Inebilizumab, a B Cell-Depleting Anti-CD19 Antibody for the Treatment of Autoimmune Neurological Diseases: Insights from Preclinical Studies

Abstract

Exaggerated or inappropriate responses by B cells are an important feature in many types of autoimmune neurological diseases. The recent success of B-cell depletion in the treatment of multiple sclerosis (MS) has stimulated the development of novel B-cell-targeting therapies with the potential for improved efficacy. CD19 has emerged as a promising target for the depletion of B cells as well as CD19-positive plasmablasts and plasma cells. Inebilizumab (MEDI-551), an anti-CD19 antibody with enhanced antibody-dependent cell-mediated cytotoxicity against B cells, is currently being evaluated in MS and neuromyelitis optica. This review discusses the role of B cells in autoimmune neurological disorders, summarizes the development of inebilizumab, and analyzes the recent results for inebilizumab treatment in an autoimmune encephalitis mouse model. The novel insights obtained from these preclinical studies can potentially guide future investigation of inebilizumab in patients.

Structure-Based Approaches to Antigen-Specific Therapy of Myasthenia Gravis

“…These observations suggest that autoantibodies directed to nAChR α1 MIR play a major role in the pathogenesis of MG [41]. It is now clear that many MIR-directed autoantibodies bind a composite epitope consisting of the original MIR (α1, [67][68][69][70][71][72][73][74][75][76] and the N-terminal helix (α1, 2-14) (N-helix) and surrounding regions (α1, [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32]. The structural analyses above and published biochemical data suggest that some MIR-directed autoantibodies (e.g., mAb35 and mAb198) bind epitopes centered around the MIR/N-helix core region while others (e.g., mAb192) seems to require epitopes outside the MIR/N-helix core.…”

“…Using B cell surface marker CD20 [70][71][72] or possibly CD19 [73] as the target, disease-causing B cells can be depleted at the cost of killing normal B cells. For example, an ongoing clinical trial, NCT02110706, is testing if rituximab, which targets CD20 on B cells, can be a safe and beneficial therapeutics for MG.…”

Promise, Progress, and Pitfalls in the Search for Central Nervous System Biomarkers in Neuroimmunological Diseases: A Role for Cerebrospinal Fluid Immunophenotyping

“…B cell CD19 expression is broader than that of CD20 during B cell development and initiated earlier (pro-B cell stage). 102 Plasma cells are not targeted by anti-CD20. 103 The anti-CD19 monoclonal antibody, inebilizumab, has progressed to clinical trials for MS, NMO, and systemic sclerosis.…”

Development of a CD19 PET tracer for detecting B cells in a mouse model of multiple sclerosis

“…Alternatively, the lack of signal could have been due to CD20 not being expressed by plasmablasts and plasma cells known to be present in the CNS of MS patients [11,12].…”

“…In contrast to CD20-targeting tracers, a PET tracer for CD19 would provide a major advantage because of its potential to detect a broader range of B cell subsets, including pro-B cells, antibodysecreting plasmablasts, circulating plasma cells, and a subset of plasma cells in the bone marrow. Importantly, CD19 does not appear to undergo internalization and is not expressed on T cells (whereas CD20 is), making it a more attractive and specific imaging target [12]. Furthermore, tracers targeting CD19 will enable visualization of B cells that escape CD20 therapy, and ultimately assist with patient stratification, dosing, and therapy monitoring.…”