Imprime PGG-Mediated Anti-Cancer Immune Activation Requires Immune Complex Formation.
Imprime PGG-Mediated Anti-Cancer Immune Activation Requires Immune Complex Formation.
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DOI：
10.1371/journal.pone.0165909
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Bose N
中科院分区：
文献类型：
--
作者：
Chan AS;Jonas AB;Qiu X;Ottoson NR;Walsh RM;Gorden KB;Harrison B;Maimonis PJ;Leonardo SM;Ertelt KE;Danielson ME;Michel KS;Nelson M;Graff JR;Patchen ML;Bose N
ImPrime PGG(IMPRIME)是一种静脉给药的可溶性β-葡聚糖，在肿瘤靶向或抗血管生成抗体的多个2期临床试验中显示出令人信服的疗效。从机制上讲，IMPRIME作为病原体相关分子模式(PAMP)直接激活天然免疫效应细胞，触发协同抗癌免疫反应。在这里，使用健康受试者的全血，我们证明了不良诱导的抗癌功能依赖于与自然产生的抗β葡聚糖抗体(ABA)形成免疫复合体。ImPrime-ABA复合体的形成主要通过经典的补体途径激活补体，并被iC3b调理。免疫复合物的结合依赖于补体受体3和FCG受体IIa，激发中性粒细胞和单核细胞的表型激活和增强趋化因子的产生，使这些效应细胞通过产生活性氧和抗体依赖的细胞吞噬作用来杀死抗体调理的肿瘤细胞。重要的是，这些先天免疫细胞的改变在低ABA水平的受试者中并不明显，但可以通过补充外源ABA来挽救。总之，这些数据表明，预先存在的ABA对于IMPRIME介导的抗癌免疫激活是必不可少的，并表明治疗前的ABA水平可能提供一个可信的患者选择生物标志物来描述最有可能从IMPRIME为基础的治疗中受益的患者。
Imprime PGG (Imprime), an intravenously-administered, soluble β-glucan, has shown compelling efficacy in multiple phase 2 clinical trials with tumor targeting or anti-angiogenic antibodies. Mechanistically, Imprime acts as pathogen-associated molecular pattern (PAMP) directly activating innate immune effector cells, triggering a coordinated anti-cancer immune response. Herein, using whole blood from healthy human subjects, we show that Imprime-induced anti-cancer functionality is dependent on immune complex formation with naturally-occurring, anti-β glucan antibodies (ABA). The formation of Imprime-ABA complexes activates complement, primarily via the classical complement pathway, and is opsonized by iC3b. Immune complex binding depends upon Complement Receptor 3 and Fcg Receptor IIa, eliciting phenotypic activation of, and enhanced chemokine production by, neutrophils and monocytes, enabling these effector cells to kill antibody-opsonized tumor cells via the generation of reactive oxygen species and antibody-dependent cellular phagocytosis. Importantly, these innate immune cell changes were not evident in subjects with low ABA levels but could be rescued with exogenous ABA supplementation. Together, these data indicate that pre-existing ABA are essential for Imprime-mediated anti-cancer immune activation and suggest that pre-treatment ABA levels may provide a plausible patient selection biomarker to delineate patients most likely to benefit from Imprime-based therapy.
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影响因子：
3.4
作者：
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通讯作者：
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DOI：
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DOI：
10.1007/s00262-010-0914-1
发表时间：
2010-12
期刊：
Cancer immunology, immunotherapy : CII
影响因子：
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作者：
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通讯作者：
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