Tumor targeting of the IL‐15 superagonist RLI by an anti‐GD2 antibody strongly enhances its antitumor potency
Tumor targeting of the IL‐15 superagonist RLI by an anti‐GD2 antibody strongly enhances its antitumor potency
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抗 GD2 抗体对 IL-15 超级激动剂 RLI 的肿瘤靶向作用大大增强了其抗肿瘤效力
DOI：
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发表时间：
2013
影响因子：
6.4
通讯作者：
Y. Jacques
中科院分区：
文献类型：
--
作者：
Marie Vincent;A. Bessard;D. Cochonneau;G. Teppaz;V. Solé;M. Maillasson;S. Birklé;L. Garrigue;A. Quéméner;Y. Jacques
免疫细胞因子（ICKs）利用针对肿瘤相关抗原的抗体将细胞因子靶向到肿瘤环境中，通常比相应的非偶联细胞因子具有更高的治疗指数。已经开发出了多种具有显著抗肿瘤作用的小鼠肿瘤模型，其中一些，特别是基于白细胞介素（IL）‐2的肿瘤模型，正在进行II期临床试验。尽管IL - 15在体外与IL - 2具有相同的生物活性，但目前认为IL - 15在抗肿瘤免疫治疗策略中具有更好的潜力，并且在临床前研究中显示其毒性低于IL - 2。我们之前开发了融合蛋白RLI，将人类IL - 15Rα - sushi+结构域的可溶性形式与人类IL - 15连接起来。在小鼠和人类癌症模型中，RLI显示出比IL - 15更好的体外生物活性，以及更高的体内抗肿瘤作用。在ICK的背景下，我们研究了RLI与一种靶向GD2神经节苷脂的抗体的作用，GD2神经节苷脂是一种在许多神经胚层肿瘤上表达的有效肿瘤靶点。抗GD2 - RLI完全保留了RLI的细胞因子潜能和抗体效应功能（抗体依赖性细胞毒性和补体依赖性细胞毒性）。在两种免疫功能小鼠（皮下EL4和转移性NXS2）的同基因肿瘤模型中显示出较强的抗肿瘤活性。其治疗效果高于RLI和抗GD2单独或联合使用。我们认为这与其双功能（细胞因子和抗体）性质有关。
Immunocytokines (ICKs) targeting cytokines to the tumor environment using antibodies directed against a tumor‐associated antigen often have a higher therapeutic index than the corresponding unconjugated cytokines. Various ICKs displaying significant antitumoral effects in several murine tumor models have already been developed, and some of them, in particular interleukin (IL)‐2‐based ICKs, are in Phase II clinical trials. Although sharing common biological activities with IL‐2 in vitro, IL‐15 is now considered as having a better potential in antitumor immunotherapeutical strategies and has been shown to be less toxic than IL‐2 in preclinical studies. We previously developed the fusion protein RLI, linking a soluble form of human IL‐15Rα‐sushi+ domain to human IL‐15. RLI showed better biological activities than IL‐15 in vitro as well as higher antitumoral effects in vivo in murine and human cancer models. Here, we investigated, in the context of an ICK, the effect of associating RLI with an antibody targeting the GD2 ganglioside, a validated tumoral target expressed on many neurectodermal tumors. Anti‐GD2‐RLI fully retained the cytokine potential of RLI and the antibody effector functions (antibody‐dependent cellular cytotoxicity and complement‐dependent cytotoxicity). It displayed strong antitumor activities in two syngeneic cancer models in immunocompetent mice (subcutaneous EL4 and metastatic NXS2). Its therapeutic potency was higher than those of RLI and anti‐GD2 alone or in combination. We suggest that this is related to its bifunctional (cytokine and antibody) nature.
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影响因子：
32.4
作者：
Mortier, Erwan;Advincula, Rommel;Ma, Averil
通讯作者：
Ma, Averil
影响因子：
3.9
作者：
Birklé, S;Zeng, G;Aubry, J
通讯作者：
Aubry, J
影响因子：
5.7
作者：
Kermer, Vanessa;Baum, Volker;Mueller, Dafne
通讯作者：
Mueller, Dafne
影响因子：
20.3
作者：
Berger, Carolina;Berger, Michael;Riddell, Stanley R.
通讯作者：
Riddell, Stanley R.
白介素15生物学及其在癌症中的治疗意义。
影响因子：
13.8
作者：
Steel JC;Waldmann TA;Morris JC
通讯作者：
Morris JC