用双特异性抗体衍生物对CD47-SIRPα“别吃我”信号通路进行CD20选择性抑制，可增强达雷妥尤单抗、阿仑单抗和奥滨尤妥珠单抗的抗癌活性。
CD20-selective inhibition of CD47-SIRPα "don't eat me" signaling with a bispecific antibody-derivative enhances the anticancer activity of daratumumab, alemtuzumab and obinutuzumab.
作者信息
van Bommel Peter E, He Yuan, Schepel Ilona, Hendriks Mark A J M, Wiersma Valerie R, van Ginkel Robert J, van Meerten Tom, Ammatuna Emanuele, Huls Gerwin, Samplonius Douwe F, Helfrich Wijnand, Bremer Edwin
机构信息
University of Groningen, University Medical Center Groningen (UMCG), Department of Surgery, Laboratory for Translational Surgical Oncology, Groningen, The Netherlands.
University of Groningen, University Medical Center Groningen (UMCG), Department of Hematology, Groningen, The Netherlands.
出版信息
Oncoimmunology. 2017 Oct 31;7(2):e1386361. doi: 10.1080/2162402X.2017.1386361. eCollection 2018.
Here, we report on a novel bispecific antibody-derivative, designated RTX-CD47, with unique capacity for CD20-directed inhibition of CD47-SIRPα "don't eat me" signaling. RTX-CD47 comprises a CD20-targeting scFv antibody fragment derived from rituximab fused in tandem to a CD47-blocking scFv. Single agent treatment with RTX-CD47 triggered significant phagocytic removal of CD20/CD47 malignant B-cells, but not of CD20/CD47 cells, and required no pro-phagocytic FcR-mediated signaling. Importantly, treatment with RTX-CD47 synergistically enhanced the phagocytic elimination of primary malignant B cells by autologous phagocytic effector cells as induced by therapeutic anticancer antibodies daratumumab (anti-CD38), alemtuzumab (anti-CD52) and obinutuzumab (anti-CD20). In conclusion, RTX-CD47 blocks CD47 "don't eat me" signaling by cancer cells in a CD20-directed manner with essentially no activity towards CD20/CD47 cells and enhances the activity of therapeutic anticancer antibodies directed to B-cell malignancies.
在此，我们报告了一种新型双特异性抗体衍生物，命名为RTX-CD47，它具有独特的能力，可通过靶向CD20抑制CD47-SIRPα“别吃我”信号通路。RTX-CD47包含一个源自利妥昔单抗的靶向CD20的单链抗体片段（scFv），与一个阻断CD47 的scFv串联融合。用RTX-CD47进行单药治疗可引发对CD₂₀/CD₄₇恶性B细胞的显著吞噬清除，但对CD₂₀/CD₄₇细胞则无此作用，且不需要促吞噬的FcR介导的信号传导。重要的是，RTX-CD47治疗协同增强了治疗性抗癌抗体达雷妥尤单抗（抗CD38）、阿仑单抗（抗CD52）和奥滨尤妥珠单抗（抗CD20）诱导的自体吞噬效应细胞对原发性恶性B细胞的吞噬清除作用。总之，RTX-CD47以靶向CD20的方式阻断癌细胞的CD47“别吃我”信号通路，对CD₂₀/CD₄₇细胞基本无活性，并增强了针对B细胞恶性肿瘤的治疗性抗癌抗体的活性。
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