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Structural influence of antibody recruiting glycodendrimers (ARGs) on antitumoral cytotoxicity

机译：抗体募集糖细胞（Args）对抗肿瘤细胞毒性的结构影响

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The recruitment of endogenous antibodies against cancer cells has become a reliable antitumoral immunotherapeutic alternative over the last decade. The covalent attachment of antibody and tumor binding modules (ABM and TBM) within a single, well-defined synthetic molecule was indeed demonstrated to promote the formation of an interacting ternary complex between both the antibodies and the targeted cell, which usually results in the simultaneous immune-mediated cellular destruction. In a preliminary study, we have described the first Antibody Recruiting Glycodendrimers (ARGs), combining cRGD as ligands for the alpha(V)beta(3)-expressing melanoma cell line M21 and Rha as ligand for natural IgM, and demonstrated that multivalency is an essential requirement to form this complex. In the present study, we synthesized a new series of ARGs composed of ABMs, i.e. self-condensed rhamnosylated cyclopeptide and polylysine dendrimer, which have been conjugated to the TBM with or without spacer. Flow cytometry and confocal microscopy experiments with human serum and different cell lines revealed that the ABM geometry significantly influences the ternary complex formation in M21, whereas no significant binding occurs in BT 549 having low integrin expression. In addition, we demonstrate with a cellular viability assay that ARGs induce high level of cytotoxicity against M21 which is also in close correlation with the ABM structure. In particular, we have shown that ARG combining cyclopeptide core and branches, with or without spacer, induce 40-57% of selective cytotoxicity against M21 cells in the presence of human serum as the unique source of immunity effectors. Finally, we also highlight that the spacer between ABM and TBM enables an increase of the immune-mediate cytotoxicity even with ABM of lower valency.
机译：在过去十年中募集对癌细胞的内源性抗体已成为可靠的抗肿瘤免疫治疗替代品。在单个明确定义的合成分子内的抗体和肿瘤结合模块（ABM和TBM）的共价附着是为了促进抗体和靶细胞之间的相互作用的三元复合物的形成，这通常会导致同时的免疫介导的细胞破坏。在初步研究中，我们已经描述了第一抗体募集糖细胞（ARGS），将CRGD作为α（v）β（3） - 表达黑色素瘤细胞系M21和Rha作为天然IgM的配体，并证明了多价是形成这种复杂的基本要求。在本研究中，我们合成了由ABMS组成的新系列args，即自浓rhamnosylated环肽和聚赖氨酸树枝状体，其与具有或不具有间隔物的TBM缀合。流式细胞术和与人血清和不同细胞系的共聚焦显微镜实验表明，ABM几何形状显着影响M21中的三元复合物形成，而在具有低整联蛋白表达的BT 549中没有发生显着结合。此外，我们用细胞活性测定来证明诱导对M21的高水平细胞毒性，其也与ABM结构密切相关。特别地，我们已经表明，将环肽核和分支，有或没有间隔组合，诱导40-57％在人血清存在下针对M21细胞的选择性细胞毒性，作为免疫效应器的独特源。最后，我们还强调了ABM和TBM之间的间隔能够增加免疫介导细胞毒性，即使是低价的ABM。

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  • 来源
    《Biomaterials Science》 |2021年第11期|共10页
  • 作者

    Todaro Biagio; Achilli Silvia; Liet Benjamin; Laigre Eugenie; Tiertant Claire; Goyard David; Berthet Nathalie; Renaudet Olivier;

  • 作者单位

    Univ Grenoble Alpes CNRS DCM UMR 5250 F-38000 Grenoble France;

    Univ Grenoble Alpes CNRS DCM UMR 5250 F-38000 Grenoble France;

    Univ Grenoble Alpes CNRS DCM UMR 5250 F-38000 Grenoble France;

    Univ Grenoble Alpes CNRS DCM UMR 5250 F-38000 Grenoble France;

    Univ Grenoble Alpes CNRS DCM UMR 5250 F-38000 Grenoble France;

    Univ Grenoble Alpes CNRS DCM UMR 5250 F-38000 Grenoble France;

    Univ Grenoble Alpes CNRS DCM UMR 5250 F-38000 Grenoble France;

    Univ Grenoble Alpes CNRS DCM UMR 5250 F-38000 Grenoble France;

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  • 正文语种 eng
  • 中图分类 分子生物学;
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