Immune-stimulating antibody conjugates elicit robust myeloid activation and durable antitumor immunity

被引：146

作者：

Ackerman, Shelley E. ^{[1
,2
,3
]}

Pearson, Cecelia I. ^{[3
]}

Gregorio, Joshua D. ^{[3
]}

Gonzalez, Joseph C. ^{[3
]}

Kenkel, Justin A. ^{[3
,4
]}

Hartmann, Felix J. ^{[4
]}

Luo, Angela ^{[3
]}

Ho, Po Y. ^{[3
]}

LeBlanc, Heidi ^{[3
]}

Blum, Lisa K. ^{[3
]}

Kimmey, Samuel C. ^{[4
,5
]}

Luo, Andrew ^{[3
]}

Nguyen, Murray L. ^{[3
]}

Paik, Jason C. ^{[4
]}

Sheu, Lauren Y. ^{[4
]}

Ackerman, Benjamin ^{[6
]}

Lee, Arthur ^{[3
]}

Li, Hai ^{[3
]}

Melrose, Jennifer ^{[3
]}

Laura, Richard P. ^{[3
]}

Ramani, Vishnu C. ^{[3
]}

Henning, Karla A. ^{[3
]}

Jackson, David Y. ^{[3
]}

Safina, Brian S. ^{[3
]}

Yonehiro, Grant ^{[3
]}

Devens, Bruce H. ^{[3
]}

Carmi, Yaron ^{[4
,7
]}

Chapin, Steven J. ^{[3
]}

Bendall, Sean C. ^{[4
]}

Kowanetz, Marcin ^{[3
]}

Dornan, David ^{[3
]}

Engleman, Edgar G. ^{[4
]}

Alonso, Michael N. ^{[3
,4
]}

机构：

[1] Stanford Univ, Sch Med, Dept Bioengn, Stanford, CA 94305 USA

[2] Stanford Univ, Sch Engn, Dept Bioengn, Stanford, CA 94305 USA

[3] Bolt Biotherapeut Inc, Redwood City, CA 94063 USA

[4] Stanford Univ, Sch Med, Dept Pathol, Stanford, CA 94305 USA

[5] Stanford Univ, Sch Med, Dept Dev Biol, Stanford, CA 94305 USA

[6] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA

[7] Tel Aviv Univ, Sackler Sch Med, Dept Pathol, Tel Aviv, Israel

来源：

NATURE CANCER | 2021年 / 2卷 / 01期

基金：

美国国家卫生研究院; 瑞士国家科学基金会;

关键词：

FC-GAMMA RECEPTORS; NON-HODGKINS-LYMPHOMA; ANTIGEN PRESENTATION; DENDRITIC CELLS; TYROSINE KINASE; BREAST-CANCER; MACROPHAGES; INDUCTION; CYTOMETRY; RESPONSES;

D O I：

10.1038/s43018-020-00136-x

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

Innate pattern recognition receptor agonists, including Toll-like receptors (TLRs), alter the tumor microenvironment and prime adaptive antitumor immunity. However, TLR agonists present toxicities associated with widespread immune activation after systemic administration. To design a TLR-based therapeutic suitable for systemic delivery and capable of safely eliciting tumor-targeted responses, we developed immune-stimulating antibody conjugates (ISACs) comprising a TLR7/8 dual agonist conjugated to tumor-targeting antibodies. Systemically administered human epidermal growth factor receptor 2 (HER2)-targeted ISACs were well tolerated and triggered a localized immune response in the tumor microenvironment that resulted in tumor clearance and immunological memory. Mechanistically, ISACs required tumor antigen recognition, Fc gamma-receptor-dependent phagocytosis and TLR-mediated activation to drive tumor killing by myeloid cells and subsequent T-cell-mediated antitumor immunity. ISAC-mediated immunological memory was not limited to the HER2 ISAC target antigen since ISAC-treated mice were protected from rechallenge with the HER2(-) parental tumor. These results provide a strong rationale for the clinical development of ISACs. Alonso and colleagues develop immune-stimulating antibody conjugates capable of specific delivery of TLR7/8 agonists to tumors, which induces durable antitumor immunity.

引用

页码：18 / +

页数：36

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