Barth Matthew J, Mavis Cory, Czuczman Myron S, Hernandez-Ilizaliturri Francisco J
Department of Pediatrics, Roswell Park Cancer Institute, Buffalo, New York.
Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York. Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York.
Clin Cancer Res. 2015 Oct 1;21(19):4391-7. doi: 10.1158/1078-0432.CCR-15-0056. Epub 2015 May 11.
Mantle cell lymphoma (MCL) is a mature B-cell lymphoma considered to be incurable with current treatments, including first-line rituximab in combination with multiagent chemotherapy and for those eligible, high-dose chemotherapy and stem cell support or rituximab maintenance. On the other hand, achieving a complete remission by high-sensitive flow cytometry is associated with prolonged duration of remission, stressing the need to develop and/or incorporate novel agents into the management of MCL. To this end, we examined the activity of ofatumumab, an anti-CD20 monoclonal antibody with distinct binding and immunologic properties compared to rituximab, in MCL preclinical models.
MCL cells were labeled with (51)Cr before incubation with rituximab or ofatumumab (10 μg/mL) plus human serum or effector cells. (51)Cr-release was measured and the percentage of lysis was calculated. Surface CD20, CD55, and CD59 were measured by Imagestream analysis. SCID mice inoculated subcutaneously with Z138 cells were assigned to control versus four doses of ofatumumab or rituximab (10 mg/kg/dose).
Ofatumumab exhibited enhanced in vitro complement-dependent cytotoxicity activity compared with rituximab in MCL cell lines, despite a high degree of in vitro resistance to rituximab associated with low CD20 levels and/or high expression of complement inhibitory proteins. Ofatumumab also delayed tumor progression and prolonged survival in a murine model of MCL.
Our results demonstrate that ofatumumab is more effective than rituximab in MCL preclinical models, including in the presence of rituximab resistance, and support the clinical investigation of ofatumumab in combination with standard systemic chemotherapy in MCL (NCT01527149).
套细胞淋巴瘤（MCL）是一种成熟B细胞淋巴瘤，目前的治疗方法包括一线利妥昔单抗联合多药化疗，以及对于符合条件者采用高剂量化疗和干细胞支持或利妥昔单抗维持治疗，均被认为无法治愈。另一方面，通过高灵敏度流式细胞术实现完全缓解与缓解期延长相关，这凸显了开发和/或将新型药物纳入MCL治疗方案的必要性。为此，我们在MCL临床前模型中研究了奥法木单抗的活性，奥法木单抗是一种抗CD20单克隆抗体，与利妥昔单抗相比具有独特的结合和免疫特性。
在与利妥昔单抗或奥法木单抗（10μg/mL）加人血清或效应细胞孵育之前，用（51）Cr标记MCL细胞。测量（51）Cr释放量并计算裂解百分比。通过Imagestream分析测量表面CD20、CD55和CD59。将皮下接种Z138细胞的SCID小鼠分为对照组和接受四剂奥法木单抗或利妥昔单抗（10mg/kg/剂量）的组。
尽管MCL细胞系对利妥昔单抗存在高度体外耐药性，与低CD20水平和/或补体抑制蛋白高表达相关，但奥法木单抗在MCL细胞系中表现出比利妥昔单抗更强的体外补体依赖性细胞毒性活性。奥法木单抗在MCL小鼠模型中也延迟了肿瘤进展并延长了生存期。
我们的结果表明，在MCL临床前模型中，包括在存在利妥昔单抗耐药性的情况下，奥法木单抗比利妥昔单抗更有效，并支持奥法木单抗联合标准全身化疗用于MCL的临床研究（NCT01527149）。
