Mamidi Srinivas, Höne Simon, Teufel Claudia, Sellner Leopold, Zenz Thorsten, Kirschfink Michael
Institute for Immunology; University of Heidelberg ; Heidelberg, Germany.
Department of Translational Oncology; National Center for Tumour Diseases (NCT) and German Cancer Research Center (DKFZ) ; Heidelberg, Germany ; Department of Medicine V; University of Heidelberg ; Heidelberg, Germany.
Oncoimmunology. 2015 Jan 22;4(3):e979688. doi: 10.4161/2162402X.2014.979688. eCollection 2015 Mar.
Complement-dependent cytotoxicity (CDC) is one of the effector mechanisms mediated by therapeutic anticancer monoclonal antibodies (mAbs). However, the efficacy of antibodies is limited by the resistance of malignant cells to complement attack, primarily due to the over-expression of one or more membrane complement regulatory proteins (mCRPs) CD46, CD55, and CD59. CD20-positive Burkitt lymphoma Raji cells and primary CLL cells are resistant to rituximab (RTX)-induced CDC whereas ofatumumab (OFA) proved to be more efficient in cell killing. Primary CLL cells but not CD52-positive acute lymphoblastic leukemia (ALL) REH cells were sensitive to alemtuzumab (ALM)-induced CDC. Upon combined inhibition on Raji and CLL cells by mCRPs-specific siRNAs or neutralizing antibodies, CDC induced by RTX and by OFA was augmented. Similarly, CDC of REH cells was enhanced after mCRPs were inhibited upon treatment with ALM. All mAbs induced C3 opsonization, which was significantly augmented upon blocking mCRPs. C3 opsonization led to enhanced cell-mediated cytotoxicity of leukemia cells exposed to PBLs or macrophages. Furthermore, opsonized CLL cells were efficiently phagocytized by macrophages. Our results provide conclusive evidence that inhibition of mCRPs expression sensitizes leukemic cells to complement attack thereby enhancing the therapeutic effect of mAbs targeting leukemic cells.
补体依赖性细胞毒性（CDC）是治疗性抗癌单克隆抗体（mAb）介导的效应机制之一。然而，抗体的疗效受到恶性细胞对补体攻击的抗性限制，主要原因是一种或多种膜补体调节蛋白（mCRP）CD46、CD55和CD59的过度表达。CD20阳性的伯基特淋巴瘤Raji细胞和原发性慢性淋巴细胞白血病（CLL）细胞对利妥昔单抗（RTX）诱导的CDC具有抗性，而奥法木单抗（OFA）在细胞杀伤方面更有效。原发性CLL细胞对阿仑单抗（ALM）诱导的CDC敏感，但CD52阳性的急性淋巴细胞白血病（ALL）REH细胞不敏感。在用mCRP特异性小干扰RNA（siRNA）或中和抗体联合抑制Raji细胞和CLL细胞后，RTX和OFA诱导的CDC增强。同样，在用ALM处理抑制mCRP后，REH细胞的CDC增强。所有mAb均诱导C3调理作用，在阻断mCRP后显著增强。C3调理作用导致暴露于外周血淋巴细胞（PBL）或巨噬细胞的白血病细胞的细胞介导细胞毒性增强。此外，调理后的CLL细胞被巨噬细胞有效吞噬。我们的结果提供了确凿的证据，即抑制mCRP表达可使白血病细胞对补体攻击敏感，从而增强靶向白血病细胞的mAb的治疗效果。
