Shravan Madireddi, Yanli Yang, Sherry H Yeh, Chen Gu, Patricia L. Sanchez, Randall J. Brezski, H. Chiu, H. Erickson, R. Cubas, G. Lazar, J. Kim
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However, as OX40 needs clustering for efficient signaling, these antibodies can only function in microenvironments where FcγR bearing cells are abundant. To overcome this limitation, we generated multimeric anti-human-OX40 antibodies, which cluster OX40 independent of FcγR mediated cross-linking. In vitro, we found that multimeric anti-OX40 induces robust signaling independent of FcγR. Compared to the bivalent antibodies, multimeric anti-OX40 generated superior immune responses in vaccination and tumor settings, in vivo. Together, multimeric antibody platforms have important implications for effective targeting of OX40 and possibly other TNFRSF members. Citation Format: Shravan Madireddi, Yanli Yang, Sherry Yeh, Chen Gu, Patricia L. Sanchez, Randall Brezski, Henry Chiu, Hans Erickson, Rafael A. Cubas, Gregory Lazar, Jeong Kim. Multimeric anti-human OX40 induces robust immune responses [abstract]. 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引用次数: 0
摘要
针对TNF受体超家族(TNFRSF)共刺激成员的激动抗体在小鼠肿瘤模型中显示出令人印象深刻的抗肿瘤免疫反应,目前正在临床研究中。为了诱导有效的共刺激信号,大多数TNFRSF成员需要在免疫细胞表面形成超分子簇。最近的研究表明,激动抗体部分通过Fcγ受体(Fcγ r)介导的交联实现这一目标,使抗体能够聚集在对立免疫细胞上表达的TNFRSF成员。OX40 (CD134)激动抗体;TNFRSF4),主要靶向T细胞,目前正处于癌症免疫治疗的临床试验中。然而,由于OX40需要聚集才能有效地传递信号,这些抗体只能在fc - γ - r承载细胞丰富的微环境中发挥作用。为了克服这一限制,我们产生了多聚体抗人OX40抗体,该抗体不依赖于FcγR介导的交联。在体外,我们发现多聚体抗ox40诱导了不依赖于FcγR的强大信号。与二价抗体相比,多聚体抗ox40在疫苗接种和肿瘤环境中产生了更好的体内免疫应答。总之,多聚抗体平台对于有效靶向OX40和其他TNFRSF成员具有重要意义。引文格式:Shravan Madireddi, Yanli Yang, Sherry Yeh, Chen Gu, Patricia L. Sanchez, Randall Brezski, Henry Chiu, Hans Erickson, Rafael A. Cubas, Gregory Lazar, Jeong Kim。多聚体抗人OX40诱导强大的免疫应答[摘要]。摘自:AACR肿瘤免疫学和免疫治疗特别会议论文集;2017年10月1-4日;波士顿,MA。费城(PA): AACR;癌症免疫,2018;6(9增刊):摘要nr A29。
Agonistic antibodies to co-stimulatory members of the TNF Receptor Superfamily (TNFRSF) have demonstrated impressive antitumor immune responses in murine tumor models and are currently under investigation in the clinic. In order to induce efficient co-stimulatory signaling, the majority of TNFRSF members require supermolecular cluster formation on the immune cell surface. Recent studies have revealed that agonistic antibodies achieve this in part by Fcγ receptor (FcγR) mediated cross-linking, enabling antibodies to cluster the TNFRSF member expressed on the opposing immune cell. Agonistic antibodies to OX40 (CD134; TNFRSF4), which primarily target T cells are currently in clinical trials for cancer immunotherapy. However, as OX40 needs clustering for efficient signaling, these antibodies can only function in microenvironments where FcγR bearing cells are abundant. To overcome this limitation, we generated multimeric anti-human-OX40 antibodies, which cluster OX40 independent of FcγR mediated cross-linking. In vitro, we found that multimeric anti-OX40 induces robust signaling independent of FcγR. Compared to the bivalent antibodies, multimeric anti-OX40 generated superior immune responses in vaccination and tumor settings, in vivo. Together, multimeric antibody platforms have important implications for effective targeting of OX40 and possibly other TNFRSF members. Citation Format: Shravan Madireddi, Yanli Yang, Sherry Yeh, Chen Gu, Patricia L. Sanchez, Randall Brezski, Henry Chiu, Hans Erickson, Rafael A. Cubas, Gregory Lazar, Jeong Kim. Multimeric anti-human OX40 induces robust immune responses [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A29.