits that mediate binding to extracellular matrix or other cellular receptors, have long been known to have a role in angiogenesis. In particular, α5β1 (the only known α5 integrin) has been defined most clearly as proangiogenic.

Normal vessels express low levels of α5β1, while expression is significantly upregulated on tumor vessels and in response to angiogenic factors. In the eye, α5β1 was highly expressed on experimentally induced CNV membranes. The interaction between α5β1 and fibronectin has been found to promote adhesion, proliferation, and cell signaling in vascular endothelial cells.

JSM6427 is a highly selective, small-molecule inhibitor of α5β1 that has been shown to induce apoptosis of endothelial cells cultured on fibronectin and to inhibit fibronectin-mediated signaling in cultured RPE cells. Systemic administration of JSM6427 induced regression of neovascular lesions in a murine model of CNV, while an α5β1-blocking monoclonal antibody inhibited laser-induced CNV in a monkey model. Together these findings support a role for α5β1 in ocular neovascular diseases such as AMD.

Methods and Results

JSM6427 selectivity for α5β1 was evaluated by in vitro binding assays while the ability of JSM6427 to inhibit CNV was investigated in a laser-induced monkey model and a growth factor–induced rabbit model. Intravitreal injections of JSM6427 (100, 300, or 1000 µg) or vehicle were administered immediately after the CNV induction procedure and at weekly intervals for 4 weeks. Fluorescein angiography was performed weekly. Ocular tolerability was evaluated ophthalmoscopically and histologically in both models; additional assessments in monkeys included electroretinography, biomicroscopy, pathological examination, and analysis of JSM6427 pharmacokinetics.

JSM6427 was highly selective for the α5β1-fibronectin interaction. Weekly intravitreal injections of JSM6427 resulted in a statistically significant dose-dependent inhibition of CNV in laser-induced and growth factor–induced models without any ocular JSM6427-related adverse effects. JSM6427 was cleared through the systemic circulation with no evidence of systemic accumulation.

Discussion and Conclusions

JSM6427 was previously shown to inhibit neovascularization in murine CNV, hypoxia-induced, and corneal models, suggesting that the α5β1-fibronectin interaction is an active contributor to angiogenesis in ocular neovascular disease. The present study extends these findings by demonstrating that JSM6427 blocks this interaction with high selectivity and potency, providing a dose-dependent reduction in CNV without evidence of ocular or retinal toxic effects.

A notable function of integrins is that they provide a linkage between extracellular molecules and the actin-based microfilament system; in many cases, proliferative responses to soluble growth factors are dependent on integrin-mediated adherence to extracellular substrates. Blocking angiogenesis through inhibition of integrin-mediated signaling has the potential to inhibit the cellular responses to growth factors as well as cytokines and other inflammatory mediators. The findings of the present study demonstrating that JSM6427 reduced the formation of CNV induced by sustained suprachoroidal release of VEGF and basic fibroblast growth factor (bFGF) support a new mode of action for JSM6427 that differentiates it from recent therapeutic approaches based on VEGF inhibition.

The results of the pharmacokinetic analysis showed that there was detectable systemic exposure after intravitreal injection of JSM6427 in monkeys, rapidly declining over 24 hours. For application in clinical trials, a sustained-release formulation of JSM6427 that will enable a continuous low-dose delivery with no significant systemic exposure is currently under development and is expected to be the targeted method of administration.

Subsequent to the positive results of these preclinical studies, a phase 1 clinical trial evaluating intravitreal JSM6427 in treating neovascular AMD is under way (clinicaltrials.gov identifier: NCT00536016). The trial includes a single-dose study (ranging from 0.15-1.5 mg per eye) and a repeated-dose study in which 4 weekly injections with the same dose range will be administered.

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Arch Ophthalmol. 2009 Oct;127(10):1329-35