CN103153340A - 对肿瘤疾病的治疗 - Google Patents
对肿瘤疾病的治疗 Download PDFInfo
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Abstract
给予特异性结合白细胞介素-1α(IL-1α)的一种单克隆抗体(mAb)对于治疗人类受试者中的肿瘤相关疾病是有用的。
Description
相关申请的交叉引用
本申请要求2010年8月23日提交的序列号61/376,097、2010年10月26日申提交的序列号为61/406,759、2010年11月8日提交的序列号为61/411,183以及2011年4月29日提交的序列号为61/480,635的美国临时专利申请的优先权,它们均通过引用以其全文结合在此。
关于联邦资助研究的声明
不适用。
发明领域
本发明总体上涉及医学、肿瘤学、以及免疫学领域。更具体地,本发明涉及一种特异性结合白细胞介素-1α(IL-1α)的抗体(Ab)用来治疗肿瘤相关疾病以及其他肿瘤相关性病理的用途。
发明背景
尽管有许多进展,在发达国家中肿瘤相关疾病(例如癌症),仍然是死亡和发病的主要原因之一。虽然现在已经揭示了肿瘤发生的许多分子机制,大多数侵袭性肿瘤的标准治疗仍然是手术切除、化学疗法以及放射疗法。虽然这些方法日益成功,但它们各自仍然引起许多不希望的副作用。例如,外科手术导致疼痛、健康组织的外伤以及伤疤。放射疗法以及化学疗法引起恶心、免疫抑制、胃溃疡、以及二次肿瘤发生。
在过去的若干年中,使用生物制剂(例如Ab)来治疗癌性肿瘤已经取得的很大进展。Ab可以直接靶向特定类型的肿瘤细胞以利用患者的免疫系统来杀死肿瘤。可替代地,它们可以靶向细胞生长因子来干涉肿瘤细胞生长。如同常规化学治疗剂一样,不是所有的抗肿瘤Ab对于治疗所有类型的肿瘤都是有用的,并且许多初始有效的抗体后来失去了效力。因此,需要新的抗肿瘤Ab。
发明概述
本发明基于的发现是,一种特异性结合IL-1α的单克隆抗体(mAb)对于治疗不同肿瘤相关疾病是有用的。
因此,本发明特征在于用于治疗人类受试者肿瘤性疾病(例如,一种结直肠癌(例如具有KRAS突变的结直肠癌)、一种EBV相关的癌症(例如鼻咽癌或伯基特淋巴瘤)、非小细胞性肺癌(NSCLC)或者与肿瘤相关的非癌性病况(例如卡斯特莱曼病))的一种药剂以及方法。该方法可以通过对受试者给予一种药物组合物来进行,该药物组合物包括一种药学上可接受的载体和有效减轻一种肿瘤相关性病理的症状和/或将受试者肿瘤大小至少减小约10%(例如,至少8%、9%、10%、15%、17%、20%、30%、40%、50%、60%、70%、80%、90%或100%)的一个量的抗-IL-1αAb。该药剂可以包括一种抗-IL-1αAb。该抗-IL-1αAb可以是一种mAb,例如一种Ig(免疫球蛋白)Gl。该抗-IL-1αAb可以是设计为MABpl的mAb或者是包括一个或多个MABpl的互补决定区(CDR)的mAb。
可以通过皮下、静脉内、肌内或直接注射到肿瘤中而将该药物组合物给予该受试者。在该方法中,所述剂量可以至少为0.25(例如,至少0.2、0.5、0.75、1、2、3、4、或5)mg/ml。
除非另有定义,在此所使用的所有技术术语均与本发明所属领域的普通技术人员通常理解的具有相同的含义。通常理解的生物学术语可以在Rieger(里格尔)等人,《遗传学术语:经典和分子》(Glossary of Genetics:Classical and Molecular),第五版,施普林格出版公司(Springer-Verlag),纽约,1991以及Lewin(卢因),《基因V》(Genes V),牛津大学出版社(OxfordUniversity Press):纽约,1994中找到。通常理解的医学术语的定义可以在《斯特曼的医学辞典》(Stedman′s Medical Dictionary),第27版,Lippincott(利平科特),Williams&Wilkins(威廉姆斯和威尔金斯),2000,中找到。
如在此所使用,一种“Ab”或“Ab”为一种免疫球蛋白(Ig)、相同的或异源的Ig的一种溶液、或Ig的一种混合物。一种“Ab”还可以指Ig的片段工程化形式,如Fab、Fab’和F(ab’)2片段;以及scFv’s、异源耦联Ab、以及采用Ig白衍生的CDR以赋予抗原特异性的类似的人工分子。一种“mAb”或“mAb”是由一个克隆B细胞系表达的一种Ab或仅含有能够与一种具体抗原的具体表位发生免疫反应的抗原结合位点的一个种类的Ab分子群。一种“多克隆Ab”或“多克隆Ab”为异源Ab的一种混合物。典型地,一种多克隆Ab将包括结合具体抗原的大量不同的Ab分子,其中这些不同Ab的至少一些与该抗原的不同表位发生免疫反应。如在此所使用,一种多克隆Ab可以是两种或多种mAb的混合物。
一种Ab的“抗原结合部分”包含在一种Ab的Fab部分的可变区内,并且是赋予Ab抗原特异性的该Ab的部分(即,典型地由该Ab的重链和轻链的CDR形成的三维口袋(three-dimensional pocket))。“Fab部分”或“Fab区”为木瓜蛋白酶消化的Ig的蛋白水解片段,该片段含有该Ig的抗原结合部分。“非Fab部分”是不在该Fab部分内的Ab部分,例如“Fc部分”或“Fc区”。Ab的“恒定区”是在可变区外的Ab部分。通常涵盖在恒定区内的是Ab的“效应子部分”,该效应子部分是结合负责促进免疫应答的其他免疫系统组分的Ab部分。因此,例如在一种Ab上结合补体组分或Fc受体(未经由抗原结合部分)的位点为该Ab的效应子部分。
当提及一种蛋白分子例如一种Ab时,“纯化的”指从天然伴随这类分子的组分中分离。典型地,当一种Ab或蛋白按重量计至少约10%(例如,9%、10%、20%、30%、40%、50%、60%、70%、80%、90%、95%、98%、99%、99.9%和100%)从其天然关联的非Ab蛋白或其他天然存在的有机分子释放时,它是纯化的。可以通过任何适当的方法,例如柱层析、聚丙烯酰胺凝胶电泳或HPLC(高效液相色谱法)分析来测量纯度。一种化学合成的蛋白或在一种细胞类型中(在其中该蛋白天然存在的细胞类型除外)产生的其他重组蛋白是“纯化的”。
对于“结合”(“bind”或“binds”)或“与……反应”是指一个分子识别并粘附于样品中的一种具体的第二分子,但基本上不识别或粘附样品中的其他分子。通常,与另一分子“特异性结合”的Ab具有对那个其他分子的大于约105、106、107、108、109、1010、1011或1012升/摩尔的Kd。
一个“治疗有效量”是能够在治疗的动物或人体内产生医学上希望的效果(例如,一种疾病或一种疾病症状的改善或预防)的量。
虽然类似或等同于在此所述的那些的方法和材料可用于本发明的实践或测试,但以下描述了适合的方法和材料。在此提及的所有出版物通过引用以其全文结合在此。在发生冲突的情况下,以包括定义的本说明书为准。另外,以下所讨论的具体实施例仅仅是说明性的而不旨在限制。
详细说明
本发明涵盖用于改善受试者体内肿瘤相关性病理的一个或多个症状的组合物和方法。以下描述的优选实施例说明了这些组合物和方法的调适。虽然如此,根据这些实施例的说明,基于以下提供的说明可以完成和/或实践本发明的其他方面。
一般方法
在此描述了涉及常规免疫学和分子生物学技术的方法。免疫学方法(例如用于抗原Ab复合物的检测和定位的测定法、免疫沉淀法、免疫印迹,等)通常在本领域是已知的,并且在方法学专著例如《当代免疫学实验手册》(Current Protocols in Immunology),Coligan(科尔根)等人编辑,约翰威利父子出版公司(John Wiley&Sons),纽约中描述。分子生物学的技术详细描述于以下专著中,例如Sambrook(萨姆布鲁克)等人编辑的《分子克隆:实验室手册》(Molecular Cloning:A LaboratoryManual),第2版,第1-3卷,冷泉港实验室出版社(Cold Spring HarborLaboratory Press),冷泉港,纽约,2001;以及Ausubel(奥苏贝尔)等人编辑的《当代分子生物学实验手册》(Current Protocols in MolecularBiology),格林出版与威利交叉科学(Greene Publishing andWiley-Interscience),纽约。Ab方法描述于《治疗性Ab手册》(Handbookof Therapeutic Abs),Dubel(杜贝尔),S.编辑,威利-VCH出版社(Wiley-VCH),2007中。在McPhee(麦克菲)和Papadakis(帕帕扎基斯)的《当代医学诊断与治疗》(Current Medical Diagnosis and Treatment)2010,第49版,麦格劳-希尔医学(McGraw-Hill Medical),2010;以及Fauci(福奇)等人的《哈里森内科学原理》(arrison’s Principles of InternalMedicine),第17版,麦格劳-希尔专业(McGraw-Hill Professional)出版,2008中描述了医疗治疗的一般方法。
肿瘤相关疾病的治疗
在此描述的这些组合物和方法对于通过给予受试者一种药物组合物来治疗哺乳动物受试者中的肿瘤相关疾病是有用的,该药物组合物包括有效改进受试者中的肿瘤相关疾病的至少一个特征的一个量的抗-IL-1α Ab。该哺乳动物受试者可以是患有肿瘤相关疾病的任何受试者,包括人类、狗、猫、马、牛、绵羊、山羊和猪。人类受试者可以是男性、女性、成人、儿童、老年人(65岁或更老)、以及患有其他疾病的那些。特别优选的受试者是那些在用化学疗法、放射疗法、外科手术和/或生物制剂治疗后病情发展的。对用一种抗-IL-1α Ab的治疗敏感的任何类型的肿瘤相关疾病可以作为目标。抗-IL-1α Ab给予被认为对治疗结直肠肿瘤(例如,具有KRAS突变的结直肠癌症)、EBV相关的肿瘤(例如鼻咽癌或伯基特淋巴瘤)、NSCLC、以及血液细胞肿瘤(例如卡斯特莱曼病)是特别有效的。带有表达IL-1α的肿瘤或被IL-1α炎症细胞渗入的肿瘤的疾病也可以被作为目标。要被改进的肿瘤相关疾病的具体特征包括肿瘤大小(例如T0、Tis、或者T1-4)、转移状态(如M0、M1)、可观测肿瘤的数目、淋巴结转移及(例如N0、N1-4、Nx)、等级(即等级1、2、3、或4)、阶段(如0、I、II、III或IV期)、细胞上或体液中某些标志物的存在或浓度(如AFP、B2M、beta-HCG、BTA、CA 15-3、CA 27.29、CA125、CA 72.4、CA 19-9、降血钙素、CEA、嗜铬粒蛋白(chromgrainin)A、表皮生长因子受体(EGFR)、激素受体、HER2、HCG、免疫球蛋白、NSE、NMP22、PSA、PAP、PSMA、S-100、TA-90和甲状腺球蛋白)、和/或相关的病理(例如,腹水或水肿)或症状(例如,恶质病、发烧、厌食或疼痛)。如果按百分比可测量,该改进可以是至少5%、10%、15%、20%、25%、30%、40%、50%、60%、70%、80%、或90%(例如肿瘤的体积或线性尺寸)。
靶向IL-1α的抗体以及其他制剂
特异性结合IL-1α并且减少受试者肿瘤相关疾病的特征的任何适合类型的Ab或者其他生物制剂(例如,一种包括一个IL-1α结合组分(例如一个IL-1受体)的融合蛋白)可能用于本发明中。例如,所使用的抗-IL-1αAb可能是mAb、多克隆Ab、mAb的混合物、或一种Ab片段或工程化Ab样分子(例如一种scFv)。Ab的Ka优选地至少为1×109M-1或更大(例如,大于9×1010M-1、8×1010M-1、7×1010M-1、6×1010M-1、5×1010M-1、4×1010M-1、3×1010M-1、2×1010M-1、或1×1010M-1)。在一个优选实施例中,本发明利用一种全人源mAb,该全人源mAb包括(i)展示出对人IL-1α的非常高亲和力(例如至少纳摩尔或皮摩尔)的一个抗原结合可变区以及(ii)一个恒定区。该人源Ab优选地是一种IgGl,虽然它也可以是不同的同种型,例如IgM、IgA、或IgE,或亚类例如IgG2、IgG3、或IgG4。特别有用的mAb的一个实例是MABp1,一种在2009年6月1日提交的美国专利申请序列号12/455,458中描述的IL-1α特异性IgG1 mAb。其他有用的mAb为包括MABp1的多个CDR的至少一种但优选为所有CDR的那些。
由于表达对人IL-1α特异性的Ig的B淋巴细胞天然存在于人类中,所以用于提高mAb的一种目前优选的方法是,首先从受试者中分离这种B淋巴细胞,然后使其永生化,使得它能够在培养中连续复制。可以用一种或多种人IL-1α抗原来免疫缺乏大量天然存在的表达答对人IL-1α特异性的Ig的B淋巴细胞的受试者,以便增加这种B淋巴细胞的数目。人mAb是通过永生化一种人Ab分泌细胞(例如一种人浆细胞)制备的。参见,例如美国专利号4,634,664。
在一个示例性方法中,从一个或多个(例如5个、10个、25个、50个、100个、1000个或更多)人类受试者中筛选在其血液中存在这种人IL-1α特异性Ab的受试者。然后那些表达希望的Ab的受试者可以被用作B淋巴细胞供体。在一个可能的方法中,从拥有表达人IL-1α特异性Ab的B淋巴细胞的人类供体获得外周血。然后从该血样中分离这种B淋巴细胞,例如通过细胞分选(例如荧光激活细胞分选,“FACS”、或磁珠细胞分选)来选择表达人IL-1α特异性Ig的B淋巴细胞。然后,根据已知的技术,通过病毒转化(例如使用EBV)或通过融合到另一种永生化细胞(例如人骨髓瘤细胞)使这些细胞永生化。然后,可以通过有限稀释法(例如选择并继代培养在微量滴定板的孔中的对人IL-1α特异性的Ig呈阳性的细胞,并重复该过程直到可以分离希望的克隆细胞系)分离在这个表达对人IL-1α特异性的Ig的群中的B淋巴细胞。参见,例如Goding(高丁)的《MAb:原理和实践》(Monoclonal Abs:Principles andPractice),59-103页,学术出版社(Academic Press),1986。那些表达对人IL-1α具有至少纳摩尔或皮摩尔的结合亲和力的Ig的克隆细胞系是优选的。可以通过常规Ig纯化程序如盐截留(salt cut)、尺寸排阻、离子交换分离、以及亲和色谱从培养基或体液(例如腹水)中纯化由这些克隆细胞系分泌的MAb。
虽然永生化的B淋巴细胞可以用于体外培养以直接产生mAb,但在某些情况下,可能令人希望的是使用异源表达系统来产生mAb。参见,例如美国专利申请号11/754,899中描述的方法。例如,可以将编码对人IL-1α特异性的mAb的基因克隆并引入一种表达载体(例如一种基于质粒的表达载体),用于进行在异源宿主细胞(例如CHO细胞、COS细胞、骨髓瘤细胞、以及大肠杆菌细胞)中表达。由于Ig包括重(H)链和轻(L)链(在一种H2L2构型中),所以可以将编码每个链的基因分别分离并在不同载体中表达。
虽然由于受试者将发展一种抗Ab应答的可能性更大所以通常是次优选的,但嵌合mAb(例如“人源化”mAb)可以用于本发明中,该嵌合mAb是具有源于不同动物种类的不同部分(例如融合到一种人Ig的恒定区融合的一种小鼠Ig的可变区)的抗原结合分子。可以通过本领域中已知方法制备这种嵌合Ab。参见,例如Morrison(莫里森)等人,《美国科学院院报》(Proc.Nat′l.Acad.Sci.USA),81:6851,1984;Neuberger(纽伯格)等人,《自然》(Nature),312:604,1984;Takeda(武田)等人,《自然》(Nature),314:452,1984。类似地,可以通过本领域已知的方法将Ab人源化。例如,可以通过不同供应商或如美国专利号5,693,762、5,530,101、或5,585,089中所述,将具有希望的结合特异性的mAb人源化。
在此所述的这些mAb是亲和成熟的,以增强或另外地通过已知的方法(例如VH和VL结构域改组(Marks(马克斯)等人,《生物/技术》(Bio/Technology)10:779-783,1992)、高变区(HVR)和/或框架残基的随机诱变(Barbas(巴巴斯)等人,《美国科学院院报》(Proc.Nat′l.Acad.Sci.USA)91:3809-3813,1994;Schier(斯科尔)等人,《基因》(Gene)169:147-155,1995;Yelton(叶尔顿)等人,《免疫学期刊》(J.Immunol.)155:1994-2004,1995;Jackson(杰克逊)等人,《免疫学期刊》(J.Immunol.)154(7):3310-9,1995;and Hawkins等人,《分子生物学期刊》(J.Mol.Biol.)226:889-896,1992))改变它们的结合特异性。一种Ab的氨基酸序列变体可以通过将适当的变化引入编码该Ab的核苷酸序列中来制备。此外,可以改变编码mAb的核酸序列的修饰(例如不改变该mAb的氨基酸序列)用于增强该mAb在某些表达系统中的产生(例如针对一种给定的表达系统的内含子去除和/或密码子优化)。还可以通过与另一种蛋白(例如另一种mAb)或非蛋白分子偶联来修饰在此所述的mAb。例如,可以将一种mAb与一种水溶性聚合物(例如聚乙二醇)或碳纳米管偶联(参见,例如Kam(卡姆)等人,《美国科学院院报》(Proc.Natl.Acad.Sci.USA)102:11600-11605,2005)。参见,美国专利申请号11/754,899。
优选地,为了确保以最小的副作用给予受试者高效价的人IL-1α特异性mAb,本发明的mAb组合物是按重量计至少0.5%、1%、2%、3%、4%、5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、20%、25%、30%、35%、40%、45%、50%、60%、70%、80%、90%、95%、96%、97%、98%、99%、99.9%(或更大百分比)纯(排除任何赋形剂)。本发明的mAb组合物可以仅包括单一类型的mAb(即,由单个克隆B淋巴细胞系产生的mAb)或可以包括两种或更多种(例如,2、3、4、5、6、7、8、9、10或更多种)不同类型的mAb的混合物。
为了修饰或增强它们的功能,人IL-1α mAb可以与另一种分子(例如细胞毒素)偶联。一种人IL-1α特异性mAb可以与一种或多种细胞毒素偶联以便更有效地杀死表达IL-1α的细胞。用于本发明的细胞毒素可以是可以与人IL-1α特异性mAb偶联的任何细胞毒性剂(例如在接触细胞后可以杀死细胞的分子)。细胞毒素的实例包括但不局限于:放射性核素(例如35S、14C、32P、125I、131I、90Y、89Zr、201Tl、186Re、188Re、57Cu、213Bi、和211At)、偶联放射性核素类、以及化学疗法剂。另外的细胞毒素的实例包括但不局限于:抗代谢药(例如5-氟尿嘧啶(5-FU)、甲氨蝶呤(MTX)、氟达拉滨,等)、抗微管剂(例如长春新碱、长春碱、秋水仙碱、紫杉烷(如紫杉醇和多西他赛),等)、烷化剂(例如环磷酰胺、美法仑、双氯乙基亚硝基脲(BCNU)等)、铂剂(例如顺铂(也称为cDDP)、卡铂、奥沙利铂、JM-216、CI-973,等)、蒽环类(例如,多柔比星、柔红霉素,等)、抗生素剂(例如,丝裂霉素C)、拓扑异构酶抑制剂(例如依托泊苷、替尼泊苷、和喜树碱)、或其他细胞毒性剂如蓖麻毒素、白喉毒素(DT)、假单胞菌外毒素(PE)A、PE40、相思豆毒素、肥皂草素、美洲商陆病毒蛋白、溴化乙锭、糖皮质激素、炭疽毒素以及其他。参见,例如美国专利号5,932,188。
虽然上述IL-1α特异性Ab优选用于本发明,但在一些情况下,可以使用特异性靶向IL-1α的其他药剂,只要它们的给予导致肿瘤相关疾病的一个特征的改进。这些其他药剂可以包括特异性结合IL-1α的小有机分子类、适体类、肽类、和蛋白类(例如,阿那白滞素或利纳西普)。
药物组合物和方法
可以在药学上可接受的载体(例如无菌生理盐水)中对动物或人给予该抗-IL-1αAb组合物,该药学上可接受的载体是基于给予模式和途径以及标准的制药实践而选择的。药学上可接受的载体连同药物配制品的清单可以在本领域内的标准文本的雷明顿氏药物科学(Remington’sPharmaceutical Sciences)以及在USP/NF中找到。可以向这些组合物中添加其他物质,并且采取其他步骤来稳定和/或保存这些组合物、和/或促进它们给予到受试者。
例如,这些Ab组合物可以是冻干的(参见Draber(德拉波尔)等人,《免疫学方法期刊》(J.Immunol.Methods.)181:37,1995;和PCT/US90/01383);溶于包括钠离子和氯离子的溶液中;溶于包括一种或多种稳定剂(例如白蛋白、葡萄糖、麦芽糖、蔗糖、山梨醇、聚乙二醇、和甘氨酸)的溶液中;过滤(例如,使用0.45μm和/或0.2μm过滤器);与β-丙内酯接触;和/或溶于包括一种杀微生物剂(例如一种去污剂、一种有机溶剂、以及一种去污剂与有机溶剂的混合物)的溶液中。
可以通过任何适合的技术向动物或人给予该Ab组合物。典型地,这种给予将是肠胃外的(例如静脉、皮下、肌内、或者腹膜内注射)。还可以通过例如注射直接对目标部位(例如瘤内)给予这些组合物。其他递送方法是本领域已知的,例如脂质体递送或从一个浸渍有该组合物的装置扩散。可以通过单次剂量、多次注射或连续输注(例如静脉内或通过腹膜透析)给予该组合物。
一个治疗有效量是能够在治疗的动物或人体内产生医学上希望的结果的量。抗-IL-1αAb组合物的一个有效量是,如通过上述一个或多个肿瘤相关疾病特征中的改进来量度,在患者中显示出临床疗效的量。如在医学领域熟知的,对于任何一种动物或人的剂量取决于很多因素,包括受试者的尺寸、体表面积、年龄、待给予的具体组合物、性别、给予的时间和途径、全身健康状况、以及同时给予的其他药物。优选的剂量在从约0.2到20(例如,0.15、0.2、0.3、0.4、0.5、1、2、3、4、5、6、7、8、9、10、15、20、30、50或100)mg/kg体重的范围内。该剂量可以重复给予,如每小时、每日、每半周、每周、每两周、每三周或每月。
实例
实例1-XilonixTM
XilonixTM是一种在稳定的等渗缓冲液(pH6.4)中的15mg/mL的MABp1的一种无菌可注射液体配制品。每10mL的I型硼硅玻璃血清瓶含有5mL该配制品,并用一种20mm的Daikyo Flurotec的丁基橡胶塞和翻转铝密封件密封。该产品储存在5℃±3℃,允许移动到室温下。该药品的确切组成如下所示:
给予方法
使用一个合适的注射器从包含药物(mAb)的一个或多个小瓶中抽出计算的体积。然后将该药物注射到一个包含100mL生理盐水(0.9%NaCl)的小IV袋中并通过倒转混合。稀释的药品可以在给予前在室温下储存3小时并输注1小时的时间,同时监控受试者输注反应的标志。该输注追加最少30mL的生理盐水来递送可能截留在输注装置中的任何产品。
实例2-用一种IL-1α特异性MAb(XilonixTM)治疗结肠直肠癌。
该人类受试者为一名63岁的女性,诊断患有转移性结直肠癌(KRAS突变阳性)。在用XilonixTM治疗前,该受试者经受了右侧大肠切除术并且据报道为T3N1MX阶段。此后她在约六个月中接受了总共12个周期的用FOLFOX的辅助性化学疗法。在完成FOLFOX约两个月后进行的断层扫描(PET CT scan)揭示在她骨盆内的一个肿块。由于明显来自肿瘤阻塞性肾积水,该受试者住院,在那时放置输尿管支架。在这不久后她开始进行FOLFIRI和Avastin并且接受了8个周期的治疗。然后该受试者经受了再分期PET CT扫描,这证实了骨盆中的疾病,并且还揭示了与转移性疾病一致的小肺部结节。胸部、腹部和骨盆的CT扫描揭示了一个12cm的盆腔肿块、一个2cm的网膜肿块、以及在用相关的输尿管支架的右侧上的肾积水。她接受了2个额外周期的FOLFIRI和Avastin。随后的PET CT扫描显示双侧肺结节的进展。然后该受试者开始了伊立替康和(西妥昔单抗)治疗。随后的PET CT扫描证实了疾病在肺中的进展。
该受试者开始用(阿霉素脂质体)、(硼替佐米)、以及(吉西他滨)进行阶段1试验,但不幸的是第一再分期提示疾病进展。她还用奥沙利铂结合阿扎胞苷(azacitydineon)完成了另一阶段1试验并且在疾病进展前完成了2个周期。当她完成了参与该最后的临床阶段1试验后,该受试者加入当前临床试验。
她加入第一剂量群中(0.25mg/ml)并且完成了方案上的5-21天的周期,因此每21天总计接受五次MABpl(0.25mg/kg)输注。在周期6的第1天,该受试者的剂量增加到0.75mg/kg。初期的PET CT扫描揭示被追踪的患者肿瘤的直径和约17%的减小。随着额外剂量的MABpl,发现患者被追踪的肿瘤的直径和超过30%的减小。胸部CT扫描显示,一个先前测量为3.5cm的气管旁淋巴结在周期6结束时减小到2.9cm。左肺转移从2.2cm减小到1.9cm,并且来自左直肌的一个植入物从3.2cm减小到2.7cm。CEA肿瘤标记物在基线为81,在周期3结束时减小到69.2,并且在周期7的第1天为27.9。该患者持续治疗了超过71周并且疾病保持稳定。
实例3-用一种IL-1α特异性MAb(XilonixTM)治疗鼻咽癌。
受试者为一名47岁的中国男子,他患有伴随组织学亚型淋巴癌(旧术语)或非角化性癌的EBV+(EB病毒)鼻咽癌。该受试者先前用顺铂、5-FU、放射疗法、(多西他赛)、Gemzar(吉西他滨)、(卡培他滨)、继承性EBV定向T细胞转移、以及(更昔洛韦)结合Gemzar(吉西他滨)治疗。在开始治疗前,该患者有疲劳、发烧和出汗的症状,并且因为腹水接受频繁的穿刺治疗。
该受试者在第0天以每两周1.25mg/kg IV开始MABpl治疗。经过3天和4天,注意到受试者疲劳、发烧和出汗的症状显著减少。腹水症状也解决了。腹部CT扫描显示其中的一个肿块的转移性肝肿瘤的大小从第1天的50.4mm减小到第36天的35.8mm(将近30%)。多种其他的肝病变在大小上减小,并且骨病变似乎稳定了。
实例4-用一种IL-1α特异性MAb(XilonixTM)治疗卡斯特莱曼症。
该受试者为一名患有卡斯特莱曼症(该变体被称为POEMS综合征)的55岁的女性。她的症状包括疲劳、水肿以及神经痛。治疗前用(利妥昔单抗)和一种调查型的抗-IL-6治疗失败了。该受试者每21天总总计给予了四次MABpl(0.75mg/kg)输注。该受试者的剂量在下一个周期中增加到1.25mg/kg。
该受试者贯穿2个再分期具有稳定的疾病,且已经被治疗了4个月以上。每次注射后约2周后,她疲劳、水肿以及神经痛的症状显著改进,并且然后逐渐复发直到下一次注射。她的RECIST(实体瘤疗效评价标准)分期标准显示在第一再分期淋巴结大小从基线增加2%,并且在第二再分期淋巴结大小从基线增加4%。
在完成7个周期后,该受试者为了尝试另一试验治疗撤回了同意治疗。在离开研究8周后,该受试者的医师要求,由于“快速疾病进展”,她被允许用MABpl重新开始治疗。自从重新开始治疗,该受试者的疾病稳定,并且她已经被研究了多于58周。
实例5-用一种IL-1α特异性MAb(XilonixTM)治疗NSCLC。
该受试者是一名84对的老年女性,该女性通过细针抽吸被诊断为具有转移性非小细胞肺癌病史。诊断后三个月,该受试者开始用Tarceva(埃罗替尼)治疗了8个月,在这时注意到了疾病进展。然后该受试者用Alimta(培美曲塞(Permetrexed))治疗了8个月11个周期,在这时由于未确定病因学的肾衰竭的发展,治疗被停止。六个月后,注意到了进展的疾病,并且该患者再次用Tarceva(埃罗替尼)治疗了3个月。在这时,她的CAT扫描显示了其肺部疾病的进一步进展,伴随着右上叶肿块体积增加、与转移一致的肺结节、以及内胸腺增大。
然后该受试者加入使用XilonixTM的一个试验。每21天通过静脉注射输注MABpl(3.75mg/kg),输注9个周期。治疗后,注意到在约30周疾病稳定,并且在最近的再分期中右肺损伤显示出形成空洞。
实例6-用一种IL-1α特异性MAb(XilonixTM)治疗非小细胞性肺癌
该受试者是一名52岁的老年女性,她在第0天被诊断为患有KRAS阳性非小细胞癌(腺癌)。第14天的一个PET/CT扫描揭示出一个4cm×3.5cm的左上叶肿块,伴随着疾病转移到肺部、肺门淋巴结、右腹股沟节点、右肾上腺、第四右肋以及骶髂关节。该受试者在扫描几周后开始用卡铂、紫杉醇和贝伐单抗开始治疗。该受试者有好的前期反应,并且在从第一次治疗约5个月时进展前完成了5个周期。在接下来六个月的时间里,该受试者进行了3个周期的多西他赛治疗和一个周期的卡铂加上培美曲塞治疗。尽管进行了该治疗,她持续进展。
该受试者随后开始用MABpl进行治疗。仅4天后,该受试者开始经历她头痛的恶化。这些开始归咎于鼻窦炎,但是MRI揭示脑转移瘤。研究者认为,这些可能在开始治疗前就存在,但是,该受试者在仅接受一剂量MABpl后就退出研究,以接受伽玛刀放射治疗。在初期MABpl剂量后,在随访的二十天中观察该受试者,并且据报道她的症状主观改善,伴随着她的胸痛降低。因此,研究者检查了一个胸部x光片,这显示出在仅用一剂后,“她的肺损伤的大小有明显降低”。发布了一份弃权证书,并且该受试者重新开始治疗。在初始MABpl剂量的四十六天后,该受试者经历了再分期,并且由RECIST标准分级,损伤的总直径和具有6%减小。
其他实施方案
应理解,虽然已经结合其详细描述,对本发明进行了描述,但前面的描述旨在说明而非限制由所附的权利要求的范围限定的本发明的范围。其他方面、优点以及改动都在以下权利要求的范围内。
Claims (15)
1.一种抗IL-1α Ab在制备用于治疗人类受试者中肿瘤相关疾病的一种药剂的用途。
2.根据权利要求1所述的用途,其中该抗-IL-1α Ab是一种mAb。
3.根据权利要求2所述的用途,其中该mAb是一种免疫球蛋白G1(IgG1)。
4.根据权利要求2所述的用途,其中该mAb包括MABp1的一个互补决定区。
5.根据权利要求2所述的用途,其中该mAb是MABpl。
6.根据权利要求1所述的用途,其中该肿瘤相关疾病是一种结直肠肿瘤相关疾病。
7.根据权利要求1所述的用途,其中该肿瘤相关疾病是一种KRAS突变结直肠肿瘤相关疾病。
8.根据权利要求1所述的用途,其中该肿瘤相关疾病与EBV感染相关。
9.根据权利要求1所述的用途,其中该肿瘤相关疾病是鼻咽癌。
10.根据权利要求1所述的用途,其中该肿瘤相关疾病是肺癌。
11.根据权利要求1所述的用途,其中该肿瘤相关疾病是一种与血液细胞肿瘤相关的非癌性病况。
12.根据权利要求1所述的用途,其中该肿瘤相关疾病是卡斯特莱曼病。
13.一种抗-IL-1α Ab在制备用于减小人类受试者中肿瘤大小的一种药剂的用途。
14.一种抗-IL-1α Ab在制备用于减少人类受试者中水肿的一种药剂的用途。
15.一种抗-IL-1α Ab在制备用于减少人类受试者中神经病变的一种药剂的用途。
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