Beta glucan enhances antibody therapy for neuroblastoma

该提案是一项口服β-葡聚糖的I期试验，可增强抗GD 2单克隆抗体的抗肿瘤作用。单克隆抗体（MoAb）在神经母细胞瘤（NB）治疗中的应用。β-葡聚糖是在许多常见食物中发现的低毒性多糖。含有β-葡聚糖的草药在临床上被替代医学从业者用作抗肿瘤治疗。在实验室中，纯β-葡聚糖在临床上被替代医学从业者用作抗肿瘤治疗。在实验室中，已证明纯β-葡聚糖可引发循环白细胞（中性粒细胞、单核细胞/巨噬细胞、NK细胞）的CR 3）C-受体3型（一种iC 3b-受体）。这些引发的白细胞可以通过抗癌抗体激活补体来杀死iC 3b靶向的肿瘤细胞。先前的报告表明，大麦β-葡聚糖可以在体外引发白细胞CR 3（CD 11b/CD 18; Mac-1; α M β 2-整联蛋白）对肿瘤细胞的细胞毒性，但前提是靶细胞被CR 3的配体之一iC 3b包被。在小鼠模型中，静脉注射酵母β-葡聚糖治疗非常成功，需要能够存款IC 3 b的抗肿瘤抗体，以及表达CR 3受体的白色细胞。由于难以分离出具有适当分子量的药用级可溶性β-葡聚糖用于患者试验，因此阻碍了这些发现向临床的转化。此外，对于需要在延长的时间段内每天静脉内施用的临床药物的实用性存在担忧。我们已经确定了一种从大麦（Hordeum vulgare）中提取的β-葡聚糖，它可以强烈增强抗癌单克隆抗体的效果。这种效应与肿瘤类型无关。人NB、黑色素瘤、淋巴瘤、乳腺癌和表皮样癌异种移植物分别在抗GD 2、抗GD 3、抗CD 2、抗HER 2和抗EGFR MoAb存在下应答。虽然补体激活是必不可少的，但其作用不依赖于抗体依赖性细胞介导的细胞毒性（ADCC）。大麦β-葡聚糖极易溶于水，对热和蛋白酶的抵抗力极强，价格低廉，易于生产和纯化，相对不会引起过敏，并且在摄入时具有极好的安全记录。3F 8是一种鼠IgG 3单克隆抗体，先前显示可激活人补体和ADCC。它有效地靶向患者的NB，临床安全有效。我们计划确定β-葡聚糖加3F 8的临床毒性，并测试大麦β-葡聚糖是否可以增强3F 8杀死缺乏膜补体抵抗因子的肿瘤（即NB），从而允许补体激活。这些发现将对人类癌症模型中的抗体和疫苗策略以及多糖作为补充/草药在基于免疫的治疗中的作用产生普遍影响。

This proposal is a phase I trial of orally administered beta-glucan that can enhance the anti-tumor effects of anti-GD2 monoclonal antibody. (MoAb) in the therapy of neuroblastoma (NB). Beta-glucans are polysaccharides of low toxicity found in many common foods. Herbal medicines containing beta-glucans are used clinically as anti-tumor treatments by alternative medicine practitioners. In the laboratory, pure beta-glucans are used clinically as anti-tumor treatments by alternative medicine practitioners. In the laboratory, pure beta-glucans have been demonstrated to prime CR3 )C-receptor type 3, an iC3b-receptor) of circulating leukocytes (neutrophils, monocyte/macrophages, NK cells). These primed leukocytes can kill tumor cells targeted with iC3b through the activation fo complement by anti-cancer antibodies. Previous reports have shown that barley beta-glucans could prime leukocyte CR3 (CD11b/CD18; Mac-1; alphaMbeta2-integrin) for cytotoxicity of tumor cells in vitro, but only if the target cells were coated with iC3b, one of the ligands for CR3. In murine models, highly successful therapy with intravenous yeast beta-glucan required anti-tumor antibodies that could deposit IC3b, plus white cells that express CR3 receptors. The translation of these findings to the clinic has been hindered by the difficulty of isolating pharmaceutical grade soluble beta-glucans of the appropriate molecular weight for patient trials. Moreover, there are concerns about the practicality of a clinical drug that needs to be administered i.v. on a daily basis over prolonged periods of time. We have identified a beta-glucan, extracted from barley (Hordeum vulgare), that strongly enhances the effects of anti-cancer MoAbs. This effect is independent of tumor type. Human NB, melanoma, lymphoma, breast cancer and epidermoid carcinoma xenografts respond in the presence of anti-GD2, anti-GD3, anti-CD2-, anti-HER2 and anti-EGFR MoAbs, respectively. While complement activation is essential, the effect is independent of antibody dependent cell-mediated cytotoxicity (ADCC). Barley beta-glucan is highly soluble in water, extremely sable against heat and protease, inexpensive, easy to produce and purify, relatively non-allergenic, and has an excellent safety record when ingested. 3F8 is a murine IgG3 MoAb previously shown to activate human complement and ADCC. It targets efficiently to NB in patients and is clinically safe and efficacious. We plan to define the clinical toxicity of beta-glucan plus 3F8 and test if barley beta-glucan can enhance 3F8, in killing a tumor (i.e. NB) deficient in membrane complement resistance factors and thus allowing complement activation. These findings will have general implications for antibody and vaccine strategies in human cancer models, and the role of polysaccharides as complementary/herbal medicine in immune-based therapies.