CN114392351B - 毛螺菌科细菌与注射用人免疫球蛋白的联合用药物 - Google Patents
毛螺菌科细菌与注射用人免疫球蛋白的联合用药物 Download PDFInfo
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Abstract
本发明公开了毛螺菌科细菌与注射用人免疫球蛋白的联合用药物，属于生物制药领域。研究表明，注射用人免疫球蛋白具有治疗放射性损伤的作用，而毛螺菌科细菌和注射用人免疫球蛋白联用能进一步增强该治疗作用。因此，本发明的联合用药物对接受放疗的病患以及意外接受过多辐照者具有重要意义。
Description
技术领域
本发明属于生物制药领域。
背景技术
癌症是人类第二大死因，放射治疗(“放疗”)是一种被广泛应用的癌症治疗手段，对于癌症治疗的贡献率高达18％，仅次于手术治疗而明显高于化学治疗和生物治疗。但不可回避的是，放射治疗伴随着不同程度的以炎症为代表的急性和以纤维化为代表慢性器官损伤。具体而言，头颈部肿瘤的放射治疗往往导致口腔粘膜炎；胸部肿瘤放射治疗往往导致慢性肺炎；盆腹部肿瘤放射治疗往往导致腹泻、慢性肠炎、肠梗阻等。而以白细胞下降、髓系偏移为代表的造血损伤和以肠炎和肠梗阻为代表的消化道损伤在多部位的放射治疗均十分常见，并将导致放射治疗提前终止,严重的降低了患者的生活质量甚至造成患者死亡。增加放射治疗的剂量也将不可避免的增加健康器官发生急慢性放射性损伤的风险。因此，降低放射治疗伴随的急慢性放射性损伤，将更大限度的促进放射治疗的临床应用，提高肿瘤患者预后的生活质量。
核技术、核工业的迅猛发展，使核能在工农业生产、科学技术研究和国防民生中的应用日益广泛。“核”的和平使用已成为全球各国不能回避的发展动力。核设施或核活动中发生偏离运行工况的状态即核事故的发生，将对放射性工作人员以及周边民众产生意外的、非自愿的照射，导致放射性损伤。因此，在核设施附近应常备治疗放射性损伤的药物。
注射用人免疫球蛋白是由多人份健康人血浆混合后，经分离纯化、病毒灭活/去除等步骤制成的免疫球蛋白产品，主要活性成分是针对各种外源性抗原和自身抗原的多克隆免疫球蛋白组合。注射用人免疫球蛋白的给药方式可分为：静注人免疫球蛋白(intravenous immunoglobulin,IVIg)、肌注人免疫球蛋白(intramuscularimmunoglobulin,IMIg)和皮下注射人免疫球蛋白(subcutaneousimmunoglobulin，SCIg)。注射用人免疫球蛋白是治疗原发性免疫缺乏症、继发性免疫缺陷病、自身免疫性疾病(川崎病、特发性血小板减少性紫瘫)的有效药物，临床使用广泛。
发明人通过研究发现，注射用人免疫球蛋白在放射性损伤中有一定的救治作用，具体体现在：辐照导致小鼠胸腺、脾脏萎缩，淋巴细胞数量减少，大肠缩短，小肠炎症水平升高，并导致死亡。而注射用人免疫球蛋白则有助于小鼠逆转前述症状，并能减少死亡。但注射用人免疫球蛋白仅在雌性中的效果显著，而在雄性中效果还有待提高(专利申请202010925913.X)。
毛螺菌科(Lachnospiraceae)细菌是一类可定植于肠道的细菌，其被报道具有消化植物源的纤维素和半纤维素的能力，以增加食物的生物利用率；它还能生产短链脂肪酸，以作为肠道上皮细胞的主要营养供给。Hao Guo等报道，使用23株Lachnospiraceae的混合物可用于治疗放射性损伤，但这23株Lachnospiraceae之间的比例不清，制备复杂，且随着Lachnospiraceae丰度降低，其治疗效果下降(Guo H等.Multi-omics analyses ofradiation survivors identify radioprotective microbes andmetabolites.Science.2020 Oct 30；370(6516):eaay9097.)。
发明内容
本发明要解决的问题是：提供一种增强注射用人免疫球蛋白在治疗放射性损伤中疗效的联合用药物。
本发明中，“放射性损伤”指放射治疗的X射线、加速器、以及放射性物质发出的α射线、β射线和/或γ射线对身体照射后产生的损伤，所述照射既包括对身体表面的照射，也包括放射性物质进入体内后对体内细胞的照射。本发明中，ATCC为美国模式培养物集存库(American type culture collection)的简写。
本发明的技术方案如下：
一种治疗放射性损伤的联合用药物，所述联合用药物含有相同或者不同规格的同时或者分别给药的毛螺菌科细菌和注射用人免疫球蛋白；
所述注射用人免疫球蛋白为：静注人免疫球蛋白、肌注人免疫球蛋白和/或皮下注射人免疫球蛋白
进一步的，所述毛螺菌科细菌为ATCC编号为BAA-2278的Lachnospiraceaebacterium。
进一步的，所述联合用药物是恢复放射性损伤后身体造血功能的药物。
进一步的，所述联合用药物是缓解放射性损伤导致的胸腺萎缩、脾脏萎缩、白细胞减少和/或炎症的药物。进一步的，所述炎症为肠炎。
进一步的，所述联合用药物是男性用药物或雄性动物用药物。
本发明还提供了前述联合用药物在制备降低放射性损伤的药物中的用途。
一种治疗肿瘤的联合用药物，所述联合用药物含有相同或者不同规格的同时或者分别给药的抗肿瘤放疗药物、毛螺菌科细菌和注射用人免疫球蛋白；
所述注射用人免疫球蛋白为：静注人免疫球蛋白、肌注人免疫球蛋白和/或皮下注射人免疫球蛋白
进一步的，所述毛螺菌科细菌为ATCC编号为BAA-2278的Lachnospiraceaebacterium。
进一步的，所述联合用药物是恢复放疗后身体造血功能的药物。
进一步的，所述联合用药物是缓解放疗导致的胸腺萎缩、脾脏萎缩、白细胞减少和/或炎症的药物。进一步的，所述炎症为肠炎。
进一步的，所述联合用药物是男性用药物或雄性动物用药物。
本发明的有益效果如下：
1)本发明的联合用药物可用于恢复辐照后的身体造血功能；
2)本发明的联合用药物可缓解辐照导致的胸腺萎缩、脾脏萎缩、白细胞减少和/或炎症；
3)本发明的联合用药物克服了单独使用IVIg无法显效治疗雄性动物放射性损伤的缺点。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
图1：胸腺外观。
图2：脾脏外观。
图3：外周血白细胞计数。
图4：TAI组和Lachnospiraceae组大肠外观。
图5：TAI组和Lachnospiraceae组小肠内TNF-α和IL-6的水平。纵坐标的mL表示提取小肠中TNF-α和IL-6所用PBS的体积，单位重量的小肠所用PBS体积一致。
图6：IVIg组和IVIg+Lachnospiraceae组大肠外观。
图7：IVIg组和IVIg+Lachnospiraceae组小肠内TNF-α和IL-6的水平。纵坐标的mL表示提取小肠中TNF-α和IL-6所用PBS的体积，单位重量的小肠所用PBS体积一致。
具体实施方式
实施例1 IVIg与Lachnospiraceae联用治疗放射性损伤
本实施例中使用的Lachnospiraceae为Lachnospiraceae bacterium(ATCC BAA-2278)。
1.方法
1.1、5Gy全身辐照分析造血损伤
雄性小鼠24只，分成2组：
①IVIg组，12只；
②IVIg+Lachnospiraceae组12只；
IVIg组在全身辐照后5min静脉注射IVIg一次，随后每周注射IVIg两次，持续两周，每次剂量为0.3g/Kg体重。
IVIg+Lachnospiraceae组在全身辐照前30min内口服Lachnospiraceae一次，辐照后5min内静脉注射IVIg一次，随后每周注射IVIg两次，持续两周，并且每两天口服Lachnospiraceae一次。每次Lachnospiraceae剂量为1*107个；每次IVIg剂量为0.3g/Kg体重。
1.2、12Gy腹部局部辐照分析肠道损伤。
雄性小鼠44只，分成4组：
①TAI组，10只；
②Lachnospiraceae组，10只；
③IVIg组，12只；
④IVIg+Lachnospiraceae组12只；
TAI组只进行腹部局部辐照，然后注射与其他组药物等体积的PBS。
Lachnospiraceae组在腹部局部照射前30min内口服Lachnospiraceae一次，以后每两天口服Lachnospiraceae一次，每次Lachnospiraceae剂量为1*107个。
IVIg组在腹部局部辐照后5min静脉注射IVIg一次，随后每周注射IVIg两次，持续两周，每次剂量为0.3g/Kg体重。
IVIg+Lachnospiraceae组在腹部局部辐照前30min内口服Lachnospiraceae一次，辐照后5min内静脉注射IVIg一次，随后每周注射IVIg两次，持续两周，并且每两天口服Lachnospiraceae一次。每次Lachnospiraceae剂量为1*107个；每次IVIg剂量为0.3g/Kg体重。
然后，对小鼠采集外周血，检测白细胞数量，并取脾脏、胸腺、小肠进行观察，进一步检测小肠内IL-6、TNF-α水平。
2.结果
全身辐照会导致小鼠胸腺、脾脏萎缩，降低造血功能，白细胞随之减少。如图1～3所示，IVIg+Lachnospiraceae组相比IVIg组的胸腺和脾脏体积显著增加，白细胞数量显著增加。表明IVIg与Lachnospiraceae联用相比单独使用IVIg可进一步恢复小鼠的胸腺、脾脏大小，进而恢复被辐照小鼠的造血功能。
腹部局部辐照会导致小鼠大肠变短，且小肠内炎性因子TNFα和IL-6会升高，发生肠炎(Li,et al.Gut commensal derived-valeric acid protects against radiationinjuries.Gut Microbes,2020,11:789-806.)。只口服Lachnospiraceae不注射IVIg(Lachnospiraceae组)，大肠长度以及小肠中炎性因子TNFα和IL-6相比TAI组无差异(图4和图5)，表明只口服Lachnospiraceae不能抑制辐照引起的炎症。如图6所示，IVIg+Lachnospiraceae组的大肠的长度比IVIg组更长；IVIg+Lachnospiraceae组小肠中炎性因子TNFα和IL-6相比IVIg组水平降低(图7)。表明IVIg与Lachnospiraceae联用相比单独使用IVIg可进一步抑制辐照导致的炎症。
本实施例的结果表明，单独使用Lachnospiraceae无法抑制辐照引起的炎症，而IVIg与Lachnospiraceae联用相比单独使用IVIg可进一步抑制辐照导致的炎症。
综上，本发明的联合用药物可用于恢复辐照后的身体造血功能，并能缓解辐照导致的胸腺萎缩、脾脏萎缩、白细胞减少和/或炎症；且该联合用药物克服了单独使用IVIg无法显效治疗雄性动物的缺点。
Claims (4)
1.一种联合用药物在制备治疗放射性损伤导致的炎症的药物中的应用，其特征在于：所述联合用药物含有相同或者不同规格的同时或者分别给药的毛螺菌科细菌和注射用人免疫球蛋白；
所述注射用人免疫球蛋白为：静注人免疫球蛋白、肌注人免疫球蛋白和/或皮下注射人免疫球蛋白。
2.如权利要求1所述的应用，其特征在于：所述毛螺菌科细菌为ATCC编号为BAA-2278的Lachnospiraceae bacterium。
3.如权利要求1所述的应用，其特征在于：所述联合用药物是男性用药物或雄性动物用药物。
4.如权利要求1所述的应用，其特征在于：所述联合用药物是缓解放疗导致的炎症的药物。
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| US5562902A (en) * | 1994-03-14 | 1996-10-08 | Arp Biomed, Inc. | Immunotherapeutic method of treating cancerous diseases by administration of intravenous immunoglobulin |
| WO2020124088A1 (en) * | 2018-12-14 | 2020-06-18 | The University Of North Carolina At Chapel Hill | Lachnospiraceae mitigates against radiation-induced hematopoietic/gastrointestinal injury and death, and promotes cancer control by radiation |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5562902A (en) * | 1994-03-14 | 1996-10-08 | Arp Biomed, Inc. | Immunotherapeutic method of treating cancerous diseases by administration of intravenous immunoglobulin |
| WO2020124088A1 (en) * | 2018-12-14 | 2020-06-18 | The University Of North Carolina At Chapel Hill | Lachnospiraceae mitigates against radiation-induced hematopoietic/gastrointestinal injury and death, and promotes cancer control by radiation |
Non-Patent Citations (2)
| Title |
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| WANG,Z. 等.Sexual dimorphism in gut microbiota dictates therapeutic efficacy of intravenous immunoglobulin on radiotherapy complications.Journal of Advanced Research.2022,第46卷123-133. * |
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