CN102448494A - 具有胞内可裂解的键的免疫共轭物 - Google Patents
具有胞内可裂解的键的免疫共轭物 Download PDFInfo
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Abstract
本发明涉及具有靶向不同患病细胞的改进能力,并包含靶向部分(诸如抗体或抗体片段)、接头和治疗部分的治疗共轭物,还涉及用于制备和使用所述共轭物的方法。
Description
发明人:Serengulam V.Govindan,Sung-Ju Moon和David M.Goldenberg
相关申请
本申请要求2009年2月13日提交的美国临时专利申请61/207,890的权益,其原文通过引用全文并入本文。
发明领域
本发明涉及靶向不同癌细胞、传染病生物体的能力改进和/或用于治疗自身免疫性疾病的治疗共轭物,该共轭物包含靶向(结合)部分和属于药物的喜树碱基团的治疗部分。靶向部分与治疗部分经由增加治疗效力的胞内可裂解的键连接。
发明背景
多年来,在特异性靶向药物疗法领域中科学家的一个目的是使用单克隆抗体(MAb)用于向人癌症特异性递送毒性剂。已经开发了肿瘤相关MAb与适当毒性剂的共轭物,但在癌症的治疗中成败参半,在其他疾病诸如传染病和自身免疫性疾病中几乎无应用。毒性剂是最通常的化疗药物,尽管还已经将发射粒子的放射性核素、或细菌或植物毒素与MAb共轭,尤其是用于癌症疗法(Sharkey和Goldenberg,CACancer J Clin.2006 Jul-Aug;56(4):226-243),以及最近,利用放射免疫共轭物用于某些传染病的临床前治疗(Dadachova和Casadevall,Q JNucl Med Mol Imaging 2006;50(3):193-204;通过引用并入本文)。
利用MAb-化疗药物共轭物的益处是:(a)化疗药物本身结构是充分确定的;(b)化疗药物通常在远离MAb抗原结合区的特定位点利用非常确定的共轭化学与MAb蛋白连接;(c)与涉及MAb和细菌或植物毒素的化学共轭物相比,MAb-化疗药物共轭物的制备更具有可重复性,因此更有商业发展前途并且容易获得管理批准;和(d)MAb-化疗药物共轭物的系统毒性比放射性核素MAb共轭物的数量级低。
对蛋白-药物共轭物的早期工作指出,一旦被靶细胞内化,为了蛋白-化疗药物共轭物成为有用的治疗,药物优选地以它原来的形式释放。Trouet等(Proc.Natl.Acad.Sci.USA 79:626-629(1982))显示了在药物和靶向部分之间利用特定肽接头的益处,所述肽接头被溶酶体裂解以释放出完整药物。尤其是,根据肿瘤中的pH经常低于正常生理pH的发现,开发了使用温和的酸可裂解的接头(如包含腙的接头)制备的MAb-化疗药物共轭物(Willner等,美国专利5,708,146;Trail等(Science 261:212-215(1993))。第一种批准的MAb-药物共轭物吉妥珠单抗奥佐米星,在抗-CD33抗体人化P67.6与强效的卡奇霉素衍生物之间掺入相似的酸不稳定性腙键。Sievers等,J Clin Oncol.19:3244-3254(2001);Hamann等,Bioconjugate Chem.13:47-58(2002)。在一些情况,制备在化疗药物与MAb之间具有还原性不稳定的阻隔的二硫键的MAb-化疗药物共轭物(Liu等,Proc Natl Acad Sci USA 93:8618-8623(1996))。
又一种可裂解的接头包括组织蛋白酶B-不稳定的二肽间隔物,诸如Phe-Lys或Val-Cit,类似于Trouet等的包含1至4个氨基酸的溶酶体不稳定性肽间隔物,在药物与二肽之间另外掺入可折叠的间隔物(Dubowchik等,Bioconjugate Chem.13:855-869(2002);Firestone等,美国专利6,214,345B1;Doronina等,Nat Biotechnol.21:778-784(2003))。后一种方法也可用于制备喜树碱的免疫共轭物(Walker等,Bioorg Med Chem Lett.12:217-219(2002))。已经研究的另一种可裂解的部分是掺入抗体与化疗药物之间的接头中的酯键。Gillimard和Saragovi已经发现,当紫杉醇的酯与抗-大鼠p75MAb即MC192或抗-人TrkA MAb即5C3共轭时,发现共轭物表现靶特异性毒性。Gillimard和Saragovi,Cancer Res.61:694-699(2001)。
在许多情况下,本发明的共轭物具备比未共轭或“裸”抗体或抗体片段更大的效力,尽管这种未共轭的靶向分子已经用于特定的情形。例如,对于癌症,裸抗体已经在淋巴瘤(坎帕斯和RITUXAN)、结肠直肠癌和其他癌(ERBITUX和阿瓦斯汀)、乳腺癌(赫赛汀)以及目前处于临床开发的许多癌症(如,依帕珠单抗)的治疗中起作用。在大多数此类情况中,临床使用已经包括将这些裸抗体或未共轭抗体与其他疗法诸如化疗或放疗组合。
大量抗体也可用于治疗自身免疫疾病和其他免疫失调疾病,诸如肿瘤坏死因子(TNF)和B细胞(RITUXAN)抗体用于治疗关节炎,并且正被研究用于其他这类疾病,诸如B细胞抗体、RITUXAN和依帕珠单抗用于治疗系统性红斑狼疮和舍格伦氏综合症、以及青少年糖尿病和多发性硬化。裸抗体也正被研究用于败血症和败血病性休克、阿尔茨海默病、和传染性疾病。抗-传染性单克隆抗体的开发最近由Reichert和Dewitz综述(Nat Rev Drug Discovery 2006;5:191-195),通过引用并入本文,概述了已经寻求针对其的裸抗体疗法的重点病原体,只有针对2种病原体(呼吸道合胞病毒和耐甲氧西林金黄色葡萄球菌(Staphylococcus aureus))的抗体处于III期临床试验或被销售,针对25种其他病原体的抗体处于临床研究,针对20种病原体的抗体在临床研究期间中断。
对开发更强效的抗-病原体或抗癌症抗体和其他结合部分存在需要。可开发这种抗体介导的治疗以裸(未共轭)、放射性标记、或药物/毒素共轭物的形式用于治疗许多不同病原体,包括细菌、真菌、病毒和寄生虫。对开发更有效的用于治疗癌症、病原体和其他疾病的带有胞内可裂解接头的抗体共轭物进一步存在需要。在递送药物/毒素或放射性核素共轭物的情形中,这可通过直接抗体共轭或通过称为预靶向的间接方法实现,其中双特异性的抗体用于靶向病损,而治疗剂通过与集中在病原体、癌症或被治疗的无论何种病损的双特异性抗体的臂之一结合而二次靶向(Goldenberg等,J Clin Oncol.2006 Feb10;24(5):823-34.;Goldenberg等,J Nucl Med.2008 Jan;49(1):158-63,各自通过引用全文并入本文)。
发明概要
通过提供用于制备药物-结合部分共轭物的改进方法和组合物,本发明解决了本领域未满足的需要。公开的方法和组合物可用于治疗其他治疗形式难治的或对其他治疗形式响应性差的多种疾病和病症,并可包括针对其可开发的或可获得或已知的用于选择性靶向的适合的靶向(结合)部分的疾病。优选地,靶向部分是抗体、抗体片段、双特异性的或其他多价抗体、或其他基于抗体的分子或化合物。抗体可以是各种同种型,优选地IgG1、IgG2a、IgG3、IgG4或IgA,可以是嵌合人-小鼠抗体、嵌合人-灵长类动物抗体、人化抗体(人构架区与鼠高变(CDR)区)、或完全人抗体、以及其变体,诸如半-IgG4抗体(称为“单抗体(unibodies)”),如van der Neut Kolfschoten等(Science 2007;317:1554-1557)所述,通过引用并入本文。然而,可使用本领域已知的其他结合部分,诸如适体、avimer或靶向肽。针对其存在这种靶向部分的优选疾病或病症为,例如,癌症、免疫失调病症(包括自身免疫性疾病和炎性疾病)、和感染性生物造成的疾病。
因此,公开的方法和组合物可适用于治疗靶向部分用于对其递送细胞毒性剂的疾病和病症。这种疾病或病症的特征可以是,存在当例如在癌症或病原性生物体感染的免疫疗法中使用未共轭或裸露的靶向部分时没有充分受影响的靶分子或靶细胞(关于用于疾病疗法的抗体与同位素、药物和毒素的免疫共轭物的制备方法,参见,例如美国专利No.4,699,784;4,824,659;5,525,338;5,677,427;5,697,902;5,716,595;6,071,490;6,187,284;6,306,393;6,548,275;6,653,104;6,962,702;7,033,572;7,147,856;7,259,240和美国专利申请公布No.20050175582(目前弃权);20050136001;20040166115(目前弃权);20040043030(目前弃权);20030068322(目前弃权)和20030026764(目前弃权),上述每一个专利和专利申请的实施例部分通过引用并入本文)。
在优选实施方案中,喜树碱(CPT)及其类似物和衍生物是优选的化疗部分,尽管本发明不限于此。在本发明范围中的其他化疗部分有紫杉烷(如,浆果赤霉素III、泰素)、埃坡霉素、蒽环霉素药物(如,阿霉素(DOX)、表柔比星、吗啉代阿霉素(吗啉代-DOX)、氰基吗啉代-阿霉素(氰基吗啉代-DOX)和2-吡咯啉基阿霉素(2-PDOX);参见Priebe W(编著),ACS symposium series 574(ACS专题论文集系列574),American Chemical Society(美国化学学会),WashingtonD.C.出版,1995(332pp)和Nagy等,Proc.Natl.Acad.Sci.USA 93:2464-2469,1996),由格尔德霉素示例的苯醌袢霉素(DeBoer等,Journal ofAntibiotics 23:442-447,1970;Neckers等,Invest.New Drugs17:361-373,1999)、等等。优选地,在本发明优选实施方案的免疫共轭物中,靶向部分连接于至少一个化疗部分;优选地1至约5个化疗部分;最优选地约7至约12个化疗部分。
关于药物的CPT基团,在含水缓冲液中不溶性的问题和其结构中E-环的δ-内酯部分在生理条件下不稳定的问题是相关的。一种方法是用氨基酸酰化20-羟基,并偶联该氨基酸的α-氨基与聚-L-谷氨酸(Singer等,The Camptothecins:Unfolding Their Anticancer Potential(喜树碱:展现其抗癌潜力),Liehr J.G.,Giovanella,B.C.和Verschraegen(编著),NYAcad Sci.,NY 922:136-150(2000))。这一方法依赖于聚合分子向肿瘤位置的被动扩散。这种甘氨酸共轭也已被报道为制备CPT的水溶性衍生物(Vishnuvajjala等,美国专利No.4,943,579)和制备PEG衍生化CPT(Greenwald等J.Med.Chem.39:1938-1940(1996))的方法。在后一种情形,已经在开发CPT的水溶性和长效作用形式的范畴中设想该方法,藉以增强CPT的体内半衰期,药物在体内循环中从其共轭物逐渐释放。水溶性CPT衍生物的一个例子是CPT-11。有关CPT-11的药理学和其体内转化为活性SN-38的深入临床数据是可获得的(Iyer和Ratain,Cancer Chemother Pharmacol.42:S31-43(1998);Mathijssen等,Clin Cancer Res.7:2182-2194(2002);Rivory,Ann NYAcad Sci.922:205-215,2000))。活性形式SN-38比CPT-11更强效约2至3个数量级。
在某些示例性实施方案中,抗体或抗体片段的药物共轭物可用于将治疗药物靶向于病原体,诸如细菌、病毒、真菌和寄生虫。在优选实施方案中,这种药物-共轭靶向部分可与其他治疗方式,诸如抗真菌、抗生素和抗病毒药物和/或裸抗体、免疫调节剂(如干扰素、白介素、和/或细胞因子)联合使用。放射免疫疗法用于治疗感染性生物的用途公开于,例如,美国专利No.4,925,648;5,332,567;5,439,665;5,601,825;5,609,846;5,612,016;6,120,768;6,319,500;6,458,933;6,548,275;和美国专利申请公布No.20020136690和20030103982,上述每一个专利和专利申请的实施例部分通过引用并入本文。
在有关癌症治疗的某些实施方案中,药物共轭物可与手术、放疗、化疗、使用裸抗体的免疫疗法、放射免疫疗法、免疫调节剂、疫苗等等联合使用。相似的组合在对靶向部分顺从的其他疾病诸如自身免疫性疾病的治疗中是优选的。例如,喜树碱共轭物可与TNF抑制剂、B细胞抗体、干扰素、白介素和用于治疗自身免疫性疾病的其他有效药剂联合,所述自身免疫性疾病诸如类风湿性关节炎、系统性红斑狼疮、舍格伦氏综合症、多发性硬化、血管炎以及I型糖尿病(青少年糖尿病)。这些组合疗法可允许在组合中给予较低剂量的每种治疗剂,从而减少某些严重的副作用,并可能减少所需的治疗过程。对于病毒性疾病,药物免疫共轭物可与其他治疗药物、免疫调节剂、裸MAb或疫苗(如,针对肝炎、HIV或乳头瘤病毒的MAb、或基于这些病毒的免疫原的疫苗)组合。针对这些和其他病毒病原体的抗体和基于抗原的疫苗是本领域已知的,在一些情况中,已经处于市售。
在一个实施方案中,本发明涉及制备共轭物的方法,其中药物首先用第一接头衍生化,该第一接头包含能够与另外包含靶向部分-偶联基团的第二接头联合的反应性部分;其中第一接头还具备用于水溶性的确定的聚乙二醇(PEG)部分、和任选地胞内肽酶可裂解的或胞内体和溶酶体囊泡环境的低pH环境可裂解的胞内可裂解部分、和任选的药物与第一接头之间的氨基酸间隔物;其中第二接头包含能够通过称为‘链接化学’的铜(+1)离子催化的乙炔-叠氮化物环加成反应与药物-(第一接头)共轭物反应的反应性基团。优选地,确定的PEG部分是具有确定数目的单体亚基的低分子量PEG,如以下讨论的。
另一实施方案涉及制备如上段讨论的共轭物的方法,其中第二接头具有单个靶向部分-偶联基团,但多个反应性基团能够与药物-(第一接头)共轭物反应,从而放大与靶向部分共轭的药物分子的数目。
进一步的实施方案涉及制备共轭物的方法,其中接头首先与药物共轭,从而产生药物-接头共轭物;其中所述药物-接头共轭物制备包括选择性保护和脱保护包含多个官能团的药物中更具反应性的基团;其中所述药物-接头共轭物任选地不纯化;且其中所述药物-接头共轭物随后与单克隆抗体或片段共轭。
又一实施方案是用本文所述的共轭物治疗癌症(恶性肿瘤)、自身免疫性疾病、感染、或传染性病损的方法。替代实施方案涉及由所要求保护的方法制备的药物-靶向部分共轭物和/或进行所要求保护的方法的试剂盒。
在一个实施方案中,本发明涉及免疫共轭物,包括:
(a)靶向部分;
(b)化疗部分;和
(c)经由靶向部分-结合基团共价连接于靶向部分和经由胞内可裂解部分共价连接于化疗部分的接头。在另一实施方案中,本发明涉及免疫共轭物,包括:
(a)靶向部分;
(b)化疗部分;和
(c)经由靶向部分-结合基团共价连接于靶向部分和经由胞内可裂解部分共价连接于化疗部分的接头;其中与治疗部分连接的所述接头还包括L-氨基酸或由最多4个L-氨基酸构成的多肽。
在一个实施方案中,胞内可裂解部分是碳酸酯,包括化疗部分的活化羟基和取代的乙二胺部分或4-氨基苄醇,4-氨基苄醇经由其氨基连接于结束于靶向部分-结合基团的交联接头;且其中取代的乙二胺部分衍生自天然L氨基酸,该氨基酸的羧酸基团被羟甲基部分代替;且其中4-氨基苄醇任选地在苄型位置被C1-C10烷基取代。
在优选实施方案中,胞内可裂解部分是碳酸酯,包括化疗部分的活化羟基和取代的乙二胺,取代的乙二胺经由其氨基连接于L-氨基酸或包括最多4个L-氨基酸部分的多肽;其中N末端连接于结束于靶向部分-结合基团的交联接头;且其中取代的乙二胺部分衍生自天然L氨基酸,该氨基酸的羧酸基团被羟甲基部分代替。
在另一优选实施方案中,胞内可裂解部分是碳酸酯,包括化疗部分的活化羟基和4-氨基苄醇或在苄型位置被C1-C10烷基取代的取代的4-氨基苄醇,4-氨基苄醇经由其氨基连接于L-氨基酸或包括最多4个L-氨基酸部分的多肽;其中N末端连接于结束于靶向部分-结合基团的交联接头。
在某些实施方案中,化疗部分的氨基与取代的、胺保护的、乙醇胺部分或4-氨基苄醇的活化羟基偶联,4-氨基苄醇经由其氨基连接于L-氨基酸或包括最多4个L-氨基酸部分的多肽;其中N末端连接于结束于靶向部分-结合基团的交联接头;其中所述取代的乙二胺部分任选地衍生自L氨基酸,该氨基酸的羧酸基团被羟甲基部分代替;且其中4-氨基苄醇任选地在苄型位置被C1-C10烷基取代。然后双官能的药物衍生物与靶向部分共轭以获得如以上讨论的免疫共轭物。在免疫共轭物靶向疾病部位后,免疫共轭物被胞吞和分解代谢以释放药物-接头部分;其中取代的乙二胺部分的自由氨基通过在氨基甲酸酯部分的羰基亲核攻击而参与游离药物的释放。
附图简述
图1.用MAb-CL2A-SN-38共轭物对携带Capan 1人胰腺癌的无胸腺裸小鼠的临床前体内疗法。
图2.用MAb-CL2A-SN-38共轭物对携带BxPC3人胰腺癌的无胸腺裸小鼠的临床前体内疗法。
图3.用hMN-14-CL2A-SN-38共轭物对携带LS174T人结肠癌的无胸腺裸小鼠的临床前体内疗法。
发明详述
定义
在以下的说明中,使用了许多术语,并提供以下定义以促进对要求保护的主题的理解。未在本文明确定义的术语按照其普通和通常的含义使用。
除非另外指明,否则一表示“一个或多个”。
如本文所用,术语大约指在一个数字的加或减10%范围内。例如,“大约100”指90和110之间的任何数字。
如本文所用,术语靶向部分指与靶分子、细胞、颗粒、组织或聚集物特异性结合或选择性结合的分子、复合物或聚集物。本领域技术人员将理解,特异性结合是指结合特定靶而对其他靶没有交叉反应性,而选择性结合是指优先结合特定靶。在优选实施方案中,靶向部分是抗体、抗体片段、双特异性的抗体或其他基于抗体的分子或化合物。然而,靶向部分的其他例子是本领域已知的并可使用,诸如适体、avimer、受体结合配体、核酸、生物素-亲和素结合对、结合肽或蛋白、等等。术语“靶向部分”和“结合部分”在本文同义使用。
如本文所述,抗体指全长(即天然存在的或者通过正常的免疫球蛋白基因片段重组过程形成的)免疫球蛋白分子(如IgG抗体),或者免疫球蛋白分子的抗原结合部分,如抗体片段。在所要求保护的主题范围内,抗体或抗体片段可被共轭或以其他方式衍生化。这种抗体包括但不限于IgG1、IgG2a、IgG3、IgG4(和IgG4亚型)、以及IgA同种型。
抗体片段是抗体的一部分,如F(ab′)2、F(ab)2、Fab′、Fab、Fv、scFv(单链Fv)、单结构域抗体(DAB或VHH)等等,包括以上提到的IgG4的半分子(van der Neut Kolfschoten等(Science2007;317(14Sept):1554-1557)。无论结构如何,抗体片段与完整抗体识别的相同抗原结合。术语“抗体片段”还包括通过结合特异抗原形成复合体,执行抗体类似作用的任何合成或遗传工程蛋白质。例如,抗体片段包括由可变区组成的分离片段,如由重链和轻链的可变区组成的“Fv”片段,其中轻链和重链可变区通过肽连接体连接的重组单链多肽分子(“scFv蛋白”)和由氨基酸残基组成的模仿高变区的最小识别单位,如CDR。可以以不同方法构建Fv片段,得到多价和/或多特异性结合形式。在多价的情况下,其具有抗特异性表位的一个以上结合位点,而多特异形式与一个以上表位(相同抗原的或抗一种抗原和不同抗原)结合。本文所用的术语抗体组分包括整个抗体、融合蛋白及其片段。
裸抗体一般是未与治疗剂共轭的整个抗体。之所以这样,是因为抗体分子的Fc部分提供了效应子或免疫功能,如补体固定和ADCC(抗体依赖性细胞毒性),该功能使得可能导致细胞裂解的机制运转起来。不过,可能Fc部分并非是抗体的治疗功能所必需的,而是其他机制如细胞凋亡、抗血管发生、抗转移活性、抗粘附活性(诸如抑制异型粘附或同型粘附)和干扰信号转导途径,开始运行并干扰疾病进展。裸抗体包括包括鼠抗体的多克隆抗体和单克隆抗体及其片段、以及某些重组抗体,如嵌合抗体、人化抗体或人抗体及其片段。因此,在一些情况,“裸抗体”也可是指“裸”抗体片段。如本文定义的,“裸”与“未共轭”同义,表示未与治疗剂连接或共轭。
自身免疫性疾病是身体产生针对其自身组织的免疫应答导致的病症。例子包括III类自身免疫性疾病,诸如免疫介导的血小板减少症、急性特发性血小板减少性紫癜和慢性特发性血小板减少性紫癜、皮肌炎、舍格伦氏综合症、多发性硬化、西登哈姆氏舞蹈病(Sydenham’s chorea)、重症肌无力、系统性红斑狼疮、狼疮性肾炎、风湿热、多腺体综合征、大疱性类天疱疮、糖尿病、亨-舍二氏紫癜、链球菌感染后肾炎、结节性红斑、高安氏动脉炎、阿狄森氏病、类风湿性关节炎、结节病、溃疡性结肠炎、多形性红斑、IgA肾病、结节性多动脉炎、强直性脊柱炎、古德帕斯丘综合征、闭塞性血栓性脉管炎、舍格伦综合征、原发性胆汁性肝硬变、桥本甲状腺炎、甲状腺毒症、硬皮病、慢性活动性肝炎、类风湿性关节炎、多肌炎/皮肌炎、多软骨炎、寻常天疱疮、韦格纳氏肉芽肿病、膜性肾病、肌萎缩侧索硬化、脊髓痨、巨细胞动脉炎/多肌痛、恶性贫血、急进性肾小球肾炎和纤维化肺泡炎,如2002年3月1日提交的美国临时申请序列No.60/360,259公开的,其实施例部分通过引用并入本文。
嵌合抗体是这样的重组蛋白,其含有包括源于一个物种抗体(优选为啮齿动物抗体,更优选为鼠抗体)的互补决定区(CDR)在内的重链抗体和轻链抗体二者的可变结构域,而该抗体分子的恒定结构域源于人抗体的恒定结构域。对于兽医应用,嵌合抗体的恒定结构域可源于其他物种如灵长类动物、猫或狗的恒定结构域。
人化抗体是这样的重组蛋白,其中将来自于一个物种抗体如鼠抗体的CDR从鼠抗体的重链和轻链可变链上转移到人重链和轻链可变结构域(构架区)之中。该抗体分子的恒定结构域源于人抗体的恒定结构域。在一些情况中,可修饰人化抗体构架区的特定残基,尤其是接触或接近CDR序列的残基,例如用来自原始的鼠科动物、啮齿类动物、非人灵长类动物或其他抗体的相应残基代替。
人抗体是例如由转基因小鼠获得的抗体,该小鼠已被“改造”以响应抗原刺激产生人抗体。在这种技术中,将人重链和轻链基因座的元件引入到衍生自含有内源重链和轻链基因座的靶向破坏的胚胎干细胞系的小鼠株系中。转基因小鼠可合成对各种抗原具有特异性的人抗体,并且该小鼠可用于生产分泌人抗体的杂交瘤。用于获得来自转基因小鼠的人抗体的方法由Green等,Nature Genet.7:13(1994),Lonberg等,Nature 368:856(1994)以及Taylor等,Int.Immun.6:579(1994)描述。也可通过基因或染色体转染法、以及噬菌体展示技术构建全人抗体,所有这些方法都是本领域公知的。例如参见McCafferty等,Nature 348:552-553(1990)关于由来自未免疫供体的免疫球蛋白可变结构域基因库在体外生产人抗体及其片段。在这种技术中,将抗体可变结构域基因框内克隆到丝状噬菌体的主要或次要外壳蛋白基因中,并作为功能性抗体片段展示在噬菌体颗粒的表面。由于该丝状颗粒含有所述噬菌体基因组的单链DNA拷贝,所以基于所述抗体功能性质的选择也导致编码表现出那些性质的抗体的基因的选择。以这种方式,所述噬菌体模拟B细胞的一些性质。噬菌体展示能够以多种形式进行,有关综述,参见如Johnson和Chiswell,Current Opinion in Structural Biology3:5564-571(1993)。人抗体也可由体外活化的B细胞产生。参见美国专利No.5,567,610和5,229,275,上述每一个专利的实施例部分通过引用并入本文。
本文所用的传染病是包括病原体诸如细菌、立克次氏体、支原体、原生动物、真菌、病毒、寄生虫、或其他微生物剂感染的疾病。例子包括导致AIDS的人免疫缺陷病毒(HIV)、结核分支杆菌(Mycobacterium of tuberculosis)、无乳链球菌(Streptococcusagalactiae)、耐甲氧西林金黄色葡萄球菌、嗜肺性军团病菌(Legionellapneumophilia)、酿脓链球菌(Streptococcus pyogenes)、大肠杆菌(Escherichia coli)、淋病奈瑟氏菌(Neisseria gonorrhosae)、脑膜炎奈瑟氏菌(Neisseria meningitidis)、肺炎球菌属(Pneumococcus)、新型隐球菌(Cryptococcus neoformans)、荚膜组织胞浆菌(Histoplasmacapsulatum)、B型流感嗜血杆菌(Hemophilis influenzae B)、苍白密螺旋体(Treponema pallidum)、莱姆病螺旋体、西尼罗病毒、绿脓假单胞菌(Pseudomonas aeruginosa)、麻风分枝杆菌(Mycobacterium leprae)、流产杆菌(Brucella abortus)、狂犬病病毒、流感病毒、巨细胞病毒、I型单纯疱疹病毒、II型单纯疱疹病毒、人血清细小样病毒、呼吸道合胞病毒、水痘-带状疱疹病毒、乙型肝炎病毒、丙型肝炎病毒、麻疹病毒、腺病毒、人T细胞白血病病毒、埃-巴二氏病毒(Epstein-Barrvirus)、鼠白血病病毒、腮腺炎病毒、水泡性口膜炎病毒、辛德比斯病毒(sindbis virus)、淋巴细胞性脉络丛脑膜炎病毒、疣病毒、蓝舌病病毒、仙台病毒、猫白血病病毒、呼肠孤病毒、脊髓灰质炎病毒、猿猴病毒40、鼠乳房肿瘤病毒、登革热病毒、风疹病毒、恶性疟原虫(Plasmodium falciparum)、间日疟原虫(Plasmodium vivax)、鼠弓形体(Toxoplasma gondii)、让氏锥虫(Trypanosoma rangeli)、克氏锥虫(Trypanosoma cruzi)、罗德西亚锥虫(Trypanosoma rhodesiensei)、布氏锥虫(Trypanosoma brucei)、曼森血吸虫(Schistosoma mansoni)、日本血吸虫(Schistosoma japanicum)、牛巴贝虫(Babesia bovis)、柔嫩艾美球虫(Elmeria tenella)、盘尾丝虫(Onchocerca volvulus)、热带利什曼原虫(Leishmania tropica)、旋毛线虫(Trichinella spiralis)、小泰累尔梨浆虫(Theileria parva)、水泡绦虫(Taenia hydatigena)、羊绦虫(Taeniaovis)、牛肉绦虫(Taenia saginata)、细粒棘球绦虫(Echinococcusgranulosus)、科特氏中殖孔绦虫(Mesocestoides corti)、关节炎支原体(Mycoplasma arthritidis)、猪鼻支原体(M.hyorhinis)、口腔支原体(M.orale)、精氨酸支原体(M.arginini)、莱氏无胆甾原体(Acholeplasmalaidlawii)、唾液支原体(M.salivarium)和肺炎支原体(M.pneumoniae)。列出针对感染性生物体(抗毒素和抗病毒抗体)、以及其他靶的抗体的综述包含于Casadevall,Clin Immunol 1999;93(1):5-15,通过引用并入本文。
治疗剂是与结合部分如抗体或抗体片段、或其亚片段分别、同时或相继地给药的分子或原子,并且可用于疾病的治疗。治疗剂的实例包括但不限于抗体、抗体片段、共轭物、药物、细胞毒性剂、促细胞凋亡剂、毒素、核酸酶(包括DNA酶和RNA酶)、激素、免疫调节剂、螯合剂、硼化合物、光敏剂或染料、放射性同位素或放射性核素、寡核苷酸、干扰RNA、肽、抗血管发生剂、化疗剂、细胞因子、趋化因子、前药、酶、结合蛋白或肽、或其组合。
共轭物是与治疗剂例如上所述的治疗剂共轭的抗体组分或其他靶向部分。本文所用的术语“共轭物”和“免疫共轭物”可交换地使用。
如本文所用,术语抗体融合蛋白指重组制备的抗原结合分子,其中一种或多种天然抗体、单链抗体或抗体片段连接(融合)于另一部分,诸如蛋白或肽毒素、细胞因子、激素等等。在某些优选实施方案中,融合蛋白可包括融合在一起的两种或多种相同或不同的抗体、抗。体片段或单链抗体,这些抗体可结合于相同抗原或不同抗原上的相同表位、不同表位。抗体融合蛋白至少包括一个特异性结合位点。融合蛋白的化合价指示融合蛋白对单个抗原或表位具有的结合臂或位点的总数;即单价、双价、三价或多价。抗体融合蛋白的多价意味着它在与抗原结合时可以利用多个相互作用,因而可以增强与抗原、或与不同抗原结合的亲和力。特异性指示抗体融合蛋白能与多少种抗原或表位结合;即单特异性、双特异性、三特异性、多特异性。根据这些定义,天然抗体如IgG为双价,因为它有两个结合臂,但是它是单特异性,因为它结合一种抗原或表位。单特异性、多价融合蛋白对同一抗原或表位具有多于一个的结合位点。例如,单特异性二链抗体是具有两个与同一抗原有反应性的结合位点的融合蛋白。融合蛋白可包含不同抗体组分的多价或多特异性组合、或者同一抗体组分的多个拷贝。融合蛋白可额外包含治疗剂。
免疾调节剂是一种治疗剂,当存在时,它改变、抑制或刺激身体的免疫系统。典型地,有用的免疫调节剂刺激免疫细胞增殖或者在免疫应答级联中激活,例如巨噬细胞、树突状细胞、B-细胞和/或T-细胞。然而,在一些情况中,免疫调节剂可阻遏免疫细胞的增殖或活化,如对自身免疫性疾病的治疗性治疗。本文描述的免疫调节剂的例子是细胞因子,其是与特异性抗原接触时一个细胞群(例如预处理的T淋巴细胞)释放的大约5-20kDa的可溶性小蛋白,它作为细胞间的细胞间介质起作用。如本领域技术人员应理解的那样,细胞因子的例子包括淋巴因子、单核因子、白介素和几种相关的信号传导分子,例如肿瘤坏死因子(TNF)和干扰素。趋化因子是一组细胞因子。一些白介素和干扰素是刺激T细胞或其他免疫细胞增殖的细胞因子的例子。
CPT是喜树碱的缩写,并且在本申请中CPT用于表示喜树碱本身或喜树碱的类似物或衍生物。具有所示的编号和用字母A-E标记的环的喜树碱和一些其类似物的结构在以下图表1中以式1提供。
图表1
喜树碱共轭物
下述方法中设想了用于制备化疗药物与靶向部分(TM)、例如抗体(MAb)的共轭物的方法。公开的方法代表本发明的优选实施方案。(1)药物的溶解度通过如下方式增强:在药物与靶向载体之间放置确定的聚乙二醇(PEG)部分(即,包含确定数目的单体单元的PEG),其中确定的PEG是低分子量PEG,优选地包含1-30个单体单元,更优选地包含1-12个单体单元;(2)第一接头在一端连接药物,在另一端终止于乙炔基或叠氮化物基;该第一接头包含确定的PEG部分,在一端带有叠氮化物或乙炔基,在另一端带有不同反应性基团诸如羧酸或羟基,所述双官能的确定的PEG与氨基醇的胺基连接,氨基醇的羟基与药物上碳酸酯形式的羟基连接;可选地,所述确定的双官能的PEG的非叠氮化物(或乙炔)部分任选地与L-氨基酸或多肽N末端连接,C末端连接于氨基醇的氨基,氨基醇的羟基分别连接于药物的碳酸酯或氨基甲酸酯形式的羟基;(3)第二接头,包括靶向部分-偶联部分和与第一接头的叠氮化物(或乙炔)基互补的反应性基团即乙炔(或叠氮化物),经由乙炔-叠氮化物环加成反应与药物-(第一接头)共轭物反应以提供可用于与疾病靶向部分诸如疾病-靶向抗体共轭的最终的双官能药物产物;(4)抗体-偶联基团设计为硫醇或硫醇-反应性基团;(5)在制备包括CPT类似物诸如SN-38的药物-接头前体中设想了在C-20碳酸酯存在下用于选择性再生10-羟基的方法;(6)还使用药物中的反应性羟基(诸如SN-38中的酚羟基)的其他保护基,例如,诸如叔丁基二甲基甲硅烷基或叔丁基二苯基甲硅烷基,这些在将衍生化药物连接于靶向-载体物-偶联部分之前通过四丁基氟化铵脱保护;和(6)CPT类似物的10-羟基可选地被保护为酯或碳酸酯而不是‘BOC’从而双官能的CPT与靶向部分共轭而不需要之前将此保护基脱保护,此保护基在施用生物共轭物后在生理pH条件下容易被脱保护。在称为‘链接化学’的乙炔-叠氮化物偶联中,叠氮化物部分可在L2上,乙炔部分可在L3上。可选地,L2可包含乙炔,L3可包含叠氮化物。‘链接化学’是乙炔部分与叠氮化物部分之间的铜(+1)-催化的环加成反应,并且在生物共轭方面是相对较新的技术(Kolb HC和SharplessKB,DrugDiscov Today 2003;8:1128-37)。链接化学在水溶液中在接近中性的pH条件下发生,因此是适用于药物共轭。链接化学的益处在于其是化学选择性的,补充了其他公知共轭化学诸如硫醇-马来酰亚胺反应。在以下讨论中,当共轭物包含抗体或抗体片段时,可取代另一种类型的结合部分,诸如适体、avimer或靶向肽。
一种示例性优选实施方案涉及通式2的、药物衍生物与抗体的共轭物,
MAb-[L2]-[L1]-[AA]m-[A’]-药物(2)
其中MAb是疾病-靶向抗体;L2是包括抗体-偶联部分和一个或多个乙炔(或叠氮化物)基的交联接头的组分;L1包括确定的PEG,在一端带有与L2中乙炔(或叠氮化物)部分互补的叠氮化物(或乙炔),在另一端带有反应性基团(诸如羧酸或羟基);AA是L-氨基酸;m是数值为0、1、2、3或4的整数;且A’是另外的间隔物,选自乙醇胺、4-羟基苄醇、4-氨基苄醇或取代或未取代的乙二胺。‘AA’的L氨基酸选自丙氨酸、精氨酸、天冬酰胺、天冬氨酸、半胱氨酸、谷氨酰胺、谷氨酸、甘氨酸、组氨酸、异亮氨酸、亮氨酸、赖氨酸、甲硫氨酸、苯丙氨酸、脯氨酸、丝氨酸、苏氨酸、色氨酸、酪氨酸和缬氨酸。如果A’基团包括羟基,则其分别连接于以碳酸酯或氨基甲酸酯形式的药物的羟基或氨基。
在式2的优选实施方案中,A’是衍生自L-氨基酸的取代的乙二胺,其中氨基酸的羧酸基团被羟甲基部分代替。A’可衍生自以下L-氨基酸的任一种:丙氨酸、精氨酸、天冬酰胺、天冬氨酸、半胱氨酸、谷氨酰胺、谷氨酸、甘氨酸、组氨酸、异亮氨酸、亮氨酸、赖氨酸、甲硫氨酸、苯丙氨酸、脯氨酸、丝氨酸、苏氨酸、色氨酸、酪氨酸和缬氨酸。
在式2的优选实施方案的共轭物的一个例子中,m是0,A’是L-缬氨醇,药物由SN-38示例。所得结构如式3所示。
在式2的优选实施方案的共轭物的另一个例子中,m是1并且由衍生化L-赖氨酸表示,A’是L-缬氨醇,药物由SN-38示例。结构如式4所示。
在这一实施方案中,利用用于赖氨酸氨基的正交保护基,首先在氨基酸诸如赖氨酸的羧酸和缬氨醇的氨基之间形成酰胺键。去除赖氨酸N末端上的保护基,保持赖氨酸侧链上的保护基完整,并且N末端与另一端带有叠氮化物(或乙炔)的确定的PEG上的羧基偶联。然后将缬氨醇的羟基连接于10-羟基保护的SN-38的20-氯甲酸酯衍生物,将这一中间产物与携带靶向载体-结合部分以及链接环加成化学中牵涉的互补乙炔(或叠氮化物)基的L2组分偶联。最后,去除赖氨酸侧链和SN-38两处的保护基提供了式3所示的本例子的产物。
尽管不希望受限于理论,但是细胞内蛋白水解后产生的小的MW SN-38产物即缬氨醇-SN-38碳酸酯,具有经由牵涉缬氨醇的氨基和碳酸酯的羰基的分子内环化而释出完整SN-38的另外途径。
在另一优选实施方案中,通式2的A’是A-OH,其中A-OH是可折叠部分诸如4-氨基苄醇或在苄型位置用C1-C10烷基取代的取代的4-氨基苄醇,取代的4-氨基苄醇经由其氨基连接于L-氨基酸或包含最多4个L-氨基酸部分的多肽;其中N末端与终止于靶向部分-结合基团的交联接头连接。
以下提供优选实施方案的一个例子,其中通式(2)的A’的A-OH实施方案衍生自取代的4-氨基苄醇,通式(2)中‘AA’包括m=1的单个L-氨基酸,且药物以SN-38示例。结构如下所示(式5,称为MAb-CLX-SN-38)。AA的单个氨基酸选自以下L-氨基酸的任一种:丙氨酸、精氨酸、天冬酰胺、天冬氨酸、半胱氨酸、谷氨酰胺、谷氨酸、甘氨酸、组氨酸、异亮氨酸、亮氨酸、赖氨酸、甲硫氨酸、苯丙氨酸、脯氨酸、丝氨酸、苏氨酸、色氨酸、酪氨酸和缬氨酸。4-氨基苄醇部分(A’的A-OH实施方案)上的取代基R是氢或选自C1-C10烷基的烷基。
式5的MAb-CLX-SN-38的一个实施方案,其中单个氨基酸AA是L-赖氨酸且R=H,并且药物由SN-38示例(式6;称为MAb-CL2A-SN-38)。
在含10-羟基的喜树碱诸如SN-38的范畴内,其他实施方案是可能的。在SN-38作为药物的例子中,对药物的更有反应性的10-羟基进行衍生化,留下20-羟基不受影响。在通式2中,A’是取代的乙二胺。这种实施方案的一个例子由下式‘7’表示,其中用取代的乙二胺将SN-38的酚羟基衍生化为氨基甲酸酯,用4-氨基苄醇将二胺的另一个胺衍生化为氨基甲酸酯,4-氨基苄醇的氨基连接于Phe-Lys二肽。在这一结构(式7)中,R和R′独立地是氢或甲基。当R=R′=甲基时,其称为MAb-CL17-SN-38或MAb-CL2E-SN-38。
在优选实施方案中,AA包括可被胞内肽酶裂解的多肽部分,优选地二肽、三肽或四肽。例子有:Ala-Leu、Leu-Ala-Leu和Ala-Leu-Ala-Leu(Trouet等,1982)。
在另一优选实施方案中,共轭物的L1组分包含具有1-30个重复单体单元的确定的聚乙二醇(PEG)间隔物。在进一步的优选实施方案中,PEG是具有1-12重复单体单元的确定的PEG。PEG的引入可包括利用市售可得的异双官能化的PEG衍生物。异双官能PEG可包含叠氮化物或乙炔基。包含8个重复单体单元的确定的异双官能PEG,其中‘NHS’为琥珀酰亚胺基的例子以下式8提供:
在优选实施方案中,L2具有多个乙炔(或叠氮化物)基(范围为2-40个,但优选地为2-20个,更优选地为2-5个)和单个靶向载体-结合部分。
包含多个药物分子和单个靶向载体-结合部分的抗体的代表性SN-38共轭物如下所示。这种结构的‘L2’组分悬挂于2个炔属基团,导致连接两个叠氮化物-悬挂的SN-38分子。与MAb的成键由琥珀酰亚胺表示。
在优选实施方案中,当双官能的药物包含硫醇反应性的部分作为抗体-结合基团时,利用硫醇化试剂在抗体的赖氨酸基团上产生抗体上的硫醇。通过修饰MAb赖氨酸基团向抗体引入硫醇基的方法是本领域公知的(Wong,Chemistry of protein conjugation andcross-linking(蛋白共轭和交联的化学),CRC Press,Inc.,Boca Raton,FL(1991),第20-22页中)。可选地,利用还原剂诸如二硫苏糖醇(DTT)对抗体上链间二硫化物键的轻度还原(Willner等,Bioconjugate Chem.4:521-527(1993))可在抗体上产生7-至-10个硫醇;这具有在远离抗原结合区的MAb链间区中掺入多个药物部分的益处。
在优选实施方案中,优选的化疗部分选自由以下组成的组:阿霉素(DOX)、表柔比星、吗啉代阿霉素(吗啉代-DOX)、氰基吗啉代-阿霉素(氰基吗啉代-DOX)、2-吡咯啉基阿霉素(2-PDOX)、CPT、10-羟基喜树碱、SN-38、托泊替康、勒托替康、9-氨基喜树碱、9-硝基喜树碱、紫杉烷、格尔德霉素、袢霉素和埃坡霉素。在更优选的实施方案中,化疗部分是SN-38。优选地,在优选实施方案的共轭物中,靶向部分连接于至少一个化疗部分;优选地为1至约12个化疗部分;最优选地为约6至约12个化疗部分。
而且,在优选实施方案中,接头组分‘L2’包括与在所述靶向部分的一个或多个赖氨酸侧链氨基引入的硫醇反应性残基反应的硫醇基。在这种情况下,由本领域充分描述的实验方案将抗体用硫醇反应性基团诸如马来酰亚胺、乙烯砜、溴乙酰胺或碘乙酰胺预衍生化。
在这些实施方案的范畴中,令人惊讶地开发了一种方法,由此方法可制备CPT药物-接头,其中CPT另外具有10-羟基。这一方法包括但不限于,将10-羟基保护为叔丁氧羰基(BOC)衍生物,随后制备药物-接头共轭物的倒数第二的中间产物。通常,去除BOC基要求用强酸诸如三氟乙酸(TFA)处理。在这些条件下,包含待去除的保护基的CPT 20-O-接头碳酸酯也对裂解敏感,从而获得未修饰的CPT。事实上,如本领域中发表的,利用用于接头分子的赖氨酸侧链的轻度可还原的甲氧基三苯甲基(MMT)保护基的基本原理准确地避免这一可能性(Walker等,2002)。发现通过使反应进行较短的时间(最佳地为3-至-5分钟)而选择性去除酚BOC保护基是可能的。在这些条件下,主要产物是其中去除了10-羟基位置的‘BOC’,而‘20’位置的碳酸酯完整的产物。
一种替代方法包括用‘BOC’以外的基团保护CPT类似物的10-羟基位置,从而最终产物易于与抗体共轭而不需要使10-OH保护基脱保护。将10-OH转化为酚碳酸酯或酚酯的10-羟基保护基,在体内施用共轭物后容易被生理pH条件或被酯酶脱保护。He等已经描述了,在生理条件下去除在10位置的苯酚碳酸酯比去除10-羟基喜树碱20位置的叔碳酸酯更快(He等,Bioorganic&Medicinal Chemistry 12:4003-4008(2004))。SN-38上的10-羟基保护基可以是‘COR’,其中R可以是取代的烷基诸如“N(CH3)2-(CH2)n-”,其中n是1-10,且其中末端氨基任选地呈水溶性增强的季盐形式;或简单的烷基残基诸如“CH3-(CH2)n-”,其中n是0-10;或可以是烷氧基部分诸如“CH3-(CH2)n-O-”,其中n是0-10;或“N(CH3)2-(CH2)n-O-”,其中n是2-10;或“R1O-(CH2-CH2-O)n-CH2-CH2-O-”,其中R1是乙基或甲基,n是数值为0-10的整数。如果最终衍生物将是碳酸酯,那么通过用所选试剂的氯甲酸酯处理将容易制备这些10-羟基衍生物。通常,利用三乙胺作为碱,用等摩尔的二甲基甲酰胺中的氯甲酸酯处理包含10-羟基的喜树碱诸如SN-38。在这些条件下,20-OH位置不受影响。对于形成10-O-酯,使用所选试剂的酰基氯。
在制备通式2的药物衍生物与抗体的共轭物的优选方法中,其中描述符L2、L1、AA和A-X如前面的部分所述,首先制备双官能的药物部分[L2]-[L1]-[AA]m-[A-X]-药物,随后将双官能的药物部分与靶向部分TM共轭。
在制备通式2的药物衍生物与抗体的共轭物的优选方法中,其中描述符L2、L1、AA和A-OH如前面的部分所述,通过经由酰胺键首先将A-OH与AA的C末端连接、随后通过将AA的胺末端与L1的羧酸基偶联,从而制备双官能的药物部分。如果AA不存在(即m=0),则A-OH经由酰胺键直接连接于L1。通过经由链接化学借助于L1和L2中叠氮化物(或乙炔)与乙炔(或叠氮化物)基之间的反应,将交联接头[L1]-[AA]m-[A-OH]连接于药物的羟基或氨基,随后连接于L1部分。
在一个实施方案中,靶向部分TM是单克隆抗体(MAb)。在进一步的实施方案中,靶向部分可以是多价和/或多特异性的MAb。靶向部分可以是鼠、嵌合、人化或人单克隆抗体,所述抗体可以是完整的、片段(Fab、Fab’、F(ab)2、F(ab’)2)或亚片段(单链构建体)形式,或为IgG1、IgG2a、IgG3、IgG4、IgA同种型,或其亚分子。
在优选实施方案中,靶向部分是与癌症或恶性细胞上表达的抗原或抗原表位反应的单克隆抗体。癌细胞优选地是来自造血肿瘤、癌、肉瘤、黑素瘤或神经胶质肿瘤的细胞。根据本发明待治疗的优选恶性肿瘤是恶性实体瘤或造血肿瘤。
在优选实施方案中,胞内可裂解的部分可在通过MAb-药物共轭物与其受体的结合而内化到细胞中后被裂解,尤其是被酯酶和肽酶裂解。
靶向部分优选地是抗体(包括完全人抗体、非人抗体、人化抗体或嵌合抗体)、或抗体片段(包括酶促或重组产生的片段)、或掺入有来自抗体或抗体片段的序列的结合蛋白。抗体、片段和结合蛋白可以是如上定义的多价和多特异性的或多价和单特异性的。
一般抗体技术
用于制备针对实际上任何靶抗原的单克隆抗体的技术是本领域公知的。例如,参见Kohler和Milstein,Nature 256:495(1975),以及Coligan等(编),CURRENTPROTOCOLS IN IMMUNOLOGY(免疫学最新实验方案),第1卷,第2.5.1-2.6.7页(John Wiley&Sons,1991)。简言之,单克隆抗体可如下获得:即用包括抗原的组合物注射小鼠,取出脾脏以获得B淋巴细胞,使所述B淋巴细胞与骨髓瘤细胞融合以产生杂交瘤,克隆所述杂交瘤,选择产生针对所述抗原的抗体的阳性克隆,培养产生针对所述抗原的抗体的所述克隆,并从所述杂交瘤培养物中分离所述抗体。
MAb可通过许多充分建立的技术从杂交瘤培养物中分离和纯化。此类分离技术包括蛋白A或蛋白G琼脂糖亲和层析、大小排阻层析以及离子交换层析。例如,参见Coligan第2.7.1-2.7.12页及第2.9.1-2.9.3页。也参见Baines等,“Purification of ImmunoglobulinG(IgG)(免疫球蛋白G(IgG)的纯化),”于METHODS IN MOLECULARBIOLOGY(分子生物学方法),第10卷,第79-104页(The HumanaPress,Inc.1992)。
在初次引起针对免疫原的抗体后,可对抗体进行测序并随后通过重组技术制备。鼠源抗体和抗体片段的人化和嵌合是本领域技术人员众所周知的,如以下所述。
本领域技术人员将认识到,所要求保护的方法和组合物可利用本领域已知的多种抗体的任一种抗体。使用的抗体可以从多种已知来源商购获得的。例如,多种分泌抗体的杂交瘤细胞系可从美国典型培养物保藏中心(American Type Culture Collection,ATCC,Manassas,VA)获得。大量针对不同疾病靶的抗体(包括但不限于肿瘤相关抗原)已经保藏在ATCC和/或已经公布了可变区序列,并且可有效用于所要求保护的方法和组合物。参见,如,美国专利No.7,312,318;7,282,567;7,151,164;7,074,403;7,060,802;7,056,509;7,049,060;7,045,132;7,041,803;7,041,802;7,041,293;7,038,018;7,037,498;7,012,133;7,001,598;6,998,468;6,994,976;6,994,852;6,989,241;6,974,863;6,965,018;6,964,854;6,962,981;6,962,813;6,956,107;6,951,924;6,949,244;6,946,129;6,943,020;6,939,547;6,921,645;6,921,645;6,921,533;6,919,433;6,919,078;6,916,475;6,905,681;6,899,879;6,893,625;6,887,468;6,887,466;6,884,594;6,881,405;6,878,812;6,875,580;6,872,568;6,867,006;6,864,062;6,861,511;6,861,227;6,861,226;6,838,282;6,835,549;6,835,370;6,824,780;6,824,778;6,812,206;6,793,924;6,783,758;6,770,450;6,767,711;6,764,688;6,764,681;6,764,679;6,743,898;6,733,981;6,730,307;6,720,15;6,716,966;6,709,653;6,693,176;6,692,908;6,689,607;6,689,362;6,689,355;6,682,737;6,682,736;6,682,734;6,673,344;6,653,104;6,652,852;6,635,482;6,630,144;6,610,833;6,610,294;6,605,441;6,605,279;6,596,852;6,592,868;6,576,745;6,572,856;6,566,076;6,562,618;6,545,130;6,544,749;6,534,058;6,528,625;6,528,269;6,521,227;6,518,404;6,511,665;6,491,915;6,488,930;6,482,598;6,482,408;6,479,247;6,468,531;6,468,529;6,465,173;6,461,823;6,458,356;6,455,044;6,455,040、6,451,310;6,444,206;6,441,143;6,432,404;6,432,402;6,419,928;6,413,726;6,406,694;6,403,770;6,403,091;6,395,276;6,395,274;6,387,350;6,383,759;6,383,484;6,376,654;6,372,215;6,359,126;6,355,481;6,355,444;6,355,245;6,355,244;6,346,246;6,344,198;6,340,571;6,340,459;6,331,175;6,306,393;6,254,868;6,187,287;6,183,744;6,129,914;6,120,767;6,096,289;6,077,499;5,922,302;5,874,540;5,814,440;5,798,229;5,789,554;5,776,456;5,736,119;5,716,595;5,677,136;5,587,459;5,443,953、5,525,338,上述每一个专利的实施例部分通过引用并入本文。这些仅是示例性的,大量其他抗体和其杂交瘤是本领域已知的。本领域技术人员将认识到,通过简单搜索针对感兴趣的所选疾病相关靶的抗体的ATCC、NCBI和/或USPTO数据库,可获得针对几乎任何疾病相关抗原的抗体序列或分泌抗体的杂交瘤。利用本领域公知的标准技术,可将克隆抗体的抗原结合结构域扩增,切割,连接到表达载体中,转染到适合的宿主细胞,并用于蛋白质产生。利用本文公开的技术,可将分离的抗体与治疗剂(诸如喜树碱)共轭。
嵌合和人化抗体
嵌合抗体是其中人抗体的可变区被例如小鼠抗体的可变区取代,而包括小鼠抗体的互补决定区(CDR)的重组蛋白。嵌合抗体在被施用至受治疗者时表现出降低的免疫原性和增加的稳定性。构建嵌合抗体的方法为本领域所众所周知的(例如Leung等,1994,Hybridoma13:469)。
嵌合单克隆抗体可通过将小鼠免疫球蛋白重链和轻链可变区的小鼠CDR转移至人抗体的相应结构域进行人化。所述嵌合单克隆抗体的小鼠骨架区(FR)也被替换为人FR序列。为了保留人化单克隆的稳定性和抗原特异性,可将一个或多个人FR残基替换为小鼠的对等残基。人化单克隆抗体可用于受治疗者的治疗性治疗。生产人化单克隆抗体的技术为本领域所众所周知(例如,参见Jones等,1986,Nature,321:522;Riechmann等,Nature,1988,332:323;Verhoeyen等,1988,Science,239:1534;Carter等,1992,Proc.Nat′l Acad.Sci.USA,89:4285;Sandhu,Crit.Rev.Biotech.,1992,12:437;Tempest等,1991,Biotechnology 9:266;Singer等,J.Immun.,1993,150:2844)。
其他实施方案可涉及非人灵长类动物抗体。在狒狒中培养治疗有用的抗体的一般技术可参见,例如Goldenberg等,WO 91/11465(1991)和Losman等,Int.J.Cancer 46:310(1990)。在另一实施方案中,抗体可以是人单克隆抗体。此类抗体可从已改造为响应抗原攻击生产特异性人抗体的转基因小鼠中获得,如以下讨论的。
人抗体
使用组合方法或使用人免疫球蛋白基因座转化的转基因动物生产完全人抗体的方法为本领域已知(例如,Mancini等,2004,NewMicrobiol.27:315-28;Conrad和Scheller,2005,Comb.Chem.HighThroughput Screen.8:117-26;Brekke和Loset,2003,Curr.Opin.Phamacol.3:544-50;其均通过引用并入本文)。所述完全人抗体预期表现出比嵌合抗体或人化抗体更小的副作用,并在体内充当基本上内源的人抗体。在某些实施方案中,本发明要求保护的方法和程序可利用通过所述技术生产的人抗体。
在一个可选实施方案中,可使用噬菌体展示技术生产人抗体(例如,Dantas-Barbosa等,2005,Genet.Mol.Res.4:126-40,通过引用并入本文)。人抗体可从正常人或表现出特定疾病状态(如癌症)的人中生产(Dantas-Barbosa等,2005)。从患病个体构建人抗体的优点是循环抗体库可能偏好针对疾病相关抗原的抗体。
在此方法的一个非限制性实例中,Dantas-Barbosa等(2005)从骨肉瘤患者构建了人Fab抗体片段的噬菌体展示文库。一般而言,从循环血淋巴细胞获得总RNA(同上)。从μ、γ和κ链抗体库克隆重组的Fab并将其插入噬菌体展示文库(同上)。RNA可通过使用对重链和轻链免疫球蛋白序列特异的引物转化为cDNA,并用于制备Fab cDNA文库(Marks等,1991,J.Mol.Biol.222:581-97,通过引用并入本文)。文库构建根据下列文献执行:Andris-Widhopf等(2000,选自:PhageDisplay Laboratory Manual(噬菌体展示实验手册),Barbas等(编著),第1版,Cold Spring Harbor Laboratory Press,Cold Spring Harbor,NY,第9.1至9.22页,通过引用并入本文)。用限制性内切酶消化最终的Fab片段,将其插入噬菌体基因组以制备噬菌体展示文库。所述文库可通过标准噬菌体展示方法进行筛选。熟练的技术人员应理解此技术仅是示例性的,可使用任何已知的通过噬菌体展示制备和筛选人抗体或抗体片段的方法。
在另一可选实施方案中,可使用上述标准免疫方案,可以使用经过遗传工程改造生产人抗体的转基因动物来生产针对基本上任何免疫原性靶的抗体。用于从转基因小鼠获得人抗体的方法描述在Green等,Nature Genet.7:13(1994),Lonberg等,Nature 368:856(1994),和Taylor等,Int.Immun.6:579(1994)中。所述系统的非限制性实例如Abgenix(Fremont,CA)的XenoMouse(例如,Green等,1999,J.Immunol.Methods 231:11-23,通过引用并入本文)。在XenoMouse和类似动物中,小鼠抗体基因已被灭活,并替换为功能性人抗体基因,而小鼠免疫系统的剩余部分则保持完整。
XenoMouse已转化了种系配置的YAC(酵母人工染色体),所述YAC包含部分人IgH和Igκ基因座,包括可变区序列的大部分以及辅助基因和调控序列。可使用人可变区库生产产生抗体的B细胞,所述B细胞可通过已知的技术加工成杂交瘤。使用靶抗原免疫的XenoMouse将通过正常的免疫应答产生人抗体,所述人抗体可通过上述标准技术进行收获和/或生产。有多个种系的XenoMouse可用,每个种系均能产生不同类别的抗体。已显示转基因生产的人抗体具有治疗潜力,并保留普通人抗体的药代动力学特性(Green等,1999)。熟练技术人员应理解,本发明要求保护的组合物和方法不限于使用XenoMouse系统,而可利用经过基因工程改造以生产人抗体的任何转基因动物。
抗体片段的生产
所要求保护的方法和/或组合物的一些实施方案可涉及抗体片段。这种抗体片段可通过常规方法,例如通过全长抗体的胃蛋白酶或木瓜蛋白酶消化获得。例如,抗体片段可通过用胃蛋白酶酶切抗体生产,以提供表示为F(ab′)2的5S片段。该片段可进一步使用硫醇还原剂切割,并且任选地使用因二硫键切割产生的巯基的封闭基团,以生产3.5S的Fab′单价片段。可选地,利用胃蛋白酶酶切产生两个单价Fab片段和一个Fc片段。用于产生抗体片段的示例方法公开在美国专利No.4,036,945;美国专利No.4,331,647;Nisonoff等,1960,Arch.Biochem.Biophys.,89:230;Porter,1959,Biochem.J.,73:119;Edelman等,1967,METHODS IN ENZYMOLOGY(酶学方法),第422页(Academic Press),和Coligan等,(编著),1991,CURRENTPROTOCOLS IN IMMUNOLOGY(免疫学最新实验方案),(John Wilcy&Sons)。
也可以使用其他切割抗体的方法,例如分离重链以形成单价轻链-重链片段,进一步切割片段,或者其他酶促技术、化学技术或基因技术,只要所述片段结合被完整抗体所识别的抗原即可。例如,Fv片段包括VH链与VL链的缔合。这种缔合可以是非共价的,如Inbar等,1972,Proc.Nat′l.Acad.Sci.USA,69:2659所述。可选地,可变链可由分子间二硫化物键连接,或被化学物诸如戊二醛交联。参见Sandhu,1992,Crit.Rev.Biotech.,12:437。
优选地,Fv片段包括由肽接头连接的VH链和VL链。这些单链抗原结合蛋白(scFv)通过构建包含由寡核苷酸接头序列连接的编码VH结构域和VL结构域的DNA序列的结构基因来制备。将结构基因插入表达载体,随后将表达载体引入宿主细胞诸如大肠杆菌。重组的宿主细胞合成单条多肽链,其中接头肽桥接两个V结构域。用于产生scFv的方法是本领域公知的。参见Whitlow等,1991,Methods:ACompanion to Methods inEnzymology(方法:酶学方法的参考书)2:97;Bird等,1988,Science,242:423;美国专利No.4,946,778;Pack等,1993,Bio/Technology,11:1271,和Sandhu,1992,Crit.Rev.Biotech.,12:437。
另一种形式的抗体片段是单结构域抗体(dAb),有时称为单链抗体。用于产生单结构域抗体的技术是本领域公知的(参见,如,Cossins等,Protein Expression and Purification,2007,51:253-59;Shuntao等,Molec Immunol 2006,43:1912-19;Tanha等,J.Biol.Chem.2001,276:24774-780)。其他类型的抗体片段可包括一个或多个互补决定区(CDR)。通过构建编码感兴趣抗体的CDR的基因,可获得CDR肽(“最小识别单元”)。这种基因可如下制备,例如,通过利用聚合酶链式反应从抗体产生细胞的RNA合成可变区。参见Larrick等,1991,Methods:A Companion to Methods in Enzymology(方法:酶学方法的参考书)2:106;Ritter等(编著),1995,MONOCLONAL ANTIBODIES:PRODUCTION,ENGINEERING AND CLINIC AL APPLICATION(单克隆抗体:产生、工程化与临床应用),第166-179页(CambridgeUniversity Press);Birch等,(编著),1995,MONOCLONALANTIBODIES:PRINCIPLES AND APPLICATIONS(单克隆抗体:原理与应用),第137-185页(Wiley-Liss,Inc.)
抗体变化
在某些实施方案中,抗体的序列,诸如抗体的Fc部分,可被改变以优化共轭物的生理学特征,诸如血清半衰期。取代蛋白质中的氨基酸序列的方法是本领域广泛已知的,诸如通过定点诱变(如Sambrook等,Molecular Cloning,A laboratorymanual(分子克隆实验手册),第2版,1989)。在优选实施方案中,变化可包括在Fc序列中添加或去除一个或多个糖基化位点(如,美国专利No.6,254,868,其实施例部分通过引用并入本文)。在其他优选实施方案中,可在Fc序列中进行特定的氨基酸取代(如,Hornick等,2000,J Nucl Med41:355-62;Hinton等,2006,J Immunol 176:346-56;Petkova等2006,Int Immunol 18:1759-69;美国专利No.7,217,797;各自通过引用并入本文)。
双特异性和多特异性抗体
双特异性抗体在大量生物医学应用中有用。例如,具有用于肿瘤细胞表面抗原和T细胞表面受体的结合位点的双特异性抗体可指导具体肿瘤细胞被T细胞裂解。识别神经胶质瘤和T细胞上的CD3表位的双特异性抗体已经成功地用于治疗人患者的脑瘤(Nitta等Lancet.1990;355:368-371)。在某些实施方案中,用于本文公开的治疗剂共轭的技术和组合物可使用双特异性或多特异性抗体作为靶向部分。
产生双特异性或多特异性抗体的许多方法是已知的,例如,美国专利No.7,405,320中公开的,其实施例部分通过引用并入本文。双特异性抗体可由细胞杂交瘤方法产生,该方法包括融合两个不同杂交瘤,每个杂交瘤产生识别不同抗原性位点的单克隆抗体(Milstein和Cuello,Nature,1983;305:537-540)。
用于产生双特异性抗体的另一种方法利用异双官能交联接头来化学地连系两个不同的单克隆抗体(Staerz等Nature.1985;314:628-631;Perez等Nature.1985;316:354-356)。双特异性的抗体还可如下产生:将两个亲本单克隆抗体各自还原为对应的半分子,然后混合并允许再氧化以获得杂合结构(Staerz和Bevan.Proc Natl AcadSci U S A.1986;83:1453-1457)。另一种替代方法包括利用适当的接头化学交联两个或三个各自纯化的Fab’片段(参见如,欧洲专利申请0453082)。
其他方法包括通过经由逆转录病毒衍生的穿梭载体将不同的选择标记基因转移到相应亲本杂交瘤中,然后融合亲本杂交瘤来改进产生杂交杂交瘤的效率(DeMonte等Proc Natl Acad Sci U S A.1990,87:2941-2945);或用包含不同抗体的重链和轻链基因的表达质粒转染杂交瘤细胞系。
同类的VH和VL结构域可用具有适当组成和长度的肽连接体(通常由超过12个的氨基酸残基组成)连接以形成具有结合活性的单链Fv(scFv)。生产scFv的方法公开于美国专利No.4,946,778和美国专利No.5,132,405,上述每个专利的实施例部分通过引用并入本文。将所述肽连接体的长度减至小于12个氨基酸残基而阻止位于同一条链的VH和VL结构域配对,而强制在不同链上的具有互补结构域的VH和VL结构域进行配对,从而形成功能性多聚体。用3至12个氨基酸残基的连接体连接的VH和VL结构域的多肽链主要形成二聚体(称为二链抗体)。使用0至2个氨基酸残基的连接体,则有利于形成三聚体(称为三链抗体)和四聚体(称为四链抗体),但是除连接体长度之外,寡聚化的准确模式似乎还依赖于V-结构域的组成以及方向(VH-连接体-VL或VL-连接体-VH)。
用于产生多特异性或双特异性抗体的这些技术表现出在低产率、纯化必要性、低稳定性或技术的劳动密集性方面的多种困难。最近,已经使用称为“对接锁定”(DNL)的技术来产生几乎任何期望抗体、抗体片段和其他效应分子的组合(参见,如美国专利No.7,550,143;7,521,056;7,534,866;7,527,787和USSN 11/925,408,上述每个专利的实施例通过引用并入本文)。该技术利用互补的蛋白结合结构域,称为锚定结构域(AD)和二聚和对接结构域(DDD),它们互相结合,允许组装从二聚体、三聚体、四聚体、五聚体到六聚体的复杂结构。这些以高产率形成稳定复合体,而不要求深入的纯化。DNL技术允许组装单特异性、双特异性或多特异性抗体。本领域已知的用于制备双特异性或多特异性抗体的任何技术可用来实践本发明要求保护的方法。
在各种实施方案中,本文公开的共轭物可以是复合的、多特异性抗体的部分。这种抗体可包含两个或多个具有不同特异性的不同抗原结合位点。多特异性的复合体可结合于同一抗原的不同表位,或可选地可结合于两种不同抗原。一些更优选的靶组合包括表1中所列的靶组合。这是优选组合的例子的列表,不意为是穷举的。
表1.多特异性的抗体的一些例子
第一靶 | 第二靶 |
MIF | 第二种促炎性效应细胞因子,尤其是HMGB-1、TNF-α、IL-1或IL-6 |
MIF | 促炎性效应趋化因子,尤其是MCP-1、RANTES、MIP-1A或MIP-1B |
MIF | 促炎性效应受体,尤其是IL-6R、IL-13R和IL-15R |
MIF | 凝血因子,尤其是TF或凝血酶 |
MIF | 补体因子,尤其是C3、C5、C3a或C5a |
MIF | 补体调节蛋白,尤其是CD46、CD55、CD59和mCRP |
MIF | 癌症相关的抗原或受体 |
HMGB-1 | 第二种促炎性效应细胞因子,尤其是MIF、TNF-α、IL-1或IL-6 |
HMGB-1 | 促炎性效应趋化因子,尤其是MCP-1、RANTES、MIP-1A,或MIP-1B |
HMGB-1 | 促炎性效应受体癌症相关的MCP-1、RANTES、MIP-1A或MIP-1B |
HMGB-1 | 凝血因子,尤其是TF或凝血酶 |
HMGB-1 | 补体因子,尤其是C3、C5、C3a,或C5a |
HMGB-1 | 补体调节蛋白,尤其是CD46、CD55、CD59和mCRP |
HMGB-1 | 癌症相关的抗原或受体 |
TNF-α | 第二种促炎性效应细胞因子,尤其是MIF、HMGB-1、TNF-α、IL-1或IL-6 |
TNF-α | 促炎性效应趋化因子,尤其是MCP-1、RANTES、MIP-1A或MIP-1B |
TNF-α | 促炎性效应受体,尤其是IL-6R、IL-13R和IL-15R |
TNF-α | 凝血因子,尤其是TF或凝血酶 |
TNF-α | 补体因子,尤其是C3、C5、C3a或C5a |
TNF-α | 补体调节蛋白,尤其是CD46、CD55、CD59和mCRP |
TNF-α | 癌症相关的抗原或受体 |
LPS | 促炎性效应细胞因子,尤其是MIF、HMGB-1、TNF-α、IL-1或IL-6 |
LPS | 促炎性效应趋化因子,尤其是MCP-1、RANTES、MIP-1A或MIP-1B |
LPS | 促炎性效应受体,尤其是IL-6R、IL-13R和IL-15R |
LPS | 凝血因子,尤其是TF或凝血酶 |
LPS | 补体因子,尤其是C3、C5、C3a或C5a |
LPS | 补体调节蛋白,尤其是CD46、CD55、CD59和mCRP |
TF或凝血酶 | 促炎性效应细胞因子,尤其是MIF、HMGB-1、TNF-α、IL-1或IL-6 |
TF或凝血酶 | 促炎性效应趋化因子,尤其是MCP-1、RANTES、MIP-1A或MIP-1B |
TF或凝血酶 | 促炎性效应受体,尤其是IL-6R、IL-13R和IL-15R |
TF或凝血酶 | 补体因子,尤其是C3、C5、C3a或C5a |
TF或凝血酶 | 补体调节蛋白,尤其是CD46、CD55、CD59和mCRP |
TF或凝血酶 | 癌症相关的抗原或受体 |
另外其他的组合,诸如对于癌症治疗优选的组合,包括CD20抗体+CD22抗体、CD74抗体+CD20抗体、CD74抗体+CD22抗体、CEACAM5(CEA)抗体+CEACAM6(NCA)抗体、胰岛素样生长因子(ILGF)+CEACAM5抗体、EGP-1(如,RS-7)+ILGF抗体、CEACAM5+EGFR抗体。这种抗体不仅需要组合使用,而且可组合成多种形式的融合蛋白(诸如IgG、Fab、scFv等),如以下所描述:美国专利No.6,083,477;6,183,744和6,962,702和美国专利申请公布No.20030124058;20030219433;20040001825;20040202666;20040219156;20040219203;20040235065;20050002945;20050014207;20050025709;20050079184;20050169926;20050175582;20050249738;20060014245和20060034759,上述每个专利和专利申请的实施例部分通过引用并入本文。
靶抗原和示例性抗体
在优选实施方案中,使用了识别或结合标记物或肿瘤相关的抗原的抗体,这些抗原是以高水平在靶细胞上表达的,并且主要或者只能在相对正常组织为病变的细胞上表达,并且使用了能够迅速内化的抗体。可用于本发明范围内的抗体包括具有上述特性的MAb(并显示不同水平地内化进入细胞和微生物的区别性特征),并且涉及但不限于以下MAb在癌症中的用途:LL1(抗-CD74)、LL2和RFB4(抗-CD22)、RS7(抗-上皮糖蛋白-1(EGP-1))、PAM-4和KC4(均为抗-粘蛋白)、MN-14(抗-癌胚抗原(CEA,也称为CD66e)、Mu-9(抗-结肠-特异性抗原-p)、Immu 31(抗甲胎蛋白)、TAG-72(如CC49)、Tn、J591或HuJ591(抗-PSMA(前列腺特异性膜抗原))、AB-PG1-XG1-026(抗-PSMA二聚体)、D2/B(抗-PSMA)、G250(抗-碳酸酐酶IX MAb)和hL243(抗-HLA-DR)。这种抗体是本领域已知的(如,美国专利No.5,686,072;5,874,540;6,107,090;6,183,744;6,306,393;6,653,104;6,730.300;6,899,864;6,926,893;6,962,702;7,074,403;7,230,084;7,238,785;7,238,786;7,256,004;7,282,567;7,300,655;7,312,318;和美国专利申请公布No.20040185053;20040202666;20050271671;20060193865;20060210475;20070087001;上述每个专利和专利申请的实施例部分通过引用并入本文)。可用的具体已知抗体包括hPAM4(美国专利No.7,282,567)、hA20(美国专利No.7,251,164)、hA19(美国专利No.7,109,304)、hIMMU31(美国专利No.7,300,655)、hLL1(美国专利No.7,312,318)、hLL2(美国专利No.7,074,403)、hMu-9(美国专利No.7,387,773)、hL243(美国专利No.7,612,180)、hMN-14(美国专利No.6,676,924)、hMN-15(美国专利No.7,541,440)、hR1(美国临时专利申请61/145,896)、hRS7(美国专利No.7,238,785)、hMN-3(美国专利No.7,541,440)、AB-PG1-XG1-026(美国专利申请No.11/983,372,保藏为ATCC PTA-4405和PTA-4406)和D2/B(WO2009/130575),每篇提及的专利或申请相关的附图和实施例通过引用并入本文。
可利用所述共轭物靶向的其他有用的抗原包括碳酸酐酶IX、B7、CCCL19、CCCL21、CSAp、HER-2/neu、BrE3、CD1、CD1a、CD2、CD3、CD4、CD5、CD8、CD11A、CD14、CD15、CD16、CD18、CD19、CD20(如,C2B8、hA20、1F5MAb)、CD21、CD22、CD23、CD25、CD29、CD30、CD32b、CD33、CD37、CD38、CD40、CD40L、CD44、CD45、CD46、CD52、CD54、CD55、CD59、CD64、CD67、CD70、CD74、CD79a、CD80、CD83、CD95、CD126、CD133、CD138、CD147、CD154、CEACAM5、CEACAM-6、甲胎蛋白(AFP)、VEGF(如AVASTIN纤连蛋白剪接变体)、ED-B纤连蛋白(如,L19)、EGP-1、EGP-2(如,17-1A)、EGF受体(ErbB1)(如,ERBITUX)、ErbB2、ErbB3、因子H、FHL-1、Flt-3、叶酸受体、Ga 733、GROB、HMGB-1、缺氧诱导因子(HIF)、HM1.24、HER-2/neu、胰岛素样生长因子(ILGF)、IFN-γ、IFN-α、IFN-β、IL-2R、IL-4R、IL-6R、IL-13R、IL-15R、IL-17R、IL-18R、IL-2、IL-6、IL-8、IL-12、IL-15、IL-17、IL-18、IL-25、IP-10、IGF-1R、Ia、HM1.24、神经节糖苷、HCG、L243结合的HLA-DR抗原、CD66抗原、即,CD66a-d或其组合、MAGE、mCRP、MCP-1、MIP-1A、MIP-1B、巨噬细胞移动抑制因子(MIF)、MUC1、MUC2、MUC3、MUC4、MUC5、胎盘生长因子(PlGF)、PSA(前列腺特异性抗原)、PSMA、PAM4抗原、NCA-95、NCA-90、A3、A33、Ep-CAM、KS-1、Le(y)、间皮素、S100、腱生蛋白、TAC、Tn抗原、Thomas-Friedenreich抗原、肿瘤坏死抗原、肿瘤血管生成抗原、TNF-α、TRAIL受体(R1和R2)、VEGFR、RANTES、T101、以及癌干细胞抗原、补体因子C3、C3a、C3b、C5a、C5、和致癌基因产物。
CD66抗原由具有相似结构CD66a-e的5种不同糖蛋白组成,分别由癌胚抗原(CEA)基因家族成员BCG、CGM6、NCA、CGM1和CEA编码。这些CD66抗原(如,CEACAM6)主要在粒细胞、消化道正常上皮细胞和各种组织的肿瘤细胞中表达。还包括作为癌症的适当靶的是睾丸癌抗原诸如NY-ESO-1(Theurillat等,Int.J.Cancer 2007;120(11):2411-7)、以及髓细胞性白血病(Kozlov等,Cancer Genet.Cytogenet.2005;163(1):62-7)和B细胞疾病中的CD79a、和用于非霍奇金氏淋巴瘤的CD79b(Poison等,Blood 110(2):616-623),所有文献通过引用全文并入本文。大量前述抗原公开于2002年11月15日提交的美国临时申请No.60/426,379,题目是“Use of Multi-specific,Non-covalent Complexes for Targeted Delivery of Therapeutics(多特异性、非共价复合体用于靶向递送治疗的用途)”,所述申请通过引用并入本文。属于更耐受治疗的前体恶性细胞群的癌症干细胞(Gan,J CellMol.Med.2007 Dec 5[Epub ahead of print];Hill和Perris,J.Natl.Cancer Inst.2007;99(19:1435-40),具有可在某些癌症类型中被靶向的抗原,诸如前列腺癌(Maitland等,Ernst Schering Found.Sympos.Proc.2006;5:155-79)、非小细胞肺癌(Donnenberg等,J.Control Release2007;122(3):385-91)和成胶质细胞瘤(Beier等,Cancer Res.2007;67(9):4010-5)中的CD133、和结肠直肠癌(Dalerba等,Proc.Natl.Acad.Sci.USA 2007;104(24)10158-63)、胰腺癌(Li等,Cancer Res.2007;67(3):1030-7)和头颈鳞状细胞癌(Prince等,Proc.Natl.Acad.Sci.USA2007;104(3)973-8)中的CD44。
多发性骨髓瘤治疗中,已经描述了针对以下的适合靶向抗体:例如,CD38和CD138(Stevenson,Mol Med 2006;12(11-12):345-346;Tassone等,Blood 2004;104(12):3688-96)、CD74(Stein等,同上)、CS1(Tai等,Blood 2007;Oct 9(epub ahead of print)和CD40(Tai等,2005;Cancer Res.65(13):5898-5906)。
最近对适合抗原的综合分析(集群分配,Cluster Designation或CD)关注造血恶性细胞,如流式细胞术所示,其可以是筛选适用于药物-共轭免疫疗法的抗体的指导,参见Craig和Foon,Blood prepublishedonline January 15,2008;DOL 10.1182/blood-2007-11-120535,通过引用并入本文。
在另一优选实施方案中,所使用的抗体能迅速内化,然后重新表达,加工并且呈递到细胞表面上,使得细胞能够连续摄入并且增加循环共轭物。最优选的抗体/抗原对的例子是LL1,即一种抗-CD74MAb(恒定链,II类特异性侣伴蛋白,Ii)(参见,如美国专利No.6,653,104;7,312,318;上述每个专利的实施例部分通过引用并入本文)。CD74抗原是在B细胞淋巴瘤(包括多发性骨髓瘤)和白血病、某些T细胞淋巴瘤、黑素瘤、结肠癌、肺癌和肾癌、成胶质细胞瘤和某些其他癌(Ong等,Immunology 98:296-302)、以及某些自身免疫疾病中高表达。关于CD74抗体在癌症中的用途的综述包含于Stein等,Clin Cancer Res.2007 Sep 15;13(18 Pt 2):5556s-5563s,通过引用并入本文。
优选地用抗-CD74抗体治疗的疾病包括,但不限于非霍奇金氏淋巴瘤、霍奇金氏淋巴瘤、黑素瘤、肺癌、肾癌、结肠癌、多形性成胶质细胞瘤、组织细胞瘤、骨髓性白血病和多发性骨髓瘤。CD74抗原在靶细胞表面上短时间连续表达,然后进行抗原的内化,并且再次表达所述抗原,使得靶向性LL1抗体与它携带的任何化疗部分一起内化。这使得可以在所述细胞内积累高的治疗浓度的LL1-化疗药物共轭物。内化的LL1-化疗药物共轭物是通过溶酶体和内含体循环的,并且化疗部分以活性形式在靶细胞内释放。
对接锁定(DNL)
在某些优选实施方案中,双特异性或多特异性抗体可利用对接锁定技术产生(参见,如,美国专利No.7,521,056;7,550,143;7,534,866;7,527,787和美国专利申请No.11/925,408;上述每个专利和专利申请的实施例部分通过引用并入本文)。DNL方法利用cAMP依赖性蛋白激酶(PKA)的调节性(R)亚基与A-激酶锚定蛋白(AKAP)的锚定结构域(AD)之间发生的特定蛋白/蛋白相互作用(Baillie等,FEBS Letters.2005;579:3264;Wong和Scott,Nat.Rev.Mol.Cell Biol.2004;5:959)。在第二信使cAMP与R亚基的结合触发的最充分研究的信号转导途径中起关键作用的PKA,在1968年首次从兔骨骼肌分离(Walsh等,J.Biol.Chem.1968;243:3763)。全酶的结构由被R亚基保持为失活形式的两个催化亚基构成(Taylor,J.Biol.Chem.1989;264:8443)。发现PKA的同工酶具有两种类型的R亚基(RI和RII),每种类型具有α亚型和β亚型(Scott,Pharmacol.Ther.1991;50:123)。R亚基已经仅作为稳定二聚体被分离,二聚结构域显示为由前44个氨基末端残基组成(Newlon等,Nat.Struct.Biol.1999;6:222)。cAMP与R亚基的结合导致释放用于广谱丝氨酸/苏氨酸激酶活性的活性催化亚基,所述催化亚基通过PKA经由与AKAP对接产生的区域化而定位于朝向所选的底物(Scott等,J.Biol.Chem.1990;265;21561)。
自从第一种AKAP,微管相关蛋白-2,在1984年表征以来(Lohmann等,Proc.Natl.Acad.Sci USA.1984;81:6723),鉴定了多于50种的AKAP,其定位于不同的亚细胞位点(包括质膜、肌动蛋白细胞骨架、细胞核、线粒体和内质网),在从酵母到人的物种中具有不同结构(Wong和Scott,Nat.Rev.Mol.Cell Biol.2004;5:959)。AKAP用于PKA的AD是14-18个残基的两亲螺旋(Carr等,J.Biol.Chem.1991;266:14188)。AD的氨基酸序列在单独AKAP之间完全变化,报道对RII二聚体的结合亲和力从2nM变化到90nM(Alto等,Proc.Natl.Acad.Sci.USA.2003;100:4445)。有趣地,AKAP将仅结合于二聚体R亚基。对于人RIIα,AD结合于由23个氨基末端残基形成的疏水表面(Colledge和Scott,Trends Cell Biol.1999;6:216)。因此,人RIIα的二聚结构域和AKAP结合结构域二者都位于相同的N末端44个氨基酸的序列中(Newlon等,Nat.Struct.Biol.1999;6:222;Newlon等,EMBO J.2001;20:1651),该序列在本文称为DDD。
我们已经开发了平台技术来利用人RIIα的DDD和某些氨基酸序列的AD作为极好的接头模块对,以用于对接此后称为A和B的任何两个实体为非共价复合体,通过在DDD和AD二者的重要位置引入半胱氨酸残基以便于形成二硫化物键,所述非共价复合体可进一步被锁定为稳定连系的结构。“对接锁定”方法的一般方法如下。实体A通过将DDD序列连接于A的前体,形成此后称为a的第一组分而构建。因为DDD序列将实现自发形成二聚体,因此A将由a2构成。实体B通过将AD序列连接于B的前体,形成此后称为b的第二组分而构建。a2中包含的DDD的二聚基序将产生用于结合b中包含的AD序列的对接位点,从而促进a2与b简便缔合形成由a2b构成的二元、三聚复合体。用随后的反应使得这一结合事件不可逆,以经由二硫化物桥共价固定两个实体,这基于有效局部浓度的原理而非常有效地发生,因为最初结合的相互作用将放置在DDD和AD二者上的反应性硫醇基接近(Chimura等,Proc.Natl.Acad.Sci.USA.2001;98:8480)以位点特异性连接。
通过连接远离两种前体的官能团的DDD和AD,还预计这种位点特异性连接保留两种前体的最初活性。这种方法性质是模块化的,可能可用于位点特异性和共价地连接宽范围的物质,包括肽、蛋白、抗体、抗体片段和具有宽范围活性的其他效应部分。利用构建AD和DDD共轭效应物的融合蛋白方法,可将几乎任何蛋白或肽掺入DNL构建体中。然而,该技术不是限制性的,可采用其他共轭方法。
已知用于制备融合蛋白的多种方法,包括核酸合成、杂交和/或扩增以产生编码感兴趣融合蛋白的合成的双链核酸。这种双链核酸可通过标准分子生物学技术插入表达载体用于产生融合蛋白(参见,如Sambrook等,Molecular Cloning,A laboratory manual(分子克隆实验手册),第2版,1989)。在这种优选实施方案中,AD部分和/或DDD部分可连接于效应蛋白或肽(诸如抗体或片段)的N末端或C末端。然而,本领域技术人员将认识到,AD部分或DDD部分与效应部分的连接位点可变化,取决于效应部分的化学性质和效应部分牵涉在其生理活性中的部分。利用本领域已知的技术,诸如使用二价交联剂和/或其他化学共轭技术,可进行多种效应部分的位点特异性连接。
在优选实施方案中,融合蛋白通过对接锁定(DNL)技术组装,所述技术公开于如,Rossi EA等,Proc Natl Acad Sci USA 2006;103:6841-6846;美国专利No.7,521,056;7,550,143;7,534,866;7,527,787和美国专利申请No.11/925,408;所述每个专利和专利申请的实施例部分通过引用并入本文。可用在DNL方法中形成合成复合体的示例性DDD和AD序列在以下公开。
DDD1
SHIQIPPGLTELLQGYTVEVLRQQPPDLVEFAVEYFTRLREAR
A(SEQ ID NO:1)
DDD2
CGHIQIPPGLTELLQGYTVEVLRQQPPDLVEFAVEYFTRLREA
RA(SEQ ID NO:2)
AD1
QIEYLAKQIVDNAIQQA(SEQ ID NO:3)
AD2
CGQIEYLAKQIVDNAIQQAGC(SEQ ID NO:4)
DNL序列变体
在替代性实施方案中,AD部分和/或DDD部分的序列变体可用来构建DNL复合体。AD结构域与DDD结构域的结构-功能关系已经是研究的主题(参见,如,Burns-Hamuro等,2005,Protein Sci14:2982-92;Carr等,2001,J Biol Chem 276:17332-38;Alto等,2003,Proc Natl Acad Sci USA 100:4445-50;Hundsrucker等,2006,BiochemJ 396:297-306;Stokka等,2006,Biochem J 400:493-99;Gold等,2006,Mol Cell 24:383-95;Kinderman等,2006,Mol Cell 24:397-408)。
例如,Kinderman等(2006)检查了AD-DDD结合相互作用的晶体结构,推断人DDD序列包含对于二聚体形成或AKAP结合重要的大量保守氨基酸残基,在以下SEQ ID NO:1中加下划线(参见Kinderman等,2006的图1,通过引用并入本文)。本领域技术人员将认识到,在设计DDD序列的序列变体时,人们将期望避免改变任何加下划线的残基,而可对二聚化和AKAP结合次要的残基进行保守性氨基酸取代。
来自蛋白激酶A的人DDD序列
SHIQIPPGLTELLQGYTVEVLRQQPPDLVEFAVEYFTRLREARA(SEQ ID NO:1)
Alto等(2003)进行了对各种AKAP蛋白的AD序列的生物信息学分析,以设计RII选择性AD序列,称为AKAP-IS(SEQ ID NO:5),对DDD的结合常数为0.4nM。设计AKAP-IS序列作为与PKA结合的AKAP的肽拮抗剂。AKAP-IS序列中,取代倾向于减少对DDD结合处的残基在SEQ ID NO:3中加下划线。
AKAP-IS序列
QIEYLAKQIVDNAIQQA(SEQ ID NO:3)
相似地,Gold(2006)利用晶体学和肽筛选来开发SuperAKAP-IS序列(SEQ ID NO:5),表现出对PKA的RII同种型的选择性比对RI同种型的选择性高5个数量级。加下划线的残基指示相对于AKAP-IS序列,增加与RIIα的DDD部分结合的氨基酸取代的位置。在这一序列中,N末端Q残基编号为残基号4,C末端A残基编号为残基号20。可进行取代以影响对RIIα的亲和力的残基是残基8、11、15、16、18、19和20(Gold等,2006)。预期在某些替代性实施方案中,SuperAKAP-IS序列可代替AKAP-IS AD部分序列用来制备DNL构建体。可代替AKAP-IS AD序列的其它替代性序列显示在SEQ IDNO:6-8中。相对于AKAP-IS序列的取代加下划线。预计如同AKAP-IS序列(SEQ ID NO:3),AD部分还可包括另外的N末端残基半胱氨酸和甘氨酸和C末端残基甘氨酸和半胱氨酸,如SEQ ID NO:4所示。
SuperAKAP-IS
QIEYVAKQIVDYAIHQA(SEQ ID NO:5)
替代性AKAP序列
QIEYKAKQIVDHAIHQA(SEQ ID NO:6)
QIEYHAKQIVDHAIHQA(SEQ ID NO:7)
QIEYVAKQIVDHAIHQA(SEQ ID NO:8)
Stokka等(2006)还开发了AKAP结合PKA的肽竞争剂,显示在SEQ ID NO:9-11中。肽拮抗剂命名为Ht31(SEQ ID NO:9)、RIAD(SEQID NO:10)和PV-38(SEQ ID NO:11)。Ht-31肽对PKA的RII同种型表现出较大亲和力,而RIAD和PV-38对RI显示出更高亲和力。
Ht31
DLIEEAASRIVDAVIEQVKAAGAY(SEQ ID NO:9)
RIAD
LEQYANQLADQIIKEATE(SEQ ID NO:10)
PV-38
FEELAWKIAKMIWSDVFQQC(SEQ ID NO:11)
Hundsrucker等(2006)开发了AKAP结合PKA的另外其他的肽竞争剂,与RII形式的PKA的DDD的结合常数低至0.4nM。各种AKAP拮抗性肽的序列提供在Hundsrucker等的表1中(通过引用并入本文)。在不同AKAP蛋白的AD结构域之间高度保守的残基通过参考AKAPIS序列加下划线而指出。残基与Alto等(2003)观察到的相同,添加了C末端丙氨酸残基(参见Hundsrucker等(2006)的图4,通过引用并入本文)。对RII DDD序列具有尤其高的亲和力的肽拮抗剂的序列显示在SEQ ID NO:12-14中。
AKAP-IS
QIEYLAKQIVDNAIQQA(SEQ ID NO:3)
AKAP7δ-wt-pep
PEDAELVRLSKRLVENAVLKAVQQY(SEQ ID NO:12)
AKAP7δ-L304T-pep
PEDAELVRTSKRLVENAVLKAVQQY(SEQ ID NO:13)
AKAP7δ-L308D-pep
PEDAELVRLSKRDVENAVLKAVQQY(SEQ ID NO:14)
Carr等(2001)检查了来自人和非人蛋白的不同AKAP-结合DDD序列之间序列同源性的程度,鉴定了DDD序列中在不同DDD部分之间表现为最高度保守的残基。这些在以下通过参考SEQ ID NO:1的人PKA RIIαDDD序列加下划线而标出。尤其保守的残基进一步以斜体标出。这些残基与Kinderman等(2006)建议为对于结合AKAP蛋白重要的残基重叠但不相同。
本领域技术人员将认识到,通常在来自不同蛋白的DDD序列和AD序列中高度保守的氨基酸残基是进行氨基酸取代时优选保持不变的残基,而较不高度保守的残基可更容易地改变以产生本文所述的AD序列和/或DDD序列的序列变体。
氨基酸取代
在替代性实施方案中,公开的方法和组合物可包括产生和使用具有一个或多个取代的氨基酸残基的蛋白或肽。例如,用于制备DNL构建体的DDD和/或AD序列可如上所述地被修饰。
本领域技术人员将知晓,通常,氨基酸取代一般包括用相对相似特性的另一氨基酸代替一个氨基酸(即,保守性氨基酸取代)。各种氨基酸的特性和氨基酸取代对蛋白结构和功能的作用已经是深入研究的主题,是本领域的知识。
例如,可考虑氨基酸的亲水性指数(Kyte&Doolittle,1982,J.Mol.Biol.,157:105-132)。氨基酸的相对亲水性特征有助于所得蛋白的二级结构,这反过来限定蛋白与其他分子的相互作用。基于疏水性和电荷特征,对每种氨基酸指定了一个亲水性指数(Kyte&Doolittle,1982),分别是:异亮氨酸(+4.5);缬氨酸(+4.2);亮氨酸(+3.8);苯丙氨酸(+2.8);半胱氨酸/胱氨酸(+2.5);甲硫氨酸(+1.9);丙氨酸(+1.8);甘氨酸(-0.4);苏氨酸(-0.7);丝氨酸(-0.8);色氨酸(-0.9);酪氨酸(-1.3);脯氨酸(-1.6);组氨酸(-3.2);谷氨酸(-3.5);谷氨酰胺(-3.5);天冬氨酸(-3.5);天冬酰胺(-3.5);赖氨酸(-3.9);和精氨酸(-4.5)。在进行保守性取代时,优选使用亲水性指数在±2内的氨基酸,在±1内更优选,在±0.5内甚至更优选。
氨基酸取代还可考虑氨基酸残基的亲水性(如,美国专利No.4,554,101)。已经对氨基酸残基指定了亲水性值:精氨酸(+3.0);赖氨酸(+3.0);天冬氨酸(+3.0);谷氨酸(+3.0);丝氨酸(+0.3);天冬酰胺(+0.2);谷氨酰胺(+0.2);甘氨酸(0);苏氨酸(-0.4);脯氨酸(-0.5.+-.1);丙氨酸(-0.5);组氨酸(-0.5);半胱氨酸(-1.0);甲硫氨酸(-1.3);缬氨酸(-1.5);亮氨酸(-1.8);异亮氨酸(-1.8);酪氨酸(-2.3);苯丙氨酸(-2.5);色氨酸(-3.4)。优选用具有相似亲水性的氨基酸代替氨基酸。
其他考虑包括氨基酸侧链的大小。例如,用具有庞大侧链的氨基酸如色氨酸或酪氨酸代替具有紧密侧链的氨基酸诸如甘氨酸或丝氨酸通常不是优选的。不同氨基酸残基对蛋白二级结构的影响也是考虑事项。通过经验研究,已经确定了氨基酸残基对蛋白结构域采取α-螺旋、β-折叠或反转二级结构的趋势的影响,是本领域已知的(参见,如,Chou&Fasman,1974,Biochemistry,13:222-245;1978,Ann.Rev.Biochem.,47:251-276;1979,Biophys.J.,26:367-384)。
基于这些考虑和深入的经验研究,构思了保守性氨基酸取代的表,并且是本领域已知的。例如:精氨酸和赖氨酸;谷氨酸和天冬氨酸;丝氨酸和苏氨酸;谷氨酰胺和天冬酰胺;以及缬氨酸、亮氨酸和异亮氨酸。可选地:Ala(A)leu、ile、val;Arg(R)gln、asn、lys;Asn(N)his、asp、lys、arg、gln;Asp(D)asn、glu;Cys(C)ala、ser;Gln(Q)glu、asn;Glu(E)gln、asp;Gly(G)ala;His(H)asn、gln、lys、arg;Ile(I)val、met、ala、phe、leu;Leu(L)val、met、ala、phe、ile;Lys(K)gln、asn、arg;Met(M)phe、ile、leu;Phe(F)leu、val、ile、ala、tyr;Pro(P)ala;Ser(S)、thr;Thr(T)ser;Trp(W)phe、tyr;Tyr(Y)trp、phe、thr、ser;Val(V)ile、leu、met、phe、ala。
氨基酸取代的其他考虑包括残基位于蛋白内部或暴露于溶剂的情形。对于内部残基,保守性取代将包括:Asp和Asn;Ser和Thr;Ser和Ala;Thr和Ala;Ala和Gly;Ile和Val;Val和Leu;Leu和Ile;Leu和Met;Phe和Tyr;Tyr和Trp。(参见,如,rockefeller.edu上的PROWL网站)。对于暴露于溶剂的残基,保守性取代将包括:Asp和Asn;Asp和Glu;Glu和Gln;Glu和Ala;Gly和Asn;Ala和Pro;Ala和Gly;Ala和Ser;Ala和Lys;Ser和Thr;Lys和Arg;Val和Leu;Leu和Ile;Ile和Val;Phe和Tyr(同上)。已经构建了多种矩阵来帮助选择氨基酸取代,诸如PAM250评分矩阵、Dayhoff矩阵、Grantham矩阵、McLachlan矩阵、Doolittle矩阵、Henikoff矩阵、Miyata矩阵、Fitch矩阵、Jones矩阵、Rao矩阵、Levin矩阵和Risler矩阵(同上)。
确定氨基酸取代时,人们可能还考虑分子间或分子内键的存在,诸如带正电荷的残基(如,His、Arg、Lys)与带负电荷的残基(如,Asp、Glu)之间的离子键(盐桥)的形成或附近半胱氨酸残基之间的二硫键。
在编码的蛋白序列中以任何氨基酸取代任何其他氨基酸的方法是公知的,对于本领域技术人员是常规实验事项,例如通过定点诱变技术,或通过合成和组装编码氨基酸取代的寡核苷酸并剪接到表达载体构建体中。
Avimer
在某些实施方案中,本文描述的结合部分可包括一个或多个avimer序列。Avimer是针对各种靶分子的亲和性和特异性有些类似于抗体的一类结合蛋白。它们是通过体外外显子改组和噬菌体展示从人胞外受体结构域生成的(Silverman等,2005,Nat.Biotechnol.23:1493-94;Silverman等,2006,Nat.Biotechnol.24:220)。得到的多结构域蛋白可包含多个独立的结合结构域,与单表位结合蛋白相比,此蛋白可表现出改善的亲和性(一些情况下为亚纳摩尔)和特异性(同上)。在不同的实施方案中,可将avimer连接至例如DDD和/或AD序列以用于本发明要求保护的方法和组合物。有关构建和使用avimer的方法的其他详情,请参见,例如美国专利申请公布No.20040175756、20050048512、20050053973、20050089932和20050221384,其各自的实施例部分均通过引用并入本文。
噬菌体展示
所要求保护的组合物和/或方法的某些实施方案可涉及各种靶分子、细胞或组织的结合肽和/或肽模拟物。结合肽可由本领域已知的任何方法鉴定,包括但不限于噬菌体展示技术。用于产生不同肽群体的多种噬菌体展示方法和技术是本领域公知的。例如,美国专利No.5,223,409;5,622,699和6,068,829公开了用于制备噬菌体文库的方法。噬菌体展示技术包括遗传操纵噬菌体,从而在其表面上表达小的肽(Smith和Scott,1985,Science 228:1315-1317;Smith和Scott,1993,Meth.Enzymol.21:228-257)。除了肽以外,较大的蛋白结构域诸如单链抗体也可在噬菌体颗粒表面上展示(Arap等,1998,Science279:377-380)。
对指定器官、组织、细胞类型或靶分子选择性的靶向氨基酸序列可通过淘选分离(Pasqualini和Ruoslahti,1996,Nature 380:364-366;Pasqualini,1999,The Quart.J.Nucl.Med.43:159-162)。简言之,将包含推测靶向肽的噬菌体文库给予完整生物体或分离的器官、组织、细胞类型或靶分子,收集包含结合的噬菌体的样品。可从靶器官、组织、细胞类型或靶分子洗脱与靶结合的噬菌体,然后将其通过在宿主细菌中生长而扩增。
在某些实施方案中,可在淘选的轮次之间在宿主细菌中繁殖噬菌体。不同于被噬菌体裂解,相反细菌可分泌展示特定插入物的噬菌体的多个拷贝。如果需要,可将扩增的噬菌体再次暴露于靶器官、组织、细胞类型或靶分子,收集用于另一轮淘选。可进行多轮淘选,直到获得选择性或特定结合物(binder)的群体。肽的氨基酸序列可通过对对应于噬菌体基因组中靶向肽插入物的DNA进行测序来确定。然后可通过标准蛋白化学技术产生鉴定的靶向肽为合成的肽(Arap等,1998,Smith等,1985)。
在一些实施方案中,可使用减法实验方案来进一步减少背景噬菌体结合。减法的目的是从文库除去结合目标靶以外的靶的噬菌体。在替代性实施方案中,可将噬菌体文库针对对照细胞、组织或器官进行预筛选。例如,可在针对对照正常细胞系预筛选文库后鉴定肿瘤结合肽。减法之后,可将文库针对感兴趣的分子、细胞、组织或器官筛选。其他减法实验方案的方法是已知的,可用于实践所要求保护的方法,例如在美国专利No.5,840,841、5,705,610、5,670,312和5,492,807中公开的方法。
适体
在某些实施方案中,使用的靶向部分可以是适体。构建适体和确定适体的结合特征的方法是本领域公知的。例如,这种技术公开在美国专利No.5,582,981、5,595,877和5,637,459中,其每一个的实施例部分通过引用并入本文。用于制备和筛选结合感兴趣的特定靶的适体的方法是公知的,例如美国专利No.5,475,096和美国专利No.5,270,163,其每一个的实施例部分通过引用并入本文。
适体可由任何已知的方法制备,包括合成方法、重组方法和纯化方法,可单独使用或与对同一靶特异性的其他配体联合使用。通常,最少大约3个核苷酸、优选地至少5个核苷酸是实现特异性结合所需的。序列短于10个碱基的适体可以是适用的,而10、20、30或40个核苷酸的适体可以是优选的。
适体可被分离、测序、和/或扩增或合成为常规的DNA或RNA分子。可选地,感兴趣的适体可包括修饰的寡聚体。适体中通常存在的任何羟基可被膦酸酯基团、磷酸酯基团代替,被标准保护基保护,或被活化以制备与其他核苷酸的另外的键,或可与固体支持物共轭。一个或多个磷酸二酯键可被替代性连接基团代替,诸如P(O)O被P(O)S、P(O)NR2、P(O)R、P(O)OR′、CO或CNR2代替,其中R是H或烷基(1-20C)且R′是烷基(1-20C);此外,该基团可经由O或S连接于相邻的核苷酸。不需要寡聚体中的所有键相同。
共轭方案
优选共轭方案是基于在中性或酸性pH温和的硫醇-马来酰亚胺、硫醇-乙烯砜、硫醇-溴乙酰胺或硫醇-碘乙酰胺反应。这消除了对用于共轭的较高pH条件的需要,这是例如当采用活性酯时必需的。示例性共轭方案的进一步细节在以下实施例部分描述。
治疗性治疗
在另一方面,本发明涉及治疗受治疗者的方法,包括向受治疗者施用治疗有效量的如本文所述的治疗共轭物。可用本文所述的治疗共轭物治疗的疾病包括但不限于B细胞恶性肿瘤(如,利用例如LL2MAb的非霍奇金氏淋巴瘤和慢性淋巴细胞性白血病;参见美国专利No.6,183,744)、内胚层来源的消化系统上皮的腺癌、癌症诸如乳腺癌和非小细胞肺癌、以及其他癌、肉瘤、神经胶质肿瘤、骨髓性白血病等等。尤其是,有利地使用针对抗原,如,恶性实体瘤或造血肿瘤,如胃肠癌、肺癌、乳腺癌、前列腺癌、卵巢癌、睾丸癌、脑癌或淋巴瘤、肉瘤或黑素瘤产生或相关的癌胚抗原的抗体。取决于疾病状态和共轭物的耐受性,这种治疗可给予一次或重复给予,还可最佳地联合其他治疗方式使用,所述其他治疗方式诸如手术、外部辐射、放射免疫疗法、免疫疗法、化疗、反义疗法、干扰RNA疗法、基因疗法等等。每种组合将适合于肿瘤类型、阶段、患者情况和此前疗法,以及主治医师考虑的其他因素。
本文所用的术语“受治疗者”是指任何动物(即,脊椎动物和无脊椎动物),包括但不限于哺乳动物(包括人)。这不意为该术语限于特定年龄或性别。因此,成年和新生的受治疗者、以及胎儿,无论雄性或雌性,都被该术语涵盖。
在优选实施方案中,包含Mu-9 MAb的治疗共轭物可用于治疗结肠直肠癌、以及胰腺癌和卵巢癌,如美国专利No.6,962,702和7,387,772公开的,其每一个的实施例部分通过引用并入本文。此外,包含PAM4 MAb的治疗共轭物可用于治疗胰腺癌,如美国专利No.7,238,786和7,282,567公开的,其每一个的实施例部分通过引用并入本文。
在另一优选实施方案中,包含RS7 MAb(结合上皮糖蛋白-1[EGP-1]抗原)的治疗共轭物可用于治疗癌,诸如肺、胃、膀胱、乳腺、卵巢、子宫和前列腺的癌,如美国专利No.7,238,785中公开的,其实施例部分通过引用并入本文。
在另一优选实施方案中,利用人化、嵌合和人抗体形式,包含抗-AFP MAb的治疗共轭物可用于治疗肝细胞癌、干细胞肿瘤和其他产生AFP的肿瘤,如美国专利No.7,300,655中公开的,其实施例部分通过引用并入本文。
在另一优选实施方案中,包含抗-腱生蛋白抗体的治疗共轭物可用于治疗造血肿瘤和实体瘤,并且包含针对腱生蛋白的抗体的共轭物可用于治疗实体瘤,优选地脑癌如成胶质细胞瘤。
在优选实施方案中,用于治疗人疾病的抗体是人的或人化(CDR-移植的)形式的抗体;不过,可以使用鼠和嵌合形式的抗体。同物种IgG分子作为递送剂是最优选的,以使得免疫响应最小。当考虑重复治疗时这是尤其重要的。对于人、人或人化IgG抗体从患者产生抗-IgG免疫响应的可能性较小。抗体诸如hLL1和hLL2在结合靶细胞上的内化抗原后快速内化,这意味着被携带的化疗药物也快速内化到细胞中。然而,具有较慢内化速率的抗体也可用于实现选择性疗法。
在另一优选实施方案中,治疗共轭物可用于针对病原体,因为针对病原体的抗体是已知的。例如,特异性结合传染性病损产生或相关的标志的抗体和抗体片段,所述传染性病损包括病毒、细菌、真菌和寄生虫感染,例如由病原体,诸如细菌、立克次氏体、支原体、原生动物、真菌和病毒导致的,并且与这种微生物相关的抗原和产物公开于,尤其公开于Hansen等的美国专利No.3,927,193和Goldenberg的美国专利No.4,331,647、4,348,376、4,361,544、4,468,457、4,444,744、4,818,709和4,624,846(其每一个的实施例部分通过引用并入本文)以及上文引用的Reichert和Dewitz。在优选实施方案中,病原体选自由以下组成的组:HIV病毒、结核分支杆菌、无乳链球菌、耐甲氧西林金黄色葡萄球菌、嗜肺性军团病菌、酿脓链球菌、大肠杆菌、淋病奈瑟氏菌、脑膜炎奈瑟氏菌、肺炎球菌属、新型隐球菌、荚膜组织胞浆菌、B型流感嗜血杆菌、苍白密螺旋体、莱姆病螺旋体、绿脓假单胞菌、麻风分枝杆菌、流产杆菌、狂犬病病毒、流感病毒、巨细胞病毒、I型单纯疱疹病毒、II型单纯疱疹病毒、人血清细小样病毒、呼吸道合胞病毒、水痘-带状疱疹病毒、乙型肝炎病毒、丙型肝炎病毒、麻疹病毒、腺病毒、人T细胞白血病病毒、埃-巴二氏病毒、鼠白血病病毒、腮腺炎病毒、水泡性口膜炎病毒、辛德比斯病毒、淋巴细胞性脉络丛脑膜炎病毒、疣病毒、蓝舌病病毒、仙台病毒、猫白血病病毒、呼肠孤病毒、脊髓灰质炎病毒、猿猴病毒40、鼠乳房肿瘤病毒、登革热病毒、风疹病毒、西尼罗病毒、恶性疟原虫、间日疟原虫、鼠弓形体、让氏锥虫、克氏锥虫、罗德西亚锥虫、布氏锥虫、曼森血吸虫、日本血吸虫、牛巴贝虫、柔嫩艾美球虫(Elmeria tenella)、盘尾丝虫、热带利什曼原虫、旋毛线虫、小泰累尔梨浆虫、水泡绦虫、羊绦虫、牛肉绦虫、细粒棘球绦虫、科特氏中殖孔绦虫、关节炎支原体、猪鼻支原体、口腔支原体、精氨酸支原体、莱氏无胆甾原体、唾液支原体和肺炎支原体,如美国专利No.6,440,416中公开的,其实施例部分通过引用并入本文。
在更优选的实施方案中,包含抗-gp120和其他这种抗-HIV抗体的本发明药物共轭物可用作AIDS患者HIV的治疗;针对结核分支杆菌的抗体的药物共轭物适于用作药物难治性结核的治疗。已经检查了抗-gp120MAb(抗HIV MAb)与毒素诸如假单胞菌外毒素的融合蛋白的抗病毒特性(Van Oigen等,J Drug Target,5:75-91,1998)。治疗AIDS患者的HIV感染的尝试失败了,可能是因为效力不足或不可接受的宿主毒性。本发明的药物共轭物有利地缺少蛋白毒素的这种毒性副作用,因此有利地用于治疗AIDS患者的HIV感染。这些药物共轭物可单独给予,或与当单独提供时在这种患者中有效的其他抗生素或治疗剂联合给予。候选抗-HIV抗体包括Johansson等(AIDS.2006 Oct3;20(15):1911-5)所述的抗-包被蛋白抗体、以及Polymun(Vienna,Austria)描述和销售的抗-HIV抗体,还描述在美国专利5,831,034、美国专利5,911,989、Vcelar等,AIDS 2007;21(16):2161-2170和Joos等,Antimicrob.Agens Chemother.2006;50(5):1773-9中,所有文献都通过引用并入本文。为了克服抗药性,用于HIV的优选靶向剂是这些抗体的各种组合。
在另一优选实施方案中,可利用本发明优选实施方案的治疗共轭物进行治疗的疾病包括但不限于免疫失调疾病和相关的自身免疫性疾病(包括III类自身免疫病,如免疫介导的血小板减少,如急性特发性血小板减少性紫瘢和慢性特发性血小板减少性紫瘢、皮肌炎、干燥综合征、多发性硬化、西登哈姆舞蹈病、重症肌无力、系统性红斑狼疮、狼疮肾炎、风湿热、多腺体综合征、大疱性类天疱疮、糖尿病、过敏性紫瘢、链球菌感染后肾炎、结节性红斑、高安动脉炎、阿狄森氏病、类风湿性关节炎、结节病、溃疡性结肠炎、多形性红斑、IgA肾病、结节性多动脉炎、强直性脊柱炎、肺出血肾炎综合征、血栓闭塞性脉管炎、干燥综合征、原发性胆汁性肝硬化、桥本甲状腺炎、甲状腺毒症、硬皮病、慢性活动性肝炎、类风湿性关节炎、多肌炎/皮肌炎、多软骨炎、寻常天疱疮、韦格纳氏肉芽肿、膜性肾病、肌萎缩性侧索硬化、脊髓痨、巨细胞动脉炎/多肌痛、恶性贫血、急进性肾小球肾炎和纤维化肺泡炎,以及青少年糖尿病,如2002年3月1日提交的美国临时申请No.60/360,259(期满)中公开的。可用于这些疾病的典型抗体包括但不限于与以下反应的抗体:HLA-DR抗原、B细胞和浆细胞抗原(如,CD19、CD20、CD21、CD22、CD23、CD4、CD5、CD8、CD14、CD15、CD19、CD20、CD21、CD22、CD23、CD25、CD33、CD37、CD38、CD40、CD40L、CD46、CD52、CD54、CD74、CD80、CD126、CD138、B7、MUC1、Ia、HM1.24和HLA-DR)、IL-6、IL-17。因为许多这些自身免疫性疾病受异常B细胞群产生的自身抗体影响,所以由包括本文所述的这种抗体-治疗剂共轭物在内的治疗共轭物消耗这些B细胞是自身免疫性疾病疗法的优选方法,尤其是在某些情况中,当联合B细胞抗体与HLA-DR抗体和/或T细胞抗体(包括靶向IL-2作为抗原的抗体,诸如抗-TAC抗体)时。在优选实施方案中,也可共轭抗-B细胞、抗-T细胞、或抗-巨噬细胞或可用于治疗患有自身免疫性疾病的患者的其他这种抗体以获得更有效的疗法,来控制所述自身免疫性疾病中牵涉的宿主响应,可单独提供或联合其他治疗剂诸如TNF抑制剂或TNF抗体、未共轭B-或T细胞抗体等提供。
在优选实施方案中,更有效地掺入细胞和病原体可通过利用多价、多特异性或多价、单特异性抗体来实现。这种二价和双特异性抗体的例子见于美国专利No.7,387,772;7,300,655;7,238,785;和7,282,567,其每一个的实施例部分通过引用并入本文。这些多价或多特异性抗体对于表达多种抗原靶和甚至同一抗原靶的多个表位的癌症和感染性生物(病原体)的靶向尤其优选,但所述癌症和感染性生物(病原体)通常逃避用于免疫疗法的抗体靶向和充分结合,因为细胞或病原体上单个抗原靶的表达或可获得性不足。通过靶向多种抗原或表位,所述抗体显示对靶更高的结合和停留时间,从而提供与本发明中被靶向的药物更高的饱和。
在另一优选实施方案中,联合本发明的喜树碱共轭物使用的治疗剂可包括一种或多种同位素。可用于治疗患病组织的放射性同位素包括但不限于:111In、177Lu、212Bi、213Bi、211At、62Cu、67Cu、90Y、125I、131I、32P、33P、47Sc、111Ag、67Ga、142Pr、153Sm、161Tb、166Dy、166Ho、186Re、188Re、189Re、212Pb、223Ra、225Ac、59Fe、75Se、77As、89Sr、99Mo、105Rh、109Pd、143Pr、149Pm、169Er、194Ir、198Au、199Au和211Pb。治疗性放射性核素优选地具有范围为20至6,000keV的衰变能量,优选地对于俄歇粒子发射体范围为60至200keV,对于β粒子发射体范围为100-2,500keV,对于α粒子发射体范围为4,000-6,000keV。有用的发射β粒子的核素的最大衰变能量优选地是20-5,000keV,更优选地是100-4,000keV,最优选地是500-2,500keV。随着发射俄歇粒子基本上衰变的放射性核素也是优选的。例如,Co-58、Ga-67、Br-80m、Tc-99m、Rh-103m、Pt-109、In-111、Sb-119、I-125、Ho-161、Os-189m和Ir-192。有用的发射β粒子的核素的衰变能量优选地为<1,000keV,更优选地为<100keV,最优选地为<70keV。随着α粒子的产生实质上衰变的放射性核素也是优选的。这种放射性核素包括但不限于:Dy-152、At-211、Bi-212、Ra-223、Rn-219、Po-215、Bi-211、Ac-225、Fr-221、At-217、Bi-213和Fm-255。有用的发射α粒子的放射性核素的衰变能量优选地为2,000-10,000keV,更优选地为3,000-8,000keV,最优选地为4,000-7,000keV。其他可能有用的放射性同位素包括11C、13N、15O、75Br、198Au、224Ac、126I、133I、77Br、113mIn、95Ru、97Ru、103Ru、105Ru、107Hg、203Hg、121mTe、122mTe、125mTe、165Tm、167Tm、168Tm、197Pt、109Pd、105Rh、142Pr、143Pr、161Tb、166Ho、199Au、57Co、58Co、51Cr、59Fe、75Se、201Tl、225Ac、76Br、169Yb、等等。
例如,利用与抗体或共轭物连接的螯合基团,可递送放射性核素和其他金属。大环螯合物诸如NOTA、DOTA和TETA可与多种金属和放射性金属一起使用,尤其是可分别与镓、钇和铜的放射性核素一起使用。通过根据感兴趣的金属定制环大小,可使得这种金属-螯合物复合体非常稳定。可使用其他环型螯合物,诸如用于络合223Ra的大环聚醚。
与本文所述的喜树碱共轭物联合使用的治疗剂包括化疗药物,如长春花生物碱类、蒽环类抗生素、表鬼臼毒素类、紫杉醇类、抗代谢物、烷化剂、抗生素、Cox-2抑制剂、抗有丝分裂剂、抗血管生成剂和促细胞调亡剂,特别是阿霉素、氨甲喋吟、紫杉酚、其他喜树碱类、以及其他形式的这些和其它类别的抗癌剂等。其他癌症化疗药物包括氮芥类、烷基磺酸酯类、亚硝基脲类、三氮烯类、叶酸类似物、嘧啶类似物、嘌呤类似物、铂配位复合物、激素等。合适的化疗剂描述在REMINGTON′S PHARMACEUTICAL SCIENCES(雷明顿药物科学),第19版(MackPublishing Co.1995),和GOODMAN AND GILMAN′STHE PHARMACOLOGICAL BASIS OF THERAPEUTICS(治疗的药理学基础),第7版(MacMillan Publishing Co.1985)以及这些出版物的修订版中。其他合适的化疗剂如实验性药物是本领域技术人员公知的。
可使用的示例性药物包括但不限于,5-氟尿嘧啶、aplidin、阿扎立平、阿那曲唑、蒽环类、苯达莫司汀、博来霉素、硼替佐米、苔藓抑素-1、白消安、卡奇霉素、喜树碱、卡铂、10-羟基喜树碱、卡莫司汀、塞来昔布、苯丁酸氮芥、顺铂(CDDP)、Cox-2抑制剂、伊立替康(CPT-11)、SN-38、卡铂、克拉屈滨、喜树碱类、环磷酰胺、阿糖胞苷、达卡巴嗪、多西紫杉醇、放线菌素D、柔红霉素、阿霉素、2-吡咯啉阿霉素(2P-DOX)、氰基-吗啉代阿霉素、葡糖苷酸阿霉素、葡糖苷酸表柔比星、雌莫司汀、表鬼臼毒素、雌激素受体结合剂、依托泊苷(VP16)、葡糖苷酸依托泊苷、磷酸依托泊苷、氟尿苷(FUdR)、3′,5′-O-二油酰基-FudR(FUdR-dO)、氟达拉滨、氟他胺、法呢基-蛋白转移酶抑制剂、吉西他滨、羟基脲、伊达比星、异环磷酰胺、L-天冬酰胺酶、来那度胺、亚叶酸、洛莫司汀、氮芥、美法仑、巯嘌呤、6-巯嘌呤、甲氨蝶呤、米托蒽醌、光神霉素、丝裂霉素、米托坦、诺维本、亚硝基脲、普卡霉素、丙卡巴肼、紫杉醇、喷司他丁、PSI-341、雷洛昔芬、司莫司汀、链佐星、他莫昔芬、泰素、替莫唑胺(DTIC的含水形式)、反铂、沙利度胺、硫鸟嘌呤、塞替派、替尼泊苷、托泊替康、乌拉莫司汀、长春瑞滨、长春碱、长春新碱和长春花生物碱。这种药物可以是本文所述的共轭物的部分,或可选地可在共轭物之前、同时或之后与所述共轭物联合施用。可选地,一种或多种本领域已知的治疗性裸抗体可与所述共轭物联合使用。示例治疗性裸抗体描述在前面的部分中。
可与喜树碱共轭物配合使用的治疗剂还可包括与靶向部分共轭的毒素。可用于此用途的毒素包括蓖麻毒素、相思豆毒素、核糖核酸酶(RNA酶)、DNA酶I、葡萄球菌肠毒素-A、美洲商陆抗病毒蛋白、白树毒蛋白、白喉毒素、绿脓杆菌外毒素和绿脓杆菌内毒素(例如,参见Pastan等,Cell(1986),47:641,Sharkey和Goldenberg,CA CancerJ Clin.2006 Jul-Aug;56(4):226-43)。适合用于本发明的其他毒素为本领域技术人员已知,并公开于U.S.6,077,499中。
又一类的治疗剂可包括一种或多种免疫调节剂。有用的免疫调节剂可选自细胞因子、干细胞生长因子、淋巴毒素、造血因子、集落刺激因子(CSF)、干扰素(IFN)、红细胞生成素、血小板生成素和其组合。特别有用的是淋巴毒素诸如肿瘤坏死因子(TNF)、造血因子,诸如白介素(IL)、集落刺激因子,诸如粒细胞-集落刺激因子(G-CSF)或粒细胞巨噬细胞-集落刺激因子(GM-CSF)、干扰素,诸如干扰素-α、-β或-γ、和干细胞生长因子,诸如命名为“S1因子”的。细胞因子中包括生长激素诸如人生长激素、N-甲硫氨酰人生长激素和牛生长激素;甲状旁腺激素;甲状腺素;胰岛素;胰岛素原;松弛素;松弛素原;糖蛋白激素诸如滤泡激素(FSH)、促甲状腺激素(TSH)和促黄体激素(LH);肝生长因子;前列腺素、成纤维细胞生长因子;促乳素;胎盘催乳质、OB蛋白;肿瘤坏死因子-α和-β;苗勒氏抑制物质;小鼠促性腺素相关肽;抑制素;活化素;血管内皮生长因子;整联蛋白;血小板生成素(TPO);神经生长因子诸如NGF-β;血小板生长因子;转化生长因子(TGF)诸如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;干扰素诸如干扰素-α、-β和-γ;集落刺激因子(CSF)诸如巨噬细胞-CSF(M-CSF);白介素(IL)诸如IL-1、IL-1α、IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9、IL-10、IL-11、IL-12;IL-13、IL-14、IL-15、IL-16、IL-17、IL-18、IL-21、IL-25、LIF、kit-配体或FLT-3、血管他丁、血小板反应蛋白、内皮他丁、肿瘤坏死因子和LT。本文所用的术语细胞因子包括来自天然来源或来自重组细胞培养物的蛋白,和天然序列细胞因子的生物活性等价物。
有用的趋化因子包括RANTES、MCAF、MIP1-α、MIP1-β和IP-10。
制剂和施用
共轭物的适合施用途径包括但不限于口服、胃肠外、直肠、经粘膜、肠施用、肌内、皮下、髓内、鞘内、直接心室内、静脉内、玻璃体内、腹膜内、鼻内或眼内注射。优选的施用途径是胃肠外。可选地,人们可能以局部方式而不是系统方式施用化合物,例如,经由直接注射化合物到实体瘤中。
免疫轭合物可根据制备药学上可用的组合物的已知方法配制,由此所述免疫轭合物在混合物中与药学上合适的赋形剂混合。无菌磷酸缓冲盐水是药学上合适的赋形剂的一个实例。其他合适的赋形剂是本领域技术人员众所周知的。例如,参见Ansel等,PHARMACEUTICALDOSAGE FORMS AND DRUG DELIVERY SYSTEMS(药物剂型和药物递送系统),第5版(Lea&Febiger 1990),和Gennaro(编),REMINGTON’S PHARMACEUTICAL SCIENCES(雷明顿药物科学),第18版(MackPublishing Company 1990),以及它们的修订版。
可配制本发明的免疫轭合物和裸抗体用于静脉内给药,例如经由弹丸注射和连续输注。优选地,将本发明的抗体经少于约4小时的时间,更优选地经少于约3小时的时间输注。例如,前25-50mg可在30分钟(优选地甚至15min)内输注,其余的经后2-3小时输注。注射用制剂可提供为单位剂量的形式,例如,在安瓿瓶中和在多剂量容器中,添有防腐剂。所述组合物可采取诸如在油性或水性媒介物中的悬液、溶液或乳剂形式,并且可含有配制剂,如悬浮剂、稳定剂和/或分散剂。可选地,所述活性成分可以是散剂形式,以在使用前用合适的载体如无菌无热原的水重构。
可采用另外的药学方法以控制治疗性轭合物的作用持续时间。缓释剂可通过使用聚合物络合或吸收所述免疫轭合物制备。例如,生物可相容的聚合物包括聚(乙烯-共-乙酸乙烯酯)基质以及硬脂酸二聚体和癸二酸的聚酸酐共聚物基质。Sherwood等,Bio/Technology 10:1446(1992)。免疫轭合物由此基质的释放速率取决于所述免疫轭合物的分子量、基质内免疫轭合物的量、以及分散颗粒的大小。Saltzman等,Biophys.J.55:163(1989);Sherwood等,同上。其他固体剂量形式描述于Ansel等,PHARMACEUTICAL DOSAGE FORMS ANDDRUG DELIVERY SYSTEMS(药物剂型和药物递送系统)第5版(Lea&Febiger 1990),和Gennaro(编),REMINGTON′SPHARMACEUTICAL SCIENCES(雷明顿药物科学),第18版(MackPublishing Company 1990)以及它们的修订版中。
一般,对人施用的免疫轭合物的剂量将根据诸如患者的年龄、体重、身高、性别、一般医学状况和以前病史的因素而变。可能期望为受者提供剂量在约1mg/kg到约25mg/kg范围内的免疫轭合物作为单次静脉内输注,尽管视情形而定,也可施用更低或更高的剂量。对于70kg的患者,1-20mg/kg的剂量是例如70-1,400mg,或对于1.7-m的患者,剂量是41-824mg/m2。该剂量可视需要而重复,例如,每周一次共4-10周,每周一次共8周,或每周一次共4周。也可以不太频繁地给予,例如每隔一周持续数月,或每月一次或每季度一次持续数月,如维持疗法所需的。
可选地,免疫共轭物可每2或3周施用一个剂量,重复共至少3个剂量。或,每周两次,持续4-6周。如果剂量低至大约200-300mg/m2(对于1.7-m的患者每剂量340mg,或对于70kg的患者4.9mg/kg),可每周施用一次或甚至两次,持续4至10周。可选地,剂量时间表可减少,即每2或3周一次,持续2-3个月。然而已经确定,即使较高的剂量,诸如每周一次20mg/kg或每2-3周一次,可通过慢速静脉输注施用重复的给药周期。给药时间表可任选地以其他间隔重复,所述剂量可通过多种肠胃外路径给予,并适当地调整剂量和日程。
在优选实施方案中,免疫共轭物可用于癌症的治疗。癌症的例子包括但不限于,癌、淋巴瘤、成胶质细胞瘤、黑素瘤、肉瘤、和白细胞、骨髓瘤或淋巴恶性肿瘤。这种癌症的更具体例子在以下记录,并且包括:鳞状细胞癌(如,上皮鳞状细胞癌)、尤因肉瘤、维尔姆斯氏瘤、星形细胞瘤、肺癌(包括小细胞肺癌、非小细胞肺癌、肺的腺癌和肺的鳞状癌)、腹膜癌、肝细胞癌、胃癌(包括胃肠癌)、胰腺癌、多形性成胶质细胞瘤、宫颈癌、卵巢癌、肝癌、膀胱癌、肝癌、肝细胞癌、神经内分泌肿瘤、甲状腺髓样癌、甲状腺分化癌、乳腺癌、卵巢癌、结肠癌、直肠癌、子宫内膜癌或子宫癌、唾液腺癌、肾癌、前列腺癌、外阴癌、肛门癌、阴茎癌、以及头颈癌。术语“癌症”包括原发性恶性细胞或肿瘤(如,其细胞还未迁移到受治疗者体内最初恶性肿瘤或肿瘤的位置以外的位置)和继发性恶性细胞或肿瘤(如,由恶性细胞或肿瘤细胞转移、迁移到不同于最初肿瘤位置的第二位置形成的)。
癌症或恶性肿瘤的其他例子包括但不限于:急性儿童成淋巴细胞性白血病、急性成淋巴细胞性白血病、急性淋巴细胞性白血病、急性骨髓性白血病、肾上腺皮质癌、成人(原发性)肝细胞癌、成人(原发性)肝癌、成人急性淋巴细胞性白血病、成人急性骨髓性白血病、成人霍奇金淋巴瘤、成人淋巴细胞性白血病、成人非霍奇金淋巴瘤、成人原发性肝癌、成人软组织肉瘤、AIDS相关淋巴瘤、AIDS相关恶性肿瘤、肛门癌、星形细胞瘤、胆管癌、膀胱癌、骨癌、脑干神经胶质瘤、脑肿瘤、乳腺癌、肾盂和输尿管癌、中枢神经系统(原发性)淋巴瘤、中枢神经系统淋巴瘤、小脑星形细胞瘤、大脑星形细胞瘤、宫颈癌、儿童(原发性)肝细胞癌、儿童(原发性)肝癌、儿童急性成淋巴细胞性白血病、儿童急性骨髓性白血病、儿童脑干神经胶质瘤、儿童小脑星形细胞瘤、儿童大脑星形细胞瘤、儿童颅外生殖细胞瘤、儿童霍奇金病、儿童霍奇金淋巴瘤、儿童下丘脑和视觉通路神经胶质瘤、儿童成淋巴细胞性白血病、儿童成神经管细胞瘤、儿童非霍奇金淋巴瘤、儿童松果体和幕上原始神经外胚层肿瘤、儿童原发性肝癌、儿童横纹肌肉瘤、儿童软组织肉瘤、儿童视觉通路和下丘脑神经胶质瘤、慢性淋巴细胞性白血病、慢性骨髓性白血病、结肠癌、皮肤T细胞淋巴瘤、胰腺内分泌胰岛细胞癌、子宫内膜癌、室管膜瘤、上皮癌、食道癌、尤因氏肉瘤和相关肿瘤、胰腺外分泌癌、颅外生殖细胞瘤、性腺外生殖细胞肿瘤、肝外胆管癌、眼癌、女性乳腺癌、高歇氏病、胆囊癌、胃癌、胃肠道类癌瘤、胃肠肿瘤、生殖细胞瘤、妊娠性滋养层细胞瘤、毛细胞白血病、头颈癌、肝细胞癌、霍奇金淋巴瘤、高丙种球蛋白血症、下咽癌、肠癌、眼内黑素瘤、胰岛细胞癌、胰岛细胞胰腺癌、卡波西肉瘤、肾癌、喉癌、唇和口腔癌、肝癌、肺癌、淋巴增生疾病、巨球蛋白血症、男性乳腺癌、恶性间皮瘤、恶性胸腺瘤、成神经管细胞瘤、黑素瘤、间皮瘤、转移性隐匿性原发性鳞状颈部癌、转移性原发性鳞状颈部癌、转移性鳞状颈部癌、多发性骨髓瘤、多发性骨髓瘤/浆细胞肿瘤、骨髓增生异常综合征、骨髓性白血病、骨髓性白血病、骨髓增生性疾病、鼻腔和副鼻窦癌、鼻咽癌、成神经细胞瘤、非霍奇金淋巴瘤、非黑素瘤皮肤癌、非小细胞肺癌、隐匿性原发性转移性鳞状颈部癌、口咽癌、骨-/恶性纤维肉瘤、骨肉瘤/恶性纤维组织细胞瘤、骨肉瘤/骨的恶性纤维组织细胞瘤、卵巢上皮癌、卵巢生殖细胞瘤、卵巢低恶性度肿瘤、胰腺癌、异常蛋白血症、真性红细胞增多症、甲状旁腺癌、阴茎癌、嗜铬细胞瘤、垂体瘤、原发性中枢神经系统淋巴瘤、原发性肝癌、前列腺癌、直肠癌、肾细胞癌、肾盂和输尿管癌、成视网膜细胞瘤、横纹肌肉瘤、唾液腺癌、结节病肉瘤、赛谢综合征、皮肤癌、小细胞肺癌、小肠癌、软组织肉瘤、鳞状颈部癌、胃癌、幕上原始神经外胚层和松果体瘤、T细胞淋巴瘤、睾丸癌、胸腺癌、甲状腺癌、肾盂和输尿管移行细胞癌、移行肾盂和输尿管癌、滋养叶瘤、输尿管和肾盂细胞癌、尿道癌、子宫癌、子宫肉瘤、阴道癌、视觉通路和下丘脑神经胶质瘤、外阴癌、Waldenstrom巨球蛋白血症、维耳姆斯氏瘤、和任何其他过度增生疾病、以及位于以上列出的器官系统中的瘤形成。
本文描述和要求保护的方法和组合物可用于治疗恶性或恶变前病症,和阻止向包括但不限于上述疾患的瘤或恶性状态进展。这种用途在已知或怀疑此前进展为瘤形成或癌症的病症是必要的,尤其是,当发生了由增生、组织转化组成的非瘤性细胞生长,或最尤其是,发生了发育不良时(这种异常生长状态的综述参见Robbins和Angell,Basic Pathology(基础病理学),第2版,W.B.Saunders Co.,Philadelphia,pp.68-79(1976))。
发育不良经常是癌症的前兆,主要发现于上皮。它是非瘤性细胞生长的最无序形式,包括失去单独细胞一致性和失去细胞的结构方向。当存在慢性刺激或炎症时发育不良特性地发生。可治疗的发育不良疾患包括但不限于,汗闭性外胚叶发育不良、异侧发育不良、窒息性胸廓发育不良、心一指发育不良、支气管肺发育不良、大脑发育不良、颈部发育不良、软骨外胚层发育不良、锁骨头颅发育不良、先天性外胚层发育不良、颅骨骨干发育不良、颅腕跗发育不良、颅骨干骺端发育不良、牙质发育不良、骨干发育不良、外胚层发育不良、釉质发育不良、脑-眼发育不良、偏侧骨骺发育不良、多发性骨骺发育不良、点状骨骺发育不良、上皮发育不良、面-指(趾)-生殖器发育不良、家族性颌骨纤维性发育不良、家族性白色皱襞发育不良、纤维肌性发育不良、骨纤维发育不良、旺盛骨性发育不良、遗传性肾脏-视网膜发育不良、有汗性外胚叶发育不良、少汗性外胚叶发育不良、淋巴细胞减少性胸腺发育不良、乳房发育不良、下颌面骨发育不良、干骺端发育不良、蒙底尼发育不良、单骨性纤维性发育不良、粘膜上皮发育不良、多发性骨骺发育不良、眼耳脊椎发育不良、眼齿指发育不良、眼与脊椎发育不良、牙原性发育不良、opthalmomandibulomelic发育不良、根尖周牙骨质发育不良、多骨纤维性发育不良、软骨不全性脊柱骨骺发育不良、视网膜发育不良、中隔-眼发育不良、脊柱骨骺发育不良和ventriculoradial发育不良。
可治疗的其他瘤前疾患包括但不限于,良性增殖失调疾患(如,良性肿瘤、纤维囊肿病、组织肥大、肠息肉病或腺瘤、和食管发育不良)、粘膜白斑病、角化病、博温氏病、农夫皮肤、日光性唇炎和日光性角化病。
在优选实施方案中,本发明的方法用于抑制癌症的生长、进展和/或转移,尤其是以上列出的那些癌症。
其他过度增生疾病、疾患和/或病症包括但不限于,恶性肿瘤和相关疾患的进展和/或转移,诸如白血病(包括急性白血病(如,急性淋巴细胞性白血病、急性髓细胞性白血病(包括成髓细胞性、早幼粒细胞性、骨髓单核细胞性、单核细胞性和红白血病))和慢性白血病(如,慢性髓细胞性(粒细胞)白血病和慢性淋巴细胞性白血病))、真性红细胞增多症、淋巴瘤(如,霍奇金病和非霍奇金病)、多发性骨髓瘤、Waldenstrom巨球蛋白血症、重链病、和实体瘤,包括但不限于、肉瘤和癌诸如纤维肉瘤、粘液肉瘤、脂肪肉瘤、软骨肉瘤、成骨肉瘤、脊索瘤、血管肉瘤、内皮肉瘤、淋巴管肉瘤、淋巴管内皮肉瘤、滑膜瘤、间皮瘤、尤因氏瘤、平滑肌肉瘤、横纹肌肉瘤、结肠癌、胰腺癌、乳腺癌、卵巢癌、前列腺癌、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、皮脂腺癌、乳头状癌、乳头状腺癌、囊腺癌、髓样癌、支气管癌、肾细胞癌、肝癌、胆管癌、恶性合胞体瘤、精原细胞瘤、胚胎癌、维尔姆斯氏瘤、宫颈癌、睾丸肿瘤、肺癌、小细胞肺癌、膀胱癌、上皮癌、神经胶质瘤、星形细胞瘤、成神经管细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、成血管细胞瘤、听神经瘤、少突神经胶质细胞瘤、脊膜瘤、黑素瘤、成神经细胞瘤和成视网膜细胞瘤。
试剂盒
多个实施方案可涉及包含适于治疗患者患病组织的组分的试剂盒。示例性试剂盒可包含本文所述的至少一种共轭抗体或其他靶向部分。如果包含用于施用的组分的组合物未配制为用于经由消化道递送,诸如通过口服递送,则可包括能够经由一些其他途径递送试剂盒组分的装置。用于诸如胃肠外递送的应用的一种类型的装置是用于注射组合物到受治疗者体内的注射器。还可使用吸入装置。
所述试剂盒组分可包装在一起或者分开包装在两个或更多的容器中。在一些实施方案中,所述容器可以是包含适合重建的组合物的无菌、冻干制剂的小瓶。试剂盒还可包含适于重建和/或稀释其他试剂的一种或多种缓冲液。可使用的其他容器包括但不限于:袋、盘、盒、管或类似容器。试剂盒组分可无菌包装并保存在所述容器中。可包括的另一组分为给使用试剂盒的人员的使用说明。
实施例
本发明的多个实施方案由以下实施例阐释,而不限制其范围。
总论
以下使用的缩写有:DCC,二环己基碳二亚胺;NHS,N-羟基琥珀酰亚胺;DMAP,4-二甲基氨基吡啶;EEDQ,2-乙氧基-1-乙氧基羰基-1,2-二氢喹啉;MMT,单甲氧基三苯甲基;PABOH,对氨基苄醇;PEG,聚乙二醇;SMCC,琥珀酰亚胺基4-(N-马来酰亚胺甲基)环己烷-1-羧酸酯;TBAF,四丁基氟化铵;TBDMS,叔丁基二甲基氯硅烷。
以下实施例中的羟基化合物的氯甲酸酯利用三光气和DMAP,按照Moon等(J.Medicinal Chem.51:6916-6926,2008)所述的实验方案制备,所述文献通过引用并入。萃取流程是指用氯仿、二氯甲烷或乙酸乙酯萃取,并任选地用饱和碳酸氢盐、水和饱和氯化钠洗涤。除非另外指明,否则快速色谱利用230-400目硅胶和甲醇-二氯甲烷梯度,利用多达15%v/v甲醇-二氯甲烷进行。反相HPLC以方法A或方法B进行,方法A利用装有柱前过滤器的7.8×300mm C18 HPLC柱,并利用溶剂梯度为100%溶剂A至100%溶剂B,以流速3mL/分钟持续10分钟,和以流速4.5mL/分钟保持在100%溶剂B,持续5或10分钟;方法B利用装有柱前过滤器的4.6×30mm Xbridge C18 2.5μm柱,利用的溶剂梯度为100%溶剂A至100%溶剂B,流速1.5mL/分钟,持续4min,和100%溶剂B,流速2mL/分钟,持续1分钟。溶剂A是0.3%乙酸铵溶液、pH 4.46,而溶剂B是9∶1乙腈-乙酸铵溶液(0.3%)、pH 4.46。HPLC由设置在360nm和254nm的二重管线内吸光度检测器监测。
实施例1:CL6-SN-38的制备
CL6-SN-38在路线-1中表示。将可商购获得的O-(2-叠氮基乙基)-O’-(N-二乙醇酰基-2-氨乙基)庚乙二醇(‘PEG-N3’;227mg)以DCC(100mg)、NHS(56mg)和催化量的DMAP在10mL二氯甲烷中活化10min。向此混合物加入L-缬氨醇(46.3mg),在室温搅拌反应混合物1h。过滤,随后去除溶剂,快速色谱产生214mg透明油状物。将此中间产物(160mg)与10-O-BOC-SN-38-20-O-氯甲酸酯反应,后者是利用三光气和DMAP从10-O-BOC-SN-38(123mg)产生的。在4mL二氯甲烷中进行偶联反应10min,由快速色谱纯化反应混合物,获得为泡沫物质的130mg(45%产率)产物。HPLC:tR 11.80min;电喷射质谱:M+Na:m/z 1181。
链接环加成所需的含马来酰亚胺的炔属试剂,即4-(N-马来酰亚胺甲基)-N-(2-丙炔基)环己烷-1-羧酰胺,通过利用1.1当量二异丙基乙胺将0.107g SMCC与0.021mL炔丙胺(0.018g;1.01当量)在二氯甲烷中反应而制备。1h后去除溶剂,由快速色谱纯化产物获得83mg产物(无色粉末)。电喷射质谱以正离子模式显示在m/e 275(M+H)的多个峰和在m/e 192的基峰,与对C15H18N2O3计算的结构一致:275.1390(M+H),测量值:275.1394(准确质量)。
将上述叠氮基中间产物(126mg)溶解在DMSO(1.5mL)和水(0.4mL)中,与60mg 4-(N-马来酰亚胺甲基)-N-(2-丙炔基)环己烷-1-羧酰胺和15mg溴化亚铜反应,在室温搅拌30min。在对反应混合物的萃取流程后,快速色谱法得到116mg(75%产率)环加成产物。HPLC:tR11.20min;电喷射质谱:M+H和M+Na分别为m/z 1433和1456。最后,用TFA(5mL)、二氯甲烷(1mL)、苯甲醚(0.1mL)和水(0.05mL)将混合物脱保护,随后用乙醚沉淀,之后快速色谱法产生为胶状物质的产物CL6-SN-38。HPLC:tR 9.98min;电喷射质谱:M+H和M-H(负离子模式)分别在m/z 1333和1356。
路线-1
实施例2:CL7-SN-38的制备
该合成在路线-2示意地显示。在氩气下,将L-缬氨醇(40mg)与可商购获得的Fmoc-Lys(MMT)-OH(253mg)和EEDQ(107mg)在10mL无水二氯甲烷中在室温反应3h。萃取流程,随后快速色谱法得到为淡黄色液体的产物Fmoc-Lys(MMT)-缬氨醇(200mg;~70%产率)。HPLC:tR 14.38min;电喷射质谱:M+H:m/z 727。将这一中间产物(200mg)用二乙胺(10mL)脱保护,快速色谱后获得纯度~90%的产物(135mg)。HPLC:tR 10.91min;电喷射质谱:M+Na为m/z 527。在EEDQ(72mg,1.1当量)存在下,将这一产物(135mg)与可商购获得的O-(2-叠氮基乙基)-O’-(N-二乙醇酰基-2-氨乙基)庚乙二醇(‘PEG-N3’;150mg,1.1当量)在10mL二氯甲烷中偶联,在室温搅拌过夜。由快速色谱法纯化粗制物,获得为淡黄色油的240mg纯化产物(~87%产率)。HPLC:tR 11.55min;电喷射质谱:M+H和M+Na分别在m/z 1041和1063。
将这一中间产物(240mg)与10-O-TBDMS-SN-38-20-O-氯甲酸酯反应,后者利用三光气和DMAP从10-O-TBDMS-SN-38(122mg)产生。偶联反应在5mL二氯甲烷中进行10min,由快速色谱法纯化反应混合物,获得为淡黄色泡沫的327mg产物。电喷射质谱:M+H为m/z1574。将全部产物与10mL二氯甲烷中的0.25mmol TBAF反应5min,将反应混合物稀释到100mL,用盐水洗涤。将粗产物(250mg)溶解在DMSO(2mL)和水(0.4mL)中,与114mg 4-(N-马来酰亚胺甲基)-N-(2-丙炔基)环己烷-1-羧酰胺(如实施例1所述地制备)和30mg溴化亚铜反应,在室温搅拌1h。快速色谱法得到150mg倒数第二个中间产物。最后,用TFA(0.5mL)和苯甲醚(0.05mL)在二氯甲烷(5mL)中的混合物将MMT基脱保护3min,随后由快速色谱法纯化,产生为胶状物质的69mg CL7-SN-38。HPLC:tR 9.60min;电喷射质谱:M+H和M-H(负离子模式)分别为m/z 1461和1459。
路线-2
实施例3:CL6-SN-38-10-O-CO2Et的制备
将实施例1的CL6-SN-38(55.4mg)溶解在二氯甲烷(5mL)中,与氯甲酸乙酯(13.1mg;11.5μL)和二异丙基乙胺(52.5mg;71μL)反应,在氩气下搅拌20min。用100mL二氯甲烷稀释反应混合物,用各100mL的0.1M HCl、半饱和碳酸氢钠和盐水洗涤,干燥。去除溶剂后,快速色谱法得到59mg标题产物。HPLC:tR 10.74min;准确质量:计算值1404.6457(M+H)和1426.6276(M+Na);测量值:1404.6464(M+H)和1426.6288(M+Na)。
实施例4:CL7-SN-38-10-O-C02Et的制备
利用实施例3所述的实验方案和纯化,将实施例2的CL7-SN-38的前体(80mg)转化为10-O-氯甲酸酯。产率:60mg。HPLC:tR 12.32min;电喷射质谱:M+H和M-H(负离子模式)分别为m/z 1806和1804。利用二氯乙酸和苯甲醚在二氯甲烷中将此物质脱保护,获得标题产物。HPLC:tR 10.37min;电喷射质谱:M+H在m/z 1534。
实施例5:CL6-SN-38-10-O-COR和CL7-SN-38-10-O-COR的制备
本实施例显示,SN-38的10-OH基被保护为碳酸酯或酯而不是‘BOC’,从而最终产物容易与抗体共轭而不需要脱保护10-OH保护基。体内施用蛋白共轭物后,这一基团容易在生理pH条件下脱保护。在这些共轭物中,‘R’可以是取代的烷基诸如(CH2)n-N(CH3)2,其中n是2-10;或简单烷基诸如(CH2)n-CH3,其中n是0-10;或可以是烷氧基部分诸如“CH3-(CH2)n-O-”,其中n是0-10;或取代的烷氧基部分诸如O-(CH2)n-N(CH3)2,其中n是2-10,且其中末端氨基任选地呈用于增强水溶性的季盐形式,或“R1O-(CH2-CH2-O)n-CH2-CH2-O-”,其中R1是乙基或甲基且n是数值为0-10的整数。在后面的目录的最简单形式中,R=“-O-(CH2)2-OCH3”。如果最终衍生物将是碳酸酯,这些10-羟基衍生物容易用氯甲酸酯处理所选试剂来制备。通常,将含10-羟基的喜树碱(诸如SN-38)利用三乙胺作为碱、用摩尔当量的氯甲酸酯在二甲基甲酰胺中处理。在这些条件下,20-OH位置不受影响。对于形成10-O-酯,使用所选试剂的酰基氯。利用高级中间产物,方便地实现这种衍生物,如对实施例3和4的简单碳酸乙酯阐释的。
实施例6:CL6-紫杉醇的制备
按照实施例1所述的实验方案,将缬氨醇与路线-1的‘PEG-N3’偶联。将产物与0.4摩尔当量的三光气、3.1摩尔当量的DMAP在二氯甲烷中反应。5分钟后,在室温将如此形成的氯甲酸酯与等摩尔量的紫杉醇反应15分钟。将紫杉醇的反应性2’-羟基(侧链仲羟基)与交联接头的氯甲酸酯反应。由快速色谱法分离产物。将这一中间产物(0.1mmol)溶解在DMSO(1.5mL)和水(0.4mL)中,与60mg 4-(N-马来酰亚胺甲基)-N-(2-丙炔基)环己烷-1-羧酰胺(如实施例1所述地制备)和15mg溴化亚铜反应,在室温搅拌30min。在对反应混合物的萃取流程后,快速色谱法得到双官能的紫杉醇,即CL6-紫杉醇。
实施例7:CL7-紫杉醇的制备
将L-缬氨醇(40mg)与可商购获得的Fmoc-Lys(MMT)-OH反应,然后将产物与O-(2-叠氮基乙基)-O’-(N-二乙醇酰基-2-氨乙基)庚乙二醇(‘PEG-N3’)反应,如实施例2所述。这一衍生物的氯甲酸酯由实施例-6的方法形成,将其与等摩尔量的紫杉醇反应。将紫杉醇的反应性2’-羟基(侧链仲羟基)与交联接头的氯甲酸酯反应。然后利用4-(N-马来酰亚胺甲基)-N-(2-丙炔基)环己烷-1-羧酰胺(如实施例1所述地制备)的链接环加成以类似实施例6所述的方式进行,最后用二氯乙酸和苯甲醚处理产物以实现在温和条件下去除‘MMT’基。这一过程得到CL7-紫杉醇。
实施例8:CL6-[吗啉代阿霉素]的制备
按照实施例1所述的实验方案,将缬氨醇与路线-1的‘PEG-N3’偶联。将产物与0.4摩尔当量的三光气、3.1摩尔当量的DMAP在二氯甲烷中反应。5分钟后,在室温将如此形成的氯甲酸酯与等摩尔量的吗啉代阿霉素反应15分钟。将吗啉代阿霉素的伯羟基与交联接头的氯甲酸酯反应。由快速色谱法分离产物。将这一中间产物(0.1mmol)溶解在DMSO(1.5mL)和水(0.4mL)中,与60mg 4-(N-马来酰亚胺甲基)-N-(2-丙炔基)环己烷-1-羧酰胺(如实施例1所述地制备)和15mg溴化亚铜反应,在室温搅拌30min。在对反应混合物的萃取流程后,快速色谱法得到双官能的紫杉醇,即CL6-[吗啉代阿霉素]。
实施例9:CL7-[吗啉代阿霉素]的制备
将L-缬氨醇(40mg)与可商购获得的Fmoc-Lys(MMT)-OH反应,然后将产物与O-(2-叠氮基乙基)-O’-(N-二乙醇酰基-2-氨乙基)庚乙二醇(‘PEG-N3’)反应,如实施例2所述。这一衍生物的氯甲酸酯由实施例-6的方法形成,将其与等摩尔量的吗啉代阿霉素反应。将吗啉代阿霉素的伯羟基与交联接头的氯甲酸酯反应。然后利用4-(N-马来酰亚胺甲基)-N-(2-丙炔基)环己烷-1-羧酰胺(如实施例1所述地制备)的链接环加成以类似实施例6所述的方式进行,最后用二氯乙酸和苯甲醚处理产物以实现在温和条件下去除‘MMT’基。这一过程得到CL7-[吗啉代阿霉素]。
实施例10:CL2A-SN-38的制备
在室温向可商购获得的Fmoc-Lys(MMT)-OH(0.943g)、对氨基苄醇(0.190g)在二氯甲烷(10mL)中的混合物加入EEDQ(0.382g)并搅拌4h。萃取流程,随后快速色谱法产生1.051g为白色泡沫的物质。所有HPLC分析通过第0148段‘总论’中阐明的方法B进行。HPLC保留时间:3.53min.,电喷射质谱在m/e 745.8(M+H)和m/e 780.3(M+Cl-)显示峰,与结构一致。将这一中间产物(0.93g)溶解在二乙胺(10mL)中并搅拌2h。去除溶剂后,在己烷中洗涤残余物,获得为无色沉淀的0.6g中间产物(路线-3中的(2))(HPLC测为91.6%纯)。HPLC保留时间:2.06min。电喷射质谱在m/e 523.8(M+H)、m/e 546.2(M+Na)和m/e522.5(M-H)显示峰。
利用EEDQ,将这一粗制中间产物(0.565g)与可商购获得的O-(2-叠氮基乙基)-O’-(N-二乙醇酰基-2-氨乙基)庚乙二醇(‘PEG-N3’,0.627g)在二氯甲烷(10mL)中偶联。去除溶剂和快速色谱法产生0.99g产物(路线-3中(3);淡黄色油;87%产率)。HPLC保留时间:2.45min。电喷射质谱在m/e 1061.3(M+H)、m/e 1082.7(M+Na)和m/e 1058.8(M-H)显示峰,与结构一致。在氩气下将这一中间产物(0.92g)与10-O-TBDMS-SN-38-20-O-氯甲酸酯(路线-3中的(5))在二氯甲烷(10mL)反应10min。由快速色谱法纯化混合物,获得为淡黄色油的0.944g(路线-3中的(6);产率=68%)。HPLC保留时间:4.18min。向二氯甲烷(10mL)中的这一中间产物(0.94g)加入TBAF(THF中1M,0.885mL)和乙酸(0.085mL)在二氯甲烷(3mL)中的混合物,然后搅拌10min。用二氯甲烷(100mL)稀释混合物,以0.25M柠檬酸钠和盐水洗涤。去除溶剂产生0.835g黄色油状产物。HPLC保留时间:2.80min.,(99%纯度)。电喷射质谱在m/e 1478(M+H)、m/e 1500.6(M+Na)、m/e1476.5(M-H)、m/e 1590.5(M+TFA)显示峰,与结构一致。
在CuBr(0.0083g)、DIEA(0.01mL)和三苯基膦(0.015g)存在下,将这一叠氮基-衍生的SN-38中间产物(0.803g)与4-(N-马来酰亚胺甲基)-N-(2-丙炔基)环己烷-1-羧酰胺(0.233g)在二氯甲烷(10mL)中反应18h。萃取流程包括用0.1M EDTA(10mL)洗涤,快速色谱法产生为黄色泡沫的0.891g(产率=93%),HPLC保留时间:2.60min。电喷射质谱在m/e 1753.3(M+H)、m/e 1751.6(M-H)、1864.5(M+TFA)显示峰,与结构一致。最后,用二氯乙酸(0.3mL)和苯甲醚(0.03mL)在二氯甲烷(3mL)中的混合物将倒数第二中间产物(0.22g)脱保护,随后用乙醚沉淀,产生为浅黄色粉末的0.18g(97%产率)CL2A-SN-38(路线-3中的(7))。HPLC保留时间:1.88min。电喷射质谱在m/e 1480.7(M+H)、1478.5(M-H)显示峰,与结构一致。
路线-3:CL2A-SN-38的制备
实施例11:CL2E-SN-38的制备
将二氯甲烷(50mL)中的N,N’-二甲基乙二胺(3mL)与单甲氧基三苯甲基氯(1.7g)反应。搅拌1h后,减压下去除溶剂,通过萃取流程回收粗产物(黄色油;2.13g)。所有HPLC分析通过第0148段‘总论’中阐明的方法B进行。HPLC保留时间:2.28min。在原处将这一中间产物(路线-4中的(1);0.93g)加入活化的SN-38,后者(路线-4中的(2))通过在DMF中SN-38(0.3g)与氯甲酸对硝基苯酯(0.185g)和DIEA(0.293mL)反应1h而制备。去除溶剂后,在失活的硅胶上纯化残余物,获得为白色固体的0.442g。
用三氟乙酸(1mL)和苯甲醚(0.1mL)在二氯甲烷(5mL)中的混合物将这一中间产物(0.442g)脱保护,随后用乙醚沉淀,获得为白色固体的0.197g产物(路线-4中的(3))。将这一中间产物((3);0.197g)与掺入活化的含叠氮化物二肽的PEG-接头(路线-4中的(5))偶联,该活化是通过PEG-接头(路线-4中的(4);0.203g)与双(4-硝基苯基)碳酸酯(0.153g)和DIEA(0.044mL)在二氯甲烷(8mL)中反应而进行的。快速色谱产生为玻璃状固体的0.2g 叠氮化物-衍生的SN-38中间产物(路线-4中的(6))。HPLC保留时间:2.8min。电喷射质谱在m/e 1740.5(M+H)、m/e 1762.9(M+Na)、m/e1774.9(M+Cl-)显示峰,与结构一致。在CuBr(0.007g)、DIEA(0.008mL)和三苯基膦(0.012g)存在下,将这一中间产物(路线-4中的(6);0.2g)在二氯甲烷中以4-(N-马来酰亚胺甲基)-N-(2-丙炔基)环己烷-1-羧酰胺(0.067g)进行链接环加成18h。进行包括用0.1MEDTA处理的反应混合物的流程,随后快速色谱法产生为浅黄色泡沫的0.08g倒数第二中间产物。HPLC:tR=2.63min。电喷射质谱在m/e2035.9(M+Na+)、m/e 2047.9(M+Cl-)显示峰,与结构一致。最后,用三氟乙酸(0.2mL)、苯甲醚(0.12mL)和水(0.06mL)在二氯甲烷(2mL)中的混合物将这一中间产物(0.08g)脱保护,随后用乙醚沉淀产生为浅黄色粉末的0.051g产物CL17-SN-38(也称为CL2E-SN-38)(产率=69%)。HPLC保留时间:1.95min.,~99%纯度。电喷射质谱在m/e1741.1(M+H)、1775.5(M+Cl-)显示峰,与结构一致。
路线-4:CL2E-SN-38的制备
实施例12:双官能的SN-38产物与轻度还原的抗体共轭
这些研究中使用抗-CEACAM5人化MAb hMN-14、抗-CD22人化MAb hLL2、抗-CD20人化MAb hA20、抗-EGP-1人化MAb hRS7和抗-粘蛋白人化MAb hPAM4。在含5.4mM EDTA的40mM PBS,pH 7.4中,在37℃(浴)将每种抗体用50至70倍摩尔过量的二硫苏糖醇(DTT)还原45min。由尺寸排阻色谱和/或渗滤纯化还原产物,缓冲液交换到pH6.5的适当缓冲液中。由Ellman检验确定硫醇含量,并且在6.5至8.5SH/IgG范围中。可选地,将抗体用Tris(2-羧乙基)膦(TCEP)在pH 5-7范围的磷酸盐缓冲液中还原,随后在原处共轭。利用7-15%v/v的DMSO作为共溶剂,将还原的MAb与以下物质反应:~10至15倍摩尔过量的实施例1的‘CL6-SN-38’、或实施例2的‘CL7-SN-38’、或实施例3的‘CL6-SN-38-10-O-CO2Et’、或实施例4的‘CL7-SN-38-10-O-CO2Et’、实施例10的CL2A-SN-38、或实施例11的CL2E-SN-38,并在室温孵育20min。将共轭物由离心SEC,通过疏水柱,最后通过超滤-渗滤纯化。在366nm的吸光度测定产物的SN-38,将其与标准值关联,而蛋白浓度从280nm处的吸光度推断,对SN-38在这一波长的吸光度的溢出校正。以这种方式确定SN-38/MAb取代比。将纯化的共轭物作为冻干制剂储存在玻璃小瓶中,在真空下加帽,储存在-20℃冰箱中。对这些共轭物的一些获得SN-38摩尔取代比(MSR),其通常在5至7的范围,如表2所示。
表2:一些共轭物中的SN-38/MAb摩尔取代比(MSR)
实施例15:在人胰腺癌或结肠癌临床前模型中的体内治疗效力
对具有皮下人胰腺或结肠肿瘤异种移植物的对免疫缺乏免疫力的无胸腺裸小鼠(雌性)用特异性CL2A-SN-38共轭物或对照共轭物治疗,或不治疗。观察特异性共轭物的治疗效力。图1显示Capan 1胰腺肿瘤模型,其中hRS7(抗-EGP-1)、hPAM4(抗-粘蛋白)和hMN-14(抗-CEACAM5)抗体的特异性CL2A-SN-38共轭物显示比对照hA20-CL2A-SN-38共轭物(抗-CD20)和未治疗对照更好的效力。类似地,在人胰腺癌的BXPC3模型中,特异性hRS7-CL2A-SN-38显示比对照治疗更好的治疗效力(图2)。同样,在人结肠癌的侵入性LS174T模型中,用特异性hMN-14-CL2A-SN-38治疗比无治疗更有效(图3)。
实施例16:用抗-gp120MAb的SN-38共轭物治疗消除HIV感染
利用实施例7所述的条件还原一种靶向HIV包膜蛋白gp120的MAb,抗-gp120抗体诸如P4/D10,将还原的MAb与20倍摩尔过量的实施例2中所述的药物接头CL7-SN-38反应。获得每抗体带有~8个药物分子取代的抗-gp120-SN-38共轭物。利用未受感染的Jurkat-T细胞与完全HIV-感染的Jurkat T细胞(以99.8∶0.2至95∶5的比例)的不同混合物进行所述共轭物的体外HIV抑制检验,用100至0.00001μg/mL的共轭物、非特异性hRS7-CL7-SN38共轭物对照、裸抗体和HIV阴性血清的系列稀释物处理。将如此处理的细胞在RPMI 1640培养基中以37℃培养7天,然后由ELISA试验检验HIV抑制。这一实验显示特异性药物共轭物对HIV细胞内扩散的强和特异性的抑制。体内效力通过向小鼠施加同构的HIV-感染细胞连同特异性和非特异性SN-38共轭物来检验。为此,将HIV-1/MuLV假型病毒感染的原代鼠脾细胞腹膜内转移到小鼠组,同时施用免疫共轭物。10天后收集腹膜细胞。尽管在对照小鼠证明了传染性HIV存在,但是在用100μg或更少抗-gp120-SN-38共轭物治疗的小鼠中未检测到传染性HIV。用对照共轭物治疗的小鼠未观察到保护。
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从上面的描述,本领域技术人员容易确认本发明的基本特征,不脱离本发明的主旨和范围,能对本发明进行各种改变和修饰,使它适合各种应用和条件而不用过度的试验。这里引用的所有的专利、专利申请和公开物通过引用作为参考。
Claims (59)
1.一种下式的药物与靶向部分的共轭物:
TM-[L2]-[L1]-[AA]m-[A’]-药物,其中TM是疾病靶向部分;药物是化疗部分;L2是包含抗体-偶联部分和一个或多个乙炔基或叠氮化物基的交联接头的部分;L1在一端包含带有与L2中的乙炔部分或叠氮化物部分互补的叠氮化物或乙炔的确定的PEG,在另一端包含反应性基团诸如羧酸或羟基;AA是L氨基酸,其中m是数值为0、1、2、3或4的整数;且当m>1时,由AA表示的氨基酸可相同或不同;且A’是另外的间隔物。
2.如权利要求1所述的共轭物,其中AA选自由以下组成的组:丙氨酸、精氨酸、天冬酰胺、天冬氨酸、半胱氨酸、谷氨酰胺、谷氨酸、甘氨酸、组氨酸、异亮氨酸、亮氨酸、赖氨酸、甲硫氨酸、苯丙氨酸、脯氨酸、丝氨酸、苏氨酸、色氨酸、酪氨酸和缬氨酸。
3.如权利要求1所述的共轭物,其中所述A’间隔物选自由以下组成的组:乙醇胺、4-羟基苄醇、4-氨基苄醇、取代的乙二胺和取代的乙二胺。
4.如权利要求3所述的共轭物,其中A’是取代的乙二胺,且衍生自选自以下的L-氨基酸:丙氨酸、精氨酸、天冬酰胺、天冬氨酸、半胱氨酸、谷氨酰胺、谷氨酸、甘氨酸、组氨酸、异亮氨酸、亮氨酸、赖氨酸、甲硫氨酸、苯丙氨酸、脯氨酸、丝氨酸、苏氨酸、色氨酸、酪氨酸和缬氨酸,其中所述氨基酸的羧酸基团被羟甲基部分代替。
5.如权利要求1所述的共轭物,其中所述疾病靶向部分是鼠、嵌合、灵长类动物化、人化、或人单克隆抗体(MAb),且所述抗体是呈完整、片段(Fab、Fab’、F(ab)2、F(ab’)2)或亚片段(单链构建体)形式。
6.如权利要求4所述的共轭物,其中所述疾病靶向部分是嵌合、灵长类动物化、人化或人单克隆抗体(MAb),且所述抗体具有人IgG1或人IgG4抗体的恒定结构域和铰链结构域。
7.如权利要求5所述的共轭物,其中所述疾病靶向部分具有人IgG4抗体的恒定结构域和铰链结构域,其中所述铰链的丝氨酸228被脯氨酸代替。
8.如权利要求5所述的共轭物,其中所述抗体具有人IgG1抗体的恒定结构域和铰链,其中一个或多个Fc氨基酸被突变以增加所述抗体在血液中的半衰期,或其中Fc的一个或多个糖部分被缺失、或一个或多个糖部分被添加以增加所述抗体的血液半衰期。
9.如权利要求5所述的共轭物,其中所述MAb是内化抗体。
10.如权利要求5所述的共轭物,其中所述抗体连接于1至12个药物部分。
11.如权利要求5所述的共轭物,其中所述MAb选自由以下组成的组:LL1、LL2、RFB4、A19、A20、1F5、RS7、PAM4、MN-3、MN-14、MN-15、Mu-9、R1、AFP-31、L19、G250、J591、CC49、L243、AB-PG1-XG1-026、D2/B和Immu-31。
12.如权利要求5所述的共轭物,其中所述抗体-偶联部分是硫醇反应性的,且选自由以下组成的组:马来酰亚胺、乙烯砜、溴乙酰胺和碘乙酰胺。
13.如权利要求1所述的共轭物,其中所述PEG是具有1-30个单体单元的确定的PEG,优选地是具有1-12个单体单元的确定的PEG。
14.如权利要求1所述的共轭物,其中所述药物选自由以下组成的组:阿霉素(DOX)、表柔比星、吗啉代阿霉素(吗啉代-DOX)、氰基吗啉代-阿霉素(氰基吗啉代-DOX)、2-吡咯啉基阿霉素(2-PDOX)、喜树碱(CPT)、10-羟基喜树碱、SN-38、托泊替康、勒托替康、9-氨基喜树碱、9-硝基喜树碱、紫杉烷、格尔德霉素、袢霉素和埃坡霉素。
15.如权利要求1所述的共轭物,其中所述药物选自由以下组成的组:喜树碱(CPT)、10-羟基喜树碱、SN-38、托泊替康、勒托替康、9-氨基喜树碱和9-硝基喜树碱。
16.如权利要求15所述的共轭物,其中所述药物是SN-38。
18.如权利要求17所述的共轭物,其中MAb-CL2A-SN-38或MAb-CL6-SN-38或MAb-CL7-SN-38或MAb-CLX-SN-38中SN-38的10-羟基位置是利用‘COR’部分的10-O-酯或10-O-碳酸酯衍生物,其中R基团是取代的烷基残基诸如“N(CH3)2-(CH2)n-”,其中n是2-10,且其中末端氨基任选地呈用于增强水溶性的季盐形式;或烷基残基诸如“CH3-(CH2)n-”,其中n是0-10;或烷氧基残基诸如“CH3-(CH2)n-O-”,其中n是0-10;或“N(CH3)2-(CH2)n-O-”,其中n是2-10;或“R1O-(CH2-CH2-O)n-CH2-CH2-O-”,其中R1是乙基或甲基且n是数值为010的整数。
19.如权利要求1所述的共轭物,其中[AA]m是肽部分,优选地为二肽、三肽或四肽,选自Ala-Leu、Leu-Ala-Leu和Ala-Leu-Ala-Leu。
20.如权利要求5所述的共轭物,其中所述MAb结合于选自由以下组成的组的抗原:碳酸酐酶IX、B7、CCCL19、CCCL21、CSAp、HER-2/neu、BrE3、CD1、CD1a、CD2、CD3、CD4、CD5、CD8、CD11A、CD14、CD15、CD16、CD18、CD19、CD20、CD21、CD22、CD23、CD25、CD29、CD30、CD32b、CD33、CD37、CD38、CD40、CD40L、CD44、CD45、CD46、CD52、CD54、CD55、CD59、CD64、CD67、CD70、CD74、CD79a、CD80、CD83、CD95、CD126、CD133、CD138、CD147、CD154、CEACAM5、CEACAM-6、甲胎蛋白(AFP)、VEGF、ED-B纤连蛋白、EGP-1、EGP-2、EGF受体(ErbB1)、ErbB2、ErbB3、因子H、FHL-1、Flt-3、叶酸受体、Ga 733、GROB、HMGB-1、缺氧诱导因子(HIF)、HM1.24、HER-2/neu、胰岛素样生长因子(ILGF)、IFN-γ、IFN-α、IFN-β、IL-2R、IL-4R、IL-6R、IL-13R、IL-15R、IL-17R、IL-18R、IL-2、IL-6、IL-8、IL-12、IL-15、IL-17、IL-18、IL-25、IP-10、IGF-1R、Ia、HM1.24、神经节糖苷、HCG、HLA-DR、CD66a-d、MAGE、mCRP、MCP-1、MIP-1A、MIP-1B、巨噬细胞移动抑制因子(MIF)、MUC1、MUC2、MUC3、MUC4、MUC5、胎盘生长因子(PlGF)、PSA(前列腺特异性抗原)、PSMA、PSMA二聚物、PAM4抗原、NCA-95、NCA-90、A3、A33、Ep-CAM、KS-1、Le(y)、间皮素、S100、腱生蛋白、TAC、Tn抗原、Thomas-Friedenreich抗原、肿瘤坏死抗原、肿瘤血管生成抗原、TNF-α、TRAIL受体(R1和R2)、VEGFR、RANTES、T101、癌干细胞抗原、补体因子C3、C3a、C3b、C5a、C5和致癌基因产物。
21.如权利要求5所述的共轭物,其中所述MAb是多特异性的,具有靶向靶细胞或病原体中包含的至少两个不同抗原或表位的多个结合臂,并且一个或多个靶向臂与CPT共轭。
22.如权利要求21所述的共轭物,其中所述多特异性的MAb是包含选自以下的一种或多种抗体的双特异性和/或二价抗体构建体:LL1、LL2、RFB4、A19、A20、1F5、RS7、PAM4、MN-3、MN-14、MN-15、Mu-9、R1、AFP-31、L19、G250、J591、CC49、L243、AB-PG1-XG1-026、D2/B和Immu-31。
23.如权利要求21所述的共轭物,其中所述多特异性的抗体结合选自以下的组的两种或多种抗原:碳酸酐酶IX、B7、CCCL19、CCCL21、CSAp、HER-2/neu、BrE3、CD1、CD1a、CD2、CD3、CD4、CD5、CD8、CD11A、CD14、CD15、CD16、CD18、CD19、CD20、CD21、CD22、CD23、CD25、CD29、CD30、CD32b、CD33、CD37、CD38、CD40、CD40L、CD44、CD45、CD46、CD52、CD54、CD55、CD59、CD64、CD67、CD70、CD74、CD79a、CD80、CD83、CD95、CD126、CD133、CD138、CD147、CD154、CEACAM5、CEACAM-6、甲胎蛋白(AFP)、VEGF、ED-B纤连蛋白、EGP-1、EGP-2、EGF受体(ErbB1)、ErbB2、ErbB3、因子H、FHL-1、Flt-3、叶酸受体、Ga 733、GROB、HMGB-1、缺氧诱导因子(HIF)、HM1.24、HER-2/neu、胰岛素样生长因子(ILGF)、IFN-γ、IFN-α、IFN-β、IL-2R、IL-4R、IL-6R、IL-13R、IL-15R、IL-17R、IL-18R、IL-2、IL-6、IL-8、IL-12、IL-15、IL-17、IL-18、IL-25、IP-10、IGF-1R、Ia、HM1.24、神经节糖苷、HCG、HLA-DR、CD66a-d、MAGE、mCRP、MCP-1、MIP-1A、MIP-1B、巨噬细胞移动抑制因子(MIF)、MUC1、MUC2、MUC3、MUC4、MUC5、胎盘生长因子(PlGF)、PSA(前列腺特异性抗原)、PSMA、PSMA二聚物、PAM4抗原、NCA-95、NCA-90、A3、A33、Ep-CAM、KS-1、Le(y)、间皮素、S100、腱生蛋白、TAC、Tn抗原、Thomas-Friedenreich抗原、肿瘤坏死抗原、肿瘤血管生成抗原、TNF-α、TRAIL受体(R1和R2)、VEGFR、RANTES、T101、癌干细胞抗原、补体因子C3、C3a、C3b、C5a、C5和致癌基因产物。
24.如权利要求1所述的共轭物,其中所述靶向部分是融合蛋白。
25.如权利要求24所述的共轭物,其中所述融合蛋白包括抗体或抗体片段。
26.如权利要求24所述的共轭物,其中所述融合蛋白通过对接锁定技术构建。
27.如权利要求5所述的共轭物,其中所述MAb是与癌症、恶性细胞、感染性生物或自身免疫性疾病相关的抗原或所述抗原的表位具有反应性。
28.如权利要求27所述的共轭物,其中所述癌症是造血肿瘤、癌、肉瘤、黑素瘤或神经胶质肿瘤。
29.如权利要求27所述的共轭物,其中所述感染性生物选自由以下组成的组:人免疫缺陷病毒(HIV)、结核分支杆菌、无乳链球菌、耐甲氧西林金黄色葡萄球菌、嗜肺性军团病菌、酿脓链球菌、大肠杆菌、淋病奈瑟氏菌、脑膜炎奈瑟氏菌、肺炎球菌属、B型流感嗜血杆菌、苍白密螺旋体、莱姆病螺旋体、西尼罗病毒、绿脓假单胞菌、麻风分枝杆菌、流产杆菌、狂犬病病毒、流感病毒、巨细胞病毒、I型单纯疱疹病毒、II型单纯疱疹病毒、人血清细小样病毒、呼吸道合胞病毒、水痘-带状疱疹病毒、乙型肝炎病毒、麻疹病毒、腺病毒、人T细胞白血病病毒、埃-巴二氏病毒、鼠白血病病毒、腮腺炎病毒、水泡性口膜炎病毒、辛德比斯病毒、淋巴细胞性脉络丛脑膜炎病毒、疣病毒、蓝舌病病毒、仙台病毒、猫白血病病毒、呼肠孤病毒、脊髓灰质炎病毒、猿猴病毒40、鼠乳房肿瘤病毒、登革热病毒、风疹病毒、恶性疟原虫、间日疟原虫、鼠弓形体、让氏锥虫、克氏锥虫、罗德西亚锥虫、布氏锥虫、曼森血吸虫、日本血吸虫、牛巴贝虫、柔嫩艾美球虫、盘尾丝虫、热带利什曼原虫、旋毛线虫、小泰累尔梨浆虫、水泡绦虫、羊绦虫、牛肉绦虫、细粒棘球绦虫、科特氏中殖孔绦虫、关节炎支原体、猪鼻支原体、口腔支原体、精氨酸支原体、莱氏无胆甾原体、唾液支原体和肺炎支原体。
30.如权利要求27所述的共轭物,其中所述自身免疫性疾病选自由以下组成的组:免疫介导的血小板减少症、皮肌炎、舍格伦氏综合症、多发性硬化、西登哈姆氏舞蹈病、重症肌无力、系统性红斑狼疮、狼疮性肾炎、风湿热、类风湿性关节炎、多腺体综合征、大疱性类天疱疮、糖尿病、亨-舍二氏紫癜、链球菌感染后肾炎、结节性红斑、高安氏动脉炎、阿狄森氏病、结节病、溃疡性结肠炎、多形性红斑、IgA肾病、结节性多动脉炎、强直性脊柱炎、古德帕斯丘综合征、闭塞性血栓性脉管炎、原发性胆汁性肝硬变、桥本甲状腺炎、甲状腺毒症、硬皮病、慢性活动性肝炎、多肌炎/皮肌炎、多软骨炎、寻常天疱疮、韦格纳氏肉芽肿病、膜性肾病、肌萎缩侧索硬化、脊髓痨、巨细胞动脉炎/多肌痛、恶性贫血、急进性肾小球肾炎、纤维化肺泡炎和青少年糖尿病。
31.如权利要求1所述的共轭物,其中所述共轭物呈适于胃肠外施用的形式。
32.一种用于产生权利要求1所述的共轭物的方法,其中所述接头首先与所述药物共轭,从而产生药物-接头共轭物,且其中所述药物-接头共轭物随后与疾病靶向部分共轭。
33.如权利要求32所述的方法,其中双官能的药物部分如下制备:首先经由酰胺键将A’连接于AA的C末端,然后将AA的胺末端与L1的羧酸基团偶联;其中,如果m是零,A’经由酰胺键与L1直接连接;其中所述交联接头[L1]-[AA]m-[A’]与药物上的羟基或氨基连接,随后通过L1和L2中的叠氮化物(或乙炔)基团与乙炔(或叠氮化物)基团经由链接化学反应而连接到L1部分。
34.如权利要求32所述的方法,其中‘AA’选自由以下组成的组:丙氨酸、精氨酸、天冬酰胺、天冬氨酸、半胱氨酸、谷氨酰胺、谷氨酸、甘氨酸、组氨酸、异亮氨酸、亮氨酸、赖氨酸、甲硫氨酸、苯丙氨酸、脯氨酸、丝氨酸、苏氨酸、色氨酸、酪氨酸和缬氨酸。
35.如权利要求32所述的方法,其中A’是取代的乙二胺,且衍生自选自以下的L-氨基酸:丙氨酸、精氨酸、天冬酰胺、天冬氨酸、半胱氨酸、谷氨酰胺、谷氨酸、甘氨酸、组氨酸、异亮氨酸、亮氨酸、赖氨酸、甲硫氨酸、苯丙氨酸、脯氨酸、丝氨酸、苏氨酸、色氨酸、酪氨酸和缬氨酸,其中所述氨基酸的羧酸基团被羟甲基部分代替;或A’是4-氨基苄醇部分;或A’是取代的乙二胺。
36.如权利要求32所述的方法,其中所述疾病靶向部分是鼠、嵌合、灵长类化、人化、或人单克隆抗体(MAb),且所述抗体呈完整、片段(Fab、Fab’、F(ab)2、F(ab’)2)或亚片段(单链构建体)形式。
37.如权利要求36所述的方法,其中所述MAb是内化抗体。
38.如权利要求36所述的方法,其中所述抗体连接于1至12个药物部分。
39.如权利要求36所述的方法,其中所述MAb选自由以下组成的组:LL1、LL2、RFB4、A19、A20、1F5、RS7、PAM4、MN-3、MN-14、MN-15、Mu-9、R1、AFP-31、L19、G250、J591、CC49、L243、AB-PG1-XG1-026、D2/B和Immu-31。
40.如权利要求36所述的方法,其中所述抗体-偶联部分是硫醇反应性的,且选自由以下组成的组:马来酰亚胺、乙烯砜、溴乙酰胺和碘乙酰胺。
41.如权利要求32所述的方法,其中所述PEG是具有1-30个单体单元的确定的PEG,优选地是具有1-12个单体单元的确定的PEG。
42.如权利要求32所述的方法,其中所述药物选自由以下组成的组:阿霉素(DOX)、表柔比星、吗啉代阿霉素(吗啉代-DOX)、氰基吗啉代-阿霉素(氰基吗啉代-DOX)、2-吡咯啉基阿霉素(2-PDOX)、喜树碱(CPT)、10-羟基喜树碱、SN-38、托泊替康、勒托替康、9-氨基喜树碱、9-硝基喜树碱、紫杉烷、格尔德霉素、袢霉素和埃坡霉素。
43.如权利要求32所述的方法,其中所述药物选自由以下组成的组:喜树碱(CPT)、10-羟基喜树碱、SN-38、托泊替康、勒托替康、9-氨基喜树碱和9-硝基喜树碱。
44.如权利要求43所述的方法,其中所述药物是SN-38。
46.如权利要求45所述的方法,其中MAb-CL2A-SN-38或MAb-CL6-SN-38或MAb-CL7-SN-38或MAb-CLX-SN-38中SN-38的10-羟基位置是利用‘COR’部分的10-O-酯或10-O-碳酸酯衍生物,其中R基团是取代的烷基残基诸如“N(CH3)2-(CH2)n-”,其中n是2-10,且其中末端氨基任选地呈用于增强水溶性的季盐形式;或烷基残基诸如“CH3-(CH2)n-”,其中n是0-10;或烷氧基残基诸如“CH3-(CH2)n-O-”,其中n是0-10;或“N(CH3)2-(CH2)n-O-”,其中n是2-10;或“R1O-(CH2-CH2-O)n-CH2-CH2-O-”,其中R1是乙基或甲基且n是数值为0-10的整数。
47.如权利要求32所述的方法,其中[AA]m是肽部分,优选地二肽、三肽或四肽,选自:Ala-Leu、Leu-Ala-Leu和Ala-Leu-Ala-Leu。
48.如权利要求35所述的方法,其中所述MAb结合于选自由以下组成的组的抗原:碳酸酐酶IX、B7、CCCL19、CCCL21、CSAp、HER-2/neu、BrE3、CD1、CD1a、CD2、CD3、CD4、CD5、CD8、CD11A、CD14、CD15、CD16、CD18、CD19、CD20、CD21、CD22、CD23、CD25、CD29、CD30、CD32b、CD33、CD37、CD38、CD40、CD40L、CD44、CD45、CD46、CD52、CD54、CD55、CD59、CD64、CD67、CD70、CD74、CD79a、CD80、CD83、CD95、CD126、CD133、CD138、CD147、CD154、CEACAM5、CEACAM-6、甲胎蛋白(AFP)、VEGF、ED-B纤连蛋白、EGP-1、EGP-2、EGF受体(ErbB1)、ErbB2、ErbB3、因子H、FHL-1、Flt-3、叶酸受体、Ga 733、GROB、HMGB-1、缺氧诱导因子(HIF)、HM1.24、HER-2/neu、胰岛素样生长因子(ILGF)、IFN-γ、IFN-α、IFN-β、IL-2R、IL-4R、IL-6R、IL-13R、IL-15R、IL-17R、IL-18R、IL-2、IL-6、IL-8、IL-12、IL-15、IL-17、IL-18、IL-25、IP-10、IGF-1R、Ia、HM1.24、神经节糖苷、HCG、HLA-DR、CD66a-d、MAGE、mCRP、MCP-1、MIP-1A、MIP-1B、巨噬细胞移动抑制因子(MIF)、MUC1、MUC2、MUC3、MUC4、MUC5、胎盘生长因子(PlGF)、PSA(前列腺特异性抗原)、PSMA、PSMA二聚物、PAM4抗原、NCA-95、NCA-90、A3、A33、Ep-CAM、KS-1、Le(y)、间皮素、S100、腱生蛋白、TAC、Tn抗原、Thomas-Friedenreich抗原、肿瘤坏死抗原、肿瘤血管生成抗原、TNF-α、TRAIL受体(R1和R2)、VEGFR、RANTES、T101、癌干细胞抗原、补体因子C3、C3a、C3b、C5a、C5、和致癌基因产物。
49.如权利要求36所述的方法,其中所述MAb是多特异性的,具有靶向靶细胞或病原体中包含的至少两个不同抗原或表位的多个结合臂,并且一个或多个靶向臂与CPT共轭。
50.如权利要求32所述的方法,其中所述靶向部分是融合蛋白。
51.如权利要求50所述的方法,其中所述融合蛋白包括抗体或抗体片段。
52.如权利要求50所述的方法,其中所述融合蛋白通过对接锁定技术构建。
53.如权利要求36所述的方法,其中所述MAb对癌症、恶性细胞、感染性生物或自身免疫性疾病相关的抗原或其表位是反应性的。
54.一种治疗疾病的方法,所述方法包括向受治疗者施用权利要求1所述的共轭物。
55.如权利要求54所述的方法,其中所述共轭物与选自以下的一种或多种治疗方式联合施用:未共轭抗体、放射性标记抗体、药物-共轭抗体、毒素-共轭抗体、基因疗法、化疗、治疗肽、寡核苷酸、局部放疗、手术和干扰RNA疗法。
56.如权利要求54所述的方法,其中所述疾病是癌症、病原性生物感染或自身免疫性疾病。
57.如权利要求56所述的方法,其中所述癌症是造血肿瘤、癌、肉瘤、黑素瘤或神经胶质肿瘤。
58.如权利要求56所述的方法,其中所述病原性生物选自由以下组成的组:人免疫缺陷病毒(HIV)、结核分支杆菌、无乳链球菌、耐甲氧西林金黄色葡萄球菌、嗜肺性军团病菌、酿脓链球菌、大肠杆菌、淋病奈瑟氏菌、脑膜炎奈瑟氏菌、肺炎球菌属、B型流感嗜血杆菌、苍白密螺旋体、莱姆病螺旋体、西尼罗病毒、绿脓假单胞菌、麻风分枝杆菌、流产杆菌、狂犬病病毒、流感病毒、巨细胞病毒、I型单纯疱疹病毒、II型单纯疱疹病毒、人血清细小样病毒、呼吸道合胞病毒、水痘-带状疱疹病毒、乙型肝炎病毒、麻疹病毒、腺病毒、人T细胞白血病病毒、埃-巴二氏病毒、鼠白血病病毒、腮腺炎病毒、水泡性口膜炎病毒、辛德比斯病毒、淋巴细胞性脉络丛脑膜炎病毒、疣病毒、蓝舌病病毒、仙台病毒、猫白血病病毒、呼肠孤病毒、脊髓灰质炎病毒、猿猴病毒40、鼠乳房肿瘤病毒、登革热病毒、风疹病毒、恶性疟原虫、间日疟原虫、鼠弓形体、让氏锥虫、克氏锥虫、罗德西亚锥虫、布氏锥虫、曼森血吸虫、日本血吸虫、牛巴贝虫、柔嫩艾美球虫、盘尾丝虫、热带利什曼原虫、旋毛线虫、小泰累尔梨浆虫、水泡绦虫、羊绦虫、牛肉绦虫、细粒棘球绦虫、科特氏中殖孔绦虫、关节炎支原体、猪鼻支原体、口腔支原体、精氨酸支原体、莱氏无胆甾原体、唾液支原体和肺炎支原体。
59.如权利要求56所述的方法,其中所述自身免疫性疾病选自由以下组成的组:免疫介导的血小板减少症、皮肌炎、舍格伦氏综合症、多发性硬化、西登哈姆氏舞蹈病、重症肌无力、系统性红斑狼疮、狼疮性肾炎、风湿热、类风湿性关节炎、多腺体综合征、大疱性类天疱疮、糖尿病、亨-舍二氏紫癜、链球菌感染后肾炎、结节性红斑、高安氏动脉炎、阿狄森氏病、结节病、溃疡性结肠炎、多形性红斑、IgA肾病、结节性多动脉炎、强直性脊柱炎、古德帕斯丘综合征、闭塞性血栓性脉管炎、原发性胆汁性肝硬变、桥本甲状腺炎、甲状腺毒症、硬皮病、慢性活动性肝炎、多肌炎/皮肌炎、多软骨炎、寻常天疱疮、韦格纳氏肉芽肿病、膜性肾病、肌萎缩侧索硬化、脊髓痨、巨细胞动脉炎/多肌痛、恶性贫血、急进性肾小球肾炎、纤维化肺泡炎和青少年糖尿病。
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