Immune-stimulating antibody conjugates elicit robust myeloid activation and durable antitumor immunity.
Immune-stimulating antibody conjugates elicit robust myeloid activation and durable antitumor immunity.
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DOI：
10.1038/s43018-020-00136-x
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发表时间：
2021-01
期刊：
影响因子：
22.7
通讯作者：
Alonso, Michael N.
中科院分区：
文献类型：
--
作者：
Ackerman, Shelley E.;Pearson, Cecelia I.;Gregorio, Joshua D.;Gonzalez, Joseph C.;Kenkel, Justin A.;Hartmann, Felix J.;Luo, Angela;Ho, Po Y.;LeBlanc, Heidi;Blum, Lisa K.;Kimmey, Samuel C.;Luo, Andrew;Nguyen, Murray L.;Paik, Jason C.;Sheu, Lauren Y.;Ackerman, Benjamin;Lee, Arthur;Li, Hai;Melrose, Jennifer;Laura, Richard P.;Ramani, Vishnu C.;Henning, Karla A.;Jackson, David Y.;Safina, Brian S.;Yonehiro, Grant;Devens, Bruce H.;Carmi, Yaron;Chapin, Steven J.;Bendall, Sean C.;Kowanetz, Marcin;Dornan, David;Engleman, Edgar G.;Alonso, Michael N.
先天模式识别受体，包括 Toll 样受体 (TLR)，可以改变肿瘤微环境并启动适应性抗肿瘤免疫。然而，由于全身给药后与广泛免疫激活相关的毒性，TLR 激动剂的耐受性不佳。为了设计一种适合全身给药并能够引发肿瘤靶向反应的治疗方法，我们开发了一类新型免疫刺激抗体偶联物 (ISAC)，其中包含与肿瘤靶向抗体偶联的 TLR7/8 激动剂。全身施用的抗 HER2 ISAC 在体内具有良好的耐受性，并引发瘤内骨髓细胞的强烈激活，从而导致肿瘤清除和随后的免疫记忆。体外效力和体内效力需要由完整 Fc 功能和 TLR 激动驱动的串联活性，以实现吞噬作用和 T 细胞介导的抗肿瘤免疫。 ISAC 介导的免疫记忆不仅限于 HER2，因为 ISAC 治疗的小鼠可以免受 HER2 阴性肿瘤的再次攻击。这些结果为 ISAC 的临床开发提供了强有力的理论依据，并表明 FcγR 和 TLR7/8 信号传导之间的协同作用有助于 ISAC 介导的抗肿瘤免疫机制。
Innate pattern recognition receptors, including toll-like receptors (TLRs), can alter the tumor microenvironment and prime adaptive anti-tumor immunity. However, TLR agonists have not been well-tolerated due to toxicities associated with widespread immune activation following systemic administration. To design a therapeutic that is suitable for systemic delivery and capable of eliciting a tumor-targeted response, we developed a novel class of immune-stimulating antibody conjugates (ISACs) comprising a TLR7/8 agonist conjugated to tumor-targeting antibodies. Systemically administered anti-HER2 ISACs were well-tolerated in vivo and elicited robust activation of intratumoral myeloid cells, resulting in tumor clearance and subsequent immunological memory. In vitro potency and in vivo efficacy required tandem activity driven by intact Fc functionality and TLR agonism to enable phagocytosis and T cell-mediated anti-tumor immunity. ISAC-mediated immunological memory was not limited to HER2, as ISAC-treated mice were protected from rechallenge with a HER2-negative tumor. These results provide strong rationale for the clinical development of ISACs and show that synergy between FcγR and TLR7/8 signaling contributes to the mechanism of ISAC-mediated anti-tumor immunity.
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DOI：
10.1126/science.1198704
发表时间：
2011-05-06
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Bendall SC;Simonds EF;Qiu P;Amir el-AD;Krutzik PO;Finck R;Bruggner RV;Melamed R;Trejo A;Ornatsky OI;Balderas RS;Plevritis SK;Sachs K;Pe'er D;Tanner SD;Nolan GP
通讯作者：
Nolan GP
DOI：
10.1124/jpet.106.109058
发表时间：
2006-12-01
影响因子：
3.5
作者：
Braselmann, Sylvia;Taylor, Vanessa;Masuda, Esteban S.
通讯作者：
Masuda, Esteban S.
DOI：
10.1073/pnas.0510801103
发表时间：
2006-02-07
影响因子：
11.1
作者：
Lee, J;Wu, CCN;Carson, DA
通讯作者：
Carson, DA
影响因子：
16.6
作者：
Kondratova, Maria;Czerwinska, Urszula;Kuperstein, Inna
通讯作者：
Kuperstein, Inna
影响因子：
45.3
作者：
Davis, TA;Grillo-López, AJ;Levy, R
通讯作者：
Levy, R