Development of repebody for treating age-related macular degeneration

Abstract

Age-related macular degeneration (AMD) is the principal cause of irreversible vision loss in the elderly people. In AMD, the abnormal neovascularization into the retina is induced by the excess amount of vascular endothelial growth factor (VEGF) and proliferative angiogenic responses by the elevated levels of complement component C5a, leading to severe central vision loss. Therefore, inhibition of angiogenesis by neutralizing VEGF or C5a has been considered as a potent therapy for AMD. In this regard, we developed a novel therapeutic agent based on non-antibody scaffold, termed repebody, for treating of AMD. In Chapter 1, we have demonstrated that VEGF-specific repebody effectively suppresses the CNV formation. We developed a repebody with high affinity and specificity toward human VEGF. The repebody remarkably inhibited cellular proliferation and migration by preventing VEGF to binding to its receptors, resulting in blockade of VEGF-induced signaling pathways. It was shown that the repebody significantly suppressed the CNV formation and vascular leakage in vivo. Chapter 2 describes the development of high-affinity repebody targeting complement component 5a (C5a). We successfully developed C5a-specific repebody with low nanomolar binding affinity through module-based engineering and modular evolution approach. In order to obtain insight of interactions between the repebody and C5a, we determined the crystal structure of repebody/C5a complex. In consistent with the structural analysis, the resulting repebody was shown to significantly suppress C5a-induced proinflammatory responses of human monocytes by disrupting the interactions between C5a and its receptor. In this study, we successfully developed repebodies inhibiting the activity of VEGF and C5a, respectively. Our results suggest that the developed repebodies have great potentials in therapy of AMD as well as other diseases related in VEGF and C5a.