The anti-NgR1 antibody, 1D9, rescues rat retinal ganglion cells after optic nerve transection and ocular hypertension-induced glaucoma

Abstract

The neuronal leucine rich repeat protein, Nogo66 receptor [NgR1], interacts with at least three CNS myelin proteins [Nogo, MAG and OMgp] and mediates the inhibition of neurite growth. Here we report a monoclonal anti-NgR1 antibody, 1D9, that in addition to inhibiting these interactions in vitro, exhibits neuroprotective properties in vitro and in vivo. Structural analyses performed on the co-crystal complex of the 1D9 Fab and a soluble fragment of NgR1 (sNgR310) indicate that this antibody binds near the junction of the N-terminus cap and leucine rich repeat domain on NgR1. Treatment with 1D9 protected primary neuronal cultures from insults derived from serum withdrawal. Direct intravitreal administration of 1D9 Fab, but not the full 1D9 mAb, consistently promoted the survival of retinal ganglion cells in an optic nerve transection model and an ocular hypertension induced glaucoma model in rat. The lack of activity of the full 1D9 mAb may be partially attributed to NgR1 activation via receptor cross-linking as demonstrated by rhoA activation assay. These results suggest that 1D9 Fab may confer neuroprotection to specific subsets of neurons. Equal contribution: B Hu, A Jirik, and Q Fu Corresponding authors: KF So and DHS Lee