The in vivo mechanism of action of CD20 monoclonal antibodies depends on local tumor burden
The in vivo mechanism of action of CD20 monoclonal antibodies depends on local tumor burden
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DOI：
10.3324/haematol.2011.047159
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发表时间：
2011-12-01
期刊：
影响因子：
--
通讯作者：
Leusen, Jeanette H. W.
中科院分区：
文献类型：
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作者：
Boross, Peter;Jansen, J. H. Marco;Leusen, Jeanette H. W.
背景CD20单抗广泛应用于临床。抗体依赖性细胞毒性、补体依赖性细胞毒性和细胞直接死亡被认为是CD20抗体的重要效应功能。然而，CD20抗体在体内CD20免疫治疗作用机制中的具体作用尚未得到很好的确定。设计与方法我们在EL4-CD20细胞的低和高肿瘤负荷的腹膜同基因小鼠模型中研究了I型(利妥昔单抗和Of atumab)和II型CD20抗体(HuMab-11B8)CD20抗体的体内作用机制。在肿瘤负荷低的情况下，补体对I型和II型CD20抗体均有足够的肿瘤杀伤作用。相反，在高肿瘤负荷条件下，激活Fc-Gamma R(特别是Fc-Gamma RIII)、活性补体和补体受体3对肿瘤杀伤都是必不可少的。我们的数据表明，补体增强的抗体依赖的细胞毒性可能在体内严重影响CD20抗体对肿瘤的杀伤作用。II型CD20抗体11B8是补体激活的不良诱导剂，对高肿瘤负荷无效。结论肿瘤负荷影响CD20抗体体内作用机制。低肿瘤负荷可以通过补体单独消除，而高肿瘤负荷的消除需要多种效应机制。
BackgroundCD20 monoclonal antibodies are widely used in clinical practice. Antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity and direct cell death have been suggested to be important effector functions for CD20 antibodies. However, their specific contributions to the in vivo mechanism of action of CD20 immunotherapy have not been well defined.Design and MethodsHere we studied the in vivo mechanism of action of type I (rituximab and ofatumumab) and type II (HuMab-11B8) CD20 antibodies in a peritoneal, syngeneic, mouse model with EL4-CD20 cells using low and high tumor burden.ResultsInterestingly, we observed striking differences in the in vivo mechanism of action of CD20 antibodies dependent on tumor load. In conditions of low tumor burden, complement was sufficient for tumor killing both for type I and type II CD20 antibodies. In contrast, in conditions of high tumor burden, activating Fc gamma R (specifically Fc gamma RIII), active complement and complement receptor 3 were all essential for tumor killing. Our data suggest that complement-enhanced antibody-dependent cellular cytotoxicity may critically affect tumor killing by CD20 antibodies in vivo. The type II CD20 antibody 11B8, which is a poor inducer of complement activation, was ineffective against high tumor burden.ConclusionsTumor burden affects the in vivo mechanism of action of CD20 antibodies. Low tumor load can be eliminated by complement alone, whereas elimination of high tumor load requires multiple effector mechanisms.