Structure of the LINGO-1–Anti-LINGO-1 Li81 Antibody Complex Provides Insights into the Biology of LINGO-1 and the Mechanism of Action of the Antibody Therapy

Abstract

Multiple sclerosis (MS) is an autoimmune-inflammatory disease of the central nervous system (CNS) with prominent demyelination and axonal injury. While most MS therapies target the immunologic response, there is a large unmet need for treatments that can promote CNS repair. LINGO-1 (leucine-rich repeat and Ig-containing Nogo receptor interacting protein-1) is a membrane protein selectively expressed in the CNS that suppresses myelination, preventing the repair of damaged axons. We are investigating LINGO-1 antagonist antibodies that lead to remyelination as a new paradigm for treatment of individuals with MS. The anti-LINGO-1 Li81 antibody,BIIB033, is currently in clinical trials and is the first MS treatment targeting CNS repair. Here, to elucidate the mechanism of action of the antibody, we solved the crystal structure of the LINGO-1-Li81 Fab complex and used biochemical and functional studies to investigate structurefunction relationships. Li81 binds to the convex surface of the leucine-rich repeat domain of LINGO-1 within repeats 4-8. Fab binding blocks contact points used in the oligomerization of LINGO-1 and produces a stable complex containing two copies each of LINGO-1 and Fab that results from a rearrangement of contacts stabilizing the quaternary structure of LINGO-1. The formation of the LINGO-1-Li81 Fab complex masks functional epitopes within the Ig domain of LINGO-1 that are important for its biologic activity in oligodendrocyte differentiation. These studies provide new insights into the structure and biology of LINGO-1 and how Li81 monoclonal antibody can block its function.

A decade from discovery to therapy: Lingo-1, the dark horse in neurological and psychiatric disorders

“…Just recently the crystalline tetrameric formation of Lingo-1 has been confirmed by Pepinsky et. al., in addition to showing for the first time that Lingo-1 is also present as a tetramer on cells expressing full-length Lingo-1 (Pepinsky et al, 2014). This tetrameric formation on transfected cells is indicative of oligomer formation being an intrinsic property of Lingo-1 in the absence of its ligands or co-receptors (Pepinsky et al, 2014).…”

“…Stage I clinical trials have demonstrated that BIIB033 is safe for use in humans, both in healthy controls, and multiple sclerosis patients, and has been found to be well tolerated, up to 100 mg/kg, and is able to cross the blood brain barrier resulting in cerebral spinal fluid levels of greater than 90% effective concentration when given at intravenous doses of greater than 10 mg/kg (Tran et al, 2012(Tran et al, , 2014. Further to this, structural studies examining how BIIB033 binds to Lingo-1 have shown that its binding to the convex surface of the leucine-rich repeat domain of Lingo-1 within repeats 4-8, blocks the Lingo-1-Lingo-1 contact points and prevents oligomerization of the protein (Pepinsky et al, 2014). This indicates that BIIB033 interferes with the ability of Lingo-1 to form homotetramers, with the rearrangement of the quaternary structure of…”

“…Lingo-1 providing a model for how the antibody inhibits Lingo-1 function in oligodendrocytes (Pepinsky et al, 2014). Phase II clinical trials for BIIB033 are currently underway, and will provide vital information on the impact of targeting Lingo-1 as a treatment for multiple sclerosis (Brugarolas and Popko, 2014).…”

Effect of retinoic acid on expression of LINGO-1 and neural regeneration after cerebral ischemia

“…Researches have shown that LINGO-1 inhibited differentiation of oligodendrocytes and synthesis of myelin through interactions of cells in multiple sclerosis [8] . Antibodies against LINGO-1 promoted the remyelination in multiple sclerosis patients [9] . Knockout of LINGO-1 gene promoted the differentiation of oligodendrocytes and remyelination [10] .…”

Extracellular cues influencing oligodendrocyte differentiation and (re)myelination

“…Even though direct effects on cells of the OLG lineage were not demonstrated in these studies, antibody antagonists of LINGO-1 were developed as the next step toward clinical intervention, and their use in preclinical animal studies provided great promise for promoting remyelination by antagonizing LINGO-1 function (Mi et al, 2009, 2007; Rudick et al, 2008; Sun et al, 2015; Zhang et al, 2015). These encouraging results led to the development of a fully human IgG1 monoclonal antibody (BIIB033/Li81) that binds human LINGO-1 with high affinity and specificity (Mi et al, 2013; Pepinsky et al, 2014, 2011). Results from phase I safety trials indicated that administration of BIIB033 is safe for use in humans and is well tolerated (Brugarolas and Popko, 2014; Tran et al, 2014).…”