Elezanumab, a clinical stage human monoclonal antibody that selectively targets repulsive guidance molecule A to promote neuroregeneration and neuroprotection in neuronal injury and demyelination models

• Published in: Neurobiology of disease 2021-11, Vol.159, p.105492, Article 105492
• Main Authors: Huang, Lili, Fung, Emma, Bose, Sahana, Popp, Andreas, Böser, Preethne, Memmott, John, Kutskova, Yuliya A., Miller, Renee, Tarcsa, Edit, Klein, Corinna, Veldman, Geertruida M., Mueller, Bernhard K., Cui, Yi-Fang
• Format: Article
• Language: English
• Subjects: ABT-207; ABT-555; Animals; BMP; Cuprizone - toxicity; Demyelination; Elezanumab; Encephalomyelitis, Autoimmune, Experimental - chemically induced; Encephalomyelitis, Autoimmune, Experimental - physiopathology; GPI-Linked Proteins - antagonists & inhibitors; Mice; Monoamine Oxidase Inhibitors - toxicity; Monoclonal antibody; Nerve Regeneration - drug effects; Nerve Regeneration - physiology; Nerve Tissue Proteins - antagonists & inhibitors; Neuroprotection; Neuroprotection - drug effects; Neuroregeneration; Optic Nerve - drug effects; Optic Nerve - physiology; Optic nerve crush; Optic Nerve Injuries - physiopathology; Optic neuritis; Optic Neuritis - physiopathology; Recovery of Function - drug effects; Recovery of Function - physiology; Remyelination; Retina - drug effects; RGMa; Surface Plasmon Resonance; Targeted EAE
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2021.105492

Repulsive guidance molecule A (RGMa) is a potent inhibitor of axonal growth and a regulator of neuronal cell death. It is up-regulated following neuronal injury and accumulates in chronic neurodegenerative diseases. Neutralizing RGMa has the potential to promote neuroregeneration and neuroprotection. Previously we reported that a rat anti-N terminal RGMa (N-RGMa) antibody r5F9 and its humanized version h5F9 (ABT-207) promote neuroprotection and neuroregeneration in preclinical neurodegenerative disease models. However, due to its cross-reactivity to RGMc/hemojuvelin, ABT-207 causes iron accumulation in vivo, which could present a safety liability. Here we report the generation and characterization of a novel RGMa-selective anti-N-RGMa antibody elezanumab, which is currently under Phase 2 clinical evaluation in multiple disease indications. Elezanumab, a human monoclonal antibody generated by in vitro PROfusion mRNA display technology, competes with ABT-207 in binding to N-RGMa but lacks RGMc cross-reactivity with no impact on iron metabolism. It neutralizes repulsive activity of soluble RGMa in vitro and blocks membrane RGMa mediated BMP signaling. In the optic nerve crush and optic neuritis models, elezanumab promotes axonal regeneration and prevents retinal nerve fiber layer degeneration. In the spinal targeted experimental autoimmune encephalomyelitis (EAE) model, elezanumab promotes axonal regeneration and remyelination, decreases inflammatory lesion area and improves functional recovery. Finally, in the mouse cuprizone model, elezanumab reduces demyelination, which is consistent with its inhibitory effect on BMP signaling. Taken together, these preclinical data demonstrate that elezanumab has neuroregenerative and neuroprotective activities without impact on iron metabolism, thus providing a compelling rationale for its clinical development in neurodegenerative diseases. •Elezanumab binds N-terminal RGMa, blocks BMP signaling and lacks RGMc cross-reactivity with no impact on iron metabolism•Elezanumab promotes axonal regeneration and prevents RNFL degeneration in optic nerve crush and neuritis models•Elezanumab promotes axonal regeneration and improves functional recovery in a spinal tEAE model•Elezanumab reduces demyelination in a cuprizone-induced demyelination model