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Tine Van Bergen, Sara Van de Veire, Evelien Vandewalle, Lieve Moons, Jean Herman, Victoria Smith, Ingeborg Stalmans; Targeting LOXL2 With An Inhibitory Monoclonal Antibody (AB0023): New Therapeutic Approach For Ocular Diseases Associated With Fibrosis. Invest. Ophthalmol. Vis. Sci. 2011;52(14):4547.
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Lysyl oxidase-like protein 2 (LOXL2) is known to be involved in the crosslinking of collagen and elastin, and also to play a role in "aberrant" wound healing or fibrosis. We have previously shown that LOXL2 was upregulated in a rabbit model of glaucoma surgery and a mouse model of choroidal neovascularization (CNV). The aim of this study was to investigate the efficacy of a monoclonal antibody against LOXL2 (AB0023) in both preclinical models.
Treatment with AB0023 (study eye) and vehicle (control eye) was initiated in rabbits (n=6) on day 0 after trabeculectomy by giving an intracameral injection (0.6 mg) and a subconjunctival (SC) injection (0.3 mg). Thereafter, repeated injections were given twice a week SC (0.3 mg) until 30 days after the surgery. In C75Bl/6 mice, CNV was induced by placing 3 laser spots. The anti-LOXL2 antibody (n =10) and vehicle (n=10) were administered every other day intraperitoneally (0.75mg) until day 35. Treatment outcome was studied by clinical investigation (IOP, bleb area and bleb survival) and by analysis of angiogenesis (CD31), inflammation (CD45) and collagen deposition (Sirius Red).
In the trabeculectomy model, treatment using the anti-LOXL2 antibody significantly improved surgical outcome by increasing bleb area (p<0.001) and bleb survival (p=0.0005) compared to control. Analyses of the different immunohistological stainings on day 30 showed a significant reduction in angiogenesis (47%; p=0.01), inflammation (34%; p=0.0003) and fibrosis (16%; p=0.01) compared to control. In the CNV-model, AB0023 was also able to significantly reduce angiogenesis (43%; p=0.0003), inflammation (34%; p=0.0005) and fibrosis (26%; p=0.006) on day 35 compared to vehicle treated mice.
Targeting LOXL2 with an inhibitory monoclonal antibody (AB0023) is efficacious in reducing angiogenesis, inflammation and fibrosis in a rabbit model of glaucoma surgery, and a murine model of CNV. These results render LOXL2 an appealing target for ocular fibrotic diseases, and point to the potential therapeutic benefits of the monoclonal antibody AB0023 in these diseases.
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