CN101484587B - Igf-ir拮抗剂作为辅药用于前列腺癌的治疗 - Google Patents
Igf-ir拮抗剂作为辅药用于前列腺癌的治疗 Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
Abstract
本发明涉及一种使用雄激素剥夺治疗和胰岛素样生长因子受体(IGF-IR)拮抗剂治疗前列腺癌的方法。尽管前列腺癌对雄激素剥夺治疗(ADT)的响应率高,但存活的癌细胞不可避免地变成雄激素非依赖性的(AI),随后出现肿瘤生长。本发明抑制或延迟雄激素依赖性癌向雄激素非依赖性癌的转化,显著降低了复发风险并改善了治疗效果。
Description
联邦基金
本发明的一部分得到了美国政府国立卫生研究院基金CA85859和国防部W81XWH-04-1-0912基金的支持。因此,美国政府拥有本发明的某些权利。
相关申请的交叉引用
本发明主张2006年2月3日递交的美国申请60/765,072的优先权,其全文通过引用的方式纳入本文。
发明领域
本发明涉及一种使用雄激素剥夺治疗和胰岛素样生长因子受体(IGF-IR)拮抗剂治疗前列腺癌的方法。该方法抑制或延迟雄激素依赖性癌向雄激素非依赖性癌的转化,显著降低复发风险并改善治疗效果。
发明背景
前列腺癌是美国男性最常见的非皮肤癌,也是美国男性癌症死亡的第二常见病因。多数前列腺癌最初是雄激素依赖性的(AD)。前列腺癌细胞起初需要雄激素用于连续增殖。使用手术方式(睾丸切除术)或药物方式(GnRH激动剂或雌激素)经雄激素剥夺治疗(ADT)去除睾酮,会快速诱导敏感前列腺癌细胞的凋亡。基于前列腺特异抗原(PSA)的减少和肿瘤体积的稳定或减少,阳性反应率为约86%。细胞死亡一般发生在最初几天至一周内。但是,阳性反应后是一段生长停滞期,其间剩余细胞往往不会死亡。激素去除后的18-36个月时,90%的情况重新出现生长。无一例外的是,存活的癌细胞成为雄激素非依赖性或对雄激素失去应答,随后发生雄激素非依赖性的(AI)肿瘤生长。由于ADT最初很有效,利用ADT的优点并延长或增强其效应的治疗会有很大的益处。
雄激素非依赖性似乎是由多种机制引起的。雄激素受体基因的突变在诊断时很罕见,但在暴露于抗雄激素的氟他胺后会增加。但是,大多数患者没有发生这些突变,这些突变也不能解释多数激素非依赖性的疾病。与局部疾病相比,晚期疾病中,高水平bcl-2发生的频率更高。因此,随病程进展,诱导凋亡的能力随之下降。携带肿瘤抑制基因p53突变、丢失TGF-β受体以及表达肽生长因子的细胞的增殖有可能参与了激素非依赖状态的发生。但是,这些过程没有解释其发生的速度和频率。
胰岛素样生长因子受体(IGF-IR)是广泛的跨膜酪氨酸激酶受体,其对于胚胎和产后期的正常生长和发育是必不可少的。IGF-IR可刺激细胞增殖、细胞分化、细胞大小变化和防止细胞发生凋亡。它还被视为细胞转化的准必需因子(综述:Adams等人,Cell.MoI.Life Sci.57:1050-93(2000);Baserga,Oncogene 19:5574-81(2000))。IGF-IR位于大多数细胞类型的细胞表面,充当生长因子IGF-I和IGF-II(以下合称IGF)的信号转导分子。IGF-IR还结合胰岛素,但亲和力比其与IGF的结合亲和力小三个数量级。IGF-IR是预形成的异型四聚体,含有以二硫键共价连接的两条α链和两条β链。受体亚基被合成为180kd的单条多肽链的一部分,该多肽随后经蛋白酶切形成α(130kd)亚基和β(95kd)亚基。整条α链位于细胞外,含有配体结合的位点。β链具有跨膜域、酪氨酸激酶域和C端延伸部分,该C端延伸部分是细胞分化和转化所需的,但对于有丝分裂原信号转导和防止凋亡不是必需的。
IGF-IR与胰岛素受体(IR)高度相似,尤其是在β链序列内(70%同源性)。由于该同源性,近来研究业已证实这些受体可形成含有一个IR二聚体和一个IGF-IR二聚体的杂合分子(Pandini等人,Clin.Canc.Res.5:1935-19(1999))。杂合分子的形成发生在正常细胞和转化细胞内,而且杂合分子的含量取决于两种同型二聚体受体(IR和IGF-ER)在细胞内的浓度。在一项39份乳腺癌标本的研究中,尽管IR和IGF-IR在所有肿瘤样本中均发生了过表达,但杂交受体的含量始终比这两种同型受体的水平高大约3倍(Pandini等人,Clin.Canc.Res.5:1935-44(1999))。尽管杂交受体由IR和IGF-IR对组成,但杂交分子选择性结合到IGF上,其亲和力与IGF-IR的类似,还可微弱地结合到胰岛素上(Siddle和Soos,The IGF System.Humana Press,pp.199-225.1999)。因此这些杂交分子可在正常细胞和转化细胞内结合IGF,并传导信号。
IGF-I的内分泌表达主要受生长激素调控,主要产生于肝脏,但近来证据表明许多其他组织类型也可表达IGF-I。因此该配体在许多类型的肿瘤细胞内受内分泌和旁分泌以及自分泌的调控(Yu,H和Rohan,J.,J.Natl.CancerInst.92:1472-89(2000))。
雄激素受体(AR)由3个功能域和结构域组成:N端(调节)域;介导特异结合到靶DNA序列(配体-反应性元件)上的DNA结合域(Interpro检索号IPR001628);以及激素结合域。N端域(NTD)是雄激素受体所特有的,其大约跨越开始的530个残基;高度保守的DNA结合域小一些(约65个残基),位于蛋白质的中间部分;激素配体结合域(LBD)位于受体的C端。没有配体时,类固醇激素受体被认为与核组分微弱结合,激素结合大大提高了受体亲和力。雄激素受体(AR)、雄激素和前列腺癌之间的相互作用很复杂。AR在细胞核与细胞质之间的分配受雄激素和去除雄激素的影响。例如,AR免疫反应性仅在生长于完整雄性小鼠身上的LuCaP35细胞的核内观察到,但在生长于完整但随后去势的雄性小鼠身上的LuCaP35细胞的细胞质和细胞核内均观察到强烈的免疫反应性。
发明概述
本发明涉及雄激素依赖性肿瘤例如前列腺癌的治疗。前列腺肿瘤一般受雄激素例如睾酮的刺激,并表现出雄激素依赖性的(AD)生长。因此,前列腺癌的治疗一般包括阻断前列腺癌细胞的雄激素。但是,大部分前列腺癌最终转化为雄激素非依赖性的(AI)。业已发现施用IGF-IR拮抗剂并联用雄激素剥夺治疗(ADT)可抑制或防止AD肿瘤向AI肿瘤的转化。
因此,本发明提供了一种通过采用雄激素剥夺治疗和IGF-IR拮抗剂治疗雄激素依赖性癌的方法。在本发明的一个实施方式中,所述雄激素依赖性癌是前列腺癌。
根据本发明,所述IGF-IR拮抗剂可以是细胞外拮抗剂或细胞内拮抗剂,并且可使用一种以上的拮抗剂。概括而言,本发明涉及抑制IFG-IR信号转导,涉及调节该途径的组分以抑制肿瘤细胞从AD到AI的转化。细胞外拮抗剂包括但不限于结合IFG-IR或其配体(IGF)的蛋白质或其它生物分子。在本发明的某些实施方式中,所述细胞外拮抗剂抑制IGF-IR结合到IGF上。在一个实施方式中,所述结合蛋白是抗体,例如IMC-A12。在另一实施方式中,所述结合蛋白是IGF-IR可溶的配体结合片段。细胞内IGF-IR拮抗剂可为生物分子,但通常是小分子。在本发明的一个实施方式中,所述IGF-IR拮抗剂是选自AG1024、NVP-AEW541和BMS-554417的小分子。
可通过例如测定IGF-IR信号转导途径组分的状态来观察抑制IGF-IR信号转导的各种拮抗剂的效力。在一个实施方式中,Akt磷酸化的减少表示IGF-IR被抑制。在另一实施方式中,存活蛋白或微管蛋白β-肽(TUBB)表达的下降表示IGF-IR信号转导被抑制。
本发明的IGF-IR拮抗剂与任何形式的ADT一同使用。在本发明的一个实施方式中,ADT包括睾丸切除术。在本发明的另一实施方式中,ADT包括施用促性腺激素释放激素的类似物。在另一实施方式中,ADT包括施用抗雄激素物质。在又一实施方式中,施用肾上腺雄激素抑制剂。根据本发明,可联用两种或更多的ADT方法。
本发明还提供了经Akt的信号转导的抑制。因此,本发明包括施用活化Akt的信号转导蛋白的调节剂。在一个实施方式中,这种调节剂是EGFR的拮抗剂。
根据本发明,IGF-IR拮抗剂是作为ADT的辅药施用的。在一个实施方式中,大致同时启动ADT和施用IGF-IR拮抗剂。在另一实施方式中,首先启动ADT,随后在雄激素依赖性癌成为雄激素非依赖性之前施用IGF-ER拮抗剂。本发明还提供了与ADT和IGF-ER拮抗剂一同使用的抗肿瘤剂。在本发明的一个实施方式中,IGF-IR拮抗剂与ADT药剂一同用作前列腺癌手术治疗或放疗的新辅药。
本发明还提供了在一个剂型中包含IGF-ER拮抗剂和ADT药剂的组合物。
附图简述
图1示出了一项观察皮下异种移植LuCap35的SCID小鼠的研究。当平均肿瘤大小达到400mm3时,所有小鼠被去势。对照组小鼠只进行去势。其它两组去势后一周到两周,开始每周施用三次IMC-A12。
图2示出了去势对照小鼠、去势后一周接受IMC-A12处理的小鼠(早)和去势后两周接受IMC-A12处理的小鼠(晚)的PSA水平。
图3示出了以IGF刺激IGF-IR和/或以IMC-A12拮抗IGF-IR后雄激素受体(AR)的分布。经蛋白印迹测定细胞质和细胞核AR的水平。
图4示出了IGF-IR拮抗剂(IMC-A12)对未去势小鼠(左栏)体内LuCaP35雄激素依赖性异种移植肿瘤和去势小鼠(右栏)体内LuCaP35V雄激素非依赖性异种移植肿瘤的雄激素受体(AR)分布的效应。
图5示出了AP分数与肿瘤体积之间的相关性。R=0.66,p<0.01。仅去势组的数值表示为空心圆环,去势+A12(早)和(晚)的数值表示为实心圆环。数值是每个肿瘤100个被评分的细胞核的平均值。
图6示出了A12皮下处理的肿瘤在两个时间段之间的基因表达变化。在阵列上有足够数据进行测试的3170个独特基因中,与早期相比,晚期(此时肿瘤开始复发)有21个发生上调(包括许多受雄激素调控的基因,表示为“*”),41个发生下调,q值≤10%。
图7A示出了存活蛋白拷贝数目分数和肿瘤体积之间的相关性(r=0.66,p≤0.01)。图7B示出了微管蛋白β肽3拷贝数目分数与肿瘤体积之间的相关性(r=0.59,p≤0.01)。仅去势组的数值表示为空心圆环,去势+A12(早)和(晚)的数值表示为实心圆环。每个数值是三次PCR的平均值。
发明详述
业已发现IGF-IR的抑制剂可用于前列腺癌的治疗。具体而言,与单独使用ADT相比,施用IGF-IR拮抗剂并联合雄激素剥夺治疗(ADT)可使治疗效果得到改善。
业已观察到雄激素上调胰岛素样生长因子-I受体的表达,可能使前列腺癌对IGF-I的效应敏感。与之类似,在前列腺癌细胞上所观察到的雄激素非依赖性转化可源自增加雄激素受体信号转导的细胞适应,例如AR水平升高会使细胞对低水平的循环雄激素敏感或AR突变可允许其被非雄激素类固醇活化。的确,证据表明IGF-I信号转导可实际上介导AR易位至肿瘤细胞的细胞核,并导致AR依赖性基因的上调。因此,人们认为在激素去除疗法后,IGF-I在缺乏雄激素循环水平下通过促进AR信号转导,可促进雄激素依赖性前列腺癌向雄激素非依赖性前列腺癌的转化。近来来自男性和人前列腺异种移植的数据也显示目前去除雄激素的方法未能将前列腺雄激素降低到不再活化雄激素受体的水平。前列腺实际上可从数种类固醇前体以及有可能从乙酸盐合成DHT。
因此,抑制IGF-I信号转导并结合激素去除治疗可防止或延长前列腺癌转化为雄激素非依赖性疾病的时间,显著延迟复发的发生。因此IGF-IR的拮抗剂可为雄激素剥夺策略的有效辅药,以治疗新近诊断和局部晚期或转移的激素依赖性前列腺癌。
联合使用IGF-IR拮抗剂以及去除雄激素还具有阻断IGF介导的从凋亡恢复的潜力。IGF-IR抑制凋亡的机制包括抑制ras-raf-map激酶、PI3激酶(包括mTOR和forkhead信号转导)以及14-3-3。IGF-IR抑制可延长去除雄激素的效应的另一种机制是在最初的凋亡后保持肿瘤处于细胞周期停滞。
之前研究已证实当IGF-IR拮抗剂用于治疗雄激素依赖性和雄激素非依赖性前列腺癌的异种移植物时可具有积极效果。异种移植物的生长虽然变慢,但并没有被阻滞或逆转。现在已发现IGF-IR拮抗剂与雄激素剥夺治疗(ADT)联合应用时,其对于前列腺癌的治疗尤为有效。一般而言,前列腺肿瘤转变为雄激素非依赖性的,并对ADT不敏感。正如之前所观察到,这些雄激素不敏感性肿瘤往往对IGF-IR拮抗剂不表现出强烈的反应。但是,正如本文所证实,前列腺肿瘤从AD进展为AI的时间被ADT与IGF-IR拮抗剂联合治疗显著延长。在该延长期内,肿瘤体积减少,PSA水平下降。联合治疗降低了单独使用ADT所发生的复发高风险,并减低了发生转移癌的风险。以IGF-IR拮抗剂处理对于可能出现或已被诊断有迁移灶的晚期前列腺癌的治疗也是有益的。
在掺入前列腺癌细胞的模型中,AP从细胞质到细胞核的易位被视为不仅是由雄激素刺激所诱导的,也是由IGF-IR刺激所诱导的(尽管程度稍轻)。即使在雄激素存在的情况下,AR在雄激素和IGF存在下所发生的易位也会被IGF-IR拮抗剂降低。
在前列腺中,去势后仍可检测到低水平的雄激素。另有报道称经Akt进行信号转导的IGF-IR表达首先因去势而下降,但随后增加,而且生长因子对Akt的刺激增强了AR对低水平雄激素的信号转导。
正如本文所示,以IGF-IR拮抗剂进行的治疗显著延迟了去势小鼠的肿瘤再生长。而且,核AP的下降与肿瘤体积的下降有良好的相关性。这表明IGF-IR信号转导的抑制在抑制AR所驱动的肿瘤进展中起了极大的作用。在本文所述的实验中,使用结合IGF-IR的名为A12的抗体可抑制IGF-IR的信号转导。使用A12和类似抗体的先前实验表明各种信号转导分子(包括ERK和MAPK,尤其是Akt)的磷酸化(即活化)水平降低。抑制IGF-IR的效应已在许多肿瘤细胞类型中观察到,其中包括M12前列腺肿瘤系(Wu,J.D等人,2005,Clin.Cancer Res.11:3065-74)和MCF7乳腺癌细胞(Burtrum,D等人,2003,Cancer Res.63:8912-21)。因此,应理解的是,在本文IGF-IR拮抗剂上所观察到的相同或相似辅药活性也可在对Akt活化表现出相同或相似效应的药剂上观察到。
观察到使用IGF-IR拮抗剂治疗会抑制AR易位到细胞核。可经组织化学方法或经荧光显微镜以及在AP诱导基因的表达下降中观察到这种抑制。IGF-IR经Akt活化调控与抗去势相关的两种基因即存活蛋白和微管蛋白β-肽。与仅去势小鼠相比,这些基因的表达在接受IGF-IR拮抗剂的去势小鼠内受到抑制。对AP易位和Akt活化的基因表达的类似抑制效应也表现在对Akt特异抑制剂或明显涉及Akt的另一信号转导途径的拮抗剂的反应。
根据本发明可使用许多IGF-IR拮抗剂。IGF-IR拮抗剂可以是细胞外拮抗剂或细胞内拮抗剂。细胞外和细胞内IGF-IR拮抗剂可为例如通过与受体细胞外结合区域相互作用(即细胞外拮抗剂)、通过抑制IGF-IR胞内酪氨酸激酶域的磷酸化或通过抑制与任何其它参与IGF-IR信号转导途径的细胞组分的活化的相互作用而抑制IGF-IR活化的生物分子、小分子、或任何其它物质,它们最终抑制基因活化或细胞增殖。
在本发明的一个实施方式中,细胞外IGF-IR拮抗剂与受体的细胞外配体结合区通过拮抗剂与受体细胞外结合区之间足够的物理或化学相互作用而相互作用,使得IGF-IR与其配体的结合被阻断,并且受体的酪氨酸激酶活性受到抑制。本领域技术人员会理解,这些包括缔合或键合的化学相互作用的实例为本技术领域所知晓,其中包括拮抗剂与细胞外结合区之间的共价键合、离子键合、氢键等。在本发明的一个实施方式中,所述细胞外IGF-IR拮抗剂是生物分子。生物分子包括但不限于结合IGF-IR的抗体或抗体片段。在另一实施方式中,所述IGF-IR拮抗剂可为阻断配体与IGF-IR结合的小分子。在另一实施方式中,所述细胞外拮抗剂是隔离或降解IGF-IR配体的物质。一个实例是结合IGF的IGF-IR的可溶细胞外片段。这类物质的另一实例是可结合IGF从而限制IGF受体活化的IGF结合蛋白(IGFBP),例如IGFBP-1、IGFBP-2和IGFBP-3。在本发明的另一实施方式中,小分子抑制剂结合到IGF-IR的配体结合域上,并通过IGF-IR配体阻断结合和受体活化。
尽管不希望受任何理论所束缚,一般认为细胞外IGF-IR拮抗剂抑制了IGF-IR活化后其细胞外区域的构象变化所启动的所有信号转导级联反应。这种抑制包括表面IGF-IR以及被内化到细胞内的IGF-IR。例如,人们认为活化的受体酪氨酸激酶(RTK)可通过包被网格蛋白的小窝被内化到内含体,但仍保持其信号转导活性。内化后,这些受体或再循环到细胞表面,或在内含体或溶酶体内被降解。
另外一种抑制IGF-IR介导的信号转导的途径是下调IGF-IR的表达。在本发明的一个实施方式中,IGF-IR拮抗剂结合到受体上并促进受体的内化和降解。在另一实施方式中,IGF-IR拮抗剂减少受体的表达。
在本发明的语境中,生物分子包括所有氨基酸、核苷酸、脂质和一般具有650D以上分子量的单糖聚合物。因此,生物分子包括例如寡肽、多肽、肽和蛋白质、低聚核苷酸和多聚核苷酸,例如DNA和RNA,和低聚糖和多聚糖。生物分子还包括任何上述分子的衍生物。例如,生物分子的衍生物包括脂质和糖基化衍生物或寡肽、多肽、肽和蛋白质。生物分子的衍生物还包括低聚糖和多聚糖的脂质衍生物,例如脂多糖。最典型的生物分子是抗体或抗体的功能衍生物。
小分子包括有机化合物,例如杂环、肽、糖、类固醇等、有机金属化合物、有机化合物的盐和有机金属化合物和无机化合物。小分子的原子是通过共价键和离子键连接在一起的,前者一般见于小有机化合物,例如小分子酪氨酸激酶抑制剂,而后者一般见于小无机化合物。小有机分子的原子排列可能代表链,例如碳碳链或碳-杂原子链,或可能代表含有碳原子的环,例如苯或多环体系,或碳原子和杂原子的组合,即杂环,例如嘧啶或喹唑啉。尽管小分子可具有任意分子量,但除去其分子量不大于650D以外,它们一般包括本身会被视为生物分子的分子。小分子包括天然化合物,例如激素、神经递质、核苷酸、氨基酸、糖、脂质及其衍生物以及经传统有机合成、生物介导合成或二者组合而合成的化合物。例如参见Ganesan,DrugDiscov.Today 7(1):47-55(Jan.2002);Lou,Drug Discov.Today,6(24):1288-1294(Dec.2001)。所述化合物可被修饰以增强效力、稳定性、药物配伍性等。
细胞内IGF-IR拮抗剂可为生物分子,例如突变受体亚基、细胞内结合蛋白(例如细胞内表达的抗体片段)等。在一个优选实施方式中,所述细胞内拮抗剂是小分子。小分子抑制剂包括但不限于修饰或阻断IGF-IR的ATP结合域、底物结合区域或激酶域的小分子。小分子抑制剂还包括IGF-IR信号转导途径其它组分的抑制剂物质,这些信号转导途径包括但不限于ras-有丝分裂原活化的蛋白激酶(MAPK)途径和磷脂酰肌醇-3激酶(PI3K)-Akt途径。
为了鉴定拮抗剂,可使用高通量的生化、酶学或细胞测定筛选小分子文库的抑制活性。可设计检测方法以检测受试化合物抑制IGF-IR与IGF-IR配体或底物IRS-I结合或抑制IGF-IR二聚体形成功能受体的能力。细胞内IGF-ER拮抗剂可通过结合到携带激酶域的胞内区域或抑制携带激酶域的胞内区域的活化,或通过结合到参与IGF-IR信号转导途径的任意细胞内蛋白或抑制参与IGF-IR信号转导途径的任意细胞内蛋白的活化,抑制IGF-IR的酪氨酸激酶活性。IGF-IR的小分子拮抗剂包括例如胰岛素样生长因子-I受体选择性激酶抑制剂NVP-AEW541(Garcia-Echeverria,C等人,2004,Cancer Cell 5:231-9)和NVP-ADW742(Mitsiades,C等人,2004,CancerCell 5:221-30)、选择性抑制IGF-IR和HER2的INSM-18(Insmed Incorporated)以及通过阻断底物结合抑制磷酸化的酪氨酸激酶抑制剂tryphostin AG1024和AG1034(Parrizas,M.等人,1997,Endocrinology 138:1427-33),这两种酪氨酸激酶抑制剂对IFG-IR磷酸化抑制的IC50显著低于IR磷酸化抑制的IC50。环木脂体衍生物鬼臼苦素(PPP)是另一种IGF-IR拮抗剂,其抑制IGF-IR磷酸化,但不影响IR活性(Gimita,A等人,2004,Cancer Res.64:236-42)。其它小分子IGF-IR拮抗剂包括苯并咪唑衍生物BMS-536924(Wittman,M.等人,2005,J.Med.Chem.48:5639-43)和BMS-554417(Haluska P.等人,2006,CancerRes.66:362-71),它们几乎均等地抑制IGF-IR和IR。对于除抑制IGF-IR外还抑制受体的化合物而言,应注意到直接结合测定所测量的体外IC50值可能不能反映离体或体内(即完整细胞或生物体内)所测量的IC50值。例如,若需避免抑制IR,当体外抑制IR的化合物用于体内且其浓度可有效抑制IGF-IR时,可能不会明显影响受体的活性。
反义寡脱氧核苷酸、反义RNA和小分子抑制性RNA(siRNA)可用于靶向降解mRNA,从而防止蛋白质翻译。因此,受体酪氨酸激酶和IGF信号转导的其它关键蛋白质的表达可被抑制。反义寡核苷酸抑制基因表达的能力是在25年以前发现的(Zamecnik和Stephenson,1978,Proc.Natl.Acad.SciUSA.75:280-84)。反义寡核苷酸与mRNA和前体mRNA进行碱基配对,可潜在干扰RNA加工和信息翻译的多个步骤,其中包括剪接、多聚腺苷酸化、输出、稳定性和蛋白质翻译(Sazani和Kole,2003,J.Clin.Invest.112:481-86)。但是,最有力和最广泛使用的两种反义策略是通过RNaseH降解mRNA或前体mRNA和通过靶向异常剪接点改变剪接。RNaseH识别DNA/RNA异二聚体,并在DNA寡核苷酸的5′端和3′端之间从大约中间切割RNA。经反义寡核苷酸抑制IGF-IR例示于Wraight,Nat.Biotechnol.18:521-6。
固有的RNA介导的机制可调控mRNA稳定性、信息翻译和染色质组织(Mello和Conte,2004,Nature.431:338-42)。而且,外源引入的长双链RNA(dsRNA)是在许多低等生物体内进行基因沉默的有效手段。但是在哺乳动物中,长dsRNA会引发强烈的毒性反应,该反应与病毒感染和干扰素生成的效应有关(Williams,1997,Biochem.Soc.Trans.25:509-13)。为了避免这种情况,Elbashir与同事(Elbashir等人,2001,Nature.411:494-98)开始使用由19聚双链体组成的siRNA,其中每条链上具有5′磷酸和3′端的两个突出碱基,这些siRNA被引入细胞后可选择性降解靶向mRNA。
干扰dsRNA在哺乳动物体内的作用通常涉及两个酶催化步骤。首先,RNaseIII类型的酶Dicer将dsRNA切割为21-23聚体的siRNA片段。随后,RNA-诱导的沉默复合物(RISC)解开RNA双链体的螺旋,将其中一条链与同源mRNA的互补区域配对,并在siRNA链5′端上游的10个核苷酸处启动切割(Hannon,2002,Nature.418:244-51)。化学合成的长度为19-22碱基的短siRNA不需Dicer步骤,可直接进入RISC装置。应注意的是,RNA双链体的任一条链均有可能被加载到RISC复合物上,但寡核苷酸的组成会影响链的选择。因此,为了实现特定mRNA靶的选择性降解,利用反义链5′端较弱的碱基配对,双链体应优先加载反义链组分(Khvorova,2003,Cell115:209-16)。外源siRNA可提供为合成的寡核苷酸或从质粒或病毒载体表达(Paddison和Hannon,2003,Curr.Opin.MoI.Ther.5:217-24)。后一种情况下,前体分子通常表达为短发夹RNA(shRNA),其含有4-8个核苷酸的环和19-30个核苷酸的茎;它们随后被Dicer切割形成功能siRNA。
依据本发明使用的抗IGF-IR抗体表现出一种或多种下列性质:
1)所述抗体结合到IGF-IR的外部域上,并抑制IGF-I或IGF-II结合到IGF-IR上。可通过例如使用纯化受体或膜结合受体经直接结合分析测定抑制。在该实施方式中,本发明所述抗体或其片段优选以至少与IGF-IR天然配体(IGF-I和IGF-II)相同的强度结合到IGF-IR上。
2)所述抗体中和IGF-IR。配体例如IGF-I或IGF-II结合到IGF-IR的外部细胞外结构域可刺激β亚基自身磷酸化和IGF-IR底物(包括MAPK、Akt和IRS-1)的磷酸化。
IGF-IR的中和包括通常与信号转导相关的一种或多种活性的抑制、减少、失活和/或破坏。可通过体内、离体或体外利用例如组织、培养细胞或纯化的细胞组分测定中和。中和包括IGF-IR/IR异型二聚体以及IGF-IR同型二聚体的抑制。因此,中和IGF-IR具有各种效应,其中包括抑制、减少、失活和/或破坏生长(增殖和分化)、血管生成(血管募集、侵袭和转移)以及细胞迁移和转移(细胞粘附和侵袭)。
IGF-IR中和的一种衡量标准是受体的酪氨酸激酶活性的抑制。可通过熟知的方法测定酪氨酸激酶的抑制,例如测量重组激酶受体的自身磷酸化水平和/或天然或合成底物的磷酸化。因此,在本发明的语境中,磷酸化分析可用于测定中和抗体。可使用例如ELISA测定或蛋白印迹中特异识别磷酸化酪氨酸的抗体检测磷酸化。一些用于酪氨酸激酶活性的测定见于Panek等人,1997,J.Pharmacol.Exp.Thera.283:1433-44和Batley等人,1998,LifeSci.62:143-50。本发明的抗体在对配体作出响应的细胞内引起IGF-IR酪氨酸磷酸化至少下降约75%,优选为至少约85%,更优选为至少约90%。
IGF-IR中和的另一种测量标准是IGF-IR下游底物磷酸化的抑制。因此,可测量MAPK、Akt或IRS-1的磷酸化水平。底物磷酸化的下降至少为约50%,优选为至少约65%,更优选为至少约80%。
此外,可利用蛋白质表达的检测方法来测定IGF-IR中和,其中所测量蛋白质受IGF-IR酪氨酸激酶活性的调控。这类与癌进展和抗药性相关的蛋白质的一个实例是存活蛋白,它是凋亡抑制蛋白(IAP)家族的成员。尽管存活蛋白调控较为复杂,且受一种以上途径介导,业已证实Akt所介导的调控和IGF-I所促进的提高。例如参见Zhang等人,2005,Oncogene,24:2474-82。分析基因表达的方法包括检测蛋白质表达的免疫组化、检测基因扩增的荧光原位杂交(FISH)、竞争性放射配体结合分析、固相基质印迹技术,例如RNA印记和DNA印迹、逆转录酶聚合酶链式反应(RT-PCR)和ELISA。例如参见Grandis等人,1996,Cancer,78:1284-92;Shimizu等人,1994,JapanJ.Cancer Res.,85:567-71;Sauter等人,1996,Am.J.Path.,148:1047-53;Collins,1995,Glia15:289-96;Radinsky等人,1995,Clin.Cancer Res.1:19-31;Petrides等人,1990,Cancer Res.50:3934-39;Hoffmann等人,1997,AnticancerRes.17:4419-26;Wikstrand等人,1995,Cancer Res.55:3140-48。
也可使用离体分析来测定IGF-IR中和。例如,使用受体配体在抑制剂存在或不存在的情况下刺激细胞系,经有丝分裂原分析,可观察受体酪氨酸激酶抑制。MCF7乳腺癌细胞系(美国典型培养物保藏中心(ATCC),Rockville,MD)是表达IGF-IR并受IGF-I或IGF-II刺激的细胞系。另一种方法涉及检测表达IGF-IR的肿瘤细胞或转染表达IGF-IR的细胞的生长抑制。还可使用肿瘤模型例如注射到小鼠体内的人肿瘤细胞来观察抑制。
本发明所述抗体不受IGF-IR中和的任何特定机制的限制。本发明所述抗IGF-IR抗体可在细胞外结合到IGF-IR细胞表面受体,阻断配体(例如IGF-I或IGF-II)的结合和随后受体相关的酪氨酸激酶所介导的信号转导,并阻止IGF-IR和其它参与信号转导级联反应的下游蛋白的磷酸化。
3)所述抗体下调IGF-IR。位于细胞表面的IGF-IR的量取决于受体蛋白的生成、内化和降解。可通过检测受体或结合在受体上分子的内化,间接测量位于细胞表面上IGF-IR的量。例如,可通过用标记抗体接触表达IGF-IR的细胞来测量受体内化。随后洗脱(strip)、收集和计数膜结合抗体。通过裂解细胞和检测裂解液中的标记来测量内化抗体。
另外一种方法是在使用抗IGF-IR抗体或其它物质处理后直接测量细胞表面上受体的量,例如通过荧光活化细胞分拣分析染色细胞的IGF-IR表面表达。染色细胞于37℃温育,选择不同时间点检测荧光强度。作为对照,部分染色细胞群体可在4℃温育(该条件下停止受体内化)。
可使用特异识别IGF-IR并且不阻断或不与受试抗体竞争结合的不同抗体来检测和测量细胞表面的IGF-IR。(Burtrum等人,2003,CancerRes.63:8912-21)。使用本发明抗体处理表达IGF-IR的细胞引起细胞表面IGF-IR的减少。在一个优选实施方式中,使用本发明抗体处理后,该减少至少为约70%,更优选至少为约80%,甚至更优选至少为约90%。明显的减少可早在4小时内即可观察到。
下调的另一种衡量标准是细胞内总受体蛋白的减少,其反映了细胞内部受体的降解。因此,使用本发明抗体处理细胞(尤其是癌细胞)会引起总细胞IGF-IR的减少。在一个优选实施方式中,该减少至少为约70%,更优选至少为约80%,甚至更优选至少为约90%。
对于人类对象的治疗,所述抗体优选为人抗体,但也可为人化抗体或嵌合抗体。一种结合IGF-IR的优选人抗体是A12(参见WO2005016970)。另一种优选的人抗体是2F8(参见WO2005016970)。可用的抗体还包括与IMC-A12或IMC-2F8竞争结合到IGF-IR上的抗IGF-IR抗体,以及结合其它表位的抗体(即结合其它表位并表现出上述性质例如配体阻断、受体内化等但不与IMC-A12或IMC-2F8竞争的抗体)。依据本发明可用的中和抗IGF-IR抗体的其它非限制性实例见于Wang等人(WO2003/1000008;US2004/0018191)和Singh等人(WO2003/106621;US2003/0235582)的描述。
表1列出了本文所提及的几种抗体的核苷酸序列和氨基酸序列。
本发明可使用的抗体包括完全免疫球蛋白、免疫球蛋白的抗原结合片段以及包含免疫球蛋白抗原结合域的抗原结合蛋白。免疫球蛋白的抗原结合片段包括例如Fab、Fab′和F(ab′)2。业已研发了保留结合特异性但具有其它可取性质的其它抗体片段,其中可取性质包括例如双特异性、多价(多于两个的结合位点)和结构紧凑(例如仅有结合域)。
单链抗体包括两个可变域,但缺乏完整抗体的部分或全部恒定域,其中单链抗体源自完整抗体。因此,它们可克服使用完整抗体所带来的一些问题。例如,单链抗体的重链恒定区往往没有与其它生物分子的某些所不希望的相互作用。此外,单链抗体比完整抗体小得多,可具有比完整抗体更大的渗透性,这使得单链抗体可更有效地定位并结合到靶抗原结合位点。而且,与完整抗体相比,单链抗体相对较小的大小使其不易在接受者体内引起不需要的免疫反应。
多个单链抗体,其中每条链具有经第一肽连接物共价连接的一个VH域和一个VL域,可被至少一个或多个肽连接物共价连接形成多价的单链抗体,该单链抗体可为单特异性的或多特异性的。多价单链抗体的每条链包括一个可变轻链片段和一个可变重链片段,并经肽连接物连接到至少一条其它链上。所述肽连接物由至少15个氨基酸残基组成。氨基酸残基的最大数目是约100个。
两个单链抗体可结合起来形成双抗体,它也被称为双价二聚体。双抗体具有两条链和两个结合位点,可为单特异性的或双特异性的。双抗体的每条链包括连接到VL域上的VH域。这些域通过连接物连接起来,这些连接物短到可防止同一链上不同域之间的配对,从而驱使不同链上互补域的配对,以重新生成两个抗原结合位点。与之类似,三个单链抗体可结合起来形成三链抗体,它也被称为三价三聚体。三链抗体是以VL或VH域的氨基端直接融合到VL或VH域的羧基端而形成的(即没有任何连接物序列)。三链抗体可为单特异性的、双特异性的或三特异性的。还研发出双价的双特异性抗体,其具有每个抗原结合位点。例如,Zhu(WO01/90192)描述了具有四个结合位点的抗体,它原本具有天然抗体的结构,保留了天然抗体的效应子功能。Zhu(WO2006/020258)公开了掺入两个双抗体和Ig恒定区的双特异性抗体。
因此,本发明抗体及其片段包括但不限于特异结合抗原的天然抗体、如(Fab’)2的双价片段、如Fab的单价片段、单链抗体、单链Fv(scFv)、单域抗体、多价单链抗体、双抗体、三链抗体等。
本文以IMC-A12例示了IGF-IR拮抗剂,它是一种结合IGF细胞外结构域并阻断IGF结合的人单克隆抗体。国际公开WO 2005/016970提供了IMC-A12和类似人抗体的性质。
本发明IGF-IR拮抗剂对雄激素依赖性前列腺癌细胞的效应包括一种或多种下列效应。1)IGF在没有雄激素的情况下可介导AR活化或易位。本发明IGF-IR拮抗剂阻断IGF介导的易位。2)IGF-IR拮抗剂介导增强细胞杀伤或抑制肿瘤细胞增殖。3)AR介导的雄激素受体活化的基因表达被减少。表现出AR介导表达的基因包括例如PSA和TMPPSS2(一种跨膜丝氨酸蛋白酶)。
依据本发明,将IGF-IR拮抗剂施用给患有前列腺癌的对象,同时给予雄激素剥夺治疗(ADT,也称为激素疗法)。ADT的目的是降低体内雄性激素(雄激素,例如睾酮)的水平。主要产生于睾丸的雄激素实际上可刺激前列腺癌细胞的生长。降低雄激素水平通常可使前列腺癌缩小或生长得更慢。
ADT用于几种场合:作为不能进行手术或放疗或因癌细胞已扩散到前列腺以外不能被这些治疗治愈的患者的一线(初始)治疗;初始治疗例如手术或放疗后,如果仍存在癌症或癌症复发;在某些癌症复发高风险组的男性中作为初始治疗即放疗的补充(辅助);以及在手术或放疗(新辅药治疗)前,用于试图缩小肿瘤体积并使其它治疗更有效。依据本发明,联合施用IGF-IR拮抗剂与ADT,其中ADT是在原本就会使用ADT的任何场合下施用。IGF-IR拮抗剂是增强和/或延长ADT效果的辅药。
有数种方法用于ADT。睾丸切除术包括去除睾丸,睾丸产生90%以上的雄激素,其中多数为睾酮。除去这一来源后,多数前列腺癌会缩小。虽然睾丸切除术是永久性的,并导致一般与体内激素水平变化有关的许多副作用,但睾丸切除术可能是降低雄激素生成最廉价也最简单的方式,可作为简单的门诊方法进行。
促性腺激素释放激素(LHRH)类似物(也称为LHRH激动剂)通过降低睾丸所产生的雄激素(其中主要为睾酮),可降低睾酮水平,其效果与睾丸切除术一样有效。每月或每3、4、6或12个月注射或皮下放置LHRH类似物作为植入小的植入物。LHRH类似物的实例包括醋酸亮丙瑞林、戈舍瑞林和曲普瑞林。LHRH类似物的可能副作用与睾丸切除术的类似,主要是由激素水平变化引起的。
抗雄激素物质阻断机体利用任何雄激素的能力。甚至在睾丸切除术后或在以LHRH类似物处理过程中,肾上腺仍产生少量的雄激素。这类药物包括氟他胺、比卡鲁胺和尼鲁米特。这些药物通常以丸剂形式每日服用。
抗雄激素治疗经常与睾丸切除术或LHRH类似物结合起来。该组合称为联合雄激素剥夺(CAB)。而且,如果睾丸切除术或LHRH类似物本身不再有效,可加入抗雄激素物质。近来几项研究比较了单独使用抗雄激素物质的效果和使用LHRH激动剂的效果。多数研究发现存活率没有差别,但少数研究发现抗雄激素物质效果略小些。
抗雄激素物质对业已接受睾丸切除术治疗或以LHRH激动剂治疗的患者的副作用通常不严重。腹泻是主要的副作用,但也可发生恶心、肝部疾患和疲倦。与LHRH激动剂主要的差别在于抗雄激素物质的性副作用更少,单独使用时能维持性欲和勃起。
可施用肾上腺雄激素抑制剂,因为肾上腺所产生的低水平雄激素可能足以提供持续的刺激。去除雄激素后,一群前列腺癌细胞可变得对雄激素高度敏感,肾上腺是5%至10%外周睾酮的来源。抑制肾上腺雄激素生成最常使用的两种药剂是氨鲁米特和酮康唑。
抑制雄激素药物的其它实例包括己烯雌酚(DES)、醋酸甲地孕酮、醋酸环丙孕酮和泼尼松。雌激素曾经是晚期前列腺癌男性进行睾丸切除术的主要替代选择,但由于其可能具有副作用,其中包括血管凝块和乳房增大,雌激素已基本上被LHRH类似物和抗雄激素物质所取代。
依据本发明,在启动ADT之前、同时或之后进行IGF-IR拮抗剂的治疗疗程。IGF-IR拮抗剂的施用疗程应与ADT一致,但无需完全一致。例如,IGF-IR拮抗剂可在去除雄激素后的复原过程中施用。在本发明的一个实施方式中,去除雄激素以治疗原发性肿瘤或转移性肿瘤的24个月内,施用IGF-IR拮抗剂。在另一实施方式中,停止供应雄激素后的18个月内施用IGF-IR拮抗剂。在本发明的一个实施方式中,ADT治疗后在细胞死亡期间或行将结束时施用IGF-IR拮抗剂,它将防止或延迟AI细胞的随后派生(outgrowth)。在本发明的一个实施方式中,在去除雄激素后的两周内开始施用IGF-IR拮抗剂。在另一实施方式中,去除雄激素后的一周内开始施用。
本发明的IGF-IR拮抗剂可与中和其它参与肿瘤生长的受体的拮抗剂一起施用。尤为关注的是参与信号转导途径的受体,其中包括Akt。例如,经EGFR或HER2(erbB2)进行的信号转导被视为参与了Akt的活化。因此,本发明IGF-IR拮抗剂可与EGFR或HER2的细胞内或细胞外拮抗剂联合使用。
EGFR或HER2的拮抗剂包括结合EGFR或HER2的细胞外结构域的抗原结合蛋白,可阻断一种或多种配体的结合和/或中和配体诱导的活化。所述拮抗剂还包括结合到EGFR的配体并抑制EGFR结合到所述配体上的抗体或其它结合蛋白。EGFR的配体包括例如EGF、TGF-α、双调蛋白、发夹结合EGF(HB-EGF)和β-动物纤维素。EGF和TGF-α被视为导致EGFR介导刺激的主要内源配体,但业已表明TGF-a促进血管发生的能力更强。EGFR拮抗剂还包括抑制EGFR与其它EGFR受体亚基的二聚化(即EGFR同二聚体)或抑制EGFR与其它生长因子受体(例如HER2)异二聚化的物质。EGFR拮抗剂还包括生物分子和小分子,例如直接作用于EGFR细胞质域以抑制EGFR介导的信号转导的合成激酶抑制剂。(cetuximab;C225)是结合到EGFR并阻断配体结合的EGFR拮抗剂抗体的一个实例。是具有鼠M225可变域(例如参见WO 96/40210)和人恒定域的嵌合IgG1抗体。Zhu(WO 2005/090407)公开了一种被称为11F8的人抗EGFR抗体。其它EGFR抗体包括EMD 72000(matuzumab)、VectibixTM(panitumumab;ABX-EGF)、TheraCIM(nimotuzumab)和Hu-Max-EGFR(zalutumumab)。小分子EGFR拮抗剂的一个实例是IRESS ATM(ZD1939),它是一种喹唑啉(quinozaline)衍生物,可作为ATP模拟物抑制EGFR。参见美国专利5,616,582(Zeneca Limited)。小分子EGFR拮抗剂的另一实例是TARCEVATM(OSI-774),它是4-(取代苯基氨基)喹唑啉衍生物[6,7-双(2-甲氧基-乙氧基)-喹唑啉-4-基]-(3-乙炔基-苯基)胺盐酸盐]EGFR抑制剂。参见WO 96/30347(PfizerInc.);Moyer等人,Cancer Res.,57:4838-48(1997);Pollack等人,J.Pharmacol.,291:739-48(1999)。TARCEVATM可通过抑制EGFR的磷酸化及其下游PI3/Akt和MAP(有丝分裂原活化蛋白)激酶信号转导途径,导致p27介导的细胞周期停滞,从而发挥作用。参见Hidalgo等人在2001年5月12-15日期间在加州旧金山举行的第37届ASCO年会上所递交的摘要281。
虽然可单独施用各种拮抗剂,但在某些场合下将两种拮抗剂的功能融合到单个分子如双特异性抗体或双抑制剂是可取的。双特异性抗体经改造,可将IGF-IR特异性与不同RTK或其它细胞表面分子特异性结合起来。IGF-IR特异性与EGFR特异性或HER2特异性的结合尤为有用。Zhu(WO2006/020258)提供了一个结合IGF-IR和EGFR的双特异性抗体的实例。与之类似,可利用或可筛选得到抑制IGF-IR和第二细胞组分的小分子。正如上文所述,INSM-18(Insmed/加州大学旧金山分校)抑制IGF-DR和HER2/neu。
本发明的另一方面涉及药物组合物,其含有本发明所述拮抗剂或其药用盐、水合物或前体药物以及药用载体。这类组合物可为IGF-IR拮抗剂和ADT药剂的单独组合物或含有这二者的单一组合物。
本发明所述组合物可为固体或液体形式(溶液或混悬液)。给药途径包括例如口服、胃肠外(静脉、腹腔、皮下或肌内)、局部、经皮和吸入。
对于口服给药而言,IGF-IR拮抗剂可用例如加入惰性稀释剂或可吸收载体的液体剂型施用,或被掺入到固体剂型。口服液体或固体剂型的实例包括例如溶液剂、混悬剂、糖浆剂、乳剂、片剂、锭剂、胶囊剂(包括软明胶胶囊)等。利用例如糖衣延迟崩解或控制活性化合物的扩散,口服剂型可制备为持续释放的产品。需要时,所述组合物还可包括增溶剂。
可注射剂型的实例包括灭菌注射用液体,其包括例如溶液剂、乳剂和混悬剂。可注射剂型还包括固体,例如注射前需重建、溶解或悬浮的灭菌粉剂。将所需量的EGF-IR拮抗剂和/或ADT药剂掺入到适宜的溶剂中并添加各种上文列举的其它所需成分,经过滤灭菌后,制备成灭菌注射用溶液。载体一般包括例如灭菌水、生理盐水、注射用有机酯、花生油、植物油等。可在可施用形式中包含缓冲剂、防腐剂等。通过加热、辐射、微过滤和/或加入各种抗细菌剂和抗真菌剂如对羟基苯甲酸酯、三氯叔丁醇、苯酚、山梨酸、硫柳汞等,可制备灭菌制剂。
对于局部给药,可单独或同时施用本发明的IGF-IR拮抗剂和ADT药剂的凝胶剂、霜剂、软膏剂或涂布剂。用于该用途的典型载体包括疏水或亲水碱、油状或醇液体和干燥粉末。IGF-IR拮抗剂和ADT药剂还可被掺入到凝胶或基质中用于膏药,视情况以经皮载体进行化合物的可控释放。IGF-IR拮抗剂和ADT药剂还可通过已知方法制备,用于直肠给药。
对于吸入给药,本发明的IGF-IR拮抗剂和ADT药剂可溶解于或悬浮于或被吸附于适宜的载体,用于雾化器、气溶剂或干粉吸入器。
适宜的剂量可由医师或有资格的医务人员决定,取决于例如待治疗疾病性质、给药途径、治疗时间和患者情况等因素。IGF-IR拮抗剂和ADT药剂可按需要施用,以获得所需的治疗效果。给药频率取决于例如所使用剂型的性质。本领域技术人员会理解剂量和治疗频率取决于个体患者的耐受性和所使用的阻断剂或抑制剂的药理学和药物代谢动力学性质。理想情况下,人们希望所使用的药剂实现可饱和的药物代谢动力学。抗IGF-IR抗体的负荷剂量的范围可为约10mg/m2到约1000mg/m2,优选为约200mg/m2到约400mg/m2。施用负荷剂量后可另外给予数次约200mg/m2到约400mg/m2范围内的每日剂量或每周剂量。IGF-IR抗体的例示性剂量是400mg/m2的负载剂量和250mg/m2的每周输注剂量。(欲了解人和其它哺乳动物mg/kg和mg/m2之间的转换,请参看Freireich,EJ等人,1966,Cancer Chemother.Rep.50:219-44)监测患者的副反应,副反应严重时则中断治疗。ADT药剂的有效剂量为本领域所熟知。
本领域技术人员还会知道如何监测治疗进程,以确定有效的剂量。对前列腺癌而言,其中一种方式是监测PSA水平。另一种方式是监测前列腺酸性磷酸酶(PAP)。监测前列腺癌的其它方法包括超声、计算层析X射线照相术(CT)、磁共振成像(MRI)等。还可检测组织样本中AR的表达和细胞分布以及存活蛋白和/或TUBB的表达。
在本发明的某些实施方式中,联合IGF-IR拮抗剂和ADT的治疗可使用一种或多种抗肿瘤剂。例如,正如上文所指出,ADT通常被用作前列腺肿瘤放射治疗的新辅药。当抗肿瘤剂是辐射时,受治疗患者的辐射源可为外部的(外部照射放射治疗-EBRT)或内部的(近程放射治疗-BT)
所述抗肿瘤剂可为烷化剂或抗代谢物。烷化剂的实例包括但不限于顺铂、环磷酰胺、美法仑和达卡巴嗪。抗代谢物的实例包括但不限于多柔比星、柔红霉素、帕利他西和吉西他滨。
可用的抗肿瘤剂还包括有丝分裂抑制剂,例如紫杉烷、多西紫杉醇和帕利他西(paclitaxil)。拓扑异构酶抑制剂是另一类可与本发明抗体联合使用的抗肿瘤剂。它们包括拓扑异构酶I或拓扑异构酶II的抑制剂。拓扑异构酶I抑制剂包括伊立替康(CPT-11)、氨基喜树碱、喜树碱、DX-8951f和托泊替康。拓扑异构酶II抑制剂包括依托泊苷(VP-16)和替尼泊苷(VM-26)。目前正在评估其它物质的拓扑异构酶抑制剂活性和作为抗肿瘤剂的有效性。在一个优选实施方式中,所述拓扑异构酶抑制剂是伊立替康(CPT-11)。
在本申请全文中,引用了各种出版物、参考文本、教材、技术手册、专利和专利申请。这些出版物、专利、专利申请和其它文件的教导和公开内容通过引用的方式全部并入本申请,以更加充分地描述本发明所属的技术领域状态。
应理解并应预料到的是,本领域技术人员可对本文所公开的发明原则作出各种变动,而这些改变被涵盖在本发明的范围内。
下文的实施例进一步阐述了本发明,但不应理解为以任何方式限制本发明的范围。常规方法(例如用于载体和质粒构建以及抗体和抗体片段表达的方法)的详细描述可得自各种出版物,其中包括Sambrook,J等人,(1989)Molecular Cloning:A Laboratory Manual,2nded.,Cold Spring HarborLaboratory Press;Coligan,J等人.(1994)Current Protocols in Immunology,Wiley & Sons,Incorporated;Enna,SJ等人.(1991)Current Protocols inPharmacology,Wiley & Sons,Bonifacino和J.S.等人.(1999)Current Protocolsin Cell Biology,Wiley & Sons。本文所提及的所有参考文献全文并入本文。
实施例
IGF-IR的拮抗作用抑制ADT后的肿瘤再生长。
建立临床前模型以测试利用人单克隆IGF-IR抗体(IMC-A12)和去势在去势后抑制IGF-IR信号转导对前列腺癌复发的效果。在该研究中,将LuCaP35(雄激素响应性人前列腺癌细胞系)异种移植物皮下植入到雄性SCID小鼠的胁部。LuCaP35可转化为雄激素不依赖性的状态,可用于评估与该过程相关的分子变化。起初,PSA水平下降,肿瘤体积减小,但60-120天后,观察到肿瘤的再生。LuCaP35具有转移潜能,可导致混合骨损伤。生长在完整雄性小鼠中的LuCaP35是雄激素敏感性的,对去除雄激素作出的反应与患者身上通常见到的反应相同。
LuCaP35细胞被皮下植入到雄性SCID小鼠的胁部。当肿瘤体积达到ca.400mm3时,小鼠被去势,将其分成3组,每组20只。组1对照只接受去势处理;组2接受去势处理,去势后七天,每周3次腹腔注射IMC-A12,持续14天;组3去势后14天接受IMC-A12,持续14天。给予IMC-A1214天后,没有再给予其他治疗。去势后1周或2周开始给予2周的A12,这些时间是基于LuCaP35细胞系的已发布数据,其表明去势诱导的最大程度的凋亡发生在去势四天以内(Corey,E等人,2003,Prostate 99:392-401)。由于抑制IGF-IR信号转导会导致细胞周期停滞和防止细胞发生凋亡,因此决定在去势后凋亡“完全结束”后开始施用A12(Corey等人,2003;Tennant,M等人,2003,Prostate,56:115-22)。
每周从眼窝窦收集血样。分离血清,使用IMx Total PSA Assay(AbbottLaboratories,Abbott Park,IL)测定PSA水平。每周测量两次肿瘤,以公式:体积=LXW2/2估算肿瘤体积。若肿瘤达到1000mm3或动物体重的减轻超过原体重的20%时处死小鼠。处死动物前1小时,腹腔注射BrdU,以测定体内肿瘤细胞增殖速率。
去势后,所有小鼠的肿瘤生长最初都发生停滞。(图1)以IMC-A12处理的小鼠中,肿瘤体积随研究的进行下降,没有发生肿瘤特异性的死亡。在未处理的小鼠群中,第5周时肿瘤平均体积的增加变得明显起来,其中第4周开始出现肿瘤特异性死亡(处死),并在随后的研究中继续发生肿瘤特异性死亡。请注意:对于没有接受IMC-A12的小鼠,平均肿瘤体积的曲线被人为压低,这是因为每次死亡从平均肿瘤组中除去了大的肿瘤。
监测LuCaP35异种移植小鼠的PSA水平。所有小鼠最初对去除激素均作出反应,并在去势后第一周观察到类似的PSA水平下降(图2)。在只接受去势处理的小鼠中,PSA最初下降后,随后在大约第二周时开始升高。相反,接受IMC-A12处理的去势小鼠的PSA水平没有升高,仍维持在基线附近。
经测定肿瘤体积和PSA增加,该研究证实与单独去势相比,利用IGF-IR抗体IMC-A12在去势后阻断IGF-IR信号转导及表达会使肿瘤体积明显下降(p<0.001),并显著延迟出现AI肿瘤再生的时间(p<0.001)。
在只接受去势处理的对照动物中,肿瘤生长中断了大约4周,但之后升高。在只接受去势处理的动物中,一半以上因去势后9周时出现肿瘤生长而被处死,大多数动物到16周结束时均被处死。相反,接受IMC-A12的所有动物在16周后均存活。
体内结果证实抑制IGF-IR信号转导的有效性。值得注意的是,IGF-IR拮抗剂连续施用了14天,随后停止施用。在另一项研究中,其中A12以类似的方式施用,施用A12后在研究后期观察到部分肿瘤的再生。组2和组3的40只动物中有2只因研究结束时肿瘤体积过大不得不被处死。IGF-IR拮抗剂的维持剂量会无限期地延迟肿瘤再生的时间。
为了研究A12处理的肿瘤的体积下降与AR易位是否相关,依照图5所示对来自三组的每只动物的肿瘤进行AR免疫组化。细胞核AR染色分数分配给来自每个肿瘤的100个细胞核。两人以盲法为细胞核计分,两个计分的均值作为该组织的分数。肿瘤体积与核AR强度有显著阳性相关性,r=0.66,p≤0.01。
IGF-IR的拮抗作用抑制AR易位。
评测IGF-IR刺激和拮抗对雄激素受体定位的效应。在存在或不存在IMC-A12、加或不加IGF-1刺激的情况下培养LuCaP35细胞(图3)。从处理细胞制备细胞质和细胞核提取物,并以PAGE检测。利用ERK水平实现相等的泳道上样量。以IGF-1刺激的细胞中,IMC-A12引起细胞核内雄激素受体比例下降。
还通过免疫组化评测雄激素受体的易位。(图4)。将LuCaP35(AD)异种移植肿瘤生长在完整雄性小鼠体内,将LuCaP35V(AI)异种移植肿瘤生长在去势小鼠体内。受试小鼠以IMC-A12处理。制备肿瘤的连续切片,并以AR特异抗体进行染色。在完整对照小鼠中,AR在雄激素依赖性的LuCaP35组织中主要定位于细胞核。在来自以IMC-A12处理的受试动物组织中,观察到AR染色位于细胞质中。在去势对照小鼠中,AR在雄激素非依赖性的LuCaP35v细胞中分布于细胞核和细胞质之间。在来自以IMC-A12处理的受试动物组织中,AR染色主要位于细胞质中。
在一个类似实验中,利用荧光显微镜研究组织培养中的AR定位。以10-8M DHT处理导致AR明显从细胞质重新分配到细胞核。单独使用IGF-1处理导致AR部分被重分配至细胞核,IMC-A12完全逆转了这一效应。
IGF-IR的拮抗作用抑制AR依赖性的基因表达。
凋亡抑制剂--存活蛋白在数种前列腺癌细胞系中强烈表达。在具有完整雄激素受体的细胞中,以DHT刺激雄激素可增加存活蛋白表达。还观察到AKT介导了存活蛋白的表达,这是因为IGF诱导的AKT信号转导即使在AR阴性的细胞系中也增加了存活蛋白的表达。检测存活蛋白差异表达的基因芯片实验表明IMC-A12处理降低了存活蛋白的表达。
依据前人方法[ref]利用源自前列腺表达数据库(PEDB)的克隆构建定制cDNA微阵列,该数据库是面向公众开放的人前列腺表达序列标签(EST)数据的序列库。(Nelson,P.S.等人,2002,Nucl.Acids Res.30:218-20)。Cy3和Cy5荧光染料标记方法、微阵列玻片杂交方法和阵列处理方法已有描述(Tusher,V.等人,2001,Proc.Natl.Acad.Sci.U.S.A.98:5116-21)。
每一实验组收集三个肿瘤。为了提供用于cDNA微阵列的参考标准RNA,从生长在添加有10%胎牛血清(FBS;Life Technologies,Rockville,MD)的不含染料的RPMI-1640培养基中的对数期LNCaP、DU145、PC3和CWR22rV1细胞系(美国典型培养物保藏中心,Manassas,VA)分离并收集等量的总RNA。利用Trizol(Invitrogen,SanDiego,CA)从收集的肿瘤和细胞系中分离总RNA。使用Ambion MessageAmpTM II Amplification Kit(AmbionInc,Austin,TX)进行一轮mRNA的扩增,并经琼脂糖凝胶电泳和A260吸光度评估样品的质量和数量。标记杂交探针,依据前人方法进行阵列实验的质量对照(Tusher,V.等人,2001)。使用SAM方法(Chu,G.,Narasimhan,B.,Tibshirani,R.& Tusher,V.,2002,Significance analysis of microarrays(sam)software,Stanford University)测定与处理组相关的基因表达的差异,其中错误发现率(FDR)≤10%视为差异显著(37)。使用Cluster3.0软件(de Hoon等人,2004,Bioinformatics 20:1453-4)经基因和样品的物监督系统聚类来评测样品之间的相似性,并用Tree View(Page,R.D.,1996,Comput.Appl.Biosci.12:357-8)观看样品之间的相似性。
依据前人的引物和方法(Wu,J等人,2006,Clin.Cancer Res.12:6153-60)经PCR检测存活蛋白和TUBB。纯化靶cDNA的标准PCR片段。使用10ng/μl至10-3pg/μl的连续标准稀释液进行实时PCR,以产生标准曲线。使用来自每一组收集肿瘤的1μg总RNA以Superscript First Strand Synthesis System(Invitrogen)进行cDNA第一链合成。依据厂家实验方案(Roche,Nutley,NJ)使用Roche Lightcycler在20μl反应混合物中进行实时RT-PCR,该反应混合物由1μl cDNA第一链、特异引物组和Lightcycler FastStart DNA MasterPlus SYBR Green组成。RT-PCR产物以Lightcycler software v3.5进行熔解曲线分析。经琼脂糖凝胶电泳确认扩增子大小。每份样品重复测量2次。
去势并结合IGF-IR拮抗剂可在肿瘤复发前导致AR基因表达下降。在cDNA微阵列上分析来自每组在表2所示时间范围内所收集肿瘤的RNA样品。SAM的双样本t检验(q-值≥100%)未发现组1在各时间段内有基因发生显著改变。此外,已知受雄激素调控的基因的无监督系统聚类没有在两个时间段内分开。这点可能并不出人意料,因为与组2和组3在第40天相比,该组的许多动物有PSA复发和升高的细胞核AR分数。相反,A12处理的肿瘤在两个时间段内有明显的基因表达变化。在阵列上有足够数据进行检测的3170个独特基因中,与早期相比,后期(此时肿瘤开始复发)有21个发生上调(包括许多受雄激素调控的基因),41个发生下调,其中q值≤10.0%(图6)。而且,已知受雄激素调控的基因的无监督系统聚类清晰地将A12处理的两个时间段区分为两个不同的聚类。这些数据表明细胞核的AR表达与AR转录活性和前列腺癌经AR活化而发生进展有关。
存活蛋白和β微管蛋白的表达被IGF-IR拮抗剂显著降低。微阵列研究测得存活蛋白表达在以A12抗体处理的肿瘤中下降。正如图7A所示,提取自肿瘤的RNA的Qt-RTPCR证实存活蛋白拷贝数与肿瘤体积有显著的正相关性,r=0.66,p≤0.01。近来推测参与IGF-IR诱导的肿瘤形成的第二个基因是β-微管蛋白,TUBB(O′Connor,R.,2003,Horm.Metab.Res.35:771-7;Geller,J等人,1984,J.Urol.132:693-700)。微阵列显示TUBB发生下降,如图7B所示,TUBB在肿瘤样品中与肿瘤体积呈正相关,r=0.59,p≤0.01;与组1相比,TUBB在组2和组3中显著下降。在组1的微阵列上不随时间发生变化但在组2和组3动物的两个早期时间段内发生下降的第三个基因是PSA。经血清PSA水平的类似方式证实PSA表达的变化。
增殖和凋亡
采用Apop-Direct试剂盒以末端脱氧核苷酸转移酶介导的缺口末端标记(TUNEL)测定和丙锭(propidium,PI)染色(BD BioScience)依据前人方法(Wu,J.D等人,2005,Clin.Cancer Res.,11:3065-74)测定凋亡。简而言之,先后以10%中性缓冲甲醛(NBF)和70%乙醇在-20℃下对来自单细胞混悬液的1×106个细胞进行30min的固定。洗涤数次后,细胞以0.1%Triton X-100进行渗透,并以结合FITC的dUTP和末端脱氧核糖核酸转移酶-(TdT)在37℃下进行1h的温育,细胞随后以PI/RNase缓冲液(100μg/ml PI,50μg/mlRNase)在室温下温育60min。使用BD FACscan经流式细胞术分析样品。数据以CellQuestPRO软件进行分析。还依据厂家推荐说明,以Apop-Tag试剂盒(Millipore Co,MA)对甲醛固定组织经TUNEL检测测定凋亡。测定每张组织切片的每300个细胞的凋亡细胞。
正如表3所示,组1肿瘤的增殖显著大于组2和组3,p≤0.01。相反,TUNEL染色所测得的凋亡在组1中高于组2和组3,见表3。
序列表
<110>英克隆系统公司
华盛顿大学
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450 455 460
cac aac cac tac acg cag aag agc ctc tcc ctg tct ccg ggt aaa tga 1440
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
465 470 475
<210>4
<211>479
<212>PRT
<213>Homo sapiens
<400>4
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
20 25 30
Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe
35 40 45
Ser Ser Tyr Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
50 55 60
Glu Trp Met Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala
65 70 75 80
Gln Lys Phe Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser
85 90 95
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Ala Pro Leu Arg Phe Leu Glu Trp Ser Thr Gln
115 120 125
Asp His Tyr Tyr Tyr Tyr Tyr Met Asp Val Trp Gly Lys Gly Thr Thr
130 135 140
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
145 150 155 160
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
165 170 175
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
180 185 190
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
195 200 205
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
210 215 220
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
225 230 235 240
Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His
245 250 255
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
260 265 270
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
275 280 285
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
290 295 300
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
305 310 315 320
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
325 330 335
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
340 345 350
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
355 360 365
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
370 375 380
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
385 390 395 400
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
405 410 415
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
420 425 430
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
435 440 445
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
450 455 460
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
465 470 475
<210>5
<211>327
<212>DNA
<213>Homo sapiens
<220>
<221>CDS
<222>(1)..(327)
<400>5
tct tct gag ctg act cag gac cct gct gtg tct gtg gcc ttg gga cag 48
Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln
1 5 10 15
aca gtc agg atc aca tgc caa gga gac agc ctc aga agc tat tat gca 96
Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala
20 25 30
agc tgg tac cag cag aag cca gga cag gcc cctgta ctt gtc atc tat 144
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr
35 40 45
ggt aaa aac aac cgg ccc tca ggg atc cca gac cga ttc tct ggc tcc 192
Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
agc tca gga aac aca gct tcc ttg acc atc act ggg gct cag gcg gaa 240
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
65 70 75 80
gat gag gct gac tat tac tgt aac tcc cgg gac aac agt gat aac cgt 288
Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Asn Ser Asp Asn Arg
85 90 95
ctg ata ttt ggc ggc ggg acc aag ctg acc gtc ctc agt 327
Leu Ile Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Ser
100 105
<210>6
<211>109
<212>PRT
<213>Homo sapiens
<400>6
Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr
35 40 45
Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Asn Ser Asp Asn Arg
85 90 95
Leu Ile Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Ser
100 105
<210>7
<211>702
<212>DNA
<213>Homo sapiens
<220>
<221>CDS
<222>(1)..(699)
<400>7
atg gga tgg tca tgt atc atc ctt ttt cta gta gca act gca act gga 48
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
gta cat tca tct tct gag ctg act cag gac cct gct gtg tct gtg gcc 96
Val His Ser Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala
20 25 30
ttg gga cag aca gtc agg atc aca tgc caa gga gac agc ctc aga agc 144
Leu Gly Gln Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser
35 40 45
tat tat gca agc tgg tac cag cag aag cca gga cag gcc cct gta ctt 192
Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu
50 55 60
gtc atc tat ggt aaa aac aac cgg ccc tca ggg atc cca gac cga ttc 240
Val Ile Tyr Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe
65 70 75 80
tct ggc tcc agc tca gga aac aca gct tcc ttg acc atc act ggg gct 288
Ser Gly Ser Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala
85 90 95
cag gcg gaa gat gag gct gac tat tac tgt aac tcc cgg gac aac agt 336
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Asn Ser
100 105 110
gat aac cgt ctg ata ttt ggc ggc ggg acc aag ctg acc gtc ctc agt 384
Asp Asn Arg Leu Ile Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Ser
115 120 125
cag ccc aag gct gcc ccc tcg gtc act ctg ttc ccg ccc tcc tct gag 432
Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu
130 135 140
gag ctt caa gcc aac aag gcc aca ctg gtg tgt ctc ata agt gac ttc 480
Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe
145 150 155 160
tac ccg gga gcc gtg aca gtg gcc tgg aag gca gat agc agc ccc gtc 528
Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val
165 170 175
aag gcg gga gtg gag acc acc aca ccc tcc aaa caa agc aac aac aag 576
Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys
180 185 190
tac gcg gcc agc agc tat ctg agc ctg acg cct gag cag tgg aag tcc 624
Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser
195 200 205
cac aga agc tac agc tgc cag gtc acg cat gaa ggg agc acc gtg gag 672
His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu
210 215 220
aag aca gtg gcc cct gca gaa tgc tct tga 702
Lys Thr Val Ala Pro Ala Glu Cys Ser
225 230
<210>8
<211>233
<212>PRT
<213>Homo sapiens
<400>8
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala
20 25 30
Leu Gly Gln Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser
35 40 45
Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu
50 55 60
Val Ile Tyr Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe
65 70 75 80
Ser Gly Ser Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala
85 90 95
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Asn Ser
100 105 110
Asp Asn Arg Leu Ile Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Ser
115 120 125
Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu
130 135 140
Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe
145 150 155 160
Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val
165 170 175
Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys
180 185 190
Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser
195 200 205
His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu
210 215 220
Lys Thr Val Ala Pro Ala Glu Cys Ser
225 230
<210>9
<211>327
<212>DNA
<213>Homo sapiens
<220>
<221>CDS
<222>(1)..(327)
<400>9
tct tct gag ctg act cag gac cct gct gtg tct gtg gcc ttg gga cag 48
Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln
1 5 10 15
aca gtc agg atc aca tgc caa gga gac agc ctc aga agc tat tat gca 96
Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala
20 25 30
acc tgg tac cag cag aag cca gga cag gcc cct att ctt gtc atc tat 144
Thr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ile Leu Val Ile Tyr
35 40 45
ggt gaa aat aag cgg ccc tca ggg atc cca gac cga ttc tct ggc tcc 192
Gly Glu Asn Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
agc tca gga aac aca gct tcc ttg acc atc act ggg gct cag gca gaa 240
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
65 70 75 80
gat gag gct gac tac tat tgt aaa tct cgg gat ggc agt ggt caa cat 288
Asp Glu Ala Asp Tyr Tyr Cys Lys Ser Arg Asp Gly Ser Gly Gln His
85 90 95
ctg gtg ttc ggc gga ggg acc aag ctg acc gtc cta ggt 327
Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
100 105
<210>10
<211>109
<212>PRT
<213>Homo sapiens
<400>10
Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala
20 25 30
Thr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ile Leu Val Ile Tyr
35 40 45
Gly Glu Asn Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Lys Ser Arg Asp Gly Ser Gly Gln His
85 90 95
Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
100 105
<210>11
<211>702
<212>DNA
<213>Homo sapiens
<220>
<221>CDS
<222>(1)..(699)
<400>11
atg gga tgg tca tgt atc atc ctt ttt cta gta gca act gca act gga 48
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
gta cat tca tct tct gag ctg act cag gac cct gct gtg tct gtg gcc 96
Val His Ser Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala
20 25 30
ttg gga cag aca gtc agg atc aca tgc caa gga gac agc ctc aga agc 144
Leu Gly Gln Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser
35 40 45
tat tat gca acc tgg tac cag cag aag cca gga cag gcc cct att ctt 192
Tyr Tyr Ala Thr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ile Leu
50 55 60
gtc atc tat ggt gaa aat aag cgg ccc tca ggg atc cca gac cga ttc 240
Val Ile Tyr Gly Glu Asn Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe
65 70 75 80
tct ggc tcc agc tca gga aac aca gct tcc ttg acc atc act ggg gct 288
Ser Gly Ser Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala
85 90 95
cag gca gaa gat gag gct gac tac tat tgt aaa tct cgg gat ggc agt 336
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Lys Ser Arg Asp Gly Ser
100 105 110
ggt caa cat ctg gtg ttc ggc gga ggg acc aag ctg acc gtc cta ggt 384
Gly Gln His Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
115 120 125
cag ccc aag gct gcc ccc tcg gtc act ctg ttc ccg ccc tcc tct gag 432
Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu
130 135 140
gag ctt caa gcc aac aag gcc aca ctg gtg tgt ctc ata agt gac ttc 480
Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe
145 150 155 160
tac ccg gga gcc gtg aca gtg gcc tgg aag gca gat agc agc ccc gtc 528
Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val
165 170 175
aag gcg gga gtg gag acc acc aca ccc tcc aaa caa agc aac aac aag 576
Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys
180 185 190
tac gcg gcc agc agc tat ctg agc ctg acg cct gag cag tgg aag tcc 624
Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser
195 200 205
cac aga agc tac agc tgc cag gtc acg cat gaa ggg agc acc gtg gag 672
His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu
210 215 220
aag aca gtg gcc cct gca gaa tgc tct tga 702
Lys Thr Val Ala Pro Ala Glu Cys Ser
225 230
<210>12
<211>233
<212>PRT
<213>Homo sapiens
<400>12
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala
20 25 30
Leu Gly Gln Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser
35 40 45
Tyr Tyr Ala Thr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ile Leu
50 55 60
Val Ile Tyr Gly Glu Asn Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe
65 70 75 80
Ser Gly Ser Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala
85 90 95
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Lys Ser Arg Asp Gly Ser
100 105 110
Gly Gln His Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
115 120 125
Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu
130 135 140
Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe
145 150 155 160
Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val
165 170 175
Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys
180 185 190
Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser
195 200 205
His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu
210 215 220
Lys Thr Val Ala Pro Ala Glu Cys Ser
225 230
<210>13
<211>15
<212>DNA
<213>Homo sapiens
<220>
<221>CDS
<222>(1)..(15)
<400>13
agc tat gct atc agc 15
Ser Tyr Ala Ile Ser
1 5
<210>14
<211>5
<212>PRT
<213>Homo sapiens
<400>14
Ser Tyr Ala Ile Ser
1 5
<210>15
<211>51
<212>DNA
<213>Homo sapiens
<220>
<221>CDS
<222>(1)..(51)
<400>15
ggg atc atc cct atc ttt ggt aca gca aac tac gca cag aag ttc cag 48
Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe Gln
1 5 10 15
ggc 51
Gly
<210>16
<211>17
<212>PRT
<213>Homo sapiens
<400>16
Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210>17
<211>63
<212>DNA
<213>Homo sapiens
<220>
<221>CDS
<222>(1)..(63)
<400>17
gcg cca tta cga ttt ttg gag tgg tcc acc caa gac cac tac tac tac 48
Ala Pro Leu Arg Phe Leu Glu Trp Ser Thr Gln Asp His Tyr Tyr Tyr
1 5 10 15
tac tac atg gac gtc 63
Tyr Tyr Met Asp Val
20
<210>18
<211>21
<212>PRT
<213>Homo sapiens
<400>18
Ala Pro Leu Arg Phe Leu Glu Trp Ser Thr Gln Asp His Tyr Tyr Tyr
1 5 10 15
Tyr Tyr Met Asp Val
20
<210>19
<211>33
<212>DNA
<213>Homo sapiens
<220>
<221>CDS
<222>(1)..(33)
<400>19
caa gga gac agc ctc aga agc tat tat gca agc 33
Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser
1 5 10
<210>20
<211>11
<212>PRT
<213>Homo sapiens
<400>20
Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser
1 5 10
<210>21
<211>21
<212>DNA
<213>Homo sapiens
<220>
<221>CDS
<222>(1)..(21)
<400>21
ggt aaa aac aac cgg ccc tca 21
Gly Lys Asn Asn Arg Pro Ser
1 5
<210>22
<211>7
<212>PRT
<213>Homo sapiens
<400>22
Gly Lys Asn Asn Arg Pro Ser
1 5
<210>23
<211>33
<212>DNA
<213>Homo sapiens
<220>
<221>CDS
<222>(1)..(33)
<400>23
aac tcc cgg gac aac agt gat aac cgt ctg ata 33
Asn Ser Arg Asp Asn Ser Asp Asn Arg Leu Ile
1 5 10
<210>24
<211>11
<212>PRT
<213>Homo sapiens
<400>24
Asn Ser Arg Asp Asn Ser Asp Asn Arg Leu Ile
1 5 10
<210>25
<211>33
<212>DNA
<213>Homo sapiens
<220>
<221>CDS
<222>(1)..(33)
<400>25
caa gga gac agc ctc aga agc tat tat gca acc 33
Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Thr
1 5 10
<210>26
<211>11
<212>PRT
<213>Homo sapiens
<400>26
Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Thr
1 5 10
<210>27
<211>21
<212>DNA
<213>Homo sapiens
<220>
<221>CDS
<222>(1)..(21)
<400>27
ggt gaa aat aag cgg ccc tca 21
Gly Glu Asn Lys Arg Pro Ser
1 5
<210>28
<211>7
<212>PRT
<213>Homo sapiens
<400>28
Gly Glu Asn Lys Arg Pro Ser
1 5
<210>29
<211>33
<212>DNA
<213>Homo sapiens
<220>
<221>CDS
<222>(1)..(33)
<400>29
aaa tct cgg gat ggc agt ggt caa cat ctg gtg 33
Lys Ser Arg Asp Gly Ser Gly Gln His Leu Val
1 5 10
<210>30
<211>11
<212>PRT
<213>Homo sapiens
<400>30
Lys Ser Arg Asp Gly Ser Gly Gln His Leu Val
1 5 10
<210>31
<211>24
<212>DNA
<213>Homo sapiens
<220>
<221>CDS
<222>(1)..(24)
<400>31
agc agt ggt gat tac tac tgg agt 24
Ser Ser Gly Asp Tyr Tyr Trp Ser
1 5
<210>32
<211>8
<212>PRT
<213>Homo sapiens
<400>32
Ser Ser Gly Asp Tyr Tyr Trp Ser
1 5
<210>33
<211>48
<212>DNA
<213>Homo sapiens
<220>
<221>CDS
<222>(1)..(48)
<400>33
tac atc tat tac agt ggg agc acc gac tac aac ccg tcc ctc aag agt 48
Tyr Ile Tyr Tyr Ser Gly Ser Thr Asp Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210>34
<211>16
<212>PRT
<213>Homo sapiens
<400>34
Tyr Ile Tyr Tyr Ser Gly Ser Thr Asp Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210>35
<211>33
<212>DNA
<213>Homo sapiens
<220>
<221>CDS
<222>(1)..(33)
<400>35
gtg tcg att ttt gga gtg ggg aca ttt gac tac 33
Val Ser Ile Phe Gly Val Gly Thr Phe Asp Tyr
1 5 10
<210>36
<211>11
<212>PRT
<213>Homo sapiens
<400>36
Val Ser Ile Phe Gly Val Gly Thr Phe Asp Tyr
1 5 10
<210>37
<211>363
<212>DNA
<213>Homo sapiens
<220>
<221>CDS
<222>(1)..(363)
<400>37
cag gtg cag ctg cag gag tcg ggc cca gga ctg gtg aag cct tca cag 48
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
acc ctg tcc ctc acc tgc act gtc tct ggt ggc tcc atc agc agt ggt 96
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly
20 25 30
gat tac tac tgg agt tgg atc cgc cag ccc cca ggg aag ggc ctg gag 144
Asp Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu
35 40 45
tgg att ggg tac atc tat tac agt ggg agc acc gac tac aac ccg tcc 192
Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asp Tyr Asn Pro Ser
50 55 60
ctc aag agt cga gtc acc atg tcc gta gac acg tcc aag aat cag ttt 240
Leu Lys Ser Arg Val Thr Met Ser Val Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
tcc ctg aag gtc aac tct gtg acc gcc gca gac acg gct gtg tat tac 288
Ser Leu Lys Val Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
tgt gcg aga gtg tcg att ttt gga gtg ggg aca ttt gac tac tgg ggc 336
Cys Ala Arg Val Ser Ile Phe Gly Val Gly Thr Phe Asp Tyr Trp Gly
100 105 110
cag ggc acc ctg gtc acc gtc tca agc 363
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210>38
<211>121
<212>PRT
<213>Homo sapiens
<400>38
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly
20 25 30
Asp Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asp Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Arg Val Thr Met Ser Val Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Val Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Val Ser Ile Phe Gly Val Gly Thr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210>39
<211>30
<212>DNA
<213>Homo sapiens
<220>
<221>CDS
<222>(1)..(30)
<400>39
agg gcc agt cag agt gtt agc agc tac tta 30
Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu
1 5 10
<210>40
<211>10
<212>PRT
<213>Homo sapiens
<400>40
Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu
1 5 10
<210>41
<211>21
<212>DNA
<213>Homo sapiens
<220>
<221>CDS
<222>(1)..(21)
<400>41
gat gca tcc aac agg gcc act 21
Asp Ala Ser Asn Arg Ala Thr
1 5
<210>42
<211>7
<212>PRT
<213>Homo sapiens
<400>42
Asp Ala Ser Asn Arg Ala Thr
1 5
<210>43
<211>24
<212>DNA
<213>Homo sapiens
<220>
<221>CDS
<222>(1)..(24)
<400>43
cac cag tat ggt agc aca cct ctc 24
His Gln Tyr Gly Ser Thr Pro Leu
1 5
<210>44
<211>8
<212>PRT
<213>Homo sapiens
<400>44
His Gln Tyr Gly Ser Thr Pro Leu
1 5
<210>45
<211>321
<212>DNA
<213>Homo sapiens
<220>
<221>CDS
<222>(1)..(321)
<400>45
gaa att gtg atg aca cag tct cca gcc acc ctg tct ttg tct cca ggg 48
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Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
tta gcc tgg tac caa cag aaa cct ggc cag gct ccc agg ctc ctc atc 144
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
tat gat gca tcc aac agg gcc act ggc atc cca gcc agg ttc agt ggc 192
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
agt ggg tct ggg aca gac ttc act ctc acc atc agc agc cta gag cct 240
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
gaa gat ttt gca gtg tat tac tgt cac cag tat ggt agc aca cct ctc 288
Glu Asp Phe Ala Val Tyr Tyr Cys His Gln Tyr Gly Ser Thr Pro Leu
85 90 95
act ttc ggc gga ggg acc aag gcg gag atc aaa 321
Thr Phe Gly Gly Gly Thr Lys Ala Glu Ile Lys
100 105
<210>46
<211>107
<212>PRT
<213>Homo sapiens
<400>46
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys His Gln Tyr Gly Ser Thr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Ala Glu Ile Lys
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<210>47
<211>357
<212>DNA
<213>Mus musculus
<220>
<221>CDS
<222>(1)..(357)
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Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln
1 5 10 15
agc ctg tcc atc acc tgc aca gtc tct ggt ttc tca tta act aac tat 96
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr
20 25 30
ggt gta cac tgg gtt cgc cag tct cca gga aag ggt ctg gag tgg ctg 144
Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
gga gtg ata tgg agt ggt gga aac aca gac tat aat aca cct ttc aca 192
Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr
50 55 60
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Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe
65 70 75 80
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Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly
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Thr Leu Val Thr Val Ser Ala
115
<210>48
<211>119
<212>PRT
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Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
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<210>49
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Asp Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly
1 5 10 15
gaa aga gtc agt ttc tcc tgc agg gcc agt cag agt att ggc aca aac 96
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn
20 25 30
ata cac tgg tat cag caa aga aca aat ggt tct cca agg ctt ctc ata 144
Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile
35 40 45
aag tat gct tct gag tct atc tct ggg atc cct tcc agg ttt agt ggc 192
Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
agt gga tca ggg aca gat ttt act ctt agc atc aac agt gtg gag tct 240
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser
65 70 75 80
gaa gat att gca gat tat tac tgt caa caa aat aat aac tgg cca acc 288
Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr
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<210>50
<211>107
<212>PRT
<213>Mus musculus
<400>50
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20 25 30
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35 40 45
Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser
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Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105
Claims (9)
1.IGF-IR拮抗剂与促黄体激素释放激素(LHRH)类似物或肾上腺雄激素抑制剂在制备用于抑制雄激素依赖性癌生长的药物中的应用。
2.如权利要求1所述的应用,其中所述雄激素依赖性癌是前列腺癌。
3.如权利要求1所述的应用,其中促黄体激素释放激素(LHRH)类似物或肾上腺雄激素抑制剂和所述IGF-IR拮抗剂大约在相同时间施用。
4.如权利要求1所述的应用,其中所述IGF-IR拮抗剂在施用促黄体激素释放激素(LHRH)类似物或肾上腺雄激素抑制剂之后且雄激素依赖性癌变成雄激素非依赖性癌之前施用。
5.如权利要求1所述的应用,其中所述IGF-IR拮抗剂是细胞外拮抗剂。
6.如权利要求5所述的应用,其中所述细胞外拮抗剂是结合IGF-IR的抗体。
7.如权利要求5所述的应用,其中所述细胞外拮抗剂是IMC-A12。
8.如权利要求1所述的应用,其中所述促黄体激素释放激素(LHRH)类似物或肾上腺雄激素抑制剂和所述IGF-IR拮抗剂与抗肿瘤剂一同施用。
9.如权利要求8所述的应用,其中所述抗肿瘤剂是辐射。
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Application Number | Priority Date | Filing Date | Title |
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US76507206P | 2006-02-03 | 2006-02-03 | |
US60/765,072 | 2006-02-03 | ||
PCT/US2007/003164 WO2007092453A2 (en) | 2006-02-03 | 2007-02-03 | Igf-ir antagonists as adjuvants for treatment of prostate cancer |
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CN101484587A CN101484587A (zh) | 2009-07-15 |
CN101484587B true CN101484587B (zh) | 2014-02-12 |
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CN200780012266.6A Expired - Fee Related CN101484587B (zh) | 2006-02-03 | 2007-02-03 | Igf-ir拮抗剂作为辅药用于前列腺癌的治疗 |
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US (1) | US7972600B2 (zh) |
EP (1) | EP1984011A4 (zh) |
JP (1) | JP5198289B2 (zh) |
KR (1) | KR101353706B1 (zh) |
CN (1) | CN101484587B (zh) |
AP (1) | AP2008004569A0 (zh) |
AU (1) | AU2007212447B2 (zh) |
CA (1) | CA2641310C (zh) |
CR (1) | CR10188A (zh) |
EA (1) | EA017265B1 (zh) |
EC (1) | ECSP088706A (zh) |
IL (1) | IL193203A0 (zh) |
MX (1) | MX2008009977A (zh) |
NO (1) | NO20083444L (zh) |
UA (1) | UA95945C2 (zh) |
WO (1) | WO2007092453A2 (zh) |
ZA (1) | ZA200807012B (zh) |
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- 2007-02-03 AP AP2008004569A patent/AP2008004569A0/xx unknown
- 2007-02-03 CN CN200780012266.6A patent/CN101484587B/zh not_active Expired - Fee Related
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2008
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Patent Citations (1)
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WO2005016970A2 (en) * | 2003-05-01 | 2005-02-24 | Imclone Systems Incorporated | Fully human antibodies directed against the human insulin-like growth factor-1 receptor |
Non-Patent Citations (1)
Title |
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Jennifer D. Wu等.In vivo Effects of the Human Type I Insulin-Like Growth Factor Receptor Antibody A12 on Androgen-Dependent and Androgen-Independent Xenograft Human Prostate Tumors.《Clinical Cancer Research》.2005,第11卷(第8期),第3065-3074页. * |
Also Published As
Publication number | Publication date |
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ECSP088706A (es) | 2008-10-31 |
CN101484587A (zh) | 2009-07-15 |
CA2641310C (en) | 2013-08-20 |
UA95945C2 (ru) | 2011-09-26 |
KR101353706B1 (ko) | 2014-02-18 |
AU2007212447A1 (en) | 2007-08-16 |
CA2641310A1 (en) | 2007-08-16 |
IL193203A0 (en) | 2009-08-03 |
MX2008009977A (es) | 2009-02-27 |
CR10188A (es) | 2008-11-18 |
WO2007092453A3 (en) | 2008-12-24 |
EP1984011A4 (en) | 2010-08-18 |
JP2009525348A (ja) | 2009-07-09 |
JP5198289B2 (ja) | 2013-05-15 |
US7972600B2 (en) | 2011-07-05 |
EA200870231A1 (ru) | 2009-12-30 |
EA017265B1 (ru) | 2012-11-30 |
EP1984011A2 (en) | 2008-10-29 |
KR20080090566A (ko) | 2008-10-08 |
US20090175868A1 (en) | 2009-07-09 |
AU2007212447B2 (en) | 2013-02-21 |
ZA200807012B (en) | 2009-12-30 |
NO20083444L (no) | 2008-10-31 |
WO2007092453A2 (en) | 2007-08-16 |
AP2008004569A0 (en) | 2008-08-31 |
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