Anti-CD20 monoclonal antibody with enhanced affinity for CD16 activates NK cells at lower concentrations and more effectively than rituximab
Anti-CD20 monoclonal antibody with enhanced affinity for CD16 activates NK cells at lower concentrations and more effectively than rituximab
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DOI：
10.1182/blood-2006-04-020057
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发表时间：
2006-10-15
期刊：
影响因子：
20.3
通讯作者：
Weiner, George J.
中科院分区：
文献类型：
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作者：
Bowles, Julie A.;Wang, Siao-Yi;Weiner, George J.
越来越多的证据表明，单克隆抗体 (mAb) 对 CD16 (Fc gamma RIII) 的亲和力在 mAb 介导抗肿瘤活性的能力中发挥着核心作用。我们评估了当 CD20(+) 恶性 B 细胞也存在时，CD16 多态性以及对靶抗原和 CD16 的亲和力发生改变的 mAb 如何影响自然杀伤 (NK) 细胞表型。该单克隆抗体由利妥昔单抗 (R)、对 CD20 具有增强亲和力的抗 CD20 (AME-B) 以及对 CD20 和 CD16 具有增强亲和力的抗 CD20 (AME-D) 组成。需要更高浓度的 mAb 来诱导 CD16 调节、CD54 上调以及对具有较低亲和力 CD16 多态性的受试者的 NK 细胞产生抗体依赖性细胞毒性 (ADCC)。无论 CD16 多态性如何，AME-D 诱导 NK 激活所需的 mAb 剂量均较低。在单克隆抗体饱和浓度下，AME-D 的 NK 激活峰值更高。 CD16 调节、CD54 上调和 ADCC 的测量也发现了类似的结果。这些数据表明，无论 CD16 多态性如何，涂有对 CD16 亲和力增强的 mAb 的细胞在低 mAb 浓度和饱和 mAb 浓度下都能更有效地激活 NK 细胞，而与 CD16 多态性无关，并且它们为此类 mAb 的临床开发提供了进一步的证据，目的是改善对 mAb 的临床反应。
Growing evidence indicates that the affinity of monoclonal antibodies (mAbs) for CD16 (Fc gamma RIII) plays a central role in the ability of the mAb to mediate antitumor activity. We evaluated how CD16 polymorphisms, and mAb with modified affinity for target antigen and CD16, affect natural killer (NK) cell phenotype when CD20(+) malignant B cells were also present. The mAb consisted of rituximab (R), anti-CD20 with enhanced affinity for CD20 (AME-B), and anti-CD20 with enhanced affinity for both CD20 and CD16 (AME-D). Higher concentrations of mAb were needed to induce CD16 modulation, CD54 up-regulation, and anti body-dependent cellular cytotoxicity (ADCC) on NK cells from subjects with the lower affinity CD16 polymorphism. The dose of mAb needed to induce NK activation was lower with AME-D irrespective of CD16 polymorphism. At saturating mAb concentrations, peak NK activation was greater for AME-D. Similar results were found with measurement of CD16 modulation, CD54 up-regulation, and ADCC. These data demonstrate that cells coated with mAb with enhanced affinity for CD16 are more effective at activating NK cells at both low and saturating mAb concentrations irrespective of CD16 polymorphism, and they provide further evidence for the clinical development of such mAbs with the goal of improving clinical response to mAb.