Enhanced Natural Killer Cell Immunotherapy by Rationally Assembling Fc Fragments of Antibodies onto Tumor Membranes,Advanced Materials

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Enhanced Natural Killer Cell Immunotherapy by Rationally Assembling Fc Fragments of Antibodies onto Tumor Membranes
Advanced Materials ( IF 27.4 ) Pub Date : 2018-12-14 , DOI: 10.1002/adma.201804395
Tianjiao Ji _{1,

2,

3} , Jiayan Lang _{2,

3,

4} , Bo Ning ₅ , Feifei Qi _{2,

3} , Hui Wang ₆ , Yinlong Zhang _{2,

3} , Ruifang Zhao _{2,

3} , Xiao Yang _{2,

3} , Lijing Zhang _{1,

2,

3} , Wei Li ₇ , Xinghua Shi ₆ , Zhihai Qin ₁ , Ying Zhao _{2,

3} , Guangjun Nie _{2,

3}

Affiliation

Recent advances in cancer immunotherapy have exploited the efficient potential of natural killer (NK) cells to kill tumor cells through antibody‐dependent cell‐mediated cytotoxicity (ADCC). However, this therapeutic strategy is seriously limited by tumor antigen heterogeneity since antibodies can only recognize specific antigens. In this work, modified antibodies or their Fc fragments that can target solid tumors without the necessity of specific antigen presentation on tumors are developed. Briefly, Fc fragments or therapeutic monoclonal antibodies are conjugated with the N‐terminus of pH low insertion peptide so that they will selectively assemble onto the membrane of solid tumor cells via the conformational transformation of the peptide by responding to the acidic tumor microenvironment. The inserted Fc fragments or antibodies can efficiently activate NK cells, initiating ADCC and killing multiple types of tumor cells, including antigen‐negative cancer cells. In vivo therapeutic results also exhibit significant efficacy on both primary solid tumors and tumor metastasis. These modified Fc fragments and antibodies present strong potential to overcome the limitation of tumor antigen heterogeneity, broadening the applications of NK cell immunotherapy on solid tumor treatment.

中文翻译：

通过合理地将抗体的Fc片段组装到肿瘤膜上来增强自然杀伤细胞免疫治疗。

癌症免疫疗法的最新进展已经利用了自然杀伤（NK）细胞通过抗体依赖性细胞介导的细胞毒性（ADCC）杀死肿瘤细胞的有效潜力。但是，由于抗体只能识别特定的抗原，因此这种治疗策略受到肿瘤抗原异质性的严重限制。在这项工作中，开发了可靶向实体瘤而无需在肿瘤上特异性呈递抗原的修饰抗体或其Fc片段。简而言之，将Fc片段或治疗性单克隆抗体与pH低插入肽的N末端缀合，以便它们通过响应酸性肿瘤微环境而通过肽的构象转化选择性地组装在实体肿瘤细胞的膜上。插入的Fc片段或抗体可以有效激活NK细胞，启动ADCC并杀死多种类型的肿瘤细胞，包括抗原阴性癌细胞。体内治疗结果对原发性实体瘤和肿瘤转移也显示出显着的功效。这些修饰的Fc片段和抗体具有克服肿瘤抗原异质性的强大潜力，从而拓宽了NK细胞免疫疗法在实体瘤治疗中的应用。

更新日期：2018-12-14

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