Lapalombella Rosa, Gowda Aruna, Joshi Trupti, Mehter Najma, Cheney Carolyn, Lehman Amy, Chen Ching-Shih, Johnson Amy J, Caligiuri Michael A, Tridandapani Susheela, Muthusamy Natarajan, Byrd John C
Department of Medicine, Division of Hematology-Oncology, The Ohio State University, Columbus, OH 43210, USA.
Br J Haematol. 2009 Mar;144(6):848-55. doi: 10.1111/j.1365-2141.2008.07548.x. Epub 2009 Jan 12.
Antibody-based therapies, such as rituximab and alemtuzumab, have contributed significantly to the treatment of Chronic Lymphocytic leukaemia (CLL). The CD40 antigen is expressed predominantly on B-cells and represents a potential target for immune-based therapies. SGN-40 is a humanized IgG1 monoclonal antibody currently in Phase I/II clinical trials for indolent lymphomas, diffuse large B cell lymphomas and Multiple Myeloma. Its biological effect on CLL cells has not been studied. The present study demonstrated that SGN-40 mediated modest apoptosis in a subset of patients with secondary cross-linking but did not mediate complement-dependent cytotoxicity. SGN-40 also mediated antibody-dependent cellular cytotoxicity (ADCC) predominantly through natural killer (NK) cells. Previous studies by our group and others have demonstrated that lenalidomide upregulates CD40 expression on primary B CLL cells and activates NK-cells. We therefore examined for the combinatorial effect of lenalidomide and SGN-40 and demonstrated that both enhanced direct apoptosis and ADCC against primary CLL B cells. These data together provide justification for clinical trials of SGN-40 and lenalidomide in combination for CLL therapy.
基于抗体的疗法，如利妥昔单抗和阿仑单抗，对慢性淋巴细胞白血病（CLL）的治疗有显著贡献。CD40抗原主要在B细胞上表达，是基于免疫疗法的一个潜在靶点。SGN-40是一种人源化IgG1单克隆抗体，目前正处于针对惰性淋巴瘤、弥漫性大B细胞淋巴瘤和多发性骨髓瘤的I/II期临床试验阶段。其对CLL细胞的生物学效应尚未得到研究。本研究表明，SGN-40在一部分发生二次交联的患者中介导适度的细胞凋亡，但不介导补体依赖性细胞毒性。SGN-40还主要通过自然杀伤（NK）细胞介导抗体依赖性细胞毒性（ADCC）。我们团队和其他团队之前的研究表明，来那度胺可上调原发性B CLL细胞上的CD40表达并激活NK细胞。因此，我们研究了来那度胺和SGN-40的联合效应，结果表明二者均可增强对原发性CLL B细胞的直接凋亡作用和ADCC。这些数据共同为SGN-40和来那度胺联合用于CLL治疗的临床试验提供了依据。
