Targeting key angiogenic pathways with a bispecific CrossMAb optimized for neovascular eye diseases. Issue 11 (14th October 2016)

• Record Type: Journal Article
• Authors: Regula, Jörg T; Lundh von Leithner, Peter; Foxton, Richard; Barathi, Veluchamy A; Cheung, Chui Ming Gemmy; Bo Tun, Sai Bo; Wey, Yeo Sia; Iwata, Daiju; Dostalek, Miroslav; Moelleken, Jörg; Stubenrauch, Kay G; Nogoceke, Everson; Widmer, Gabriella; Strassburger, Pamela; Koss, Michael J; Klein, Christian; Shima, David T; Hartmann, Guido
• Is Part Of: EMBO molecular medicine. Volume 8:Issue 11(2016)
• Page Start: 1265
• Page End: 1288
• Publication Date: 2016-10-14
• Subjects: age‐related macular degeneration -- angiogenesis -- angiopoietin‐2 -- Fc receptor -- vascular endothelial growth factor; Molecular biology -- Periodicals; Medical genetics -- Periodicals; Pathology, Molecular -- Periodicals; 616.04205
• DOI: 10.15252/emmm.201505889
• Languages: English
• ISSNs: 1757-4676

Abstract

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. Synopsis: The ratio of angiopoietins ANG‐1 and ANG‐2 regulates vessel quiescence and neoangiogenesis as well as barrier function. It also acts as a switch from health to neovascular eye diseases. ANG‐2, but not ANG‐1 levels are strongly upregulated in neovascular eye diseases. ANG‐2 works in concert with VEGF‐A to mediate pathological angiogenesis and endothelial dysfunction. Combined inhibition of ANG‐2 and VEGF‐A is more efficacious than anti‐VEGF‐A monotherapy in rodent models of choroidal neovascularization. The combination prevents vessel leakiness and neovascularization and its consequences such as increased retinal apoptosis or loss of retinal functionality. A bispecific antibody (CrossMAb RG7716) was generated with a modified Fc region optimized for use in ophthalmology. It reduced lesion severity better than anti‐VEGF‐A monotherapy in a laser‐induced model of CNV in non‐human primates. Abstract : The ratio of angiopoietins ANG‐1 and ANG‐2 regulates vessel quiescence and neoangiogenesis as well as barrier function. It also acts as a switch from health to neovascular eye diseases.