title: Targeting key angiogenic pathways with a bispecific CrossMAb optimized for neovascular eye diseases.
abstract: Anti-angiogenic therapies using biological molecules that neutralize vascular endothelial growth factor-A (VEGF-A) have revolutionized treatment of retinal vascular diseases including age-related macular degeneration (AMD). This study reports preclinical assessment of a strategy to enhance anti-VEGF-A monotherapy efficacy by targeting both VEGF-A and angiopoietin-2 (ANG-2), a factor strongly upregulated in vitreous fluids of patients with retinal vascular disease and exerting some of its activities in concert with VEGF-A. Simultaneous VEGF-A and ANG-2 inhibition was found to reduce vessel lesion number, permeability, retinal edema, and neuron loss more effectively than either agent alone in a spontaneous choroidal neovascularization (CNV) model. We describe the generation of a bispecific domain-exchanged (crossed) monoclonal antibody (CrossMAb; RG7716) capable of binding, neutralizing, and depleting VEGF-A and ANG-2. RG7716 showed greater efficacy than anti-VEGF-A alone in a non-human primate laser-induced CNV model after intravitreal delivery. Modification of RG7716's FcRn and FcγR binding sites disabled the antibodies' Fc-mediated effector functions. This resulted in increased systemic, but not ocular, clearance. These properties make RG7716 a potential next-generation therapy for neovascular indications of the eye.
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center München, Penzberg, Germany.
authors.forename: Jörg T
authors.initials: JT
authors.lastname: Regula
authors.affiliation: Department of Ocular Biology and Therapeutics, UCL London Institute of Ophthalmology, London, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Lundh von Leithner
authors.affiliation: Department of Ocular Biology and Therapeutics, UCL London Institute of Ophthalmology, London, UK.|Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Richard
authors.initials: R
authors.lastname: Foxton
authors.affiliation: Translational Pre-Clinical Model Platform, Singapore Eye Research Institute The Academia, Singapore, Singapore.|The Ophthalmology & Visual Sciences Academic Clinical Program, DUKE-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: Veluchamy A
authors.initials: VA
authors.lastname: Barathi
authors.affiliation: Translational Pre-Clinical Model Platform, Singapore Eye Research Institute The Academia, Singapore, Singapore.
authors.forename: Chui Ming Gemmy
authors.initials: CM
authors.lastname: Cheung
authors.affiliation: Translational Pre-Clinical Model Platform, Singapore Eye Research Institute The Academia, Singapore, Singapore.
authors.forename: Sai Bo
authors.initials: SB
authors.lastname: Bo Tun
authors.affiliation: Translational Pre-Clinical Model Platform, Singapore Eye Research Institute The Academia, Singapore, Singapore.
authors.forename: Yeo Sia
authors.initials: YS
authors.lastname: Wey
authors.affiliation: Department of Ocular Biology and Therapeutics, UCL London Institute of Ophthalmology, London, UK.
authors.forename: Daiju
authors.initials: D
authors.lastname: Iwata
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Dostalek
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center München, Penzberg, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Moelleken
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center München, Penzberg, Germany.
authors.forename: Kay G
authors.initials: KG
authors.lastname: Stubenrauch
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Everson
authors.initials: E
authors.lastname: Nogoceke
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Widmer
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Pamela
authors.initials: P
authors.lastname: Strassburger
authors.affiliation: Department of Ophthalmology, Goethe University, Frankfurt am Main, Germany.|Department of Ophthalmology, Ruprecht Karls University, Heidelberg, Germany.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Koss
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Zürich, F. Hoffmann-La Roche Ltd, Zürich, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Klein
authors.affiliation: Department of Ocular Biology and Therapeutics, UCL London Institute of Ophthalmology, London, UK.
authors.forename: David T
authors.initials: DT
authors.lastname: Shima
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland guido.hartmann@roche.com.
authors.forename: Guido
authors.identifier: 0000-0002-5967-9711
authors.initials: G
authors.lastname: Hartmann
mesh_terms: D042702:Angiopoietin-2 / Q000037:antagonists & inhibitors*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000302:isolation & purification / Q000494:pharmacology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005128:Eye Diseases / Q000188:drug therapy* / Q000473:pathology; D007155:Immunologic Factors / Q000008:administration & dosage* / Q000302:isolation & purification / Q000494:pharmacology; D008252:Macaca fascicularis; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
chemical_list: D042702:Angiopoietin-2; D000911:Antibodies, Monoclonal; D007155:Immunologic Factors; D042461:Vascular Endothelial Growth Factor A
keywords: Fc receptor; age‐related macular degeneration; angiogenesis; angiopoietin‐2; vascular endothelial growth factor