Safety and tolerability of an anti-CD19 monoclonal antibody, MEDI-551, in subjects with systemic sclerosis: a phase I, randomized, placebo-controlled, escalating single-dose study

Abstract

BackgroundSystemic sclerosis (SSc) is a clinically heterogeneous, life-threatening disease characterized by fibrosis, microvasculopathy, and autoimmunity. Extensive nonclinical and clinical data implicate B cells in the pathogenesis of SSc. MEDI-551 is an investigational humanized monoclonal antibody that targets the B cell surface antigen CD19 and mediates antibody-dependent, cell-mediated cytotoxicity of B cells. This clinical study evaluated the safety and tolerability, pharmacokinetics, and pharmacodynamics of MEDI-551 in subjects with SSc.MethodsThis phase I multicenter, randomized, double-blind, placebo-controlled, single escalating dose study enrolled adult subjects with either limited or diffuse cutaneous SSc. A single intravenous dose of MEDI-551 was administered, and safety and tolerability were evaluated. MEDI-551 pharmacokinetics (PK), pharmacodynamics, and immunogenicity were also assessed. Safety assessments included the incidence of adverse events and changes in clinical and laboratory results. MEDI-551 serum concentrations, effects on circulating and tissue B cells and plasma cells (PCs), and antidrug antibodies were analyzed. Modified Rodnan skin score (MRSS) and pulmonary function tests were used to explore the clinical effect of MEDI-551.ResultsThe study enrolled 28 subjects with SSc (mean age, 47.3 years; 67.9 % female). Twenty-four received a single dose of MEDI-551 (0.1–10.0 mg/kg) and four received placebo. Treatment-emergent adverse events (TEAEs) occurred in 95.8 % of subjects in the MEDI-551 group and in 75.0 % of subjects in the placebo group; the majority of TEAEs were mild or moderate in severity. Two serious adverse events were considered possibly related to the study drug. One death, deemed not related to the study drug, occurred in a MEDI-551-treated subject. MEDI-551 exhibited linear PK in the dose range of 1.0 to 10.0 mg/kg, and more rapid clearance at lower doses. Dose-dependent depletion of circulating B cells and plasma cells was observed. MRSS assessments suggest a possible clinical effect of MEDI-551 on affected skin.ConclusionsA single escalating dose of MEDI-551 was tolerable and safe in this subject population. B cell depletion was achieved and was dose dependent. A signal of clinical effect was observed. Based on these results, further investigation of MEDI-551 as a disease-modifying treatment for SSc is warranted.Trial registrationwww.clinicaltrials.gov identifier, NCT00946699; registered 23 July 2009.

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

“…In addition, inebilizumab was well tolerated and most treatment-emergent adverse events were mild or moderate in severity. Although levels of pathogenic autoantibodies were not analyzed in this study, levels of total immunoglobulins from the majority of inebilizumab-treated patients were within the normal range during the course of monitoring, except in seven subjects presenting lower-than-normal levels of IgG, immunoglobulin A (IgA), or immunoglobulin M (IgM) [44]. These results suggest that further evaluation of inebilizumab in autoimmune diseases, including the autoimmune neurological disorders MS and NMO, is warranted.…”

“…One of these is inebilizumab (MEDI-551), which was developed at MedImmune and has progressed into clinical trials [43,44]. Inebilizumab was derived from the mouse anti-human mAb HB12b, which had already shown impressive activity in depletion of B cells in transgenic mice carrying the human CD19 gene (hCD19 Tg) [45].…”

“…In the phase 1 clinical trial of inebilizumab in patients with either limited or diffuse cutaneous SSc (NCT00946699), inebilizumab treatment led to a rapid, robust, and durable depletion of B cells in whole blood [44]. This pharmacodynamic effect was accompanied by a rapid and significant reduction of plasma cells in both blood and affected skin, indicating that inebilizumab can deplete plasma cells in circulation and in diseased tissue [44,46].…”

“…This pharmacodynamic effect was accompanied by a rapid and significant reduction of plasma cells in both blood and affected skin, indicating that inebilizumab can deplete plasma cells in circulation and in diseased tissue [44,46]. Inebilizumab-treated patients, but not placebo-treated patients, showed an improvement trend in the Modified Rodnan Skin Score from baseline [44], although this was a small study and the clinical activity of inebilizumab must be confirmed by future studies. In addition, inebilizumab was well tolerated and most treatment-emergent adverse events were mild or moderate in severity.…”

Translating Autoimmune Pathogenesis into Targeted Therapies for Systemic Sclerosis

“…Using a different approach, Schiopu et al utilised a humanised anti-CD19 monoclonal antibody (MEDI-551) to deplete B-cells [91]. As noted by the authors, the CD19 antigen is expressed on a wider range of B-cell subsets than the CD20 antigen.…”