CN102026669B - 缀合物在制备用于治疗间皮瘤的药物中的用途 - Google Patents
缀合物在制备用于治疗间皮瘤的药物中的用途 Download PDFInfo
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Abstract
本发明提供了用于治疗恶性胸膜间皮瘤的细胞因子和靶向肽的缀合物,其中所述的靶向肽能够结合至肿瘤相关血管上表达的受体或结合至与肿瘤血管相关的细胞外基质成分。特别地,本发明提供了包含与含有NGR基序的肽连接的细胞因子TNF的缀合物。本发明还提供了包含此类缀合物的药物组合物,以及包含溶解于适当缓冲液中的缀合物的药物制剂。
Description
发明领域
本发明涉及癌症治疗,具体地,本发明涉及细胞因子和靶向肽的缀合物用于治疗恶性胸膜间皮瘤(MPM)的用途。更具体地,本发明涉及包含含有NGR基序的肽和TNF的缀合物(NGR-TNF)用于治疗MPM的用途。
背景技术
恶性胸膜间皮瘤(MPM)是罕见的侵袭性肿瘤,其主要产生自胸腔的表面浆膜细胞,通常与不良的预后相关。全球MPM的发病率在不断上升,并且因为在过去的年间增加了对石棉的暴露,预计在未来的10-20年将上升。
还没有治疗MPM的护理标准,并且仅有少数患者适于任意可能的治愈治疗。细胞毒化疗的并发症强烈地影响了医生在治疗老年人(65岁及以上)和/或不良体力状态(PS≥2)患者中的选择,因为频繁且严重的共发病事件的发生能够使治疗复杂化(Repetto,J.Support Oncol.2003,1(4Suppl.2):18-24)。根据Eastern Cooperative OncologyGroup(ECOG,Robert Comis M.D.,Group Chair)的体力状态(PS)是医生和研究者用于评估患者的疾病如何进展、评估疾病如何影响患者的日常生活能力以及决定合适的治疗和预后的尺度和标准(Oken,等1982Am J Clin Oncol 5:649-655)。体力状态2确认“非卧床患者,能够进行所有的自我护理,但是不能进行任何的工作活动。达到和约超过50%的清醒时间”。在间皮瘤患者的治疗中必须考虑如上所述的人口统计方面,考虑到疾病发生的中位年龄是74岁,并且超过50%的患者在诊断时具有2或更差的体力状态(Chapman等,Thorax 2008,63(5):435-439)。
在过去的20年,已经研究了几种方法,尽管已证实含铂的方案比不含铂的组合更有效,但它们就无进展存活(相对强的存活预测参数)、存活和毒性而言的效果看起来也是普通的(Fennell等,Nat.Clin.Pract.Oncol.2008,5(3):136-147)。
Ceresoli等在The Oncologist 2007,12:850-863中综述了MPM治疗的当前进展和临床数据。单形式治疗(外科手术、放疗和化疗)无法延长患者的生存。
与顺铂联合的培美曲塞二钠是批准用于治疗患有不可切除恶性胸膜间皮瘤的未进行化学治疗的患者的第一个且唯一的上市化疗剂。然而,与顺铂单化疗相比,这一化疗方法仅能达到使无进展存活(5.7对3.9个月)和总存活(12.1对9.3个月)少量增加。此外,即使在所选择的患者人群(中位年龄60岁;Karnofsky体力状态至少70,其确认患者能自我护理且不能进行正常活动或进行有效工作;或甚至更好的体力状态)中进行这一化疗组合,也还有未预期到的毒性且导致几个与治疗相关的死亡。毒性是因为干扰了高半胱氨酸代谢,并导致治疗方案的改变,即通过添加预防使用维生素B 12和叶酸盐作为对治疗的补充。在意向-治疗(ITT)人群中使用培美曲塞加补充完全维生素的顺铂的严重毒性发生率比单独用顺铂治疗的人群的发生率更高(Vogelzang等.J Clin Oncol 2003,21(14):2636-2644)。
目前,已在II期临床试验中评估了几种生物剂,但是没有哪个试剂是有效的,即使在第一线和联合治疗中测试也如此,在一些情况下显示出不安全的毒性样式。临床研究已集中于在MPM中高表达的表皮生长因子受体(EGFR)上(Destro等.Lung Cancer 2006;51:207-215;Edwards等,Lung cancer,2006;54:399-407),以及集中于这一疾病的重要自分泌生长因子血管内皮生长因子(VEGF)和血小板来源的生长因子(PDGF)上。已经研究了这些受体的抑制剂用于一线治疗间皮瘤的用途。
具体地,在II期临床试验中,批准用于治疗晚期非小细胞性肺癌并且在体外显示出对间皮瘤细胞显著的抗增殖效果(Janne等,CancerRes 2002,62:5242-5247)的EGFR抑制剂gefitinib 作为一线治疗没有产生活性,其中位无进展存活少于3个月,尽管97%的间皮瘤患者具有EGFR过表达(Govindan等.Clin Cancer Res,2005;11:2300-2304)。在这一研究中,gefitinib显示出一类特殊的毒性模式,其具有最通常的3级不良事件(3级:严重副作用),表现为腹泻、皮疹和疲劳。
类似地,已知影响c-Kit和PDGFα及β受体,且批准用于治疗慢 性髓细胞样白血病的伊马替尼(Imatinib, )(2-苯基氨基嘧啶酪氨酸激酶抑制剂)就肿瘤进展时间(<3个月)而言,作为一线单试剂治疗没有显示出效果。此外,在40%的患者中由于副作用而中断治疗。主要的副作用是水肿(踝、面部、外阴部和肺),有时导致胸膜或腹膜渗漏的恶化、恶心和呕吐(Mathy等,Lung cancer 200550:83-86)
已研究了血管形成抑制剂的用途(Ceresoli等,The Oncologist 2007,12:850-863)。已报道了使用SU5416的某些活性,所述SU5416是靶向VEGF受体Flt-1和KDR/Flk的高选择性受体酪氨酸激酶抑制剂,其受到过高的血栓风险的阻碍。
当施与没有进行化学治疗的患者作为一线治疗时,VEGF和PDGF受体酪氨酸激酶抑制剂Valatanib(PTK787)显示出4个月的中位无进展存活。3/4级毒性(3级:严重副作用;4级:危及生命或致残副作用)导致胃肠道出血、嗜中性白细胞减少症、淋巴细胞减少、恶心/呕吐、增加的ALT/AST、高血压(Jahan等,J.Clin.Oncol.,2006ASCO AnnualMeeting Proceedings Part I.Vol.24,N°18S(June supplement),2006:7081)。
在双盲、安慰剂对照、随机的II期试验中,对阻断VEGF与其受体结合的重组人抗-VEGF单克隆抗体贝伐单抗(Bevacizumab)作为与化疗联合的一线治疗进行了评估。在之前未治疗的患者中,贝伐单抗加顺铂和2,2-二氟脱氧胞嘧啶核苷(BGC)的联合没有达到主要研究终点,在中位无进展存活(BGC的6.9个月对单独化疗的6.0个月,p=0.88)或中位总存活(GCB的15.6个月对单独化疗的14.7个月,p=0.91)中没有任何的显著改良。此外,在贝伐单抗臂观察到不同毒性的统计学显著更高的发生率,所述毒性由以下组成:脱发、高血压、鼻出血、蛋白尿、口腔炎以及非中性白细胞减少感染(Karrison等,J Clin Oncol.25(18S(6月20日增刊)),2007:7526)。
目前进行的所有临床试验显示即使目前已批准用于治疗某些类型肿瘤的药物诸如伊马替尼或gefitinib对间皮瘤也没有作用。此外,在间皮瘤前临床模型中显示有效的药物在人中也没有作用。这些数据证实药物抗某些类肿瘤的抗肿瘤活性不能预测其在另一癌症类型中的抗肿瘤活性。影响不同器官的不同类型肿瘤具有不同的病因、不同的分子变化基础谱、以及不同的生长方式。本领域技术人员不能预测 显示出治疗一种肿瘤有效的药物是否对另一肿瘤类型有效。
目前,没有标准的治疗用于MPM一线化疗后进展的患者。这一患者人群患有非常具有侵袭性的疾病,在仅使用最佳支持性护理时所报道的中位无进展存活为1.5个月(Jassem等,J Clin Oncol.2008;26(10):1698-704)。复发的肿瘤对二线治疗几乎总是比其首先提供和治疗时更具耐性(Broxterman等,Drug Resist Updat.2003;6(3):111-27)。此外,患者对进一步治疗的忍受能力一般比在一线化疗后更差(Berthold等,J Clin Oncol.2005;23(32):8247-8252)。
二线治疗的目的不仅是在癌症治疗中有效,而且还是对患者相对安全和低毒的样式。
已在间皮瘤的二线治疗中研究了几种试剂,但没有观察到效果和毒性的改进。
最近,已报道了一个随机、多中心的III期试验,其在之前治疗过的间皮瘤患者中测验培美曲塞加最佳支持性护理对单独的最佳支持性护理。尽管证实接受化疗的臂(3.7个月,95%2CI:3.0-4.4)比最佳支持性护理的臂(1.5个月,95%CI:1.4-1.7)有统计学显著更长的疾病进展时间,但没有显示总存活的改善(分别是8.4对9.7个月)。最常见的3/4级毒性主要是血液和非血液毒性,诸如热性嗜中性白细胞减少症和疲劳(Jassem等,J Clin Oncol 2008;26(10):1698-704)。
在单臂、多中心II期研究中,在患有不可切除的间皮瘤患者中研究了贝伐单抗加erlotinib的联合,其中所述患者之前已接受了在先化疗方案。不幸的是,在这一临床试验中没有临床反应,其肿瘤进展时间为2.7个月。毒性模式的特征是几种3级毒性,包括皮疹、腹泻、血栓形成(Jackman等,J Thorac Oncol 2007;2(8):S602)。在另一单臂、多中心II期研究中,用多靶向酪氨酸激酶抑制剂sorafenib治疗之前未治疗的患者或之前接受了化疗的患者。在预治疗的患者中,中位无故障存活是3.6个月。3/4级毒性导致手足反应和疲劳(Janne P等,J ClinOncol 2007;25(18S):Abstract 7707)。
因此,需要具有有利毒性模式的用于治疗间皮瘤的有效药物。本发明实现了这一需求。我们出人意料地发现包含靶向肽和细胞因子的缀合物对治疗恶性胸膜间皮瘤有效,并且此类缀合物具有良好的耐受毒性模式。
WO 01/61017公开了TNF或IFNγ和CD13受体配体(尤其是含有NGR基序的肽)之间的缀合产物。在该专利中公开的数据显示TNF缀合物在淋巴瘤和黑色素瘤小鼠模型的治疗中有效。此外,IFNγ和含有NGR基序的肽的缀合物在淋巴瘤和纤维肉瘤小鼠模型中具有强力的抗肿瘤效果(Curnis等,Cancer Res.2005;65(7):2906-2913)。已公开了各种细胞因子和肿瘤靶向部分的缀合物(WO 03/092737),并且已证实了(WO 03/093478)包含此类缀合物的药物组合物在不诱导负反馈机制活化的极低剂量下是有效的。WO 2006/067633公开了含有NGR基序降解产物的肽,其能够靶向αvβ3整联蛋白,以及公开了包含这些肽和细胞因子的缀合物。这些文件中没有公开细胞因子缀合物用于治疗恶性胸膜间皮瘤的有效性。
发明概述
本发明涉及癌症治疗领域,并且具体地涉及恶性胸膜间皮瘤的治疗。
目前作为一线治疗的参考方案是顺铂加培美曲塞的联合,其为一个具攻击性的化疗方法,就无进展存活和中位存活具有少量的增加,以及具有严重毒作用。更重要的是,考虑到疾病的自然历史,大多数患者在诊断的一年内死亡,认为在二线设置中新试剂的可利用性是较重要的。不幸的是,没有可用于MPM一线化疗后进展的患者的标准治疗,并且最佳支持性护理仍是用于这些患者的参考方法。
已作为单试剂或组合研究了几种新药,但没有哪种是有效的。尤其是目前尚未报道无进展及总存活的增加,而在II期和III期临床试验中观察到了3级(严重副作用)或4级(危及生命或致残副作用)毒性的高发生。
我们已出人意料地发现施与包含靶向肽和细胞因子的缀合物对治疗间皮瘤是有效的,尤其是就无进展存活的增加和缀合物良好的耐受毒性样式而言更是如此。
具体而言,已观察到施与包含通过氨基酸G(甘氨酸)与人TNF连接的靶向肽CNGRC的缀合物给标准一线化疗方案难以治疗或对其耐受的患者带来临床益处。对试验第一阶段登记的患者的初步分析显示7个患者(44%;95%置信区间(CI)20-68%)具有稳定的疾病(SD)作为最 佳反应,中位持续时间是4.4个月(范围,1.6-7.1+月)。在4.5个月估计的无进展存活率为37%(95%CI 10-65%),以及3位患者(19%)在6个月无进展。
在研究的终点,通过治疗57位患者得到的总结果显示NGR-hTNF使得利用最佳支持性护理所观察到的无进展存活加倍,其中所述的最佳支持性护理是在缺乏标准治疗情况下用于这些患者人群的参考治疗。此外,用NGR-hTNF获得的结果就无进展存活而言与用联合治疗(诸如2,2-二氟脱氧胞嘧啶核苷加长春瑞滨,或贝伐单抗加erlotinib)所得到的相当,但其优点是仅施与一种药物,并且所述药物不具有与那些药物相关的毒性。
这些数据显示细胞因子和靶向肽的缀合物可成功地用于治疗间皮瘤,甚至作为化疗方案难以治疗或对其耐受的患者的二线治疗,这意味着甚至在比其首先提供并治疗时更具耐性的肿瘤中也有效。
此外,以三周一次或一周一次方案的低剂量施与(0.8μg/m2)与可控且有利的毒性模式相关,仅有一位患者(2%)经历了3级毒性,没有4级不良事件事件,目前也没有报道治疗相关的死亡。每位患者的主要1级(轻度副作用)或2级(中度副作用)毒性为暂时性输注相关全身性症状,包括寒颤(持续约15-30分钟)。观察到的低毒性样式是治疗间皮瘤的关键优点,尤其是考虑到疾病发作的中位年龄是74岁。
因此,二线治疗的目的,即就无进展存活和对患者的低毒性模式而言的有效性,通过本发明的缀合物用于治疗间皮瘤的用途而完全实现,并且清楚地显示了它们用于一线治疗的有效性。
发明声明
根据本发明的一个方面,提供了包含靶向肽和细胞因子的缀合物,其用于治疗间皮瘤。
优选地,所述细胞因子是TNFα、TNFβ、IFNγ、IL12。
根据本发明的优选方面,提供了缀合物,其中所述的靶向肽是含有NGR或isoDGR或RGD基序的肽。
优选地,所述靶向肽是含有NGR基序的肽。
更优选地,所述靶向肽选自线性或环状
CNGRCVSGCAGRC,NGRAHA,GNGRG,CVLNGRMEC,CNGRC,CNGRCG,LNGRE,YNGRTLQCICTGNGRGEWKCE,LQCISTGNGRGEWKCE,CICTGNGRGEWKC,CISTGNGRGEWKC,MRCTCVGNGRGEWTCY,MRCTSVGNGRGEWTCY,CTCVGNGRGEWTC和CTSVGNGRGEWTC。
根据本发明的优选方面,提供了缀合物,其中所述的细胞因子是通过间隔子与靶向肽CNGRC连接的TNF。优选地,该间隔子是G(甘氨酸)。
根据本发明的其它方面,提供了治疗间皮瘤的方法,其包括施与用于治疗间皮瘤的包含靶向肽和细胞因子的缀合物。
根据本发明的另一方面,提供了药物组合物,其包含有效量的包含靶向肽和细胞因子的缀合物,以及可药用载体和稀释剂。
根据本发明的优选方面,提供了药物组合物,其包含有效量的包含通过间隔子G与靶向肽CNGRC连接的TNF的缀合物,以及可药用载体和稀释剂。
更优选地,该药物组合物用于治疗间皮瘤。
根据本发明的其它方面,提供了药物制剂,其含有浓度为0.01至10mg/ml的包含通过间隔子G与靶向肽CNGRC连接的TNF的缀合物,以及可药用载体和稀释剂。
优选地,该药物制剂由溶于50mM Na2HPO4、150mM NaCl的溶液中的0.150mg/ml包含通过间隔子G与靶向肽CNGRC连接的TNF的缀合物组成。
发明详述
本发明各种优选特征和实施方案的详细描述将以非限制性实施例的方式进行描述。
本发明可通过本领域技术人员来实现,除非另外指出,本领域技术人员将应用化学、分子生物学、微生物学、重组DNA和免疫学的普通技术。所有此类技术均在公开文献中得以公开和解释。例如,参见J.Sambrook,E.F.Fritsch,and T.Maniatis,1989,Molecular Cloning:A Laboratory Manual,第二版,Books 1-3,Cold Spring HarborLaboratory Press;Ausubel,F.M.等(1995and periodic supplements;Current Protocols in Molecular Biology,第9、13和16章,John Wiley&Sons,New York,N.Y.);B.Roe,J.Crabtree,和A.Kahn,1996,DNA Isolation and Sequencing:Essential Techniques,John Wiley&Sons;J.M.Polak和James O′D.McGee,1990,In Situ Hybridization:Principlesand Practice;Oxford University Press;M.J.Gait(Editor),1984,Oligonucleotide Synthesis:A Practical Approach,IrI Press;以及D.M.J.Lilley和J.E.Dahlberg,1992,Methods of Enzymology:DNA StructurePart A:Synthesis and Physical Analysis of DNA Methods inEnzymology,Academic Press。所有的这些出版物通过引用并入本文。
靶向肽
本文所使用的术语“肽”包括多肽和蛋白质。术语“多肽”包括单链多肽分子以及多个多肽复合物,其中单个组分多肽通过共价或非共价方式连接。术语“多肽”包括两个或更多个氨基酸长度的肽,一般具有超过5、10、20、30、40、50或100个氨基酸。
可在本发明中应用的肽可包括D或L构型的氨基酸。此外,可使用修饰的肽,例如以减少免疫原性,以增加在患者体内的循环半衰期,以增强生物可利用性和/或增强效力和/或特异性。
已经公开了多种方法来修饰用于治疗应用的肽。可将肽连接到各种聚合物上,诸如聚乙二醇(PEG)和聚丙二醇(PPG)(例如参见美国专利第5,091,176号、第5,214,131号和美国专利5,264,209号),或连接至双功能交联剂,诸如3-(2-吡啶基二硫基)丙酸N-琥珀酰亚胺酯、6-[3-(2-吡啶基二硫基)丙酰氨基]己酸琥珀酰亚胺酯,以及6-[3-(2-吡啶基二硫基)丙酰氨基]己酸磺基琥珀酰亚胺酯(参见美国专利5,580,853)。
本文所使用的术语靶向肽的意思是如之前所定义的肽,其能够结合至肿瘤相关血管上表达的受体,或结合至与肿瘤血管相关的细胞外基质成分。
缀合物的靶向肽可靶向至以下受体:CD13/氨基肽酶N或整联蛋白。
氨基肽酶是一大组参与许多生物过程的酶,诸如蛋白和多肽的成熟、调控以及降解。特别地,体外和体内研究最近已证实氨基酸序列NGR的受体氨基肽酶N(CD13/APN)在血管发生中起多种作用,并且对于病理状态下从已存在的血管产生新血管是关键的,而在胚胎-胎儿 发育和正常成年功能的血管重新形成中不重要(Pasqualini,Koivunen等,2000;Arap,Kolonin等,2002Bhagwat,Lahdenranta等2001;Bhagwat,Petrovic等,2003;Fukasawa,Fujii等,2006;Rangel,Sun等,2007)。
因此,在优选的实施方案中,靶向肽是含有NGR基序的肽。含有NGR基序的肽以及鉴定此类肽的方法公开于WO 98/10795和WO99/13329,其在此通过引用并入本文。
在特别优选的实施方案中,所述靶向肽选自线性或环状
CNGRCVSGCAGRC,NGRAHA,GNGRG,CVLNGRMEC,CNGRC,CNGRCG,LNGRE,YNGRTLQCICTGNGRGEWKCE,LQCISTGNGRGEWKCE,CICTGNGRGEWKC,CISTGNGRGEWKC,MRCTCVGNGRGEWTCY,MRCTSVGNGRGEWTCY,CTCVGNGRGEWTC和CTSVGNGRGEWTC。
整联蛋白分子包括两个非共价缔合的跨膜糖蛋白亚单位,称为α和β。由于相同的整联蛋白分子在不同的细胞类型中可具有不同的配体结合特异性,因此似乎附加的细胞类型特异性因子可与整联蛋白相互作用调节它们的结合活性。α和β亚单位可以以不同方式结合以形成整联蛋白受体。整联蛋白的自然配体是细胞外基质蛋白的黏着蛋白,诸如纤连蛋白、玻璃粘连蛋白、胶原蛋白、层粘连蛋白。
许多整联蛋白,尤其是αvβ3整联蛋白,识别氨基酸序列RGD(精氨酸-甘氨酸-天冬氨酸)。在其它实施方案中,该靶向肽是能够结合αVβ3整联蛋白的肽,尤其是含有RDG基序的肽。
αvβ3整联蛋白的其它配体是含有NGR基序降解产物的肽。这些肽的详细描述公开于WO 2006/067633,其在此通过引用并入本文。在其它实施方案中,靶向肽是含有NGR基序降解产物的肽,尤其是含有isoDGR基序的肽。
在尤其优选的实施方案中,该靶向肽选自线性或环状
CisoDGRCVSGCAGRC,isoDGRAHA,GisoDGRG,CVLisoDGRMEC,CisoDGRC,CisoDGRCG,LisoDGRE,YisoDGRT,LQCICTGisoDGRGEWKCE,LQCISTGisoDGRGEWKCE,CICTGisoDGRGEWKC,CISTGisoDGRGEWKC,MRCTCVGisoDGRGEWTCY,MRCTSVGisoDGRGEWTCY,CTCVGisoDGRGEWTC或CTSVGisoDGRGEWTC。
缀合物
本发明涉及包含与细胞因子连接的靶向肽的缀合物用于治疗间皮瘤的用途。可用于本发明缀合物的细胞因子的非限制性列表是TNFα、TNFβ、IFNα、IFNβ、IFNγ,IL-1、2、4、6、7、12、15、EMAPII、血管内皮生长因子(VEGF)、PDGF、PD-ECGF或趋化因子。
优选的细胞因子是TNFα、TNFβ、IFNγ,IL12。
如本文所使用的术语“连接”的意思是,靶向肽通过化学偶联而与细胞因子相缔合,以形成融合蛋白,其中第一序列(靶向肽)能够将第二肽转运至靶细胞。因此,缀合物的靶向肽通过它们的多肽骨架与细胞因子连接,并且通过在宿主细胞中遗传表达编码这些蛋白的DNA序列、或直接合成蛋白、或通过交联剂偶联相关的预先形成的序列来获得所得到的融合肽。
所述靶向肽可以与所述细胞因子直接连接,或通过间隔子与所述细胞因子间接连接。所述间隔子可以是单个氨基酸、氨基酸序列或有机残基例如6-氨基辛基-N-羟基琥珀酰亚胺。
在一个实施方案中,所述靶向肽优选连接到所述细胞因子N末端或C末端,因而避免对细胞因子与其受体结合的任何干扰。备选地,所述肽可以连接到氨基酸残基,所述氨基酸残基是酰氨键或羧基键接受体,所述接受体可以是所述分子上天然存在的或者是用遗传工程技术人工插入的。所述缀合物通过使用包含编码所述肽的5’-毗连序列或3’毗连序列的cDNA而制备。
TNF-α
TNF-α:人类TNF-α是233个氨基酸残基的、未糖基化多肽,其或者是作为跨膜蛋白,或者是作为可溶性蛋白存在。当TNF-α作为26kDa膜结合蛋白表达时,其由一个29氨基酸残基的胞质结构域、一个28氨基酸残基的跨膜区段以及一个176氨基酸残基的细胞外区组成。所述可溶性蛋白通过一种85kDa TNF-α转化酶(TACE)的蛋白水解切割而产生,其切割76个氨基酸的片段(233个氨基酸序列的残基1-76),产生17kDa、157个氨基酸残基的分子,该分子通常作为同源三聚体循环。可在Swiss Institute of Bioinformatics.www.expasy.com,UniProtKB/Swiss-Prot database的ExPASy(Expert Protein Analysis System)蛋白质组服务器上找到TNF-α跨膜和可溶蛋白的序列,登录号为P01375。
TNF-α是多效性跨膜蛋白,具有广泛的细胞和组织生物活性,从增强增殖到对肿瘤细胞的直接毒性、天然及获得性免疫反应的活化以及对内皮的影响(Watanabe,Niitsu等,1988;Fajardo,Kwan等,1992)。
根据本发明的优选方面,提供了TNF和CNGRC肽之间的缀合产物,其中优选地,TNF的氨基末端与该肽连接,优选通过间隔子连接,其用于治疗间皮瘤。优选地,所述间隔子是G(甘氨酸)。
IFNγ
干扰素γ(IFN-γ)是主要由T-淋巴细胞和自然杀伤细胞(Farrar,等,1993;Boehm等,1997)产生的多效细胞因子,其促进抗肿瘤反应。IFN-γ作为两个非共价结合的多肽亚单位的同二聚体存在。人IFN-γ的序列可在NCBI(http://www.ncbi.nlm.nih.gov)网站,蛋白质数据库中找到,登录号为AAB59534。
IFN-γ可通过在许多肿瘤细胞类型中诱导抗增殖和促-凋亡作用、通过抑制肿瘤血管发生以及活化自然杀伤细胞和抗肿瘤的巨噬细胞而促进抗肿瘤反应。
根据本发明优选的方面,提供了IFN-γ和CNGRC肽之间的缀合产物用于治疗间皮瘤的用途,其中优选地,IFN-γ的氨基末端与该肽连接,优选通过间隔子连接,所述间隔子优选为G(甘氨酸)
IL12
IL12(p70)是糖基化的异质二聚体,其由二硫化物连接的p40和p35亚单位组成,所述亚单位由两个独立的基因编码。正确的异质二聚体组装在生产细胞内发生。IL12诱导IFNγ和其它下游蛋白质,包括IFNγ可诱导的蛋白-10(IP10),以及由IFNγ诱导的单核因子(Mig),活化免疫反应和抑制血管发生。在IL12肿瘤周围施与之后,或通过应用遗传修饰以产生IL12的肿瘤细胞,已观察到抗肿瘤活性。可在NCBI(http://www.ncbi.nlm.nih.gov)网站,蛋白质数据库中找到人IL12的序列,登录号为M65271(人p35亚单位)和M65272人(p40亚单 位)。
药物组合物
本发明的其它目的是用于治疗个体的药物制剂,其中该制剂包含治疗有效量的包含靶向肽和细胞因子的缀合物。在优选的方面,该药物制剂包含通过间隔子G(甘氨酸)与靶向肽CNGRC连接的细胞因子TNF的缀合物,在尤其优选的方面,该制剂用于治疗间皮瘤。
任选地,该制剂可包含可药用载体、稀释剂、赋形剂或佐剂。药物载体、赋形剂或稀释剂的选择可基于意图的施与途径和标准药物实践来选择。药物制剂可包含任何合适的粘合剂、润滑剂、悬浮剂、包衣剂、增溶剂、以及其它可有助于或增加病毒进入靶部位的载体试剂(诸如,例如脂质递送系统)作为载体、赋形剂或稀释剂,或在载体、赋形剂或稀释剂之外还包含这些物质。合适的载体和稀释剂包括等渗盐水溶液,例如磷酸盐缓冲盐水。可用于本发明的赋形剂的描述可在The Handbook of Pharmaceutical Excipients,第二版,编辑Wade&Weller,American Pharmaceutical Association中找到。本发明的制剂可用于肠胃外、肌肉内、静脉内、皮下、眼内、口服或经皮施与。在本发明优选的方面,该制剂用于肠胃外施与,以无菌水溶液的形式,其可含有其它物质,例如足够的盐或单糖,以使得该溶液与血液等渗。用于肠胃外施与的制剂包含可注射溶液或混悬液,以及用于输注的液体。为了制备肠胃外形式,将有效量的活性组分溶解或悬浮于无菌载体中,任选地添加赋形剂,诸如增溶剂、等渗剂、防腐剂、稳定剂、乳化剂或分散剂,并且随后将其分装于密封的小瓶或安瓿中。
可制备用于每日、每周或每月施与的药物制剂,以获得期望的剂量。可制备用于每2、4、6、8、10或12小时施与的制剂。
所描述的施与途径和剂量方案仅意图作为指引,因为有经验的医师将能够基于具体个体的年龄、体重和反应而确定最适于单个受试者的实际剂量。
治疗
本发明的缀合物、组合物和制剂将用于间皮瘤的治疗。如本文所使用,词语治疗包括治愈、缓解和预防治疗。
实施例1
NGR-hTNF的制备
人重组NGR-TNF由连接至靶向肽CNGRCG的C端的人可溶TNFα1-157组成,通过重组DNA技术制备并如WO01/61017所描述的那样纯化,所述专利通过引用并入本文。
NGR-TNF制剂
配制经纯化的人重组NGR-TNF以获得待施与患者的药物产物。药物制剂由溶解于3mlI型玻璃小瓶中1ml/瓶的磷酸盐缓冲盐水中的0.01至10mg/ml人重组NGR-TNF组成。
用于输注溶液浓缩物的优选制剂显示于表1。
表1:NGR-hTNF制剂
将药物产物储存于-80℃。
在输注给患者之前,用含有1mg/ml人血清白蛋白(HSA)的0.9%NaCl将磷酸盐缓冲盐水(PBS)中的NGR-hTNF稀释至适当浓度。当以极低浓度存在时,HSA的存在是必要的,以通过吸附至血管和管道而避免NGR-hTNF的损失。
实施例II
NGR-hTNF用于治疗间皮瘤
患者选择
本研究包含了通知,同意了的以下患者(pts):他们具有上皮、肉瘤状和混合恶性胸膜间皮瘤(MPM)的组织学或细胞学确认,具有根据用于恶性间皮瘤的改进的RECIST标准通过计算机断层摄影术(CT) 扫描或磁共振成像(MRI)可测得的损害。
表2:根据Eastern Cooperative Oncology Group(ECOG)的体力状态
患者需要至少18岁,之前不超过一次全身治疗方案治疗(之前胸膜内包括博来霉素在内的细胞毒素剂治疗不认为是全身性的),他们在进入本研究之前的28天内没有在先的化疗或放疗,或在14天内没有手术;ECOG体力状态0-2(对于体力状态的定义,参见表2);足够的基线骨髓、肝和肾功能,定义为:嗜中性粒细胞>1.5x109/L且血小板>100x109/L、胆红素<1.5x正常上限(ULN)、在没有肝转移时天冬氨酸转氨酶(AST)和/或丙氨酸转氨酶(ALT)<2.5x ULN、在有肝转移时AST和/或(ALT)<5x ULN,血清肌酸酐<1.5x ULN;没有任何的以下状况:即其中血容量过多和其结果(例如,增加搏出量,升高血压)或血液稀释将表现出患者的风险;正常的心脏功能以及没有不可控的高血压。
如果患者具有以下情况,则会被排除:具有并行的抗癌治疗;在本研究中接受了任何其它的研究试剂;牵连中枢神经系统的临床体征;活跃的或不受控制的全身性疾病/感染,与本方案不相容的严重疾病或医疗状态;对人白蛋白制品或任何其它赋形剂的已知超敏/过敏反应;可能妨碍符合本研究方案的任何心理、家族、社会或地理条件。怀孕或哺乳的妇女没有包含在本研究中(可能分娩的妇女在登记前14天内必须提供阴性的怀孕测试)或在本研究中没有进行有效的避孕措 施的妇女也没包含在本研究中。
研究设计和统计方法
本研究被计划为多中心II期单臂、开放标记、非随机研究,其应用Simon两期设计方法进行,其中使用了在第一和第二期分别包括的16和27位患者。
本研究的主要终点是定义为无进展存活(PFS)的抗肿瘤活性。二级终点包括肿瘤生长控制率(TGCR),总存活(OS)和安全性。还包括了实验性成像(DCE-MRI)和药物代谢动力学研究。
根据NCI Common Toxicity Criteria版本3.0分级系统登记毒性。
考虑到有利的毒性模式,随后修正了该方案,以研究施与NGR-hTNF的更密集的时间方案,即以每周一次的基础给予相同的剂量0.8μg/m2。根据方案修正,如果在最先3周的时间中最先的6名患者中≤1名患者经历任何的4级血液的或3-4级非血液毒性(除了用恰当的措施可迅速控制的恶心、呕吐和发烧除外),则再将6名患者包括到测试中,以在更大的人群中测试这种每周一次的方案的可行性。总的来说,如果12名患者中≤2名患者经历任何的4级血液的或3-4级非血液毒性,则认为这一方案是安全的。此外,如果在治疗终点之后有患者过早地由于毒性而中断了治疗,将继续随访直到完成该研究直到任何其它相关的毒性已消退或通过临床判断。如果可实施的话,在患者由于除毒性之外的任何其它原因并且在有记录的疾病进展之前中断治疗的情况下,计划每8周一次随访,以便临床评估和疾病评估,直到进展的第一个体征或开始新的抗癌治疗。
治疗计划
患者通过每3周一次(q3w)或每周一次60分钟的iv输注接受0.8μg/m2剂量的NGR-hTNF。在存在寒颤的情况下,根据研究人员的判断,允许用对乙酰氨基酚治疗作为下一周期的预防。不需要形式剂量修正。治疗的持续时间与临床结果(RECIST标准所记载的)相关。在稳定的疾病或目标反应的情况下,持续治疗,直到越来越严重的疾病、不可接受的毒性、患者拒绝或医师决定。
患者评定
患者基线评定包括初始的医学评价以及化学和仪器检查。必须在治疗开始前的14天之内进行所有的调查,并且由病史、体格检查的完全评估组成,其中所述的体格检查包括生命体征诸如血压、体温,以及所有临床症状和ECOG体力状态的评估、心电图(ECG);进行全血细胞计数以包括红细胞、血红蛋白、红细胞比容、总白细胞、嗜中性粒细胞、淋巴细胞、单核细胞、嗜酸性粒细胞、嗜碱性粒细胞以及其它、血小板。进行血清化学评估,包括凝血酶原时间(PT、INR)、部分凝血致活酶时间(PTT)、肌酸酐、脲、总胆红素、白蛋白、葡萄糖、碱性磷酸酶(ALP)、尿酸、乳酸脱氢酶、(LDH)、γ-谷氨酰转肽酶(γGT)、ALT、AST、电解质(Na+、K+、Ca++)。
根据用于恶性间皮瘤的经修正的RECIST标准确认肿瘤评估。如果通过当地的准则可实施的话,仅在基线上进行HIV、HBV、HCV的筛选测试。在有生育潜力的妇女中需要进行血清怀孕测试。
在治疗期间,用包括与每一周期前进行的基线所描述的相同参数的体格检查以及ECOG体力状态、ECG(如果临床相关的话)、全血细胞计数和血清化学评估患者。
每6周一次地评估肿瘤评价:通过相同的方法再次调查发现涉及初始评估的所有部位;通过相同的方法以及如可能的话通过同一人测量在初始评估期间选择作为靶标的所有损害。
结果
第一阶段分析
在征募入第一年研究的总共42名患者中,对所登记并治疗的首先16名患者进行第一阶段分析。患者通过每3周一次(q3w)的60分钟iv输注接受0.8μg/m2剂量的NGR-hTNF。约75%的患者是男性;中位年龄是64岁(48至80岁);ECOG体力状态分别是0(7位患者)1(6位患者)和2(3位患者)。与肉瘤状(12.5%)、混合(6%)和未知(12.5%)组织学确定的MPM相比,大多数患者(69%)患有上皮MPM。总体上,完成了58个周期(中位2,范围是1-9)。7名患者(44%;95%CI 20-68%)具有稳定的疾病(SD),其中位持续时间是4.4个月(范围是1.6-7.1+)。SD患者靶损害的最大改变是从17%收缩至6%增长。在4.5个 月估计的PFS率是37%(95%CI 10-65%),并且3位患者(19%)在6个月是无进展的。
每个患者的主要1-2级毒性是输注相关的全身症状,包括寒颤(56%)和疲劳(31%)。没有观察到3-4级治疗相关不良事件或毒性相关的死亡。
第二阶段分析
总共有43名患者征募入该研究,包括属于第一阶段的16名患者和属于第二阶段的27名患者。患者通过每3周一次(q3w)的60分钟iv输注接受0.8μg/m2剂量的NGR-hTNF。63%的患者是男性;中位年龄是64岁(54至80岁);ECOG体力状态分别是0(24位患者)1(10位患者)和2(9位患者)。与非上皮组织学(21%)相比,大多数患者(79%)患有上皮MPM。总体上,完成了170个周期(中位2,范围是1-18个周期)。1名患者(2%)具有部分反应(目前该患者在14.3个月后无进展),以及18名患者(42%)具有稳定的疾病(SD),其中位持续时间是4.4个月(范围是2.2-13.7+)。SD患者靶损害的最大改变是从17%收缩至6%增长。估计的PFS是2.8个月(95%CI,1.9-3.7个月)。一位具有2的体力状态的年长患者和一位对之前的治疗完全无效的患者分别经历了10.9和10.5个月的延长的无进展时间。在9个月的中位随访时间后,目前尚未得到中位存活。
根据修正方案治疗的患者
此外,在完成第二阶段的研究后,并且按照修正方案,在随后的组群中再征募了14名患者,研究每周一次以0.8μg/m2相同剂量给予的NGR-hTNF。每周一次的剂量方案没有改变NGR-hTNF毒性模式。此外,没有不良事件严重程度或频率的增加。再者,没有3-4级药物相关毒性或毒性相关死亡的报道。所有患者均可评估反应,并且7位(50%)具有中位持续时间为8.1个月的SD。中位无进展存活为3.0个月。对每周一次的组群的这些进一步数据确认了NGR-hTNF的安全毒性模式和效力。
结论
综上,在57位患者(43位每三周一次治疗,以及14位每周一次地治疗)中通过NGR-hTNF得到的总结果确认了其在治疗晚期MPM中作为二线治疗的重要作用。在这一背景中,当与单独的最佳支持性护理(1.5个月)相比时,仅有培美曲塞显示出了就无进展存活而言的临床益处(3.6个月)。然而,考虑到基于培美曲塞的组合方案是一线治疗的选择,目前没有可用于在一线治疗后进展的MPM患者(即,全部患者)的标准二线治疗。特别地,NGR-hTNF使得单独用最佳支持性护理所观察到的无进展存活加倍,其中所述的最佳支持性护理仍是在缺乏标准治疗的情况下用于这一患者人群的参考方法。此外,通过NGR-hTNF作为单试剂得到的这些效力结果也比得上通过两种化疗剂(2,2-二氟脱氧胞嘧啶核苷加长春瑞滨)和两种靶向剂(贝伐单抗加erlotinib)的组合或单试剂(sunitinib)得到的最佳结果,而没有与这些试剂相关的严重毒性。最后,在9个月的中位随访后,目前还没得到中位存活。因此,在这一背景中,用NGR-hTNF治疗获得的中位总存活必然将比用积极治疗或单独最佳支持性护理登记的中位存活(即,约8-9个月)更长。
每位患者的主要1-2级毒性是输注相关的全身症状,包括寒颤(71%)和疲劳(36%)。仅有一位患者具有3级治疗相关的毒性,且没有观察到4级治疗相关不良事件或毒性相关的死亡。
总之,NGR-hTNF在之前用化疗治疗的MPM患者中显示出有利的且可控制的毒性模式,具有长效疾病控制的证据。
Claims (8)
1.包含靶向肽和细胞因子的缀合物在制备用于治疗间皮瘤的药物中的用途,其中所述的靶向肽是含有NGR,isoDGR或RGD基序的肽,并且其中所述细胞因子是TNFα或TNFβ。
2.权利要求1的用途,其中所述的靶向肽是含有NGR基序的肽。
3.权利要求2的用途,其中所述的靶向肽选自线性或环状CNGRCVSGCAGRC,NGRAHA,GNGRG,CVLNGRMEC,CNGRC,CNGRCG,LNGRE,YNGRT LQCICTGNGRGEWKCE,LQCISTGNGRGEWKCE,CICTGNGRGEWKC,CISTGNGRGEWKC,MRCTCVGNGRGEWTCY,MRCTSVGNGRGEWTCY,CTCVGNGRGEWTC和CTSVGNGRGEWTC。
4.权利要求2或3的用途,其中所述的细胞因子是通过间隔子G与靶向肽CNGRC连接的TNF。
5.药物组合物在制备用于治疗间皮瘤的药物中的用途,所述药物组合物包含有效量的包含靶向肽和细胞因子的缀合物,以及可药用载体和稀释剂,其中所述靶向肽是含有NGR,isoDGR或RGD基序的肽,并且其中所述细胞因子是TNFα或TNFβ。
6.权利要求5的用途,其中所述的缀合物包含通过间隔子G与靶向肽CNGRC连接的TNF。
7.药物制剂在制备用于治疗间皮瘤的药物中的用途,所述药物制剂含有浓度为0.01至10mg/ml的包含通过间隔子G与靶向肽CNGRC连接的TNF的缀合物,以及可药用载体和稀释剂。
8.药物制剂在制备用于治疗间皮瘤的药物中的用途,所述药物制剂由溶于50mM Na2HPO4、150mM NaCl的溶液中的0.150mg/ml的包含通过间隔子G与靶向肽CNGRC连接的TNF的缀合物组成。
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