医学
免疫系统
TLR7型
免疫疗法
癌症研究
肿瘤微环境
免疫原性
抗原
单克隆抗体
癌症免疫疗法
药理学
抗体
免疫学
Toll样受体
先天免疫系统
作者
Filip Janků,Sae‐Won Han,Toshihiko Doi,Alessio Amatu,Jaffer A. Ajani,Yasutoshi Kuboki,Alex Cortez,Susan E. Cellitti,Ping Mahling,Kulandayan K. Subramanian,Heidi A. Schoenfeld,Sarah M. Choi,Lori A. Iaconis,Lang Ho Lee,Marc Pelletier,Glenn Dranoff,Vasileios Askoxylakis,Salvatore Siena
出处
期刊:Cancer immunology research
[American Association for Cancer Research]
日期:2022-09-20
卷期号:10 (12): 1441-1461
被引量:19
标识
DOI:10.1158/2326-6066.cir-21-0722
摘要
Immune-stimulator antibody conjugates (ISAC) combining tumor-targeting monoclonal antibodies with immunostimulatory agents allow targeted delivery of immune activators into tumors. NJH395 is a novel, first-in-class ISAC comprising a Toll-like receptor 7 (TLR7) agonist conjugated to an anti-HER2 antibody via a noncleavable linker payload. Preclinical characterization showed ISAC-mediated activation of myeloid cells in the presence of antigen-expressing cancer cells, with antigen targeting and TLR7 agonism contributing to antitumor activity. Safety, efficacy, immunogenicity, pharmacokinetics, and pharmacodynamics were investigated in a phase I, multicenter, open-label study in patients with HER2+ non-breast advanced malignancies (NCT03696771). Data from 18 patients enrolled in single ascending dose escalation demonstrated delivery of the TLR7-agonist payload in HER2+ tumor cells and induction of type I IFN responses, which correlated with immune modulation in the tumor microenvironment. Cytokine release syndrome was a common, but manageable, drug-related adverse event. Antidrug antibodies and neuroinflammation at high doses represented significant clinical challenges. Data provide proof-of-mechanism and critical insights for novel immunotherapies.
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