title: 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.
abstract: A potent VEGF inhibitor with novel antibody architecture and antigen binding mode has been developed. The molecule, hereafter referred to as VEGF dual dAb (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, inhibition of VEGF receptor binding assays (RBAs), and VEGF-driven 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.
authors.affiliation: From BioPharm Innovation.
authors.forename: Adam
authors.initials: A
authors.lastname: Walker
authors.affiliation: Molecular Discovery Research.
authors.forename: Chun-Wa
authors.initials: CW
authors.lastname: Chung
authors.affiliation: Molecular Discovery Research.
authors.forename: Margarete
authors.initials: M
authors.lastname: Neu
authors.affiliation: From BioPharm Innovation.
authors.forename: Manish
authors.initials: M
authors.lastname: Burman
authors.affiliation: From BioPharm Innovation.
authors.forename: Thil
authors.initials: T
authors.lastname: Batuwangala
authors.affiliation: From BioPharm Innovation.
authors.forename: Gavin
authors.initials: G
authors.lastname: Jones
authors.affiliation: From BioPharm Innovation.
authors.forename: Chi-Man
authors.initials: CM
authors.lastname: Tang
authors.affiliation: From BioPharm Innovation.
authors.forename: Michael
authors.initials: M
authors.lastname: Steward
authors.affiliation: BioPharm Discovery, and.
authors.forename: Michael
authors.initials: M
authors.lastname: Mullin
authors.affiliation: BioPharm Discovery, and.
authors.forename: Nadia
authors.initials: N
authors.lastname: Tournier
authors.affiliation: BioPharm Discovery, and.
authors.forename: Alan
authors.initials: A
authors.lastname: Lewis
authors.affiliation: From BioPharm Innovation,; BioPharm Discovery, and.
authors.forename: Justyna
authors.initials: J
authors.lastname: Korczynska
authors.affiliation: BioPharm Process Research, GSK Medicine's Research Centre, Stevenage, Herts SG1 2NY, United Kingdom.
authors.forename: Vicky
authors.initials: V
authors.lastname: Chung
authors.affiliation: From BioPharm Innovation,. Electronic address: ian.r.catchpole@gsk.com.
authors.forename: Ian
authors.initials: I
authors.lastname: Catchpole
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000068258:Bevacizumab / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D000069579:Ranibizumab / Q000494:pharmacology*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000494:pharmacology*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D061905:Single-Domain Antibodies / Q000737:chemistry / Q000494:pharmacology*; D013552:Swine; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*
chemical_list: D020533:Angiogenesis Inhibitors; D011993:Recombinant Fusion Proteins; D061905:Single-Domain Antibodies; D042461:Vascular Endothelial Growth Factor A; C533178:aflibercept; D000068258:Bevacizumab; D040262:Receptors, Vascular Endothelial Growth Factor; D000069579:Ranibizumab
keywords: angiogenesis; antibody engineering; drug action; protein-protein interaction; retinal degeneration; single-domain antibody (sdAb, nanobody); vascular endothelial growth factor (VEGF)