Role of crosslinking for agonistic CD40 monoclonal antibodies as immune therapy of cancer.
Role of crosslinking for agonistic CD40 monoclonal antibodies as immune therapy of cancer.
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DOI：
10.1158/2326-6066.cir-13-0152
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发表时间：
2014-01
影响因子：
10.1
通讯作者：
Vonderheide RH
中科院分区：
文献类型：
--
作者：
Richman LP;Vonderheide RH
肿瘤坏死因子受体超家族激动剂有望成为治疗癌症的新疗法。最近关于激动性抗小鼠TNF受体（TNFR）如CD40的数据表明，fc受体（FcR）的特异性参与是最佳抗肿瘤效果所必需的，这促使人们相应地设计抗人CD40和其他TNFR单抗。CP-870,893是一种完全的人抗cd40单抗，被选中的部分原因是它是一种IgG2，被认为对FcR的反应性较差；然而，CP-870,893已在多个临床试验中对黑色素瘤、胰腺癌和其他癌症患者的有益活性进行了评估。在这里，我们证实了抗小鼠CD40单抗的活性依赖于fc - γ riib接合，在fc - γ riib - / -小鼠中显著降低，并且在fc交联后抗小鼠CD40单抗增强了抗原提呈细胞的活化。相比之下，cp -870,893介导的人B细胞的活化不被抗igg交联增强，也不被用作F(ab)'2试剂。与可溶性的CP-870,893单抗相比，用表达cd32的K562细胞交联CP-870,893产生了fc依赖性的一些激活标记物的表达适度增加。与IgG1抗cd20单抗利妥昔单抗相比，CP-870,893的经典fc依赖性功能（如抗体依赖性细胞毒性（ADCC）和补体介导的细胞毒性（CMC））最小，后者在平行实验中介导ADCC和CMC。抗小鼠CD40单抗竞争CD40配体结合位点，而CP-870,893不竞争。因此，fc交联不是激动性抗人CD40单抗的必要条件，其效力更多地依赖于识别的CD40表位和获得的信号强度。
Agonists of the TNF superfamily of receptors hold promise as novel therapy for cancer. Recent data on agonistic anti-murine TNF receptors (TNFR) such as CD40 suggest that the specific engagement of Fc-receptor (FcR) is required for optimal antitumor effects, prompting calls to engineer anti-human CD40 and other TNFR mAb accordingly. CP-870,893 is a fully human anti-CD40 mAb, selected in part because it is an IgG2 which is presumed to have poor reactivity with FcR; however, CP-870,893 has been evaluated in multiple clinical trials with beneficial activity in patients with melanoma, pancreatic and other cancers. Here, we confirmed that the activity of anti-murine CD40 mAb was dependent on FcγRIIB engagement, was decreased significantly in FcγRIIB−/− mice, and upon Fc-crosslinking anti-mouse CD40 mAb enhanced the activation of antigen presenting cells. In contrast, the CP-870,893-mediated activation of human B cells was not enhanced with anti-IgG-crosslinking nor abrogated when used as an F(ab)'2 reagent. Crosslinking of CP-870,893 using the CD32-expressing K562 cells yielded an Fc-dependent modest increase in the expression of some activation markers relative to that of the soluble CP-870,893 mAb. Classic Fc-dependent functions such as antibody-dependent cellular cytotoxicity (ADCC) and complement-mediated cytotoxicity (CMC) were minimal for CP-870,893 as compared to the IgG1 anti-CD20 mAb rituximab, which mediated both ADCC and CMC in parallel assays. Anti-mouse CD40 mAb competed for the CD40 ligand binding site, but CP-870,893 did not. Thus, Fc-crosslinking is not an essential requirement for agonistic anti-human CD40 mAb, whose potency is more dependent on the CD40 epitope recognized and the strength of the signal achieved.