Glyco-engineered anti-EGFR mAb elicits ADCC by NK cells from colorectal cancer patients irrespective of chemotherapy.
Glyco-engineered anti-EGFR mAb elicits ADCC by NK cells from colorectal cancer patients irrespective of chemotherapy.
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DOI：
10.1038/bjc.2014.35
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发表时间：
2014-03-04
影响因子：
8.8
通讯作者：
Ross, P.
中科院分区：
文献类型：
--
作者：
Oppenheim, D. E.;Spreafico, R.;Etuk, A.;Malone, D.;Amofah, E.;Pena-Murillo, C.;Murray, T.;McLaughlin, L.;Choi, B. S.;Allan, S.;Belousov, A.;Passioukov, A.;Gerdes, C.;Umana, P.;Farzaneh, F.;Ross, P.
表皮生长因子受体 (EGFR) 在结直肠癌 (CRC) 中过度表达，并与不良预后相关，使其成为单克隆抗体 (mAb) 治疗的有吸引力的靶点。 IgG1 mAb 治疗功效的一个组成部分是它们通过携带 CD16 受体的自然杀伤 (NK) 细胞刺激抗体依赖性细胞毒性 (ADCC)。由于癌症患者的 NK 细胞功能受损，并且可能在化疗后进一步受损，因此评估旨在进一步增强 ADCC 的免疫治疗策略是否可行至关重要。通过流式细胞术对化疗前、化疗期间和化疗后的 CRC 患者的主要白细胞群进行免疫表型分析。在针对 K562 细胞的细胞毒性测定中评估了不依赖于 ADCC 的 NK 细胞功能。通过脱颗粒测定来测量 NK 细胞对 EGFR+ A431 癌细胞的 ADCC 依赖性杀伤作用，其中 ADCC 是由 GA201 诱导的，GA201 是一种经过糖基工程改造以增强 ADCC 的抗 EGFR 单克隆抗体。在这里，我们证实了癌症患者体内 NK 细胞功能失调的观察结果。然而，GA201 能够在 CRC 患者 NK 细胞中诱导强大的 NK 细胞依赖性细胞毒性，有效克服其损伤。这些发现支持评估 GA201 联合化疗对 CRC 患者的治疗潜力。
The epidermal growth factor receptor (EGFR) is overexpressed in colorectal cancer (CRC), and is correlated with poor prognosis, making it an attractive target for monoclonal antibody (mAb) therapy. A component of the therapeutic efficacy of IgG1 mAbs is their stimulation of antibody-dependent cellular cytotoxicity (ADCC) by natural killer (NK) cells bearing the CD16 receptor. As NK cells are functionally impaired in cancer patients and may be further compromised upon chemotherapy, it is crucial to assess whether immunotherapeutic strategies aimed at further enhancing ADCC are viable. CRC patients before, during and after chemotherapy were immunophenotyped by flow cytometry for major white blood cell populations. ADCC-independent NK cell functionality was assessed in cytotoxicity assays against K562 cells. ADCC-dependent killing of EGFR+ A431 cancer cells by NK cells was measured with a degranulation assay where ADCC was induced by GA201, an anti-EGFR mAb glyco-engineered to enhance ADCC. Here, we confirm the observation that NK cells in cancer patients are dysfunctional. However, GA201 was able to induce robust NK cell-dependent cytotoxicity in CRC patient NK cells, effectively overcoming their impairment. These findings support the evaluation of the therapeutic potential of GA201 in combination with chemotherapy in CRC patients.
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DOI：
10.1073/pnas.0611655104
发表时间：
2007-04-10
影响因子：
11.1
作者：
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通讯作者：
Strominger, Jack L.
影响因子：
3.4
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
6.6
作者：
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通讯作者：
Schielzeth, Holger
影响因子：
11.5
作者：
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通讯作者：
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