CN1373672A - 应用结合cd20的拮抗剂阻断对外来抗原的免疫应答 - Google Patents
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Abstract
本申请描述用结合CD20的拮抗剂阻断哺乳动物体内对外来抗原的免疫应答的方法。
Description
发明领域
本发明涉及应用结合CD20的拮抗剂阻断哺乳动物体内对外来抗原的免疫应答。
发明背景
淋巴细胞是血细胞生成过程中由骨髓产生的多种类型白细胞中的一种。淋巴细胞主要有两类:B淋巴细胞(B细胞)和T淋巴细胞(T细胞)。本发明特别感兴趣的淋巴细胞是B淋巴细胞。
B细胞在骨髓中成熟,离开骨髓时在其细胞表面表达与抗原结合的抗体。当天然B细胞首次与其膜结合抗体特异的抗原相遇时,细胞开始迅速分裂,其子代分化成记忆B细胞和称为“浆细胞”的效应细胞。记忆B细胞寿命很长,并继续表达与其亲代细胞具有相同特异性的膜结合抗体。浆细胞不产生膜结合抗体,而代之产生可分泌型的抗体,可分泌的抗体是体液免疫的重要效应分子。
CD20抗原(也称为人B淋巴细胞限制性分化抗原Bp35)是前B细胞和成熟B淋巴细胞上的疏水性跨膜蛋白,分子量大约35kD(Valentine等生物学化学杂志264(19):11282-11287(1989);和Einfeld等,欧洲分子生物学组织杂志7(3):711-717(1988))。该抗原也在大于90%的B细胞非霍奇金淋巴瘤(NHL)上表达(Anderson等,血液63(6):1424-1433(1984)),但在造血干细胞,原B细胞,正常浆细胞或其它正常组织中未发现(Tedder等,免疫学杂志135(2):973-979,1985)。CD20在细胞周期启动和分化的活化过程早期阶段起调节作用(Tedder等,同上),并可能发挥钙离子通道的功能(Tedder等,细胞生物学杂志14D:195(1990))。
由于CD20在B细胞淋巴瘤中表达,这一抗原可作为用于“靶向”这类淋巴瘤的候选者。实质上,这种靶向可如下归纳:将B细胞表面抗原CD20的特异性抗体给予患者。这些抗CD20抗体与正常和恶性B细胞(表面的)CD20抗原特异结合;与表面抗原CD20结合的抗体可引起肿瘤性B细胞的破坏和耗竭。此外,具有破坏肿瘤潜力的化学制剂或放射活性标记能与抗CD20抗体偶联,从而将所述制剂特异性“运送”至肿瘤性B细胞。不管用什么方法,一个主要目的是破坏肿瘤;可根据所使用的具体抗CD20抗体确定具体方法,因此,靶向CD20抗原的现有方法很多。
rituximab(RITUXAN)抗体是一种遗传工程化鼠/人嵌合单克隆抗CD20抗体。Rituximab在1998年4月7日授权的美国专利5,736,137号(Anderson等)中称为“C2B8”的抗体。RITUXAN被指示用于治疗复发或难治的低级或滤泡性CD20阳性B细胞非霍奇金淋巴瘤。体外作用机制研究显示RITUXAN与人补体结合,并通过补体依赖性细胞毒作用(CDC)裂解淋巴样B细胞系(Reff等,血液83(2):435-445(1994))。此外,在抗体依赖的细胞性细胞毒作用(ADCC)试验中有显著活性。最近,RITUXAN在氚标胸腺嘧啶掺入实验中显示抗增殖效应并直接诱导凋亡,而其它抗CD20抗体则不能(Maloney等,血液88(10):637a(1996))。实验还发现RITUXAN与化疗和毒素有协同作用。尤其是RITUXAN使耐药的人B细胞淋巴瘤细胞系对阿霉素,CDDP,VP-16,白喉毒素和蓖麻毒蛋白的细胞毒效应较敏感(Demidem等,癌症化疗及放射性药物(Cancer Chemotherapy &Radiopharmaceuticals)12(3):177-186(1997))。体内临床前研究显示RITUXIMAB使来源于弥猴(cynomolgus)外周血,淋巴结和骨髓的B细胞耗竭,推测是通过补体和细胞介导的过程完成(Reff等,血液83(2):435-445(1994))。
发明概述
首先,本发明提供一种阻断哺乳动物体内针对外来抗原的免疫应答的方法,该方法包括向哺乳动物给药治疗有效量的与CD20结合的拮抗剂,其中所述的哺乳动物未患恶性肿瘤。
进一步地,本发明提供治疗哺乳动物的方法,该方法包括向哺乳动物给药一种治疗剂并进一步向哺乳动物给药与CD20结合的拮抗剂,其中所述治疗剂不是与CD20结合的拮抗剂而且在哺乳动物体内具备免疫原性,而所述拮抗剂可阻断哺乳动物体内的针对该治疗剂的免疫应答。
本发明进一步提供一种治疗哺乳动物的移植物抗宿主或宿主抗移植物疾病的方法,包括向哺乳动物给药治疗有效量的与CD20结合的拮抗剂。
另外,本发明还提供一种使等待移植的哺乳动物脱敏的方法,该方法包含向哺乳动物给药治疗有效量的与CD20结合的拮抗剂。
本发明进一步涉及一种在上述方法中使用的制品。例如,所述制品可包括一个容器及其中所含的组合物,还包括一种包装插页,所述组合物包含一种与CD20结合的拮抗剂,所述插页可指导用户用所述组合物治疗已经或将要暴露于外来抗原的患者。所述制品任选还包含第二个容器及其中所含的第二种组合物,该第二种组合物包含一种治疗剂。
优选实施方案详述
I.定义
“CD20”抗原是在90%以上来自外周血或淋巴器官的B细胞表面发现的一种~35kDa的非糖基化磷蛋白。CD20在早期前B细胞发育阶段表达,并保持到浆细胞分化。CD20在正常B细胞和恶性B细胞上均可发现。文献中CD20亦称为“B淋巴细胞限制性抗原”或“Bp35”。例如,在Clark等PNAS(USA)82:1766(1985)有对CD20抗原的描述。
“外来抗原”是指针对暴露于它的哺乳动物来说是非内源性的或非天然的分子。外来抗原可以引发哺乳动物体内的免疫应答,例如,体液和/或T细胞介导的反应。一般情况下,外来抗原可以诱导针对它们的抗体的产生。本发明关注的外来抗原的实例包括具备免疫原性的治疗剂,例如,抗体等蛋白,尤其是包含非人的氨基酸残基的抗体(例如啮齿类,嵌合/人源化,和灵长类的抗体);毒素(任选与靶向分子如抗体偶联,其中该靶向分子可能也具有免疫原性);基因治疗病毒载体,如逆转录病毒和腺病毒;移植物;感染因子(例如细菌和病毒);同种异体抗原(即同一种群中一些成员具有而其它成员不具有的抗原)例如血型抗原、人淋巴细胞抗原(HLA)、血小板抗原、表达在移植器官上的抗原、血液成分、妊娠抗原(Rh)和血友病因子(例如因子VIlI和因子IX)的不同。
“阻断针对外来抗原的免疫应答”是指降低或阻止因暴露于外来抗原引起的至少一种免疫应答。例如,可以减弱对外来抗原的体液反应,即,通过阻止或减少哺乳动物体内针对该抗原的抗体的产生。或者,或另外可抑制独特型;“减弱(pacify)”对同种异型抗体覆盖的细胞的消除;和/或通过损耗抗原提呈细胞而影响同种异体抗原的提呈。
本发明中所治疗的哺乳动物通常是“未患恶性疾病的”,因此还没有被诊断为患有恶性疾病或癌症,例如B细胞淋巴瘤。急性淋巴母细胞性白血病(ALL),慢性淋巴细胞性白血病(CLL),毛细胞白血病(Hairy cell leukemia),慢性成髓细胞性白血病,或移植后淋巴细胞增生性紊乱(PTLD)(post-transplant lymphoproliferative disorder)。
术语“治疗剂”是指用于治疗患者体内某种疾病或病症的化合物或组合物。治疗剂可以包含多肽如抗体;毒素(任选与靶向分子如抗体偶联);基因治疗病毒载体和/或血友病因子(例如因子VIII和因子IX)。治疗剂通常以治疗有效量给予哺乳动物以治疗目的疾病或病症,其用量可导致在所治疗的哺乳动物体内激发出针对治疗剂的免疫应答。
此处所使用的“多肽”通常是指包含大约十个以上氨基酸的肽和蛋白。哺乳动物多肽的实例包括以下分子例如,肾素、生长激素包括人生长激素;牛生长激素;生长激素释放因子;甲状旁腺素;甲状腺刺激激素;脂蛋白;1-抗胰蛋白酶;胰岛素A链;胰岛素B链;前胰岛素;血小板生成素;卵泡刺激素;降钙素;黄体化激素(luteinizing hormone);胰高血糖素;凝血因子如因子VIIIC,因子IX,组织因子,和冯维勒布兰德(von Willebrands)因子;抗凝血因子如蛋白C;心钠素;肺表面活性剂;纤维蛋白溶酶原激活剂如尿激酶或人尿或组织纤维蛋白溶酶原激活剂(t-PA);铃蟾肽;凝血酶;造血生长因子;肿瘤坏死因子α和β;脑啡肽酶;血清白蛋白例如人血清白蛋白;苗勒(mullerian)-抑制物质;松弛素A链;松弛素B链;前松弛素(prorelaxin);小鼠促性腺素相关肽;微生物蛋白如β内酰胺酶;DNA酶;抑制素;活化素;血管内皮细胞生长因子(VEGF);激素或生长因子的受体;整联蛋白;蛋白A或D;类风湿因子;神经营养因子如来源于脑的神经营养因子(BDNF),神经营养蛋白-3,-4,-5或-6(NT-3,NT-4,NT-5或NT-6),或神经生长因子例如NGF;心营养蛋白(心肥大因子)例如心营养蛋白-1(CT-1);血小板衍生的生长因子(PDGF);成纤维细胞生长因子例如aFGF和bFGF;表皮生长因子(EGF);转化生长因子(TGF)例如TGF-α和TGF-β,包括TGF-1,TGF-2,TGF-3,TGF-4或TGF-5;胰岛素样生长因子-I和-II(IGF-I和IGF-II);去(des)(1-3)-IGF-I(脑IGF-I),胰岛素样生长因子结合蛋白;CD蛋白例如CD3,CD4,CD8和CD20;红细胞生成素;骨诱导因子;免疫毒素;骨形态发生蛋白(BMP)(bone morphogenetic protein);干扰素例如干扰素α,β和γ;血清白蛋白例如人血清白蛋白(HAS)或牛血清白蛋白(BSA);集落刺激因子(CSF),例如M-CSF,GM-CSF和G-CSF;白细胞介素(Il)如IL-1到IL-10;细胞因子(见下文);超氧化物歧化酶;T细胞受体;表面膜蛋白;促衰变因子;病毒抗原例如AIDS包膜的一部分;转运蛋白;归巢受体;地址素(adderssin);调节蛋白;抗体;和上述任何多肽的片段或变体。
本发明所用的术语“移植物”是指来源于向受体进行移植的供体的生物物质。移植物包括多种多样的物质,例如,分离的细胞例如胰岛细胞;组织例如新生儿的羊膜,骨髓,造血祖细胞,和眼组织如角膜组织;器官如皮肤,心脏,肝脏,脾脏,胰腺,甲状腺小叶,肺,肾脏,管状器官(如肠道,血管或食管),等等。管状器官能用来代替食管、血管或胆管的损伤部分。皮肤移植物不但可用于烧伤,还可用作损伤肠管的被膜或用来修补某些缺损例如隔疝。移植物来源于任何哺乳动物,包括人,无论生死。优选移植物是骨髓或者器官如心脏,并且移植物的供体和宿主的HLAII类抗原是相匹配的。
此处所用术语“哺乳动物宿主”是指任何相容的移植接受者。“相容的”是指将接受移植物的哺乳动物宿主。宿主优选是人。如果移植物的供体和宿主都是人,为提高组织相容性,优选他们的HLAII类抗原相匹配。
此处所用术语“供体”是指提供移植物的死或活的哺乳动物。优选,供体是人。人供体优选自愿的有血缘关系同时体检正常的供体,而且供体和受体有相同的主要ABO血型,因为跨越主要血型的障碍可能不利于同种异体移植物的存活。但是,移植在某些情况下是可能的,例如,O型供体的肾脏可移植给A、B或AB型的接受者。
术语“移植”和它的变称是指移植物进入到宿主体内,无论是同基因移植(syngeneic)(供体和接受者遗传背景相同)、同种异体移植(供体和接受者遗传背景不同但属同一物种)或异种移植(供体和接受者来自不同物种)。所以,在典型的实施过程中,宿主是人,移植物是同基因移植物,来源于具有相同或不同遗传背景的人。在另一种情况下,移植物来自与移植接受者不同的另一物种,例如将狒狒的心脏移植给人类宿主,并且包括从种系发生方面相隔很远的动物,例如,将猪心瓣膜,或者动物β胰岛细胞或神经细胞移植给人宿主。
“基因治疗”是指将核酸导入待治疗的哺乳动物体内的常规方法。核酸可以编码目的多肽或者反意核酸。基因治疗载体或组合物的一个或多个成分在用它们治疗的哺乳动物体内可能存在免疫原性。例如,病毒载体(如腺病毒、I型单纯疱疹病毒或逆转录病毒);脂质;和/或组合物中的靶向分子可能诱导用它们治疗的哺乳动物体内的免疫应答。
“使等待移植的哺乳动物脱敏”的表述是指在对哺乳动物进行移植之前降低或去除对移植物的过敏(allergic)敏感性或反应性。这可以通过任何机制获得,例如减少脱敏哺乳动物体内的抗供体抗体,如当这些抗供体抗体针对人淋巴细胞抗原(HLA)时。
本文中“自身免疫病”是一种源自个体自身组织或直接针对个体自身组织的非恶性疾病。本文中自身免疫病特别排除了恶性疾病或肿瘤性疾病,尤其排除了B细胞淋巴瘤,急性淋巴母细胞性白血病(ALL),慢性淋巴细胞性白血病(CLL),毛细胞(Hairy cell)白血病和慢性成髓细胞性白血病。自身免疫病实例包括,但不限于,炎性应答如炎性皮肤疾病包括牛皮癣和皮炎(如特应性皮炎);系统性硬皮病和硬化症;与炎性肠疾病有关的应答(如克罗恩氏(Crohn’s)病和溃疡性结肠炎);呼吸窘迫综合征(包括成人呼吸窘破综合征;ARDS);皮炎;脑脊膜炎;脑炎;色素膜炎;结肠炎;肾小球肾炎;过敏性疾病如湿疹和哮喘,以及涉及T细胞浸润和慢性炎性应答的其它疾病;动脉粥样硬化;白细胞粘附缺陷;类风湿性关节炎;系统性红斑狼疮(SLE);糖尿病(如I型糖尿病或胰岛素依赖性糖尿病);多发性硬化症;雷诺氏(Reynaud’s)综合征;自身免疫性甲状腺炎;过敏性脑脊髓炎;斯耶格伦氏(Sjorgen’s)综合征;幼年型糖尿病;常见于结核、结节病、多肌炎、肉芽肿病和脉管炎中的,涉及细胞因子和T淋巴细胞所介导的急性和迟发型超敏反应的免疫应答;恶性贫血(阿狄森氏(Addison’s)病);与白细胞渗出有关的疾病;中枢神经系统(CNS)炎性病变;多器官损伤综合征;溶血性贫血(包括但不限于冷球蛋白血症;或库姆斯氏(Combs)阳性贫血);重症肌肌无力;抗原抗体化合物介导的疾病;抗肾小球基底膜疾病;抗磷脂综合征;过敏性神经炎;格雷夫斯氏(Graves’s)综合征;兰-伊氏(Lambert-Eaton)肌无力综合征;大疱性类天疱疮;天疱疮;自身免疫性多内分泌腺病;赖特尔氏(Reiter’s)病;全身肌强直(stiff-man)综合征;贝切特氏(Behcet)病;巨细胞性动脉炎;免疫化合物性肾炎;IgA型肾病;IgM型多发性神经病;免疫性血小板减少性紫癜(ITP)或自身免疫性血小板减少症等。
“拮抗剂”是通过与CD20结合能破坏或耗竭哺乳动物中的B细胞和/或例如通过减少或阻止B细胞所激发的体液应答而干扰B细胞的一或多种功能的分子。拮抗剂优选能耗竭所治疗的哺乳动物中的B细胞(即降低循环B细胞水平)。这种耗竭可通过多种机制获得,如抗体依赖性细胞介导的细胞毒作用(ADCC)和/或补体依赖性细胞毒作用(CDC),对B细胞增殖的抑制和/或对B细胞死亡的诱导(即通过凋亡)。本发明的拮抗剂包括与CD20结合的抗体、合成序列肽或天然序列肽以及小分子拮抗剂,可任选偶联或融合于一种细胞毒制剂。优选拮抗剂包含一种抗体。
“抗体依赖性细胞介导的细胞毒作用”和“ADCC”指一种细胞介导的反应,其中表达Fc受体(FcR)的非特异性细胞毒细胞(如自然杀伤(NK)细胞,中性粒细胞,和巨噬细胞)识别靶细胞上结合的抗体,并随后引起靶细胞的裂解。介导ADCC的主要细胞即NK细胞仅表达FcγRIII,而单核细胞表达FcγRI,FcγRII和FcγRIII。Raveth和Kinet在免疫学年鉴9:457-92(1991),464页的表3中总结了造血细胞上的FcR表达。为评估目的分子的ADCC活性,可进行体外ADCC试验,如美国专利5,500,362号或5,821,337号中所述。这类试验中有用的效应细胞包括外周血单个核细胞(PBMC)和自然杀伤(NK)细胞。任选或另外,目的分子的ADCC活性可在体内评估,例如采用Clynes等PNAS(USA)95:652-656(1998)中公开的动物模型。
“人效应细胞”是表达一种或多种FcR并执行效应物的功能的白细胞。优选所述细胞表达至少FcγRIII并执行ADCC效应物的功能。例如可介导ADCC的人白细胞包括人外周血单个核细胞(PBMC),自然杀伤(NK)细胞,单核细胞,细胞毒T细胞和中性粒细胞;其中优选PBMC和NK细胞。
术语“Fc受体”或“FcR”用于描述与抗体Fc区结合的受体。优选的FcR是天然序列的人FcR。而且,优选的FcR是与IgG抗体结合的受体(γ受体),其包括FcγRI,FcγRII和FcγRIII亚型,以及这些受体的等位基因变体和可替换的剪接形式。FcγRII受体包括FcγRIIA(“活化型受体”)和FcγRIIB(“抑制型受体”),二者的氨基酸序列相似,主要区别在其胞浆结构域。活化型受体FcγRIIA在其胞浆结构域包含一个基于免疫受体酪氨酸的活化基序(ITAM)。抑制型受体FcγRIIB在其胞浆结构域包含一个基于免疫受体酪氨酸的抑制基序(ITIM)(见Daeron,免疫学年鉴15:203-234(1997))。在Ravetch和Kinet,免疫学年鉴9:457-92(1991);Capel等,免疫方法(免疫学方法)4:25-34(1994);和de Haas等,实验室及临床医学杂志(J.Lab.Clin.Med.)126:330-41(1995)中对FcR进行了综述。其它FcR,包括将来被确定的,均被包含在术语“FcR”中。该术语也包括新生期的受体,FcRn,其负责将母体的IgG转运至胎儿(Guyer等,免疫学杂志117:587(1976)和Kim等,免疫学杂志24:249(1994))。
“补体依赖性细胞毒作用”或“CDC”是指在补体存在时分子裂解标靶的能力。补体活化途径由补体系统第一个成分(Clq)结合至一个与同源抗原形成化合物的分子(如抗体)来启动。为评价补体活化,可如Gazzano-Santoro等,免疫学方法杂志202:163(1996)所述进行CDC试验。
“生长抑制”拮抗剂是指那些阻止或减少可与拮抗剂结合之抗原的表达细胞增殖的拮抗剂。例如拮抗剂可在体内或体外阻止或减少B细胞的增殖。
“诱导凋亡”的拮抗剂是指那些可诱导例如,B细胞程序性细胞死亡的拮抗剂,所述凋亡可通过标准凋亡试验,如annexin V的结合,DNA片段化,细胞皱缩,内质网膨胀,细胞碎裂,和/或膜泡(称为凋亡小体)形成确定。
这里的术语“抗体”用其最广泛的意义,尤其包含完整的单克隆抗体,多克隆抗体,由至少两个完整抗体形成的多特异性抗体(例如双特异性抗体),以及能显示所需生物学活性的任何抗体片段。
“抗体片段”包括完整抗体的一部分,优选包括抗体的抗原结合区或可变区。抗体片段的实例包括Fab,Fab’,F(ab’)2,和Fv片段;二价抗体;线性化抗体;单链抗体分子;和由抗体片段构成的多特异性抗体。
“天然抗体”通常是约150,000道尔顿的异源四聚体糖蛋白,由两个相同的轻链(L)和两个相同的重链(H)构成。每条轻链通过一个共价二硫键与重链连接,免疫球蛋白不同型的重链中二硫键数目不同。每条重链和轻链还具有规则间隔的链内二硫键。每个重链在其一个端有可变区(VH),紧接着多个恒定区。每个轻链在其一端有可变区(VL),而另一端有恒定区;轻链恒定区与重链第一恒定区并列,轻链的可变区与重链的可变区并列。认为某些氨基酸残基在轻链和重链的可变区之间形成一个界面。
术语“可变的”是指不同抗体的可变区特定部分序列差异很大,且这些部分在每种抗体与其特定抗原的结合和特异性中有用。然而在抗体整个可变区中可变性的分布并不均等。它集中在轻链和重链可变区的三个被称为高变区的节段中。可变区的更高度保守部分被称为框架区(FR)。天然轻链和重链的可变区分别包含四个FR,它们大多采用β折叠构象,通过三个高变区相连,这些高变区形成环状,有时形成β折叠结构的一部分。每条链的高变区通过FR紧密连接,并与其他链的高变区共同形成抗体的抗原结合位点(见Kabat等,具有免疫学意义的蛋白的序列,第5版,Public HealthService,National Institutes of Health,Bethesda,MD.(1991))。恒定区不直接参与抗体对抗原的结合,但显示多种效应功能,如使抗体参与抗体依赖性细胞介导的细胞毒作用(ADCC)。
抗体经木瓜蛋白酶消化产生两个相同的称为“Fab”的抗原结合片段和一个残余“Fc”片段,每个Fab片段具有单个抗原结合位点,Fc的名称反映了其容易形成结晶的能力。胃蛋白酶处理产生一个F(ab’)2片段,它有两个抗原结合位点并仍能与抗原交叉结合。
“Fv”是包含完整的抗原识别和抗原结合位点的最小抗体片段。这个区域是由一条重链和一个轻链可变区紧密、非共价结合成的二聚体。在VH-VL二聚体表面,每个可变区的三个高变区在此构型上相互作用,从而限定一个抗原结合位点。六个高变区共同赋予抗体以抗原结合特性。但即使单个可变区(或Fv中仅包含三个抗原特异性高变区的那一半)也能识别并结合抗原,只是比完整结合位点的亲和力低。
Fab片段还包含轻链恒定区和重链的第一恒定区(CH1)。Fab’不同于Fab片段之处在于,其重链CH1区的羧基端添加了数个残基,其中包括来自抗体铰链区的一或多个半胱氨酸。本文中Fab’-SH指一种Fab’,其中恒定区的半胱氨酸残基有至少一个游离巯基。F(ab’)2抗体片段最初是作为Fab’片段对且它们之间有铰链区半胱氨酸的形式产生的。抗体片段的其它化学连接也是已知的。
脊椎动物任何物种的抗体(免疫球蛋白)的“轻链”可以是两种完全不同的型(κ和λ)之一,型别区分的依据是其恒定区氨基酸序列。
抗体依据其重链恒定区氨基酸序列分为不同的类。完整抗体有五大类:IgA,IgD,IgE,IgG和IgM,其中几种能进一步分为亚型(同种型),例如IgG1,IgG2,IgG3,IgG4,IgA和IgA2。对应于不同类抗体的重链恒定区分别被称为α,δ,ε,γ和μ。免疫球蛋白不同类的亚单位和三维构型是已知的。
“单链Fv”或“scFv”抗体片段包括抗体的VH和VL结构域,这些结构域存在于单个多肽链上。优选Fv多肽在VH和VL结构域之间还包含一个多肽接头,它能使scFv形成抗原结合所需的结构。关于scFv的综述见Pluckthun在《单克隆抗体的药理学》,第113卷,Rosenburg和Moore编,Springer-Verlag,New York,第269-315页(1994)。
术语“二价抗体(diabodies)”是指具有两个抗原结合位点的小分子抗体片段,这些片段在一条多肽链(VH-VL)上含有相连的一个重链可变区(VH)和一个轻链可变区(VL)。利用一种非常短的接头,其使得同一条链上的两个结构域无法配对,不得不与另一条链上的互补结构域配对,从而形成两个抗原结合位点。在EP 404,097;WO93/11161;和Hollinger等,美国国家科学院学报,90:6444-6448(1993)中有对二价抗体的更详细描述。
本文中术语“单克隆抗体”指从实质上均一的抗体群获得的抗体,即包含该群体的单个抗体除了可能自然发生的很少量突变以外都相同。单克隆抗体均以高度特异性直接针对单个抗原位点。此外,与通常包括针对不同决定簇(表位)的不同抗体的传统(多克隆)抗体制剂相比,每种单克隆抗体直接针对抗原上的单个决定簇。单克隆抗体除了具有特异性,其优势还在于,它们是通过杂交瘤培养而合成的,无其它免疫球蛋白的污染。修饰语“单克隆的”指抗体获自实质上均一的抗体群的特征,不应理解为限定由任何具体方法产生抗体。例如根据本发明使用的单克隆抗体可以用由Kohler等,自然,256:495(1975)首次描述的杂交瘤方法来制备,或用重组DNA法(如美国专利4,816,567)来制备。“单克隆抗体”还可以是用Clackson等,自然,352:624-628(1991)和Marks等,分子生物学杂志,222:581-597(1991)所述技术从噬菌体抗体库中分离得到。
本文中单克隆抗体具体包括“嵌合”抗体(免疫球蛋白),其中所述嵌合抗体中重链和/或轻链的一部分等同于或同源于来自特定物种的抗体或属于特定抗体类或亚类的抗体的相应序列,链的其余部分等同于或同源于来自其它物种的抗体或属于另一抗体类或亚类的抗体的相应序列,只要它们展示所需生物学活性(见美国专利4,816,567;Morrison等,美国国家科学院学报,81:6851-6855(1984))。本文的目标嵌合抗体包括“灵长类化(primatized)”抗体,其包含源于非人灵长类可变区的抗原结合序列(如OldWorld Monkey,如狒狒,猕猴(rhesus)或恒河猴(cynomolgus monkey))和人的恒定区序列(美国专利5,693,780)。
“人源化”形式的非人(如鼠)抗体是包含源于非人免疫球蛋白的最小序列的嵌合抗体。在多数情况下,人源化抗体是下述人免疫球蛋白(受者(recipient)抗体),其中受者的高变区残基被非人物种如小鼠、大鼠、兔或非人灵长类(供者(donor)抗体)的具有所需特异性、亲和力和能力(capacity)的高变区的残基取代。在一些例子中,人免疫球蛋白框架区(FR)残基被相应的非人残基取代。而且人源化抗体可包含未在受者抗体或供者抗体中发现的残基。这些修饰旨在进一步改进抗体的功能。一般情况下,人源化抗体基本上包含至少一个、通常两个完整可变区,其中所有或基本上所有高变环对应于非人免疫球蛋白的那些,所有或基本上所有FR是人的免疫球蛋白序列中的那些。人源化抗体任选还包含免疫球蛋白、通常为人免疫球蛋白的恒定区(Fc)的至少一部分。详见Jones等,自然321:522-525(1986);Riechmann等,自然332:323-329(1988);和Presta,Curr.Op.Struct.Biol.2:593-596(1992)。
本文中术语“高变区”是指抗体中负责抗原结合的氨基酸残基。高变区含有“互补决定区”或“CDR”的氨基酸残基(例如轻链可变区的残基24-34(L1),50-56(L2)和89-97(L3),重链可变区的残基31-35(H1),50-65(H2)和95-102(H3);Kabat等,具有免疫学意义的蛋白的序列,第5版,Public HealthService,National Institutes of Health,Bethesda,MD.(1991)),和/或“高变环”的残基(例如轻链可变区的残基26-32(L1),50-52(L2)和91-96(L3),重链可变区的残基26-32(H1),53-55(H2)和96-101(H3);Chothia和Lesk,分子生物学杂志196:901-917(1987))。“框架区”或“FR”残基是除本文所定义的高变区残基以外的可变区残基。
“结合”目的抗原如CD20的拮抗剂是下述拮抗剂,其能以足够的亲和力结合该抗原,因而其可作为靶向表达该抗原的细胞的治疗剂。
与CD20抗原结合的抗体有:“C2B8”现在被称为“rituximab”(“RITUXAN”)(美国专利5,736,137,引入作为参考);钇-[90]-标记的2B8鼠抗体“Y2B8”(美国专利5,736,137,引入作为参考);任选用131I标记鼠IgG2a“B1”产生“131I-B1”抗体(BEXXARTM)(美国专利5,595,721,引入作为参考);鼠单克隆抗体“IF5”(Press等Blood 69(2)):584-591(1987));“嵌合2H7”抗体(美国专利5,677,180,引入作为参考);和可从国际白细胞分型小组(International Leukocyte Typing Workshop)获得的单克隆抗体L27,G28-2,93-1B3,B-C1或NU-B2(Valentine等,在《白细胞分型III》(McMichael编,第440页,Oxford University Press(1987))。
本文中术语“rituximab”或“RITUXAN”指经遗传工程改造的、针对CD20抗原的嵌合鼠/人单克隆抗体,在美国专利5,736,137(引入作为参考)中命名为“C2B8”。该抗体是含小鼠轻链和重链可变区序列及人的恒定区序列的IgG1κ型免疫球蛋白。Rituximab结合CD20的亲和力为约8.0nM。
“分离”的拮抗剂是已经从其自然环境组分中鉴定并分离和/或回收的拮抗剂。其自然环境中的污染成分有,可干扰该拮抗剂的诊断和治疗应用的物质,可能包括酶、激素和其它蛋白或非蛋白溶质。在优选实施方案中,,该拮抗剂的纯度应达到:(1)经Lowery法确定的拮抗剂比重为95%以上,最优选99%以上,(2)足以获得用旋转杯状(spinning cup)序列分析仪所测至少15个残基的N端或内部氨基酸序列,(3)通过还原或非还原条件下的SDS-PAGE以及考马斯亮蓝染色、优选银染所证实的均质性。分离的拮抗剂包括重组细胞内的原位拮抗剂,因为该拮抗剂的自然环境中的至少一种组分已不存在。但一般情况下分离的拮抗剂可通过至少一个纯化步骤来制备。
需要治疗的“哺乳动物”是指归为哺乳动物的任何动物,包括人、家畜和农场动物,以及动物园里的动物、参与运动项目的动物或宠物如狗、马、猫、牛等。优选所述哺乳动物为人类。
“治疗”是指治疗方法和预防措施。需要治疗者包括已经患病者,以及需要对疾病进行预防者。因此,哺乳动物可能被诊断为已患病或对所述疾病易感。
“治疗有效量”是指能有效阻止,改善或治疗目标疾病的拮抗剂的量。
本文用于辅助治疗的术语“免疫抑制剂”是指能抑制或掩盖所治哺乳动物的免疫系统的物质。这将包括能抑制细胞因子的产生,下调或抑制自身抗原的表达,或掩盖MHC抗原的物质。这些制剂的例子包括2-氨基-6-芳基-5-取代的嘧啶(见美国专利4,665,077,其全文引入本文作参考);抗增殖剂,如硫唑嘌呤;leflunomide或sirolimus,环磷酰胺;溴麦角环肽;达那唑;氨苯砜;戊二醛(它掩盖MHC抗原,如美国专利4,120,649所述);抗MHC抗原和MHC片段的抗独特型抗体;环孢菌素A;类固醇如糖皮质激素,例如强的松,甲基强的松龙和地塞米松;细胞因子或细胞因子受体拮抗剂包括抗IFN-γ,-β或-α抗体,抗TNF-α抗体,抗TNF-β抗体,抗IL-2抗体和抗IL-2受体抗体;抗LFA-1抗体,包括抗CD11a和抗CD18抗体;抗L3T4抗体;抗淋巴细胞抗体,如多克隆抗淋巴细胞抗体;全(pan)-T抗体,优选抗CD3或抗CD4/CD4a抗体;包含LFA-3结合结构域的可溶性肽(公开于7/26/90的WO90/08187);链激酶;TGF-β;链道酶;源于宿主的RNA或DNA;FK506;RS-61443;脱氧精胍菌素;雷帕霉素;T细胞受体(Cohen等,美国专利5,114,721);T细胞受体片段(Offner等,科学,251:430-432(1991));WO90/11294;Ianeway,自然,341:482(1989);和WO91/01133);和T细胞受体抗体(EP 340,109)例如T10B9。
本文中术语“细胞毒制剂”是指抑制或阻止细胞功能和/或引起细胞破坏的物质。该术语旨在包括放射性核素(例如At211,I131,I125,Y90,Re186,Re188,Sm153,Bi212,P32和镥的放射性同位素),化疗制剂,毒素如小分子毒素或细菌、真菌、植物或动物来源的酶活性毒素,或它们的片段。
“化疗制剂”是在癌症治疗中使用的化学化合物。化疗制剂实例包括烷化剂,如噻替哌(thiotepa);环膦酰胺(cyclosphamide)(CYTOXANTM);烷基磺酸酯如白消安(busulfan),英丙舒凡(improsulfan)和哌泊舒凡(piposulfan);氮丙啶如苄替哌(benzodopa),卡波醌(carboquone),美妥替哌(meturedopa)和尿烷亚胺(uredopa);氮丙啶和methylamelamine包括六甲蜜胺(altretamine),三乙撑蜜胺(triethylenemelamine),三亚乙基磷酰胺,三亚乙基硫代磷酰胺和三羟甲基蜜胺(trimethylolomelamine);氮芥(nitrogenmustards)如苯丁酸氮芥,萘氮芥,胆磷酰胺(cholophosphamide),雌氮芥(estramustine),异环磷酰胺(ifosfamide),氮芥(mechlorethamine),盐酸氧氮芥;左旋苯丙氨酸氮芥(melphalan),新氮芥(novembichin),胆甾醇苯乙酸氮芥,松龙苯芥(prednimustine),曲磷胺(trofosfamide),尿嘧啶氮芥;亚硝基脲(nitrosureas)如亚硝基脲氮芥(carmustine),氯脲菌素(chlorozotocin),福莫司汀(fotemustine),洛莫司汀(lomustine),尼莫司汀(nimustine),雷莫司汀(ranimustine);抗生素如阿克拉霉素,放线菌素,authramycin,重氮丝氨酸,博来霉素,放线菌素C(cactinomycin),加利车霉素(calicheamicin),carabicin,洋红霉素(chromomycin),嗜癌素(carzinophilin),色霉素,放线菌素D,道诺红菌素(daunorubicin),地托比星(detorubicin),6-重氮-5-氧-L-正亮氨酸,阿霉素(doxorubicin),表阿霉素(epirubicin),依索比星(esorubicin),伊达比星(idarubicin),发波霉素(marcellomycin),丝裂霉素,霉酚酸,诺加霉素(nogalamycin),橄榄霉素(olivomycin),培洛霉素(peplomycin),potfiromycin,嘌呤霉素,三铁阿霉素(quelamycin),罗多比星(rodorubicin),链黑菌素;链脲霉素(streptozocin),杀结核菌素,乌苯美司(ubenimex),净司他丁(zinostatin),佐柔比星(zorubicin);抗代谢药如氨甲蝶呤,5-氟尿嘧啶(5-FU);叶酸类似物如二甲叶酸(denopterin),氨甲蝶呤,丁蝶翼素(pteropterin),三甲曲沙(trimetrexate);嘌呤类似物氟达拉滨(fludarabine),6-巯基嘌呤,硫咪嘌呤,硫鸟嘌呤;嘧啶类似物如安西他滨(ancitabine),阿扎胞苷(azacitidine),6-氮尿苷,卡莫氟(carmofur),阿糖胞苷,双脱氧尿苷,doxifluridine,依诺他滨(enocitabine),氟尿苷,5-FU;雄激素类如二甲睾酮,丙酸甲雄烷酮(dromostanolong propionate),环硫雄醇(epitiostanol),美雄氨(mepitiostane),睾内酯(testolactone);抗肾上腺类如氨鲁米特(aminoglutethimide),邻氯苯对氯苯二氯乙烷(mitotane),曲洛司坦(trilostane);叶酸补充剂如frolinic acid;醋葡内酯;醛磷酰胺糖苷(aldophosphamide glycoside);氨基乙酰丙酸(aminolevulinic acid);安吖啶(amsacrine);bestrabucil;比生群(biasntrene);依达曲沙(edatraxate);磷氨氮芥(defofamine);秋水仙胺;地吖醌(diaziquone);依洛尼塞(elfornithine);醋酸羟吡咔唑(elliptinium acetate);依托格鲁(etoglucid);硝酸镓;羟基脲;香菇多糖(lentinan);氯尼达明(lonidamine);米托胍腙(mitoguazone);米托蒽醌(mitoxantrone);莫哌达醇(mopidamol);二胺硝吖啶(nitracrine);喷司他丁(pintostatin);phenamet;吡柔比星(pirarubicin);鬼臼树酸(podophyllinic acid);2-乙基酰肼;丙卡巴肼(procarbazine);PSK;雷佐生(razoxane);西索菲兰(sizofiran);锗螺胺(spirogermanium);细交链孢菌酮酸;三亚胺醌;2,2′,2″-三氯三乙胺(trichlorrotriethylamine);乌拉坦(urethan);长春碱酰胺;达卡巴嗪(dacarbazine);甘露醇氮芥;二溴甘露醇(mitobronitol);二溴卫矛醇;溴丙哌嗪(pipobroman);gacytosine;阿拉伯糖苷(“Ara-C”);环磷酰胺;塞替哌(thiotepa);紫杉烷(taxoid),如紫杉醇(TAXOL,Bristol-Myers SquibbOncology,Princeton,NJ)和doxetaxel(TAXOTERE,Rhone-Poulenc Rorer,Antony,France);苯丁酸氮芥;吉西他滨(gemcitabine);6-硫代鸟嘌呤;巯基嘌呤;氨甲蝶呤;铂类似物如顺铂和卡铂;长春花碱;铂;鬼臼乙叉甙(etoposide)(VP-16);异环磷酰胺;丝裂霉素C;米托蒽醌;长春新碱;长春瑞宾(vinorelbine);新霉酰氨(navelbine);二羟基蒽酮(novantrone);替尼泊甙(teniposide);柔红霉素;氨基蝶呤;xeloda;伊拜膦酸盐(ibandronate);CPT-11;拓扑异构酶抑制剂RFS 2000;二氟甲基鸟氨酸(DMFO);维甲酸;esperamicins;capecitabine;以及上述任何物质的可药用盐,酸或衍生物。此定义还包括能调节或抑制激素对肿瘤的作用的抗激素制剂,如抗雌激素制剂包括他莫昔芬(tamoxifen),雷洛昔芬(raloxifene),芳香酶抑制剂4(5)-咪唑,4-羟基他莫昔芬,曲沃昔芬(trioxifene),keoxifene,LY117018,奥那司酮(onapristone),和托瑞米芬(Fareston);和抗雄激素制剂如氟他氨(flutamide),尼鲁米特(nilutamide),bicalutamide,亮丙瑞林(leuprolide)和戈舍瑞林(goserelin);和上述任何物质的可药用盐,酸或衍生物。
术语“细胞因子”是由一个细胞群释放的、作为细胞间介质作用于另一细胞的蛋白的总称。这类细胞因子有淋巴因子,单核因子,和传统的多肽激素。包括生长激素,如人生长激素,N-甲二磺酰人生长激素,和牛生长激素;甲状旁腺素;甲状腺素;胰岛素;前胰岛素;松驰素;前松驰素;糖蛋白激素如卵泡刺激素(FSH),甲状腺刺激激素(TSH),促黄体(生成)激素(LH);肝细胞生长因子;成纤维细胞生长因子;催乳激素;胎盘催乳素;肿瘤坏死因子-α和β;苗勒-抑制物;小鼠促性腺激素相关肽;抑制素;苯丙酸诺龙;血管内皮细胞生长因子;整联蛋白;血小板生成素(TPO);神经生长因子如NGF-β;血小板生长因子;转化生长因子(TGF)如TGF-α和TGF-β;胰岛素样生长因子-I和-II;红细胞生成素(EPO);骨诱导因子(osteoinductive factors);干扰素如干扰素-α,-β,-γ;集落刺激因子(CSF)如巨噬细胞-CSF(M-CSF);粒细胞-巨噬细胞-CSF(GM-CSF);粒细胞-CSF(G-CSF);白细胞介素(IL)如IL-1,IL-1α,IL-2,IL-3,IL-4,IL-5,IL-6,IL-7,IL-8,IL-9,IL-11,IL-12,IL-15;肿瘤坏死因子如TNF-α或TNF-β;和其它多肽因子包括LIF和kit配体(KL)。本文中术语细胞因子包括天然蛋白或来自重组细胞培养物的蛋白以及天然序列细胞因子的生物活性等效物。
本发明使用的术语“前体药物”是指药物活性物质的前体或衍生物形式,其相对于亲本药物对肿瘤细胞的细胞毒作用较小且可酶促活化或被转换成更具活性的亲本形式。例见Wilman,“癌症化疗中的前体药物”Biochemical Society Transaction,14,pp.375-382,615th Meeting Belfast(1986)和Stella等,“前体药物:一种药物定向运送的化学方法”定向药物运送,Borchardt等(编),pp.247-267,Humana press(1985)。本发明的前体药物包括,但不限于含有磷酸盐的前体药物,含有硫代磷酸盐的前体药物,含有硫酸盐的前体药物,含有肽的前体药物,D-氨基酸修饰的前体药物,糖基化的前体药物,含有β-内酰胺的前体药物,任选含有取代的苯氧乙酰胺的前体药物或任选含有取代的苯基乙酰胺的前体药物,可转化为更具细胞毒活性的游离药物的5-氟胞嘧啶和其它5-氟尿嘧啶前体药物。可衍生为本发明所用前体药物形式细胞毒药物包括,但不限于上述化疗试剂。
“脂质体”是由能向哺乳动物有效运送药物(如本文所公开的拮抗剂,和,任选地,一种化疗试剂)的各类脂质、磷脂和/或表面活性剂组成的小分子载体。通常将脂质体成分安排为一种双层形式,其类似于生物膜的脂质排列。
所用的术语“包装插页”是指通常包括在治疗产品的商业包装中,含有与这些治疗产品的使用有关的说明,用法,剂量,给药,禁忌和/或警示等的说明书。
II.拮抗剂的制备
本发明的方法和制品使用,或掺入了一种能结合CD20的拮抗剂。相应地,本文还描述了产生这类拮抗剂的方法。
用于产生或筛选拮抗剂的CD20可以是,如抗原的可溶形式或其一部分,包括所需表位。或者,或任选,在表面表达所述CD20的细胞可用于产生或筛选拮抗剂。可用于产生拮抗剂的其它形式的CD20为本领域所显而易见。
虽然优选的拮抗剂是抗体,但除抗体以外的其它拮抗剂也包括在此。例如,拮抗剂可含有任选融合至或偶联于细胞毒试剂(如本文所公开的那些)的小分子。可在小分子文库中筛选本文的目标CD20,以便鉴定能与该抗原结合的小分子。还可进一步筛选小分子的拮抗特性和/或使其与细胞毒试剂偶联。
拮抗剂也可以是经合理设计或噬菌体展示(例见WO98/35036,1998年8月13日公开)。在一个具体实施方案中,所选的分子可以是“CDR类似物”或基于抗体CDR而设计的抗体类似物。尽管所述肽本身可能就有拮抗性,但任选将此肽与细胞毒制剂融合,以便添加或增强此肽的拮抗性。
以下为本发明所用抗体拮抗剂的产生技术举例。
(i)多克隆抗体
多克隆抗体优选通过多次给动物皮下(sc)或腹膜内(ip)注射相关抗原和佐剂而产生。将所述相关抗原与针对所免疫的物种具有免疫原性的蛋白(如匙孔血蓝蛋白(keyhole limpet hemocyanin)、血清白蛋白、牛甲状腺球蛋白或大豆胰蛋白酶抑制剂)用双功能试剂或衍生试剂,如马来酰亚氨苯甲酰基硫代琥珀酰亚胺酯(通过半胱氨酸残基结合)、N-羟基琥珀酰亚胺(通过赖氨酸残基)、戊二醛、琥珀酸酐、SOCl2或R1N=C=NR(R和R1是不同烷基),进行偶联是有效的。
用所述抗原、免疫原性偶联物或衍生物免疫动物,方法是,将100μg或5μg蛋白或偶联物(分别针对兔或鼠)与3倍体积的弗氏完全佐剂混合,在多位点皮内注射该溶液。1个月后,多位点皮内注射起始量的1/5-1/10的肽或与弗氏完全佐剂的偶联物来加强免疫。7-14天后,对动物采血,测定血清中的抗体滴度。对动物的加强免疫直到滴度达到平台期为止。优选给动物加强注射相同抗原的偶联物,但也可以是偶联至不同蛋白和/或通过不同的交联剂偶联的偶联物。偶联物还可以是重组细胞培养物产生的融合蛋白。此外,可用明矾等聚集剂增强免疫应答。
(ii)单克隆抗体
单克隆抗体来自基本均一的抗体群,即该群体中的每个抗体除了可能的很小量天然突变外都相同。因此,修饰词“单克隆”指所述抗体的并非不同抗体混合物的特性。
例如,单克隆抗体可用由Kohler等,自然(1975)首次描述的杂交瘤技术制备,或用重组DNA方法制备(美国专利4,816,567)。
在杂交瘤方法中,如上所述免疫小鼠或其它适合的宿主动物如仓鼠,以激发那些产生或能产生与用于免疫之蛋白特异性结合的抗体的淋巴细胞。另外,可体外免疫淋巴细胞。然后用适当融合剂,如聚乙二醇,使淋巴细胞与骨髓瘤细胞融合,形成杂交瘤细胞(Goding,单克隆抗体:原理及应用,pp.59-103(Academic Press,1986))。
将如此制备的杂交瘤细胞接种至适当培养基中并培养,优选该培养基含有一或多种能抑制未融合的亲本骨髓瘤细胞生长或存活的物质。例如,如果亲本骨髓瘤细胞缺乏次黄嘌呤鸟嘌呤磷酸核糖基转移酶(HGPRT或HPRT),杂交瘤培养基通常将包含次黄嘌呤、氨基蝶呤和胸腺嘧啶核苷(HAT培养基),这些物质阻止HGPRT-缺陷型细胞的生长。
优选骨髓瘤细胞是那些能有效融合、支持所选抗体生成细胞以稳定的高水平产生抗体,并对诸如HAT培养基等类似培养基敏感的细胞。其中,优选的骨髓瘤细胞系是鼠骨髓瘤系,如由Salk Institute Cell DistreibutionCenter,San Diego,California USA提供的MOPC-21和MPC-11小鼠肿瘤细胞和由美国典型培养物保藏中心,Rockville,Maryland USA提供的SP-2或X63-Ag8-653细胞。也有报道称人骨髓瘤以及小鼠-人异质性骨髓瘤细胞系可用于产生人单克隆抗体(Kozbor,免疫学杂志133:3001(1984);Brodeur等,单克隆抗体制备技术及应用,pp.51-63(Marcel Dekker,Inc.,New York,1987))
可在含有生长的杂交瘤细胞的培养基中分析直接针对所述抗原的单克隆抗体的产生。杂交瘤细胞所产生的单克隆抗体的结合特异性通过免疫沉淀或通过体外结合试验,如放射免疫分析(RIA)或酶联免疫吸附试验(ELISA)来分析。
单克隆抗体的结合亲和力可通过如Muson等,Anal.Biochem.,107:220(1980)所述Scatchard分析来测定。
一旦鉴定出能产生具有所需特异性、亲和力、和/或活性的抗体的杂交瘤细胞后,将这些克隆通过有限稀释法进一步克隆并用标准方法进行培养(Goding,单克隆抗体:原理及应用,pp.59-103(Academic Press,1986))。适于此目的的培养基包括如D-MEM或RPMI-1640培养基。另外,杂交瘤细胞可作为腹水中肿瘤的形式在动物体内生长。
由亚克隆分泌的单克隆抗体可用常规免疫球蛋白纯化方法如蛋白-A-Sepharose、羟基磷灰石层析、凝胶电泳、透析或亲和层析从培养基、腹水或血清中分离。
编码单克隆抗体的DNA可用常规方法很容易地分离和测序(如利用能与编码小鼠抗体重链和轻链的基因特异结合的寡核苷酸探针)。杂交瘤细胞是这类DNA的优选来源。DNA分离后,可将其插入表达载体中,然后用此表达载体转染宿主细胞,如大肠杆菌细胞、猴COS细胞、中国仓鼠卵巢(CHO)细胞或不产生免疫球蛋白的骨髓瘤细胞,以便在重组宿主细胞中合成单克隆抗体。编码抗体的DNA在细菌中的重组表达的综述见Skerra等,Curr.Opinion in Immuno1.,5:256-262(1993)和Pluckthun,Immunol.Revs.,130:151-188(1992)。
在另一实施方案中,可从用McCafferty等,自然,348:552-554(1990)所述技术产生的抗体噬菌体文库中分离抗体或抗体片段。Clackson等,自然,352:624-628(1991)和Marks等,分子生物学杂志222:581-597(1991)分别描述了用噬菌体文库分离鼠和人的抗体。后来的文献描述了通过链改组制备高亲和力(nM范围)的人型抗体(Marks等,生物/技术10:779-783(1992)),以及用于构建大规模噬菌体文库的组合感染和体内重组方法(Waterhouse等,核酸研究21:2265-2266(1993))。因此,这些技术都可取代传统单克隆抗体杂交瘤技术来分离克隆抗体。
DNA也可通过用人类重链和轻链的恒定区编码序列取代小鼠同源序列来修饰(美国专利4,816,567;Morrison等,美国国家科学院学报81:6851(1984)),或通过将非免疫球蛋白多肽的全部或部分编码序列与免疫球蛋白编码序列共价结合来修饰。
通常用所述非免疫球蛋白多肽取代抗体恒定区,或取代抗体上一个抗原结合点的可变区,形成二价嵌合抗体,其中一个抗原结合位点特异于一种抗原而另一个抗原结合位点特异于另一种抗原。
(iii)人源化抗体
本领域已有关于人源化非人类抗体的制备方法的描述。优选人源化抗体中已导入一或多个源自非人类的氨基酸残基。这些非人类氨基酸残基常称为“引进的”残基,它们通常来自“引进的”可变区。人源化过程基本如Winter及其同事(Jones等,自然,321:522-525(1986);Riechmann等,自然,332:323-327(1988);Verhoeyen等,科学,239:1534-1536(1988))所述,用高变区序列取代人类抗体的相应序列来进行。因此,这样的“人源化”抗体是嵌合抗体(美国专利4,816,567),其中完整人类可变区的很少一部分被非人类物种的相应序列取代。实践中,人源化抗体通常是人的抗体,其中高变区残基且可能有部分FR残基被啮齿类抗体中类似位点的残基取代。
对用于制备人源化抗体的人类可变区包括重链和轻链的选择,对降低抗原性非常重要。根据所谓“最适应”方法,针对已知人类可变区序列的整个文库筛选啮齿类抗体可变区序列。将与啮齿类的序列最相似的人类序列作为人源化抗体的人框架区(FR)(Sims等,免疫学杂志,151:2296(1993);Chothia等,分子生物学杂志,196:901(1987))。另一种方法是用人类轻链或重链特定亚型的所有抗体的共有序列作为特定框架区。相同的框架可用于几种不同的人源化抗体(Carter等,美国国家科学院学报,89:4285(1992);Presta等,免疫学杂志,151:2623(1993))。
更重要的是,将抗体人源化后保留了对抗原的高亲和力和其它有利的生物特性。为达到此目的,在一种优选方法中,通过用亲本序列和人源化序列的三维模型分析亲本序列和各种概念性人源化产物来制备人源化抗体。免疫球蛋白三维模型已有商品,是本领域技术人员所熟悉的。还有用于描述和展示所选免疫球蛋白序列可能的三维构象的计算机程序。通过观察这些展示结果可分析残基在候选免疫球蛋白序列的功能中可能发挥的作用,即分析能影响候选免疫球蛋白与其抗原结合的能力的残基,通过这种方法,可从受者和引进序列中选出FR残基并组合,从而得到所需抗体性质,如对靶抗原的亲和力增加。总之,高变区残基直接并且最主要涉及对抗原结合的影响。
(iv)人类抗体
除了进行人源化以外还可制备人类抗体。例如现在已能产生如下转基因动物(如小鼠),它们通过免疫能产生人类抗体的所有成分而不产生内源免疫球蛋白。例如,有报道称,嵌合及种系(germ-line)突变小鼠中抗体重链连接区(JH)基因的纯合缺失导致内源抗体的产生被完全抑制。将人类种系免疫球蛋白基因阵列转移到这类种系突变小鼠中将导致因抗原攻击而诱导人类的抗体产生。见Jakobovits等,美国国家科学院学报,90:2551(1993);Jakobovits等,自然,362:255-258(1993);Bruggermann等,Year in Immuno.7:33(1993);和美国专利5591669,5589369和5545807。
或者,可用噬菌体展示技术(McCafferty等,自然348:552-553(1990))从未免疫供者的免疫球蛋白可变(V)区基因的所有组成而体外产生人类抗体和抗体片段。依据此技术,将抗体V区基因克隆在与丝状噬菌体(如M13或fd)主要或次要衣壳蛋白基因相同的框架内,并在噬菌体颗粒的表面展示为功能性抗体片段。因为丝状颗粒包含噬菌体基因组的单链DNA拷贝,根据抗体的功能特点进行的选择也导致对显示这些性质的抗体的编码基因进行选择。因此,噬菌体模仿了B细胞的部分特点。噬菌体展示可以以多种形式进行;这些综述见Johnson,Kevin S.和Chiswell,David J.,结构生物学的最新观点(Current Opinion in Structural Biology)3:564-571(1993)。可使用V基因片段的多个来源进行噬菌体展示。Clackson等,自然,352:624-628(1991)从免疫小鼠脾脏来源的V基因的随机组合小文库中分离了抗-恶唑酮抗体的一个多样性阵列。可基本如Marks等,分子生物学杂志222:581-597(1991),或Griffith等,EMBO J.12:725-734(1993)所述构建未免疫人类供者的V基因所有组成,并分离针对抗原多样性阵列(包括自身抗原)的抗体。亦参见美国专利5565332和5573905。
人类抗体也可通过体外激活的B细胞而产生(见美国专利5,567,610和5,229,275)。
(v)抗体片段
已开发了生成抗体片段的多种技术。传统上,这些片段通过对完整抗体的蛋白水解性消化获得(见Morimoto等,生物化学和生物物理学方法杂志(Journal of Biochemical and Biophysical Methods)24:107-117(1992))和Brennan等,科学,229:81(1985))。但现在可直接通过重组宿主细胞产生这些片段。例如,可从上述抗体噬菌体库分离抗体片段。另外,可从大肠杆菌直接回收Fab’-SH片段,并经化学连接形成F(ab’)2片段(Carter等,生物/技术10:163-167(1992))。依据另一种方法,可直接从重组宿主细胞培养中分离F(ab’)2片段。其它产生抗体片段的技术对本领域技术人员是显而易见的。在其它实施方案中,所选抗体是单链Fv片段(scFv)。见WO 93/16185;美国专利5,571,894;和美国专利5,587,458。抗体片段也可以是“线性化抗体”,如美国专利5,641,870所述。这类线性化抗体片段可以是单特异性或双特异性的。
(vi)双特异性抗体
双特异性抗体是具有针对至少两种不同表位的结合特异性的抗体。如双特异性抗体可以与CD20物的两种不同表位结合。其它这类抗体可以结合第一个CD20并再结合第二个CD20。或者,可将抗B细胞标志物的结合臂与结合白细胞上引发分子的臂结合,从而集中针对B细胞的细胞防御机制,所述引发分子如T细胞受体分子(CD2或CD3),或IgG Fc受体(FcγR)如FcγRI(CD64)、FcγRII(CD32)和FcγRIII(CD16)。双特异性抗体还可用于将细胞毒制剂定位至B细胞。这些抗体具有B细胞标志物结合臂和结合细胞毒制剂(例如皂草素,抗INF-α,长春花生物碱,蓖麻毒蛋白A链,氨甲蝶呤或放射性同位素半抗原)的臂。双特异性抗体可制备成全长抗体或抗体片段(如F(ab’)2双特异性抗体)。
制备双特异性抗体的方法是本领域已知的。完整双特异性抗体的传统制备方法是基于两种免疫球蛋白重链-轻链对的共表达,其中这两条链具有不同特异性(Millstein等,自然,305:537-539(1983))。由于免疫球蛋白重链轻链随机分配,这些杂交瘤(quadroma)可能产生10种不同抗体分子的混合物,其中只有一种具有正确的双特异性结构。对所述正确分子的纯化(通常通过亲和层析步骤来进行)非常复杂,且产量很低。类似的方法见WO93/08829和Traunecker等,EMBO J,10:3655-3659(1991)。
依据另一种方法,可将具有所需结合特异性(抗体-抗原结合位点)的抗体可变区与免疫球蛋白恒定区序列融合。该融合优选与包含铰链区的至少一部分、CH2及CH3区的免疫球蛋白重链恒定区融合。优选使含有轻链结合所需位点的第一重链恒定区(CH1)出现在至少在一种融合中。可将编码免疫球蛋白重链融合体,以及必要时,编码免疫球蛋白轻链的DNA插入不同表达载体,共转染至适当宿主生物。这使得在使用非等比的三种多肽链进行构建的实施方案中,能够较灵活地调整三种多肽片段的相互比例,以获得最佳产量。但也可在至少两种多肽链以等比例表达而获得高产时或所述比例无特别意义时,将两种或所有三种多肽链的编码序列插入同一表达载体。
在该方法的一个优选实施方案中,所述双特异性抗体由一条臂上的带有第一结合特异性的杂合免疫球蛋白重链和另一条臂上的杂合免疫球蛋白重链-轻链对(提供第二结合特异性)构成。已发现这种不对称结构有利于从非必要免疫球蛋白链的混合中分离出所需双特异性化合物,因为只有该双特异性分子的一半上存在免疫球蛋白轻链,这使得分离更加容易。此方法公开于WO94/04690中。制备双特异性抗体的进一步细节,见Suresh等,酶学方法,121:210(1986)。根据美国专利5,731,168所述的另一种方法,可改造一对抗体分子之间的界面,使得从重组细胞培养中获得的异源二聚体的百分比最大。优选的界面包括抗体恒定区CH3结构域的至少一部分。在该方法中,源于第一抗体分子的界面上的一条或多条氨基酸小侧链被较大侧链(如酪氨酸或色氨酸)取代。与所述大侧链大小相同或相近的互补“沟”可通过将氨基酸大侧链用小侧链(如丙氨酸或苏氨酸)取代而在第二抗体分子的界面上形成。这使得异二聚体的产量比其它不需要的终产物如同型二聚体的高。
双特异性抗体包括交联抗体或“异源偶联的”抗体。例如,可使异源偶联物中的抗体之一与亲和素偶联,使另一抗体与生物素偶联。有观点认为,这类抗体可用于将免疫细胞导向不想要的细胞(美国专利4676980),也可用于治疗HIV感染(WO91/00360,WO92/200373,EP03089)。异源偶联抗体可通过任何适当的交联方法制备。适当的交联制剂和多种交联技术为本领域已知,可在美国专利4676980号中获得。
从抗体片段制备双特异性抗体的技术已有文献。例如,双特异性抗体可利用化学连接制备。Brennan等,科学229:81(1985)中描述了将完整抗体经蛋白水解制备F(ab′)2片段的方法。这些片段在二巯基复合剂亚砷酸钠存在时被还原,从而稳定相邻的巯基,并阻止分子间二硫键的形成。生成的Fab′片段被转化为硫硝基苯甲酸盐(TNB)衍生物。其中一种Fab′-TNB衍生物经巯基乙胺还原成Fab′-硫醇,再与等分子量的其它Fab′-TNB衍生物混合形成双特异性抗体。如此产生的双特异性抗体可作为酶的选择性固相化中所用的试剂。
近期的进展促进了Fab′-SH片段从大肠杆菌的直接回收,该片段可经化学偶联形成双特异性抗体。Shalaby等,实验医学杂志,175:217-225(1992)中描述了完全人源化双特异性抗体F(ab′)2分子的产生。每一Fab′片段分别从大肠杆菌中分泌出来,体外直接化学偶联形成双特异性抗体。如此制备的双特异性抗体能与过表达ErbB2受体的细胞和正常人T细胞结合,还能引发人类细胞毒淋巴细胞对人乳腺肿瘤靶的裂解活性。
直接从重组细胞培养中制备并分离双特异性抗体片段的多种技术也已有描述。例如,可用亮氨酸拉链制备双特异性抗体。Kostelny等,免疫学杂志,148(5):1547-1553(1992))。将来自Fos和Jun蛋白的亮氨酸拉链肽与两种不同抗体的Fab′部分通过基因融合而连接。使抗体的同型二聚体在铰链区被还原成单体,然后被再氧化形成抗体的异二聚体。该方法也可用于制备抗体同型二聚体。由Hollinger等,美国国家科学院学报,90:6444-6448(1993))描述的“二价抗体”技术提供了另一种制备双特异性抗体片段的方法。所述片段中含有重链可变区(VH),其通过接头与轻链可变区(VL)相连,该接头非常短,使得同一链的两个结构域之间无法配对。因此,同一片段上的VH和VL结构域被迫与另一片段上的互补VL和VH结构域配对,从而形成两个抗原结合位点。此外还报道了另一种用单链Fv(sFv)二聚体来制备双特异性抗体的策略。见Gruber等,免疫学杂志,152:5368(1994)。
还考虑了二价以上的抗体。如可制备三特异性抗体。Tutt等,免疫学杂志,147:60(1991)。
III.偶联以及对拮抗剂的其它修饰
本文方法或制品中提到的拮抗剂可任选与细胞毒制剂偶联。
可用于制备这些拮抗剂-细胞毒制剂偶联物的化疗试剂如上述。
本文还涉及拮抗剂与一或多种小分子毒素,如加利车霉素,美登素(美国专利5,208,020),单端孢霉烯(trichothene),CC1065的偶联物。在本发明的一个实施方案中,使拮抗剂与一或多个美登素分子偶联(如每个拮抗剂分子与约1-10个美登素分子偶联)。美登素可转化成May-SS-Me,然后还原成May-SH3,并与修饰过的拮抗剂反应(Chari等,癌症研究52:127-131(1992))产生美登木素生物碱-拮抗剂偶联物。
另外,拮抗剂可以与一或多个加利车霉素分子结合。加利车霉素家族的抗生素能在亚pM浓度水平产生双链DNA断裂。可使用的加利车霉素结构类似物包括,但不限于γ1 I、α2 I、α3 I、N-乙酰基-γ1 I、PSAG以及θ1 I(Hinmam等,癌症研究53:3336-3342(1993)和Lode等,癌症研究58:2925-2928(1998))。
可以应用的酶活性毒素及其片段包括:白喉毒素A链、白喉毒素的非结合活性片段、外毒素A链(来自铜绿假单孢菌)、蓖麻毒蛋白A链、相思豆毒蛋白A链、蒴莲根毒素A链、α-帚曲毒素、油桐(Aleutites fordii)蛋白、石竹素蛋白、美洲商陆(Phytolaca Americana)蛋白(PAPI,PAPII,PAP-S)、苦瓜(momordica charantia)抑制因子、麻疯树毒蛋白、巴豆毒蛋白、肥皂草(sapaonaria officinalis)抑制剂,白树毒素,米托菌素(mitogellin)、局限曲菌素、酚霉素、依诺霉素和单端孢菌毒素(tricothecenes)。例见1993年10月28日公开的WO93/21232。
本发明还涉及与具有核裂解活性的化合物(如核糖核酸酶或DNA内切核酸酶如脱氧核糖核酸酶;DNase)偶联的拮抗剂。
多种放射性同位素可用于制备放射性偶联的拮抗剂,实例包括At211、I131、I125、Y90、Re186、Re188、Sm153、Bi212、P32以及Lu的放射性同位素。
拮抗剂与细胞毒制剂的偶联物可通过多种双功能蛋白偶联剂来连接,所述双功能蛋白偶联剂如:N-琥珀酰亚氨基-3-(2-吡啶基二巯基)丙酸酯(SPDP),琥珀酰亚氨基-4-(N-马来酰亚氨甲基)环己烷-1-羧酸酯,iminothiolane(IT),亚氨酸酯的双功能衍生物(如亚氨基己二酸二甲酯盐酸盐),活性酯类(如二琥珀酰亚胺基辛二酸酯),醛类(如戊二醛(glutareldehyde)),双-叠氮化合物(如双(对-叠氮基苯甲酰基)己二胺),双-重氮衍生物(如双-(对-重氮苯甲酰基)-乙二胺),二异氰酸酯(如亚甲代苯基2,6-二异氰酸酯),和双-活性氟化合物(如1,5-二氟-2,4-二硝基苯)。例如,蓖麻毒蛋白免疫毒素可如Vitetta等,科学238:1098(1987)所述制备。C14标记的1-异硫氰酸苯甲基-3-甲基二亚乙基三氨五乙酸酯(MX-DTPA)是将放射性核苷酸偶联至拮抗剂的偶联剂之一。见WO94/11026。这种接头可能是有利于细胞毒药物在细胞内释放的“可断开的接头”。例如,可使用酸不稳定型接头,肽酶敏感型接头,二甲基接头或含二硫键的接头(Chari等,癌症研究52:127-131(1992))。
或者,可通过重组技术或肽合成来获得拮抗剂与细胞毒制剂的融合蛋白。
在另一实施方案中,拮抗剂可与肿瘤预靶向中应用的“受体”(如链霉亲和素)偶联,将该拮抗剂-受体偶联物给予患者,之后用清除剂除去循环中未结合的偶联物,再给予已偶联了细胞毒制剂(如放射性核苷酸)的“配体”(如亲和素)。
本发明的拮抗剂还可与前体药物活化酶相结合,该酶可以将前体药物(如肽基化疗剂,见WO81/01145)转化为活性抗癌药物。见WO88/07378和美国专利4,975,278。
这些偶联物中的酶组分包括能作用于前体药物使其转化为活性更强的细胞毒形式的任何酶。
本发明的方法中用到的酶包括,但不限于,能将含磷酸基的前体药物转化为游离药物的碱性磷酸酶;可将含硫酸基的前体药物转化为游离药物的芳香基硫酸酯酶;将无毒的5-氟胞嘧啶转化为抗癌药物,如5-氟尿嘧啶的胞嘧啶脱氨酶;能将含肽的前体药物转化为游离药物的蛋白酶,如沙雷氏菌属蛋白酶、嗜热菌蛋白酶、枯草杆菌蛋白酶、羧肽酶和组织蛋白酶(如组织蛋白酶B和L)等;可转化含D-氨基酸取代基的前体药物的D-丙氨酰羧肽酶;能将糖基化前体药物转化为游离药物的碳水化合物裂解酶类如β-半乳糖苷酶和神经氨酸酶;能将β-内酰胺衍生的药物转化为游离药物的β-内酰胺酶;能在药物中的氨基氮处分别用苯氧乙酰基或苯乙酰基转化而使药物游离的青霉素酰胺酶如青霉素V酰胺酶或青霉素G酰胺酶。或者,可用本领域称为“抗体酶”的具有酶活性的抗体,将本发明的前体药物转化为游离的活性药物(见Massey,自然328:457-458(1987))。可如本文所述制备拮抗剂-抗体酶偶联物以便将抗体酶运送至肿瘤细胞群。
本发明的酶可通过本领域已知的技术,如上述异源双功能交联试剂的使用而与拮抗剂共价结合。或者,可以通过本领域已知的DNA重组技术(如Neuberger等,自然,312:604-608(1984))构建含至少本发明拮抗剂的抗原结合区的融合蛋白,所述拮抗剂与本发明酶的至少一个功能活性部分连接。
本文还涉及对拮抗剂的其它修饰。例如,拮抗剂可与一种非蛋白多聚物,如聚乙二醇、聚丙二醇、聚氧化烯(polyoxyalkylene)、或聚乙二醇与聚丙二醇的共聚物交联。
本文公开的拮抗剂还可配成脂质体。含拮抗剂的脂质体可通过本领域已知方法制备,如Epstein等,美国国家科学院学报82:3688(1985);Hwang等,美国国家科学院学报77:4030(1980);美国专利4,485,045和4,544,545及1997年10月23日公开的WO97/38731。在美国专利5,013,566中公开了循环寿命增加了的脂质体。
特别有效的脂质体可利用包含磷脂酰胆碱、胆固醇和PEG衍生的磷脂酰乙醇胺(PEG-PE)的脂质组合物经反相蒸发法产生。脂质体通过一定孔径大小的滤膜而挤出后获得具有所需直径的脂质体。本发明抗体的Fab’片段可如Martin等,生物学化学杂志,257:286-288(1982)所述,经二硫键交换反应与脂质体偶联。可任选在所述脂质体中包含一种化疗制剂。见Gabizon等,J-National Cancer Inst,81(19)1484(1989)。
本发明还涉及对本文所述蛋白质或肽类拮抗剂的氨基酸序列修饰。例如,可预期改进拮抗剂的结合亲和力和/或其它生物学特性。拮抗剂的氨基酸序列变体可通过在拮抗剂核酸中导入适当的核苷酸改变,或通过肽合成法来制备。所述修饰包括,如该拮抗剂的氨基酸序列中的残基缺失,和/或插入和/或取代。可对缺失、插入、和取代进行任意组合以获得最终构建体,只要该最终构建体具有所需特性。氨基酸的变化还可改变拮抗剂的翻译后加工,如改变糖基化位点的数目或位置。
一种鉴别拮抗剂中处于诱变优选位置的特定残基或区域的有效方法是Cunningham和Wells,科学244:1081-1085(1989)所述的“丙氨酸扫描诱变”。这里,鉴定一个残基或一组靶残基(例如,带电的残基如精氨酸、天冬氨酸、组氨酸、赖氨酸和谷氨酸)并用中性或带负电的氨基酸取代(最优选丙氨酸或多聚丙氨酸)取代,以便影响氨基酸与抗原的相互作用。那些证实对取代具有功能敏感性的氨基酸位置通过在取代点引入进一步的或其他的变体而改进。故,尽管引入氨基酸序列变异的位点是预先决定的,但突变本身不必是预定的。例如,为分析在指定位点处突变的作用,在所述靶密码子或区域实行丙氨酸扫描或随机诱变,并筛选所表达的具有预期活性的拮抗剂变体。
氨基酸序列插入包括氨基-和/或羧基-端的融合(其长度从一个残基至包括100个或更多残基的多肽),以及序列内单个或多个氨基酸残基的插入。末端插入的例子包括带有N-末端甲硫氨酰残基的拮抗剂或与细胞毒性多肽融合的拮抗剂。拮抗剂分子的其它插入变体包括在酶或多肽的拮抗剂的N-或C-末端进行融合,以增加拮抗剂在血清中的半衰期。
另一类变体是氨基酸取代变体。这些变体使拮抗剂分子中至少一个氨基酸残基被不同残基取代。抗体拮抗剂分子中最有兴趣进行取代诱变的位点包括高变区,也可以改变FR。保守取代见表1的“优先取代”栏。如果这些取代引起生物学活性的改变,则可引入表1中“取代举例”栏的更实质性改变,或进一步在下文的氨基酸分类中所述的更实质性改变,并筛选产物。
表1
原始残基 | 取代举例 | 优先取代 |
Ala(A) | val:leu;ile | val |
Arg(R) | lys;gln;asn | lys |
Asn(N) | gln;his;asp;lys;arg | gln |
Asp(D) | glu;asn | glu |
Cys(C) | ser;ala | ser |
Gln(Q) | asn;glu | asn |
Glu(E) | asp;gln | asp |
Gly(G) | ala | ala |
His(H) | Asn;gln;lys;arg | arg |
Ile(I) | Leu;val;met;ala;phe;正亮氨酸 | leu |
Leu(L) | 正亮氨酸;ile;val;met;ala;phe | ile |
Lys(K) | arg;gln;asn | arg |
Met(M) | leu;phe;ile | leu |
Phe(F) | leu;val;ile;ala;tyr | tyr |
Pro(P) | ala | ala |
Ser(S) | thr | thr |
Thr(T) | ser | ser |
Trp(W) | tyr;phe | tyr |
Tyr(Y) | trp;phe;thr;ser | phe |
Val(V) | ile;leu;met;phe ala;正亮氨酸 | leu |
对拮抗剂的生物学特性的实质性修改可通过选择性取代来完成,所述取代的效应在维持(a)取代区多肽骨架的结构,例如片层结构或螺旋构象,(b)该分子靶位点的电荷或疏水性,(c)侧链的大小这几方面有显著差异。天然残基根据共有的侧链特性可分为:
(1)疏水性:正亮氨酸,蛋氨酸,丙氨酸,缬氨酸,亮氨酸 异亮氨酸
(2)中性亲水:半胱氨酸,丝氨酸,苏氨酸
(3)酸性:天冬氨酸,谷氨酸
(4)碱性:天冬酰胺,谷氨酰胺,组氨酸,赖氨酸,精氨酸
(5)影响侧链定向的残基:甘氨酸,脯氨酸
(6)芳香族:色氨酸,酪氨酸,苯丙氨酸。
非保守取代将限定上述某一类的成员被另一类取代。
与维持拮抗剂正确构象有关的任何半胱氨酸残基也可被取代,如被丝氨酸取代,以提高该分子的氧化稳定性,并阻止异常交联。相反,可在拮抗剂中添加半胱氨酸连接以提高其稳定性(特别当拮抗剂为抗体片段如FV片段时)。
取代变体的特别优选类型包括取代亲本抗体高变区的一或多个残基。通常,所选用于进一步开发的变体相对于其亲本抗体应具有改进的生物学活性。产生这种取代变体的一个方便方法是利用了噬菌体展示的亲和力成熟。简单地说,使高变区的几个位点(如6-7个位点)突变以便在每一位点产生所有可能的氨基酸取代。这样产生的抗体变体以单价形式展示在丝状噬菌体颗粒上,其为与每个颗粒内包装的M13基因III产物的融合体。然后筛选噬菌体展示的变体是否具有本文所述生物学活性(如结合亲和力)。为了鉴定备选的高变区修饰位点,可通过丙氨酸扫描诱变来鉴定对抗原结合作出主要贡献的高变区残基。此外,分析抗原-抗体化合物的晶体结构以确定抗原与抗体之间的接触点也较有利。这些接触残基及其邻近残基是根据本文所述技术进行取代的候选位点。一旦产生这样的变体,如本文所述对它们全部进行筛选,选出在一或多个相关实验中具有优势特性的抗体以便进一步开发。
拮抗剂的另一种氨基酸变体改变了拮抗剂原来的糖基化模式。所谓改变就是去掉拮抗剂中的一或多个碳水化合物部分,和/或添加一或多个原本不存在于该拮抗剂中的糖基化位点。
多肽的糖基化通常为N-连接或O-连接。N-连接指将碳水化合物部分与天冬酰胺残基的侧链相连。三肽序列天冬酰胺-X-丝氨酸和天冬酰胺-X-苏氨酸(其中X是除脯氨酸以外的任何氨基酸)是使碳水化合物部分与天冬酰胺侧链酶促相连的识别序列。因此,多肽中存在上述任一种三肽序列都可产生潜在的糖基化位点。O-连接糖基化指将N-乙酰半乳糖胺、半乳糖、或木糖附着于羟基氨基酸,主要是丝氨酸、苏氨酸,但也可用5-羟脯氨酸和5-羟赖氨酸。
在拮抗剂分子中添加糖基化位点可通过改变氨基酸序列,使其包含一或多个上述三肽序列(在添加N-连接糖基化位点的情况下)而实现。这种改变也可通过在原始的拮抗剂序列中添加或取代一或多个丝氨酸或苏氨酸残基来实现(在添加O-连接的情况下)。
编码拮抗剂的氨基酸序列变体的核酸分子由本领域已知的各种方法制备。这些方法包括但不限于从天然来源分离(在天然氨基酸序列变体的情况下),或通过对早期制备的拮抗剂变体或未变异的拮抗剂进行寡核苷酸介导的(或定点)诱变,PCR诱变和盒式诱变来制备。
也可预期修饰拮抗剂的效应物功能,如以此增强拮抗剂的抗体依赖性细胞介导的细胞毒作用(ADCC)和/或补体依赖的细胞毒作用(CDC)。这可以通过在抗体拮抗剂FC区引入一或多个氨基酸取代而获得。此外,可在FC区引入半胱氨酸残基,使得在此区形成链间二硫键。由此产生的同型二聚体抗体可提高内在化能力和/或增强补体介导的细胞杀伤作用和ADCC。见Caron等,实验医学杂志176:1191-1195(1992)和Shopes,B.免疫学杂志148:2918-2922(1992)。具有增强的抗肿瘤活性的同型二聚体抗体也可用Wolffe等,癌症研究53:2560-2565(1993)所述异源双功能交联剂制备。或者,可通过工程改造产生具有双FC区并因此具有增强的补体裂解效应及ADCC能力的抗体。见Stevenson等,抗癌药物的设计(Anti-Cancer drug design)3:219-230(1989)。
为了提高拮抗剂的血清半衰期,一种方法是在拮抗剂(尤其抗体片段)上掺入一个补救受体结合表位,如美国专利5,739,277所述。本文中术语“补救受体结合表位”是指IgG(例如IgG1,IgG2、IgG3、或IgG4)Fc区中负责延长该IgG分子的体内血清半衰期的表位。
IV.药用制剂
根据本发明使用的拮抗剂的药用制剂通过将具有所需纯度的拮抗剂与任选的药用载体、赋形剂或稳定剂(雷氏药学(Remington’s PharmaceuticalSciences)第16版,Osol,A.编(1980))混合而制备,然后以冻干剂或含水剂的形式保存。可药用载体、赋形剂、稳定剂在所用剂量及浓度下对受者无毒性,并包括缓冲剂例如磷酸盐,柠檬酸盐及其它有机酸;抗氧化剂包括抗坏血酸和蛋氨酸;防腐剂(例如十八烷基二甲基苄基氯化铵;氯化己烷双胺;氯化苄烷铵(benzalkonium chloride),苯索氯铵;酚、丁醇或苯甲醇;烷基对羟基苯甲酸酯如甲基或丙基对羟基苯甲酸酯;邻苯二酚;间苯二酚;环己醇;3-戊醇;间甲酚);低分子量多肽(少于10个残基);蛋白质如血清白蛋白,明胶或免疫球蛋白;亲水聚合物如聚乙烯吡咯烷酮;氨基酸如甘氨酸,谷氨酰胺、天冬酰胺、组氨酸、精氨酸或赖氨酸;单糖,二糖及其它碳水化合物包括葡萄糖、甘露糖、或糊精;螯合剂如EDTA;糖类如蔗糖、甘露醇、海藻糖或山梨醇;成盐反离子如钠;金属化合物(例如锌-蛋白化合物);和/或非离子表面活性剂如吐温TM,PLURONICSTM或聚乙二醇(PEG)。
抗CD20抗体制剂的实例如WO98/56418所述,其已引入本文作为参考。其描述了一种液体多剂量制剂,该制剂包含40mg/ml rituximab,25mM乙酸,150mM海藻糖,0.9%苯甲醇,0.02%聚山梨酸酯(polysorbate)20,pH5.0,在2-8℃至少可保存2年。另一种抗CD20目标制剂在9.0mg/ml氯化钠,7.35mg/ml二水柠檬酸钠,0.7mg/ml聚山梨酸酯80,注射用无菌水,pH6.5中包含10mg/ml rituximab。
适于皮下给药的冻干剂见WO97/04801所述。这种冻干剂可用适当稀释剂重新恢复至高蛋白浓度,所重建的制剂可皮下给药至这里所治疗的哺乳动物。
所述制剂还可根据所治疗的具体情况而包含一种以上活性成分,优选具有互补活性但相互无负面影响的那些。例如,优选还提供细胞毒试剂,化疗试剂,细胞因子或免疫抑制剂(如作用于T细胞的那些,如环孢菌素或结合T细胞的抗体,如结合LFA-1的抗体)。所述其它试剂的有效量取决于该制剂中拮抗剂的量,疾病或病症或治疗的类型,及上述其它因素。通常应用上文所述剂量和给药方式,或迄今所用剂量的约1-99%。
活性成分也可容纳在通过凝聚技术或界面聚合作用制备的微胶囊中,如分别在胶体性质的药物运送系统(如脂质体,白蛋白小球体,微乳剂,纳米颗粒及纳米胶囊)或大乳剂(macroemulsions)中的羟甲基纤维素或明胶微胶囊和聚(异丁烯酸甲酯)微胶囊。这些技术见雷氏药学,第16版Osol,A.编(1980)。
也可制备控释制剂。控释制剂的适当实例包括含有拮抗剂的固态疏水聚合物的半通透性基质,所述基质为具有一定形状的制品,如膜或微胶囊。控释制剂实例包括聚酯、水凝胶(如聚(2-羟基乙基-异丁烯酸酯)或聚(乙烯醇),聚交酯(美国专利3,773,919),L-谷氨酸与γ乙基-L-谷氨酸酯的共聚物,不可降解的乙烯乙酸乙酯,可降解的乳酸-羟基乙酸共聚物如LUPRONDEPOTTM(由乳酸-羟基乙酸共聚物和醋酸亮丙瑞林组成的可注射的微球体),以及聚D-(-)-3-羟丁酸。
用于体内给药的制剂必须是无菌的。这可以通过除菌滤膜过滤而轻易实现。
V.用拮抗剂进行治疗
结合CD20的拮抗剂可以用来阻断哺乳动物(优选人)体内针对外来抗原的免疫应答,其中所述哺乳动物未患恶性疾病。优选,拮抗剂包含一种抗CD20的抗体。在一个实施方案中抗体未与细胞毒制剂偶联,在另一实施方案中,抗体是和细胞毒制剂偶联的(例如,Y2B8或131I-B1)。
可以使本发明预接受治疗的哺乳动物暴露于结合CD20的拮抗剂和另一种不同的治疗剂,例如,该治疗剂在哺乳动物体内具备免疫原性。在这个实施方案中,拮抗剂可以阻断被治疗的哺乳动物体内针对治疗剂的免疫应答。治疗的益处也可能包括阻断脾脏对抗体包被型细胞的清除。将治疗剂以治疗疾病或病症的有效量给予将在给药治疗剂后受益的哺乳动物。在此实施方案中,可以基本上同时或以任何次序分别将治疗剂和拮抗剂给予哺乳动物。所以,可以将拮抗剂在给药治疗剂之前给予哺乳动物,或者将治疗剂在给药拮抗剂之前给予哺乳动物。
这样,结合CD20的拮抗剂可以用来治疗哺乳动物的移植物抗宿主或宿主抗移植物疾病和/或使等待移植的哺乳动物脱敏。
含一种与CD20结合的拮抗剂的组合物可根据常规医疗实践而针对本文所述各种情况进行配制、分剂量、并给药。其中应考虑的因素包括所治疗的具体疾病或紊乱,所治疗的具体哺乳动物,具体患者的临床状况,疾病或紊乱的病因,药物的给药部位,给药方法,给药时间表,和医务人员已知的其它因素。拮抗剂的治疗有效量将参考上述因素而给予。
作为常规建议,胃肠道外途径每次给予拮抗剂的治疗有效量的范围是每天约0.1-20mg/kg患者体重,拮抗剂通常的起始剂量为约2-10mg/kg。
优选的拮抗剂是抗体,如不与细胞毒制剂偶联的RITUXAN。例如,非偶联型抗体的适当剂量可以是约20mg/m2-约1000mg/m2。在一个具体实施方案中,抗体剂量不同于目前推荐的RITUXAN。例如,可给予患者一或多剂抗体,每剂远少于375mg/m2,例如为约20mg/m2-约250mg/m2,如约50mg/m2-约200mg/m2。
此外,可给药一或多剂起始剂量的抗体,然后给药一或多剂后续剂量的抗体,其中所述后续剂量中mg/m2抗体剂量高于起始剂量中mg/m2抗体剂量。例如,起始剂量为约20mg/m2-约250mg/m2(如约50mg/m2-约200mg/m2),而后续剂量可为约250mg/m2-约1000mg/m2。
但如上所述,应在多种治疗中谨慎考虑拮抗剂的这些建议剂量。其结果是选择适当剂量和给药时间表的关键因素,如上所示。例如治疗进行性疾病和急性疾病可能需要相对较高的起始剂量。为针对疾病或紊乱获得最有效的结果,应尽可能在接近于疾病或紊乱的首次症状、诊断、表现、或发生时或在疾病或紊乱缓解期间给予拮抗剂。
拮抗剂可通过任何适当方式给药,包括胃肠道外、皮下、腹膜内、肺内、和鼻内途径,如需进行局部免疫抑制治疗,可在病损内给药。胃肠道外输注包括肌肉内、静脉内、动脉内、腹膜内、或皮下给药。此外,拮抗剂适于经脉冲输注给药,如,使用剂量递减的拮抗剂输注。优选经注射给药,最优选静脉注射或皮下注射,其取决于给药是短期的还是长期的。
可与本文拮抗剂一起给予其它化合物,如细胞毒试剂、化疗试剂、免疫抑制剂和/或细胞因子。联合给药包括同时给药各自的制剂或单一可药用制剂,还包括以任何顺序连续给药,其中优选有一段时间使两种(或所有)活性试剂同时发挥它们的生物学活性。
除了向患者给药蛋白拮抗剂,本申请还考虑通过基因治疗给药拮抗剂。这类编码拮抗剂的核酸的给药以“给予有效治疗剂量的拮抗剂”的表达形式包括在内。例见1996年3月14日公开的WO96/07321,其涉及利用基因治疗产生细胞内抗体。
有两种主要方法可将核酸(任选包含在载体中)引入患者细胞;体内和离体(ex vivo)。体内运送核酸指直接给患者注射,通常注射至需要拮抗剂的位点。离体治疗是将患者细胞取出,将核酸引入这些分离的细胞,然后将这些已改变的细胞直接给予患者或装入多孔膜中再植入患者体内(见美国专利4,892,538和5,283,187)。有多种技术可用于将核酸引入活细胞。可根据是将核酸转移至体外培养的细胞,还是转移至目标宿主的体内细胞而使用不同方法。适于将核酸转移至体外哺乳动物细胞的技术有脂质体的应用、电穿孔、显微注射、细胞融合、DEAE-葡聚糖、磷酸钙沉淀法等。常用于离体运送基因的载体是逆转录病毒。
目前优选的体内核酸转移技术包括用病毒载体(如腺病毒,单纯疱疹病毒I型或腺伴随病毒)和基于脂质的系统(可用于基因的脂质介导型转移的有效脂质有DOTMA,DOPE和DC-Chol)。某些情况下,希望提供一种带有能靶向靶细胞的试剂(如特异于细胞表面膜蛋白或靶细胞的抗体,针对靶细胞表面受体的配体,等)的核酸来源。当使用脂质体时,可使用能结合胞吞作用相关性细胞表面膜蛋白的蛋白来靶向和/或促进对下述蛋白的吸收,所述蛋白如对特定细胞类型具有向性的衣壳蛋白或其片段,在循环中进行内在化的蛋白的抗体,靶向细胞内定位和提高细胞内半衰期的蛋白。受体介导型胞吞作用的技术见Wu等,生物学化学杂志262:4429-4432(1987);和Wagner等,美国国家科学院学报,87:3410-3414(1990)。有关目前已知的基因制备和基因治疗方案的综述见Anderson等,科学256:808-813(1992)。亦参见WO93/25673。
VI.制备相关的制品
本发明另一实施方案是一种制品,其包含可用于上述疾病或紊乱的治疗的材料。所述制品包括一个容器和位于该容器表面的或与该容器相关的标签或包装插页。适当的容器有瓶子,小瓶,注射器等。容器可由各种材料如玻璃或塑料制成。该容器可内含一种能有效治疗目标疾病或紊乱的组合物,并具有无菌存取口(例如该容器可以是静脉注射袋或带有能通过皮下注射针穿刺的塞子的小瓶)。所述组合物中至少一种活性试剂是与CD20结合的拮抗剂。标签或包装插页将指明,所述组合物用于阻断针对外来抗原的免疫应答和/或治疗本文所述的各种疾病。所述制品还可包含第二个容器,该容器中含有可药用稀释液,如细菌抑制性注射用水(BWFI),磷酸盐缓冲液,Ringer’s溶液和葡萄糖溶液。在一个实施方案中,所述第二个容器持有或含有一种组合物,其中的活性制剂是一种治疗剂。所述制品还可包括具有商业需要以及符合用户需要的材料,包括其它缓冲液,稀释剂,滤器,针头,和注射器。
本发明的更详细内容通过以下非限制性实施例举例说明。本说明书中所引用的所有文献均引入作为参考。
实施例1
阻断对治疗性蛋白的免疫应答
在本实施例中,用抗CD20抗体阻断对治疗蛋白:巨核细胞生长及发育因子(MGDF,也称为血小板生成素或Mp1配体)的免疫应答。尤其,已有报道重组人MGDF的PEG化形式(PEG-rHuMGDF)可以在癌症患者和血小板供体的体内产生中和抗体。给药本发明公开的抗CD20抗体将减轻免疫应答,尤其是直接针对PEG-rHuMGDF的体液反应。
如1998年8月18日授权的美国专利5,795,569(引入本文作参考)所述制备PEG-rHuMGDF。PEG-rHuMGDF由大肠杆菌来源的人MGDF的第1-163位氨基酸(从成熟蛋白的起始处算起)组成,在该多肽N-末端的α-氨基上连接有一个聚乙二醇(PEG)分子。
可将MGDF给药至诸如化疗或放疗后的血小板减少症患者,其量适于增加患者体内的血小板计数;如0.1-1000毫克MSDF/kg体重。MGDF治疗任选与给药一种或多种其它细胞因子,如红细胞生成素(EPO),白细胞介素-3(IL-3)和粒细胞巨核细胞集落刺激因子(GM-CSF)联合。
以上述方式治疗后的患者体内抗MGDF抗体的滴度可通过适当的方法,如抗体滴度酶联免疫吸附实验(ELISA)检测。对MGDF表现为低滴度免疫应答的那些患者是用抗CD20抗体,例如RITUXAN进一步治疗的候选患者。抗CD20抗体可以在进一步用MGDF治疗之前、同时或之后给药。抗CD20抗体的适当剂量是375mg/m2,每周一次共给药四次。但可以给药较少的剂量,如约50mg/m2-约250mg/m2。向患者给药抗CD20抗体将阻止,或使上述接受MGDF和抗CD20联合治疗的患者体内的抗MGDF抗体的生成降低到一个可接受的程度。所以,具有极大治疗价值和已知免疫原性的蛋白药物与所述抗CD20抗体的联合给药将治疗与该蛋白药物给予患者相关的免疫原性副作用。
实施例2
阻断对基因治疗性病毒载体的免疫应答
已对删除了E1,E3的复制缺陷型重组腺病毒在体内转移治疗基因的能力进行了评估。还开发了在E2a和E4区中另外有删除的新载体。Christ等,Immunol.Let.57:19-25(1997)。尽管删除了这些病毒区域,早期和晚期病毒基因在体内仍有低水平的表达。抗-腺病毒抗体的产生,细胞免疫应答和对载体的早期非特异性清除构成了基因治疗成功的障碍。为了抑制抗腺病毒中和抗体的产生或将该产生降低到可接受的水平,可如本发明所述将抗CD20抗体(例如RITUXAN)给予基因治疗患者。
例如,用表达人囊性纤维化跨膜转导调节子(CFTR)(Bellon等,人类基因治疗,8:15-25(1997))的复制缺陷型腺病毒治疗囊性纤维化的患者。适当剂量的CFTR基因治疗载体(用病毒空斑形成单位,pfu限定)可通过烟雾化作用给药以便使CFTR(例如约107-约109pfu)在肺中表达。患者体内的抗-腺病毒抗体可以通过ELISA、免疫荧光和/或补体固定法检测。对那些证实有抗-腺病毒抗体的患者,于基因治疗载体再次给药之前、同时或之后给药一种抗CD20抗体(例如嵌合的2H7;美国专利号5,677,180),任选联合给药其它免疫抑制性药物(例如环磷酰胺、FK506、或阻断T细胞受体或共刺激途径的单克隆抗体)。抗CD20抗体的适当剂量是375mg/m2每周一次共四周输注。给药抗CD20抗体将降低或消除患者体内的免疫应答(例如通过降低抗-腺病毒抗体的产生),并因此促进基因治疗再处理的成功。
实施例3
阻断对移植物的免疫应答
抗CD20抗体作为联合免疫抑制方案的一部分用于预防急性排斥。在这种情况下,可以在围-移植期(peri-transplant period)给药抗CD20抗体如RITUXAN作为顺次组合方案的一部分,该方案包括针对T细胞的制剂如环孢菌素、皮质激素、霉酚酸mofetil、有或无抗IL-2受体的抗体。因此,可将抗CD20抗体视为诱导方案的一部分,与慢性免疫抑制性治疗联合使用。抗CD20抗体可以通过抑制同种异体抗体的产生和/或通过清除抗原提呈细胞而影响同种异体抗原的提呈来预防同种异体排斥反应。
治疗方案可以是在移植之前或前后(around)输注RITUXAN(375mg/m2),每周一次共四周。其它免疫抑制剂的适当剂量是:环孢菌素(5mg/kg/天);皮质激素(1mg/kg,逐渐减量);霉酚酸mofetil(1克,一天二次给予)和抗IL-2受体的抗体(1mg/kg,每周输注5次)。抗CD20抗体也可与其它诱导免疫抑制的药物,例如多克隆抗淋巴细胞抗体或单克隆抗CD3抗体;维持免疫抑制的药物,例如神经贮钙蛋白抑制剂(例如,藤霉素)和抗增殖剂(例如硫唑嘌呤、leflunomide或sirolimus);或组合方案(包括T细胞共刺激阻断剂、T细胞粘附分子阻断剂或T细胞辅助分子阻断剂)联合。
除了预防急性排斥反应,抗CD20抗体还可以用于治疗急性排斥。抗-CD20的适当剂量如上所述。在对急性排斥反应的治疗中抗CD20抗体任选与抗-CD3单克隆抗体和/或皮质激素联合使用。
抗CD20抗体也可以:(a)在移植后的较晚期单独使用,或与其它免疫抑制剂和/或共刺激阻断剂联合使用,以治疗或预防“慢性”同种异体移植物排斥反应;(b)作为对耐受的诱导方案的一部分使用;或(c)在异种移植情况下使用。
实施例4
阻断对血友病因子的免疫应答
对遗传性VIII因子缺陷病患者多次输注VIII因子制剂,产生了高滴度的抗VIII因子抗体。将抗CD20抗体如RITUXAN,以诸如上述剂量给予这种带有抗因子VIII抗体的患者。抗CD20抗体通过影响抗VIII因子抗体的产生或通过其它机制如独特型抑制作用可以阻断对因子VIII的免疫应答。
实施例5
阻断对血小板的免疫应答
对患者多次接输血小板,产生抗血小板的同种异型抗体。患者的类固醇治疗已经失败并且可能已经接受了其它的治疗(例如环孢菌素、葡萄球菌蛋白A柱等)。将抗CD20抗体(例如RITUXAN)以一定剂量,例如,如上所述的剂量给予患者。抗CD20抗体可以通过影响抗体的产生或通过其它机制例如独特型抑制作用或抑制脾脏对包被型血小板的消除而阻断或减轻免疫应答。
Claims (31)
1、一种阻断哺乳动物中针对外来抗原的免疫应答的方法,其中所述哺乳动物未患恶性疾病,该方法包括向哺乳动物给药治疗有效量的与CD20结合的拮抗剂。
2、权利要求1的方法,其中所述拮抗剂包含一种抗体。
3、权利要求1的方法,其中所述外来抗原包含一种治疗剂。
4、权利要求1的方法,其中所述外来抗原选自抗体、毒素、基因治疗的病毒载体、移植物、感染因子和同种异体抗原。
5、权利要求1的方法,其中所述哺乳动物是人。
6、权利要求2的方法,其中所述抗体不与细胞毒制剂偶联。
7、权利要求2的方法,其中所述抗体包含rituximab(RITUXAN)。
8、权利要求2的方法,其中所述抗体与一种细胞毒制剂偶联。
9、权利要求8的方法,其中所述细胞毒制剂是一种放射活性化合物。
10、权利要求9的方法,其中所述抗体包含Y2B8或131I-B1(BEXXARTM)。
11、权利要求1的方法,其包括静脉内给药所述拮抗剂。
12、权利要求1的方法,其包括皮下给药所述拮抗剂。
13、权利要求2的方法,其包括向哺乳动物给药比375mg/m2少很多的剂量的抗体。
14、权利要求13的方法,其中所述剂量是在约20mg/m2到约250mg/m2的范围内。
15、权利要求14的方法,其中所述剂量是在约50mg/m2到约200mg/m2的范围内。
16、权利要求2的方法,其包括给药一剂初始剂量的抗体,随后给药一剂后续剂量,其中在后续剂量中该抗体的mg/m2剂量超过初始剂量中该抗体的mg/m2剂量。
17、权利要求4的方法,其中所述外来抗原是一种抗体。
18、权利要求17的方法,其中所述抗体是鼠抗体。
19、权利要求4的方法,其中所述外来抗原是基因治疗的病毒载体。
20、权利要求4的方法,其中所述外来抗原是移植物。
21、权利要求4的方法,其中所述外来抗原是同种异体抗原。
22、权利要求1的方法,其包括在哺乳动物暴露于所述外来抗原之前向该哺乳动物给药所述拮抗剂。
23、权利要求22的方法,其中所述外来抗原包含一种移植物。
24、一种治疗哺乳动物的方法,其包括向哺乳动物给药一种治疗剂,该治疗剂并非与CD20结合的拮抗剂,该方法还包括向该哺乳动物给药一种能与CD20结合的拮抗剂,其中所述治疗剂在该哺乳动物体内有免疫原性并且所述拮抗剂可以阻断该哺乳动物体内针对所述治疗剂的免疫应答。
25、权利要求24的方法,其包括基本同时地向哺乳动物给药所述治疗剂和所述拮抗剂。
26、权利要求24的方法,其包括在给药所述治疗剂之前给药所述拮抗剂。
27、权利要求24的方法,其包括在给药所述拮抗剂之前给药所述治疗剂。
28、治疗哺乳动物体内的移植物排斥宿主或宿主排斥移植物疾病的方法,其包括向哺乳动物给药治疗有效量的与CD20结合的拮抗剂。
29、使等待移植的哺乳动物脱敏的方法,其包括向哺乳动物给药治疗有效量的与CD20结合的拮抗剂。
30、一种制品,其包括一个容器及其中所含的组合物,还包括一种包装插页,所述组合物包含一种与CD20结合的拮抗剂,所述插页可指导用户用所述组合物治疗已经或将要暴露于外来抗原的患者。
31、权利要求30的制品,其进一步包含第二个容器及其中所含的第二种组合物,该第二种组合物包含一种治疗剂。
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CNA200710169320XA Pending CN101264324A (zh) | 1999-07-12 | 2000-07-10 | 应用结合cd20的拮抗剂阻断对外来抗原的免疫应答 |
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IL147547A0 (en) | 2002-08-14 |
AU778863B2 (en) | 2004-12-23 |
CA2379274A1 (en) | 2001-01-18 |
KR20020027490A (ko) | 2002-04-13 |
NZ516491A (en) | 2004-11-26 |
CN101264324A (zh) | 2008-09-17 |
AU6082500A (en) | 2001-01-30 |
AU2005201189A1 (en) | 2005-04-14 |
US20100003252A1 (en) | 2010-01-07 |
JP2003528805A (ja) | 2003-09-30 |
WO2001003734A1 (en) | 2001-01-18 |
HUP0202238A2 (en) | 2002-10-28 |
EP1216056A1 (en) | 2002-06-26 |
NO20020128L (no) | 2002-02-28 |
HUP0202238A3 (en) | 2004-05-28 |
KR20080075044A (ko) | 2008-08-13 |
PL201086B1 (pl) | 2009-03-31 |
BR0013201A (pt) | 2002-04-30 |
HK1047702A1 (zh) | 2003-03-07 |
PL352758A1 (en) | 2003-09-08 |
MXPA02000419A (es) | 2004-09-10 |
ZA200200272B (en) | 2003-03-26 |
AU2005201189B2 (en) | 2008-04-03 |
NO20020128D0 (no) | 2002-01-11 |
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