Department of Cancer Immunology, Rikshospitalet-Radiumhospitalet, University Hospital, Oslo, Norway.
Department of Pathology, Rikshospitalet-Radiumhospitalet, University Hospital, Oslo, Norway; and.
FASEB J. 2018 Sep;32(9):5063-5077. doi: 10.1096/fj.201701544R. Epub 2018 Apr 16.
mAbs have emerged as a promising strategy for the treatment of cancer. However, in several malignancies, no effective antitumor mAbs are yet available. Identifying therapeutic mAbs that recognize common tumor antigens could render the treatment widely applicable. Here, a human single-chain variable fragment (scFv) antibody library was sequentially affinity selected against a panel of human cancer cell lines and an antibody fragment (named MS5) that bound to solid and blood cancer cells was identified. The MS5 scFv was fused to the human IgG1 Fc domain to generate an antibody (MS5-Fc fusion) that induced antibody-dependent cellular cytotoxicity and phagocytosis of cancer cells by macrophages. In addition, the MS5-Fc antibody bound to primary leukemia cells and induced antibody-dependent cellular cytotoxicity. In the majority of analyzed cancer cells, the MS5-Fc antibody induced cell surface redistribution of the receptor complexes, but not internalization, thus maximizing the accessibility of the IgG1 Fc domain to immune effector cells. In vitro stability studies showed that the MS5-Fc antibody was stable after 6 d of incubation in human serum, retaining ∼60% of its initial intact form. After intravenous injections, the antibody localized into tumor tissues and inhibited the growth of 3 different human tumor xenografts (breast, lymphoma, and leukemia). These antitumor effects were associated with tumor infiltration by macrophages and NK cells. In the Ramos B-cell lymphoma xenograft model, the MS5-Fc antibody exhibited a comparable antitumor effect as rituximab, a chimeric anti-CD20 IgG1 mAb. These results indicate that human antibodies with pan-cancer abilities can be generated from phage display libraries, and that the engineered MS5-Fc antibody could be an attractive agent for further clinical investigation.-Sioud, M., Westby, P., Vasovic, V., Fløisand, Y., Peng, Q. Development of a new high-affinity human antibody with antitumor activity against solid and blood malignancies.
单克隆抗体已成为癌症治疗的一种有前途的策略。然而，在几种恶性肿瘤中，还没有有效的抗肿瘤单克隆抗体。鉴定能够识别常见肿瘤抗原的治疗性单克隆抗体可以使治疗广泛适用。在这里，我们依次用一系列人癌细胞系对人源单链可变片段(scFv)抗体文库进行亲和选择，鉴定到一个结合实体瘤和血液癌细胞的抗体片段(命名为 MS5)。将 MS5 scFv 与人类 IgG1 Fc 结构域融合，生成一种抗体(MS5-Fc 融合物)，该抗体能诱导抗体依赖的细胞毒性和巨噬细胞对癌细胞的吞噬作用。此外，MS5-Fc 抗体能与原代白血病细胞结合并诱导抗体依赖的细胞毒性。在大多数分析的癌细胞中，MS5-Fc 抗体诱导受体复合物在细胞表面重新分布，但不内化，从而使 IgG1 Fc 结构域最大限度地被免疫效应细胞识别。体外稳定性研究表明，MS5-Fc 抗体在人血清中孵育 6 天后稳定，保留初始完整形式的约 60%。静脉注射后，抗体定位于肿瘤组织，并抑制 3 种不同的人肿瘤异种移植物(乳腺癌、淋巴瘤和白血病)的生长。这些抗肿瘤作用与巨噬细胞和 NK 细胞浸润肿瘤有关。在 Ramos B 细胞淋巴瘤异种移植模型中，MS5-Fc 抗体与嵌合抗 CD20 IgG1 单抗利妥昔单抗具有相当的抗肿瘤作用。这些结果表明，能够从噬菌体展示文库中产生具有泛癌能力的人源抗体，并且工程化的 MS5-Fc 抗体可能是进一步临床研究的有吸引力的候选药物。
