Winkler Mark T, Bushey Ryan T, Gottlin Elizabeth B, Campa Michael J, Guadalupe Eross S, Volkheimer Alicia D, Weinberg J Brice, Patz Edward F
Department of Radiology, Duke University Medical Center, Durham, North Carolina, United States of America.
Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America.
PLoS One. 2017 Jun 28;12(6):e0179841. doi: 10.1371/journal.pone.0179841. eCollection 2017.
Rituximab therapy for B cell chronic lymphocytic leukemia (B-CLL) has met with mixed success. Among several factors to which resistance can be attributed is failure to activate complement dependent cytotoxicity (CDC) due to protective complement regulatory proteins, including the soluble regulator complement factor H (CFH). We hypothesized that rituximab killing of non-responsive B-CLL cells could be augmented by a novel human monoclonal antibody against CFH. The B cells from 11 patients with B-CLL were tested ex vivo in CDC assays with combinations of CFH monoclonal antibody, rituximab, and a negative control antibody. CDC of rituximab non-responsive malignant B cells from CLL patients could in some cases be augmented by the CFH monoclonal antibody. Antibody-mediated cytotoxicity of cells was dependent upon functional complement. In one case where B-CLL cells were refractory to CDC by the combination of rituximab plus CFH monoclonal antibody, additionally neutralizing the membrane complement regulatory protein CD59 allowed CDC to occur. Inhibiting CDC regulatory proteins such as CFH holds promise for overcoming resistance to rituximab therapy in B-CLL.
利妥昔单抗治疗B细胞慢性淋巴细胞白血病（B-CLL）的效果不一。导致耐药的因素有多种，其中之一是由于包括可溶性调节因子补体因子H（CFH）在内的保护性补体调节蛋白未能激活补体依赖性细胞毒性（CDC）。我们推测，一种新型的抗CFH人单克隆抗体可以增强利妥昔单抗对无反应性B-CLL细胞的杀伤作用。在补体依赖细胞毒性试验中，将CFH单克隆抗体、利妥昔单抗和一种阴性对照抗体组合，对11例B-CLL患者的B细胞进行体外检测。在某些情况下，CFH单克隆抗体可增强CLL患者对利妥昔单抗无反应的恶性B细胞的补体依赖细胞毒性。细胞的抗体介导细胞毒性取决于功能性补体。在1例B-CLL细胞对利妥昔单抗加CFH单克隆抗体联合诱导的补体依赖细胞毒性难治的病例中，额外中和膜补体调节蛋白CD59可使补体依赖细胞毒性发生。抑制CFH等补体依赖细胞毒性调节蛋白有望克服B-CLL对利妥昔单抗治疗的耐药性。
