Selectively targeting disease‐restricted secretogranin III to alleviate choroidal neovascularization

Abstract

Choroidal neovascularization (CNV), a leading cause of blindness in the elderly, is routinely treated with vascular endothelial growth factor (VEGF) inhibitors that have limited efficacy and potentially adverse side effects. An unmet clinical need is to develop novel therapies against other angiogenic factors for alternative or combination treatment to improve efficacy and safety. We recently described secretogranin III (Scg3) as a disease-selective angiogenic factor, causally linked to diabetic retinopathy and acting independently of the VEGF pathway. An important question is whether such a disease-selective Scg3 pathway contributes to other states of pathological angiogenesis beyond diabetic retinopathy. By applying a novel in vivo endothelial ligand binding assay, we found that the binding of Scg3 to CNV vessels in live mice was markedly increased over background binding to healthy choriocapillaris and blocked by an Scg3-neutralizing antibody, whereas VEGF showed no such differential binding. Intravitreal injection of anti-Scg3 humanized antibody Fab (hFab) inhibited Matrigel-induced CNV with similar efficacy to the anti-VEGF drug aflibercept. Importantly, a combination of anti-Scg3 hFab and aflibercept synergistically alleviated CNV. Homozygous deletion of the Scg3 gene markedly reduced CNV severity and abolished the therapeutic activity of anti-Scg3 hFab, but not aflibercept, suggesting a role for Scg3 in VEGF-independent CNV pathogenesis and therapy. Our work demonstrates the stringent disease selectivity of Scg3 binding and positions anti-Scg3 hFab as a next-generation disease-targeted anti-angiogenic therapy for CNV.

Secretogranin III Selectively Promotes Vascular Leakage in the Deep Vascular Plexus of Diabetic Retinopathy

“…As a second approach to characterize the apparent selective retinal targeting of Scg3 and its predominant role in DR-related vascular leakage, we compared retinal vascular structures of wild-type and Scg3-deficient (Scg3 −/− ) mice. These mice were previously shown to present normal viability, body weight, behavior, fertility, and retinal development [ 18 , 21 , 22 ]. As shown in Figure 7 a, histological analyses of vascular structures in flat-mount retinas revealed no differences between wild-type and Scg3-deficient mice.…”

“…Identification of Scg3 binding to the deep plexus provides further validation of the novel binding assays developed by our group to screen for functional ligands in vivo [ 18 , 21 , 45 ]. Using the same techniques in a mouse model of ROP, we recently reported clustered binding of Scg3 to the superficial plexus coincident with pathological retinal neovascularization [ 18 ].…”

Safety and Efficacy of Systemic Anti-Scg3 Therapy to Treat Oxygen-Induced Retinopathy

“…This is supported by their distinct endothelial binding activities and patterns to OIR vs. healthy retinal vessels as well as CNV vs. healthy choroidal vessels [17,18]. Indeed, the combination of anti-Scg3 hFab and aflibercept synergistically allevi-ated CNV [17], likely through different mechanisms of action. The expression of Scg3, VEGF and VEGFR2 in OIR and healthy retinas has been previously reported [18,41].…”

“…Although anti-Scg3 hFab and aflibercept have similar efficacy to alleviate OIR, Scg3 and VEGF were reported with distinct receptor signaling pathways [15]. This is supported by their distinct endothelial binding activities and patterns to OIR vs. healthy retinal vessels as well as CNV vs. healthy choroidal vessels [17,18]. Indeed, the combination of anti-Scg3 hFab and aflibercept synergistically allevi-ated CNV [17], likely through different mechanisms of action.…”

“…All procedures of animal studies were approved by the Institutional Animal Care and Use Committee at Baylor College of Medicine. Anti-Scg3 hFab derived from anti-Scg3 mAb was engineered by Everglades Biopharma, LLC [17,18].…”