Novel mechanism of binding for a domain antibody based inhibitor 1 Novel interaction mechanism of a domain antibody based inhibitor of human vascular endothelial growth factor with greater potency than ranibizumab and bevacizumab and improved capacity over aflibercept

A potent VEGF inhibitor with novel antibody architecture and antigen binding mode has been developed. The molecule, hereafter referred to as VEGF dual dAb a (domain antibody), was evaluated in vitro for binding to VEGF and for potency in VEGF driven models and compared with other anti-VEGF biologics that have been used in ocular anti-angiogenic therapeutic regimes. VEGF dual dAb is more potent than bevacizumab and ranibizumab for VEGF binding and inhibition of VEGF RBA b (receptor binding assay) formats and when compared using in vitro models of angiogenesis; and displays comparable inhibition to aflibercept, (Eylea). VEGF dual dAb is dimeric and each monomer contains two distinct anti-VEGF domain antibodies attached via linkers to a human IgG1 Fc domain. Mechanistically, the enhanced in vitro potency of VEGF dual dAb in comparison to other anti-VEGF biologics can be explained by increased binding stoichiometry. A consistent model of the target engagement has been built based on the X-ray complexes of each of the two isolated domain antibodies with the VEGF antigen.