Beta-glucan functions as an adjuvant for monoclonal antibody immunotherapy by recruiting tumoricidal granulocytes as killer cells.
Beta-glucan functions as an adjuvant for monoclonal antibody immunotherapy by recruiting tumoricidal granulocytes as killer cells.
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发表时间：
2003-12
期刊：
影响因子：
11.2
通讯作者：
F. Hong;Richard D. Hansen;Jun Yan;D. Allendorf;J. Baran;G. Ostroff;G. D. Ross
中科院分区：
文献类型：
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作者：
F. Hong;Richard D. Hansen;Jun Yan;D. Allendorf;J. Baran;G. Ostroff;G. D. Ross
单克隆抗体可用的肿瘤杀伤机制（单克隆抗体，如生长因子受体拮抗，抗体依赖细胞介导的细胞毒性）限制了其疗效。先前的研究表明，静脉注射β -葡聚糖可能作为抗肿瘤单抗的辅助剂。β -葡聚糖已被证明通过iC3b受体补体受体3 （CR3; CD11b/CD18）发挥作用，从而通过自然产生的抗肿瘤抗体增强白细胞杀死iC3b包被的肿瘤细胞。用β -葡聚糖治疗受到天然抗体水平和通过消除抗原阳性细胞肿瘤逃逸的限制。因此，我们假设β -葡聚糖反应可以通过联合抗肿瘤单抗来改善。在BALB/c或C57Bl/6小鼠中，使用表达高水平天然抗原（例如，G（D2）神经节苷脂）或重组人MUC1的肿瘤来探索五种肿瘤模型。与单独抗肿瘤单抗或β -葡聚糖相比，单抗加β -葡聚糖联合治疗在包括乳腺、sc和肝脏肿瘤在内的所有模型中均产生了更大的肿瘤消退。无瘤存活只发生在目标抗原稳定表达的模型中。在白细胞CR3 （CD11b(-/-)）或血清C3缺乏的小鼠中，β -葡聚糖并未增强单克隆抗肿瘤反应，这证实了白细胞需要CR3，肿瘤需要iC3b。粒细胞似乎主要负责肿瘤杀灭活性，因为β -葡聚糖治疗反应在粒细胞耗尽的小鼠中没有发生。这些数据表明，已知的激活补体的单克隆抗体（例如，赫赛汀，利妥昔和艾比妥）如果与β -葡聚糖联合使用，可以显着提高治疗效果。
The tumor-killing mechanisms available to monoclonal antibodies (mAbs; e.g., antagonism of growth factor receptors, antibody-dependent cell-mediated cytotoxicity) limit efficacy. Previous studies suggested that i.v. beta-glucan might function as an adjuvant for antitumor mAbs. beta- Glucan had been shown to function via the iC3b-receptor complement receptor 3 (CR3; CD11b/CD18) thereby enhancing leukocyte killing of tumor cells coated with iC3b via naturally occurring antitumor antibodies. Therapy with beta-glucans was limited by levels of natural antibodies and by tumor escape through elimination of antigen-positive cells. Accordingly, it was hypothesized that beta-glucan responses could be improved by combined administration with antitumor mAbs. Five tumor models were explored in BALB/c or C57Bl/6 mice using tumors that expressed either high levels of naturally occurring antigens (e.g., G(D2) ganglioside) or recombinant human MUC1. In comparison with antitumor mAb or beta-glucan alone, combined treatment with mAb plus beta-glucan produced significantly greater tumor regression in all models that included mammary, s.c., and hepatic tumors. Tumor-free survival only occurred in models that incorporated stable expression of the target antigen. beta-Glucan enhancement of the mAb tumoricidal response did not occur in mice deficient in either leukocyte CR3 (CD11b(-/-)) or serum C3, confirming the requirement for CR3 on leukocytes and iC3b on tumors. Granulocytes appeared to be primarily responsible for tumoricidal activity, because beta-glucan therapeutic responses did not occur in granulocyte-depleted mice. These data suggest that the therapeutic efficacy of mAbs known to activate complement (e.g., Herceptin, Rituxan, and Erbitux) could be significantly enhanced if they were combined with beta-glucan.