Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands.
Blood. 2010 Dec 23;116(26):5930-40. doi: 10.1182/blood-2010-01-262006. Epub 2010 Sep 15.
B-lineage acute lymphoblastic leukemia (ALL) may express CD52 and CD20. Alemtuzumab (ALM) and rituximab (RTX) are therapeutic antibodies directed against CD52 and CD20, respectively, but showed limited activity against ALL in clinical trials. The mechanisms for the impaired responses remained unclear. We studied expression of CD52 and CD20 on ALL cells and found that most cases coexpressed CD52 and CD20. However, distinct CD52-negative (CD52(-)) subpopulations were detected in most cases as the result of defective glycophosphatidyl-inositol anchoring. Although ALM efficiently eradicated CD52-positive (CD52(+)) cells in NOD/scid mice engrafted with primary human ALL, CD52(-) subclones escaped therapy. In the same model, RTX showed limited activity resulting from occurrence of CD20 down-modulation. However, CD52(-) cells concurrently lacked the glycophosphatidyl-inositol-anchored complement regulators CD55 and CD59 and showed increased susceptibility to RTX-mediated complement-dependent cytotoxicity in vitro. At the same time, ALM was shown to inhibit down-modulation of CD20 in response to RTX by depleting the trogocytic capacity of phagocytic cells. Probably because of these complementary mechanisms, combined administration of ALM and RTX induced complete responses in vivo. Based on these data, we propose a mechanistic rationale for combined application of RTX and ALM in ALL.
B 细胞急性淋巴细胞白血病 (ALL) 可能表达 CD52 和 CD20。阿仑单抗 (ALM) 和利妥昔单抗 (RTX) 是分别针对 CD52 和 CD20 的治疗性抗体，但在临床试验中对 ALL 的活性有限。其反应受损的机制仍不清楚。我们研究了 ALL 细胞上 CD52 和 CD20 的表达，发现大多数病例同时表达 CD52 和 CD20。然而，由于糖磷脂酰肌醇锚定缺陷，大多数病例中都检测到明显的 CD52 阴性 (CD52(-)) 亚群。虽然 ALM 能够有效地清除 NOD/scid 小鼠中植入的原发性人 ALL 中的 CD52(+) 细胞，但 CD52(-) 亚克隆逃避了治疗。在相同的模型中，RTX 由于 CD20 下调的发生而表现出有限的活性。然而，CD52(-) 细胞同时缺乏糖磷脂酰肌醇锚定的补体调节剂 CD55 和 CD59，并且在体外表现出对 RTX 介导的补体依赖性细胞毒性的增加敏感性。同时，ALM 被证明通过耗尽吞噬细胞的吞噬能力来抑制对 RTX 反应的 CD20 下调。可能由于这些互补机制，ALM 和 RTX 的联合给药在体内诱导完全反应。基于这些数据，我们提出了 RTX 和 ALM 在 ALL 中联合应用的机制原理。
