Antibody isotype-specific engagement of Fcgamma receptors regulates B lymphocyte depletion during CD20 immunotherapy.
Antibody isotype-specific engagement of Fcgamma receptors regulates B lymphocyte depletion during CD20 immunotherapy.
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DOI：
10.1084/jem.20052283
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发表时间：
2006-03-20
影响因子：
15.3
通讯作者：
Tedder, TF
中科院分区：
文献类型：
--
作者：
Hamaguchi, Y;Xiu, Y;Komura, K;Nimmerjahn, F;Tedder, TF
CD20单克隆抗体（mAb）免疫疗法对淋巴瘤和自身免疫性疾病有效。在使用小鼠抗小鼠CD20单克隆抗体进行免疫治疗的小鼠模型中，先天单核细胞网络通过免疫球蛋白（Ig）G Fc受体（Fcγ r）依赖通路消耗B细胞，其层级为IgG2a/c>IgG1/IgG2b>IgG3。为了了解这些CD20单抗亚类差异的分子基础，在缺乏或阻断刺激FcγRI、FcγRIII、FcγRIV或FcR共γ链或抑制性FcγRIIB的小鼠中评估了B细胞耗尽。IgG1 CD20单抗通过优先（如果不是排他的话）与低亲和力的FcγRIII相互作用诱导B细胞耗损。IgG2b CD20单克隆抗体优先与中间亲和力的FcγRIV相互作用。IgG2a/c CD20单克隆抗体的效力是由fc - γ - riv相互作用产生的，而高亲和力的fc - γ - ri可能也有贡献。无论如何，在缺乏fc - γ ri和fc - γ riii的情况下，fc - γ riv可以介导IgG2a/b/c CD20 mab诱导的耗损。相反，抑制性FcγRIIB缺乏通过增强单核细胞功能显著增加CD20单抗诱导的B细胞耗竭。尽管fc γ r依赖通路调节淋巴组织中B细胞的消耗，但fc γ r依赖通路和fc γ r独立通路都有助于CD20单抗清除成熟骨髓和循环B细胞。因此，同型特异性单克隆抗体与不同FcγRs的相互作用显著促进了CD20单克隆抗体在体内的有效性，这可能对CD20和其他基于单克隆抗体的治疗具有重要的临床意义。
CD20 monoclonal antibody (mAb) immunotherapy is effective for lymphoma and autoimmune disease. In a mouse model of immunotherapy using mouse anti–mouse CD20 mAbs, the innate monocyte network depletes B cells through immunoglobulin (Ig)G Fc receptor (FcγR)-dependent pathways with a hierarchy of IgG2a/c>IgG1/IgG2b>IgG3. To understand the molecular basis for these CD20 mAb subclass differences, B cell depletion was assessed in mice deficient or blocked for stimulatory FcγRI, FcγRIII, FcγRIV, or FcR common γ chain, or inhibitory FcγRIIB. IgG1 CD20 mAbs induced B cell depletion through preferential, if not exclusive, interactions with low-affinity FcγRIII. IgG2b CD20 mAbs interacted preferentially with intermediate affinity FcγRIV. The potency of IgG2a/c CD20 mAbs resulted from FcγRIV interactions, with potential contributions from high-affinity FcγRI. Regardless, FcγRIV could mediate IgG2a/b/c CD20 mAb–induced depletion in the absence of FcγRI and FcγRIII. In contrast, inhibitory FcγRIIB deficiency significantly increased CD20 mAb–induced B cell depletion by enhancing monocyte function. Although FcγR-dependent pathways regulated B cell depletion from lymphoid tissues, both FcγR-dependent and -independent pathways contributed to mature bone marrow and circulating B cell clearance by CD20 mAbs. Thus, isotype-specific mAb interactions with distinct FcγRs contribute significantly to the effectiveness of CD20 mAbs in vivo, which may have important clinical implications for CD20 and other mAb-based therapies.
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