Abstract：
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.
RESULTS: 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.
CONCLUSIONS: 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.
BACKGROUND: Xencor, Zenas BioPharma, National Institute of Arthritis and Musculoskeletal and Skin Diseases, and National Institute of Allergy and Infectious Diseases.
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.
RESULTS: 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.
CONCLUSIONS: 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.
BACKGROUND: Xencor, Zenas BioPharma, National Institute of Arthritis and Musculoskeletal and Skin Diseases, and National Institute of Allergy and Infectious Diseases.
摘要：
背景：Obexelimab是一种双功能，非细胞溶解，结合CD19和Fcγ受体IIb以抑制B细胞的人源化单克隆抗体，成浆细胞,和表达CD19的浆细胞。我们的目的是评估安全性，临床疗效,以及obexelimab在活动性IgG4相关疾病患者中的药效学作用。
方法：我们进行了开放标签，单臂,单中心,波士顿麻省总医院的第二阶段试点试验，MA,美国。符合条件的患者年龄为18-80岁,并且具有通过IgG4相关疾病应答者指数评分为3或更高而证实的活动性IgG4相关疾病。患者每2周静脉内接受5mg/kg的obexelimab，持续24周。基线接受糖皮质激素的患者预计在入组后2个月内停止使用。主要终点是第169天IgG4相关疾病反应者指数中从基线减少2或更多的患者比例（即，主要响应者)。在任何访问时达到2或更多的减少的患者被指定为应答者。不良事件的等级为1-5（即，温和,中度,严重,危及生命,或死亡）根据“不良事件通用术语标准”分级量表（4.3版）。探索性分析是对B细胞CD19受体占有率的定量，血浆,流式细胞术总B细胞和CD4+细胞毒性T细胞计数，和免疫球蛋白浓度的比浊法。这项研究在ClinicalTrials.gov注册，NCT02725476。
结果：在2016年2月24日至2016年12月21日之间，我们招募了15名患者。中位年龄为63岁（IQR52-65）。15例患者中有10例（67%）为男性，五名(33%)是女性，和12（80％）是白人。在基线,15例患者中有12例（80％）的血清IgG4浓度中位数升高为220mg/dL（IQR124-441），中位IgG4相关疾病应答者指数评分为12分(IQR7-13).15例患者中有12例（80％）达到了主要终点（即，主要响应者)，14人（93%）被定义为反应者。在用obexelimab处理后,观察到血清B细胞和成浆细胞从基线的减少。然而,在大多数有随访数据的患者中，在最终的obexelimab剂量的42天内，血清B细胞恢复到基线浓度的75％。15例患者中有13例（87%）报告了不良事件，其中之一（输注反应）导致治疗中断。
结论：除1例患者外，所有患者均对obexelimab治疗有临床反应。在obexelimab治疗期间，循环B细胞的减少都没有凋亡的迹象，并且在治疗停止后它们的快速反弹表明，obexelimab可能导致淋巴器官或骨髓中的B细胞隔离。这些结果支持了用于治疗IgG4相关疾病的obexelimab的持续发展。
背景：Xencor，ZenasBioPharma,国家关节炎和肌肉骨骼和皮肤疾病研究所，和国家过敏和传染病研究所。
方法：我们进行了开放标签，单臂,单中心,波士顿麻省总医院的第二阶段试点试验，MA,美国。符合条件的患者年龄为18-80岁,并且具有通过IgG4相关疾病应答者指数评分为3或更高而证实的活动性IgG4相关疾病。患者每2周静脉内接受5mg/kg的obexelimab，持续24周。基线接受糖皮质激素的患者预计在入组后2个月内停止使用。主要终点是第169天IgG4相关疾病反应者指数中从基线减少2或更多的患者比例（即，主要响应者)。在任何访问时达到2或更多的减少的患者被指定为应答者。不良事件的等级为1-5（即，温和,中度,严重,危及生命,或死亡）根据“不良事件通用术语标准”分级量表（4.3版）。探索性分析是对B细胞CD19受体占有率的定量，血浆,流式细胞术总B细胞和CD4+细胞毒性T细胞计数，和免疫球蛋白浓度的比浊法。这项研究在ClinicalTrials.gov注册，NCT02725476。
结果：在2016年2月24日至2016年12月21日之间，我们招募了15名患者。中位年龄为63岁（IQR52-65）。15例患者中有10例（67%）为男性，五名(33%)是女性，和12（80％）是白人。在基线,15例患者中有12例（80％）的血清IgG4浓度中位数升高为220mg/dL（IQR124-441），中位IgG4相关疾病应答者指数评分为12分(IQR7-13).15例患者中有12例（80％）达到了主要终点（即，主要响应者)，14人（93%）被定义为反应者。在用obexelimab处理后,观察到血清B细胞和成浆细胞从基线的减少。然而,在大多数有随访数据的患者中，在最终的obexelimab剂量的42天内，血清B细胞恢复到基线浓度的75％。15例患者中有13例（87%）报告了不良事件，其中之一（输注反应）导致治疗中断。
结论：除1例患者外，所有患者均对obexelimab治疗有临床反应。在obexelimab治疗期间，循环B细胞的减少都没有凋亡的迹象，并且在治疗停止后它们的快速反弹表明，obexelimab可能导致淋巴器官或骨髓中的B细胞隔离。这些结果支持了用于治疗IgG4相关疾病的obexelimab的持续发展。
背景：Xencor，ZenasBioPharma,国家关节炎和肌肉骨骼和皮肤疾病研究所，和国家过敏和传染病研究所。
