CN1509763A - 人肿瘤坏死因子-α突变体的应用 - Google Patents
人肿瘤坏死因子-α突变体的应用 Download PDFInfo
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- CN1509763A CN1509763A CNA031089348A CN03108934A CN1509763A CN 1509763 A CN1509763 A CN 1509763A CN A031089348 A CNA031089348 A CN A031089348A CN 03108934 A CN03108934 A CN 03108934A CN 1509763 A CN1509763 A CN 1509763A
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Abstract
本发明涉及肿瘤坏死因子α(TNF-α)突变蛋白在制备治疗与异常细胞增殖有关疾病中的应用。所述的异常细胞增殖的疾病包括血液系统的失调、癌症、恶性胸腔积水、恶性腹水、心脏瓣膜再狭窄和炎症疾病。相对于原型的肿瘤坏死因子α,这些突变蛋白有更强的专一抗肿瘤活性,并且对机体的毒性低和副作用轻(只引起发烧和寒战)。此外,TNF-α突变蛋白与其他抗肿瘤药物有潜在相互增效作用,对特定癌症、恶变或者特定阶段的癌症有良好效果。
Description
技术领域
本发明涉及药物应用领域,具体涉及人肿瘤坏死因子-α突变体在治疗与异常细胞增殖有关的疾病中的应用。
背景技术
随着治疗异常细胞增殖相关性疾病(比如癌症)的方法的发展,在临床已有很多治疗方法可以选择。最近生物疗法在难治愈的肿瘤(如黑色素瘤)上的进展及美国食品和药品监督管理局(FDA)对生物治疗的批准,使得人们有希望采用新的蛋白药物来治疗一些用传统药物难以治愈的肿瘤,并且副作用比传统的化学疗法要小得多。
1.临床癌症治疗
目前用于临床癌症治疗的药物分为6大类:烷化剂、抗生素类药物、抗代谢药、生物药、激素类药、植物药。
烷基化试剂是一类能够将氢离子替换为烷基基团的多功能复合物。烷基化试剂包括但不限于二氯乙胺类(氮芥,如苯丁酸氮芥,环磷酰胺,异环磷酰胺,甲氧氮芥,左旋溶肉瘤素,尿嘧啶氮芥),环乙亚胺类(如塞替派),烷基炔硫酸盐类(如白消安),亚硝基脲(如:卡莫司汀,洛莫司汀,链佐星,),非典型烷基化试剂(六甲蜜胺、达卡巴嗪、丙卡巴肼),铂类化合物(卡铂和顺铂)。这些化合物与磷酸盐、氨基、羟基、硫氢基、羧基和咪唑基发生反应。在生理条件下,这些化合物离子化形成带正电的离子,然后结合到敏感的核酸或蛋白质上,导致细胞循环周期中止而引起细胞凋亡,因为烷基化试剂发挥作用与细胞循环周期的特定阶段无关,因此他们属于细胞周期非特异性药物。氮芥和烷基炔硫酸盐类对G1期和M期的细胞最有效。亚硝基脲、氮芥和环乙亚胺类减少细胞从G1期和S期进入M期。Chabnerand Collins eds.(1990)“Cancer Chemotherapy:Principles and Practice”,Philadelphia:JB Lippincott.
烷化剂在抗肿瘤疾病方面应用得比较广泛,不仅可用于治疗实体瘤,在治疗白血病和淋巴瘤方面也有一定的应用。在临床上这类药物常常用来治疗急性和慢性白血病、霍奇金和非霍奇金淋巴瘤、多发性骨髓瘤、脑瘤、以及乳腺癌、卵巢癌、睾丸癌肺癌、膀胱癌子宫癌、头颈癌和恶性黑素瘤。烷化剂的主要副作用是骨髓抑制,通常还有不同程度的胃肠道副作用,另外不同的化合物还会有不同的器官毒性。Black and Livingston(1990)Drugs 39:489-501;and 39:652-673.
抗生素类是一组天然产物经修饰后获得的抗肿瘤药物,其生产类似于抗生素的生产。抗生素类试剂包括但不限于蒽环霉素(如多柔比星、柔红霉素、表柔比星、伊达比星和蒽二酮),丝裂霉素C,博来霉素,放线菌素D,plicatomycin。这些抗生素类试剂通过作用于胞内不同的组分而干扰细胞的生长。例如,DNA拓扑异构酶II能够使DNA链解链,而恩环霉素能够干扰处于转录活性DNA区域的拓扑异构酶II的作用。博来霉素通常能够鳌合离子形成一种激活复合物,此复合物结合到碱基上引起DNA链断裂,导致细胞死亡。
抗生素类药物被广泛地应用于各类肿瘤疾病,包括乳腺癌、肺癌、甲状腺癌、淋巴瘤、骨髓性白血病、骨髓瘤和肉瘤。这类药物中蒽环霉素的主要毒性是骨髓抑制,尤其是粒细胞减少,伴随粒细胞减少经常会发生粘膜炎,其严重程度与骨髓抑制程度相关。当使用高剂量的蒽环霉素时还会有心脏毒性。
抗代谢物是一组能够干扰肿瘤细胞生理和分化关键代谢过程的药物。活跃分化的肿瘤细胞需要持续合成大量的核酸、蛋白质、脂类及其他重要的胞内组分。许多抗代谢物能够抑制嘌呤或嘧啶核苷的合成或者抑制DNA复制所需要的酶类。有些抗代谢物也干扰核糖核苷、RNA、氨基酸代谢及蛋白质的合成。通过干扰胞内重要组分的合成,抗代谢物能够延缓或阻止肿瘤细胞的生长。抗代谢物包括但不限于5-氟尿嘧啶(5-FU)、氮尿苷(5-FUdR)、氨甲蝶呤、亚叶酸、羟基脲、硫鸟嘌呤(6-TG)、6-巯基嘌呤(6-MP)、阿糖胞苷、喷司他丁、氟达拉滨磷酸盐、克拉屈滨(2-CDA)、天冬酰胺酶、吉西他滨。
抗代谢药物被广泛地应用于多种常见的癌症,包括结肠癌、直肠癌、乳房癌、肝癌、胃癌和胰脏癌、恶性黑素瘤、急性和慢性白血病、毛细胞癌等。抗代谢药物治疗引起的副作用多数是抑制正常组织的增殖,如骨髓或胃肠粘膜。用这类药物治疗的病人通常会发生骨髓抑制、口腔炎、痢疾和脱发等。Chen and Grem(1992)Curr.Opin.Oncol.4:1089-1098.
激素类药物是一类调节靶器官的生长和发育的药物。多数激素类药物是性激素及其衍生物和类似物,比如雌激素、雄激素、孕激素等。这些激素类药物可以作为性激素的受体的拮抗剂向下调节受体的表达和关键基因的复制。激素类药物有合成雌激素(如己烯雌酚)、抗雌激素(如他莫昔芬、托瑞米芬、氟甲睾酮、雷洛昔芬)、抗雄激素(如比卡鲁胺、尼鲁米特、氟他氨)、芳香酶抑制剂(如氨鲁米特、阿纳托(司)唑、四唑蓝)、酮康唑、戈舍瑞林乙酸盐、亮丙瑞林、甲地孕酮乙酸盐、米非司酮等。
激素类药物一般用于治疗乳腺癌、前列腺癌、黑色素瘤和脑膜炎。由于激素的主要作用是通过类固醇受体介导的,因此60%的受体敏感的乳腺癌和少于10%的受体不敏感的癌症对一线激素疗法响应。激素类药物的主要副作用是红肿,临床上常常表现为突然加剧的骨痛,损伤皮肤周围的红斑,诱导性高血钙。
植物衍生物是一组来源于植物或者在分子结构上进行了修饰的药物。植物衍生物包括但不限于以下种类,长春花碱(如:长春新碱、长春碱、长春地辛、长春利定和长春瑞滨),水溶性或不可溶的喜树碱(如20(S)-喜树碱,9-硝基喜树碱、9-氨基喜树碱、拓扑替康),鬼臼毒素(依托泊苷(VP-16)、替尼泊苷(VM-26)), 紫杉烷类(紫杉醇和多西他赛)。这些植物衍生物通常作为抗有丝分裂剂结合到微管蛋白上而抑制有丝分裂。鬼臼毒素,如依托泊甙通过影响使DNA解链的拓扑异构酶II而干扰DNA的合成。
植物衍生物用于治疗各类癌症,例如:长春新碱用于治疗白血病、霍奇金和非霍奇金淋巴瘤和早期的成神经细胞瘤、横纹肌肉瘤和Wilms肿瘤;长春碱被用于治疗淋巴瘤、睾丸瘤、肾细胞癌、蕈样肉芽肿病和Koposi's肉瘤;多西他赛在治疗晚期乳腺癌、非小细胞肺癌(NSCLC)和卵巢癌方面很有前景;依托泊甙对较广范围的肿瘤有作用,尤其是对小细胞肺癌、睾丸癌和非小细胞肺癌(NSCLC)效果显著。
植物衍生物对治疗病人有比较强的副作用。长春花生物碱有不同的临床毒性,长春花生物碱的副作用包括神经毒性、改变血小板功能、骨髓抑制和白细胞减少。紫杉醇会引起剂量限制的中性粒细胞减少。表鬼臼毒素类的主要毒性是血液系统毒性(中性粒细胞减少和血小板减少),其他的副作用有暂时性肝脏酶异常、脱发、变态反应和周围神经病。
生物制剂是一类单独使用或与化疗、放疗合用时能够引起肿瘤衰退的生物分子。生物制剂包括免疫调节蛋白(如细胞因子,抗肿瘤抗原的单克隆抗体),肿瘤抑制子基因,肿瘤疫苗。
细胞因子具有很重要的免疫调节活性。某些细胞因子如IL-2和干扰素α已证实具有抗肿瘤活性,并且已经被批准用于治疗转移性肾细胞癌和转移性恶性黑色素瘤。IL-2是一种T-细胞生长因子,其对于T-细胞介导的免疫反应具有重要作用。IL-2对某些病人的选择性抗肿瘤作用据信是由于细胞介导的免疫反应能够区分自我和非我的结果。
干扰素α的亚型超过23种,都具有交叉的活性。已经证实干扰素一α具有对抗多种实体瘤及血液系恶性疾病的活性,血液系统的恶性疾病对它特别敏感。干扰素包括干扰素α,干扰素β(纤维原细胞干扰素)和干扰素γ(纤维原细胞干扰素)。其他细胞因子包括促红细胞生成素、粒细胞集落刺激因子(filgrastin))、粒细胞巨噬细胞集落刺激因子(sargramostim)。
非细胞因子的免疫调节剂包括细菌、左旋咪唑、奥曲肽(一种能够模拟天然产生的生长激素抑制素的效果的、具长期作用的八肽)。
抗肿瘤抗原单克隆抗体是能够抗肿瘤表达的抗原、最好是肿瘤的特异性抗原的抗体。如单克隆抗体HERCEPTIN(Trastruzumab)用来抗人表皮生长因子受体2(HER2),这种受体在某些乳腺癌包括转移性乳腺癌中过量表达。HER2的过量表达与临床中的许多侵略性疾病及较差的预后相关联。HERCEPTIN作为单一药物用于治疗那些体内肿瘤过量表达HER2蛋白的转移性乳腺癌病人。
另一个抗肿瘤抗原单克隆抗体是RITUXAN(Rituximab),它能够抗淋巴瘤细胞上的CD20,能够选择性的消除正常和恶性的CD20+的前B细胞及成熟B细胞。RITUXAN作为单一药物用于治疗复发或难控制的低级或卵泡状CD20+B细胞非霍奇金淋巴瘤病人。
MYELOTARG和CAMPATH也是有希望的抗肿瘤抗原单抗。
肿瘤抑制子基因是一类具有抑制细胞生长分裂循环从而阻止肿瘤形成发展功能的试剂。肿瘤抑制子基因的突变导致细胞忽略抑制信号网络中的一种或多种组分,克服细胞循环的关键点从而导致较高的细胞生长速率,即癌症。肿瘤抑制子基因包括DPC-4,NF-1,NF-2,RB,p53,WT1,BRCA1、BRCA2。
DPC-4用于胰腺癌,参与抑制细胞分裂的细胞质途径。NF-1编码一种能够抑制复发性口疮性口炎的蛋白(属于细胞质抑制蛋白)。NF-1用于治疗神经系统方面的神经纤维瘤和嗜铬细胞瘤以及髓样白血病。NF-2编码一种核蛋白,用于治疗神经系统方面的脑[脊]膜瘤、schwanoma和室管膜瘤。RB编码pRB蛋白,这是一种重要的细胞周期抑制因子,主要用于治疗视网膜母细胞瘤,还有骨癌、膀胱癌、小细胞肺癌和乳腺癌。P53编码p53蛋白(调节细胞分裂以及能够导致细胞调亡),在很多癌症患者中发现p53的突变和/或失活。WT1用于治疗肾母细胞瘤,BRCA1用于治疗乳腺癌和卵巢癌,BRCA2用于治疗乳腺癌。抑癌基因能够被转移到癌细胞中,从而发挥它的抑癌作用。
肿瘤疫苗是一类诱导人体对肿瘤发生特异性免疫的药物。大多数肿瘤疫苗还在开发研究中,临床试验中的有肿瘤相关抗原(TAAs),TAA是那些存在于肿瘤细胞而正常细胞中没有的物质(如蛋白、酶或糖类)。由于TAAs是肿瘤细胞中特有的,为免疫系统提供了靶目标,使得免疫系统能够识别和消灭癌细胞。TAAs有神经节甙酯(GM2)、前列腺特异性抗原(PSA)、α-胎球蛋白(AFP)、癌胚抗原(CEA)(由结肠癌和其他一些腺癌提供,如乳腺癌、肺癌、胃癌和胰脏癌)、黑色素瘤抗原(MART-1,gp100,MAGE 1,3酪氨酸酶)、人乳头状瘤病毒E6和E7碎片、全细胞或肿瘤细胞裂解液的部分和同种异体癌细胞。
2.肿瘤坏死因子-α
肿瘤坏死因子-α,即恶液素,是一种主要由活化巨噬细胞产生的多功能细胞因子。肿瘤坏死因子-α在体外有多种生物效应(Manogue and Cerami(1988)in“Cellular and Molecular Aspects ofInflammation),Eds.Poste and Crooke,Plenum Press,New York,pp.123-150;Chen and Goeddel(2002)Science 296:1634-1635;and Bodmeret al.(2002)Trends Biochem.Sci.27:19-26),包括杀死变异细胞(Carswell et al.,(1975)Proc.Natl.Acad.Sci.USA 72:3666-3670)、刺激粒细胞和纤维母细胞(Old(1985)Science 230:630-632);Vilchek et al.(1986)J.Exp.Med.163:632-643);Beutler and Cerami(1987)Nature316:552-554)、损坏内皮细胞(Sato et al,(1986)J.Natl.Cancer Inst.76:1113)和抗寄生作用(Taveme et al.(1984)Clin.Exp.Immunol.67:1-4)。在体内,它作为一种内源性调节物质在炎症、免疫和宿主防御功能方面起着重要的作用,它与人和鼠的很多病理状况有关,如败血性休克、恶病质、毛细血管漏综合征、器官内出血坏死等,它能够独立地或与其他因子联合影响不同机体功能的多血质。这些效应有些对宿主有益,有些则有害,有些是直接的,有些是由其他分泌因子介导的。TNF-α的生物效应是通过结合到特定的细胞表面受体来介导的。
TNF超家族成员在免疫系统的组织和功能方面起着重要的作用,它们有共用的结构基序,TNF同源性结构域(THD),能与TNF受体的半胱氨酸富含区(CRDs)相结合(Bodmer et al.(2002)TrendsBiochem.Sci.27:19-26.)。人和鼠的TNF-α的一级结构(Pennica et al.(1984)Nature 312:724-729);and Fransen et al.(1985)Nuc1.Acid.Res.13:4417-4429)以及两个不同的TNF受体(p55-TNF-R和p75-TNF-R)的一级结构是从克隆的cDNA的碱基序列推算出来的。两个受体不仅仅与TNF-α结合,还与TNF-β或淋巴毒素具有高度亲和性(Schoenfeld et al.(1991)J.Biol.Chem.266:3863-3869)。TNF-是淋巴细胞的相关产物,具有与TNF-α非常相似的多效性活性。TNF-α和TNF-β在氨基酸序列水平上有32%的同源性。X射线晶体结构分析显示两种分子的三级结构事实上是完全相同的,只是TNF-α三聚体的分子延伸不如TNF-β三聚体,后者顶端有个喇叭口(Eck et al.(1992)J.Biol.Chem.267:2119-2122)。
除了细胞受体的相互作用,TNF-α还有类似凝集素的性质,可以作为寡糖配体(Hession et al.(1987)Science 237:1479-1484);andSherblom et al.(1988)J.Biol.Chem.263:5418-5424)。这些也说明了TNF-α蛋白在细胞表面受体上至少有两个不同的结合位点,一个是类似凝集素的,另一个是直接在细胞表面的受体。
一些TNF-α突变体在与细胞的TNF受体p55和/或p75结合时受阻,所有的突变都位于有生物活性TNF-α三聚体的锥形结构下半部(Van Ostade et al.(1991)EMBO J.10:827-836;and Van Ostade et al.(1992)Nature 361:266-269;and EP-A-0 486 908)。
TNF-α是内毒素或感染性休克的基本调节物质(Cerami andBeutler(1988)Immunol.Today 9:28-31)。感染性休克是在严重的感染情况下发生的,尤其是伴随着革兰氏阴性菌和内毒素释放的菌血症。当然,它也能由任何微生物引起,包括革兰氏阳性菌、病毒、真菌、原生动物、螺旋体和立克次体。如果引起多器官功能衰竭和循环衰竭就会导致死亡,通过向动物静脉注射LPS(或内毒素)获得了感染性休克综合征的一些特征,即低血压、系统血管抵抗力降低、白细胞减少、血小板减少和组织损伤)
除了具有免疫调节能力外,TNF-α还与各种寄生虫的成长和分化的控制有关。在感染了宿主之后,寄生虫能够诱导不同的细胞因子(如TNF)的分泌,我们拿疟疾来做例子,TNF-α在特定的条件下是具有保护作用的,如抑制啮齿动物疟疾的存活(Clark et al.(1987)J.Immunol.139:3493-3496;and Taverne et al.(1987)Clin.Exp.Immunol.67:1-4),而如果过量的产生则对宿主是有害的,会导致一些疾病。
重组TNF增强了其在治疗肿瘤方面的作用,但是TNF-α在体内总是伴随着一些毒副作用,如低血压、肝功能异常、白细胞减少、寒战和血栓。目前已有多种克服这些毒副作用的方法,如利用单抗来中和TNF-α的毒性。
综上所述,虽然发现了有数千种有潜力的药物,但是癌症的治疗伴随着并发症和副作用,这使得肿瘤的治疗始终没有最佳的治疗方法。尽管在临床上有很多可用于肿瘤治疗的抗癌药物,人们还是期待着更加有效的抗癌药物。
发明内容
本发明所要解决的技术问题是公开人肿瘤坏死因子-α(hTNF-α)突变体在治疗与异常细胞增殖有关疾病药物中的应用。特别是治疗血液系统失调、癌症、恶性胸腔积水、恶性腹水、心脏瓣膜再狭窄和炎症疾病中的应用,该药物可单独或与其他药物联合应用。该药物避免了原型TNF治疗时所产生的系统毒性及其他副作用,具有更强的专一抗肿瘤活性,同时与其他抗肿瘤药物具有潜在的相互增效作用。
本发明公开的治疗与异常细胞增殖有关疾病的药物是指人肿瘤坏死因子α突变体,所述的hTNF-α突变体蛋白与原型TNF序列(见序列1)相比,其N-端1-7位氨基酸残基缺失,在156或1 57位氨基酸残基发生了替换,替换残基为Gln、Ser、Thr、Tyr和Asn中的一种,在8-10位氨基酸残基有一个或多个被Lys或Arg残基替代,此hTNF-α突变体具有序列2、3、4或5的氨基酸序列和序列10的DNA序列;或所述的hTNF-α突变体与原型hTNF-α(序列1)的氨基酸序列相比在N-端80、90、92位氨基酸残基发生了替换,具有序列6或7的氨基酸序列;或所述的hTNF-α突变体与原型hTNF-α(序列1)的氨基酸序列相比在N-端2位氨基酸残基发生了替换,具有序列8或9的氨基酸序列。
本发明所述的与异常细胞增殖有关疾病是指血液系统的失调、癌症、恶性胸腔积水、恶性腹水、心脏瓣膜再狭窄和炎症疾病。
血液系统失调包括血细胞的不正常生长,这可以导致血细胞的生长发育不良及血液系统的恶变,如各种类型的白血病。血液系统失调包括但不限于急性髓样白血病、急性早幼粒细胞白血病、急性淋巴细胞白血病、慢性骨髓性白血病、骨髓增生异常综合征、镰状细胞性贫血。
癌症的例子包括但不限于乳腺癌、皮肤癌、骨癌、前列腺癌、肝癌、肺癌、脑癌、喉癌、胆囊癌、胰腺癌、直肠癌、副甲状腺癌、甲状腺癌、基底细胞癌、神经组织瘤、头颈癌、结肠癌、胃癌、支气管癌、肾癌、溃烂型及乳头状的鳞状细胞癌、转移性皮肤癌、骨肉瘤、尤因肉瘤、骨髓瘤、巨细胞瘤、小细胞肺癌、胆石胰岛细胞瘤、原发性脑癌、急性及慢性淋巴及粒细胞瘤、毛细胞癌、腺瘤、超常增生、髓样癌、嗜铬细胞瘤、粘膜神经瘤、增生角膜神经瘤、肾母细胞瘤、精原细胞瘤、卵巢癌、子宫颈发育不良原位瘤、成神经细胞瘤、视网膜神经胶质瘤、软组织肉瘤、恶性类癌、局部皮肤病损、横纹肌肉瘤、卡波西肉瘤、恶性高钙血症、肾细胞瘤、腺癌、多形性胶质母细胞瘤、白血病、淋巴瘤、恶性黑素瘤、鳞状细胞癌及其他癌症。
其中肺癌,包括小细胞肺癌和非小细胞肺癌,如:鳞状癌、腺癌和大细胞癌;黑色素瘤或皮肤癌,特别是恶性黑色素瘤;淋巴瘤,包括霍奇金和非霍奇金淋巴瘤,特别是恶性淋巴瘤,尤其是非霍奇金淋巴瘤。
所述的恶性胸腔积液(在胸腔中的液体),是指由癌症或其他恶性疾病引起;恶性腹水(在腹腔中的液体),是指由癌症或其他恶性疾病如肝炎引起。
hTNF-α突变体蛋白可采用不同的途径给予病人服用,如口服的、不经肠道的、腹膜内的、静脉、动脉、经皮肤给药的、舌下、肌内的、直肠的、鼻内的、脂质体、吸入、阴道、局部传输系统(如通过导尿管或支架)、皮下、关节腔内的或鞘内给药。hTNF-α突变体蛋白还可以通过缓释剂型给药。
所述的hTNF-α突变体蛋白可通过局部给药,如瘤体内、腹膜内、通过隔离的肢体灌注、通过隔离的肺部灌注、隔离的肝部灌注、或膀胱内、动脉灌注。
首选的应用,hTNF-α突变体经静脉给药,每星期给药3-5天,给药剂量范围为0.1-100μg/m2,更好的给药剂量为0.5-50μg/m2,最佳的给药剂量为1-20μg/m2。首选的低于100μg/m2的给药剂量与临床上使用的重组原型hTNF-α的几mg/m2的剂量相比低很多,首选的一个治疗周期是3-4周。
还可选择给病人每天静脉注射hTNF-α突变体蛋白,每星期注射3-5天,较好的剂量为100,000-1,000,000单位/m2,更好的剂量为200,000-800,000单位/m2,最佳剂量为400,000-800,000单位/m2,首选的治疗周期为3-4周,hTNF-α的活性单位定义是根据Meager和Das的方法所确定的国际标准单位。Meager and Das(1994)J.Immuno.Methods 170:1-13.
还可选择每天经腹膜内注射hTNF-α突变体蛋白,每星期给药1-2天,优化的给药剂量为500,000-5,000,000单位,更好的给药剂量为1,000,000-3,000,000单位,最佳的给药剂量为2,000,000-3,000,000单位,优化的给药周期为2-3周。
作为一种选择,也可采用基因治疗的方法给予病人可以表达hTNF-α突变体的表达载体。例如,病毒载体或编码hTNF-α突变体的质粒,重组逆转录病毒、腺病毒、腺相关病毒、单纯疱疹病毒、痘病毒,哺乳动物细胞表达载体也可用于转导或转染病人细胞。
下面对本发明作进一步详细描述:
本发明提供了新的、改进的治疗肿瘤类疾病的药物组成及方法。特别是,本发明的hTNF-α突变体与原型hTNF-α比较,在N-端有氨基酸缺失和替换,同时,在C-端可以有氨基酸残基替换。与原型TNF相比,这些hTNF-α突变体在临床上给病人使用时毒性降低很多,而对肿瘤的选择性和特异性提高很多。重组原型TNF在临床使用时导致许多系统毒性,如低血压、肝功能异常、白血球减少、寒战及血栓,而这些突变体的应用能减少这些系统毒性并将副作用降到最低。此外,发明者的临床数据表明可能的配合剂及本发明的hTNF-α突变体与其他抗肿瘤药物的新的组合用于治疗某些类型的癌症患者能显著提高病人的响应率并减少病人对这些抗癌药物的抗性。另外,应用本发明的方法及药物组成进行治疗能够显著提高病人的生活质量,减少病人采用传统化疗方法治疗引起的疼痛及痛苦。
1.hTNF-α突变体及其使用方法
本发明一方面提供了一种治疗具有不正常分化细胞的患者的方法。具体讲,此方法包括:给病人服用一种hTNF-α突变体蛋白,该突变体与原型TNF(氨基酸序列见序列1)相比,其N-端1-7个氨基酸残基缺失。
本发明人发现了一种与原型TNF相比具有更高的抗肿瘤活性和更低的系统毒性的突变体。虽然不希望被在此提出的理论所限制,但发明者认为N-端前七个氨基酸残基的缺失有助于提高此突变体的抗肿瘤活性。
此hTNF-α突变体进一步在156或157位氨基酸残基发生了替换,替换的残基为Gln、Ser、Thr、Tyr和Asn中的一种。虽然不希望被在此提出的理论所限制,但发明者相信C-端最后两个氨基酸残基的替换可以减少此突变体的系统毒性。
此hTNF-α突变体进一步在8-10位氨基酸残基发生了一个或多个Lys或Arg替换,虽然不希望被在此提出的理论所限制,但发明者相信8-10位氨基酸残基被碱性氨基酸如Lys和Arg替换后可以提高此突变体的抗肿瘤活性。
此hTNF-α突变体具有的氨基酸序列为序列2、3、4或5。其中具有氨基酸序列为序列2、3的为hTNF-α突变体1(hTNFm1),具有氨基酸序列为序列4、5的为突变体2(hTNFm2)。突变体1或突变体2的氨基酸序列N-端可以包括也可以不包括甲硫氨酸残基。编码此hTNF-α突变体的DNA序列如序列10。
本发明提供的一种治疗具有不正常分化细胞的患者的方法,亦包括给病人服用一种hTNF-α突变体蛋白,此突变体与原型TNF(序列1)相比,在N-端80、90、92位发生了氨基酸残基替换,具有序列6或7的氨基酸序列为hTNF-α突变体3。突变体3的氨基酸序列在N-端可以包括也可以不包括一个甲硫氨酸。
本发明提供的一种治疗具有不正常分化细胞的患者的方法,还包括给具有不正常分化细胞的病人服用一种hTNF-α突变体蛋白,与原型hTNF-α(序列1)相比,此突变体在N-端第二个氨基酸残基发生了替换,具有序列8或9氨基酸序列为hTNF-α突变体4(hTNFm4)。突变体4的氨基酸序列在N-端可以包括也可以不包括一个甲硫氨酸。
值得注意的是,本发明中的hTNF-α突变体包括TNF前体形式和成熟的TNF形式。对于原型TNF,其前体形式是26kD的分子,而成熟的TNF是切去76个氨基酸前导序列(序列11)后形成的17kD的分子(157个氨基酸,序列1)。TNF前体形式是结合在膜上的,不能自由移动,而成熟的TNF不结合在膜上,能够自由移动。作为一种选择,前体形式中的76个氨基酸的前导序列可以除去和用其他前导序列替换以利于成熟TNF分子的分泌。有许多前导序列具有这种功能,如Gray等介绍的干扰素-γ前导序列。
本发明中hTNF-α突变体还可以在氨基酸残基上进行修饰以保持其抗肿瘤活性同时进一步降低其副作用,例如,每个TNF三聚体进行少于5个氨基酸残基的修饰仍能保持其天然的细胞生物学活性。hTNF-α突变体还可以用脂类修饰形成脂质体给病人服用减少副作用。
hTNF-α突变体可以修饰的位点包括N-端的氨基基团和分子上赖氨酸残基。当这些基团活化后就利于使一些化学基团如脂肪酸结合到TNF的结构上,脂肪酸修饰后的TNF增加了其脂溶性,因此利于提高形成脂质体的效率和稳定性。
例如,hTNF-α突变体可以在赖氨酸残基上或在N-端氨基酸残基上修饰。赖氨酰基的侧链可以成为脂肪酸结合到hTNF-α突变体上的一个位点。氨基残基的修饰包括脂肪酸,最好是碳链长度为8-14个碳原子的脂肪酸,经过这种修饰后的hTNF-α突变体与脂质体具有很高的结合效率,适宜的情况下可超过80%的结合率。
本发明中的hTNF-α突变体也可以与线性或分支多聚体结合来修饰。我们相信hTNF-α突变体与多聚体结合修饰后能够延长这种生物活性物质的体内循环周期,同时降低其免疫原性。
例如,如美国专利(专利号:No.4,179,337)中所说的PEG或类似的水溶性多聚烯基氧化物可用来修饰hTNF-α突变体。为了与多聚烯基氧化物结合,一个羟基基团需要转化为可以反应的功能基团,此过程通常称为活化,得到的产物称为活化的多聚烯基氧化物。其他没有抗原性的多聚物可以类似的进行活化。
活化后的多聚物与具有亲核功能基团的治疗药物反应。通常作为结合位点的一个亲核功能基团是赖氨酸的ε-氨基,自由的羧酸基团、适于活化的羰基基团、氧化的碳水化合物组分及巯基基团都可以作为结合位点。
同样,伞状分支的PAO或PEG多聚物(美国专利:No.6,114,906)也可以修饰hTNF-α突变体,它可以与蛋白质上的生物活性亲核试剂反应形成结合体。多聚物的结合位点决定于蛋白质上的的功能基团。例如,功能基团如果是琥铂酰亚胺琥珀酸盐或碳酸盐,它可以与赖氨酸上的ε-氨基反应。另外,功能基团如果是羧酸,它可以与具有生物学活性的亲核试剂的羟基基团反应形成以酯键连接的前药。具分支的多聚物也可以活化后与蛋白质上的主链或侧链氨基基团、巯基基团、羧酸基团、具反应性的羰基基团或其他类似基团结合。
本发明中hTNF-α突变体也可以用同位素标记,通过与hTNF-α受体结合而定位于靶细胞进行放射治疗,这就类似于同位素标记的抗体用于放射免疫治疗。将同位素结合到与特定类型的靶细胞具有亲和力或具有特异性的单克隆抗体上是最有效的放射免疫治疗方法。
类似于同位素标记单克隆抗体,同位素也可用于标记hTNF-α突变体(Hunter et al.(1962)Nature 194:495;and Hnatowich et al.(1983)Science 220:613.)。典型的例子是,抗体被同位素原子131I,90Y,212Bi,186Re,221At,99mTc及其混合物标记,同样,这些同位素也可用于标记hTNF-α突变体,此外,其他一些同位素也可用于标记HTNF-α突变体。
本发明中的hTNF-α突变体还可以通过基因治疗的方法给病人服用一种表达载体,该在病人体内表达hTNF-α突变体。例如,可用来编码hTNF-α突变体的病毒载体有重组逆转录病毒、腺病毒、腺相关病毒、单纯疱疹病毒及痘病毒,这些病毒载体都可以用于转导病人细胞。另外,编码hTNF-α突变体的哺乳动物DNA表达质粒也可作为裸露的DNA给病人服用后转染病人细胞。这些表达载体可以整合到体内,表达出膜结合的TNF前体,前体在体内进一步加工后释放出可溶性的hTNF-α突变体。
编码本发明的hTNF-α突变体的多核苷酸(序列10)可以通过重组技术克隆到载体后转化宿主细胞,从而表达融合蛋白。
通常,本发明的克隆载体或表达载体采用转导、转化或转染等遗传工程技术导入宿主细胞形成基因工程菌,载体可以是质粒、病毒粒子或噬菌体等。基因工程菌能够在经调整后适于激活启动子、选择转化子或扩增编码hTNF-α突变体的多核苷酸的传统营养培养基中生长。培养的温度、pH等条件类似于宿主细胞用于表达的条件,这些条件对于技术工人来说是显而易见的。
本发明提供了一种包含编码本发明的hTNF-α突变体的多核苷酸的重组载体,此重组载体在宿主细胞中作为一个表达载体能够表达hTNF-α突变体。宿主细胞包括但不限于哺乳动物细胞(如人、猴子、兔子等)、鱼、昆虫、植物、酵母和细菌。
编码hTNF-α突变体的多核苷酸的表达受合适的启动子控制。可以采用的启动子包括但不限于腺病毒启动子如腺病毒的主要后期启动子、异源启动子如细胞巨化病毒启动子、呼吸道合胞病毒启动子、可诱导启动子、金属硫蛋白启动子、热休克启动子、白蛋白启动子、ApoAI启动子、人球蛋白启动子、病毒胸苷激酶启动子如单纯疱疹病毒胸苷激酶启动子、反转录病毒LTRs(包括修饰的反转录病毒LTRs);β-肌动蛋白启动子、人生长激素启动子。控制编码hTNF-α突变体的启动子也可以是用于原型TNF的天然启动子。
本发明还提供了一种适于表达hTNF-α突变体的重组细胞。此重组细胞可以组成型的形式表达hTNF-α突变体,也可以在存在或缺少某种物质的诱导后表达hTNF-α突变体。重组细胞包括但不限于哺乳动物细胞(如人、猴子、老鼠、兔子等)、鱼、昆虫、植物、酵母和细菌。
2.与hTNF-α突变体合用的抗癌药物
本发明的组合物包括一种hTNF-α突变体蛋白、一种非hTNF-α突变体,和一种药物赋形剂,组合物最好在治疗某种疾病上具有协同作用。当采用联合治疗比单独采用其中任何一种药物治疗获得了更好的治疗结果时,就说明几种药物起到了协同作用。具有协同作用的联合治疗的一个益处就是降低其中一种药物的剂量或同时降低几种药物的剂量,或者采用此种方法治疗能够获得较高的治疗指数同时减少毒性副作用。
许多抗肿瘤药物可以与本发明中的hTNF-α突变体(重组hTNF-α突变体1-4)联合使用来治疗各种类型的具有不正常分化细胞的疾病,如癌症。能够与hTNF-α突变体联合使用的抗肿瘤药物种类决定于需要治疗的肿瘤类型。
烷基化试剂是一类能够将氢离子替换为烷基基团的多功能复合物。烷基化试剂包括但不限于二氯乙胺类(氮芥,如苯丁酸氮芥,环磷酰胺,异环磷酰胺,甲氧氮芥,左旋溶肉瘤素,尿嘧啶氮芥),环乙亚胺类(如塞替派),烷基炔硫酸盐类(如白消安),亚硝基脲(如:卡莫司汀,洛莫司汀,链佐星,),非典型烷基化试剂(六甲蜜胺、达卡巴嗪、丙卡巴肼),铂类化合物(卡铂和顺铂)。这些化合物与磷酸盐、氨基、羟基、硫氢基,羧基和咪唑基发生反应。在生理条件下,这些化合物离子化形成带正电的离子,然后结合到敏感的核酸或蛋白质上,导致细胞循环周期中止而引起细胞凋亡,因为烷基化试剂发挥作用与细胞循环周期的特定阶段无关,因此他们属于细胞周期非特异性试剂。氮芥和烷基炔硫酸盐类对G1期和M期的细胞最有效。亚硝基脲、氮芥和环乙亚胺类减少细胞从G1期和S期进入M期。Chabnerand Collins eds.(1990)“Cancer Chemotherapy:Principles and Practice”,Philadelphia:JB Lippincott.
有些抗肿瘤药物就属于烷基化试剂,烷基化试剂包括但不限于二氯乙胺类(氮芥,如苯丁酸氮芥,环磷酰胺,异环磷酰胺,甲氧氮芥,左旋溶肉瘤素,尿嘧啶氮芥),环乙亚胺类(如塞替派),烷基炔硫酸盐类(如白消安),亚硝基脲(如:卡莫司汀,洛莫司汀,链佐星,),非典型烷基化试剂(六甲蜜胺、达卡巴嗪、丙卡巴肼),铂类化合物(卡铂和顺铂)。这些化合物与磷酸盐、氨基、羟基、硫氢基,羧基和咪唑基发生反应。在生理条件下,这些化合物离子化形成带正电的离子,然后结合到敏感的核酸或蛋白质上,导致细胞循环周期中止而引起细胞凋亡。这些烷基化试剂与本发明的HTNF-α突变体联合用于癌症的治疗具有协同效果,同时能够减少这些化疗药物治疗时产生的副作用。
有些抗肿瘤药物属于抗生素类试剂。抗生素类是一组天然产物经修饰后获得的抗肿瘤药物,其生产类似于抗生素的生产。抗生素类试剂包括但不限于蒽环霉素(如多柔比星、柔红霉素、表柔比星、伊达比星和anthracenedione),丝裂霉素C,博来霉素,放线菌素D,plicatomycin。这些抗生素类试剂通过作用于胞内不同的组分而干扰细胞的生长。例如,DNA拓扑异构酶II能够使DNA链解链,而恩环霉素能够干扰处于转录活性DNA区域的拓扑异构酶II的作用。博来霉素通常能够鳌合离子形成一种激活复合物,此复合物结合到碱基上引起DNA链断裂,导致细胞死亡。这些抗生素类试剂与本发明的HTNF-α突变体联合用于癌症的治疗具有协同效果,同时能够减少这些化疗药物治疗时产生的副作用。
有些抗肿瘤药物属于抗代谢物,抗代谢物是一组能够干扰肿瘤细胞生理和分化关键代谢过程的药物。活跃分化的肿瘤细胞需要持续的合成大量的核酸、蛋白质、脂类及其他重要的胞内组分。许多抗代谢物能够抑制嘌呤或嘧啶核苷的合成或者抑制DNA复制所需要的酶类。有些抗代谢物也干扰核糖核苷、RNA、氨基酸代谢及蛋白质的合成。通过干扰胞内重要组分的合成,抗代谢物能够延缓或阻止肿瘤细胞的生长。抗代谢物包括但不限于5-氟尿嘧啶(5-FU),氮尿苷(5-FUdR),氨甲蝶呤、亚叶酸、羟基脲、硫鸟嘌呤(6-TG)、6-巯基嘌呤(6-MP)、阿糖胞苷、喷司他丁、氟达拉滨磷酸盐、克拉屈滨(2-CDA)、天冬酰胺酶、吉西他滨。这些抗代谢物与本发明的hTNF-α突变体联合用于癌症的治疗具有协同效果,同时能够减少这些化疗药物治疗时产生的副作用。
有些抗肿瘤药物属于植物衍生物。植物衍生物是一组来源于植物或者在分子结构上进行了修饰的药物。植物衍生物包括但不限于以下种类,长春花碱(如:长春新碱、长春碱、长春地辛、长春利定和长春瑞滨),水溶性或不可溶的喜树碱(如20(S)-喜树碱,9-硝基喜树碱、9-氨基喜树碱、拓扑替康),鬼臼毒素(依托泊苷(Vp-16)、替尼泊苷(VM-26)),紫杉烷类(紫杉醇和多西他赛)。这些植物衍生物通常作为抗有丝分裂剂结合到微管蛋白上而抑制有丝分裂。在转录过程中,核酶DNA拓扑异构酶I负责使超螺旋的DNA双链松弛,通过在DAN双链中的一条链产生切口,使另一条链能够从切口绕过,喜树碱是此酶的有效的抑制剂,拓扑异构酶I弥补切口使复制得以发生。抑制拓扑异构酶I导致形成稳定的DNA拓扑异构酶复合物,并最终形成不可弥补的双链DAN缺口,从而导致细胞凋亡或其他形式的细胞死亡。鬼臼毒素通过影响使DNA解链的拓扑异构酶Ⅱ而干扰DNA的合成。这些植物衍生物与本发明的hTNF-α突变体联合用于癌症的治疗具有协同效果,同时能够减少这些化疗药物治疗时产生的副作用。
有些抗肿瘤药物属于生物制剂。生物制剂是一类单独使用或与化疗、放疗合用时能够引起肿瘤衰退的生物分子。生物制剂包括但不限于以下种类,免疫调节蛋白(如细胞因子,抗肿瘤抗原的单克隆抗体),肿瘤抑制子基因,肿瘤疫苗。这些生物制剂与本发明的hTNF-α突变体联合用于癌症的治疗具有协同效果,同时能够减少这些生物药物治疗时产生的副作用。
细胞因子具有很重要的免疫调节活性。某些细胞因子如IL-2和干扰素α已证实具有抗肿瘤活性,并且已经被批准用于治疗转移性肾细胞癌和转移性恶性黑色素瘤。IL-2是一种T-细胞生长因子,其对于T-细胞介导的免疫反应具有重要作用。IL-2对某些病人的选择性抗肿瘤作用据信是由于细胞介导的免疫反应能够区分自我和非我的结果。能够与本发明的HTNF-α突变体合用的白细胞介素包括但不限于IL-2、IL-4和IL-12。
干扰素α的亚型超过23种,都具有交叉的活性,所有的干扰素亚型都在本发明的范围之内。干扰素一α证实具有对抗多种实体瘤及血液系恶性疾病的活性,血液系统的恶性疾病对它特别敏感。能够与本发明的TNP-α突变体合用的干扰素包括但不限于干扰素α,干扰素β(纤维原细胞干扰素)和干扰素γ(纤维原细胞干扰素)。
其他可以与本发明的TNF-α突变体合用的细胞因子包括那些对造血作用和免疫功能有重要作用的细胞因子。这些细胞因子包括但不限于促红细胞生成素、粒细胞集落刺激因子(filgrastin))、粒细胞巨噬细胞集落刺激因子(sargramostim)。这些细胞因子可以与本发明的hTNF-α突变体合用以减少化疗引起的对髓细胞生成的毒性。
非细胞因子的免疫调节剂也可以与本发明的hTNF-α突变体合用以抑制不正常细胞的生长。免疫调节剂包括但不限于细菌Calmette-Guerin、左旋咪唑、奥曲肽(一种能够模拟天然产生的生长激素抑制素的效果的具长期作用的八肽)。
本发明的hTNF-α突变体还可以与TNF超家族的其他成员合用,这些物质包括但不限于原型hTNF-α、TNF-β、LT-β、OPGL、Fas配体(FasL)、TRAIL、CD27配体(CD27L)、CD30配体(CD30L)、CD40配体(CD40L)、4-1BB配体(4-1BBL)、DcR3,OX40L,TNF-γ(WO 96/14328),AIM-I(WO 97/33899),endokine-(WO 98/07880)、OPG、neutrokine-a(WO 98/18921)、OX40、神经生长因子(NGF)。
抗肿瘤抗原单克隆抗体是能够抗肿瘤表达的抗原的抗体,最好是肿瘤的特异性抗原。如单克隆抗体HERCEPTIN(Trastruzumab)用来抗人表皮生长因子受体2(HER2),这种物质在某些乳腺肿瘤包括转移性乳腺肿瘤中过量表达。HER2的过量表达与临床中的许多侵略性疾病及较差的预后相关联。HERCEPTIN作为单一药物用于治疗那些体内肿瘤过量表达HER2蛋白的转移性乳腺癌病人。本发明的hTNF-α突变体与HERCEPTIN合用治疗肿瘤具有协同作用,尤其是对转移性肿瘤。
另一个抗肿瘤抗原单克隆抗体是RITUXAN(Rituximab),它能够抗淋巴瘤细胞上的CD20,能够选择性的消除正常的和CD20+的前B细胞及成熟B细胞。RITUXAN作为单一药物用于治疗复发或难控制的低级或卵泡状CD20+B细胞非霍奇金淋巴瘤病人。本发明的hTNF-α突变体与RITUXAN合用不仅对于淋巴瘤而且对于其它类型的恶性肿瘤具有协同治疗作用。
肿瘤抑制子基因是一类具有抑制细胞生长分裂循环从而阻止肿瘤形成发展功能的试剂。肿瘤抑制子基因的突变引起细胞忽略一种或多种抑制信号网络中的组分,克服细胞循环的关键点从而导致较高的细胞生长速率,即癌症。肿瘤抑制子基因包括但不限于DPC-4,NF-1,NF-2,RB,p53,WT1,BRCA1、BRCA2。在体内给予肿瘤抑制子治疗(如经基因治疗)的同时可以合用本发明的hTNF-α突变体来治疗各种类型的癌症。
本发明的hTNF-α突变体与左旋溶肉瘤素合用治疗各种类型的癌症,最好是黑色素瘤和原发性肢体肉瘤。hTNF-α突变体和左旋溶肉瘤素可以再和干扰素-α及/或温热疗法联合治疗癌症。
本发明的hTNF-α突变体与阿霉素合用治疗各种类型的癌症,最好是恶性淋巴瘤。hTNF-α突变体与阿霉素可再和博来霉素、长春新碱及/或二甲基-三氮烯-咪唑羧酰胺合用治疗癌症。
本发明的hTNF-α突变体与RITUXAN(Rituximab)合用治疗各种类型的癌症,较好的是恶性淋巴瘤,最好是非霍奇金淋巴瘤。hTNF-α突变体与Rituximab可再和其它抗肿瘤药合用治疗癌症。
本发明的hTNF-α突变体与环磷酰胺合用治疗各种类型的癌症,较好的是恶性淋巴瘤。hTNF-α突变体与环磷酰胺可再和阿霉素、博来霉素、长春新碱、强的松合用治疗肿瘤。
本发明的HTNF-α突变体与丝裂霉素-C合用治疗各种类型的肿瘤,较好的是非小细胞肺癌,hTNF-α突变体与丝裂霉素-C可再和长春地辛(Desacetyl vinblastine amide)、顺铂合用治疗肿瘤。
本发明的hTNF-α突变体与长春瑞滨合用治疗各种类型的肿瘤,较好的是非小细胞肺癌,hTNF-α突变体与长春瑞滨可再和顺铂合用治疗肿瘤。
本发明的hTNF-α突变体与紫杉烷类(如紫杉醇和多西他赛)或它们的衍生物和类似物合用治疗各种类型的肿瘤,较好的是卵巢癌和乳腺癌,hTNF-α突变体与紫杉烷类可再和其它抗肿瘤药物合用治疗肿瘤。
本发明的hTNF-α突变体与甲磺酸伊马替尼(或GLEEVAC)合用治疗各种类型的肿瘤,较好的是白血病、胃肠道基质瘤和小细胞肺癌(SCLC),hTNF-α突变体与甲磺酸伊马替尼可再和顺铂合用治疗肿瘤。
3.单用hTNF-α突变体或与其它抗肿瘤药物合用进行治疗的适应症
使用本发明的组分进行治疗的较好的适应症包括那些不希望的或不受控制的细胞分化。那些适应症包括良性肿瘤、各种类型的癌症如原发性和转移性肿瘤、血液系统失调(如白血病、骨髓增生异常综合征和镰状细胞血症),再狭窄(如冠脉、颈动脉和脑部损害),内皮细胞的异常刺激(如动脉硬化症),由于外科手术、伤口愈合异常、异常血管生成造成的机体组织损伤,产生组织纤维化、反复的运动失调导致的疾病,器官移植产生的非高度血管化及增生响应的组织失调。
通常,良性肿瘤细胞保留其差异性特征,而且并不以完全不受控制的方式分裂,良性肿瘤通常是固定位置和非转移性的,能够用本发明治疗的特殊类型的良性肿瘤包括血管瘤、肝细胞腺瘤、空洞性血管瘤、灶性结节状增生、听神经瘤、纤维神经瘤、胆管腺瘤、胆管cystanoma、纤维瘤、脂肪瘤、平滑肌瘤、间皮瘤、畸胎瘤、粘液瘤、结节再生性增生、沙眼化脓性肉芽瘤。
肿瘤细胞变得无差异性,对体内的生长控制信号不再响应、同时以不受控制的方式扩增。恶性肿瘤具有进攻性,能够扩散到远处,即转移。恶性肿瘤通常分为两种类型:原发性的和继发性的。原发性肿瘤直接出现在他们被发现的组织。继发性肿瘤或转移性肿瘤可以来源于体内的任何部位,单目前已经扩散到远处的器官。通常的转移路线是直接生长到临近的组织结构中、通过血管或淋巴系统扩散和沿着组织表面和机体间隙(腹膜液、脑脊髓液等)跟踪扩散。
使用本发明能够治疗的特定种类的癌症或转移性肿瘤,不管是原发性的还是继发性的,包括白血病、乳腺癌、皮肤癌、骨癌、前列腺癌、肝癌、肺癌、脑癌、喉癌、胆囊癌、胰腺癌、直肠癌、副甲状腺癌、甲状腺癌、肾上腺癌、神经组织癌、头颈癌、结肠癌、胃癌、支气管癌、肾癌、基底细胞癌、溃烂型和乳头状鳞状细胞癌、转移性皮肤癌、骨肉瘤、Ewing肉瘤、veticulum细胞瘤、骨髓瘤、巨细胞瘤、小细胞肺癌、胆石胰岛细胞瘤、原发性脑癌、急性及慢性淋巴及粒细胞瘤、毛细胞癌、腺瘤、超常增生、髓样癌、嗜铬细胞瘤、粘膜神经瘤、增生角膜神经瘤、肾母细胞瘤、精原细胞瘤、卵巢癌、子宫颈发育不良原位瘤、成神经细胞瘤、视网膜神经胶质瘤、软组织肉瘤、恶性类癌、局部皮肤病损、横纹肌肉瘤、卡波西肉瘤、恶性高钙血症、肾细胞瘤、腺癌、多形性胶质母细胞瘤、白血病、淋巴瘤、恶性黑素瘤、鳞状细胞癌及其他癌症。
本发明的hTNF-α突变体单独或与其他抗肿瘤药物合用治疗肺癌,较好的是非小细胞肺癌。在美国,肺癌在男女癌症患者中的死亡率都是第一的。而且它的发病率排在第三位,仅次于前列腺癌和乳腺癌,但是更多的美国人死于肺癌而不是前列腺癌、乳腺癌和结直肠癌,因为其治愈率只有14%。(Parker et al.(1997)Cancer J.Clin.47:5-27.)
四种主要的细胞类型占了所有原发性肺癌的95%,这四种类型是:小细胞肺癌、鳞状细胞癌、腺癌(包括支气管)、大细胞(无差异化的)癌。后三种细胞类型经常集结成堆,被称为非小细胞肺癌。
鳞状细胞癌曾经是所有肺癌中发病最频繁的,鳞状细胞癌最频繁的出现在临近部分的支气管,首先是鳞状上皮化生,随着进一步生长,鳞状癌侵入基底膜并扩展到支气管腔中,产生障碍导致肺膨胀不全或肺炎。
腺癌已经成为北美最普遍的肺癌,占所有肺癌病例的35-40%。此类肿瘤起源于肺泡表面的上皮细胞或支气管粘液腺,大部分肿瘤就在起源位置周围。它们也能产生于周围的疤痕瘤。因为腺癌具有早期转移的倾向,因此在手术阶段它比鳞状细胞癌的预后更差。
大细胞癌是所有非小细胞肺癌中最少的,在所有肺癌病例中只有15%,大部分肿瘤都位于外围而且其预后类似于腺癌。
小细胞肺癌在生物学方面及临床方面都与非小细胞肺癌不同,在生物学方面,小细胞肺癌具有神经内分泌特征。这些特征导致频繁的分泌物和神经癌旁综合症。小细胞肺癌还具有更快的生长速度和更大的早期转移扩散的倾向。小细胞肺癌在各种类型的肺癌中是最具有侵略性的,从诊断发现开始不经过治疗其中位存活期只有2-4个月。
本发明的hTNF-α突变体单独使用或与其它抗肿瘤药物合用治疗恶性淋巴瘤,包括霍奇金和非霍奇金淋巴瘤。
在病理上,霍奇金的特征是存在具有突出的核仁的不正常的大细胞(里-施细胞或单核突变体)。然而,大部分肿瘤细胞是由表现正常的感染性细胞组成的混合物。霍奇金疾病可以分为几个组织学亚型。受到广泛认可的Rye分类将其分为四类:淋巴细胞主导的、小节硬化症、混合多孔性和淋巴细胞衰竭。精确的阶段划分对于制定霍奇金疾病的治疗计划是至关重要的,因此针对疾病的位置及范围需要采取不同的治疗方法。
非霍奇金淋巴瘤是变化较多的肿瘤,其共同起源是淋巴细胞。他们通常起源或存在于淋巴组织,如淋巴结、脾、骨髓或Waldeyer环,但是几乎在任何组织中都可发现他们。(Rosenberg SA(1993)“Non-Hodgkin′s lymphomas”,In Medical Oncology,second edition(Calabresi and Schein,eds.),San Francisco:McGraw-Hill,Inc.,417-33.),淋巴瘤的瘤谱很广,从具有最快扩展并致命的肿瘤到最懒惰能很好耐受并延长稳定性且在某些情况下能自发消退的肿瘤都存在。在美国,每年大约35000个新增肿瘤病人中有一个会发展,大约一半死于肿瘤。
由于非霍奇金淋巴瘤的多样性,人们试着去建立一个统一的病理分类系统。基于病理亚型和存活的相关性,非霍奇金淋巴瘤分为三个主要级别:低级、中级和高级,在不治疗的情况下,低级具有最长的存活期,高级具有最短的存活期。淋巴腺增大的慢性淋巴性白血病属于低级非霍奇金淋巴瘤。低级淋巴瘤病人的中位存活期是6.2年,转化为更具侵略性细胞类型的发生率大约是30%。
任何级别的非霍奇金淋巴瘤复发感染的预后都很差,即使是初次治疗获得了完全响应的病人,仍有一部分具有很高的复发几率并有很差的完全预后。
本发明的hTNF-α突变体单独或与其他抗肿瘤药物合用治疗黑色素瘤,包括恶性黑色素瘤、黑素瘤皮肤癌、影响皮肤的黑色素瘤,较好的是恶性黑色素瘤。
人类肿瘤中最频繁的就是皮肤肿瘤。非黑色素瘤主要是鳞状细胞和基底细胞瘤,这些肿瘤进展缓慢,通常可以早期识别并采用局部治疗方法治愈。黑色素瘤是较少见但更具侵略性的皮肤肿瘤,随着区域性及向远处扩展,他们具有相当大的致死潜力。黑色素瘤的致死病例增加速度已经超过了其他实体瘤,而且黑色素瘤比基底或鳞状细胞癌更容易转移到身体的其他部位。
血液学紊乱疾病包括血细胞的不正常生长,这会导致血细胞发育异常和血液系统恶变,如各种白血病。有急性骨髓性胞白血病、急性早幼粒细胞白血病、急性淋巴细胞白血病、慢性骨髓性白血病、骨髓发育异常综合症和镰刀型贫血等例子,还有其他疾病。
急性粒细胞白血病(AML)是成年人患急性白血病中最常见的一种。一些遗传病和免疫缺陷也引发AML。这些由于DNA稳定性缺陷引发的疾病,如范可尼氏贫血、Li-Fraumeni亲缘病、共济失调性毛细血管扩张和X染色体相关的丙球蛋白贫乏症等,会导致染色体的随机断裂。
急性原粒细胞白血病(APML)是一类特征明显的AML亚类。它的特征是含有15-17号染色体置换的原粒细胞质体。这种染色体置换会引起类维生素A酸受体的融合转录,导致APML。
急性淋巴性白血病(ALL)这类血液学紊乱疾病有各种明显的亚型临床症状。细胞遗传异常在此种病中不断发生,最常见的是9-22染色体置换,合成产生费城染色体,病人预后很糟糕。
慢性骨髓性白血病(CML)是骨髓干细胞增殖紊乱疾病。CML的特点是包括9号和22号染色体特定位置异常,产生费城染色体。常用放疗。
骨髓发育异常综合症(MDS)是由于造血干细胞及其分化细胞包括骨髓、类红细胞和单核细胞发育异常造成多种疾病并发。三种细胞中的一种或几种数量减少。MDS患者通常有贫血、嗜中性白血球减少症(感染)或者血小板减少症(出血)。一般10-70%的病人发展成为急性白血病。
异常细胞增殖可以用多种手术方法治疗,如关节手术、肠手术和瘢痕瘤手术等。那些产生纤维组织的疾病包括肺气肿、重复性颤动疾病包括腕骨隧道综合症也可以用本最新发明治疗。这个发明治疗细胞增殖紊乱疾病的另一个例子是骨瘤。
因为器官移植产生的细胞增殖包括那些可能产生排异反应的增殖可以用此发明治疗。特别是那些心脏、肺、肝脏、肾脏和其他器官或者器官系统移植手术引起的细胞增殖。
很多异常血管增生如,那些伴随风湿性关节炎、脑部水肿和损伤导致局部缺血-重灌流、大脑皮层缺血的血管增生、卵巢增生和血管肥大症(囊性卵巢综合症)、子宫内膜异位症、牛皮癣、糖尿病引发的视网膜病变及其他视血管增生疾病如早发性视网膜病(晶状体纤维化异常)斑状体变性、角膜移植排异、新血管化青光眼、Oster Webber综合症等等也适用本发明治疗。
异常血管增生相关疾病需要或引起血管生长。例如,角膜血管增生有三个阶段:血管形成前,新血管形成和血管成熟及老化。已经确认参与各种血管增生机制的有包括炎症反应中的一些参与者如白细胞、血小板、细胞因子和类花生酸。还有一些因子有待确证。
此发明的又一个应用提供了一个治疗有关不必要和异常的血管增生疾病的方法。给这类患者施用hTNF-α的突变蛋白单剂或者和其他抗血管增生药品的联合使用。
用于抑制血管增生和/或血管增生性疾病的这些药剂的剂量需要依据病情的严重程度、给药途径和其他由医生认为的有关情况来确定。一般而言,可接受的每日有效剂量足够抑制血管增生和/或血管增生性疾病。
在这个应用中,此发明可用于治疗类似视网膜/脉络膜新血管化和角膜新血管化等非良性血管增生。视网膜/脉络膜新血管化疾病包括Bests病、近视眼、视觉凹陷、Stargarts病、变形性骨炎、静脉闭塞、动脉闭塞、镰刀型贫血、类肉瘤、梅毒、弹力纤维性假黄瘤、颈动脉阻塞病、慢性葡萄膜炎/病毒、分枝菌感染、莱姆关节炎、全身性红斑狼疮、早发性视网膜病、Eales病、糖尿病性视网膜病、斑状体病变、Bechets病、导致视网膜炎或脉络膜炎的感染、假性眼网状内皮细胞真菌病、部分睫状体平坦部炎、慢性视网膜剥落、高粘综合症、弓浆虫病、外伤和激光治疗后并发症、有关rubesis的疾病(角的新血管化)、由纤维组织或含纤维组织增生包括一切形式的玻璃体视网膜增生病变导致的疾病。角膜新血管化疾病有流行性角膜炎、维他命A缺乏症、过度佩戴隐形眼睛导致疾病、遗传性过敏性角膜炎、外缘角膜炎、翼状胬肉角膜炎、干燥症、酒糟鼻、phylectenulosis、糖尿病性视网膜病、早发性视网膜病、角膜移植排异、Mooren溃疡、Terrien’s病、边缘角蛋白溶解、多动脉炎、Wegener肉状瘤、巩膜炎、periphigoid放射性角膜炎、新血管化青光眼、晶状体后纤维增生、梅毒、分枝菌感染、脂质体恶变、化学损伤、细菌性溃疡、真菌性溃疡、单一性疱疹感染、带状疱疹感染、原生动物感染和Kaposi瘤。
此发明还可用于治疗与异常血管增生相关的慢性炎症。方法是对此类疾病患者施用本品和DNA甲基化抑制因子、组蛋白去乙酰基转移酶抑制剂。慢性炎症需要毛细血管的不断生长维持炎症细胞的血液供应。炎症细胞在血液营养下产生肉芽并保持炎症状态。用这个疗法可以防止肉芽的形成,从而减轻症状。这类慢性炎症包括肠炎如局限性肠炎和溃疡性结肠炎、牛皮癣、结节病和风湿性关节炎。
肠炎如局限性肠炎和溃疡性结肠炎特征是肠胃道多处发炎和血管增生。比如局限性肠炎是慢性的透壁性的炎症,常发生在回肠和结肠,但也可以在口腔到肛门及周围的任何部位发病。局限性肠炎患者一般有慢性腹泻伴有腹痛、发烧、厌食、体重减轻和腹胀。溃疡性结肠炎也是慢性非特异的炎症和溃疡病,好发于结肠黏膜,病患有血性腹泻的特征。肠胃道中,由新生长的毛细血管包围一团炎症细胞形成的肉芽肿,它的发炎导致了多数的肠炎疾病。此发明和血管增生抑制因子的合剂可以防止肉芽的形成和血管的生长。肠炎疾病也会导致其他肠道问题如表皮的损伤。这种损伤可以在肠胃道的其他地方产生。疗法中,本品抑制血管增生可以减少炎症细胞的血液供应,防止损伤形成。
另外一种慢性炎症疾病---结节病,特征是多系统的肉芽肿病。这种病的肉芽肿会在身体的任何地方形成,所以症状要看发病的部位。肉芽肿是增生的毛细血管包围的炎症细胞。用本品抑制血管增生可以压制肉芽肿生长。
牛皮癣也是一种慢性复发性炎症疾病,患者身上有各种大小的丘疹斑块。用本品可以防止新的血管在这些丘疹附近形成,缓解症状。风湿性关节炎(RA)是在外周关节发病的非特异性慢性炎症。先认为是关节内侧的润滑膜里的血管发生了增生,形成了新的血管网络,内皮细胞释放的因子和活性氧自由基导致关节翳生长和软骨的破坏。血管增生相关因子积极参与并维持了风湿性关节炎的慢性炎症过程。单独使用本品或者与抗RA药剂联用可以防止维持炎症的新血管的形成,抗RA药品还可以缓解病痛。
在这个应用中,本发明hTNF-α变异蛋白可用于治疗多种与失控血管增生如视网膜/脉络膜新血管化和角膜新血管化有关疾病。
本发明TNF-α变异蛋白还可以和其他抗血管生长药品联用,以抑制不必须和不受控的血管增殖。抗血管增殖的药品有,类维生素A酸及其衍生物、2-甲氧基雌二醇、ANGIOSTATINTM蛋白、ENDOSTATINTM蛋白、苏拉明、角鲨胺、组织抑制因子金属蛋白酶-1、血纤维蛋白酶原激活剂抑制因子-2、软骨源抑制因子、紫杉醇、血小板因子4、硫酸鱼精蛋白、硫酸甲壳素衍生物(来源于雪花蟹甲壳)、硫酸多聚糖肽聚酶复合物(sp-pg)、星形孢菌素。还有机体代谢调节因子如脯氨酸类似物(1-氮环丁烷-2-羧基酸(LACA))、顺羟脯氨酸、d,1-3,4-去羟脯氨酸、硫氨脯氨酸、α,α-双吡啶、β-氨基丙酸腈延胡索酸盐、4-丙基-5-(4-吡啶基)-2(3h)-唑酮、甲氧喋呤、米托蒽醌、β-环糊精十四硫酸盐、eponemycin、烟曲霉素、硫代苹果酸金钠、d-青霉胺(CDPT)、β-1-抗胶原酶-血清、α-2-抗纤溶酶、比生群、氯苯扎利二钠盐、n-(2-苯甲酸基)-4-氯蒽酮酸二钠盐又称“CCA”、反应停、制管张素胆固醇、cargboxynaminolmidazole、金属蛋白酶抑制剂如BB94。其他抗血管增生药剂包括抗体、专门抗血管生长因子(bFGF、aFGF、FGF-5、VEGF同功酶、VEGF-C、HGF/SF和Ang-1/Ang-2)的单克隆抗体。见Ferrara N和Alitalo K的“血管生长因子及其抑制剂的临床应用”(1999 Nature Medicine 5:1359-1364)
4.给药途径和剂量
将本发明应用于治疗有很多种给药方法和途径。
本发明-hTNF-α可以用在合剂中。例如包括了常用的药用赋形剂和其他药用非活性物质和活性成分。这些活性成分甚至可以包括本发明中另一种hTNF-α突变体。最好的方法是在合剂中加入足够有效量的hTNF-α以得到满意的治疗效果。
本发明的hTNF-α突变蛋白可以通过非肠道、腹膜内、静脉内、动脉内、经皮内、舌下、肌肉内、直肠、口腔、鼻内、脂质体包裹、吸入、阴道、眼、局部给药(如导尿管或者支架)、皮下、脂肪组织、关节内、胸内等等多种方式单独或者同时给药。
hTNF-α突变蛋白给药途径多样,而且可以以任何制剂形式单独或者同时给药。本文中,同时给药的意思是指同时1种以上的药品治疗以取得更好的临床疗效。这种“同时”可以引申为给药时间段的重叠。例如,其他抗肿瘤药品前、同时或者后服用本发明的hTNF-α。
根据需要在指定部位得到一定的细胞毒性和抑制细胞生长的效果,与本片联合使用的药品的剂量可以变化。好的做法是总量小于TNF-α突变体和其他药品的最大耐受剂量的总和,最好也小于所有这些抗肿瘤药品的单个最大剂量。
对于缓释制剂而言,缓释时间各有不同,但尽量在1小时到6个月之间,最好是在1周至4周。配方依医嘱和病情而定,先讨论到这里。
在使用hTNF-α突变蛋白治疗前,病人可能已经经过了其他抗癌药物治疗。由于化疗导致细胞凋亡的效果,hTNF-α突变蛋白的用量应比单用hTNF-α突变蛋白治疗的用量低一些,这样可以获得疗效的同时减少其副作用。
本发明中的hTNF-α突变蛋白也可制成试剂盒。试剂盒的组成安排也应该很讲究,要包括盛放hTNF-α突变蛋白的容器和/或其他给药所需的器械。
试剂盒还可以带上指导手册。如果hTNF-α突变蛋白是以粉剂提供的,手册应介绍如何溶入输液制成药剂,怎样给病人用。还可以介绍此发明的其他给药方法。
配制好的治疗剂应装在容器或者试剂盒里提供,应可直接给药或者是需要稀释的浓缩液。如本发明里提到的治疗剂可以直接用于输液或者注射。
专业人员可以按本发明用途将其制成化合物、混合剂、试剂盒等。因此本专利已经覆盖了有关其疗效的所有改型和变种,见附加声明和同等专利。
具体实施方式
实施例1
rhTNFm1的表达和纯化
重组人TNF-α突变体1是在E.coli中表达,经纯化得到。简述如下:E.coli株HMS174,含编码rhTNFm1的质粒,在LB(Amp)中30℃培养至OD600 0.4。LB培养液1%接种到装有TH培养基的发酵罐中,30℃培养到OD600至0.4。发酵中保持pH6.8-7.0,溶氧30%以上。
发酵结束后,离心收集菌体,在冷TSE(0.1M Tris,0.2M NaCl,and 0.05M EDTA at pH 7.2)缓冲液里超声粉碎,离心取上清。加入固体硫酸铵分级沉淀。蛋白质沉淀用19mM Tris·HCl溶解并透析。离子交换层析纯化溶液中的rhTNFm1。在纯化好的rhTNFm1中加入终浓度1%的白蛋白。经国际标准方法(见Meager and Das(1994)J.Immuno.Methods 170:1-13)测定活性后,按>500000 IU/安瓿瓶分装。
实施例2
用rhTNFm1临床治疗恶性肿瘤
上述制备的重组rhTNFm1可以临床上可以治疗多种恶性肿瘤,包括恶性淋巴瘤、肺癌、恶性黑色素瘤、乳腺癌、肝癌、肾癌、结肠癌、胸腹积水、
(1)病人选择
临床试验共评价了310位病人,其中169人恶性胸腹水,141人为恶性淋巴癌、肺癌、恶性黑色素瘤、乳腺癌、肝癌、肾癌、结肠癌。
患者的选择基于如下标准:i)可测量实体瘤;ii)Karnofsky指数(KPS)≥60;iii)18-75岁;iv)主要器官正常;v)最近1个月内未经化疗、放疗和生物治疗;vi)病人签署同意书。
患者的剔除基于下列原则:i)有TNF或其衍生物过敏史;ii)怀孕或哺乳期妇女;iii)主要器官有明显损伤或功能不良;iv)发烧超过38℃;v)有明显出血倾向;vi)有低或者高血压史;vii)严重白蛋白血;viii)有强烈不依从或者抗拒用药倾向。
有下列任意情况发生停止对病人的评价:i)治疗未完全按照既定方法执行;ii)记录不完整;iii)使用没有列在既定方法中的抗癌手段。但是,因不良反应退出治疗的病人仍然计算在评估内。
肿瘤治疗效果的评估基于下列原则:I)完全有效(CR)-可见病理部位完全消失至少4周;ii)部分有效(PR)-肿瘤的最大纵与横直径变小≥50%至少4周;iii)轻微有效(MR)-肿瘤最大纵与横直径减小25%到50%至少4周;iv)稳定(SD)-肿瘤最大纵与横直径减小≤25%或增长不超过25%;v)发展(PD):肿瘤在一点或多点增大超过25%。
恶性胸腹水的治疗效果评估按照修改的Millar标准(Millar JW,Hunfer AM,Home NW.(1980)“Inerapleural immunotherapy with CP”Recurrent Maligant Pleural Effusions.Thorax 35:856):i)完全有效(CR)-胸腹水完全消失至少1个月;ii)部分有效(PR)-胸腹水等级下降1级至少1个月;iii)轻微有效(MR)-胸腹水等级下降不足1级至少1个月;iv)稳定(SD)-胸腹水稳定在原等级中至少1个月;v)发展(PD):胸腹水等级上升。
(2)rhTNFm1单独治疗
用重组rhTNFm1蛋白单独治疗患以下癌症的患者:恶性淋巴癌、肺癌、恶性黑色素瘤、乳腺癌、肝癌、肾癌、结肠癌、胸腹水。
治疗剂量为6000000-9000000 U/m2(约1-50μg/m2根据包装的生物活性)每日,一周静脉注射5次(第3天到第7天),第1、2天停。疗程3-4周。恶性肿瘤的治疗效果见表1。
表1
患者 效果 有效率(%)
病症
数量 CR PR MR SD PD CR PR CR+PR
肺癌 20 0 1 2 13 4 0.00 5.00 5.00
肝癌 12 0 0 0 10 2 0.00 0.00 0.00
结肠癌 7 0 0 0 3 4 0.00 0.00 0.00
乳腺癌 10 0 0 0 6 4 0.00 0.00 0.00
肾癌 3 0 0 1 1 1 0.00 0.00 0.00
恶性淋 71 2 18 8 32 11 2.82 25.35 28.17
巴瘤
恶性黑 18 0 2 3 10 3 0.00 11.11 11.11
色素瘤
合计 141 2 21 14 75 29 1.42 14.89 16.31
表1包括了因不良反应退出的患者,有3例恶性淋巴癌,1例肝癌,1例恶性黑色素瘤。
表2列出了按Hodgkin氏病和非Hodgkin氏淋巴瘤分类的治疗结果。每类淋巴瘤中,病人进一步分为2类:初治和复治患者。初治患者是未用任何抗癌药品治疗过的,而复治病人已经过一种或多种抗癌药物治疗。
表2中,患非Hodgkin氏淋巴癌的病人单用rhTNFm1有效。值得注意的是,2例复治病人在单用rhTNFm1完全有效。
表2
淋巴瘤 | 治疗 | 患者# | 疗效 | 有效率(%) | |||||||
CR | PR | MR | SD | PD | CR | PR | CR+PR | ||||
Hodgkin's | 初治患者 | I、II期 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
III.IV期 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | ||
合计 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | ||
复治患者 | 6 | 0 | 0 | 0 | 5 | 1 | 0 | 0 | 0 | ||
非Hodgkin's | 初治患者 | I、II期 | 4 | 0 | 3 | 1 | 0 | 0 | 0 | 75 | 75 |
III.IV期 | 5 | 0 | 3 | 0 | 2 | 0 | 0 | 60 | 60 | ||
合计 | 9 | 0 | 6 | 1 | 2 | 0 | 0 | 66.67 | 66.67 | ||
复治患者 | 56 | 2 | 12 | 7 | 25 | 10 | 3.57 | 21.43 | 25 | ||
合计 | 71 | 2 | 18 | 8 | 32 | 11 | 2.82 | 25.35 | 28.17 |
表3列出了单独用rhTNFm1治疗恶性胸腹水的结果。
表3
疗效 有效率(%)
患者 CR+P
数量 CR PR MR SD PD CR PR
R
胸积水 141 14 91 9 26 1 9.93 64.54 74.47
腹水 28 1 11 3 12 1 3.57 39.29 42.86
合计 169 15 102 12 38 2 8.88 60.36 69.23
请注意表3包括了因不良反应退出治疗的患者,其中1例恶心胸积水,1例恶性腹水。对于恶心腹水的病人,将rhTNFm1混入30-50ml生理盐水中,腹膜内注射2000000-300000U/次,一周1-2次,一个疗程2-3周。也可以交替进行腹膜内和静脉内注射rhTNFm1(6000000-9000000U/m2每天,连续28天一个疗程)。腹膜内注射rhTNFm1的治疗日不进行静脉内注射。
以上的治疗结果表明,单独用rhTNFm1治疗对非Hodgkin's淋巴癌、肺癌、恶性黑色素瘤、恶性胸腹水特别有效,对恶性胸腹水的有效率可达70%以上。
在单独使用rhTNFm1治疗过程中,不良反应比较轻微,主要是发烧和寒战。接受治疗的患者中约38%的有2度以下的发热;只有2例为3度。23%患者有寒战,其中12%轻微寒战,11%一般程度。剩下的病人既没有发烧也无寒战。
寒战多在注射rhTNFm1后30分钟内发生,有时1小时后发生,一般持续半小时以上。发烧多在注射后1-2小时发生,通常持续不到半小时,可以通过治疗前和/或治疗后使用消炎痛栓减轻症状。发烧和寒战的发生率随着治疗天数的增加而减少:第一天各约24%和17%,第七天各约10%和5%,第21天各约5%和2%。相对原型TNF-α,用本发明的rhTNFm1治疗对病人的不良反应少的多而且程度轻的多。另外,受测试病人的KPS相对治疗前大幅提高(P=0.013),在恶性胸腹水的治疗中尤其显著。
(3)rhTNFm1和其他抗肿瘤药物的比较
用rhTNFm1和化疗联合治疗恶性淋巴癌和非小细胞肺癌患者。
(a)恶性淋巴癌
恶性淋巴癌分为Hodgkin's癌(HD)和非Hodgkin's淋巴癌(NHL)。
rhTNFm1、阿霉素、博来霉素、长春新碱和二甲基-三氮烯基-咪唑基羧酰胺联合治疗HD患者。具体是,第一天和第15天,对病人静脉注射:阿霉素25mg/m2(E-ADM为40mg/m2);博来霉素10mg/m2;长春新碱2mg;二甲基-三氮烯基-咪唑基羧酰胺375mg/m2。每天注射600000-900000U/m2(约1-50μg/m2依包装的生物活性而定)rhTNFm1,一周5次(第3-7天),第1、2天不注射。疗程28天,2个疗程后评估疗效。
NHL患者用rhTNFm1、环磷酰胺、长春新碱、阿霉素、博来霉素和强的松联合治疗。具体是,第一天和第八天静脉注射环磷酰胺650mg/m2;长春新碱1.4mg/m2;阿霉素25mg/m2(E-ADM40mg/m2);第15天和第22天静脉注射博来霉素10mg/m2;第15-28天静脉注射100mg/m2强的松。rhTNFm1每日注射600000-900000U/m2(约1-50μg/m2依包装的生物活性而定),一周5次(第3-7天),第1、2天不注射。疗程28天,2个疗程后评估疗效。
联合治疗恶性淋巴癌的结果见表4。按Wilcoxon方法计算治疗组(用rhTNFm1和化疗联合治疗)和对照组(只化疗)之间的比较关系(Z值)。
表4
病症 | 组 | 患者数 | 疗效 | 有效率(%) | Z值 | P值 | |||||||
CR | PR | MR | SD | PD | CR | PR | CR+PR | ||||||
HD | 初治 | 治疗组 | 3 | 1 | 2 | 0 | 0 | 0 | 33.33 | 66.67 | 100.00 | 0.2 | 0.814 |
对照组 | 3 | 1 | 1 | 1 | 0 | 0 | 33.33 | 33.33 | 66.67 | . | . | ||
复治 | 治疗组 | 5 | 3 | 1 | 0 | 1 | 0 | 60.00 | 20.00 | 80.00 | 0.9 | 0.347 | |
对照组 | 3 | 0 | 2 | 1 | 0 | 0 | 0.00 | 66.67 | 66.67 | . | . | ||
NHL | 初治 | 治疗组 | 27 | 7 | 18 | 1 | 0 | 1 | 25.93 | 66.67 | 92.59 | 0.4 | 0.668 |
对照组 | 15 | 5 | 6 | 0 | 4 | 0 | 33.33 | 40.00 | 73.33 | . | . | ||
复治 | 治疗组 | 16 | 4 | 8 | 1 | 3 | 0 | 25.00 | 50.00 | 75.00 | 2.4 | 0.018 | |
对照组 | 10 | 0 | 3 | 2 | 4 | 1 | 0.00 | 30.00 | 30.00 | . | . | ||
恶性淋巴癌 | 治疗组 | 51 | 14 | 30 | 2 | 4 | 1 | 27.45 | 58.82 | 86.27 | 2.4 | 0.015 | |
对照组 | 31 | 6 | 11 | 3 | 10 | 1 | 19.35 | 35.48 | 54.84 | . | . |
结果表明rhTNFm1和化疗联合治疗恶性淋巴癌总体有效率(约86%)高于单独化疗的有效率(约55%),统计差异显著(P=0.015)。用rhTNFm1加化疗联合治疗NHL患者特别有效,有效率(约75%)远高于单独化疗有效率(约30%),统计差异显著(P=0.018)。另外,患者的KPS指数比治疗前明显提高(P=0.004)。相反的,对照组的KPS指数没有明显提高。
(b)非小细胞肺癌(NSCLC)
用rhTNFm1、丝裂霉素、长春地辛(去乙酰长春碱胺)和顺式铂氨联合治疗NSCLC患者。具体是,第一天和第八天静脉注射丝裂霉素-C6mg/m2,长春地辛36mg/m2。第三第四天静脉注射顺式铂氨。rhTNFm1每日注射600000-900000U/m2(约1-50μg/m2依包装的生物活性而定),一周5次(第3-7天),第1、2天不注射。疗程21天,2个疗程后评估疗效。
NSCLC病人也可以用rhTNFm1、诺维本(即失碳长春碱)和顺式铂氨联合治疗。具体是,第一天和第八天静脉注射诺维本25mg/m2,第一天静注顺式铂氨80-100mg/m2。rhTNFm1每日注射600000-900000U/m2(约1-50μg/m2依包装的生物活性而定),一周5次(第3-7天),第1、2天不注射。疗程21天,2个疗程后评估疗效。
联合治疗NSCLC的结果见表5。按Wilcoxon方法计算治疗组(用rhTNFm1和化疗联合治疗)和对照组(只化疗)之间的比较关系(Z值)。
表5
病症 | 组 | 患者数 | 疗效 | 有效率(%) | z值 | P值 | ||||||
CR | PR | MR | SD | PD | CR | PR | CR+PR | |||||
NSCLC | 治疗组 | 44 | 0 | 14 | 6 | 21 | 3 | 0.00 | 31.82 | 31.82 | 1.9 | 0.052 |
对照组 | 25 | 0 | 4 | 1 | 17 | 3 | 0.00 | 16.00 | 16.00 | . | . |
用rhTNFm1加化疗方法联合治疗NSCLC的有效率(约32)比单独化疗有效率(约16%)高很多,统计差异显著(P=0.015)。另外,治疗组病人的生活质量比治疗前明显提高(P=0.001)。相反,对照组病人的生活质量未见明显提高(P=0.668)。
序列表
[序列1]原型hTNF
Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
l 5 10 15
Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
20 25 30
Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
35 40 45
Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
50 55 60
Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
65 70 75 80
Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
85 90 95
Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
100 105 110
Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
115 120 125
Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
130 135 140
Ala Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
145 150 155
[序列2]重组hTNF突变体1
Arg Lys Arg Lys Pro Val Ala His Val Val Ala Asn Pro Gln Ala Glu
1 5 10 15
Gly Gln Leu Gln Trp Leu Asn Arg Arg Ala Asn Ala Leu Leu Ala Asn
20 25 30
Gly Val Glu Leu Arg Asp Asn Gln Leu Val Val Pro Ser Glu Gly Leu
35 40 45
Tyr Leu Ile Tyr Ser Gln Val Leu Phe Lys Gly Gln Gly Cys Pro Ser
50 55 60
Thr His Val Leu Leu Thr His Thr Ile Ser Arg Ile Ala Val Ser Tyr
65 70 75 80
Gln Thr Lys Val Asn Leu Leu Ser Ala Ile Lys Ser Pro Cys Gln Arg
85 90 95
Glu Thr Pro Glu Gly Ala Glu Ala Lys Pro Trp Tyr Glu Pro Ile Tyr
100 105 110
Leu Gly Gly Val Phe Gln Leu Glu Lys Gly Asp Arg Leu Ser Ala Glu
115 120 125
Ile Asn Arg Pro Asp Tyr Leu Asp Phe Ala Glu Ser Gly Gln Val Tyr
130 135 140
Phe Gly Ile Ile Ala Gln
145 150
[序列:3]重组hTNF突变体1’
Met Arg Lys Arg Lys Pro Val Ala His Val Val Ala Asn Pro Gln Ala
1 5 10 15
Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg Ala Asn Ala Leu Leu Ala
20 25 30
Asn Gly Val Glu Leu Arg Asp Asn Gln Leu Val Val Pro Ser Glu Gly
35 40 45
Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe Lys Gly Gln Gly Cys Pro
50 55 60
Ser Thr His Val Leu Leu Thr His Thr Ile Ser Arg Ile Ala Val Ser
65 70 75 80
Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala Ile Lys Ser Pro Cys Gln
85 90 95
Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys Pro Trp Tyr Glu Pro Ile
100 105 110
Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys Gly Asp Arg Leu Ser Ala
115 120 125
Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe Ala Glu Ser Gly Gln Val
130 135 140
Tyr Phe Gly Ile Ile Ala Gln
145 150
[序列4]重组hTNF突变体2
Pro Ser Asp Lys Pro Val Ala His Val Val Ala Asn Pro Gln Ala Glu
1 5 10 15
Gly Gln Leu Gln Trp Leu Asn Arg Arg Ala Asn Ala Leu Leu Ala Asn
20 25 30
Gly Val Glu Leu Arg Asp Asn Gln Leu Val Val Pro Ser Glu Gly Leu
35 40 45
Tyr Leu Ile Tyr Ser Gln Val Leu Phe Lys Gly Gln Gly Cys Pro Ser
50 55 60
Thr His Val Leu Leu Thr His Thr Ile Ser Arg Ile Ala Val Ser Tyr
65 70 75 80
Gln Thr Lys Val Asn Leu Leu Ser Ala Ile Lys Ser Pro Cys Gly Ala
85 90 95
Glu Ala Lys Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln
100 105 110
Leu Glu Lys Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr
115 120 125
Leu Asp Phe Ala Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
130 135 140
[序列5]重组hTNF突变体2’
Met Pro Ser Asp Lys Pro Val Ala His Val Val Ala Asn Pro Gln Ala
1 5 10 15
Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg Ala Asn Ala Leu Leu Ala
20 25 30
Asn Gly Val Glu Leu Arg Asp Asn Gln Leu Val Val Pro Ser Glu Gly
35 40 45
Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe Lys Gly Gln Gly Cys Pro
50 55 60
Ser Thr His Val Leu Leu Thr His Thr Ile Ser Arg Ile Ala Val Ser
65 70 75 80
Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala Ile Lys Ser Pro Cys Gly
85 90 95
Ala Glu Ala Lys Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe
100 105 110
Gln Leu Glu Lys Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp
115 120 125
Tyr Leu Asp Phe Ala Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala
130 135 140
Leu
145
[序列6]重组hTNF突变体3
Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
1 5 10 15
Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
20 25 30
Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
35 40 45
Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
50 55 60
Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ser
65 70 75 80
Ser Arg Ile Ala Val Ser Tyr Gln Thr His Val Val Leu Leu Ser Ala
85 90 95
Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
100 105 110
Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
115 120 125
Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
130 135 140
Ala Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
145 150 155
[序列7]重组hTNF突变体3’
Met Val Arg Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His
1 5 10 15
Val Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg
20 25 30
Arg Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln
35 40 45
Leu Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu
50 55 60
Phe Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr
65 70 75 80
Ser Ser Arg Ile Ala Val Ser Tyr Gln Thr His Val Val Leu Leu Ser
85 90 95
Ala Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala
100 105 110
Lys Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu
115 120 125
Lys Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp
130 135 140
Phe Ala Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
145 150 155
[序列8]重组hTNF突变体4
Val Lys Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val
1 5 10 15
Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg
20 25 30
Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu
35 40 45
Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe
50 55 60
Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile
65 70 75 80
Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala
85 90 95
Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys
100 105 110
Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys
115 120 125
Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe
130 135 140
Ala Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
145 150 155
[序列9]重组hTNF突变体4’
Met Val Lys Ser Ser Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His
1 5 10 15
Val Val Ala Asn Pro Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg
20 25 30
Arg Ala Asn Ala Leu Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln
35 40 45
Leu Val Val Pro Ser Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu
50 55 60
Phe Lys Gly Gln Gly Cys Pro Ser Thr His Val Leu Leu Thr His Thr
65 70 75 80
Ile Ser Arg Ile Ala Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser
85 90 95
Ala Ile Lys Ser Pro Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala
100 105 110
Lys Pro Trp Tyr Glu Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu
115 120 125
Lys Gly Asp Arg Leu Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp
130 135 140
Phe Ala Glu Ser Gly Gln Val Tyr Phe Gly Ile Ile Ala Leu
145 150 155
[序列10]重组hTNF突变体1的DNA序列
atgcgcaaac gtaagcctgt agcccatgtt gtagcaaacc ctcaagctga ggggcagctc 60
cagtggctga accgccgggc caatgccctc ctggccaatg gcgtggagct gagagataac 120
cagctggtgg tgccatcaga gggcctgtac ctcatctact cccaggtcct cttcaagggc 180
caaggctgcc cctccaccca tgtgctcctc acccacacca tcagccgcat cgccgtctcc 240
taccagacca aggtcaacct cctctctgcc atcaagagcc cctgccagag ggagacccca 300
gagggggctg aggccaagcc ctggtatgag cccatctatc tgggaggggt cttccagctg 360
gagaagggtg accgactcag cgctgagatc aatcggcccg actatctcga ctttgccgag 420
tctgggcagg tctactttgg gatcattgcc cag 453
[序列11]原型hTNF-α的前导序列的氨基酸顺序
Met Ser Thr Glu Ser Met Ile Arg Asp Val Glu Leu Ala Glu Glu Ala
1 5 10 15
Leu Pro Lys Lys Thr Gly Gly Pro Gln Gly Ser Arg Arg Cys Leu Phe
20 25 30
Leu Ser Leu Phe Ser Phe Leu Ile Val Ala Gly Ala Thr Thr Leu Phe
35 40 45
Cys Leu Leu His Phe Gly Val Ile Gly Pro Gln Arg Glu Glu Ser Pro
50 55 60
Arg Asp Leu Ser Leu Ile Ser Pro Leu Ala Gln Ala
65 70 75
Claims (30)
1.人肿瘤坏死因子-α突变蛋白在制备治疗与异常细胞增殖有关疾病药物中的应用。
2.根据权利要求1所述的应用,其特征在于其中所述的人肿瘤坏死因子-α突变蛋白是在原型hTNF-α氨基酸序列上去除N端1-7号氨基酸残基,在156或157位氨基酸残基发生了替换,替换残基为Gln、Ser、Thr、Tyr和Asn中的一种,在8-10位氨基酸残基有一个或多个被Lys或Arg残基替代,此hTNF-α突变体具有序列2、3、4或5的氨基酸序列和序列10的DNA序列。
3、根据权利要求1所述的应用,其特征在于其中所述的人肿瘤坏死因子-α突变蛋白是在原型hTNF-α氨基酸序列的N-端80、90、92位氨基酸残基发生了替换,具有序列6或7的氨基酸序列。
4、根据权利要求1所述的应用,其特征在于其中所述的人肿瘤坏死因子-α突变蛋白是在原型hTNF-α氨基酸序列的N-端2位氨基酸残基发生了替换,具有序列8或9的氨基酸序列。
5.根据权利要求1所述的应用,其特征在于其中所述的异常细胞增殖的疾病包括血液系统的失调、癌症、恶性胸腔积水、恶性腹水、心脏瓣膜再狭窄和炎症疾病。
6.根据权利要求5所述的应用,其特征在于其中所述的血液系统的失调疾病包括急性骨髓白血病、急性早幼粒细胞白血病、急性淋巴母细胞白血病、慢性骨髓性白血病、骨髓发育异常综合症和镰刀型贫血。
7.根据权利要求5所述的应用,其特征在于其中所述的癌症包括乳腺癌、皮肤癌、骨癌、前列腺癌、肝癌、脑癌、肺癌、喉癌、胆囊癌、胰腺癌、直肠癌、副甲状腺癌、甲状腺癌、肾上腺癌、中枢组织癌、头颈癌、结肠癌、胃癌、支气管癌、肾癌、基底细胞癌、溃疡型和乳突型鳞状上皮细胞癌、转移型皮肤癌、骨瘤、Ewing's瘤、veticulum细胞瘤、骨髓癌、巨细胞癌、小细胞肺癌、非小细胞肺癌、胆癌、导状细胞瘤、初级脑瘤、急慢性淋巴细胞粒细胞癌、毛细胞癌、腺癌、髓质癌、嗜铬细胞瘤、粘膜神经瘤、肠星形胶质细胞瘤、增生性角膜神经瘤、平滑肌瘤、宫颈异常及癌症、成神经细胞瘤、眼癌、软组织瘤、恶变良性肿瘤、局部皮肤损伤、霉菌性真菌感染、横纹肌肉瘤、Kaposi's癌、遗传性骨癌、恶性血钙增多、肾细胞癌、真性多血症、腺癌、多形性胶质母细胞瘤、白血病、淋巴瘤、恶性黑色素瘤、表皮癌和其他癌症和恶性肿瘤。
8、根据权利要求5所述的应用,其特征在于其中所述的癌症包括恶性淋巴癌、肺癌、恶性黑色素瘤、乳腺癌、肝癌、肾癌和结肠癌。
9、根据权利要求8所述的应用,其特征在于其中所述的恶性淋巴癌包括Hodgkin’s癌和非Hodgkin's淋巴癌。
10、根据权利要求8所述的应用,其特征在于其中所述的肺癌是指非小细胞肺癌。
11、根据权利要求5所述的应用,其特征在于其中所述的恶性胸腔积液或恶性腹水是指由癌症或其他恶性疾病引起的。
12.根据权利要求1所述的应用,其特征在于其中所述的hTNF-α突变蛋白可以通过非肠道、腹膜内、静脉内、动脉内、经皮内、舌下、肌肉内、直肠、口腔、鼻内、脂质体包裹、吸入、阴道、眼、局部、皮下、脂肪组织、关节内或胸内等多种方式给药。
13.根据权利要求1所述的应用,其特征在于其中所述的hTNF-α突变蛋白可制成缓释剂型。
14、根据权利要求1所述的应用,其特征在于hTNF-α突变体蛋白经静脉注射,每星期注射3-5天,剂量为100,000-1,000,000单位/m2。
15、根据权利要求1所述的应用,其特征在于hTNF-α突变体蛋白经腹膜内注射,每星期给药1-2天,剂量为2,000,000-5,000,000单位。
16.根据权利要求1所述的应用,其特征在于其中所述的药物可单独或与其他抗癌药物联合应用。
17.根据权利要求16所述的应用,其特征在于其中所述的抗癌药物包括烷化剂、抗生素、抗代谢药物、激素药物、植物来源药物、抗血管增生药物和生物药品。
18.根据权利要求17所述的应用,其特征在于其中所述的烷化剂包括二氯乙胺、氮丙啶、烷基酮硫酸盐、亚硝基脲、非经典烷化剂和铂化合物。
19.根据权利要求17所述的应用,其特征在于其中所述的抗生素包括阿霉素、柔毛霉素、表柔比星、去甲氧柔红霉素、大黄素、丝裂霉素C、博来霉素、放线菌素D和plicatomycin。
20.根据权利要求17所述的应用,其特征在于其中所述的抗代谢药物包括氟尿嘧啶、氟尿嘧啶脱氧核苷、氨甲喋呤、亚叶酸、羟基脲、硫鸟嘌呤、巯基嘌呤、阿糖胞苷、喷司他丁、氟达拉滨磷酸盐、克拉屈滨、天冬酰胺酶和吉西他滨。
21.根据权利要求17所述的应用,其特征在于其中所述的激素药物包括己烯雌酚、它莫西芬、托瑞米芬、氟羚甲基睾丸素、雷洛昔芬、比卡鲁胺、尼鲁米特、氟他胺、氨鲁米特、四唑、酮康唑、戈舍瑞林醋酸盐、亮丙瑞林、甲地孕酮醋酸盐和米非司酮。
22、根据权利要求17所述的应用,其特征在于其中所述的植物来源药物包括长春新碱、长春碱、长春地辛、长春利定、长春瑞宾、依托泊苷、替尼泊苷、喜树碱、紫杉酚和多烯紫杉醇。
23、根据权利要求17所述的应用,其特征在于其中所述的生物药品包括免疫调节蛋白、抗肿瘤单克隆抗体、肿瘤抑制基因和肿瘤疫苗。
24、根据权利要求23所述的应用,其特征在于其中所述的免疫调节蛋白包括白介素2、白介素4、白介素12、干扰素α、干扰素β、干扰素γ、促红细胞生成素、粒白血病集落刺激因子、粒白细胞、巨噬细胞集落刺激因子、Calmette-Guerin菌、左旋咪唑和奥曲肽。
25、根据权利要求23所述的应用,其特征在于其中所述的抗肿瘤单克隆抗体指HERPEPTIN(Trastruzumab)或者RITUXAN(美罗华)。
26、根据权利要求23所述的应用,其特征在于其中所述的肿瘤抑制基因包括DPC-4,NF-1,NF-2,RB,p53,WT1,BRCA,and BRCA2。
27、根据权利要求23所述的应用,其特征在于其中所述的肿瘤疫苗包括神经节苷脂、前列腺特异抗原、α-胎蛋白、癌胚抗原、黑色素瘤相关抗原MART-1,糖蛋白100、乳突淋瘤病毒E6片段、乳突淋瘤病毒E7片段、肿瘤自体细胞全细胞或者部分或裂解物以及异源肿瘤细胞。
28、根据权利要求27所述的应用,其特征在于还包括对患者施用增加肿瘤疫苗效果的佐剂。
29、根据权利要求28所述的应用,其特征在于其中所述的佐剂包括Calmette-Gurin菌、脂多糖内毒素、锁眼贝血蓝蛋白、白介素-2、粒白细胞-巨噬细胞集落刺激因子和环磷酰胺。
30、根据权利要求16所述的应用,其特征在于抗癌药物为左旋溶肉瘤素,与异常细胞增殖相关的疾病是和色素瘤和初级肢体癌。
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US10/327,619 | 2002-12-20 | ||
US10/327,619 US20040121971A1 (en) | 2002-12-20 | 2002-12-20 | Therapeutic use of tumor necrosis factor-alpha mutein |
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CN (1) | CN1509763A (zh) |
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Cited By (8)
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US7485698B2 (en) | 2003-10-31 | 2009-02-03 | Gen-Ichiro Soma | Pharmaceutical composition for preventing or treating malignant glioma |
CN105753986A (zh) * | 2016-04-24 | 2016-07-13 | 赵磊 | 一类抗cd20靶向抗体及用途技术领域 |
CN106620656A (zh) * | 2017-03-03 | 2017-05-10 | 上海唯科生物制药有限公司 | 一种肿瘤坏死因子舌下给药制剂及其制备方法 |
CN106729633A (zh) * | 2017-03-03 | 2017-05-31 | 上海唯科生物制药有限公司 | 一种肿瘤坏死因子直肠给药制剂及其制备方法 |
CN107033232A (zh) * | 2016-02-04 | 2017-08-11 | 上海亨臻实业有限公司 | 一种低生物活性的肿瘤坏死因子α突变蛋白及其制法和用途 |
CN107207578A (zh) * | 2014-12-05 | 2017-09-26 | 阿姆丘尔公司 | 用于治疗癌症和血管生成相关疾病的CD44v6‑衍生的环肽 |
CN109374889A (zh) * | 2011-07-08 | 2019-02-22 | 索隆-基特林癌症研究协会 | 标记的hsp90抑制剂的用途 |
CN113272320A (zh) * | 2018-11-19 | 2021-08-17 | 得克萨斯大学体系董事会 | 自杀基因 |
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US20110142887A1 (en) * | 2009-12-15 | 2011-06-16 | Immunovative Therapies Ltd. | Methods and compositions for liquidation of tumors |
US7064127B2 (en) * | 2003-12-19 | 2006-06-20 | Mount Sinai School Of Medicine Of New York University | Treatment of hepatic fibrosis with imatinib mesylate |
JP2008528006A (ja) * | 2005-01-28 | 2008-07-31 | アポロ ライフ サイエンシズ リミテッド | 分子およびそのキメラ分子 |
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SE445884B (sv) * | 1982-04-30 | 1986-07-28 | Medinvent Sa | Anordning for implantation av en rorformig protes |
EP0897987B1 (en) * | 1989-10-24 | 2001-02-28 | Chiron Corporation | Secretion of human protein linked to gamma interferon signal peptide |
SK376492A3 (en) * | 1992-04-02 | 1995-06-07 | Hoffmann La Roche | Tnf - muteins and method of their production |
US5579033A (en) * | 1992-05-20 | 1996-11-26 | International Business Machines Corporation | Pointing device for retrofitting onto the keyboard of an existing computer system |
KR970005042B1 (ko) * | 1993-02-09 | 1997-04-11 | 한일합성섬유공업 주식회사 | 종양괴사인자-알파 뮤테인 |
-
2002
- 2002-12-20 US US10/327,619 patent/US20040121971A1/en not_active Abandoned
-
2003
- 2003-04-03 CN CNA031089348A patent/CN1509763A/zh active Pending
- 2003-12-19 WO PCT/US2003/040756 patent/WO2004082595A2/en not_active Application Discontinuation
- 2003-12-19 US US10/741,161 patent/US20060263331A1/en not_active Abandoned
- 2003-12-19 AU AU2003303964A patent/AU2003303964A1/en not_active Abandoned
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CN105753986B (zh) * | 2016-04-24 | 2019-12-10 | 赵磊 | 一类抗cd20靶向抗体及用途 |
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CN113272320A (zh) * | 2018-11-19 | 2021-08-17 | 得克萨斯大学体系董事会 | 自杀基因 |
Also Published As
Publication number | Publication date |
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AU2003303964A1 (en) | 2004-10-11 |
WO2004082595A2 (en) | 2004-09-30 |
US20060263331A1 (en) | 2006-11-23 |
AU2003303964A8 (en) | 2004-10-11 |
WO2004082595A3 (en) | 2005-01-20 |
US20040121971A1 (en) | 2004-06-24 |
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