Fc-engineered anti-CD40 antibody enhances multiple effector functions and exhibits potent in vitro and in vivo antitumor activity against hematologic malignancies
Fc-engineered anti-CD40 antibody enhances multiple effector functions and exhibits potent in vitro and in vivo antitumor activity against hematologic malignancies
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DOI：
10.1182/blood-2010-01-265280
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发表时间：
2010-10-21
期刊：
影响因子：
20.3
通讯作者：
Zhukovsky, Eugene A.
中科院分区：
文献类型：
--
作者：
Horton, Holly M.;Bernett, Matthew J.;Zhukovsky, Eugene A.
CD40 在各种 B 系恶性肿瘤中高表达，是肿瘤疾病有吸引力的免疫治疗靶点。先前的工作表明，对抗体的 Fc 结构域进行改造以增加与 Fc γ 受体 (Fc γ Rs) 的结合可显着增强 Fc 介导的免疫效应器功能和体外和体内抗肿瘤活性。我们开发了一种类似 Fc 工程的人源化抗 CD40 抗体，以增加 Fc gamma R 结合 (XmAbCD40)，并将其功效与抗 CD40 天然 IgG1 类似物和抗 CD20 抗体利妥昔单抗的功效进行了比较。相对于抗 CD40 IgG1，XmAbCD40 针对 B 淋巴瘤、白血病和多发性骨髓瘤细胞系的抗体依赖性细胞介导的细胞毒性 (ADCC) 提高了 150 倍，并且显着增强了针对原发性肿瘤的 ADCC。 XmAbCD40 在增强 ADCC（在细胞系和原发性肿瘤中）和增强抗体依赖性细胞吞噬作用方面也优于利妥昔单抗。 XmAbCD40 显着抑制播散性和建立的小鼠异种移植物中的淋巴瘤生长，并且比 IgG1 类似物或利妥昔单抗更有效。为消除 Fc gamma R 结合而构建的抗 CD40 抗体并未显示出肿瘤生长的减少，表明 XmAbCD40 的体内抗肿瘤活性主要通过 Fc gamma R 依赖性机制介导。这些数据表明XmAbCD40显示出有效的抗肿瘤功效，值得进一步评估其治疗CD40(+)恶性肿瘤的效果。 (血液.2010;116(16):3004-3012)
CD40 is highly expressed on various B-lineage malignancies and represents an attractive immunotherapy target for neoplastic disease. Previous work showed that engineering the Fc domain of an antibody for increased binding to Fc gamma receptors (Fc gamma Rs) significantly enhanced Fc-mediated immune effector function and antitumor activity in vitro and in vivo. We developed a humanized anti-CD40 antibody similarly Fc-engineered for increased Fc gamma R binding (XmAbCD40) and compared its efficacy with that of an anti-CD40 native IgG1 analog and the anti-CD20 antibody rituximab. XmAbCD40 increased antibody-dependent cell-mediated cytotoxicity (ADCC) up to 150-fold relative to anti-CD40 IgG1 against B-lymphoma, leukemia, and multiple myeloma cell lines, and significantly enhanced ADCC against primary tumors. XmAbCD40 was also superior to rituximab in enhancing ADCC (both in cell lines and primary tumors) and in augmenting antibody-dependent cellular phagocytosis. XmAbCD40 significantly inhibited lymphoma growth in disseminated and established mouse xenografts and was more effective than the IgG1 analog or rituximab. An anti-CD40 antibody constructed to abrogate Fc gamma R binding showed no reduction of tumor growth, indicating that the in vivo antitumor activity of XmAbCD40 is primarily mediated via Fc gamma R-dependent mechanisms. These data demonstrate that XmAbCD40 displays potent antitumor efficacy and merits further evaluation for the treatment of CD40(+) malignancies. (Blood.2010;116(16):3004-3012)