德国杜伊斯堡-埃森大学Alexander Röth团队研究了sutimlimab治疗冷凝集素病的效果。2021年4月8日，《新英格兰医学杂志》发表了这一成果。

冷凝集素病是一种罕见的自身免疫性溶血性贫血，以典型补体通路激活引起的溶血为特征。Sutimlimab是一种人源化单克隆抗体，可选择性靶向C1s蛋白，C1复合丝氨酸蛋白酶负责激活这一途径。

研究组进行了一项为期26周的多中心、开放性、单组研究，以评估静脉注射sutimlimab治疗冷凝集素病和近期有输血史患者的疗效和安全性。复合主要终点是血红蛋白水平正常化至12 g/dL及以上，或血红蛋白水平与基线相比，升高2 g/dL及以上，没有输血或方案禁止的药物治疗。

共有24名患者入选并接受至少一剂sutimlimab；13名患者（54%）符合复合主要终点的标准。在治疗评估时（第23、25和26周），血红蛋白水平的最小二乘平均升高2.6 g /dL。从第3周到研究结束，患者的平均血红蛋白水平保持在11 g/dL及以上。平均胆红素水平在第3周恢复正常。从第5周到第26周，共有17名患者（71%）没有接受输血。

在第1周观察到有临床意义的疲劳减轻，并在整个研究过程中没有反弹。通过功能检测，经典补体途径的活性被迅速抑制。血红蛋白水平升高、胆红素水平降低和疲劳减轻与经典补体途径的抑制相一致。22例（92%）患者在治疗期间至少发生一次不良事件。7名患者（29%）至少发生过一次严重不良事件，研究人员未确定这些事件是否与sutimlimab有关。没有一例患者发生脑膜炎球菌感染。

研究结果表明，sutimlimab治疗冷凝集素病患者，在经典补体通路中选择性上游抑制活性可迅速停止溶血，增加血红蛋白水平，并减少疲劳。

附：英文原文

Title: Sutimlimab in Cold Agglutinin Disease

Author: Alexander Rth, M.D.,, Wilma Barcellini, M.D.,, Shirley D’Sa, M.D.,, Yoshitaka Miyakawa, M.D., Ph.D.,, Catherine M. Broome, M.D.,, Marc Michel, M.D.,, David J. Kuter, M.D., D.Phil.,, Bernd Jilma, M.D.,, Tor H.A. Tvedt, M.D., Ph.D.,, Joachim Fruebis, Ph.D.,, Xiaoyu Jiang, Ph.D.,, Stella Lin, Ph.D.,, Caroline Reuter, M.D., M.S.C.I.,, Jaime Morales-Arias, M.D.,, William Hobbs, M.D., Ph.D.,, and Sigbjrn Berentsen, M.D., Ph.D.

Issue&Volume: 2021-04-07

Abstract:

Background

Cold agglutinin disease is a rare autoimmune hemolytic anemia characterized by hemolysis that is caused by activation of the classic complement pathway. Sutimlimab, a humanized monoclonal antibody, selectively targets the C1s protein, a C1 complex serine protease responsible for activating this pathway.

Methods

We conducted a 26-week multicenter, open-label, single-group study to assess the efficacy and safety of intravenous sutimlimab in patients with cold agglutinin disease and a recent history of transfusion. The composite primary end point was a normalization of the hemoglobin level to 12 g or more per deciliter or an increase in the hemoglobin level of 2 g or more per deciliter from baseline, without red-cell transfusion or medications prohibited by the protocol.

Results

A total of 24 patients were enrolled and received at least one dose of sutimlimab; 13 patients (54%) met the criteria for the composite primary end point. The least-squares mean increase in hemoglobin level was 2.6 g per deciliter at the time of treatment assessment (weeks 23, 25, and 26). A mean hemoglobin level of more than 11 g per deciliter was maintained in patients from week 3 through the end of the study period. The mean bilirubin levels normalized by week 3. A total of 17 patients (71%) did not receive a transfusion from week 5 through week 26. Clinically meaningful reductions in fatigue were observed by week 1 and were maintained throughout the study. Activity in the classic complement pathway was rapidly inhibited, as assessed by a functional assay. Increased hemoglobin levels, reduced bilirubin levels, and reduced fatigue coincided with inhibition of the classic complement pathway. At least one adverse event occurred during the treatment period in 22 patients (92%). Seven patients (29%) had at least one serious adverse event, none of which were determined by the investigators to be related to sutimlimab. No meningococcal infections occurred.

Conclusions

In patients with cold agglutinin disease who received sutimlimab, selective upstream inhibition of activity in the classic complement pathway rapidly halted hemolysis, increased hemoglobin levels, and reduced fatigue.

DOI: 10.1056/NEJMoa2027760

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2027760