Evaluation of the safety, efficacy, and mechanism of action of obexelimab for the treatment of patients with IgG4-related disease: an open-label, single-arm, single centre, phase 2 pilot trial

被引:0
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作者
Perugino, Cory A. [1 ,2 ]
Wallace, Zachary S. [1 ]
Zack, Debra J. [3 ]
Quinn, Shauna M. [4 ]
Poma, Allen [4 ]
Fernandes, Ana [1 ]
Foster, Paul [3 ]
DeMattos, Steve [3 ]
Burington, Bart [3 ]
Liu, Hang [2 ]
Allard-Chamard, Hugues [5 ,6 ]
Smith, Nathan [7 ]
Kai, Xin [2 ]
Xing, Kelly [2 ]
Pillai, Shiv [2 ]
Stone, John H. [1 ,8 ]
机构
[1] Harvard Med Sch, Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, Boston, MA USA
[2] Massachusetts Inst Technol & Harvard, Massachusetts Gen Hosp, Ragon Inst, Cambridge, MA USA
[3] Xencor, Pasadena, CA USA
[4] Clin Dev, Zenas Biopharm, Waltham, MA USA
[5] Univ Sherbrooke, Fac Med & Sci St, Div Rheumatol, Sherbrooke, PQ, Canada
[6] Ctr Rech Clin Etienne Le Bel, Sherbrooke, PQ, Canada
[7] Penn State Coll Med, Hershey, PA USA
[8] Harvard Med Sch, Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA
来源
LANCET RHEUMATOLOGY | 2023年 / 5卷 / 08期
关键词
FC-GAMMA-RIIB; B-CELLS; RITUXIMAB; RECEPTOR; COENGAGEMENT; SUPPRESSION; ACTIVATION; STATEMENT; ANTIBODY; OUTCOMES;
D O I
暂无
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background Obexelimab is a bifunctional, non-cytolytic, humanised monoclonal antibody that binds CD19 and Fc gamma receptor IIb to inhibit B cells, plasmablasts, and CD19-expressing plasma cells. We aimed to evaluate the safety, clinical efficacy, and pharmacodynamic effects of obexelimab in patients with active IgG4-related disease. Methods We conducted an open-label, single-arm, single centre, phase 2 pilot trial at the Massachusetts General Hospital in Boston, MA, USA. Eligible patients were aged 18-80 years and had active IgG4-related disease confirmed by an IgG4-related disease responder index score of 3 or more. Patients received 5 mg/kg of obexelimab intravenously every 2 weeks for 24 weeks. Patients on glucocorticoids at baseline were expected to discontinue usage within 2 months following enrolment. The primary endpoint was the proportion of patients with a decrease of 2 or more from baseline in the IgG4-related disease responder index at day 169 (ie, primary responders). Patients who achieved a decrease of 2 or more at any visit were designated as responders. Adverse events were graded on a scale of 1-5 (ie, mild, moderate, severe, life-threatening, or death) according to the Common Terminology Criteria for Adverse Events grading scale (version 4.3). Exploratory analyses were quantification of B-cell CD19 receptor occupancy, plasmablast, total B-cell and CD4+ cytotoxic T-cell count by flow cytometry, and immunoglobulin concentrations by nephelometry. This study is registered with ClinicalTrials.gov, NCT02725476. Findings Between Feb 24, 2016, and Dec 21, 2016, we enrolled 15 patients. The median age was 63 years (IQR 52-65). Ten (67%) of 15 patients were male, five (33%) were female, and 12 (80%) were White. At baseline, 12 (80%) of 15 patients had an elevated median serum IgG4 concentration of 220 mg/dL (IQR 124-441), and the median IgG4-related disease responder index score was 12 (IQR 7-13). 12 (80%) of 15 patients achieved the primary endpoint (ie, primary responders), 14 (93%) were defined as responders. Reductions from baseline in serum B cells and plasmablasts were observed following treatment with obexelimab. However, in most patients with follow-up data, serum B cells recovered to 75% of baseline concentrations within 42 days of the final obexelimab dose. 13 (87%) of 15 patients reported adverse events, one of which (an infusion reaction) resulted in treatment discontinuation. Interpretation All patients except for one had clinical responses to obexelimab treatment. Both reductions in circulating B cells without evidence of apoptosis during obexelimab treatment and their rapid rebound after treatment discontinuation suggest that obexelimab might lead to B-cell sequestration in lymphoid organs or the bone marrow. These results support the continued development of obexelimab for the treatment of IgG4-related disease. Funding Xencor, Zenas BioPharma, National Institute of Arthritis and Musculoskeletal and Skin Diseases, and National Institute of Allergy and Infectious Diseases. (c) 2023 Published by Elsevier Ltd. All rights reserved.
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页码:E442 / E450
页数:9
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