TWI797067B - 包含細菌菌株之組合物 - Google Patents
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Abstract
本發明提供包含細菌菌株之組合物,其用於治療及預防癌症。
Description
本發明處於包含自哺乳動物消化道分離之細菌菌株的組合物及此類組合物在治療疾病中之用途的領域。
認為人類腸在出生前為無菌的,但其在出生之後立即暴露於多種多樣的母體及環境微生物中。此後,發生微生物定殖及繼承之動態時段,其受諸如遞送模式、環境、膳食及宿主基因型之因素影響,該等因素均影響腸道微生物群之組成,尤其在生命早期。隨後,微生物群穩定化且變得像成人[[1]]。人類腸道微生物群含有超過500-1000種不同系統型,該等系統型基本上屬於兩種主要細菌門:擬桿菌門及厚壁菌門[[2]]。在人類腸道之細菌定殖中出現的成功共生關係得到多種多樣的代謝、結構、保護及其他有益功能。經過定殖之腸道的代謝活性增強確保在其他情況下難消化之膳食組分降解,釋放為宿主提供重要營養來源之副產物。類似地,腸道微生物群之免疫重要性得到充分認識,並且例示性於具有受損之免疫系統的無菌動物中,該免疫系統在引入共生細菌後得到功能復原[[3]-,[[4]],[5]]。 已在諸如發炎性腸病(IBD)之胃腸病症中記錄微生物群組成之劇烈變化。舉例來說,在IBD患者中,梭菌屬集群XIVa細菌之水準降低,而大腸桿菌之數目增加,表明腸道內共生體及病生菌之平衡便宜[[6]-,[[7]],[[8]],[9]]。有趣的是,此微生物菌群失調亦與T效應細胞群體之不平衡相關聯。 在認識到某些細菌菌株對動物腸道可能具有之潛在正面作用的情況下,已提出用於治療各種疾病之各種菌株(參見例如[[10]-,[[11]],[[12]],[13]])。另外,已提出用於治療不與腸直接相關之各種發炎性及自體免疫性疾病的某些菌株(包括大多乳桿菌及雙叉桿菌菌株)(綜述參見[[14]]及[[15]])。然而,介於不同疾病與不同細菌菌株之間的關係及特定細菌菌株對腸道及在全身性水準下及對任何特定類型之疾病的精確作用未得到充分表徵。舉例而言,某些腸球菌屬種已牽涉造成癌症[[16]]。 在此項技術中要求治療疾病之新方法。亦需要表徵腸道細菌之潛在作用以使得可研發使用腸道細菌之新療法。
本發明人已研發出用於治療及預防疾病之新療法。特定言之,本發明人已研發出用於治療及預防癌症之新療法。特定言之,本發明人已鑑別出,雞腸球菌(Enterococcus gallinarum)種之細菌菌株可對治療及預防癌症有效。如實例中所描述,經口投與包含雞腸球菌之組合物可在癌症之小鼠模型中減小腫瘤尺寸。 在較佳實施例中,本發明提供一種包含雞腸球菌種之細菌菌株的組合物,其用於治療或預防癌症,諸如乳癌、肺癌或肝癌之方法中。本發明人已鑑別出,用包含雞腸球菌種之細菌菌株的組合物處理可在乳癌、肺癌或肝癌之小鼠模型中減少腫瘤生長。在某些實施例中,該組合物用於在治療癌症中減小腫瘤尺寸或預防腫瘤生長之方法中。使用雞腸球菌之組合物可對在治療癌症中減小腫瘤尺寸或預防腫瘤生長尤其有效。 在本發明之較佳實施例中,組合物中之細菌菌株為雞腸球菌之細菌菌株。亦可使用緊密相關之菌株,諸如16s rRNA序列與雞腸球菌之細菌菌株的16s rRNA序列至少95%、96%、97%、98%、99%、99.5%或99.9%一致的細菌菌株。較佳地,該細菌菌株之16s rRNA序列與SEQ ID NO:1或2至少95%、96%、97%、98%、99%、99.5%或99.9%一致。較佳地,序列一致性係相對於SEQ ID NO:2。較佳地,用於本發明中之細菌菌株具有由SEQ ID NO:2表示之16s rRNA序列。 因此,本發明亦提供一種包含16s rRNA序列與雞腸球菌之細菌菌株的16s rRNA序列至少95%一致之細菌菌株的組合物,其用於治療或預防癌症之方法中。特定言之,本發明提供一種包含16s rRNA序列與SEQ ID NO:2至少95%一致之細菌菌株的組合物,其用於治療或預防癌症之方法中。在一些實施例中,組合物中之細菌菌株不為雞腸球菌之細菌菌株。在一些實施例中,組合物中之細菌菌株不為雞腸球菌之細菌菌株,但為緊密相關之菌株。 在某些實施例中,本發明之組合物用於經口投與。經口投與本發明之菌株可對治療癌症有效。另外,經口投藥對於患者及醫師為便利的,且允許遞送至腸中及/或部分或完全在腸中定殖。 在某些實施例中,本發明之組合物包含一或多種醫藥學上可接受之賦形劑或載劑。 在某些實施例中,本發明之組合物包含已經凍乾之細菌菌株。凍乾為用於製備允許遞送細菌之穩定組合物的有效且便利之技術。 在某些實施例中,本發明提供一種包含如上文所描述之組合物的食物產品。 在某些實施例中,本發明提供一種包含如上文所描述之組合物的疫苗組合物。 另外,本發明提供一種治療或預防癌症之方法,其包含投與包含雞腸球菌種之細菌菌株的組合物。 在研發上文之發明中,本發明人已鑑別出且表徵尤其適用於療法之細菌菌株。展示本發明之雞腸球菌菌株對治療癌症有效。因此,在另一態樣中,本發明提供一種以寄存編號NCIMB 42488寄存之雞腸球菌或其衍生物的細胞。本發明亦提供包含此類細胞之組合物,或此類細胞的生物學純培養物。本發明亦提供一種以寄存編號NCIMB 42488寄存之雞腸球菌菌株或其衍生物的細胞,其用於療法,特定言之用於癌症之療法中。類似地,本發明提供一種16s rRNA序列與SEQ ID NO:2至少95%一致之細菌菌株或其衍生物的細胞。本發明亦提供包含此類細胞之組合物,或此類細胞的生物學純培養物。本發明亦提供16s rRNA序列與SEQ ID NO:2至少95%一致之細菌菌株或其衍生物的細胞,其用於療法,特定言之用於治療或預防癌症之療法中。
細菌菌株 本發明之組合物包含雞腸球菌種之細菌菌株。實例展現,此種之細菌適用於治療或預防癌症。 本發明亦提供包含16s rRNA序列與雞腸球菌之細菌菌株的16s rRNA序列至少95%一致之細菌菌株的組合物,其用於療法中,例如用於治療或預防癌症之方法中。特定言之,本發明亦提供包含16s rRNA序列與SEQ ID NO:2至少95%一致之細菌菌株的組合物,其用於療法中,例如用於治療或預防癌症之方法中。在一些實施例中,組合物中之細菌菌株不為雞腸球菌之細菌菌株,但為緊密相關之菌株。 本發明提供一種雞腸球菌,其用於療法中,例如用於治療或預防癌症。類似地,本發明提供一種包含雞腸球菌種之細菌菌株的組合物,其用於療法中,例如用於治療或預防癌症。在某些實施例中,本發明之組合物包含16s rRNA序列與SEQ ID NO:2至少95%一致之細菌菌株,舉例而言,該細菌菌株為雞腸球菌,且該組合物不含有任何其他細菌屬。在某些實施例中,本發明之組合物包含16s rRNA序列與SEQ ID NO:2至少95%一致之細菌菌株的單一菌株,舉例而言,該細菌菌株為雞腸球菌,且該組合物不含有任何其他細菌菌株或種。 雞腸球菌形成球菌狀細胞,大多成對或成短鏈。其不移動,且血液瓊脂或營養瓊脂上之集落為環狀且光滑的。雞腸球菌與藍斯費氏D群抗血清反應。雞腸球菌之模式菌株為F87/276 = PB21 = ATCC 49573 = CCUG 18658 = CIP 103013 = JCM 8728 = LMG 13129 = NBRC 100675 = NCIMB 702313 (以前NCDO 2313) = NCTC 12359[[17]]。雞腸球菌之16S rRNA基因序列的GenBank寄存編號為AF039900 (本文揭示為SEQ ID NO:1)。例示性雞腸球菌菌株描述於[17]中。 以寄存編號NCIMB 42488寄存之雞腸球菌細菌在實例中進行測試,且在本文中亦稱為菌株MRX518。提及MRX518及MRx0518可互換地使用。所測試之MRX518菌株的16S rRNA序列提供於SEQ ID NO:2中。菌株MRX518由4D Pharma Research Ltd. (Life Sciences Innovation Building, Aberdeen, AB25 2ZS, Scotland)於2015年11月16日在國際寄存單位NCIMB, Ltd. (Ferguson Building, Aberdeen, AB21 9YA, Scotland)寄存為「腸球菌屬」,且指定寄存編號NCIMB 42488。MRX518於106年1月19日以寄存編號BCRC910765寄存於食品工業發展研究所。 菌株MRX518之基因組包含染色體及質體。菌株MRX518之染色體序列提供於SEQ ID NO:3中。菌株MRX518之質體序列提供於SEQ ID NO:4中。此等序列使用PacBio RS II平台來產生。 亦預期與在實例中所測試之菌株緊密相關的細菌菌株對治療或預防癌症有效。在某些實施例中,用於本發明中之細菌菌株的16s rRNA序列與雞腸球菌之細菌菌株的16s rRNA序列至少95%、96%、97%、98%、99%、99.5%或99.9%一致。較佳地,用於本發明中之細菌菌株的16s rRNA序列與SEQ ID NO:1或2至少95%、96%、97%、98%、99%、99.5%或99.9%一致。較佳地,序列一致性係相對於SEQ ID NO:2。較佳地,用於本發明中之細菌菌株具有由SEQ ID NO:2表示之16s rRNA序列。 亦預期作為以寄存編號42488寄存之細菌之生物型的細菌菌株對治療或預防癌症有效。生物型為具有相同或極類似生理學及生物化學特徵之緊密相關菌株。 作為以寄存編號NCIMB 42488寄存之細菌之生物型且適合用於本發明中的菌株可藉由對以寄存編號NCIMB 42488寄存之細菌的其他核苷酸序列進行定序來鑑別。舉例而言,可對基本上完整基因組進行定序,且用於本發明中之生物型菌株可跨其完整基因組之至少80% (例如跨至少85%、90%、95%或99%,或跨其完整基因組)具有至少95%、96%、97%、98%、99%、99.5%或99.9%序列一致性。舉例而言,在一些實施例中,生物型菌株跨其基因組之至少98%具有至少98%序列一致性,或跨其基因組之99%具有至少99%序列一致性。用於鑑別生物型菌株的其他適合之序列可包括hsp60或重複序列,諸如BOX、ERIC、(GTG)5
或REP[[18]]。生物型菌株之序列可與以寄存編號NCIMB 42488寄存之細菌的相對應序列具有至少95%、96%、97%、98%、99%、99.5%或99.9%序列一致性。在一些實施例中,生物型菌株之序列與寄存為NCIMB 42488之菌株MRX518的相對應序列具有至少95%、96%、97%、98%、99%、99.5%或99.9%序列一致性,且該生物型菌株包含與SEQ ID NO:2至少99%一致(例如至少99.5%或至少99.9%一致)之16S rRNA序列。在一些實施例中,生物型菌株之序列與寄存為NCIMB 42488之菌株MRX518的相對應序列具有至少95%、96%、97%、98%、99%、99.5%或99.9%序列一致性,且該生物型菌株具有SEQ ID NO:2之16S rRNA序列。 在某些實施例中,用於本發明中之細菌菌株的染色體與SEQ ID NO:3具有序列一致性。在較佳實施例中,跨SEQ ID NO:3之至少60% (例如跨至少65%、70%、75%、80%、85%、95%、96%、97%、98%、99%或100%),用於本發明中之細菌菌株的染色體與SEQ ID NO:3具有至少90%序列一致性(例如至少92%、94%、95%、96%、97%、98%、99%或100%序列一致性)。舉例而言,用於本發明中之細菌菌株的染色體可跨SEQ ID NO:3之70%與SEQ ID NO:3具有至少90%序列一致性,或跨SEQ ID NO:3之80%與SEQ ID NO:3具有至少90%序列一致性,或跨SEQ ID NO:3之90%與SEQ ID NO:3具有至少90%序列一致性,或跨SEQ ID NO:3之100%與SEQ ID NO:3具有至少90%序列一致性,或跨SEQ ID NO:3之70%與SEQ ID NO:3具有至少95%序列一致性,或跨SEQ ID NO:3之80%與SEQ ID NO:3具有至少95%序列一致性,或跨SEQ ID NO:3之90%與SEQ ID NO:3具有至少95%序列一致性,或跨SEQ ID NO:3之100%與SEQ ID NO:3具有至少95%序列一致性,或跨SEQ ID NO:3之70%與SEQ ID NO:3具有至少98%序列一致性,或跨SEQ ID NO:3之80%與SEQ ID NO:3具有至少98%序列一致性,或跨SEQ ID NO:3之90%與SEQ ID NO:3具有至少98%序列一致性,或跨SEQ ID NO:3之95%與SEQ ID NO:3具有至少98%一致性,或跨SEQ ID NO:3之100%與SEQ ID NO:3具有至少98%序列一致性,或跨SEQ ID NO:3之90%與SEQ ID NO:3具有至少99.5%序列一致性,或跨SEQ ID NO:3之95%與SEQ ID NO:3具有至少99.5%一致性,或跨SEQ ID NO:3之98%與SEQ ID NO:3具有至少99.5%一致性,或跨SEQ ID NO:3之100%與SEQ ID NO:3具有至少99.5%序列一致性。 在某些實施例中,用於本發明中之細菌菌株的質體與SEQ ID NO:4具有序列一致性。在較佳實施例中,跨SEQ ID NO:4之至少60% (例如跨至少65%、70%、75%、80%、85%、95%、96%、97%、98%、99%或100%),用於本發明中之細菌菌株的質體與SEQ ID NO:4具有至少90%序列一致性(例如至少92%、94%、95%、96%、97%、98%、99%或100%序列一致性)。舉例而言,用於本發明中之細菌菌株的質體可跨SEQ ID NO:4之70%與SEQ ID NO:4具有至少90%序列一致性,或跨SEQ ID NO:4之80%與SEQ ID NO:4具有至少90%序列一致性,或跨SEQ ID NO:4之90%與SEQ ID NO:4具有至少90%序列一致性,或跨SEQ ID NO:4之100%與SEQ ID NO:4具有至少90%序列一致性,或跨SEQ ID NO:4之70%與SEQ ID NO:4具有至少95%序列一致性,或跨SEQ ID NO:4之80%與SEQ ID NO:4具有至少95%序列一致性,或跨SEQ ID NO:4之90%與SEQ ID NO:4具有至少95%序列一致性,或跨SEQ ID NO:4之100%與SEQ ID NO:4具有至少95%序列一致性,或跨SEQ ID NO:4之70%與SEQ ID NO:4具有至少98%序列一致性,或跨SEQ ID NO:4之80%與SEQ ID NO:4具有至少98%序列一致性,或跨SEQ ID NO:4之90%與SEQ ID NO:4具有至少98%序列一致性,或跨SEQ ID NO:4之100%與SEQ ID NO:4具有至少98%一致性。 在某些實施例中,用於本發明中之細菌菌株的染色體與SEQ ID NO:3具有序列一致性,且其質體與SEQ ID NO:4具有序列一致性。 在某些實施例中,用於本發明中之細菌菌株的染色體與SEQ ID NO:3 (例如如上文所描述)具有序列一致性,且其16S rRNA序列與SEQ ID NO:1或2 (例如如上文所描述)中之任一者具有序列一致性,較佳地,其中16s rRNA序列與SEQ ID NO:2至少99%一致,更佳地,其包含SEQ ID NO:2之16S rRNA序列,且其視情況包含與SEQ ID NO:4 (例如如上文所描述)具有序列一致性之質體。 在某些實施例中,用於本發明中之細菌菌株的染色體與SEQ ID NO:3 (例如如上文所描述)具有序列一致性,且其視情況包含與SEQ ID NO:4 (如上文所描述)具有序列一致性之質體,且對治療或預防癌症有效。 在某些實施例中,用於本發明中之細菌菌株的染色體與SEQ ID NO:3 (例如如上文所描述)具有序列一致性,且其16S rRNA序列與SEQ ID NO:1或2 (例如如上文所描述)具有序列一致性,且其視情況包含與SEQ ID NO:4 (如上文所描述)具有序列一致性之質體,且對治療或預防癌症有效。 在某些實施例中,用於本發明中之細菌菌株的16s rRNA序列與由SEQ ID NO:2表示之16s rRNA序列至少99%、99.5%或99.9%一致(舉例而言,其包含SEQ ID NO:2之16S rRNA序列),且其染色體跨SEQ ID NO:3之至少90%與SEQ ID NO:3具有至少95%序列一致性,且其視情況包含與SEQ ID NO:4 (如上文所描述)具有序列一致性之質體,且其對治療或預防癌症有效。 在某些實施例中,用於本發明中之細菌菌株的16s rRNA序列與由SEQ ID NO:2表示之16s rRNA序列至少99%、99.5%或99.9%一致(例如其包含SEQ ID NO:2之16S rRNA序列),且其染色體跨SEQ ID NO:3之至少98% (例如跨至少99%或至少99.5%)與SEQ ID NO:3具有至少98%序列一致性(例如至少99%或至少99.5%序列一致性),且其視情況包含與SEQ ID NO:4 (如上文所描述)具有序列一致性之質體,且其對治療或預防癌症有效。 在某些實施例中,用於本發明中之細菌菌株為雞腸球菌,且其16s rRNA序列與由SEQ ID NO:2表示之16s rRNA序列至少99%、99.5%或99.9%一致(例如其包含SEQ ID NO:2之16S rRNA序列),且其染色體跨SEQ ID NO:3之至少98% (例如跨至少99%或至少99.5%)與SEQ ID NO:3具有至少98%序列一致性(例如至少99%或至少99.5%序列一致性),且其視情況包含與SEQ ID NO:4 (如上文所描述)具有序列一致性之質體,且其對治療或預防癌症有效。 或者,作為以寄存編號NCIMB 42488寄存之細菌之生物型且適合用於本發明中的菌株可藉由使用寄存編號NCIMB 42488寄存及限制性片段分析及/或PCR分析,例如藉由使用經螢光擴增之片段長度多形現象(FAFLP)及重複DNA元件(rep)-PCR指紋識別、或蛋白質特徵、或部分16S或23s rDNA定序來鑑別。在較佳實施例中,此類技術可用於鑑別其他雞腸球菌菌株。 在某些實施例中,作為以寄存編號NCIMB 42488寄存之細菌之生物型且適合用於本發明中的菌株為當藉由經擴增核糖體DNA限制分析(ARDRA)來分析時,例如當使用Sau3AI限制酶時提供與以寄存編號NCIMB 42488寄存之細菌相同之模式的菌株(例示性方法及指導參見例如[[19]])。或者,生物型菌株鑑別為與以寄存編號NCIMB 42488寄存之細菌具有相同碳水化合物醱酵模式的菌株。在一些實施例中,碳水化合物醱酵模式使用API 50 CHL面板(bioMérieux)來測定。在一些實施例中,在本發明中所用之細菌菌株為: (i) 對以下中之至少一者(例如至少2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17者或所有)呈陽性:L-阿拉伯糖、D-核糖、D-木糖、D-半乳糖、D-葡萄糖、D-果糖、D-甘露糖、N-乙醯基葡糖胺、扁桃苷、熊果苷、水楊苷、D-纖維二糖、D-麥芽糖、蔗糖、D-海藻糖、龍膽二糖、D-塔格糖及葡糖酸鉀;及/或 (ii) 對以下中之至少一者(例如至少2、3、4者或所有)呈中間陽性:D-甘露糖醇、甲基-αD-吡喃葡糖苷、D-乳糖、澱粉及L-海藻糖; 較佳地如藉由API 50 CHL分析(較佳地使用來自bioMérieux之API 50 CHL面板)所測定。 適用於本發明之組合物及方法中的其他雞腸球菌菌株,諸如以寄存編號NCIMB 42488寄存之細菌的生物型可使用任何適當方法或策略,包括實例中所描述之分析來鑑別。舉例而言,用於本發明中之菌株可藉由以下來鑑別:在厭氧YCFA中培養及/或將細菌投與至II型膠原蛋白誘發之關節炎小鼠模型中,且隨後評定細胞激素水準。特定言之,具有與以寄存編號NCIMB 42488寄存之細菌類似之生長模式、代謝類型及/或表面抗原的細菌菌株可適用於本發明。適用之菌株將具有與NCIMB 42488菌株相當之免疫調節活性。特定言之,生物型菌株將對癌症疾病模型引起與實例中所示作用相當的作用,其可藉由使用實例中所描述之培養及投藥方案來鑑別。 在一些實施例中,在本發明中所用之細菌菌株為: (i) 對以下中之至少一者(例如至少2、3、4、5、6、7者或所有)呈陽性:甘露糖醱酵、麩胺酸脫羧酶、精胺酸芳基醯胺酶、苯丙胺酸芳基醯胺酶、焦麩胺酸芳基醯胺酶、酪胺酸芳基醯胺酶、組胺酸芳基醯胺酶及絲胺酸芳基醯胺酶;及/或 (ii) 對以下中之至少一者(例如至少2者或所有)呈中間陽性:β-半乳糖苷酶-6-磷酸酯、β-葡糖苷酶及N-乙醯基-β-胺基葡糖苷酶;及/或 (iii) 對以下中之至少一者(例如至少2、3、4、5、6者或所有)呈陰性:棉子糖醱酵、脯胺酸芳基醯胺酶、白胺醯基甘胺酸芳基醯胺酶、白胺酸芳基醯胺酶、丙胺酸芳基醯胺酶、甘胺酸芳基醯胺酶及麩胺醯基麩胺酸芳基醯胺酶, 較佳地如藉由碳水化合物、胺基酸及硝酸鹽代謝之分析及視情況鹼性磷酸酶活性之分析所測定,更佳地如藉由快速ID 32A分析(較佳地使用來自bioMérieux之快速ID 32A系統)所測定。 在一些實施例中,在本發明中所用之細菌菌株為: (i) 對以下中之至少一者(例如至少2、3或所有4個)呈陰性:甘胺酸芳基醯胺酶、棉子糖醱酵、脯胺酸芳基醯胺酶及白胺酸芳基醯胺酶,例如如藉由碳水化合物、胺基酸及硝酸鹽代謝之分析所測定,較佳地如藉由快速ID 32A分析(較佳地使用來自bioMérieux之快速ID 32A系統)所測定;及/或 (ii) 對L-海藻糖醱酵呈中間陽性,較佳地如藉由API 50 CHL分析(較佳地使用來自bioMérieux之API 50 CHL面板)所測定。 在一些實施例中,在本發明中所用之細菌菌株為細胞外ATP製造者,舉例而言,如使用ATP分析套組(Sigma-Aldrich,MAK190)所量測,產生6-6.7 ng/μl (例如6.1-6.6 ng/μl或6.2-6.5 ng/μl或6.33 ± 0.10 ng/μl) ATP之製造者。細菌細胞外ATP可具有多效性作用,包括使T細胞受體介導之信號傳導活化(Schenk等人, 2011)、促進腸Th17細胞分化(Atarashi等人, 2008)及藉由使NLRP3炎性體活化來誘導促炎性介體IL-1β分泌(Karmarkar等人, 2016)。因此,作為細胞外ATP製造者之細菌菌株適用於治療或預防癌症。 在一些實施例中,用於本發明中之細菌菌株包含以下三個基因中之一或多者:移動元件蛋白;木糖ABC轉運體,透性酶組分;及FIG00632333:假想蛋白。舉例而言,在某些實施例中,用於本發明中之細菌菌株包含編碼以下之基因:移動元件蛋白及木糖ABC轉運體,透性酶組分;移動元件蛋白及FIG00632333:假想蛋白;木糖ABC轉運體,透性酶組分及FIG00632333:假想蛋白;或移動元件蛋白,木糖ABC轉運體,透性酶組分及FIG00632333:假想蛋白。 本發明之尤佳菌株為以寄存編號NCIMB 42488寄存之雞腸球菌菌株。此為在實例中所測試之例示性MRX518菌株,且展示其對治療疾病有效。因此,本發明提供一種以寄存編號NCIMB 42488寄存之雞腸球菌菌株或其衍生物的細胞,諸如經分離之細胞。本發明亦提供一種包含以寄存編號NCIMB 42488寄存之雞腸球菌菌株或其衍生物之細胞的組合物。本發明亦提供以寄存編號NCIMB 42488寄存之雞腸球菌菌株的生物學純培養物。本發明亦提供一種以寄存編號NCIMB 42488寄存之雞腸球菌菌株或其衍生物的細胞,其用於療法,特定言之用於本文所描述之疾病的療法中。以寄存編號NCIMB 42488寄存之菌株的衍生物可為子代菌株(後代)或由原始菌株培養(次選殖)之菌株。 本發明之菌株的衍生物可例如在遺傳層面進行修飾,而不消除生物活性。特定言之,本發明之衍生物菌株具有治療活性。衍生菌株將具有與原始NCIMB 42488菌株相當之免疫調節活性。特定言之,衍生菌株將對癌症疾病模型引起與實例中所示作用相當的作用,其可藉由使用實例中所描述之培養及投藥方案來鑑別。NCIMB 42488菌株之衍生物一般將為NCIMB 42488菌株之生物型。 提及以寄存編號NCIMB 42488寄存之雞腸球菌菌株的細胞涵蓋安全性及治療功效特徵與以寄存編號NCIMB 42488寄存之菌株相同的任何細胞,且本發明涵蓋此類細胞。因此,在一些實施例中,提及以寄存編號NCIMB 42488寄存之雞腸球菌菌株的細胞僅係指以NCIMB 42488寄存之MRX518菌株,且並不指不以NCIMB 42488寄存之細菌菌株。在一些實施例中,提及以寄存編號NCIMB 42488寄存之雞腸球菌菌株的細胞係指安全性及治療功效特徵與以寄存編號NCIMB 42488寄存之菌株相同,但並非以NCIMB 42488寄存之菌株的細胞。 在較佳實施例中,本發明之組合物中的細菌菌株為活的,且能夠部分或完全地在腸中定殖。 治療癌症 在較佳實施例中,本發明之組合物用於治療或預防癌症。實例展現,投與本發明之組合物可在多種腫瘤模型中引起腫瘤生長減少。 在某些實施例中,用本發明之組合物治療引起腫瘤尺寸減小或腫瘤生長減少。在某些實施例中,本發明之組合物用於減小腫瘤尺寸或減少腫瘤生長。本發明之組合物可對減小腫瘤尺寸或減少其生長有效。在某些實施例中,本發明之組合物用於患有實體腫瘤之患者中。在某些實施例中,本發明之組合物用於在治療癌症中減少或預防血管生成。本發明之組合物可對免疫或發炎性系統起作用,該等系統在血管生成中起主要作用。在某些實施例中,本發明之組合物用於預防癌轉移。 在某些實施例中,本發明之組合物用於治療或預防乳癌。實例展現,本發明之組合物可對治療乳癌有效。在某些實施例中,本發明之組合物用於在治療乳癌中減小腫瘤尺寸、減少腫瘤生長或減少血管生成。在較佳實施例中,癌症為乳房癌。在較佳實施例中,癌症為IV期乳癌。 在某些實施例中,本發明之組合物用於治療或預防肺癌。實例展現,本發明之組合物可對治療肺癌有效。在某些實施例中,本發明之組合物用於在治療肺癌中減小腫瘤尺寸、減少腫瘤生長或減少血管生成。在較佳實施例中,癌症為肺癌。 在某些實施例中,本發明之組合物用於治療或預防肝癌。實例展現,本發明之組合物可對治療肝癌有效。在某些實施例中,本發明之組合物用於在治療肝癌中減小腫瘤尺寸、減少腫瘤生長或減少血管生成。在較佳實施例中,癌症為肝癌(肝細胞癌)。 在某些實施例中,本發明之組合物用於治療或預防結腸癌。實例展現,本發明之組合物對結腸癌細胞起作用且可對治療結腸癌有效。在某些實施例中,本發明之組合物用於在治療結腸癌中減小腫瘤尺寸、減少腫瘤生長或減少血管生成。在較佳實施例中,癌症為結腸直腸腺癌。 在某些實施例中,本發明之組合物用於治療或預防癌瘤。實例展現,本發明之組合物可對治療許多類型之癌瘤有效。在某些實施例中,本發明之組合物用於治療或預防非免疫原性癌症。實例展現,本發明之組合物可對治療非免疫原性癌症有效。 本發明之組合物對癌症的治療作用可由促炎性機制介導。實例2、4及5展現多種促炎性細胞激素之表現可在投與MRX518後增加。炎症可具有癌症抑制作用[[20]]且正研究諸如TNFα之促炎性細胞激素作為癌症療法[[21]]。實例中所示的諸如TNF之基因的上調可指示,本發明之組合物可適用於經由類似機制治療癌症。CXCR3配位體(CXCL9、CXCL10)及IFNγ可誘導型基因(IL-32)之上調可指示,本發明之組合物引起IFNγ型反應。IFNγ為可刺激殺腫瘤活性之強效巨噬細胞活化因子[[22]],且例如CXCL9及CXCL10亦具有抗癌作用[[23]-[24][25]]。因此,在某些實施例中,本發明之組合物用於在治療癌症中促進炎症。在較佳實施例中,本發明之組合物用於在治療癌症中促進Th1炎症。Th1細胞產生IFNγ且具有強效抗癌作用[20]。在某些實施例中,本發明之組合物用於治療早期癌症,諸如未轉移之癌症,或0期或1期癌症。促進炎症對早期癌症可更有效[20]。在某些實施例中,本發明之組合物用於促進炎症以增強第二抗癌劑之作用。在某些實施例中,治療或預防癌症包含提高一或多種細胞激素之表現水準。舉例而言,在某些實施例中,治療或預防癌症包含提高IL-1β、IL-6及TNF-α中之一或多者的表現水準,例如IL-1β及IL-6、IL-1β及TNF-α、IL-6及TNF-α、或IL-1β、IL-6及TNF-α中之所有三個。已知提高IL-1β、IL-6及TNF-α中之任一者的表現水準指示治療癌症之功效。 實例4及5展現,當如本文所描述之細菌菌株與脂多醣(LPS)組合使用時,存在IL-1β之協同性增加。已知LPS引起促炎性作用。因此,在某些實施例中,治療或預防包含與上調IL-1β之藥劑組合使用如本文所描述之細菌菌株。在某些實施例中,治療或預防包含與LPS組合使用如本文所描述之細菌菌株。因此,本發明之組合物可另外包含上調IL-1β之藥劑。因此,本發明之組合物可另外包含LPS。 在某些實施例中,本發明之組合物用於治療先前已接受化學療法之患者。在某些實施例中,本發明之組合物用於治療未耐受化學療法治療之患者。本發明之組合物可尤其適合於此類患者。 在某些實施例中,本發明之組合物用於預防復發。本發明之組合物可適合於長期投藥。在某些實施例中,本發明之組合物用於預防癌症進程。 在某些實施例中,本發明之組合物用於治療非小細胞肺癌。在某些實施例中,本發明之組合物用於治療小細胞肺癌。在某些實施例中,本發明之組合物用於治療鱗狀細胞癌。在某些實施例中,本發明之組合物用於治療腺癌。在某些實施例中,本發明之組合物用於治療腺腫瘤、類癌瘤或未分化癌瘤。 在某些實施例中,本發明之組合物用於治療肝母細胞瘤、膽管癌、膽管細胞囊腺癌或因病毒感染所致之肝癌。 在某些實施例中,本發明之組合物用於治療侵襲性乳腺管癌、乳腺管原位癌或侵襲性小葉癌。 在其他實施例中,本發明之組合物用於治療或預防急性淋巴母細胞性白血病(ALL)、急性骨髓性白血病、腎上腺皮質癌、基底細胞癌、膽管癌、膀胱癌、骨腫瘤、骨肉瘤/惡性纖維組織細胞瘤、腦幹神經膠質瘤、腦腫瘤、小腦星形細胞瘤、大腦星形細胞瘤/惡性神經膠質瘤、室管膜瘤、神經管胚細胞瘤、腦幕上原始神經外胚層瘤、乳癌、支氣管腺瘤/類癌、伯基特氏淋巴瘤(Burkitt's lymphoma)、類癌瘤、子宮頸癌、慢性淋巴球性白血病、慢性骨髓性白血病、慢性骨髓增生病症、結腸癌、皮膚T細胞淋巴瘤、子宮內膜癌、室管膜瘤、食道癌、尤文氏肉瘤(Ewing's sarcoma)、眼內黑素瘤、視網膜母細胞瘤、膽囊癌、胃癌、胃腸類癌瘤、胃腸基質腫瘤(GIST)、生殖細胞瘤、神經膠質瘤、兒童視覺路徑及下丘腦、霍奇金淋巴瘤、黑素瘤、胰島細胞癌、卡波西肉瘤(Kaposi sarcoma)、腎細胞癌、喉癌、白血病、淋巴瘤、間皮瘤、神經母細胞瘤、非霍奇金淋巴瘤、口咽癌、骨肉瘤、卵巢癌、胰臟癌、副甲狀腺癌、咽癌、垂體腺瘤、漿細胞瘤形成、前列腺癌、腎細胞癌、視網膜母細胞瘤、肉瘤、睪丸癌、甲狀腺癌或子宮癌。 本發明之組合物在與其他治療劑組合使用時可尤其有效。本發明之組合物的免疫調節作用在與更直接抗癌劑組合時可為有效的。因此,在某些實施例中,本發明提供一種包含雞腸球菌種之細菌菌株及抗癌劑的組合物。在較佳實施例中,抗癌劑為免疫檢查點抑制劑、靶向抗體免疫療法、CAR-T細胞療法、溶瘤病毒或細胞生長抑制藥物。在較佳實施例中,組合物包含選自由以下組成之群的抗癌劑:Yervoy (伊匹單抗(ipilimumab),BMS);Keytruda (派立珠單抗(pembrolizumab),Merck);Opdivo (納武單抗(nivolumab),BMS);MEDI4736 (AZ/MedImmune);MPDL3280A (Roche/Genentech);曲美單抗(Tremelimumab) (AZ/MedImmune);CT-011 (皮立珠單抗(pidilizumab),CureTech);BMS-986015 (利瑞路單抗(lirilumab),BMS);MEDI0680 (AZ/MedImmune);MSB-0010718C (Merck);PF-05082566 (Pfizer);MEDI6469 (AZ/MedImmune);BMS-986016 (BMS);BMS-663513 (優瑞路單抗(urelumab),BMS);IMP321 (Prima Biomed);LAG525 (Novartis);ARGX-110 (arGEN-X);PF-05082466 (Pfizer);CDX-1127 (瓦里木單抗(varlilumab);CellDex Therapeutics);TRX-518 (GITR Inc.);MK-4166 (Merck); JTX-2011 (Jounce Therapeutics);ARGX-115 (arGEN-X);NLG-9189 (因多莫得(indoximod),NewLink Genetics);INCB024360 (Incyte);IPH2201 (Innate Immotherapeutics/AZ);NLG-919 (NewLink Genetics);抗VISTA (JnJ);艾帕斯塔(Epacadostat) (INCB24360,Incyte);F001287 (Flexus/BMS);CP 870893 (University of Pennsylvania);MGA271 (Macrogenix);艾瑪圖單抗(Emactuzumab) (Roche/Genentech);高倫替布(Galunisertib) (Eli Lilly);尤洛庫普魯單抗(Ulocuplumab) (BMS);BKT140/BL8040 (Biokine Therapeutics);巴維昔單抗(Bavituximab) (Peregrine Pharmaceuticals);CC 90002 (Celgene);852A (Pfizer);VTX-2337 (VentiRx Pharmaceuticals);IMO-2055 (Hybridon,Idera Pharmaceuticals);LY2157299 (Eli Lilly);EW-7197 (Ewha Women's University,Korea);維羅非尼(Vemurafenib) (Plexxikon);達拉菲尼(Dabrafenib) (Genentech/GSK);BMS-777607 (BMS);BLZ945 (Memorial Sloan-Kettering Cancer Centre);Unituxin (迪奴圖單抗(dinutuximab),United Therapeutics Corporation);Blincyto (布林莫單抗(blinatumomab),Amgen);Cyramza (雷莫蘆單抗(ramucirumab),Eli Lilly);Gazyva (歐比托珠單抗(obinutuzumab),Roche/Biogen);Kadcyla (阿多-曲妥珠單抗恩他新(ado-trastuzumab emtansine),Roche/Genentech);Perjeta (帕妥珠單抗(pertuzumab),Roche/Genentech);Adcetris (貝倫妥單抗維多汀(brentuximab vedotin),Takeda/Millennium);Arzerra (奧伐木單抗(ofatumumab),GSK);Vectibix (帕尼單抗(panitumumab),Amgen);Avastin (貝伐單抗(bevacizumab),Roche/Genentech);Erbitux (西妥昔單抗(cetuximab),BMS/Merck);Bexxar (托西莫單抗(tositumomab)-I131,GSK);Zevalin (替伊莫單抗泰澤坦(ibritumomab tiuxetan),Biogen);Campath (阿侖單抗(alemtuzumab),Bayer);Mylotarg (吉妥單抗奧唑米星(gemtuzumab ozogamicin),Pfizer);Herceptin (曲妥珠單抗(trastuzumab),Roche/Genentech);Rituxan (利妥昔單抗(rituximab),Genentech/Biogen);沃洛昔單抗(volociximab) (Abbvie);恩納瓦單抗(Enavatuzumab) (Abbvie);ABT-414 (Abbvie);埃羅妥珠單抗(Elotuzumab) (Abbvie/BMS);ALX-0141 (Ablynx);奧紮利珠單抗(Ozaralizumab) (Ablynx);阿西替單抗(Actimab)-C (Actinium);阿西替單抗-P (Actinium);米拉珠單抗(Milatuzumab)-dox (Actinium);Emab-SN-38 (Actinium);納圖蒙單抗依塔菲那托克斯(Naptumonmab estafenatox) (Active Biotech);AFM13 (Affimed);AFM11 (Affimed);AGS-16C3F (Agensys);AGS-16M8F (Agensys);AGS-22ME (Agensys);AGS-15ME (Agensys);GS-67E (Agensys);ALXN6000 (薩馬里珠單抗(samalizumab),Alexion);ALT-836 (Altor Bioscience);ALT-801 (Altor Bioscience);ALT-803 (Altor Bioscience);AMG780 (Amgen);AMG 228 (Amgen);AMG820 (Amgen);AMG172 (Amgen);AMG595 (Amgen);AMG110 (Amgen);AMG232 (阿達木單抗(adecatumumab),Amgen);AMG211 (Amgen/MedImmune);BAY20-10112 (Amgen/Bayer);里樂木單抗(Rilotumumab) (Amgen);德諾單抗(Denosumab) (Amgen);AMP-514 (Amgen);MEDI575 (AZ/MedImmune);MEDI3617 (AZ/MedImmune);MEDI6383 (AZ/MedImmune);MEDI551 (AZ/MedImmune);莫昔土莫單抗帕蘇多托克斯(Moxetumomab pasudotox) (AZ/MedImmune);MEDI565 (AZ/MedImmune);MEDI0639 (AZ/MedImmune);MEDI0680 (AZ/MedImmune);MEDI562 (AZ/MedImmune);AV-380 (AVEO);AV203 (AVEO);AV299 (AVEO);BAY79-4620 (Bayer);阿內圖單抗拉夫坦辛(Anetumab ravtansine) (Bayer);凡替克土單抗(vantictumab) (Bayer);BAY94-9343 (Bayer);西羅珠單抗(Sibrotuzumab) (Boehringer Ingleheim);BI-836845 (Boehringer Ingleheim);B-701 (BioClin);BIIB015 (Biogen);歐比托珠單抗(Obinutuzumab) (Biogen/Genentech);BI-505 (Bioinvent);BI-1206 (Bioinvent);TB-403 (Bioinvent);BT-062 (Biotest) BIL-010t (Biosceptre);MDX-1203 (BMS);MDX-1204 (BMS);萊西單抗(Necitumumab) (BMS);CAN-4 (Cantargia AB);CDX-011 (Celldex);CDX1401 (Celldex);CDX301 (Celldex);U3-1565 (Daiichi Sankyo);帕特里土單抗(patritumab) (Daiichi Sankyo);替加珠單抗(tigatuzumab) (Daiichi Sankyo);尼妥珠單抗(nimotuzumab) (Daiichi Sankyo);DS-8895 (Daiichi Sankyo);DS-8873 (Daiichi Sankyo);DS-5573 (Daiichi Sankyo);MORab-004 (Eisai);MORab-009 (Eisai);MORab-003 (Eisai);MORab-066 (Eisai);LY3012207 (Eli Lilly);LY2875358 (Eli Lilly);LY2812176 (Eli Lilly);LY3012217(Eli Lilly);LY2495655 (Eli Lilly);LY3012212 (Eli Lilly);LY3012211 (Eli Lilly);LY3009806 (Eli Lilly);西妥木單抗(cixutumumab) (Eli Lilly);法蘭土單抗(Flanvotumab) (Eli Lilly);IMC-TR1 (Eli Lilly);雷莫蘆單抗(Ramucirumab) (Eli Lilly);嗒巴單抗(Tabalumab) (Eli Lilly);紮木單抗(Zanolimumab) (Emergent Biosolution);FG-3019 (FibroGen);FPA008 (Five Prime Therapeutics);FP-1039 (Five Prime Therapeutics);FPA144 (Five Prime Therapeutics);卡托莫西單抗(catumaxomab) (Fresenius Biotech);IMAB362 (Ganymed);IMAB027 (Ganymed);HuMax-CD74 (Genmab);HuMax-TFADC (Genmab);GS-5745 (Gilead);GS-6624 (Gilead);OMP-21M18 (登西珠單抗(demcizumab),GSK);馬帕木單抗(mapatumumab) (GSK);IMGN289 (ImmunoGen);IMGN901 (ImmunoGen);IMGN853 (ImmunoGen);IMGN529 (ImmunoGen);IMMU-130 (Immunomedics);米拉珠單抗-dox (Immunomedics);IMMU-115 (Immunomedics);IMMU-132 (Immunomedics);IMMU-106 (Immunomedics);IMMU-102 (Immunomedics);依帕珠單抗(Epratuzumab) (Immunomedics);昔瓦土單抗(Clivatuzumab) (Immunomedics);IPH41 (Innate Immunotherapeutics);達土木單抗(Daratumumab) (Janssen/Genmab);CNTO-95 (英妥木單抗(Intetumumab),Janssen);CNTO-328 (思圖昔單抗(siltuximab),Janssen);KB004 (KaloBios);莫格利珠單抗(mogamulizumab) (Kyowa Hakko Kirrin);KW-2871 (依美昔單抗(ecromeximab),Life Science);索尼普西珠單抗(Sonepcizumab) (Lpath);馬爾吉土西單抗(Margetuximab) (Macrogenics);伊諾貝利圖珠單抗(Enoblituzumab) (Macrogenics);MGD006 (Macrogenics);MGF007 (Macrogenics);MK-0646 (達洛圖單抗(dalotuzumab),Merck);MK-3475 (Merck);Sym004 (Symphogen/Merck Serono);DI17E6 (Merck Serono);MOR208 (Morphosys);MOR202 (Morphosys);Xmab5574 (Morphosys);BPC-1C (恩斯土昔單抗(ensituximab),Precision Biologics);TAS266 (Novartis);LFA102 (Novartis);BHQ880 (Novartis/Morphosys);QGE031 (Novartis);HCD122 (魯卡木單抗(lucatumumab),Novartis);LJM716 (Novartis);AT355 (Novartis);OMP-21M18 (登西珠單抗(Demcizumab),OncoMed);OMP52M51 (Oncomed/GSK);OMP-59R5 (Oncomed/GSK);凡替克土單抗(vantictumab) (Oncomed/Bayer);CMC-544 (奧英妥珠單抗(inotuzumab ozogamicin),Pfizer);PF-03446962 (Pfizer);PF-04856884 (Pfizer);PSMA-ADC (Progenics);REGN1400 (Regeneron);REGN910 (內斯瓦庫單抗(nesvacumab),Regeneron/Sanofi);REGN421 (伊諾替珠單抗(enoticumab),Regeneron/Sanofi);RG7221、RG7356、RG7155、RG7444、RG7116、RG7458、RG7598、RG7599、RG7600、RG7636、RG7450、RG7593、RG7596、DCDS3410A、RG7414 (帕薩珠單抗(parsatuzumab))、RG7160 (伊姆加土珠單抗(imgatuzumab))、RG7159 (奧賓圖珠單抗(obintuzumab))、RG7686、RG3638 (奧那組單抗(onartuzumab))、RG7597 (Roche/Genentech);SAR307746 (Sanofi);SAR566658 (Sanofi);SAR650984 (Sanofi);SAR153192 (Sanofi);SAR3419 (Sanofi);SAR256212 (Sanofi),SGN-LIV1A (林妥珠單抗(lintuzumab),Seattle Genetics);SGN-CD33A (Seattle Genetics);SGN-75 (沃爾希珠單抗馬佛多坦(vorsetuzumab mafodotin),Seattle Genetics);SGN-19A (Seattle Genetics) SGN-CD70A (Seattle Genetics);SEA-CD40 (Seattle Genetics);替伊莫單抗泰澤坦(ibritumomab tiuxetan) (Spectrum);MLN0264 (Takeda);加尼圖單抗(ganitumab) (Takeda/Amgen);CEP-37250 (Teva);TB-403 (Thrombogenic);VB4-845 (Viventia);Xmab2512 (Xencor);Xmab5574 (Xencor);尼妥珠單抗(nimotuzumab) (YM Biosciences);卡魯單抗(Carlumab) (Janssen);NY-ESO TCR (Adaptimmune);MAGE-A-10 TCR (Adaptimmune);CTL019 (Novartis);JCAR015 (Juno Therapeutics);KTE-C19 CAR (Kite Pharma);UCART19 (Cellectis);BPX-401 (Bellicum Pharmaceuticals);BPX-601 (Bellicum Pharmaceuticals);ATTCK20 (Unum Therapeutics);CAR-NKG2D (Celyad);Onyx-015 (Onyx Pharmaceuticals);H101 (Shanghai Sunwaybio);DNX-2401 (DNAtrix);VCN-01 (VCN Biosciences);Colo-Ad1 (PsiOxus Therapeutics);ProstAtak (Advantagene);Oncos-102 (Oncos Therapeutics);CG0070 (Cold Genesys);Pexa-vac (JX-594,Jennerex Biotherapeutics);GL-ONC1 (Genelux);T-VEC (Amgen);G207 (Medigene);HF10 (Takara Bio);SEPREHVIR (HSV1716,Virttu Biologics);OrienX010 (OrienGene Biotechnology);Reolysin (Oncolytics Biotech);SVV-001 (Neotropix);Cacatak (CVA21,Viralytics);愛甯達(Alimta) (Eli Lilly)、順鉑、奧沙利鉑、伊立替康、醛葉酸、甲胺喋呤、環磷醯胺、5-氟尿嘧啶、 載卡迪(Zykadia) (Novartis)、塔芬拉(Tafinlar) (GSK)、夏克瑞(Xalkori) (Pfizer)、易瑞沙(Iressa) (AZ)、吉諾特夫(Gilotrif) (Boehringer Ingelheim)、特羅凱(Tarceva) (Astellas Pharma)、哈拉溫(Halaven) (Eisai Pharma)、維利帕尼(Veliparib) (Abbvie)、AZD9291 (AZ)、艾樂替尼(Alectinib) (Chugai)、LDK378 (Novartis)、Genetespib (Synta Pharma)、Tergenpumatucel-L (NewLink Genetics)、GV1001 (Kael-GemVax)、提瓦替尼(Tivantinib) (ArQule);環磷氮介(Cytoxan) (BMS);安可平(Oncovin) (Eli Lilly);阿德力黴素(Adriamycin) (Pfizer);健擇(Gemzar) (Eli Lilly);希羅達(Xeloda) (Roche);艾克斯普拉(Ixempra) (BMS);阿布拉生(Abraxane) (Celgene);亮丙星(Trelstar) (Debiopharm);紫杉德(Taxotere) (Sanofi);雷沙瓦(Nexavar) (Bayer);IMMU-132 (Immunomedics);E7449 (Eisai);瑟默多克斯(Thermodox) (Celsion);考美曲克(Cometriq) (Exellxis);隆瑟夫(Lonsurf) (Taiho Pharmaceuticals);坎普土沙(Camptosar) (Pfizer);UFT (Taiho Pharmaceuticals);及TS-1 (Taiho Pharmaceuticals)。 在一些實施例中,一或多種16s rRNA序列與SEQ ID NO:2至少95%一致,例如作為雞腸球菌的細菌菌株為本發明之組合物中僅有的治療活性劑。在一些實施例中,組合物中之細菌菌株為本發明之組合物中僅有的治療活性劑。 投藥模式 較佳地,本發明之組合物待向胃腸道投與以便使得能夠將本發明之細菌菌株遞送至腸中及/或使其部分或完全在腸中定殖。一般而言,本發明之組合物經口投與,但其可經直腸、鼻內或經由頰內或舌下途徑投與。 在某些實施例中,本發明之組合物可以泡沫、噴霧或凝膠形式投與。 在某些實施例中,本發明之組合物可以栓劑形式投與,諸如經直腸栓劑,例如以可可油(可可脂)、合成硬脂(例如suppocire、witepsol)、甘油-明膠、聚乙二醇或皂甘油組合物形式投與。 在某些實施例中,本發明之組合物經由管(諸如鼻胃管、口胃管、胃管、空腸造口管(J管)、經皮內窺鏡胃造口術(PEG))或口(諸如可通向胃、空腸的胸壁口及其他適合通口)向胃腸道投與。 本發明之組合物可投與一次,或其可作為治療方案之部分依序投與。在某些實施例中,本發明之組合物待每日投與。 在本發明之某些實施例中,根據本發明之治療伴隨有評定患者之腸道微生物群。若本發明之菌株的遞送及/或部分或完全定殖未達成以至於未觀測到功效,則可重複治療,或若遞送及/或部分或完全定殖成功且觀測到功效,則可停止治療。 在某些實施例中,本發明之組合物可向懷孕動物(例如哺乳動物,諸如人類)投與,以便降低其子代在子宮內及/或在出生後產生癌症的可能性。 本發明之組合物可向已診斷患有癌症或已鑑別為具有癌症之風險的患者投與。組合物亦可作為預防性手段投與以在健康患者中預防癌症之產生。 本發明之組合物可向已鑑別為具有異常腸道微生物群之患者投與。舉例而言,該患者可具有減少或不存在之雞腸球菌定殖。 本發明之組合物可以食物產品,諸如營養補充劑形式投與。 一般而言,本發明之組合物用於治療人類,但其可用於治療動物,包括單胃哺乳動物,諸如家禽、豬、貓、犬、馬或兔。本發明之組合物可適用於增強動物之生長及表現。若向動物投與,則可使用經口管飼。 組合物 一般而言,本發明之組合物包含細菌。在本發明之較佳實施例中,組合物以冷凍乾燥形式調配。舉例而言,本發明之組合物可包含有包含本發明之細菌菌株的顆粒或明膠膠囊,例如硬明膠膠囊。 較佳地,本發明之組合物包含凍乾之細菌。細菌之凍乾為公認程序,且相關指導可在例如參考文獻[[26]-[27][28]]中獲得。 或者,本發明之組合物可包含活的活性細菌培養物。 在一些實施例中,本發明之組合物中的細菌菌株未經失活,例如未經加熱失活。在一些實施例中,本發明之組合物中的細菌菌株未經殺滅,例如未經加熱殺滅。在一些實施例中,本發明之組合物中的細菌菌株未經減毒,例如未經加熱減毒。舉例而言,在一些實施例中,本發明之組合物中的細菌菌株未經殺滅、失活及/或減毒。舉例而言,在一些實施例中,本發明之組合物中的細菌菌株為存活的。舉例而言,在一些實施例中,本發明之組合物中的細菌菌株為活的。舉例而言,在一些實施例中,本發明之組合物中的細菌菌株能夠部分或完全地在腸中定殖。舉例而言,在一些實施例中,本發明之組合物中的細菌菌株為活的,且能夠部分或完全地在腸中定殖。 在一些實施例中,組合物包含活細菌菌株及已經殺滅之細菌菌株的混合物。 在較佳實施例中,對本發明之組合物進行囊封以使得能夠將細菌菌株遞送至腸中。囊封保護組合物不降解直至遞送至目標位置為止,其經由例如在化學或物理刺激(諸如壓力、酶活性或物理崩解)下破裂(其可藉由pH變化來觸發)來進行。可使用任何適當之囊封方法。例示性囊封技術包括在多孔基質內截留、在固體載劑表面上附接或吸附、藉由絮凝或用交聯劑自聚集及在微孔膜或微囊之後機械密閉。對可適用於製備本發明之組合物的囊封的指導可在例如參考文獻[[29]]及[[30]]中獲得。 組合物可經口投與,且可以錠劑、膠囊或散劑形式投與。因為雞腸球菌為厭氧菌,所以囊封之產品為較佳的。可包括其他成分(舉例而言,諸如維生素C)作為氧清除劑及益菌生受質以改善活體內遞送及/或部分或完全定殖及存活率。或者,本發明之益生菌組合物可以食品或營養產品(諸如基於乳汁或乳清的經醱酵之乳製品)形式或以醫藥產品形式經口投與。 組合物可調配為益生菌。 本發明之組合物包括治療有效量的本發明之細菌菌株。治療有效量之細菌菌株足以對患者發揮有益作用。治療有效量之細菌菌株可足以使得遞送至患者之腸中及/或部分或完全在患者之腸中定殖。 舉例而言,對於成人,細菌之適合日劑量可為約1 × 103
至約1 × 1011
菌落形成單位(CFU);舉例而言,1 × 107
至約1 × 1010
CFU;在另一個實例中,1 × 106
至約1 × 1010
CFU。 在某些實施例中,相對於組合物之重量,組合物以約1 × 106
至約1 × 1011
CFU/g之量含有細菌菌株;舉例而言,約1 × 108
至約1 × 1010
CFU/g。劑量可為例如1 g、3 g、5 g及10 g。 通常,益生菌(諸如本發明之組合物)視情況與至少一種適合之益菌生化合物組合。益菌生化合物通常為不可消化之碳水化合物(諸如寡醣或多醣)或糖醇,其在上消化道中不進行降解或吸收。已知益菌生包括商業產品,諸如菊糖及反式半乳糖-寡醣。 在某些實施例中,相對於總重量組成,本發明之益生菌組合物以約1至約30重量%之量包括益菌生化合物(例如5至20重量%)。碳水化合物可選自由以下組成之群:果寡醣(或FOS)、短鏈果寡醣、菊糖、異麥芽糖-寡醣、果膠、木寡醣(或XOS)、聚殼糖-寡醣(或COS)、β-葡聚糖、阿拉伯膠改性及抗性澱粉、聚葡萄糖、D-塔格糖、阿拉伯膠纖維、刺槐、燕麥及柑橘纖維。在一個態樣中,益菌生為短鏈果寡醣(為簡單起見,在本文下文中展示為FOSs-c.c),該FOSs-c.c不為可消化碳水化合物,其一般藉由使甜菜糖轉化來獲得且包括鍵結有三個葡萄糖分子之蔗糖分子。 本發明之組合物可包含醫藥學上可接受之賦形劑或載劑。此類適合之賦形劑的實例可見於參考文獻[[31]]中。用於治療用途的可接受之載劑或稀釋劑為在醫藥技術中熟知的,且描述於例如參考文獻[[32]]中。適合之載劑的實例包括乳糖、澱粉、葡萄糖、甲基纖維素、硬脂酸鎂、甘露糖醇、山梨糖醇及其類似物。適合之稀釋劑的實例包括乙醇、丙三醇及水。醫藥載劑、賦形劑或稀釋劑之選擇可鑒於預期投藥途徑及標準醫藥實踐來選擇。醫藥組合物可包含任何適合之黏合劑、潤滑劑、懸浮劑、塗佈劑、增溶劑作為載劑、賦形劑或稀釋劑,或作為除載劑、賦形劑或稀釋劑以外的部分。適合之黏合劑的實例包括澱粉、明膠、天然糖(諸如葡萄糖、無水乳糖、自由流動乳糖、β-乳糖)、玉米甜味劑、天然及合成膠(諸如阿拉伯膠、黃蓍或海藻酸鈉)、羧甲基纖維素及聚乙二醇。適合之潤滑劑的實例包括油酸鈉、硬脂酸鈉、硬脂酸鎂、苯甲酸鈉、乙酸鈉、氯化鈉及其類似物。防腐劑、穩定劑染料及甚至調味劑可提供於醫藥組合物中。防腐劑之實例包括苯甲酸鈉、山梨酸及對羥基苯甲酸之酯。亦可使用抗氧化劑及懸浮劑。 本發明之組合物可調配為食物產品。舉例而言,食物產品可提供除本發明之治療作用以外的營養益處,諸如在營養補充劑中。類似地,食物產品可藉由與常見食物商品而非與醫藥組合物更類似而調配為增強本發明之組合物的味道或使組合物之消費更有吸引力。在某些實施例中,本發明之組合物調配為基於乳汁之產品。術語「基於乳汁之產品」意謂脂肪含量不同的任何液體或半固體之基於乳汁或乳清之產品。基於乳汁產品可為例如,牛乳、山羊乳、綿羊乳、脫脂乳、全奶、由乳粉及乳清在不經任何加工的情況下重組之乳汁、或經過加工之產品,諸如酸乳酪、凝固乳、凝乳、酸乳、酸化全乳、黃油乳及其他酸乳製品。另一個重要組包括乳汁飲料,諸如乳清飲料、醱酵乳、濃縮乳、嬰兒或幼兒乳;調味乳、冰淇淋;含乳汁食品,諸如糖果。 在某些實施例中,本發明之組合物含有單一細菌菌株或種且不含有任何其他細菌菌株或種。此類組合物可僅包含微量或生物學上不相關量的其他細菌菌株或種。此類組合物可為基本上不含其他種之生物體的培養物。因此,在一些實施例中,本發明提供一種包含雞腸球菌種之一或多種菌株的組合物,其不含有來自任何其他種之細菌或其僅包含微量或生物學上不相關量的來自另一個種之細菌,其用於療法中。 在一些實施例中,本發明之組合物包含超過一種細菌菌株或種。舉例而言,在一些實施例中,本發明之組合物包含來自相同種內之超過一種菌株(例如超過1、2、3、4、5、6、7、8、9、10、15、20、25、30、35、40或45種菌株),且視情況不含有來自任何其他種之細菌。在一些實施例中,本發明之組合物包含來自相同種內之少於50種菌株(例如少於45、40、35、30、25、20、15、12、10、9、8、7、6、5、4或3種菌株),且視情況不含有來自任何其他種之細菌。在一些實施例中,本發明之組合物包含來自相同種內之1-40、1-30、1-20、1-19、1-18、1-15、1-10、1-9、1-8、1-7、1-6、1-5、1-4、1-3、1-2、2-50、2-40、2-30、2-20、2-15、2-10、2-5、6-30、6-15、16-25或31-50種菌株,且視情況不含有來自任何其他種之細菌。在一些實施例中,本發明之組合物包含來自相同屬內之超過一個種(例如超過1、2、3、4、5、6、7、8、9、10、12、15、17、20、23、25、30、35或40個種),且視情況不含有來自任何其他屬之細菌。在一些實施例中,本發明之組合物包含來自相同屬內之少於50個種(例如少於50、45、40、35、30、25、20、15、12、10、8、7、6、5、4或3個種),且視情況不含有來自任何其他屬之細菌。在一些實施例中,本發明之組合物包含來自相同屬內之1-50、1-40、1-30、1-20、1-15、1-10、1-9、1-8、1-7、1-6、1-5、1-4、1-3、1-2、2-50、2-40、2-30、2-20、2-15、2-10、2-5、6-30、6-15、16-25或31-50個種,且視情況不含有來自任何其他屬之細菌。本發明包含前述之任何組合。 在一些實施例中,組合物包含微生物共生物種。舉例而言,在一些實施例中,組合物包含16s rRNA序列與SEQ ID NO:2至少95%一致,例如作為雞腸球菌的細菌菌株作為微生物共生物種之部分。舉例而言,在一些實施例中,細菌菌株與一或多種(例如至少2、3、4、5、10、15或20種)來自其他屬之其他細菌菌株組合存在,該細菌菌株可與其他細菌菌株一起在腸中活體內共生地存活。舉例而言,在一些實施例中,組合物包含16s rRNA序列與SEQ ID NO:2至少95%一致,例如作為雞腸球菌的細菌菌株與來自不同屬之細菌菌株組合。在一些實施例中,微生物共生物種包含自單一生物體(例如人類)之糞便樣品獲得的兩種或超過兩種細菌菌株。在一些實施例中,發現微生物共生物種在自然界中不在一起。舉例而言,在一些實施例中,微生物共生物種包含自至少兩個不同生物體之糞便樣品獲得的細菌菌株。在一些實施例中,兩個不同生物體來自相同物種,例如兩個不同人類,例如兩個不同人類嬰兒。在一些實施例中,兩個不同生物體為人類嬰兒及成人。在一些實施例中,兩個不同生物體為人類及非人類哺乳動物。 在一些實施例中,本發明之組合物另外包含安全性及治療功效特徵與菌株MRX518相同,但並非寄存為NCIMB 42488之MRX518或並非雞腸球菌的細菌菌株。 在其中本發明之組合物包含超過一種細菌菌株、種或屬的一些實施例中,個別細菌菌株、種或屬可用於單獨、同時或依序投與。舉例而言,組合物可包含超過一種細菌菌株、種或屬全部,或該等細菌菌株、種或屬可分開地儲存且分開、同時或依序投與。在一些實施例中,超過一種細菌菌株、種或屬分開地儲存,但在使用之前混合在一起。 在一些實施例中,用於本發明中之細菌菌株係自人類嬰兒糞便獲得。在其中本發明之組合物包含超過一種細菌菌株的一些實施例中,所有細菌菌株係自人類嬰兒糞便獲得,或若存在其他細菌菌株,則其僅以微量存在。細菌可在自人類嬰兒糞便獲得之後加以培養且用於本發明之組合物中。 根據本發明使用之組合物可或可不需要營銷許可。 在某些實施例中,本發明提供以上醫藥組合物,其中該細菌菌株經凍乾。在某些實施例中,本發明提供以上醫藥組合物,其中該細菌菌株經噴霧乾燥。在某些實施例中,本發明提供以上醫藥組合物,其中該細菌菌株經凍乾或噴霧乾燥且其中其為活的。在某些實施例中,本發明提供以上醫藥組合物,其中該細菌菌株經凍乾或噴霧乾燥,且其中其為活的。在某些實施例中,本發明提供以上醫藥組合物,其中該細菌菌株經凍乾或噴霧乾燥,且其中其能夠部分或完全地在腸中定殖。在某些實施例中,本發明提供以上醫藥組合物,其中該細菌菌株經凍乾或噴霧乾燥,且其中其為活的且能夠部分或完全地在腸中定殖。 在一些情況下,經凍乾或噴霧乾燥之細菌菌株在投與之前進行復原。在一些情況下,復原藉由使用本文所描述之稀釋劑來進行。 本發明之組合物可包含醫藥學上可接受之賦形劑、稀釋劑或載劑。 在某些實施例中,本發明提供一種醫藥組合物,其包含:如在本發明中所用之細菌菌株;及醫藥學上可接受之賦形劑、載劑或稀釋劑;其中該細菌菌株之量足以在向有需要之個體投與時治療病症;且其中該病症為乳癌。在較佳實施例中,癌症為乳房癌。在較佳實施例中,癌症為IV期乳癌。 在某些實施例中,本發明提供一種醫藥組合物,其包含:如在本發明中所用之細菌菌株;及醫藥學上可接受之賦形劑、載劑或稀釋劑;其中該細菌菌株之量足以在向有需要之個體投與時治療病症;且其中該病症為肺癌。在較佳實施例中,癌症為肺癌。 在某些實施例中,本發明提供一種醫藥組合物,其包含:如在本發明中所用之細菌菌株;及醫藥學上可接受之賦形劑、載劑或稀釋劑;其中該細菌菌株之量足以在向有需要之個體投與時治療病症;且其中該病症為肝癌。在較佳實施例中,癌症為肝癌(肝細胞癌)。 在某些實施例中,本發明提供一種醫藥組合物,其包含:本發明之細菌菌株;及醫藥學上可接受之賦形劑、載劑或稀釋劑;其中該細菌菌株之量足以在向有需要之個體投與時治療病症;且其中該病症為結腸癌。在較佳實施例中,癌症為結腸直腸腺癌。 在某些實施例中,本發明提供一種醫藥組合物,其包含:本發明之細菌菌株;及醫藥學上可接受之賦形劑、載劑或稀釋劑;其中該細菌菌株之量足以在向有需要之個體投與時治療病症;且其中該病症為癌瘤。 在某些實施例中,本發明提供一種醫藥組合物,其包含:本發明之細菌菌株;及醫藥學上可接受之賦形劑、載劑或稀釋劑;其中該細菌菌株之量足以在向有需要之個體投與時治療病症;且其中該病症為非免疫原性癌症。 在某些實施例中,本發明提供一種醫藥組合物,其包含:本發明之細菌菌株;及醫藥學上可接受之賦形劑、載劑或稀釋劑;其中該細菌菌株之量足以在向有需要之個體投與時治療病症;且其中該病症選自由以下組成之群:非小細胞肺癌、小細胞肺癌、鱗狀細胞癌、腺癌、腺腫瘤、類癌瘤、未分化癌瘤。 在某些實施例中,本發明提供一種醫藥組合物,其包含:本發明之細菌菌株;及醫藥學上可接受之賦形劑、載劑或稀釋劑;其中該細菌菌株之量足以在向有需要之個體投與時治療病症;且其中該病症選自由以下組成之群:肝母細胞瘤、膽管癌、膽管細胞囊腺癌或因病毒感染所致之肝癌。 在某些實施例中,本發明提供一種醫藥組合物,其包含:本發明之細菌菌株;及醫藥學上可接受之賦形劑、載劑或稀釋劑;其中該細菌菌株之量足以在向有需要之個體投與時治療病症;且其中該病症選自由以下組成之群:侵襲性乳腺管癌、乳腺管原位癌或侵襲性小葉癌。 在某些實施例中,本發明提供一種醫藥組合物,其包含:本發明之細菌菌株;及醫藥學上可接受之賦形劑、載劑或稀釋劑;其中該細菌菌株之量足以在向有需要之個體投與時治療病症;且其中該病症選自由以下組成之群:急性淋巴母細胞性白血病(ALL)、急性骨髓性白血病、腎上腺皮質癌、基底細胞癌、膽管癌、膀胱癌、骨腫瘤、骨肉瘤/惡性纖維組織細胞瘤、腦幹神經膠質瘤、腦腫瘤、小腦星形細胞瘤、大腦星形細胞瘤/惡性神經膠質瘤、室管膜瘤、神經管胚細胞瘤、腦幕上原始神經外胚層瘤、乳癌、支氣管腺瘤/類癌、伯基特氏淋巴瘤、類癌瘤、子宮頸癌、慢性淋巴球性白血病、慢性骨髓性白血病、慢性骨髓增生病症、結腸癌、皮膚T細胞淋巴瘤、子宮內膜癌、室管膜瘤、食道癌、尤文氏肉瘤、眼內黑素瘤、視網膜母細胞瘤、膽囊癌、胃癌、胃腸類癌瘤、胃腸基質腫瘤(GIST)、生殖細胞瘤、神經膠質瘤、兒童視覺路徑及下丘腦、霍奇金淋巴瘤、黑素瘤、胰島細胞癌、卡波西肉瘤、腎細胞癌、喉癌、白血病、淋巴瘤、間皮瘤、神經母細胞瘤、非霍奇金淋巴瘤、口咽癌、骨肉瘤、卵巢癌、胰臟癌、副甲狀腺癌、咽癌、垂體腺瘤、漿細胞瘤形成、前列腺癌、腎細胞癌、視網膜母細胞瘤、肉瘤、睪丸癌、甲狀腺癌或子宮癌。 在某些實施例中,本發明提供以上醫藥組合物,其中相對於組合物重量,細菌菌株之量為每公克約1 × 103
至約1 × 1011
菌落形成單位。 在某些實施例中,本發明提供以上醫藥組合物,其中該組合物以1 g、3 g、5 g或10 g之劑量投與。 在某些實施例中,本發明提供以上醫藥組合物,其中該組合物藉由選自由以下組成之群的方法投與:經口、經直腸、皮下、經鼻、頰內及舌下。 在某些實施例中,本發明提供以上醫藥組合物,其包含選自由以下組成之群的載劑:乳糖、澱粉、葡萄糖、甲基纖維素、硬脂酸鎂、甘露糖醇及山梨糖醇。 在某些實施例中,本發明提供以上醫藥組合物,其包含選自由以下組成之群的稀釋劑:乙醇、丙三醇及水。 在某些實施例中,本發明提供以上醫藥組合物,其包含選自由以下組成之群的賦形劑:澱粉、明膠、葡萄糖、無水乳糖、自由流動乳糖、β-乳糖、玉米甜味劑、阿拉伯膠、黃蓍、海藻酸鈉、羧甲基纖維素、聚乙二醇、油酸鈉、硬脂酸鈉、硬脂酸鎂、苯甲酸鈉、乙酸鈉及氯化鈉。 在某些實施例中,本發明提供以上醫藥組合物,其進一步包含防腐劑、抗氧化劑及穩定劑中之至少一者。 在某些實施例中,本發明提供以上醫藥組合物,其包含選自由以下組成之群的防腐劑:苯甲酸鈉、山梨酸及對羥基苯甲酸之酯。 在某些實施例中,本發明提供以上醫藥組合物,其中當將該組合物在約4℃或約25℃下儲存於密封容器中且將該容器置放於具有50%相對濕度之氛圍中時,如以菌落形成單位為單位所量測,細菌菌株之至少80%在至少約以下時段之後保留:1個月、3個月、6個月、1年、1.5年、2年、2.5年或3年。 在一些實施例中,本發明之組合物在包含如本文所描述之組合物的密封容器中提供。在一些實施例中,密封容器為藥囊或瓶子。在一些實施例中,本發明之組合物在包含如本文所描述之組合物的注射器中提供。 在一些實施例中,本發明之組合物可以醫藥調配物形式提供。舉例而言,組合物可以錠劑或膠囊形式提供。在一些實施例中,膠囊為明膠膠囊(「gel-cap」)。 在一些實施例中,本發明之組合物經口投與。經口投藥可涉及吞咽,以使化合物進入胃腸道;及/或經頰、經舌或舌下投藥,藉此使化合物直接自口進入血流。 適合於經口投與之醫藥調配物包括固體栓、固體微顆粒、半固體及液體(包括多個相或分散系統),諸如錠劑;含有多顆粒或奈米顆粒之軟或硬膠囊、液體(例如水溶液)、乳液或散劑;口含錠(包括液態填充之口含錠);咀嚼片;凝膠;快速分散劑型;膜;珠劑;噴霧劑;及頰內/黏膜黏附性貼片。 在一些實施例中,醫藥調配物為腸溶調配物,亦即胃耐受性調配物(例如對胃pH具有耐受性),其適合於藉由經口投藥來將本發明之組合物遞送至腸中。腸溶調配物在細菌或組合物之另一種組分對酸敏感,例如在胃條件下易於降解時可尤其適用。 在一些實施例中,腸溶調配物包含腸溶包衣。在一些實施例中,調配物為包覆腸溶包衣劑型。舉例而言,調配物可為包覆腸溶包衣錠劑或包覆腸溶包衣膠囊或其類似物。腸溶包衣可為習知腸溶包衣,例如用於進行經口遞送之錠劑、膠囊或其類似物的習知包衣。調配物可包含膜包衣,例如腸溶聚合物(例如酸不可溶聚合物)之薄膜層。 在一些實施例中,腸溶調配物固有地具有腸溶性,例如具有胃耐受性而不需要腸溶包衣。因此,在一些實施例中,調配物為不包含腸溶包衣之腸溶調配物。在一些實施例中,調配物為由熱膠凝材料製成之膠囊。在一些實施例中,熱膠凝材料為纖維素材料,諸如甲基纖維素、羥甲基纖維素或羥丙基甲基纖維素(HPMC)。在一些實施例中,膠囊包含不含有任何成膜聚合物之殼層。在一些實施例中,膠囊包含殼層,且該殼層包含羥丙基甲基纖維素而不包含任何成膜聚合物(例如參見[[33] ])。在一些實施例中,調配物為固有地腸溶性膠囊(例如,來自Capsugel之Vcaps®)。 在一些實施例中,調配物為軟膠囊。軟膠囊為由於添加存在於膠囊殼層中之軟化劑,諸如丙三醇、山梨糖醇、麥芽糖醇及聚乙二醇而可具有一定彈性及柔軟度的膠囊。軟膠囊可例如基於明膠或澱粉來產生。基於明膠之軟膠囊可商購自各種供應商。視投藥方法(諸如經口或經直腸)而定,軟膠囊可具有各種形狀,其可為例如圓形、橢圓形、長橢圓形或魚雷形。軟膠囊可藉由習知製程產生,諸如藉由謝勒製程(Scherer process)、阿克傑製程(Accogel process)或滴液或吹製製程。 培養方法 用於本發明中之細菌菌株可使用如在例如參考文獻[[34]-[35][36]]中所詳述之標準微生物學技術來培養。 用於培養之固體或液體培養基可為YCFA瓊脂或YCFA培養基。YCFA培養基可包括(每100 ml,大致值):酪腖(Casitone) (1.0 g)、酵母提取物(0.25 g)、NaHCO3
(0.4 g)、半胱胺酸(0.1 g)、K2
HPO4
(0.045 g)、KH2
PO4
(0.045 g)、NaCl (0.09 g)、(NH4
)2
SO4
(0.09 g)、MgSO4
·7H2
O (0.009 g)、CaCl2
(0.009 g)、刃天青(0.1 mg)、血晶素(1 mg)、生物素(1 μg)、鈷胺素(1 μg)、對胺基苯甲酸(3 μg)、葉酸(5 μg)及吡哆胺(15 μg)。 用於疫苗組合物中之細菌菌株 本發明人已鑑別出,本發明之細菌菌株適用於治療或預防癌症。此很可能為本發明之細菌菌株對宿主免疫系統具有之作用的結果。因此,當作為疫苗組合物投與時,本發明之組合物亦可適用於預防癌症。在某些此類實施例中,本發明之細菌菌株為活的。在某些此類實施例中,本發明之細菌菌株能夠部分或完全地在腸中定殖。在某些此類實施例中,本發明之細菌菌株為活的且能夠部分或完全地在腸中定殖。在其他某些此類實施例中,本發明之細菌菌株可經殺滅、失活及/或減毒。在某些此類實施例中,組合物可包含疫苗佐劑。在某些實施例中,組合物用於經由注射,諸如經由皮下注射來投與。 概述 除非另外指明,否則本發明之實踐將採用此項技術內之化學、生物化學、分子生物學、免疫學及藥理學之習知方法。此類技術充分解釋於文獻中。參見例如參考文獻[[37]]及[[38]- [39] [40] [41] [42] [43] [44]]等。 術語「包含」涵蓋「包括」以及「由……組成」,例如「包含」X之組合物可獨佔地由X組成,或可包括其他物質,例如X+Y。 與數值x
有關之術語「約」為視情況選用的,且意謂例如x
±10%。 字語「基本上」不排除「完全」,例如「基本上不含」Y之組合物可完全不含Y。必要時,可自本發明之定義忽略字語「基本上」。 提及兩個核苷酸序列之間的序列一致性百分比意謂當比對時,該百分比之核苷酸在比較該兩個序列時相同。此比對及同源性或序列一致性百分比可使用此項技術中已知之軟體程式來測定,例如參考文獻[[45]]之部分7.7.18中所描述的彼等軟體程式。較佳之比對藉由史密斯-沃特曼同源性檢索算法(Smith-Waterman homology search algorithm)使用仿射間隙檢索來測定,其中間隙開放罰分為12且間隙擴展罰分為2,BLOSUM矩陣為62。史密斯-沃特曼同源性檢索算法揭示於參考文獻[[46]]中。 除非具體陳述,否則包含許多步驟之製程或方法可在該方法開始或結束時包含額外步驟,或可包含額外插入步驟。另外,若適宜步驟可經組合,忽略或以替代性次序進行。 本文描述本發明之各種實施例。應瞭解,在各實施例中指定之特徵可與其他指定之特徵組合以提供其他實施例。特定言之,本文中突出顯示為適合、典型或較佳之實施例可彼此組合(除了當其相互排斥時之外)。 用於進行本發明之模式 實例1 -細菌接種體在癌症之小鼠模型中的功效概述
此研究在四種腫瘤模型中測試包含根據本發明之細菌菌株之組合物的功效。材料 測試物質
-細菌菌株#MRX518。參考物質
-抗CTLA-4抗體(純系:9H10,目錄:BE0131,同型:敘利亞倉鼠IgG1,Bioxcell)。測試及參考物質媒劑
-細菌培養基(酵母提取物、酪腖、脂肪酸培養基(YCFA))。在向小鼠注射之每日,用PBS (參考號:BE14-516F,Lonza, France)稀釋抗體。處理劑量
-細菌:在200 µL中2×108
。抗CTLA-4以每次注射10 mg/kg注射。根據小鼠之最新體重,以每次投與10 mL/kg之給藥體積投與抗CTLA-4 (亦即,對於一隻稱重為20 g之小鼠,將投與200 µL之測試物質)。投藥途徑
-藉由經口管飼(經口,PO)經由導管投與細菌接種體。每日對導管進行去汙。將抗CTLA-4注射至小鼠之腹膜腔中(腹膜內,IP)。細菌菌株之培養條件
-用於細菌菌株之培養條件如下: • 用移液管將10 mL YCFA (來自所製備之10 mL E&O實驗室瓶)加入亨蓋特管(Hungate tube)中 • 密封該等管且使用注射器輸入及排氣系統用CO2
吹掃 • 對亨蓋特管進行高壓滅菌 • 當冷卻時,用1 mL丙三醇儲備液接種亨蓋特管 • 將該等管置放在靜態37℃培育箱中持續約16小時。 • 第二天,採集1 mL此繼代培養物,且接種10 mL之YCFA (再次為經預溫熱且經吹掃之亨蓋特管,全部一式兩份) • 將其置放在靜態37℃培育箱中持續5至6小時癌細胞株及培養條件
- 所用細胞株詳述於下表中:
在移植增生性乳房肺泡結節之後,自在BALB/cCRGL小鼠中出現之可移植鼠類乳房癌確立EMT-6細胞株[[47]]。 自攜有因移植原發性路易斯肺癌(primary Lewis lung carcinoma)所致之腫瘤的C57BL小鼠的肺確立LL/2 (LLC1)細胞株[[48]]。 Hepa 1-6細胞株為在C57/L小鼠中出現之BW7756小鼠肝癌的衍生物[[49]]。細胞培養條件
-在37℃下在潮濕氛圍中以單層形式生長所有細胞株(5% CO2
,95%空氣)。培養基及補充劑指示於下表中:
對於實驗使用,藉由在中/不含鈣或鎂之漢克氏培養基(Hanks' medium) (參考號:BE10-543F,Lonza)中用胰蛋白酶-維爾烯(參考號:BE17-161E,Lonza)處理5分鐘來自培養燒瓶分離黏附之腫瘤細胞,且藉由添加完全培養基來中和。在血球計中對細胞進行計數,且將藉由0.25%錐蟲藍排出分析來評定其存活力。動物之使用
- 自CHARLES RIVER (L'Arbresles)獲得具有匹配重量及年齡之健康雌性Balb/C (BALB/cByJ)小鼠用於EMT6模型實驗。 自CHARLES RIVER (L'Arbresles)獲得具有匹配重量及年齡之健康雌性C57BL/6 (C57BLl6J)小鼠用於LL/2 (LLC1)及Hepa1-6模型實驗。 根據FELASA指導原則將動物維持在SPF健康狀況下,且遵循根據法國及歐洲關於實驗室動物照護及使用之規章及NRC指南的動物收容及實驗程序[[50],[51]]。將動物維持在處於受控環境條件下之收容室中:溫度:22±2℃,濕度55±10%,光照期(12小時光/12小時暗),HEPA過濾之空氣,每小時15次空氣交換而不進行再循環。如所描述,為動物圍欄提供具有襯墊材料的無菌且恰當之空間、食品及水、環境及社會強化(群體收容):通風架中之900 cm2
籠(參考號:綠色,Tecniplast),Epicea襯墊(SAFE),10 kGy輻射之飼料(A04-10,SAFE),用於具有免疫活性之嚙齒動物的全面食品(R/M-H擠出物),來自水瓶之水。實驗設計及處理 抗腫瘤活性 , EMT6 模型
處理時程-將開始首次給藥視為D0。在D0,使用Vivo manager®軟體(Biosystemes, Couternon, France)將未經移植之小鼠根據其個體體重隨機分成9/8隻之組。在D0,小鼠接受媒劑(培養基)或細菌菌株。在D14,如下文所描述,對所有小鼠用EMT-6腫瘤細胞進行移植。在D24,來自陽性對照組之小鼠接受抗CTLA-4抗體處理。 處理時程概述於下表中:
如下文所描述進行動物監測。 在動物中誘發EMT6腫瘤-在D14,藉由向小鼠右側腹皮下注射含1×106
個EMT-6細胞之200 µL RPMI 1640來誘發腫瘤。 安樂死-當各小鼠達到如下文所描述之人道終點時,或在起始給藥後最長6週之後,對該小鼠進行安樂死。抗腫瘤活性, LL/2 (LLC1) 模型
處理時程-將開始首次給藥視為D0。在D0,使用Vivo manager®軟體(Biosystemes, Couternon, France)將未經移植之小鼠根據其個體體重隨機分成7組,每組9/8隻。在D0,小鼠將接受媒劑(培養基)或細菌菌株。在D14,如下文所描述,對所有小鼠用LL/2腫瘤細胞進行移植。在D27,來自陽性對照組之小鼠接受抗CTLA-4抗體處理。 處理時程概述於下表中:
如下文所描述進行動物監測。 在動物中誘發LL/2 (LLC1)腫瘤-在D14,藉由向小鼠右側腹皮下注射含1×106
個LL/2 (LLC1)細胞之200 µL RPMI 1640來誘發腫瘤。 安樂死-當各小鼠達到如下文所描述之人道終點時,或在起始給藥後最長6週之後,對該小鼠進行安樂死。抗腫瘤活性, Hepa1-6 模型
處理時程-將開始首次給藥視為D0。在D0,使用Vivo manager®軟體(Biosystemes, Couternon, France)將未經移植之小鼠根據其個體體重隨機分成7組,每組9隻。在D0,小鼠接受媒劑(培養基)或細菌菌株。在D14,如下文所描述,對所有小鼠用Hepa 1-6腫瘤細胞進行移植。在D16,來自陽性對照組之小鼠接受抗CTLA-4抗體處理。 處理時程概述於下表中:
如下文所描述進行動物監測。 藉由脾內注射在動物中正位誘發Hepa 1-6腫瘤細胞腫瘤-在D14,經由向小鼠中脾內注射來移植含一百萬(1×106
)個Hepa 1-6腫瘤細胞之50 µL RPMI 1640培養基來誘發腫瘤。簡言之,在左肋下側腹做出小切口,且自腹內取出脾臟。在無菌紗布墊上暴露脾臟,且用27規格針頭在目視控制下注射細胞懸浮液。在細胞接種之後,切除脾臟。 安樂死-當各小鼠達到如下文部分所描述之人道終點時,或在起始給藥後最長6週之後,對該小鼠進行安樂死。 在安樂死時評估腫瘤負荷-在終止時,採集肝臟且稱重。動物監測
臨床監測-用測徑規一週兩次量測腫瘤之長度及寬度,且藉由此式估計腫瘤體積[[52]]:人道終點[[53]]:疼痛、受苦或痛苦之跡象:疼痛姿勢、疼痛面具、行為;腫瘤超出正常體重之10%但未超出2000 mm3
;腫瘤干擾步行或營養;潰瘍腫瘤或組織侵蝕;連續3日保持20%體重損失;不良身體條件、消瘦、惡病體質、脫水;對外部刺激之自發反應長期不存在;快速吃力呼吸、貧血、顯著出血;神經跡象:繞圈、抽搐、麻痺;體溫持續降低;腹部膨脹。 麻醉-對以下所有程序使用異氟烷氣體麻醉:手術或腫瘤接種、i.v.注射、血液採集。對立體定位手術程序使用氯胺酮及甲苯噻嗪麻醉。 鎮痛-卡洛芬或多模式卡洛芬/丁丙諾啡鎮痛方案相對於手術程序嚴重性進行調試。對所有疼痛程序提供非藥理學照護。另外,根據主治獸醫之建議提供不干擾研究(主題處理)之藥理學照護。 安樂死-藉由過量氣體麻醉(異氟烷),繼而藉由頸椎脫位術或放血來進行動物之安樂死。結果 抗腫瘤活性 , EMT6 模型
結果展示於圖1中。相對於兩種陰性對照物,用本發明之細菌菌株處理產生腫瘤體積明顯減小。如將預期的,陽性對照物亦產生腫瘤體積減小。抗腫瘤活性, LL/2 (LLC1) 模型
結果展示於圖2中。相對於兩種陰性對照物,用本發明之細菌菌株處理產生腫瘤體積明顯減小。抗腫瘤活性 , Hepa1-6 模型
結果展示於圖3中。未經處理之陰性對照物似乎並非如所預期,此係因為肝臟重量在此組中比在其他組中低。然而,媒劑陰性對照組及陽性對照組兩者似乎如所預期,此係因為用媒劑單獨處理之小鼠的肝臟比用抗CTLA4抗體處理之小鼠大,反映媒劑陰性對照組中之較大腫瘤負荷。相對於媒劑陰性對照組中之小鼠,用本發明之細菌菌株處理產生肝臟重量明顯減少(且因此腫瘤負荷明顯降低)。 此等資料指示,菌株MRX518可適用於治療或預防癌症,且尤其適用於在乳癌、肺癌及肝癌中減小腫瘤體積。 實例2 - PCR基因分析 在PCR基因分析中研究細菌MRX518之純培養物。實驗存在兩個組:1)將MRX518與人類結腸細胞(CaCo2)一起共培養以調查細菌對宿主之作用,及2)將MRX518在用IL1刺激之CaCo2細胞上共培養以模仿細菌在發炎性環境中之作用。經由基因表現分析來評估兩種情境下之作用。結果展示在下文中:
此等資料似乎展示兩種基因表現標記- CXCR1/2配位體(CXCL3、CXCL2、CXCL1、IL-8),其與促炎性細胞遷移相關聯;及CXCR3配位體(CXCL9、CXCL10),其更具體言之指示IFN-γ型反應,該等反應亦由IL-32支持,其為IFN-γ可誘導型。 實例 3 - 穩定性測試
將含有至少一種本文所描述之細菌菌株的本文所描述之組合物在25℃或4℃下儲存於密封容器中,且將該容器置放於具有30%、40%、50%、60%、70%、75%、80%、90%或95%相對濕度之氛圍中。如以藉由標準方案測定之菌落形成單位為單位所量測,細菌菌株之至少50%、60%、70%、80%或90%在1個月、2個月、3個月、6個月、1年、1.5年、2年、2.5年或3年之後保留。實例 4 - 與 MRX518+LPS 相比較 , 由 MRX518 誘導的不成熟樹突狀細胞中之細胞激素產生 概述
此研究測試細菌菌株MRX518單獨及與脂多醣(LPS)組合對不成熟樹突狀細胞中之細胞激素產生的作用。 自周邊血液單核細胞(PBMC)分離單核球群體。隨後使單核球細胞分化成不成熟樹突狀細胞。以200,000個細胞/孔接種不成熟樹突狀細胞,且與最終濃度為107
/ml之MRX518一起培育,其中以最終濃度100 ng/ml視情況添加LPS。陰性對照物涉及用RPMI培養基單獨培育細胞,且陽性對照物用最終濃度為100 ng/ml之LPS培育細胞。隨後分析細胞之細胞激素含量。 結果
此等實驗之結果可見於圖4a-d中。與陰性對照物相比較,單獨添加MRX518引起細胞激素IL-6及TNF-α之水準顯著增加(圖4a及c)。與陰性對照物相比較,添加LPS (陽性對照)引起IL-6及TNF-α之水準增加,但IL-1β不增加(圖4b)。MRX518及LPS之組合引起所產生IL-1β之水準協同性增加(圖4d)。 結論
MRX518具有誘導不成熟樹突狀細胞中之更高IL-6及TNF-α細胞激素產生的能力。LPS及MRX518組合可增加不成熟樹突狀細胞中細胞激素IL-1β之水準。此等資料指示,MRX518單獨或與LPS組合可增加發炎性細胞激素IL-1β、IL-6及TNF-α,其促進可抑制癌症之炎症。用MRX518單獨或與LPS組合可誘導可能限制腫瘤生長之細胞激素。 實例 5 - 與 MRX518+LPS 相比較 , 由 MRX518 誘導的 THP-1 細胞中之細胞激素產生 概述
此研究測試細菌菌株MRX518單獨及與LPS組合對THP-1細胞中之細胞激素產生的作用,該等THP-1細胞為用於單核球及巨噬細胞之模型細胞株。 用5 ng/mL佛波醇-12-肉豆蔻酸酯-13-乙酸酯(PMA)將THF-1細胞分化至M0培養基中持續48小時。隨後在添加或不添加最終濃度為100 ng/ml之LPS的情況下,將此等細胞與最終濃度為108
/ml之MRX518一起培育。隨後洗去細菌,且使細胞在正常生長條件下培育24小時。隨後對細胞進行短暫離心,且分析所得上清液之細胞激素含量。 結果
此等實驗之結果可見於圖5a-c中。與無細菌及細菌沈降物對照物相比較,在無LPS的情況下添加MRX518引起IL-1β、IL-6及TNF-α之細胞激素水準增加。添加LPS及MRX518引起細胞激素產生之水準協同性增加。 結論
MRX518具有誘導THP-1細胞中之細胞激素產生的能力,該細胞激素產生可在添加LPS的情況下協同地增加。此等資料指示,MRX518單獨或與LPS組合可增加發炎性細胞激素IL-1β、IL-6及TNF-α,其促進可抑制癌症之炎症。用MRX518單獨或與LPS組合可誘導可能限制腫瘤生長之細胞激素。 序列 SEQ ID NO:1 (雞腸球菌16S rRNA基因- AF039900) SEQ ID NO:2 (雞腸球菌菌株MRX518之共同16S rRNA序列)SEQ ID NO:3 (菌株MRX518染色體序列) -參見電子序列表 SEQ ID NO:4 (菌株MRX518質體序列) -參見電子序列表。
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圖 1 :
乳癌之小鼠模型-腫瘤體積。圖 2 :
肺癌之小鼠模型-腫瘤體積。圖 3 :
肝癌之小鼠模型-肝臟重量。圖 4A :
不成熟樹突狀細胞中之細胞激素水準(pg/ml) (無細菌)。圖 4B :
在添加LPS之後的不成熟樹突狀細胞中之細胞激素水準(pg/ml)。圖 4C :
在添加MRX518之後的不成熟樹突狀細胞中之細胞激素水準(pg/ml)。圖 4D :
在添加MRX518及LPS之後的不成熟樹突狀細胞中之細胞激素水準(pg/ml)。圖 5A :
THP-1細胞中之細胞激素水準(無細菌)。圖 5B :
在添加細菌沈降物之後的THP-1細胞中之細胞激素水準。圖 5C :
在單獨或與LPS組合添加MRX518之後的THP-1細胞中之細胞激素水準。
國外寄存
GB英國;National Collections of Industria, Food and Marine Bacteria (NCIMB);2015/11/16;NCIMB 42488國內寄存
食品工業發展研究所;106年1月19日;BCRC910765
<110> 英商4D製藥研究有限公司(4D PHARMA RESEARH LIMITED)
<120> 包含細菌菌株之組合物
<130> P067592
<140> TW 105138159
<141> 2016-11-21
<150> GB 1520502.4
<150> 2016-11-20
<150> GB 1604924.9
<150> 2016-03-23
<160> 4
<170> SeqWin2010,version 1.0
<210> 1
<211> 1506
<212> DNA
<213> 雞腸球菌
<210> 2
<211> 1444
<212> DNA
<213> 雞腸球菌菌株MRX518
<210> 3
<211> 3127431
<212> DNA
<213> 雞腸球菌菌株MRX518
<210> 4
<211> 42883
<212> DNA
<213> 雞腸球菌菌株MRX518
Claims (23)
- 一種包含16s rRNA序列與SEQ ID NO:2至少95%一致之細菌菌株的組合物用於製備治療實體腫瘤之醫藥品的用途,其中該細菌菌株係雞腸球菌(Enterococcus gallinarum )種之細菌菌株。
- 如請求項1之用途,其中跨SEQ ID NO:3之至少90%,該細菌菌株之染色體與SEQ ID NO:3具有至少95%序列一致性。
- 如請求項1或2之用途,其中該實體腫瘤係肺癌、乳癌、肝癌或結腸癌。
- 如請求項1或2之用途,其中該醫藥品係用於減小腫瘤尺寸、減少腫瘤生長、預防癌轉移或預防血管生成。
- 如請求項1或2之用途,其中該細菌菌株之16s rRNA序列與雞腸球菌之細菌菌株的16s rRNA序列至少97%一致。
- 如請求項1或2之用途,其中該細菌菌株之16s rRNA序列與SEQ ID NO:1或2至少97%一致。
- 如請求項6之用途,其中該細菌菌株之16s rRNA序列與SEQ ID NO:2至少97%一致,或其中該細菌菌株具有由SEQ ID NO:2表示之16s rRNA序列。
- 如請求項1或2之用途,其中該醫藥品係用於經口投與。
- 如請求項1或2之用途,其中該組合物包含一或多種醫藥學上可接受之賦形劑或載劑。
- 如請求項1或2之用途,其中該細菌菌株經凍乾。
- 如請求項1或2之用途,其中該細菌菌株為活的,且能夠部分或完全地在腸中定殖。
- 如請求項1或2之用途,其中該組合物包含雞腸球菌之單一菌株。
- 如請求項1或2之用途,其中該組合物包含該雞腸球菌細菌菌株作為微生物共生物種之部分。
- 一種包含如請求項1至13中任一項之用途中所定義之組合物的食物產品。
- 一種疫苗組合物,其包含如請求項1至13中任一項之用途中所定義之組合物。
- 一種雞腸球菌菌株的細胞,該菌株以寄存編號BCRC910765寄存。
- 一種組合物,其包含如請求項16之細胞。
- 如請求項17之組合物,其包含醫藥學上可接受之載劑或賦形劑。
- 一種雞腸球菌菌株的生物學純培養物,該菌株以寄存編號BCRC910765寄存。
- 一種以寄存編號BCRC910765寄存之雞腸球菌菌株的細胞用於製備治療實體腫瘤之醫藥品的用途。
- 如請求項20之用途,其中該實體腫瘤係肺癌、乳癌、肝癌或結腸癌。
- 如請求項20之用途,其中該醫藥品係用於減小腫瘤尺寸、減少腫瘤生長、預防癌轉移或預防血管生成。
- 一種組合物用於製備治療實體腫瘤之醫藥品的用途,其中該組合物包含一或多種雞腸球菌種之細菌菌株,且其不含有來自任何其他種之細菌或其僅包含微量或生物學上不相關量的來自另一種之細菌。
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2018
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2019
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Non-Patent Citations (1)
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期刊 K. Sivieri et al., Probiotic Enterococcus faecium CRL 183 inhibit chemically induced colon cancer in male Wistar rats. European Food Research and Technology. volume 228, (2008) p231–237. |
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