Ozanezumab is a monoclonal antibody (mAb) designed for the treatment of amyotrophic lateral sclerosis (ALS) and multiple sclerosis. Ozanezumab targets a protein called Neurite Outgrowth Inhibitor (NOGO-A) or Reticulon 4. NOGO-A is a protein that in humans is encoded by the RTN4 gene that has been identified as an inhibitor of neurite outgrowth specific to the central nervous system. NOGO-A is found at higher than normal levels in persons with motor neurone disease (MND). This drug was developed by GlaxoSmithKline under the identifier GSK 1223249.
Nogo-A is a high molecular weight transmembrane protein that was initially identified as a potent myelin-associated inhibitor of axonal growth and regeneration expressed mostly by oligodendrocytes. It stimulates a receptor complex consisting of the Nogo66 receptor NgR1, the adaptor molecule Lingo-1, and effector components p75/Troy, which leads to the intracellular activation of the small GTPase RhoA that mediates actin depolymerization and the collapse or retraction of neurites. Nogo-A is the longest of several splice forms of the Nogo/reticulon (RTN)-4 gene and protein expression is enriched in the brain and spinal cord of rats and humans. Neuronal Nogo-A plays a role in central nervous system development and plasticity and significant time- and region-specific changes in Nogo-A expression are observed during the development of the human brain. Although the exact role of Nogo-A protein in development is not well understood, there is evidence to suggest that Nogo-A is associated with the regulation of neuronal synapse morphology and architecture, possibly via cytoskeletal reorganization, with emerging roles for Nogo-A in the stabilisation of neuronal networks, either developmentally or during the processes of memory consolidation in the mature nervous system. Indeed, Nogo-A may represent an important regulator of neuronal plasticity associated with learning and Nogo-A down regulation is associated with altered synaptic plasticity during aging and may play a role in age-related cognitive decline. There are also reports linking Nogo-A and NgR with schizophrenia. Other research suggests a role for Nogo-A in the neuronal response to hypoxia and oxidative stress and as a negative regulator of central nervous system (CNS) angiogenesis. These findings demonstrate the complexity of the emerging biological functions of Nogo-A protein in the CNS. Ozanezumab specifically binds to the transmembrane protein Nogo-A, which is a myelin-associated neurite outgrowth inhibitor, and thereby neutralizes and/or antagonizes its biological function. Anti-Nogo-A antibodies have been reported to enhance neurite outgrowth in vitro and functional recovery in vivo of neurons in a number of different animal models of human neurodegenerative diseases. It is hypothesized that by neutralizing Nogo-A-mediated inhibition of neurodegeneration, ozanezumab may be a useful therapy for neurological diseases characterized by CNS axonal injury.
Fig.1 Mechanism of action of Ozanezumab