Targeting key angiogenic pathways with a bispecific Cross MA b 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.

Bevacizumab Injection in Patients with Neovascular Age-Related Macular Degeneration Increases Angiogenic Biomarkers

“…27 Single and combined inhibition of angiopoietin 2 and VEGF-A are showing promising results in the management of ocular angiogenesis. 28 Endothelin 1 is considered a potent endogenous vasoconstrictor in small vessels, has an important regulatory role for retinal blood flow, and also may induce angiogenesis. 15 Heparin-binding EGF-like growth factor is a potent stimulator of cell proliferation and migration, promoting angiogenesis in processes such as wound healing and recovery from injury.…”

“…There are several alternative antiangiogenic ocular drugs under development. Fovista (E10030; Ophthotech, New York, NY), 36 CrossMAb (RG7716; Roche, Basel, Switzerland), 28 Conbercept (KH902; Chengdu Kanghong Biotech Co, Ltd, Sichuan, China), 37 Pazopanib (GW786034; GlaxoSmithKline, Research Triangle Park, NC), 38 AdPEDF (GenVec, Inc, Gaithersburg, MD), 39 and many others are showing interesting outcomes. In the future, we likely will have a combination of angiogenesis inhibitors, or a more effective one, that concurrently addresses various vasogenic mediators and pathways.…”

Efficacy of simultaneous VEGF ‐A/ ANG ‐2 neutralization in suppressing spontaneous choroidal neovascularization

“…JR5558 mice were supplied from a colony that was also used by Regula et al () and maintained at Charles River, Germany, and sent to F. Hoffmann‐La Roche Ltd. at 4–5 weeks old. All animals received food and water ad libitum , in a 12‐h day/night cycle, temperature‐controlled environment.…”

“…Currently, anti‐VEGF‐A therapies are the standard of care for a number of retinal neovascular diseases, including neovascular age‐related macular degeneration, and diabetic macular edema (Kim & D'Amore, ). However, additional ANG‐2 neutralization (Kienast et al , ; Regula et al , ) or Tie‐2 activation (Campochiaro et al , ) may be a way to enhance efficacy of treatment for these diseases. We aimed to replicate an in vivo study (Regula et al , ) with a bispecific anti‐VEGF‐A/ANG‐2 antibody in a spontaneous chronic CNV mouse model using JR5558 mice (Nagai et al , ), whose phenotype has been described differently elsewhere (Hasegawa et al , ).…”

Anti‐ VEGF ‐A/ ANG 2 combotherapy limits pathological angiogenesis in the eye: a replication study

“…In human eyes, higher levels of ANG2 correlate with disease severity in wet AMD (Ng et al , ). Increased intraocular ANG2 levels were also detected in patients with diabetic retinopathy and retinal vein occlusion, indicating a potential medical significance of targeting ocular ANG2 (Regula et al , ).…”