CN106573046A - 用于免疫疗法的口服组合物和方法 - Google Patents
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Abstract
本发明涉及一种组合物包含金属,所述金属化学结合至至少一种热变性的肿瘤抗原和至少一种热变性的同种异体抗原。肿瘤抗原和/或同种异体抗原是水解的。所述组合物可配制成片剂或者丸剂。通过向需要的受试者给药,例如,口服所述组合物,还提供了癌症和炎性疾病的治疗方法。
Description
相关申请的交叉引用
本申请要求2014年6月13日提交的美国临时申请61/997,902的优先权,将其全部公开内容以引用的方式并入本申请。
技术领域
本发明属于肿瘤学和免疫学领域,并广泛地涉及用于恶性和自身免疫疾病的免疫疗法的口服组合物和方法。
背景技术
在2012年,全世界估计有14.1×106个新癌症病例,8.2×106个癌症病例死亡和32.6×106个人在患着癌症的情况下存活。癌症几乎影响人体的每个器官。尽管通常的观点认为,小于5%的癌症是基因遗传的。但在炎症和癌症之间存在新的关联(参见例如Lu H、Ouyang W、Huang C的综述,Inflammation,a key event in cancer development.MolCancer Res 2006,4:221-33)。例如,存在肝癌,其中大部分是被称为肝细胞癌(HCC)的特殊类型肝癌–也已知为炎性疾病(Bishayee A.The inflammation and liver cancer.AdvExp Med Biol 2014,816:401-35,将其摘要以引用的方式并入本申请)。HCC是全世界第五常见的癌症并且致死率位列第三。每年约一百万新病例被诊断,并且具有几乎相等数目的死亡–突出了对于较好的治疗的未满足的需要。常规干预如外科手术、辐射和化疗具有严重的毒性作用并且通常不是非常有效。注意力现在转移至生物治疗,即,免疫疗法。
癌症免疫疗法依赖于使用宿主的免疫系统来预防或者消除癌症。具有三组主要的免疫疗法:基于细胞的疗法、抗体疗法和细胞因子疗法。它们均利用以下事实:癌细胞在它们的表面上经常具有微妙地不同的分子,其可被免疫系统检测。这些分子(被称为癌症或者肿瘤抗原)大部分是普通的蛋白质,但是还包括其它分子如碳水化合物。根据常规想法,通过使用这些肿瘤抗原作为靶标,免疫疗法引起免疫系统攻击肿瘤细胞。
基于细胞的疗法(更常见地被称为癌症疫苗)通常涉及从患有癌症的人(例如,从血液)移出免疫细胞。对肿瘤特异性的免疫细胞将被活化,体外生长并注射返回至患有癌症的人,其中所述免疫细胞提供针对所述癌症的免疫应答。可以以此方式使用的细胞类型为天然杀伤细胞、淋巴因子活化杀伤细胞、细胞毒性T细胞和树突细胞。第一个在临床上获准的基于细胞的疗法是Dendreon's Provenge(Sipuleucel)疫苗,其用于治疗前列腺癌。
抗体疗法目前是免疫疗法的最流行形式,具有许多获准的用于宽范围癌症的治疗。抗体是由免疫系统产生的结合至肿瘤细胞表面上的靶标抗原的蛋白质。在正常生理学中,它们被免疫系统使用以对抗病原体。每一抗体对于一种或者数种蛋白质是特异性的,并且结合至癌症抗原的那些抗体在癌症治疗中被使用。使用针对CD47、GD2神经节苷脂糖抗原、免疫检查点程序性细胞死亡1蛋白质(PD-1;也被称为CD279)及其配体、PD-1配体1(PD-Ll)和EGF受体的抗体的干预被最深入地研究。数种抗体目前被批准用于治疗癌症,例如,阿仑珠单抗、贝伐单抗、Brentuximab、西妥昔单抗、吉姆单抗、替伊莫单抗、依匹木单抗、奥法木单抗、帕尼单抗、利妥昔单抗、托西莫单抗和曲妥珠单抗。
干扰素-α和白细胞介素-2(IL-2)是细胞因子(调节和协调免疫系统行为的蛋白质)的实例。它们具有增强免疫系统的抗肿瘤活性的能力并由此可用于治疗癌症。干扰素-α用于治疗毛细胞白血病、AIDS-相关的卡波西肉瘤、滤泡淋巴瘤、慢性髓细胞样白血病和恶性黑色素瘤。IL-2用于治疗恶性黑色素瘤和肾细胞癌。
此外,某些化合物(主要是多糖化合物)可上调免疫系统并可具有抗癌性质。例如,已经测试了β-葡聚糖如香菇多糖和其它来自食用菌的多糖的抗癌潜力(例如,美国专利7,011,845)。不同于通过注射给予的其它免疫疗法,这些化合物通常口服给予。
现在将日益增多的数目的研究投入至各种癌症免疫疗法的开发。已经提出了数种途径,包括Picibanil(OK-432)-链球菌抗原的混合物(美国专利5,559,211);热激蛋白质,例如,HSP70(美国专利8,729,111和6,139,841);溶瘤病毒(美国专利8,450,106);DNA疫苗和基因疗法(美国专利8,216,595和5,631,236);各种所谓的过继细胞转移方法,包括树突细胞(美国专利申请公开US2011/0076290和US2005/0260227)、淋巴因子活化杀伤细胞(美国专利8,691,568)、细胞因子-或者趋化因子-诱导的杀伤细胞(美国专利6,716,425和6,562,347)、天然杀伤或者NK细胞(美国专利8,450,112);单独的或者与另外的刺激物混合的天然肿瘤细胞(美国专利6,207,147);单独的或者与同种异体抗原组合的肿瘤抗原(美国专利7,438,922);各种形式的肿瘤溶解物(美国专利4,108,983);单一和多重细胞因子;例如,IL-2和GM-CSF(美国专利5,478,556);各种来源的免疫辅助剂(美国专利8,216,595);单克隆抗体(美国专利8,680,247)及其各种混合物(美国专利5,126,132和7,919,079)。上面引用的专利的公开内容以引用的方式并入本文。
领域内的专家提出了大量癌症免疫疗法。当这些免疫疗法在临床试验中测试时,癌症的完全缓解(即,治愈)的情况很少发生;大部分在存活方面显示出一般的效果,通常只有几个月。因此,尽管领域中的大量努力和对于癌症免疫学的理解的巨大进步,但是很明显,需要开发更有效的免疫疗法。
发明内容
在一个方面,本发明提供包含金属的口服组合物,所述金属结合至至少一种肿瘤抗原和至少一种同种异体抗原(alloantigen)或者其片段。
在优选的实施方案中,至少一种肿瘤抗原和至少一种同种异体抗原是水解的。
在一些实施方案中,至少一种肿瘤抗原和至少一种同种异体抗原是热变性的。
在一个实施方案中,所述金属是镁。在另一实施方案中,所述金属是钙。
所述肿瘤抗原可为蛋白质、肽、半抗原、多糖、糖蛋白、脂多糖或者DNA分子。
在一些实施方案中,所述肿瘤抗原选自AFP、CEA、CD31、CD34、CD99、CD117、GCDFP-15、EMA、ETA、MPG、p97、Neu、c-myc、raf、ras、MAGE、BAGE、DAGE/Prame、GAGE、RAGE SMAGE、NAG、CQA 72/4、层粘连蛋白-P1、Yale Col.Sr.Factor、UGP、hCG、PD1(CD279)、PTPRC(CD45)、HMB-45、MART-1/Melan-A、Myo D1、MSA、M2-PK、PLAP、PSA、gp100、MUC-1、MUC-2、MUC16、TRP-1、MUM-1、CDK-4、TAG-72、CA-15-3、CA-19-9、CA-27-29、CA-72-4、CA-125、Cyfra 21-1、CYP24、NSE、AMFr、M-344、19a21 1、erb-2、p15、p21、p53、Bcr/Abl断点肽、WT1、HER-2/neu、PD-41、TCSF、GA733-2、HPV16 E7、E6、MZ2-E、B7.1、B7.2、HOM-MEL-40、HOM-MEL-55、NY-COL-2、HOM-HD-397、HOM-RCC-1.14、HOM-HD-21、HOM-NSCLC-11、HOM-MEL-2.4、HOM-TES-11、GRP78、EGFR、BRCA1、BRCA2、APC、HER2、PSA、NY-ESO-1、4-5、PSMA、PSCA、EpCam、POA、GnT-V、TERT、降钙素、钙视网膜蛋白、嗜铬粒蛋白、细胞角蛋白、结蛋白、抑制素、角蛋白、恢复蛋白、激肽释放酶、β-连环蛋白、膜联蛋白、乳腺珠蛋白、酪氨酸酶及其混合物。
在一些实施方案中,所述肿瘤抗原为来源于癌细胞的抗原,所述癌症选自肾上腺癌、肛门癌、胆管癌、膀胱癌、骨癌、脑/CNS肿瘤、乳腺癌、Castleman病、宫颈癌、结肠/直肠癌、子宫内膜癌、食道癌、尤因瘤、眼癌、胆囊癌、胃部癌症、胃肠类癌瘤、胃肠道间质瘤、妊娠滋养细胞疾病、霍奇金病、卡波西肉瘤、喉和下咽癌症、白血病例如ALL、AML、CLL、CML和CMML、淋巴瘤、非霍奇金淋巴瘤、肝癌、肺癌、恶性间皮瘤、多发性骨髓瘤、脊髓发育不良综合征、鼻腔和鼻窦癌症、鼻咽癌、成神经细胞瘤、口腔和口咽癌、骨肉瘤、卵巢癌、胰腺癌、阴茎癌、垂体瘤、前列腺癌、肾癌、视网膜母细胞瘤、横纹肌肉瘤、涎腺癌、肉瘤、基底和鳞状细胞皮肤癌、黑色素瘤、梅克尔细胞癌、小肠癌症、胃癌、睾丸癌症、胸腺癌、甲状腺癌、子宫肉瘤、阴道癌症、外阴癌、Waldenstrom巨球蛋白血症,和Wilms瘤。
在一个实施方案中,所述肿瘤抗原为AFP。
在一个实施方案中,所述同种异体抗原为白蛋白。
在一些实施方案中,在肿瘤抗原和同种异体抗原之间的重量比率为1:1至1:1,000,000,或者为1:50至1:200。
在另一方面,本发明提供包含金属的组合物,所述金属结合至至少一种热变性的、水解的同种异体抗原和至少一种热变性的、水解的肿瘤抗原,所述组合物配制为丸剂。所述金属可为镁或者钙或者能够形成有机金属键的任何其它适合的金属。水解的和变性的肿瘤抗原和水解的和变性的同种异体抗原可为肽,例如寡肽或者多肽。
在另一方面,本发明提供用于治疗需要的受试者中的癌症的方法,其包括向所述受试者口服给药治疗有效剂量的本文中公开的组合物。
在另一方面,本发明提供在受试者中诱导抗炎免疫反应的方法。所述方法包括向所述受试者口服给药治疗有效剂量的组合物,所述组合物包含结合至金属的肿瘤抗原和同种异体抗原。在一些实施方案中,所述肿瘤抗原和同种异体抗原为水解的。在其它实施方案中,其中所述肿瘤抗原和同种异体抗原为热变性的。
在又一方面,本发明提供制备所述组合物的方法,其包括:得到肿瘤抗原和同种异体抗原的混合物;将肿瘤抗原和同种异体抗原变性;和形成金属结合的变性的肿瘤抗原和金属结合的变性的同种异体抗原中的至少一种。所述方法还可包括将肿瘤抗原和同种异体抗原中的至少一种水解。
在一些实施方案中,所述肿瘤抗原得自诊断患有所需类型的癌症的供体的汇聚血液。在其它实施方案中,所述肿瘤抗原得自癌细胞系或者组织。
在一些实施方案中,所述同种异体抗原来源于非恶性细胞,所述非恶性细胞来源于外周血或者细胞系。
在一些实施方案中,所述变性步骤包括施加热。
附图说明
图1显示在本发明组合物的免疫疗法治疗之前和之后肝细胞癌患者的计算机断层摄影术(CT)扫描。图(a)显示在肿瘤被外科手术除去之前在肝的右叶中的单一大肿瘤;(b)在四个月之后多个恶性病变在左叶中复发;在此时的AFP水平为92,407IU/ml;(c)在8个月的每日单一剂量的组合物之后所有病变被清除;在此时的AFP水平下降至低于正常阙值,2.3IU/ml。在治疗之后2年,患者现在是健康的并且恢复非常良好。
图2显示用本发明疫苗组合物(10-6稀释物)实施的T淋巴细胞的48小时体外孵育对于在下行中示出的IFN-γ、TNF-α;IL-2和细胞增殖/活化标示物(即,Ki-67和CD69)的表达的代表性影响。上行代表在相同时间通过流式细胞术分析的对照未刺激的T细胞。数据显示,表达IFN-γ从1.65%增加至9.11%;TNF-α从5.05%减少至0.38%;IL-2从1.65%至1.45%;Ki-67从10.7%至44.3%;和CD69从10.5%至16.1%。
发明详述
本发明提供用于治疗和/或预防癌症和某些炎性疾病的疫苗组合物(本文中也称为疫苗、治疗性疫苗或者免疫疗法组合物),和制备和使用所述疫苗组合物的方法。
机理的理解对于实践本发明而言不是必需的,以及本发明不限于任何特定的作用机理。不过,本发明组合物在数种类型的癌症和炎性疾病中的临床经验暗示,本发明违反了目前在本领域中流行的数个教条。
第一,本发明违反了以下共识:使抗原表位保持它们的天然形式是重要的,使得它们可被受试者的免疫系统恰当地识别。所述术语"表位"代表作为能够特异性结合至抗体或者T-细胞受体的免疫原决定簇的抗原或其片段。表位通常由分子的化学活性表面组群如氨基酸或者糖侧链组成,以及通常具有特异性三维结构特征,以及特异性电荷特征。本发明组合物包括变性的和水解的抗原,其已经不可逆地失去了它们的天然构型,然而意料不到地在用于癌症和自身免疫疾病的免疫疗法中高度有效。
所述术语"免疫耐受性"不意味着免疫抑制或者变应性缺失,相反,它是具有抗炎性质的主动免疫过程,其与典型免疫活化一样有效。目前的共识认为,癌症来自于宿主的"免疫耐受性"和由此导致的免疫系统对击退癌症的失效(美国专利5,723,718)。
第三,本发明不需要免疫辅助剂或者免疫刺激剂来增强宿主的免疫反应。
第四,本发明利用同种异体抗原(同种异型抗原)连同肿瘤抗原来改善组合物效力。
第五,作为肠的上皮表面(在该处抗原被吸收)的衬里的肠细胞比树突细胞(其据信是由其他人提出的许多癌症疫苗的关键细胞)有效得多地充当抗原呈递细胞。但是迄今为止,树突细胞疫苗未能治愈任何人并且通常在不超过15%的病例中观察到临床应答。
第六,已经发现,由癌症患者的血液制造的本发明组合物与由肿瘤组织或者细胞制造的组合物同等地有效。这种现象也许是由于以下事实:即每天在字面上数百万癌细胞在人体中自发地产生,但是在大部分情况下它们不导致疾病,因为它们被免疫系统控制。
最后,本发明组合物为口服形式,这显著不同于现有技术癌症疫苗(其以注射形式制造)。当疫苗通过注射给予时,疫苗需要具有高度纯化的肿瘤抗原,因为杂质可产生不希望的不利反应–现有技术中公知的现象,这表明,多价疫苗比单价的单一表位/抗原疫苗具有更多不利反应。但是同时,具有较少数目抗原的疫苗效果较差。因此,本领域技术人员所面对的困境已经通过使本发明疫苗口服而得到解决。给予抗原混合物(不分离抗原而作为合并的混合物给予抗原)不导致任何不利反应,这是因为抗原混合物被口服给予并且宿主的粘膜免疫系统以与处理具有众多外源性抗原的食物的消化相似的方式处理它们。不同于系统性免疫,粘膜免疫系统已经被专门化和高度适应,以处理巨大的抗原多样性。
在本公开中,术语"癌症"、"肿瘤"、"恶性肿瘤"和"瘤"可互换地以及以单数形式或者复数形式使用。这些术语是指已经经历恶性转化(其使它们对于宿主有机体而言是病理性的)并以致命结果结束的细胞。数种癌症类型落在本发明范围内,其包括但不限于肾上腺癌、肛门癌、胆管癌症、膀胱癌、骨癌、脑/CNS肿瘤、乳腺癌、Castleman病、宫颈癌、结肠/直肠癌、子宫内膜癌、食道癌、尤因瘤、眼癌、胆囊癌、胃部癌症、胃肠类癌瘤、胃肠道间质瘤(GIST)、妊娠滋养细胞疾病、霍奇金病、卡波西肉瘤、肾癌、喉和下咽癌症、许多类型的白血病,例如,ALL、AML、CLL、CML和CMML,淋巴瘤、非霍奇金淋巴瘤、肝癌、肺癌、恶性间皮瘤、多发性骨髓瘤、脊髓发育不良综合征、鼻腔和鼻窦癌症、鼻咽癌、成神经细胞瘤、口腔和口咽癌、骨肉瘤、卵巢癌、胰腺癌、阴茎癌、垂体瘤、前列腺癌、肾癌、横纹肌肉瘤、视网膜母细胞瘤、涎腺癌、肉瘤、基底和鳞状细胞皮肤癌、黑色素瘤、梅克尔细胞癌、小肠癌症、胃癌、睾丸癌症、胸腺癌、甲状腺癌、子宫肉瘤、阴道癌症、外阴癌、Waldenstrom巨球蛋白血症,和Wilms瘤等等。当提及通常表现为实体瘤的癌症类型时,"临床上可检测的"肿瘤是基于肿块可检测的肿瘤;例如,通过CT扫描、磁共振成像(MRI)、X-射线、超声或者触诊。在血液癌症(即,白血病)中,通过测试例如血液样品的异常,其它诊断标准被使用。
本文使用的术语"蛋白质"是指由一个或者多个氨基酸残基组成的功能活性生物分子。肽、寡肽、多肽和蛋白质为用于描述从低分子量端至高分子量端各种长度的氨基酸串的术语。本文使用的术语"寡肽"是指含有约10至30个氨基酸的肽。尽管不存在严格的截止值,但是为了方便,本文使用的术语"多肽"是指长度超过30个氨基酸的肽片段。
本文使用的术语"有效量"或者"治疗有效量"是指在受试者中(例如,当给药于受试者时)产生希望的免疫应答所需要的本发明疫苗的剂量。
下文使用的术语"赋形剂"是指陪伴药物如丸剂、胶囊剂或者片剂的活性成分(API)配制的物质。赋形剂通常是必需的,以帮助使得口服剂量形式如丸剂或者片剂稳定和合用。适当的药学上可接受的赋形剂的选择是本领域技术人员公知的。通常,赋形剂包括抗粘附剂如硬脂酸镁;粘合剂:糖类和它们的衍生物、二糖类:蔗糖、乳糖;多糖类和它们的衍生物:淀粉、纤维素或者改性纤维素如微晶纤维素和纤维素醚如羟基丙基纤维素;糖醇类如木糖醇、山梨糖醇或者麦芽糖醇;蛋白质:明胶;合成聚合物:聚乙烯基吡咯烷酮、聚乙二醇;包衣成分:羟基丙基或者甲基纤维素膜包衣、虫胶、玉米醇溶蛋白或者其它多糖类、脂肪酸、蜡、塑料,和植物纤维;崩解剂如交联的聚合物:聚乙烯基吡咯烷酮、羧甲基纤维素(交联羧甲纤维素钠)、淀粉羟乙酸酯;填料如纤维素磷酸钙、乳糖、蔗糖、葡萄糖、甘露醇、山梨糖醇、碳酸钙,和硬脂酸镁;香料,例如,水果提取物或者人工香料如薄荷、樱桃或者茴香;各种颜料,例如,氧化钛、玫瑰红等;润滑剂如滑石或者二氧化硅,和脂肪,例如,植物硬脂(vegetable stearin)、硬脂酸镁或者硬脂酸;包括烟雾硅胶、滑石,和碳酸镁的助流剂;吸着剂;防腐剂如抗氧化剂:维生素A、维生素E、维生素C、棕榈酸视黄酯、硒、半胱氨酸、甲硫氨酸、柠檬酸、柠檬酸钠、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯;增甜剂等等。
在本公开中使用的金属的非限制性实例包括铝、锑、硼、铬、铜、金、铁、铅、锂、钠、钙、钾、镁、锰、铂、硒、硅、钠、银、钛、锶、锡、钨、钒和锌。更优选的是作为每日膳食的一部分的金属和其盐如钠、钾、钙、锰和镁,不过,在膳食中的其它同样适合的常见金属包括铁、钴、铜、锌、钼、碘和硒。更优选的是镁和钙,其为血清中的两种最丰富的二价阳离子。非优选的金属是毒性或者重金属如砷、铍、镉、铬、铅、汞和铂。在优选的实施方案中,所述金属可为镁或者钙。在一个实施方案中,所述金属为镁。所述金属可结合至活性成分(API)、肿瘤抗原和同种异体抗原,以形成不溶性析出物或者聚集物。
用于本发明公开的主题的盐的非限制性实例包括但不限于:乙酸盐、己二酸盐、藻酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、硫酸氢盐、溴化物、丁酸盐、樟脑酸盐、樟脑磺酸盐、氯化物、柠檬酸盐、环戊烷丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙烷磺酸盐、氟庚酸盐(flucoheptanoate)、富马酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、碘化物、2-羟基乙烷磺酸盐、乳酸盐、马来酸盐、甲烷磺酸盐、2-萘磺酸盐、烟酸盐、草酸盐、棕榈酸盐、果胶酸盐、过硫酸盐、苯基丙酸盐、苦味酸盐、新戊酸盐、丙酸盐、琥珀酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐、十一酸盐、有机金属盐等等。对于治疗用途,本发明化合物的盐预期为药学上可接受的。然而,非药学上可接受的或者充当惰性成分的酸和碱的盐可也使用,例如,用于制备药学上可接受的化合物的初始步骤中或者用作赋形剂。
本文使用的"金属盐"为化合物,其作为与无机或有机酸或者碱接触的金属的化学反应的结果而产生并且在目标受试者内生理耐受。酸的实例包括但不限于乙酸、苯磺酸、苯甲酸、柠檬酸、乙烷磺酸、甲酸、富马酸、羟乙酸、氢溴酸、氢氯酸、乳酸、马来酸、丙二酸、甲烷磺酸、萘-2-磺酸、硝酸、高氯酸、磷酸、水杨酸、琥珀酸、磺酸、硫酸、酒石酸、对甲苯磺酸等。碱的实例包括但不限于碱金属(例如,钠)氢氧化物、碱土金属(例如,镁)氢氧化物、氨等。不限于具有酸和碱的键的金属盐,其它金属盐也是适合的,例如含有在有机配体(即,碳、氧或者氮)和金属之间的键的有机金属化合物。
在一个方面,本发明提供组合物(也称为疫苗、疫苗组合物,或者免疫疗法组合物),其包含变性的肿瘤抗原或其片段、变性的同种异体抗原或其片段,和与上述组分结合的金属。组合物还可包含用于口服剂型的药学上可接受的赋形剂。
本文使用的"肿瘤抗原"是指由肿瘤细胞产生的抗原或者免疫原性物质,即,它可在宿主中触发免疫应答。然而,肿瘤抗原可为单一抗原或者具有多个组分。大部分情况下,所述抗原为蛋白质,但是出于本发明的目的,也包括其它形式的肿瘤抗原。肿瘤抗原可为蛋白质(包括重组蛋白质)、肽、半抗原、多糖、糖蛋白、脂多糖、DNA分子,或其混合物。本文使用的术语"重组蛋白质"是指由重组DNA的表达产生的蛋白质;所述术语"肽"是指由氨基酸构成的蛋白质的片段;当提及蛋白质时,所述术语"片段"是指从两个氨基酸残基至蛋白质的整个氨基酸序列减去一个氨基酸的任何尺寸;所述术语"半抗原"是指当附接至大载体如蛋白质时可引起免疫应答的小分子;所述术语"多糖"是指碳水化合物聚合物,其由通过糖苷连接基结合在一起的单糖单元的长链构成,多糖的公知实例为β-葡聚糖;所述术语"糖蛋白"是指含有共价附接至多肽的低聚糖链的蛋白质,糖蛋白的实例为肿瘤相关的糖蛋白72(TAG-72),其在许多癌细胞(包括卵巢细胞、乳房细胞、结肠细胞,和胰细胞)的表面上被发现;所述术语"脂多糖"(也被称为lipoglycan或者内毒素)是指由脂质和多糖组成的大分子;所述术语"DNA分子"是指编码蛋白质的多核苷酸;所述术语"癌细胞"为无控制分裂的异常细胞,其中的许多可形成肿块或者在血液中循环。
出于本公开的目的,实例肿瘤抗原包括癌胚胎抗原如甲胎蛋白(AFP)和癌胚抗原(CEA)、黑色素瘤MPG和p97、癌Neu癌基因产物、MAGE家族的成员、BAGE家族的成员、DAGE/Prame家族的成员、GAGE家族的成员、RAGE家族的成员、SMAGE家族的成员、NAG、酪氨酸酶、GnT-V、CQA 72/4、层粘连蛋白-P1、Yale Col.Sr.Factor、尿促性腺激素肽(UGP)、hCG和其链、BHCG、IL-13Rα2、PDl(CD279)、CTLA-4、PSA、Melan-A/MART-1、gp100、TRP1、MUC-1、MUC-2、β-连环蛋白、MUM-1、CDK-4、TAG-72、CA-15-3、CA-19-9、CA 72-4、CA-125、Cyfra 21-1、NSE、AMFr、M-344、19a21 1、erb-2、p15、ras的p21、突变的p53、Bcr/Abl断点肽、WT1、HER-2/neu、PD-41、TCSF、GA733-2、HPV16E7或者E6、MZ2-E、B7.1、B7.2、HOM-MEL-40、HOM-MEL-55、SSX2、NY-ESO-1、SCP1、CT7、NY-COL-2、HOM-HD-397、HOM-RCC-1.14、HOM-HD-21、HOM-NSCLC-11、HOM-MEL-2.4,和HOM-TES-11。
在一些实施方案中,本公开的肿瘤抗原可选自AFP、CEA、CD31、CD34、CD99、CD117、GCDFP-15、EMA、ETA、MPG、p97、Neu、c-myc、raf、ras、MAGE、BAGE、DAGE/Prame、GAGE、RAGESMAGE、NAG、CQA72/4、层粘连蛋白-P1、Yale Col.Sr.Factor、UGP、hCG、PD1(CD279)、PTPRC(CD45)、HMB-45、Melan-A/MART-1、Myo Dl、MSA、M2-PK、PLAP、PSA、gp100、MUC-1、MUC-2、MUC16、TRP-1、MUM-1、CDK-4、TAG-72、CA-15-3、CA-19-9、CA-27-29、CA-72-4、CA-125、Cyfra21-1、CYP24、NSE、AMFr、M-344、19a21 1、erb-2、p15、p21、p53、Bcr/Abl断点肽、HER-2/neu、PD-41、TCSF、GA733-2、HPV16E7、E6、MZ2-E、B7.1、B7.2、HOM-MEL-40、HOM-MEL-55、NY-COL-2、HOM-HD-397、HOM-RCC-1.14、HOM-HD-21、HOM-NSCLC-11、HOM-MEL-2.4、HOM-TES-11、GRP78、EGFR、BRCA1、BRCA2、APC、HER2、PSA、NY-ESO-1、4-5、PSMA、PSCA、EpCam、POA、GnT-V、TERT、降钙素、钙视网膜蛋白、嗜铬粒蛋白、细胞角蛋白、结蛋白、抑制素、角蛋白、恢复蛋白、激肽释放酶、β-连环蛋白、膜联蛋白、乳腺珠蛋白、酪氨酸酶等。
肿瘤抗原也可包括编码以上蛋白质或者肽的一个或者多个基因或者DNA序列。目前识别了约400个肿瘤抗原。抗原的定期更新的列表可在各种数据库中找到,例如在http://cancerimmunity.org/v13p15/中,将其以引用的方式并入本文中。出于本公开的目的,将不是肿瘤抗原的任何抗原视为同种异体抗原。
通过测试相应的肿瘤标示物的存在,本领域技术人员可识别特定肿瘤的存在:例如,在结肠直肠癌中:M2-PK、CEA、CA 19-9、CA 125;在乳腺癌中:CEA、CA 15-3、Cyfra 21-1;在卵巢癌中:CEA、CA 19-9、CA 125、AFP、BHCG;在子宫癌中:CEA、CA 19-9、CA 125、Cyfra21-1、SCC;在前列腺癌中:PSA、FPSA、PSCA、PSMA;在睾丸癌中:AFP、BHCG、IL-13Ra2;在胰腺/胃癌中:CEA、CA 19-9、CA 72-4;在肝癌中:CEA、AFP;在食道癌中:CEA、Cyfra 21-1;在甲状腺癌中:CEA、NSE;在肺癌中:CEA、CA 19-9、CA 125、NSE、Cyfra 21-1;和在膀胱癌中:CEA、Cyfra 21-1,和TPA。这些肿瘤标示物也可掺入本发明组合物中充当肿瘤抗原。
在一些实施方案中,所述肿瘤抗原为来源于癌细胞的抗原,所述癌症选自肾上腺癌、肛门癌、胆管癌症、膀胱癌、骨癌、脑/CNS肿瘤、乳腺癌、Castleman病、宫颈癌、结肠/直肠癌、子宫内膜癌、食道癌、尤因瘤、眼癌、胆囊癌、胃部癌症、胃肠类癌瘤、胃肠道间质瘤、妊娠滋养细胞疾病、霍奇金病、卡波西肉瘤、喉和下咽癌症、白血病(包括ALL、AML、CLL、CML,和CMML)、淋巴瘤、非霍奇金淋巴瘤、肝癌、肺癌、恶性间皮瘤、多发性骨髓瘤、脊髓发育不良综合征、鼻腔和鼻窦癌症、鼻咽癌、成神经细胞瘤、口腔和口咽癌、骨肉瘤、卵巢癌、胰腺癌、阴茎癌、垂体瘤、前列腺癌、肾癌、视网膜母细胞瘤、横纹肌肉瘤、涎腺癌、肉瘤、基底和鳞状细胞皮肤癌、黑色素瘤、梅克尔细胞癌、小肠癌症、胃癌、睾丸癌症、胸腺癌、甲状腺癌、子宫肉瘤、阴道癌症、外阴癌、Waldenstrom巨球蛋白血症,和Wilms瘤。
用于本发明的肿瘤抗原可作为独立抗原得到,例如,分离的和/或纯化的蛋白质(包括重组蛋白质)。替代地,肿瘤抗原可来源于外科手术切除的肿瘤、癌症患者的体液如血液或者腹水、原发性肿瘤细胞系或者永生化癌细胞系。优选的肿瘤细胞具有与在被治疗的受试者中的癌症相同的类型,不过这不是关键的。本领域技术人员可容易地从大量细胞系保藏机构得到癌细胞系,或者通过培养作为原始来源的肿瘤细胞而制造其它细胞系。例如,ATCC提供了一系列7种肝癌细胞系,其包括SNU-387、SNU-423、SNU-449、SNU-475、PLC/PRF/5、SK-HEP-1和HepG2/C3A。这些细胞可作为肿瘤抗原的来源单独地或者组合地用于本发明公开的组合物。在一些实施方案中,将原发性肿瘤或者癌细胞作为起始物质直接用于制备本发明组合物,而不从其分离肿瘤抗原。
本文使用的术语"同种异体抗原"或者"同种异型抗原"是指这样的抗原:其具有对于一个人特异性的个体特征,并且这些特征在相同物种如人类的其它个体中不相同。即使每一抗原由相同的基因编码,但是当一个个体的同种异体抗原与其它人的免疫系统接触时,个体间的差异足以触发免疫应答。同种异体抗原在器官移植的背景下被较好地知晓,并且大体上被分成次要和主要组织相容性抗原且可导致移植组织排斥。出于本公开的目的,同种异体抗原可被异种抗原(即,来自其它物种的抗原)替代或者与异种抗原共存,并且作为正常的、非恶性抗原,只要它们不同于肿瘤特异性抗原。可将异种抗原专门地引入,或者可作为从细胞培养基(为增强细胞生长,向其添加了例如牛或者马血清)的带出物的结果存在于组合物中。出于本公开的目的,同种异体抗原可来源于正常肝细胞;可使用例如由ScienCell Research Laboratories提供的细胞,其具有从未患病个体分离的肝细胞系如HHSEC、HH、HHSteC,和HGBF。同种异体抗原的另一容易得到的来源是外周血。
在一些实施方案中,所述同种异体抗原可来源于患者的血液或者优选来源于诊断患有癌症的多个患者。在一些实施方案中,在组合物的制备期间,将所述肿瘤细胞与细胞混悬液中的同种异体组分分离。在其它实施方案中,所述肿瘤细胞不与存在于起始未处理制备物中的同种异体细胞分离。出于本发明的目的,适合的和令人满意的是,起始未处理制备物(在变性或者水解之前)中肿瘤细胞的重量百分数小于80%、50%、40%、30%、20%、10%、5%或者甚至更低,同时剩余细胞为同种异体细胞(即,不是肿瘤细胞的那些细胞)。
使用肿瘤抗原的量作为基础,在本发明组合物中同种异体抗原的量以重量计可至少等于肿瘤抗原的量,以及也可为肿瘤抗原的量的2、3、5、10、20、30、50、100、200、300、500、1000、2000、3000、5000、10,000、20,000、30,000、50,000、100,000、200,000、300,000、500,000,或者1,000,000倍,或者甚至更多。在优选的实施方案中,以重量计在肿瘤抗原和同种异体抗原之间的比率可为1:1至1:100,000,或者为1:50至1:200。适合的比率可通过临床测试,使用领域中的公知技术测定。作为参考,循环肿瘤细胞与非肿瘤细胞的比率是在患有癌症或者处于癌变前状态的患者的外周血中发现的比率并且被认为是最佳比率。当将许多起始未处理来源样品混合时(例如,当来源样品衍生自超过一个个体时),比率将被平衡并且更接近地代表现实群体中的状况。在混合的来源中,与单一来源相比,抗原的所有组成成分将更广泛。
在一些实施方案中,将本发明公开的组合物的肿瘤抗原和同种异体抗原变性。下文使用的术语"变性"是一种处理,其中通过施加一些外部应力或者试剂,生物活性大分子如蛋白质或者核酸失去(至少部分地)它们以天然状态存在的四级结构、三级结构,和/或二级结构。在一个实施方案中,变性通过施加热完成,例如,通过在高压釜中在至少115℃的温度和在至少100kPa(15psi)的气压加热肿瘤抗原和同种异体抗原至少15分钟。高压釜的这些操作参数(温度、压力、持续时间等)可由本领域技术人员确定,例如通过在这些参数之间的已知关联。
在一些实施方案中,将本发明组合物的抗原水解,即,将它们的分子结构降低至较小尺寸的组分或者片段,例如,较小尺寸的肽(寡肽和多肽)以及游离氨基酸。水解可在变性之前、之后或者同时发生。
在优选的实施方案中,所述水解是部分的,即,少于将给定的蛋白质完全分解至游离氨基酸所需要的水解。优选地,小于10%的水解的抗原由游离氨基酸组成,更优选地,所述游离氨基酸含量小于8%,并且甚至更有利地,这种含量小于5%,或者小于3%。在优选的实施方案中,所述组合物在水解之后包含寡肽,其占据最初蛋白质的总量的至少30重量%。在进一步的实施方案中,所述寡肽可占据最初蛋白质的重量的至少35%、至少40%、至少45%、至少50%、至少55%,或者至少60%。
可用于本发明的水解反应的实例包括酸或者碱水解,由此将蛋白质暴露于酸如盐酸或者氢氧化钠。
水解程度和水解产物的组成依赖于使用的水解试剂以及实施水解反应的条件。例如,通过在110℃与6M盐酸一起加热约24小时,蛋白质如白蛋白可被完全水解成游离氨基酸。通过将此温度降低一半,例如,50℃,可将超过80%的最初蛋白质分解至寡肽和游离氨基酸,其余被水解成多肽。本领域技术人员可容易地改变反应条件以得到希望的寡肽比例或者希望的氨基酸长度。例如,如果降低盐酸浓度和/或降低反应温度,将得到更多多肽和较少游离氨基酸,并且产生的寡肽的平均链长将更大。
碱性水解牵涉碱金属氢氧化物如氢氧化钠(NaOH)或者氢氧化镁(Mg(OH)2)。例如,在6M NaOH在50℃24h的白蛋白水解可产生约80%肽收率,其余为游离氨基酸。从水解回收的肽可具有约13kDa或者更少的平均肽尺寸,并且包括平均链长为约12个氨基酸的寡肽。在一个实例中,水解产物包括肽,所述肽的超过60%大于10kD且肽的约15%为6至10kDa,和肽的约1%为1至6kDa。水解产物也包括约4%的游离氨基酸,和约8%的非可溶性蛋白质聚集物。这些数值是示例性的以及不限制本领域技术人员改变水解条件以得到不同的肽对氨基酸的比率。
水解也可通过酶催化-本领域技术人员公知的反应。这种反应天然地在消化膳食蛋白质期间出现在人体中或者当处理抗原时出现在细胞内。对于酶水解,选择本领域已知的蛋白酶如猕猴桃素(actinidin)、氨基肽酶、龙虾肽酶、羧肽酶、半胱天冬酶、组织蛋白酶、凝乳酶、糜蛋白酶、梭菌蛋白酶、胶原酶、弹性蛋白酶、内蛋白酶、外肽酶、激肽释放酶、金属蛋白质、木瓜蛋白酶、胃蛋白酶、纤溶酶、链霉蛋白酶、蛋白酶、肾素、沙雷氏菌溶素(serralysin)、枯草杆菌蛋白酶、嗜热蛋白酶(thermitase)、嗜热菌蛋白酶、紧张肽,或者胰蛋白酶,并且通过本领域技术人员已知的确立的操作将蛋白质降低至较小片段。例如,在中性pH 6.8、温度40℃,和8-12小时的孵育期的典型的蛋白酶水解可得到约30%游离氨基酸。因此,可改变水解条件以产生希望的肽对氨基酸比率。游离氨基酸含量可使用例如L-8900高速氨基酸分析仪(Hitachi,Japan)测定。
本发明的金属组分可以以各种方式引入。取决于选择的水解类型可使用的不同反应,例如,碱性或者酸性水解。例如,蛋白质经历碱性水解或者酸性水解的反应可如下所示:
蛋白质(aq)+MgCl2(aq)+2NaOH(aq)→2NaCl(aq)+Mg(OH)2(s)+Mg-R(s),
或者
蛋白质(aq)+Mg(OH)2(s)+2HCl(aq)→H2O(aq)+MgCl2(aq)+Mg-R(s),
其中R可代表蛋白质(或者肽)自由基,例如,酰胺,或者蛋白质(肽)离子,以及(s)代表固体且(aq)代表水溶液或者可溶。在前面的反应中,添加NaOH,在后面的反应中,添加HC1–在经典化学中,这种类型的反应被称为双重置换或者置换反应:AB+CD→AD+BC。在蛋白质的存在下,金属与蛋白质反应,并且发生析出或者聚集反应。应理解的是,在金属和蛋白质(或者肽)之间的键合可为本质上共价的、本质上离子的,或者具有二者的部分特征。在反应中试剂的比例通常为等摩尔比率或者等重量/体积比率,通过考虑析出的抗原的最高收率是主要目标,理想比例容易确定而不需要过度实验。
尽管上述步骤依次进行,但是这种方法也可按替换的顺序实施。换句话说,本文中公开的步骤的任何序列或者顺序不一定表明所述步骤必须以该顺序实施。本文中所述的方法的步骤可按任何顺序实践实施。此外,一些步骤可同时实施,例如,水解步骤可在高温实施,其然后将使得单独的变性步骤多余。同时步骤的另一实例为水解和析出步骤,由此金属与水解的蛋白质片段的键合可与在酸或者碱介质中的蛋白质片段化一起发生。步骤组合的又一实例是析出和析出物的干燥–这可在真空室中在高温发生–以此方式,析出、干燥和变性过程可同时进行。在这种情况下,水解步骤可为最初步骤。不管得到析出物的步骤,然后将析出物干燥,制成粉末并与药学上可接受的赋形剂混合。然后将这种混合物制成丸剂、片剂,或者胶囊剂(例如,包封活性成分和赋形剂的干燥粉末的明胶胶囊剂)。可将片剂、丸剂或者胶囊剂通过本领域公知技术进一步包衣或者以其它方式处理。
得自步骤的丸剂或者片剂的示例性组成在下表1中示出。
得自这些步骤的丸剂或者片剂的示例性组成在表1、2、3中示出。
表1.根据本发明的组合物的元素分析
在表1中,分析通过使用电感耦合等离子体原子发射光谱法(ICP-AES),通过用3种不同的溶剂(HNO3;HCl+HNO3;和HNO3+H2O2溶液)浸溶本发明组合物来实施。取决于使用的溶剂,组成可稍微改变,但是所有三个实验的结果大致一致。
表2.本发明组合物的抗原物质(API)的氨基酸组成
列在表2中的结果通过使用L-8900高速氨基酸分析仪(Hitachi,Japan),通过将样品溶解在0.02N HC1中得到。
表3.配制为丸剂的本发明组合物的药物赋形剂
本发明组合物的制备方法的说明性实施方案如下。混合的血清得自患有HCC的多个患者的外周血。将血清用盐酸水解,然后用分步添加的1M氢氧化镁析出,直到在反应容器中形成析出物。将所述析出物(其含有镁,所述镁结合至作为主要的肿瘤抗原的甲胎蛋白和血液同种异体抗原混合物,其中白蛋白将为优势物种)收集,热变性,减小至粉末并添加标准的本领域已知的赋形剂(参见表3)以形成丸剂。
含有来自其它癌症类型的肿瘤抗原的组合物可以以类似方式,使用来自患有所讨论的癌症的患者的混合的外周血的血清或者通过外科手术干预得到的肿瘤组织来制备。所述疫苗不一定是特定的癌症特异性的。通过汇聚来自患有不同癌症类型的个体的肿瘤样品或者血液,可制造广谱疫苗。为使方法便利和具有较高再现性,可使用肿瘤细胞系作为肿瘤抗原来源,例如,广谱癌症疫苗可包括以希望的重量比率混合的乳腺癌(MCF7)、脑癌(U87)、胰腺癌(PANC-1)、肝癌(Hep3B)、结肠癌(HCT-15)、宫颈癌(HeLa)、前列腺癌(DU145)和黑色素瘤(MeWo)细胞系。然后可将这些细胞系与混合的外周血的血清组合,然后如上所述进行水解、变性和/或金属诱导的析出。
在又一方面,本发明提供治疗在受试者或者患者中的癌症,和/或预防或者降低在处于患癌风险中的受试者或者患者中的癌症的可能性的方法,其包括向所述受试者口服给药有效量的本发明疫苗。出于本公开的目的,癌症包括但不限于:肝癌(例如,肝细胞瘤、肝胆管型肝癌、肝胚细胞瘤、血管肉瘤、肝细胞癌、肝细胞性腺瘤、血管瘤);肺癌(例如,支气管癌、肺泡癌、支气管腺瘤、肉瘤、淋巴瘤、软骨瘤性错构瘤、间皮瘤);心脏癌症(例如,肉瘤、粘液瘤、横纹肌瘤、纤维瘤、脂肪瘤和畸胎瘤);胃肠癌症(例如,食管、胃、胰腺、小肠和大肠的癌症);泌尿生殖器癌症(例如,肾、膀胱和尿道、前列腺、睾丸;骨癌(例如,成骨性肉瘤、纤维肉瘤、恶性纤维组织细胞瘤、软骨肉瘤、Ewing肉瘤、恶性淋巴瘤、多发性骨髓瘤、恶性巨细胞瘤脊索瘤、骨软骨瘤、良性软骨瘤、软骨母细胞瘤、软骨粘液样纤维瘤、骨样骨瘤和巨细胞瘤);神经系统和脑(例如,颅骨、脑膜、脑,和脊髓)的癌症;妇科癌症(例如,子宫、宫颈、卵巢、外阴、阴道);血液癌症(例如,涉及血液的癌症、霍奇金病、非霍奇金淋巴瘤);皮肤癌(例如,恶性黑色素瘤、基底细胞癌、鳞状细胞癌、卡波西肉瘤、发育不良痣(moles dysplasticnevi)、脂肪瘤、血管瘤、皮肤纤维瘤、瘢痕疙瘩、牛皮癣);和肾上腺癌症(例如,成神经细胞瘤)。
在一些实施方案中,将本发明疫苗与一种或多种化疗剂、一种或多种其它癌症疫苗,和/或一种或多种免疫辅助剂一起在受试者中给药。在一些实施方案中,将所述疫苗作为独立疗法给予受试者。
在另一方面,本发明提供用于治疗或者改善具有自身免疫性质的炎性疾病(也被称为"自身炎性疾病")的方法,其中使用本文中所述的疫苗组合物使宿主的免疫系统对准它自己的细胞和组织。所述病症的非限制性列表包括急性播散性脑脊髓炎、阿狄森病、丙种球蛋白缺乏血症、斑秃、肌萎缩侧索硬化、强直性脊柱炎、抗磷脂综合征、抗合成酶综合征、特应性变态反应、特应性皮炎、自身免疫再生障碍性贫血、自身免疫心肌病、自身免疫肠病、自身免疫性溶血性贫血、自身免疫肝炎、自身免疫内耳病、自身免疫淋巴细胞增生综合征、自身免疫周围神经病变、自身免疫胰腺炎、自身免疫多内分泌症、自身免疫孕酮皮炎、自身免疫血小板减少性紫癜、自身免疫荨麻疹、自身免疫葡萄膜炎、巴洛病、Beliefs病、Berger病、Bickerstaff脑炎、Blau综合征、大疱性类天疱疮、癌症、卡斯尔曼病、乳糜泻、Chagas病、慢性炎症性脱髓鞘性多发性神经病、慢性复发性多病变性骨髓炎、慢性阻塞性肺疾病、丘斯综合征、瘢痕性类天疱疮、耳蜗前庭综合征、冷凝集素疾病、补体成分2缺乏、接触性皮炎、颅动脉炎、肢端硬皮综合征、克罗恩氏病、Cushing综合征、皮肤白细胞分裂性脉管炎、Dego病、Dercum病、疱疹样皮炎、皮肌炎、1型糖尿病、弥漫性皮肤系统性硬化病、德雷斯勒综合征、药物引起的狼疮、盘状红斑狼疮、湿疹、子宫内膜异位症、起止点炎相关的关节炎、嗜酸细胞性筋膜炎、嗜酸细胞性胃肠炎、嗜酸细胞性肺炎、获得性大疱性表皮松解、结节性红斑、胎儿成红细胞增多症、特发性混合性冷球蛋白血症、埃文斯综合征、进行性骨化性纤维发育不良、纤维化肺泡炎、弗莱伯不全骨折、胃炎、胃肠类天疱疮、肾小球肾炎、肺出血肾炎综合征、格雷夫斯病、格-巴二氏综合征、桥本脑病、桥本甲状腺炎、亨诺-许兰氏紫癜、妊娠疱疹、化脓性汗腺炎、休-斯二氏综合征、低丙球蛋白血症、特发性炎性脱髓鞘疾病、特发性肺纤维化、特发性血小板减少性紫癜、IgA肾病、包涵体肌炎、间质性膀胱炎、幼年特发性关节炎、川畸病、金伯克病、科勒病、朗-爱二氏肌无力综合征、累-卡-佩三氏病、白细胞分裂性脉管炎、扁平苔癣、硬化性苔癣、线性IgA病、类狼疮性肝炎、红斑狼疮、Majeed综合征、梅尼埃病、显微镜下多血管炎、米勒-费希尔综合征、格-巴二氏综合征、混合性结缔组织病、硬斑病、穆-哈二氏病、多发性硬化、重症肌无力、显微镜下结肠炎、肌炎、发作性睡病、视神经脊髓炎、神经性肌强直、眼瘢痕性类天疱疮、眼阵挛-肌阵挛综合征、Ord甲状腺炎、奥-施二氏病、剥脱性骨软骨炎、复发性风湿病、PANDAS、潘纳病、副肿瘤性小脑变性、阵发性睡眠性血红蛋白尿症、帕-罗二氏综合征、Parsonage-Turner综合征、睫状体扁平部炎、寻常型天疱疮、恶性贫血、静脉周围脑脊髓炎、POEMS综合征、结节性多发性动脉炎、风湿性多肌痛、多肌炎、原发性胆汁性肝硬变、原发性硬化性胆管炎、渐进性炎性神经病、牛皮癣、银屑病关节炎、坏疽性脓皮病、单纯红细胞再生障碍、Rasmussen脑炎、雷诺现象、复发性多软骨炎、莱特尔综合征、下肢不宁综合征、腹膜后纤维化、类风湿性关节炎、风湿热、肉样瘤病、精神分裂症、施密特综合征、APS的另一形式、Scheuermann病、Schnitzler综合征、巩膜炎、硬皮病、血清病、塞佛病、Sjogren综合征、脊椎关节病、斯蒂尔病、僵人综合征、亚急性细菌性心内膜炎、Susac综合征、Sweet综合征、西德纳姆舞蹈病、交感性眼炎、系统性红斑狼疮、高安动脉炎、颞动脉炎、血小板减少症、托-亨二氏综合征、横贯性脊髓炎、溃疡性结肠炎、未分化结缔组织病、未分化脊椎关节病、荨麻疹性脉管炎、脉管炎、白癜风,或者韦格纳肉芽肿病。
通常,本发明的肿瘤抗原和同种异体抗原的单位剂量范围可为近似0.01μg-100mg/单个剂量,优选0.1μg-10mg/剂并且更优选1μg-5mg/剂。出于实践目的和较好的结果,用于单次摄取的剂量可为10μg至1mg。用于口服给药的优选片剂尺寸可为约0.3至约2克,约0.5至约1.2克,或者约0.8至约1克。片剂可每日服用一次,在其它实施方案中,频率增加至每日4次,最佳频率由治疗医生基于临床应答确定。
在一些实施方案中,本发明公开的疫苗的给药是经由肠途径,包括组合物的跨粘膜递送。所述方法包括使需要这种组合物的受试者的粘膜表面与有效量的组合物接触。适合的粘膜表面包括但不限于口腔、颊、鼻、阴道、宫颈、眼睛、耳、肺道、尿道消化道、皮肤、皮肤粘膜、肛门、泄殖腔,和直肠表面等。在一个实施方案中,所述给药为口服给药,由此所述组合物通过胃并如同任何食物被吸收一样在肠中被吸收。在其它实施方案中,所述组合物经舌下、经直肠,或者阴道给药。
对于口服给药,可将本发明公开的疫苗组合物每日一次作为单一丸剂剂量给药于受试者。在某些情况下,可将剂量增加至每日两次、三次、四次丸剂,持续至少14天、1个月、2个月、3个月,或者只要需要便持续下去。使用本发明组合物的疗法可持续2个月、3个月、6个月,而在一些情况下,可能需要长达1年的连续给药。
可将所述组合物给予癌症患者,不管所述疾病处于早期阶段,还是处于晚期阶段。也可将所述组合物给予没有患病但是可能处于增加的危险中,或者希望通过预防性地采用疫苗而预防癌症的人。
在一些实施方案中,将本发明的疫苗作为独立疗法给药于受试者。在其它实施方案中,本发明公开的组合物的给药可与外科手术、辐射、化疗、其它免疫疗法、激素疗法,或其任何组合联用。在一些实施方案中,本发明的疫苗在受试者中连同一种或多种化疗剂、一种或多种其它癌症疫苗,和/或一种或多种免疫辅助剂一起给药。另外的疗法可在本发明公开的组合物的给药之前、之中或者之后给药。
在本发明组合物意图用于动物或者兽医用途的情况下,所述组合物可便利地用动物饲料如谷物或者食物粒料、诱饵给药,或者在动物饮用水中给药。也可将所述组合物掺入至食物膳食中,例如通过将所述组合物喷洒至膳食上。
实施例
通过以下实施例进一步描述本发明,所述实施例不以任何方式限制本发明。
实施例1:组合物和制备
用于治疗肝癌的组合物由得自20个HCC患者的外周血的混合的血清制备,将所述血清在室温用1M盐酸水解约12小时,然后用1M氢氧化镁析出,所述氢氧化镁逐步添加,直到在反应容器中形成析出物。将所述析出物(其含有镁,所述镁结合至作为主要肿瘤抗原的甲胎蛋白和血液同种异体抗原混合物,其中白蛋白将为优势物种)收集,在商业高压釜中在110℃的温度和100kPa(15psi)的气压热变性20分钟,缩减至粉末并添加赋形剂(如表3中示出)以形成丸剂。应注意的是,在上面的操作中的水解是部分的,约80%的最初抗原破碎成尺寸为1kDa至30kDa的肽。
根据以上操作制备的丸剂含有每剂至少10微克的变性的和水解的甲胎蛋白,每剂至少100微克的变性的和水解的白蛋白,和每剂至少200微克的镁金属。
如此制备的代表性组合物的氨基酸组成在下面示出。批次间差异在小于15%的标准偏差范围内并且对临床效力没有影响。
将上面的组合物如下面的实施例2中所讨论提供给HCC患者。
提供给实施例3-13中讨论的患者的组合物含有广谱癌症疫苗,其包括水解的原发性肿瘤组织(在可利用的情况下,包括它们通过手术操作收集的转移瘤)。已被用于治疗患有各种肿瘤类型的患者的同等有效的替代物由体外生长的永生化癌细胞系制备。这种组合物含有以相同重量比率混合的乳腺癌(MCF7)、脑癌(U87)、胰腺癌(PANC-1)、肝癌(Hep3B)、结肠癌(HCT-15)、宫颈癌(HeLa)、前列腺癌(DU145)和黑色素瘤(MeWo)细胞系。将所述细胞系与来自健康个体的混合的外周血的血清组合,然后如上所述进行水解、变性和/或金属诱导的析出。
实施例2:肝癌
招收了患有晚期HCC的70个患者(由26(37.1%)个女性和44(62.9%)个男性组成,中值年龄为60岁(平均61.7±8.3))以试验本发明的疫苗组合物。在这些人中,30(42.9%)人患有乙型肝炎感染和39(56.5%)人患有丙型肝炎感染,8(11.4%)人患有双重感染,4(5.7%)人对两种病毒呈阴性,包括患有遗传性血色病的2人(2.9%),和无已知诊断的5人(7.1%)。在中值2个月的口服服用疫苗丸剂的每日剂量之后,70个患者中的47个经历了肿瘤标示物甲胎蛋白的血清水平的下降(67.1%;P=0.007,通过Wilcoxon Signed Rank检验)。基线中值AFP水平为223IU/ml(平均4,328;范围为7.2-92,407;95%CI 1,077-7,045)和治疗后值为101.2IU/ml(平均2,701;范围为0.9-54,478;95%CI 521-4,881)。AFP的减少与CT扫描上的肿瘤清除或者退化相关。中值总体存活时间不能被确立,因为70人中的65人(92.9%)在中值8个月的随访(平均11.2;范围为3-55;95%CI 8.8-13.5)之后仍然存活。在此研究中的第一个患者在55个月之前接受免疫疗法并且恢复良好而没有任何病变痕迹。没有患者经历任何不利影响,相反,它们的肝功能测试已经改善。表4示出了免疫疗法干预的结果。
表4.用本发明组合物的每日剂量治疗的患有晚期HCC的70个患者的数据
注意:=死亡的患者。
如图1中所示,来自以上70个患者的代表性患者#12在每日给药所述组合物之前和之后的CT扫描表明,在患者的肝中的多个肿瘤在治疗之后没有痕迹地消失了。
实施例3:乳腺癌
四个诊断患有乳腺癌的妇女每日一次口服服用本发明疫苗。前两个患者具有外科手术、放射疗法和化疗,但是后来发展成转移,其在每日一次口服服用疫苗分别3和6个月之后没有痕迹地消失了。第三个患者具有类似的历史,不同而是,治疗持续时间仅为1个月。第四个女士在50多岁时在常规体检中被诊断患有乳腺癌,活检发现确认了诊断。没有选择外科手术,她决定在"开-关"基础上服用癌症疫苗约1年。在1年之后,她返回医院检查,她的乳腺癌标示物保持在正常的边界处并且她不具有可检测的肿块。在任何四个妇女中未发现不利影响。
实施例4:肺癌
一个将近60岁的患有晚期非小细胞肺癌的个体选择每日两次口服服用本发明疫苗,因为在此晚期阶段不可能实施外科手术。在3个月之后,患者仍然存活,尽管存活可能性仅为1个月。他仍然明显具有肿块,但是肿块尺寸看起来减小了,并且他已经能够正常呼吸,因为最初存在于其左肺的流体已经消失。
实施例5:食道癌
一个50岁的男性注意到他的声音正在变得沙哑,并且他吞咽困难。食物卡在食管中,他在吞咽时疼痛,胸痛,胃灼热,并且具有一些体重减轻。在在医院检查之后,他被诊断患有食管癌。他服用疫苗以及一些草药4个月,而未进行外科手术和放射疗法。患者不再具有癌症并且返回工作。另一患者听说了第一患者后开始治疗,但是在此阶段,在治疗1个月之后,还不知道结果如何,只知道患者仍然存活并且具有更少的吞咽问题。
实施例6:子宫颈/子宫癌症
两个将近50岁的女士被诊断患有子宫颈/子宫癌症。一个患者经历了外科手术和化疗,然后她每日两次服用疫苗6个月。1年后,她仍然存活并且良好。第二个女士在开始流血和体重减轻之后采用了本发明的疫苗疗法。医院拒绝接纳她,因为她是不宜动手术的。在服用疫苗1周之后,她看见流血已经停止,小腹中的疼痛消失,并且在1个月之后,她体重恢复正常。到目前为止她仍然存活。
实施例7:脑肿瘤
HIV阳性患者已经经历渐进性头痛并且当行走时开始具有平衡问题,这使他基本上卧床不起。放射摄影术发现了大的脑肿瘤,其被诊断为胶质母细胞瘤。在每日服用疫苗一次服用疫苗2个月之后,患者重新获得了在无人照顾下行走的能力并且他的头痛以及肿块已经消失。第二患者(40多岁的妇女)被诊断患有脑肿瘤,其不可通过外科手术处理。服用疫苗约8个月后,她仍然在服用疫苗并且除了偶尔头痛之外没有重要症状。肿瘤明显保持在原位,但是尺寸没有增加。
实施例8:白血病
一个患有急性淋巴性白血病的13岁孩子每日两次服用疫苗,以及在6个月之后仍然存活。另一被诊断患有慢性髓细胞性白血病(CML)的30多岁患者每日一次服用疫苗,以及在1年之后仍然存活,尽管他没有进行化疗。
实施例9:膀胱肿瘤
一个被诊断患有膀胱肿瘤的成年男性患者以每日4个丸剂服用疫苗2个月。明显地,他的肿瘤不见了并且患者在1年之后仍然存活。另外两个被诊断患有相同癌症类型的患者每日一次服用疫苗;它们仍然存活超过它们的预期的死亡预后并且症状已经减轻。
实施例10:肌肉瘤
一个将近70岁的妇女被诊断在腿中具有肌肉肿瘤。她具有所述疾病的家族史,因为她的母亲和姨死于相同的疾病。她具有严重的腿和身体疼痛,其在她开始每日一次服用疫苗2-3天之后消失了。在约3个月之后,她返回至医院,在医院医生惊讶地发现她还活着并且在深入检查之后宣称她已经治愈。所述患者恢复了她的正常活动,包括每日自行车骑行和交际舞训练。
实施例11:骨癌
一个75岁男性患者具有无明显转移的骨肉瘤约3年,并且大部分时间卧床不起。他开始每日一次服用疫苗3个月,并且他的病症已经改善至以下程度:他能行走并且他对于镇痛药的需求已经显著降低。他恢复了体重并且他的尿失禁已经停止。
实施例12:前列腺癌
由于骨盆和椎骨疼痛和发现PSA比正常高,具有良性前列腺增生史的两个年龄为56和62岁的男性被怀疑具有恶性转化。没有选择外科手术,它们服用日剂量的疫苗约两个月,并且它们的症状消失了。它们的基线泌尿频率、不完全膀胱排空和排尿犹豫消失并且返回至BHP诊断前的正常水平。
实施例13:测量由本发明疫苗诱导的免疫应答。
将新鲜分离的外周血细胞用稀释一百万倍的本发明疫苗(1ppm或者1:10-6)孵育48小时。这种稀释液代表在口服之后组合物的近似生理剂量。然后在T淋巴细胞的CD4+阳性种群上实施体外生长的细胞的流式细胞术,以评价与未暴露于疫苗的对照细胞相比,本发明组合物对于在疫苗暴露的细胞中免疫活化的选择标示物的影响。结果表明,细胞的IFN-γ表达增加到几乎6倍或者600%;细胞的炎症标示物TNF-α减少为13分之一(1,300%),对于IL-2表达基本上没有影响;增加了CD69表达(其为T-细胞活化的标示物),还增加Ki-67细胞的频率(其为疫苗诱导的增殖记忆细胞的标示物)至4倍(400%))。类似的结果用CD8-阳性T细胞看见。因此,疫苗的生理浓度对于免疫细胞具有非常强和快的影响。这种抗炎效果是独特的并且从来没有用其它癌症疫苗报道过(参见例如PCT/US2012/024009,其中在29天之后Ki-67的最高增加为95%)。生物标示物的变化模式表明,本发明疫苗具有有效抗炎效果,如图2中所示。这些体外测定不限于流式细胞术,本领域技术人员可使用其它体外测定如ELISA方法、细胞因子测定的mRNA表达或者多路测定,例如描述在美国专利5,223,395、EP1664796 B1和EP1222468 B1中,将其通过引用的方式并入本文。
应当理解,尽管为了教导的清楚起见,已经通过示例和说明的方式详细描述了本发明,但是前面的描述并不旨在限制本发明的范围。对于本领域技术人员显而易见的其他方面,优点和修改在所附权利要求的范围内。
Claims (25)
1.口服组合物,其包含金属,所述金属结合至至少一种肿瘤抗原和至少一种同种异体抗原或者它们的片段。
2.权利要求1的组合物,其中所述金属为镁或者钙。
3.权利要求1的组合物,其中至少一种肿瘤抗原和至少一种同种异体抗原是水解的。
4.权利要求1的组合物,其中所述肿瘤抗原选自蛋白质、肽、半抗原、多糖、糖蛋白、脂多糖和DNA分子。
5.权利要求1的组合物,其中至少一种肿瘤抗原和至少一种同种异体抗原是热变性的。
6.权利要求4的组合物,其中所述蛋白质为AFP。
7.权利要求1的组合物,其中所述肿瘤抗原选自AFP、CEA、CD31、CD34、CD99、CD117、GCDFP-15、EMA、ETA、MPG、p97、Neu、c-myc、raf、ras、MAGE、BAGE、DAGE/Prame、GAGE、RAGESMAGE、NAG、CQA 72/4、层粘连蛋白-P1、Yale Col.Sr.Factor、UGP、hCG、PD1(CD279)、PTPRC(CD45)、HMB-45、MART-1/Melan-A、Myo D1、MSA、M2-PK、PLAP、PSA、gp100、MUC-1、MUC-2、MUC16、TRP-1、MUM-1、CDK-4、TAG-72、CA-15-3、CA-19-9、CA-27-29、CA-72-4、CA-125、Cyfra21-1、CYP24、NSE、AMFr、M-344、19a21 1、erb-2、p15、p21、p53、Bcr/Abl断点肽、WT1、HER-2/neu、PD-41、TCSF、GA733-2、HPV16E7、E6、MZ2-E、B7.1、B7.2、HOM-MEL-40、HOM-MEL-55、NY-COL-2、HOM-HD-397、HOM-RCC-1.14、HOM-HD-21、HOM-NSCLC-11、HOM-MEL-2.4、HOM-TES-11、GRP78、EGFR、BRCA1、BRCA2、APC、HER2、PSA、NY-ESO-1、4-5、PSMA、PSCA、EpCam、POA、GnT-V、TERT、降钙素、钙视网膜蛋白、嗜铬粒蛋白、细胞角蛋白、结蛋白、抑制素、角蛋白、恢复蛋白、激肽释放酶、β-连环蛋白、膜联蛋白、乳腺珠蛋白、酪氨酸酶及其混合物。
8.权利要求1的组合物,其中所述肿瘤抗原为来源于癌症细胞的抗原,所述癌症选自肾上腺癌、肛门癌、胆管癌、膀胱癌、骨癌、脑/CNS肿瘤、乳腺癌、Castleman病、宫颈癌、结肠/直肠癌、子宫内膜癌、食道癌、尤因瘤、眼癌、胆囊癌、胃部癌症、胃肠类癌瘤、胃肠道间质瘤、妊娠滋养细胞疾病、霍奇金病、卡波西肉瘤、喉和下咽癌症、包括ALL、AML、CLL、CML和CMML的白血病、淋巴瘤、非霍奇金淋巴瘤、肝癌、肺癌、恶性间皮瘤、多发性骨髓瘤、脊髓发育不良综合征、鼻腔和鼻窦癌症、鼻咽癌、成神经细胞瘤、口腔和口咽癌、骨肉瘤、卵巢癌、胰腺癌、阴茎癌、垂体瘤、前列腺癌、肾癌、视网膜母细胞瘤、横纹肌肉瘤、涎腺癌、肉瘤、基底和鳞状细胞皮肤癌、黑色素瘤、梅克尔细胞癌、小肠癌、胃癌、睾丸癌、胸腺癌、甲状腺癌、子宫肉瘤、阴道癌症、外阴癌、Waldenstrom巨球蛋白血症和Wilms瘤。
9.权利要求1的组合物,其中所述同种异体抗原为白蛋白。
10.权利要求1的组合物,其中在肿瘤抗原和同种异体抗原之间的重量比率为1:1至1:100,000,或者为1:50至1:200。
11.组合物,其包含金属,所述金属结合至至少一种热变性的、水解的同种异体抗原和至少一种热变性的、水解的肿瘤抗原,所述组合物配制为丸剂。
12.权利要求11的组合物,其中所述金属为镁或者钙。
13.权利要求11的组合物,其中所述水解的和变性的肿瘤抗原和水解的和变性的同种异体抗原为肽。
14.权利要求13的组合物,其中所述肽为寡肽。
15.权利要求13的组合物,其中所述肽为多肽。
16.治疗需要的受试者中的癌症的方法,其包括向所述受试者口服给药治疗有效剂量的根据权利要求1-15中的任一项的组合物。
17.在受试者中诱导抗炎免疫反应的方法,所述方法包括向所述受试者口服给药治疗有效剂量的组合物,所述组合物包含结合至金属的肿瘤抗原和同种异体抗原。
18.权利要求17的方法,其中所述肿瘤抗原和同种异体抗原为水解的。
19.权利要求17的方法,其中所述肿瘤抗原和同种异体抗原为热变性的。
20.一种制备组合物的方法,其包括:
得到肿瘤抗原和同种异体抗原的混合物;
将所述肿瘤抗原和所述同种异体抗原变性;
形成金属结合的变性的肿瘤抗原和金属结合的变性的同种异体抗原中的至少一种。
21.权利要求20的方法,其还包括:
水解所述肿瘤抗原和同种异体抗原中的至少一种。
22.权利要求20的方法,其中所述肿瘤抗原得自诊断患有所需类型的癌症的供体的汇集的血液。
23.权利要求20的方法,其中所述肿瘤抗原得自癌细胞系或者癌组织。
24.权利要求20的方法,其中所述同种异体抗原来源于非恶性细胞,所述非恶性细胞来源于外周血或者细胞系。
25.权利要求20的方法,其中所述变性步骤包括施加热。
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EP3154577A4 (en) | 2018-02-14 |
RU2017100120A3 (zh) | 2019-02-28 |
CN106573046B (zh) | 2021-01-12 |
CA2952042A1 (en) | 2015-12-17 |
RU2719586C2 (ru) | 2020-04-21 |
EP3154577A1 (en) | 2017-04-19 |
WO2015192120A1 (en) | 2015-12-17 |
US20170106068A1 (en) | 2017-04-20 |
US20200023046A1 (en) | 2020-01-23 |
RU2719586C9 (ru) | 2020-05-21 |
ZA201700303B (en) | 2019-01-30 |
RU2017100120A (ru) | 2018-07-13 |
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