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.

Autor:	Perugino CA; Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Cambridge, MA, USA., Wallace ZS; Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Zack DJ; Xencor, Pasadena, CA, USA., Quinn SM; Clinical Development, Zenas BioPharma, Waltham, MA, USA., Poma A; Clinical Development, Zenas BioPharma, Waltham, MA, USA., Fernandes AD; Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Foster P; Xencor, Pasadena, CA, USA., DeMattos S; Xencor, Pasadena, CA, USA., Burington B; Xencor, Pasadena, CA, USA., Liu H; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Cambridge, MA, USA., Allard-Chamard H; Division of Rheumatology, Faculté de médecine et des sciences de la santé de l'Université de Sherbrooke et Centre de Recherche Clinique Étienne-Le Bel, Sherbrooke, QC, Canada., Smith N; Penn State College of Medicine, Hershey, PA, USA., Kai X; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Cambridge, MA, USA., Xing K; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Cambridge, MA, USA., Pillai S; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Cambridge, MA, USA., Stone JH; Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: jhstone@mgh.harvard.edu.
Jazyk:	angličtina
Zdroj:	The Lancet. Rheumatology [Lancet Rheumatol] 2023 Aug; Vol. 5 (8), pp. e442-e450. Date of Electronic Publication: 2023 Jul 24.
DOI:	10.1016/S2665-9913(23)00157-1
Abstrakt:	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. Competing Interests: Declaration of interests CAP receives support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant K08AR079615). ZSW receives consulting fees from Zenas Biopharma, Sanofi, Viela Bio/Horizon Therapeutics, MedPace, and Shionogi; and has participated on advisory boards for Sanofi, Viela Bio/Horizon Therapeutics, Novartis, Visterra/Otsuka, and Shinogi. AP and SMQ are full-time employees of Zenas BioPharma. DJZ, PF, SD, and BB were full-time employees of Xencor at the time of the trial. SP has participated on advisory boards for Be Biopharma, Abpro, Paratus Sciences, and Octagon Therapeutics. JHS receives funding from National Institute of Allergy and Infectious Diseases (grant UM1AI144295); consulting fees, payment, or honoraria from Zenas BioPharma, Chemocentryx, Kyverna Therapeutics, Horizon Therapeutics, Q32 Bio, argenx, Novartis, Spruce Biosciences, PPD, Bristol-Myers Squibb, and Sanofi; and chairs the scientific advisory board for Steritas. All other authors declare no competing interests. (Copyright © 2023 Elsevier Ltd. All rights reserved.)
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