CN117979997A - 抗受体相关酪氨酸激酶(ryk)抗体和其用途 - Google Patents
抗受体相关酪氨酸激酶(ryk)抗体和其用途 Download PDFInfo
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Abstract
本文尤其提供了抗体,所述抗体与具有高效率和特异性的受体相关酪氨酸激酶(Ryk)结合。本文提供的所述抗体和抗体组合物包含例如新型轻链和重链结构域CDR以及框架区,并且尤其可用于诊断和治疗癌症和其它RYK相关疾病。在实施例中,本文提供的抗RYK抗体能够与人RYK蛋白结合,但是不能与小鼠RYK蛋白结合。
Description
相关申请的交叉引用
本申请要求于2021年8月18日提交的美国临时申请第63/234,527号的优先权,所述美国临时申请特此通过引用以其整体并出于所有目的并入。
就联邦资助的研究和开发中的发明权利的声明
本发明是在美国国立卫生研究院(National Institutes of Health)授予的CA236361下由政府支持进行的。政府享有本发明中的某些权利。
序列表
随附的序列表中的材料特此通过引用以其整体并入。名称为“048537-648001WO_SL_ST26.xml”的随附文件创建于2022年8月15日并且为120,584字节。此文件可以在使用Windows OS的计算机上使用Microsoft Word来访问。
背景技术
受体相关酪氨酸激酶(Ryk)是一种用于Wingless-int(Wnt)配体,例如,Wnt1、1Wnt3a、1Wnt5a、2以及可能地Wnt5b的高度保守的单程跨膜受体。3胞外结构域具有WIF(Wnt抑制因子-1样)结构域,所述WIF结构域可以启动利用Frizzled(Frz)受体进行的复合物形成,所述受体用于在Wnt信号传导网络中进行串扰,以影响β-连环蛋白依赖性和β-连环蛋白非依赖性(例如,非典型)Wnt信号传导通路的活化。1,4,5细胞质结构域具有酪氨酸激酶结构域,所述酪氨酸激酶结构域缺乏明显的激酶活性。5-7然而,Ryk的细胞质结构域可以被γ分泌酶切割并释放以进行核转位,8这表明其在调节细胞信号传导中可以发挥替代性作用。
显然地,Ryk主要在胚胎发育中发挥作用,在胚胎发育中,其调节轴突外生长、心血管和颅面发育以及胎儿肝脏造血。9-11,12RYK的基因组破坏导致围产儿死亡。尽管Ryk在早期发育中很重要,但其表达似乎在发育期间减弱,并且似乎没有在产后组织中明确地表达。然而,因为不存在与表达Ryk的活细胞发生反应的高亲和力的高度特异性抗Ryk单克隆抗体(mAb),所以对Ryk的产后表达有待进行研究。
然而,值得注意的是,有报告描述Ryk通过各种癌症进行的表达。5例如,Ryk明显在胶质母细胞瘤中表达,在所述胶质母细胞瘤中,其通过调节Wnt/β-连环蛋白通路的能力促进胶质母细胞瘤细胞的‘干性’。13此外,Ryk可以在乳腺癌中表达,在所述乳腺癌中,据称其促进乳腺癌肿瘤起始细胞的扩增,并且显示出增强乳腺癌细胞生长。14,15Ryk还涉及胃癌肿瘤发生。16同样,对通过各种癌症进行的Ryk表达的评估由于缺乏用其检查Ryk在癌细胞和正常产后组织上的相对表达的高度特异性抗Ryk mAb而受到阻碍。
本领域需要对表达Ryk的细胞具有高度特异性的mAb,以例如研究Ryk在早期发育和瘤形成中的功能性意义。因此,本领域需要用于靶向表达Ryk的细胞的mAb,用于检测、消除、功能性抑制、免疫介导的破坏或靶向性药物递送。用于评估Ryk在细胞上的表达的商用试剂是源自异源抗血清的抗体,例如绵羊抗Ryk(R&D系统公司(R&D systems))。这些抗Ryk抗体被选择为与Ryk结合。然而,其对人Ryk不具有特异性,并且与不表达人Ryk的细胞发生交叉反应。存在一种声称对人Ryk(例如,SAP18,华盛顿州西雅图市98121第四大街900室LSBio 2401(LSBio 2401Fourth Avenue Suite 900,Seattle WA 98121))具有特异性的可商购获得的mAb。然而,这种mAb显然与变性的人Ryk发生反应。因此,这种mAb可以用于在免疫印迹或ELISA测定中检测Ryk,但是其在流式细胞术中的用途未得到验证,因为其明显缺乏在活细胞上对细胞表面Ryk的特异性结合。总之,先前产生的抗Ryk抗体似乎不适于在患有表达Ryk的癌症的患者的疗法中潜在使用。
本文尤其提供了本领域中的这些和其它需求的解决方案。
发明内容
在一方面中提供了一种抗RYK抗体,其包含重链可变结构域和轻链可变结构域,其中所述重链可变结构域包含如SEQ ID NO:1中所示的CDR H1、如SEQ ID NO:2中所示的CDRH2以及如SEQ ID NO:3中所示的CDR H3;并且其中所述轻链可变结构域包含如SEQ ID NO:4中所示的CDR L1、如SEQ ID NO:5中所示的CDR L2以及如SEQ ID NO:6中所示的CDR L3。
在另一方面中提供了一种抗RYK抗体,其包含重链可变结构域和轻链可变结构域,其中所述重链可变结构域包含如SEQ ID NO:17中所示的CDR H1、如SEQ ID NO:18中所示的CDR H2以及如SEQ ID NO:19中所示的CDR H3;并且其中所述轻链可变结构域包含如SEQ IDNO:20中所示的CDR L1、如SEQ ID NO:21中所示的CDR L2以及如SEQ ID NO:22中所示的CDRL3。
在另一方面中提供了一种抗RYK抗体,其包含重链可变结构域和轻链可变结构域,其中所述重链可变结构域包含如SEQ ID NO:33中所示的CDR H1、如SEQ ID NO:34中所示的CDR H2以及如SEQ ID NO:35中所示的CDR H3;并且其中所述轻链可变结构域包含如SEQ IDNO:36中所示的CDR L1、如SEQ ID NO:37中所示的CDR L2以及如SEQ ID NO:38中所示的CDRL3。
在另一方面中提供了一种抗RYK抗体,其包含重链可变结构域和轻链可变结构域,其中所述重链可变结构域包含如SEQ ID NO:49中所示的CDR H1、如SEQ ID NO:50中所示的CDR H2以及如SEQ ID NO:51中所示的CDR H3;并且其中所述轻链可变结构域包含如SEQ IDNO:52中所示的CDR L1、如SEQ ID NO:53中所示的CDR L2以及如SEQ ID NO:54中所示的CDRL3。
在另一方面中提供了一种抗RYK抗体,其中所述抗RYK抗体与和包含以下的抗体相同的表位结合:重链可变结构域,所述重链可变结构域包含如SEQ ID NO:1中所示的CDRH1、如SEQ ID NO:2中所示的CDR H2以及如SEQ ID NO:3中所示的CDR H3;以及轻链可变结构域,所述轻链可变结构域包含如SEQ ID NO:4中所示的CDR L1、如SEQ ID NO:5中所示的CDR L2以及如SEQ ID NO:6中所示的CDR L3。
在另一方面中提供了一种抗RYK抗体,其中所述抗RYK抗体与和包含以下的抗体相同的表位结合:重链可变结构域,所述重链可变结构域包含如SEQ ID NO:17中所示的CDRH1、如SEQ ID NO:18中所示的CDR H2以及如SEQ ID NO:19中所示的CDR H3;以及轻链可变结构域,所述轻链可变结构域包含如SEQ ID NO:20中所示的CDR L1、如SEQ ID NO:21中所示的CDR L2以及如SEQ ID NO:22中所示的CDR L3。
在另一方面中提供了一种抗RYK抗体,其中所述抗RYK抗体与和包含以下的抗体相同的表位结合:重链可变结构域,所述重链可变结构域包含如SEQ ID NO:33中所示的CDRH1、如SEQ ID NO:34中所示的CDR H2以及如SEQ ID NO:35中所示的CDR H3;以及轻链可变结构域,所述轻链可变结构域包含如SEQ ID NO:36中所示的CDR L1、如SEQ ID NO:37中所示的CDR L2以及如SEQ ID NO:38中所示的CDR L3。
在另一方面中提供了一种抗RYK抗体,其中所述抗RYK抗体与和包含以下的抗体相同的表位结合:重链可变结构域,所述重链可变结构域包含如SEQ ID NO:49中所示的CDRH1、如SEQ ID NO:50中所示的CDR H2以及如SEQ ID NO:51中所示的CDR H3;以及轻链可变结构域,所述轻链可变结构域包含如SEQ ID NO:52中所示的CDR L1、如SEQ ID NO:53中所示的CDR L2以及如SEQ ID NO:54中所示的CDR L3。
在另一方面中提供了一种分离的核酸,其编码本文(包含其实施例)所提供的抗RYK抗体。
在另一方面中提供了一种细胞,其包含本文(包含其实施例)所提供的抗RYK抗体或本文(包含其实施例)所提供的核酸。
在另一方面中提供了一种药物组合物,其包含治疗有效量的本文(包含其实施例)所提供的抗体以及药学上可接受的赋形剂。
在另一方面中提供了一种形成能够与RYK蛋白结合的抗体的方法,所述方法包含用包含SEQ ID NO:129的序列的肽使哺乳动物免疫。
在另一方面中提供了一种检测RYK表达性细胞的方法,所述方法包含(i)使RYK表达性细胞与本文(包含其实施例)所提供的抗体接触;(ii)以及检测所述抗体与由所述细胞表达的RYK蛋白的结合。
在另一方面中提供了一种治疗有需要的受试者的癌症的方法,所述方法包含向受试者施用治疗有效量的本文(包含其实施例)所提供的抗RYK抗体。
在另一方面中提供了一种鉴定抗RYK抗体的方法,所述方法包含:(i)使抗体与第一RYK多肽接触,所述第一RYK多肽包含与SEQ ID NO:129的氨基酸残基48至57相对应的氨基酸序列;(ii)检测与所述第一RYK多肽结合的所述抗体;(iii)使所述抗体与第二RYK多肽接触,所述第二RYK多肽不包含与SEQ ID NO:129的氨基酸残基48至57相对应的氨基酸序列;以及(iv)检测未与所述第二RYK多肽结合的所述抗体,由此鉴定抗RYK抗体。
附图说明
图1展示了人RYK与小鼠RYK的胞外区的比较。示出了人(hRYK,上面的序列;SEQ IDNO:132)与小鼠(mRYK,下面的序列,SEQ ID NO:131)RYK的胞外区的氨基酸序列的比对。小点指示所述位置处的同源性,而差异由单字母氨基酸密码子指定。信号肽和WIF结构域由序列(SEQ ID NO:132)上方的线标记和指示。
图2A-2D展示了氨基酸序列和与最接近的小鼠IGHV(上面的序列)或IGKV(下面的序列)种系基因的比对,所述图针对四种被指定为以下的小鼠抗人RYK杂交瘤中的每一种杂交瘤进行描绘:2-D11(图2A,SEQ ID NO:15和SEQ ID NO:16)、7-H10(图2B,SEQ ID NO:31和SEQ ID NO:32)、11-E9(图2C,SEQ ID NO:47和SEQ ID NO:48)以及3-C12(图2D,SEQ ID NO:63和SEQ ID NO:64)。对于每个比对,上面的序列描绘了重链或轻链可变区的氨基酸序列,所述氨基酸序列开始于第一框架区的第一个密码子并且终止于第四框架区的最后一个密码子。下面的序列描绘了最同源的小鼠IGHV或IGKV种系基因的重链或轻链可变区的氨基酸序列。小点指示所述位置处的同源性,而差异由单字母氨基酸密码子指定。框架(FR)和互补决定(CDR)区标记在序列上方。
图3展示了hROR1的胞外结构域(SEQ ID NO:129)与用于绘制通过本公开中的每个抗人RYK mAb结合的结合区表位hRYK的hRYK的突变形式的比较。由氨基酸序列表示的蛋白质的名称位于左侧边缘。氨基酸由单字母氨基酸代码指示。在右侧边缘或序列上方提供的数字为下面的氨基酸残基的位置的编号。序列中的小点指示与所述位置处的hRYK的序列同源性。字母指示与存在于所述位置处的hRYK中的氨基酸不同的突变RYK的氨基酸。RYK胞外结构域的WIF结构域在氨基酸序列的上方指示,其是加下划线的。
图4A-4B展示了对抗人RYK mAb与人RYK的胞外结构域结合所需的氨基酸的牙发生(SEQ ID NO:129)。图4A展示了其中使用重组人RYK蛋白(SEQ ID NO:129)对2-D11、7-H10、3-C12、11-E9、6-B5、6-D10和绵羊抗RYK mAb的结合进行评估的实验,在所述实验中,位于胞外结构域内的在人RYK与小鼠RYK之间不同的一个氨基酸被小鼠RYK的对应氨基酸替代。将每个重组蛋白转移到尼龙膜上,用所指示的抗RYK mAb或绵羊抗RYK Ab进行探测,并且用与辣根过氧化物酶缀合的抗小鼠IgG或驴抗绵羊抗体检测。兔抗IgG印迹对蛋白质印迹和检测呈阳性,因为重组蛋白具有兔IgG标签fpr纯化。下面的小图中示出了人RYK和小鼠RYK的胞外结构域的蛋白质序列的比对,并且加方框的氨基酸指示针对每种重组蛋白进行的氨基酸改变。图4B展示了用2-D11抗体进行的用于进一步评估结合的另外的印迹,在所述印记中,取代是在前导肽内或在与人RYK蛋白(SEQ ID NO:129)的WIF结构域相邻的编码区中进行的。具有mRYK48-57的hRYK是其中位置48-57处的鼠类氨基酸被取代的人RYK,并且如同与人RYK融合的鼠类前导区的取代一样,使与人RYK的结合丧失。
图5A-5B展示了mAb 2-D11的可变区序列。图5A表示mAb 2-D11的Ig重链可变区序列。图5B表示mAb 2-D11的Igκ链可变区序列。
图6A-6B展示了mAb 7-H10的可变区序列。图6A表示mAb 7-H10的Ig重链可变区序列。图6B表示mAb 7-H10的Igκ链可变区序列。
图7A-7B展示了对2-D11和7-H10 mAb与重组人RYK2蛋白的结合的亲和力测量。分析是使用KinExA 3200仪器进行的。图7A:示出了对于2-D11 mAb(左上方的小图)和7-H10mAb(左下方的小图),在存在不断增加的摩尔(M)浓度的可溶性RYK竞争剂(x轴)的情况下,与用RYK蛋白包被的颗粒结合的抗人RYK mAb的比例(y轴)。图7B:用于与人RYK结合的2-D11mAb(右上方的小图)和7-H10 mAb(右下方的小图)的所测得的KD的95%置信区间的图解。
图8展示了2-D11抗人RYK mAb与人RYK特异性结合。2-D11 mAb与人RYK的结合是通过流式细胞术染色和对若干个细胞系的分析来评估的。将细胞在冰上用10ug/ml 2-D11抗人RYK-Alexa647缀合的mAb(阴影直方图)或等量的同种型匹配的对照mAb(空心直方图)染色20分钟,洗涤并分析。直方图描绘了如通过光散射特性确定的活细胞的相对荧光强度(x轴)。基于经染色的细胞的中值荧光强度(MFI)相对于同种型对照染色的细胞的MFI的比率,++、+和阴性对应于表1中所示的对这些和其它细胞系进行的染色的水平。
图9展示了来自成人血液、脐带血(N=2)、扁桃体(N-2)或脾脏的淋巴细胞的2-D11染色的实例。
图10展示了原代传代乳腺癌患者源性异种移植物(PDX)。源自雌激素/孕酮受体阴性和HER2阴性乳腺癌(三阴性乳腺癌(triple-negative breast cancer),TNBC)的原代传代(T1)乳腺癌PDX(M0026)。将M0026的人TNBC细胞解离为单个细胞,将所述单细胞用荧光染料缀合的同种型对照mAb(Cont mAb,深灰色直方图)或荧光染料缀合的2-D11(浅灰色阴影直方图)进行染色,并且然后在流式细胞仪上进行分析。Cont mAb染色的细胞的荧光度与未经染色的细胞(未示出)的荧光度相同。
具体实施方式
虽然在本文中示出和描述了本发明的各个实施例和方面,但是本领域的技术人员将清楚的是此类实施例和方面仅以举例的方式提供。在不脱离本发明的情况下,本领域的技术人员现在将意识到许多变化、改变和取代。应当理解的是,本文所描述的本发明的实施例的各个替代方案可以用于实践本发明。
本文所使用的章节标题仅出于组织目的,而不应被解释为对所描述的主题进行限制。在本申请中引用的所有文件或文件的部分,包含但不限于专利、专利申请、论文、书籍、手册和专著,均特此出于任何目的通过引用以其整体明确地并入。
本文所使用的缩写具有其在化学领域和生物学领域内的常规含义。本文所阐述的化学结构和化学式是根据化学领域中已知的化学价的标准规则构建的。
定义
除非另有定义,否则本文所使用的技术术语和科学术语具有与本领域普通技术人员通常理解的含义相同的含义。参见例如,Singleton等人,《微生物学和分子生物学词典(DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY)》第2版,威利父子杂志出版社(J.Wiley&Sons)(纽约州纽约市(New York,NY),1994);Sambrook等人,《分子克隆:实验室手册(MOLECULAR CLONING,A LABORATORY MANUAL)》,冷泉港出版社(Cold Springs HarborPress)(纽约冷泉港(Cold Springs Harbor,NY),1989)。与本文所描述的方法、装置和材料类似或等效的任何方法、装置和材料均可以用于实践本发明。提供以下定义以便于理解本文中频繁使用的某些术语,并且不意味着限制本公开的范围。
“核酸”是指核苷酸(例如,脱氧核糖核苷酸或核糖核苷酸)和其呈单链、双链或多链形式的聚合物或其补体;或核苷(例如,脱氧核糖核苷或核糖核苷)。在实施例中,“核酸”不包含核苷。术语“多核苷酸”、“寡核苷酸(oligonucleotide)”、“寡核苷酸(oligo)”等在通常和习惯意义上是指核苷酸的线性序列。术语“核苷”在通常和习惯意义上是指包含核碱基和五碳糖(核糖或脱氧核糖)的糖基胺。核苷的非限制性实例包含胞苷、尿苷、腺苷、鸟苷、胸苷和肌苷。术语“核苷酸”在通常和习惯意义上是指多核苷酸的单个单元,即,单体。核苷酸可以是核糖核苷酸、脱氧核糖核苷酸或其经修饰的版本。本文所设想的多核苷酸的实例包含单链和双链DNA、单链和双链RNA以及具有单链和双链DNA和RNA的混合物的杂合分子。本文所设想的核酸的实例,例如多核苷酸包含任何类型的RNA,例如mRNA、siRNA、miRNA和指导RNA,以及任何类型的DNA、基因组DNA、质粒DNA和微环DNA以及其任何片段。在多核苷酸的上下文中,术语“双链体”在通常和习惯意义上是指双链型。核酸可以是线性或支链的。例如,核酸可以是核苷酸的直链或核酸可以是支链的,例如,使得所述核酸包括核苷酸的一个或多个臂或分支。任选地,支链核酸重复分支以形成更高级结构,如树状物等。
核酸,包含例如具有硫代磷酸酯主链的核酸,可以包含一个或多个反应性部分。如本文所使用的,术语反应性部分包含能够通过共价、非共价或其它相互作用与另一种分子,例如,核酸或多肽进行反应的任何基团。举例来说,核酸可以包含通过共价、非共价或其它相互作用与蛋白质上的氨基酸或多肽进行反应的氨基酸反应性部分。
术语涵盖含有已知核苷酸类似物或经修饰的主链残基或键的核酸,所述核酸是合成的、天然存在的和非天然存在的,所述核酸具有与参考核酸类似的结合特性并且所述核酸以与参考核苷酸类似的方式代谢。此类类似物的实例包含但不限于磷酸二酯衍生物,所述磷酸二酯衍生物包含例如氨基磷酸酯、二氨基磷酸酯、硫代磷酸酯(还被称为硫代磷酸,其具有双键硫置换的含氧的磷酸盐)、二硫代磷酸酯、膦酰羧酸、膦酰羧酸酯、膦酰乙酸、膦酰甲酸、甲基膦酸酯、硼膦酸酯或O-甲基亚磷酰胺键(参见Eckstein,《寡核苷酸以及类似物:实用方法(OLIGONUCLEOTIDES AND ANALOGUES:A PRACTICAL APPROACH)》,牛津大学出版社(Oxford University Press)),以及如在5-甲基胞苷或假尿苷中对核苷酸碱基的修饰;以及肽核酸主链和键。其它类似核酸包含具有阳性主链的核酸;非离子主链、经修饰的糖和非核糖主链(例如,本领域已知的二氨基磷酸酯吗啉代寡核苷酸或锁核酸(LNA)),包含以下文献中描述的那些:美国专利第5,235,033号和第5,034,506号,以及第6章和第7章,ASC研讨会系列580(ASCSymposium Series 580),《反义研究中的碳水化合物修饰(CARBOHYDRATE MODIFICATIONS IN ANTISENSE RESEARCH)》,编者:Sanghui和Cook。含有一个或多个碳环糖的核酸也包含在核酸的一个定义内。出于多种原因,可以对核糖-磷酸主链进行修饰,例如,以增加此类分子在生理环境中或作为生物芯片上的探针的稳定性和半衰期。可以制备天然存在的核酸和类似物的混合物;可替代地,可以制备不同核酸类似物的混合物,以及天然存在的核酸和类似物的混合物。在实施例中,DNA中的核苷酸间键是磷酸二酯、磷酸二酯衍生物或两者的组合。
核酸可以包含非特异性序列。如本文中所使用的,术语“非特异性序列”是指含有未被设计成与任何其它核酸序列互补或与任何其它核酸序列仅部分互补的一系列残基的核酸序列。举例来说,非特异性核酸序列是在与细胞或生物体接触时不充当抑制性核酸的核酸残基的序列。在实施例中,非特异性核酸序列不编码生物学功能。在实施例中,非特异性核酸序列是乱序核酸序列。本文所提供的“乱序核酸序列”是包含在体外随机地彼此连接的核苷酸的重组核酸序列。在本领域中,相对于测试核酸序列的活性(生物学功能),乱序核酸序列通常用作对照或参考序列。
多核苷酸通常由四种核苷酸碱基的特定序列构成:腺嘌呤(A);胞嘧啶(C);鸟嘌呤(G);以及胸腺嘧啶(T)(当多核苷酸是RNA时,尿嘧啶(U)代替胸腺嘧啶(T))。因此,术语“多核苷酸序列”是多核苷酸分子的字母表示;可替代地,所述术语可以应用于多核苷酸分子本身。此字母表示可以输入到具有中央处理单元的计算机中的数据库中,并且用于生物信息学应用,如功能基因组学和同源性搜索。多核苷酸可以任选地包含一种或多种非标准核苷酸、核苷酸类似物和/或经修饰的核苷酸。
如本文所使用的,术语“补体”是指能够与互补核苷酸或核苷酸的序列进行碱基配对的核苷酸(例如,RNA或DNA)或核苷酸序列。如本文所描述的和本领域公知的,腺苷的互补(匹配)核苷酸是胸苷,并且鸟苷的互补(匹配)核苷酸是胞嘧啶。因此,补体可以包含与第二核酸序列的对应互补核苷酸碱基配对的核苷酸序列。补体的核苷酸可以部分或完全匹配第二核酸序列的核苷酸。当补体的核苷酸与第二核酸序列中的每个核苷酸完全匹配时,补体与第二核酸序列中的每个核苷酸形成碱基对。当补体的核苷酸与第二核酸序列的核苷酸部分匹配时,补体中的仅一些核苷酸与第二核酸序列的核苷酸形成碱基对。互补序列的实例包含编码和非编码序列,其中非编码序列含有编码序列的互补核苷酸,并且因此形成编码序列的补体。互补序列的另外的实例是有义序列和反义序列,其中正义序列含有反义序列的互补核苷酸,并且因此形成反义序列的补体。
如本文所描述的,序列的互补性可以是部分的,其中仅一些核酸根据碱基配对匹配,或是完全的,其中所有核酸根据碱基配对匹配。因此,彼此互补的两个序列可以具有指定百分比的相同的核苷酸(即,在指定区内约60%同一性,优选地65%、70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或更高同一性)。
术语“氨基酸”是指天然存在的和合成的氨基酸,以及以与天然存在的氨基酸类似的方式起作用的氨基酸类似物和氨基酸模拟物。天然存在的氨基酸是由遗传密码编码的氨基酸以及之后被修饰的那些氨基酸,例如,羟基脯氨酸、γ-羧基谷氨酸和O-磷酸丝氨酸。氨基酸类似物是指具有与天然存在的氨基酸相同的基本化学结构的化合物,即,与氢、羧基、氨基和R基团结合的α碳,例如,高丝氨酸、正亮氨酸、甲硫氨酸亚砜、甲硫氨酸甲基锍。此类类似物具有经修饰的R基团(例如,正亮氨酸)或经修饰的肽主链,但保留与天然存在的氨基酸相同的基本化学结构。氨基酸模拟物是指具有与氨基酸的一般化学结构不同的结构但以与天然存在的氨基酸类似的方式起作用的化学化合物。术语“非天然存在的氨基酸”和“非天然氨基酸”是指自然界中未发现的氨基酸类似物、合成氨基酸和氨基酸模拟物。
氨基酸在本文中可以通过其通常已知的三字母符号或通过IUPAC-IUB生物化学命名法委员会(the IUPAC-IUB Biochemical Nomenclature Commission)推荐的单字母符号来指代。同样,核苷酸可以通过其普遍接受的单字母代码来指代。
术语“多肽”、“肽”和“蛋白质”在本文中可互换使用,以指代氨基酸残基的聚合物,其中在实施例中,所述聚合物可以与不由氨基酸组成的部分缀合。所述术语适用于其中一个或多个氨基酸残基是对应天然存在的氨基酸的人造化学模拟物的氨基酸聚合物,以及适用于天然存在的氨基酸聚合物和非天然存在的氨基酸聚合物。“融合蛋白”是指编码重组地表达为单个部分的两个或更多个单独蛋白质序列的嵌合蛋白。
氨基酸或核苷酸碱基“位置”由数字表示,所数字基于其相对于N末端(或5'端)的位置顺序地标识参考序列中的每个氨基酸(或核苷酸碱基)。由于在确定最佳比对时必须考虑的缺失、插入、截短、融合等,因此通常测试序列中的通过仅从N末端进行计数而确定的氨基酸残基编号不一定与其在参考序列中的对应位置的编号相同。例如,在变体相对于所比对的参考序列具有缺失的情况下,变体中将不存在与参考序列中的缺失位点处的位置相对应的氨基酸。在所比对的参考序列中存在插入的情况下,所述插入将不与参考序列中的经编号的氨基酸位置相对应。在截短或融合的情况下,参考序列或所比对的序列中可能存在不与对应序列中的任何氨基酸相对应的氨基酸段。
当在对给定氨基酸或多核苷酸序列进行编号的上下文中使用时,术语“相对于……进行编号”或“对应于……进行编号”是指在将给定氨基酸或多核苷酸序列与参考序列进行比较时,对指定参考序列的残基进行编号。当蛋白质中的氨基酸残基占据蛋白质内的与给定残基相同的基本结构位置时,所述氨基酸残基与给定残基“相对应”。本领域的技术人员将立即认识到与具有不同编号系统的其它蛋白质中的蛋白质(例如,RYK)中的特定位置相对应的残基的同一性和位置。例如,通过用蛋白质(例如,RYK)进行简单的序列比对,在与蛋白质进行比对的其它蛋白质序列中鉴定了与蛋白质的特定位置相对应的残基的同一性和位置。例如,当所选择残基占据与位置138处的谷氨酸相同的基本空间或其它结构关系时,所选择蛋白质中的所选择残基与位置138处的谷氨酸相对应。在对于最大同源性而言将所选择蛋白质与蛋白质进行比对的一些实施例中,与谷氨酸138进行比对的所比对的所选择蛋白质中的位置与谷氨酸138相对应。代替一级序列比对,还可以使用三维结构比对,例如,其中针对与位置138处的谷氨酸的最大对应性而将所选择蛋白质的结构进行比对,并且将总体结构进行比较。在这种情况下,在结构模型中占据与谷氨酸138的基本位置相同的基本位置的氨基酸是与谷氨酸138残基相对应的氨基酸。
“经保守修饰的变体”适用于氨基酸序列和核酸序列两者。关于特定核酸序列,“经保守修饰的变体”是指编码相同或基本上相同的氨基酸序列的那些核酸。因为遗传密码的简并,所以多个核酸序列将编码任何给定蛋白质。例如,密码子GCA、GCC、GCG和GCU均编码氨基酸丙氨酸。因此,在由密码子指定丙氨酸的每个位置处,密码子可以在不改变经编码的多肽的情况下改变成所描述的对应密码子中的任何一个。此类核酸变化为“沉默变化”,所述沉默变化是经保守修饰的变化的一个物种。本文中编码多肽的每个核酸序列还描述核酸的每种可能的沉默变化。技术人员将认识到,核酸中的每个密码子(除通常为甲硫氨酸的唯一密码子的AUG和通常为色氨酸的唯一密码子的TGG之外)可以被修饰以产生功能上相同的分子。因此,编码多肽的核酸的每种沉默变化隐含在每个所描述的序列中。
关于氨基酸序列,技术人员将认识到对改变、添加或缺失经编码的序列中的单个氨基酸或小百分比的氨基酸的核酸、肽、多肽或蛋白质序列的单独取代、缺失或添加是其中改变会引起氨基酸被化学上类似的氨基酸取代的“经保守修饰的变体”。提供功能上类似的氨基酸的保守取代表在本领域中是众所周知的。此类经保守修饰的变体除了本公开的多晶型变体、种间同源物和等位基因并且不排除所述多晶型变体、种间同源物和等位基因。
以下八个基团各自含有为彼此的保守取代的氨基酸:
1)丙氨酸(A)、甘氨酸(G);
2)天冬氨酸(D)、谷氨酸(E);
3)天冬酰胺(N)、谷氨酰胺(Q);
4)精氨酸(R)、赖氨酸(K);
5)异亮氨酸(I)、亮氨酸(L)、甲硫氨酸(M)、缬氨酸(V);
6)苯丙氨酸(F)、酪氨酸(Y)、色氨酸(W);
7)丝氨酸(S)、苏氨酸(T);以及
8)半胱氨酸(C)、甲硫氨酸(M)
(参见例如,Creighton,《蛋白质(Proteins)》(1984))。
在两个或更多个核酸或多肽序列的上下文中,术语“相同”或“同一性”百分比是指如使用利用以下描述的默认参数的BLAST或BLAST 2.0序列比较算法或通过手动比对和视觉检查测量的相同的或具有指定百分比的相同的氨基酸残基或核苷酸(即,当在比较窗口或指定区之上针对最大对应性进行比较和比对时,在指定区内约60%同一性,优选地65%、70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或更高同一性)的两个或更多个序列或子序列(参见例如,NCBI网站http://www.ncbi.nlm.nih.gov/BLAST/等)。此类序列然后被称为“基本上相同”。此定义还涉及或可以应用于测试序列的补体。所述定义还包含具有缺失和/或添加的序列,以及具有取代的序列。如下文所描述的,优选的算法可以解释间隙等。优选地,在长度为至少约25个氨基酸或核苷酸的区之上,或更优选地在长度为50-100个氨基酸或核苷酸的区之上存在同一性。
“序列同一性百分比”是通过在比较窗口之上比较两个最佳比对的序列确定的,其中比较窗口中的多核苷酸序列或多肽序列的部分可以包括如相比于用于两个序列的最佳比对的参考序列(其不包括添加或缺失)的添加或缺失(即,间隙)。百分比通过以下计算:确定两个序列中出现相同核酸碱基或氨基酸残基的位置数以得到匹配的位置数,将匹配的位置数除以比较窗口中的总位置数并且将结果乘以100以得到序列同一性百分比。
为了进行序列比较,通常一个序列充当与测试序列进行比较的参考序列。当使用序列比较算法时,将测试序列和参考序列输入到计算机中,指定子序列坐标(如有必要),并且指定序列算法程序参数。可以使用默认程序参数,或者可以指定替代性参数。然后,序列比较算法基于程序参数计算测试序列相对于参考序列的序列同一性百分比。
如本文所使用的,“比较窗口”包含对选自由例如全长序列或20个至600个、约50个至约200个或约100个至约150个氨基酸或核苷酸组成的组的连续位置数中的任一个的区段的指代,其中在两个序列进行最佳比对后,序列可以与具有相同数量的连续位置的参考序列进行比较。用于比较的序列比对方法在本领域中是众所周知的。用于比较的序列的最佳比对可以例如如下进行:通过Smith和Waterman(1970)《高等应用数学(Adv.Appl.Math.)》2:482c的局部同源性算法;通过Needleman和Wunsch(1970)《分子生物学杂志(J.Mol.Biol.)》48:443的同源性比对算法;通过Pearson和Lipman(1988)《美国国家科学院院刊(Proc.Nat'l.Acad.Sci.USA)》85:2444的相似性搜索方法;通过这些算法的计算机化实施方案(威斯康星州麦迪逊科学大道575号遗传学计算机组的威斯康星遗传学软件包(Wisconsin Genetics Software Package,Genetics Computer Group,575Science Dr.,Madison,WI)中的GAP、BESTFIT、FASTA和TFASTA);或通过手动比对和视觉检查(参见例如,Ausubel等人,《当代分子生物学实验指南(Current Protocols in Molecular Biology)》(1995年增刊))。
适用于确定序列同一性和序列相似性百分比的算法的一个实例是分别在以下中描述的BLAST和BLAST 2.0算法:Altschul等人,(1977)《核酸研究(Nuc.Acids Res.)》25:3389-3402以及Altschul等人(1990)《分子生物学杂志》215:403-410。用于执行BLAST分析的软件可通过美国国家生物技术信息中心(National Center for BiotechnologyInformation)(http://www.ncbi.nlm.nih.gov/)公开获得。此算法涉及首先通过鉴定查询序列中长度为W的短字来鉴定高评分序列对(HSP),当与数据库序列中相同长度的字进行比对时,所述短字匹配或满足某一正值阈值评分T。T被称作邻域字评分阈值(Altschul等人,同上)。这些初始邻域字命中充当用于启动搜索的种子,以找到含有所述初始邻域字命中的较长HSP。字命中沿每个序列在两个方向上扩展,直到累积比对评分可以增加为止。对于核苷酸序列,使用参数M(一对匹配残基的奖励评分;总是>0)和N(错配残基的惩罚评分;总是<0)来计算累积评分。对于氨基酸序列,使用评分矩阵以计算累积评分。字命中在每个方向上的扩展将在当出现以下情况时停止:累积比对评分从其最大实现值下降了数量X;由于一个或多个负评分残基比对的累积,累积评分变为零或更低;或者到达任一序列的端部。BLAST算法参数W、T和X确定比对的灵敏度和速度。BLASTN程序(对于核苷酸序列)使用字长(W)为11、期望值(E)为10、M=5、N=-4以及对两条链的比较作为默认值。对于氨基酸序列,BLASTP程序使用字长为3并且期望值(E)为10和BLOSUM62评分矩阵(参见Henikoff和Henikoff(1989)《美国国家科学院院刊》89:10915)比对(B)为50、期望值(E)为10、M=5、N=-4,以及两条链的比较作为默认值。
BLAST算法还对两个序列之间的相似性进行统计分析(参见例如,Karlin和Altschul(1993)《美国国家科学院院刊》90:5873-5787)。由BLAST算法提供的一种相似性量度是最小总和概率(P(N)),其提供了两个核苷酸或氨基酸序列之间偶然发生匹配的概率的指示。例如,如果在测试核酸与参考核酸的比较中最小总和概率小于约0.2、更优选地小于约0.01并且最优选地小于约0.001,则核酸被视为与参考序列类似。
两个核酸序列或多肽基本上相同的指示是由第一核酸编码的多肽与针对由第二核酸编码的多肽产生的抗体发生免疫交叉反应,如下所述。因此,多肽通常与第二多肽基本上相同,例如其中两个肽的不同之处仅在于保守取代。如下所述,两个核酸序列基本上相同的另一个指示是两个分子或其补体在严格条件下彼此杂交。两个核酸序列基本上相同的又另一个指示是可以使用相同的引物来扩增序列。
如本文所提及的,“RYK”包含重组或天然存在的受体相关酪氨酸激酶(RYK)蛋白或维持RYK活性(例如,维持在相较于RYK的活性的至少50%、80%、90%、95%、96%、97%、98%、99%或100%内)的其变体或同源物中的任一种。在一些方面中,与天然存在的RYK蛋白相比,变体或同源物在整个序列或序列的一部分(例如,50、100、150或200个连续氨基酸部分)上具有至少90%、95%、96%、97%、98%、99%或100%氨基酸序列同一性。在实施例中,RYK蛋白与由UniProt参考编号P34925标识的蛋白质或与其基本上相同的变体或同源物基本上相同。
抗体是具有复杂的内部结构的大的复杂分子(分子量为约150,000个或约1320个氨基酸)。天然抗体分子含有两个相同的多肽链对,每个对具有一条轻链和一条重链。每条轻链和重链进而由两个区组成:涉及与靶抗原结合的可变(“V”)区以及与免疫系统的其它组分相互作用的恒定(“C”)区。轻链和重链可变区(本文中还分别被称为轻链可变(VL)结构域和重链可变(VH)结构域)在3维空间中聚在一起以形成与抗原(例如,细胞表面上的受体)结合的可变区。在每个轻链或重链可变区内,存在被称为互补决定区(“CDR”)的三个短区段(长度平均为10个氨基酸)。抗体可变结构域中的六个CDR(三个来自轻链并且三个来自重链)在3维空间中折叠在一起以形成对接到靶抗原上的实际抗体结合位点。CDR的位置和长度已经由以下准确定义:Kabat,E.等人,《具有免疫学意义的蛋白质序列(Sequences ofProteins of Immunological Interest)》,美国卫生与公众服务部(U.S.Department ofHealth and Human Services),1983,1987。不包含在CDR中的可变区的部分被称为框架(“FR”),所述框架形成用于CDR的环境。
如本文所提供的,“抗体变体”是指能够与抗原结合并且包含抗体或其片段的一个或多个结构域(例如,轻链可变结构域、重链可变结构域)的多肽。抗体变体的非限制性实例包含单结构域抗体或纳米抗体、单特异性Fab2、双特异性Fab2、三特异性Fab3、单价IgG、scFv、双特异性抗体、双特异性双抗体、三特异性三抗体、scFv-Fc、微抗体、IgNAR、V-NAR、hcIgG、VhH或肽体。如本文所提供的,“肽体”是指附着(通过共价或非共价连接子)到抗体的Fc结构域的肽部分。本领域已知的抗体变体的另外的非限制性实例包含软骨鱼类或骆驼科动物所产生的抗体。对来自骆驼科动物的抗体及其可变区以及其生产、分离和使用方法的一般性描述可以见于参考文献WO97/49805和WO97/49805中,所述参考文献通过引用以其整体并出于所有目的并入本文。同样地,来自软骨鱼类的抗体及其可变区以及其生产、分离和使用方法可以见于WO2005/118629中,所述参考文献通过引用以其整体并出于所有目的并入本文。
如本文所提供的,术语“CDR L1”、“CDR L2”和“CDR L3”是指抗体的可变轻(L)链的互补决定区(CDR)1、2和3。在实施例中,本文所提供的可变轻链在N末端到C末端方向上包含CDR L1、CDR L2和CDR L3。同样地,如本文所提供的,术语“CDR H1”、“CDR H2”和“CDR H3”是指抗体的可变重(H)链的互补决定区(CDR)1、2和3。在实施例中,本文所提供的可变重链在N末端到C末端方向上包含CDR H1、CDR H2和CDR H3。
如本文所提供的,术语“FR L1”、“FR L2”、“FR L3”和“FR L4”根据其在本领域中的常用含义使用,并且是指抗体的可变轻(L)链的框架区(FR)1、2、3和4。在实施例中,本文所提供的可变轻链在N末端到C末端方向上包含FR L1、FR L2、FR L3和FR L4。同样地,如本文所提供的,术语“FR H1”、“FR H2”、“FR H3”和“FR H4”根据其在本领域的常用含义使用,并且是指抗体的可变重(H)链的框架区(FR)1、2、3和4。在实施例中,本文所提供的可变重链在N末端到C末端方向上包含FR H1、FR H2、FR H3和FR H4。
示例性免疫球蛋白(抗体)结构单元包括四聚体。每个四聚体由两个相同的多肽链对构成,每个对具有一条“轻”链(约25kD)和一条“重”链(约50-70kD)。每条链的N末端限定约100个至110个或更多个氨基酸的主要负责抗原识别的可变区。术语可变轻链(VL)、可变轻链(VL)结构域或轻链可变区和可变重链(VH)、可变重链(VH)结构域或重链可变区分别是指这些轻链和重链区。如本文所提及的,术语可变轻链(VL)、可变轻链(VL)结构域和轻链可变区可互换使用。如本文所提及的,术语可变重链(VH)、可变重链(VH)结构域和重链可变区可互换使用。Fc(即,片段可结晶区)是免疫球蛋白的“碱基”或“尾部”,并且通常由取决于抗体的类别贡献两个或三个恒定结构域的两条重链构成。通过与特异性蛋白结合,Fc区确保每种抗体针对给定抗原产生适当的免疫应答。Fc区还与如Fc受体等各种细胞受体以及如补体蛋白等其它免疫分子结合。
术语“抗体”根据其在本领域的通常已知含义使用。抗体例如以完整免疫球蛋白或以通过用各种肽酶消化所产生的许多充分表征的片段的形式存在。因此,例如,胃蛋白酶消化铰链区中的二硫键下方的抗体从而产生F(ab)'2,即其本身是通过二硫键与VH-CH1连接的轻链的Fab的二聚体。F(ab)'2可以在温和条件下还原以破坏铰链区中的二硫键,由此将F(ab)'2二聚体转化为Fab'单体。Fab'单体基本上为具有铰链区的一部分的Fab(参见《基础免疫学(Fundamental Immunology)》(Paul编辑,第3版,1993))。尽管就完整抗体的消化定义了各种抗体片段,但是本领域的技术人员将理解,可以以化学方式或通过使用重组DNA方法重新合成此类片段。因此,如本文所使用的,术语抗体还包含通过修饰完整抗体所产生的抗体片段,或使用重组DNA方法重新合成的抗体片段(例如,单链Fv)或使用噬菌体展示文库鉴定的抗体片段(参见例如,McCafferty等人,《自然(Nature)》348:552-554(1990))。如本文所提及的,术语“抗体”进一步包含抗体变体,如单结构域抗体。因此,在实施例中,抗体包含单个单体可变抗体结构域。因此,在实施例中,抗体包含可变轻链(VL)结构域或可变重链(VH)结构域。在实施例中,抗体是可变轻链(VL)结构域或可变重链(VH)结构域。
为了制备单克隆或多克隆抗体,可以使用本领域已知的任何技术(参见例如,Kohler和Milstein,《自然》256:495-497(1975);Kozbor等人,《今日免疫学(ImmunologyToday)》4:72(1983);Cole等人,第77-96页,《单克隆抗体与癌症疗法(MonoclonalAntibodies and Cancer Therapy)》(1985))。“单克隆”抗体(mAb)是指源自单个克隆的抗体。用于产生单链抗体的技术(美国专利第4,946,778号)可以适于产生针对本发明的多肽的抗体。而且,转基因小鼠或如其它哺乳动物等其它生物体可以用于表达人源化抗体。可替代地,噬菌体展示技术可以用于鉴定与所选择抗原特异性结合的抗体和异聚Fab片段(参见例如,McCafferty等人,《自然》348:552-554(1990);Marks等人,《生物技术(Biotechnology)》10:779-783(1992))。
单链可变片段(scFv)通常是免疫球蛋白的重链(VH)和轻链(VL)的可变区的融合蛋白,其与10个至约25个氨基酸的短连接子肽连接。连接子通常可以富含甘氨酸用于柔性,以及富含丝氨酸或苏氨酸用于溶解度。连接子也可以将VH的N末端与VL的C末端连接,或反之亦然。
mAb的表位是mAb所结合的抗原的区。如果两种抗体各自竞争性地抑制(阻断)另一种抗体与抗原的结合,则所述两种抗体与相同或重叠的表位结合。换言之,一种抗体的1x、5x、10x、20x或100x过量将另一种抗体的结合抑制至少30%,但优选地50%、75%、90%或者甚至99%,如在竞争性结合测定中所测量的(参见例如,Junghans等人,《癌症研究(CancerRes.)》50:1495,1990)。可替代地,如果在抗原中减少或消除一种抗体的结合的基本上所有氨基酸突变减少或消除另一种抗体的结合,则两种抗体具有同一表位。如果减少或消除一种抗体的结合的一些氨基酸突变减少或消除另一种抗体的结合,则两种抗体具有重叠表位。
为了制备适于本发明和根据本发明使用的抗体,例如重组、单克隆或多克隆抗体,可以使用本领域已知的许多技术(参见例如,Kohler和Milstein,《自然》256:495-497(1975);Kozbor等人,《今日免疫学》4:72(1983);Cole等人,第77-96页,《单克隆抗体与癌症疗法》,Alan R.Liss公司(Alan R.Liss,Inc.)(1985);Coligan,《当代免疫学实验指南(Current Protocols in Immunology)》(1991);Harlow和Lane,《抗体:实验室手册(Antibodies,A Laboratory Manual)》(1988);以及Goding,《单克隆抗体:原理和实践(Monoclonal Antibodies:Principles and Practice)》(第2版,1986))。编码所关注抗体的重链和轻链的基因可以从细胞中克隆,例如,编码单克隆抗体的基因可以从杂交瘤中克隆并且用于产生重组单克隆抗体。编码单克隆抗体的重链和轻链的基因文库也可以由杂交瘤或浆细胞制备。重链和轻链基因产物的随机组合产生具有不同抗原特异性的大抗体池(参见例如,Kuby,《免疫学(Immunology)》(第3版1997))。用于产生单链抗体或重组抗体的技术(美国专利4,946,778、美国专利第4,816,567号)可以适于产生针对本发明的多肽的抗体。而且,转基因小鼠或如其它哺乳动物等其它生物体可以用于表达人源化抗体或人抗体(参见例如,美国专利第5,545,807号;第5,545,806号;第5,569,825号;第5,625,126号;第5,633,425号;第5,661,016号;Marks等人,《生物技术(Bio/Technology)》10:779-783(1992);Lonberg等人,《自然》368:856-859(1994);Morrison,《自然》368:812-13(1994);Fishwild等人,《自然生物技术(Nature Biotechnology)》14:845-51(1996);Neuberger,《自然生物技术》14:826(1996);以及Lonberg和Huszar,《国际免疫学评论(Intern.Rev.Immunol.)》13:65-93(1995))。可替代地,噬菌体展示技术可以用于鉴定与所选择抗原特异性结合的抗体和异聚Fab片段(参见例如,McCafferty等人,《自然》348:552-554(1990);Marks等人,《生物技术》10:779-783(1992))。还可以将抗体制备成双特异性的,即,能够识别两种不同的抗原(参见例如,WO 93/08829,Traunecker等人,《欧洲分子生物学学会杂志(EMBO J.)》10:3655-3659(1991);以及Suresh等人,《酶学方法(Methods inEnzymology)》121:210(1986))。抗体也可以是异源缀合物,例如,两种共价连接的抗体或免疫毒素(参见例如,美国专利第4,676,980号;第WO 91/00360号;第WO 92/200373号;以及第EP 03089号)。
用于使非人抗体人源化或灵长化的方法在本领域中是众所周知的(例如,美国专利第4,816,567号;第5,530,101号;第5,859,205号;第5,585,089号;第5,693,761号;第5,693,762号;第5,777,085号;第6,180,370号;第6,210,671号;以及第6,329,511号;第WO87/02671号;欧洲专利申请0173494;Jones等人(1986)《自然》321:522;以及Verhoyen等人(1988)《科学(Science)》239:1534)。人源化抗体在例如Winter和Milstein(1991)《自然》349:293中进一步描述。通常,人源化抗体具有从非人的来源引入到其中的一个或多个氨基酸残基。这些非人氨基酸残基通常被称为输入(import)残基,所述输入残基通常取自输入可变结构域。人源化可以基本上在Winter和其同事的方法(参见例如,Morrison等人,《美国国家科学院院刊》81:6851-6855(1984);Jones等人,《自然》321:522-525(1986);Riechmann等人,《自然》332:323-327(1988);Morrison以及Oi,《免疫学进展(Adv.Immunol.)》,44:65-92(1988);Verhoeyen等人,《科学》239:1534-1536(1988)以及Presta,《结构生物学的当代观点(Curr.Op.Struct.Biol.)》2:593-596(1992);Padlan,《分子免疫学(Molec.Immun.)》,28:489-498(1991);Padlan,《分子免疫学》,31(3):169-217(1994))之后通过用啮齿动物CDR或CDR序列取代人抗体的对应序列来进行。因此,此类人源化抗体是嵌合抗体(美国专利第4,816,567号),其中已由来自非人物种的对应序列取代基本上少于完整的人可变结构域。在实践中,人源化抗体通常是其中一些CDR残基和可能地一些FR残基被来自啮齿动物抗体中的类似位点的残基取代的人抗体。例如,包括编码人源化免疫球蛋白框架区的第一序列和编码期望的免疫球蛋白互补决定区的第二序列集的多核苷酸可以合成地或通过组合适当的cDNA和基因组DNA片段来产生。人恒定区DNA序列可以根据众所周知的程序从多种人细胞中分离。
“嵌合抗体”是以下抗体分子:其中(a)恒定区或其一部分被改变、替代或交换,使得抗原结合位点(可变区)与不同或改变类别、效应功能和/或物种的恒定区或赋予嵌合抗体新特性的完全不同的分子,例如,酶、毒素、激素、生长因子、药物连接;(b)可变区或其一部分被具有不同或改变的抗原特异性的可变区改变、替代或交换。本发明的并且用于根据本发明使用的优选抗体包含人源化和/或嵌合单克隆抗体。
当提及蛋白质或肽时,短语与抗体“特异性(或选择性)结合”或与抗体具有“特异性(或选择性)免疫反应性”是指决定蛋白质通常在蛋白质和其它生物剂的异质群体中的存在的结合反应。因此,在指定免疫测定条件下,特定抗体与特定蛋白质的结合是背景的结合的至少两倍,并且更通常地是背景的结合的10至100倍以上。在此类条件下,与抗体的特异性结合需要针对其对特定蛋白质的特异性进行选择的抗体。例如,多克隆抗体可以被选择为仅获得与所选择抗原而不与其它蛋白具有特异性免疫反应性的抗体的子集。这一选择可以通过减去与其它分子发生交叉反应的抗体来实现。可以使用多种免疫测定形式来选择与特定蛋白质具有特异性免疫反应性的抗体。例如,常规地使用固相ELISA免疫测定以选择与蛋白质具有特异性免疫反应性的抗体(对于可以用于确定特异性免疫反应性的免疫测定方式和条件的描述,参见例如,Harlow和Lane,《使用抗体:实验室手册》(1998))。
“配体”是指能够与受体或抗体、抗体变体、抗体区或其片段结合的药剂,例如多肽或其它分子。
用于将治疗剂与抗体缀合的技术是众所周知的(参见例如,Arnon等人,“用于在癌症疗法中免疫靶向药物的单克隆抗体(Monoclonal Antibodies For Immunotargeting OfDrugs In Cancer Therapy)”,于《单克隆抗体与癌症疗法》中;Reisfeld等人(编辑),第243-56页(Alan R.Liss公司1985);Hellstrom等人,“用于药物递送的抗体(AntibodiesFor Drug Delivery)”,于《受控药物递送(Controlled Drug Delivery)》(第2版)中;Robinson等人(编辑),第623-53页(Marcel Dekker公司1987);Thorpe,“癌症疗法中细胞毒剂的抗体载剂:综述(Antibody Carriers Of Cytotoxic Agents In Cancer Therapy:AReview)”,于《单克隆抗体'84:生物学和临床应用(Monoclonal Antibodies'84:Biological And Clinical Applications)》,Pinchera等人(编辑),第475-506页(1985)中;以及Thorpe等人,“抗体毒素缀合物的制备和细胞毒性特性(The Preparation AndCytotoxic Properties Of Antibody-Toxin Conjugates)”,《免疫学综述(Immunol.Rev.)》,62:119-58(1982))。如本文所使用的,术语“抗体-药物缀合物”或“ADC”是指与抗体缀合或以其它方式共价结合的治疗剂。
对于本文所描述的特异性蛋白质,所命名蛋白质包含维持蛋白质转录因子活性(例如,维持在相较于天然蛋白质的活性至少50%、80%、90%、95%、96%、97%、98%、99%或100%的活性内)的蛋白质的天然存在的形式、变体或同源物中的任一种。在一些实施例中,变体或同源物跨整个序列或序列的一部分(例如,50个、100个、150个或200个连续氨基酸部分)具有相较于天然存在的形式至少90%、95%、96%、97%、98%、99%或100%的氨基酸序列同一性。在其它实施例中,蛋白质是通过其NCBI序列参考鉴定的蛋白质。在其它实施例中,蛋白质是通过其NCBI序列参考鉴定的蛋白质、其同源物或功能片段。
术语“基因”意指参与产生蛋白质的DNA区段;其包含编码区之前和之后的区(前导和拖尾)以及个别编码区段(外显子)之间的间插序列(内含子)。前导、拖尾以及内含子包含基因转录和翻译期间必需的调节元件。进一步地,“蛋白质基因产物”是由特定基因表达的蛋白质。
术语“质粒”、“载体”或“表达载体”是指编码基因和/或基因表达所必需的调节元件的核酸分子。来自质粒的基因的表达可以顺式或反式发生。如果基因以顺式进行表达,则基因和调节元件由同一质粒编码。反式表达是指其中基因和调节元件由单独的质粒编码的情况。
术语“转染(transfection)”、“转导(transduction)”、“转染(transfecting)”或“转导(transducing)”可以互换使用并且被定义为将核酸分子或蛋白质引入到细胞的过程。使用非病毒或基于病毒的方法将核酸引入到细胞。核酸分子可以是编码完整蛋白质或其功能部分的基因序列。非病毒转染方法包含不使用病毒DNA或病毒颗粒作为递送系统以将核酸分子引入到细胞中的任何适当的转染方法。示例性非病毒转染方法包含磷酸钙转染、脂质体转染、核转染、声孔效应、通过热休克进行的转染、磁性转染和电穿孔。在一些实施例中,遵循本领域众所周知的标准程序使用电穿孔将核酸分子引入到细胞中。对于基于病毒的转染方法,可以在本文所述的方法中使用任何有用的病毒载体。病毒载体的实例包含但不限于逆转录病毒、腺病毒、慢病毒和腺相关病毒载体。在一些实施例中,遵循本领域众所周知的标准程序使用逆转录病毒载体将核酸分子引入到细胞中。术语“转染”或“转导”还指将蛋白质从外部环境引入到细胞中。通常,蛋白质的转导或转染依赖于能够穿过细胞膜的肽或蛋白质与所关注蛋白质的附着。参见例如,Ford等人(2001)《基因疗法(GeneTherapy)》8:1-4和Prochiantz(2007)《自然方法(Nat.Methods)》4:119-20。
“标记”或“可检测部分”是可通过光谱、光化学、生物化学、免疫化学、化学或其它物理手段检测的组合物。例如,有用的标记包含32P、荧光染料、电子致密试剂、酶(例如,如在ELISA中通常使用的)、生物素、地高辛(digoxigenin)或半抗原和蛋白质或可以例如通过将放射性标记掺入到与靶肽具有特异性反应性的肽或抗体中而变得可检测的其它实体。可以使用本领域已知的用于将抗体与标记缀合的任何适当方法,例如使用以下描述的方法:Hermanson,《生物缀合物技术(Bioconjugate Techniques)》1996,圣地亚哥的学术出版社公司(Academic Press,Inc.,San Diego)。
当标记或可检测部分是放射性金属或顺磁性离子时,药剂可以与另一种具有长尾部的长尾试剂发生反应,所述长尾部具有附着到长尾部以与这些离子结合的一个或多个螯合基团。长尾部可以是聚合物,如聚赖氨酸、多糖,或具有侧基的其它衍生的链或可衍生链,金属或离子可以添加到所述侧基上进行结合。可以根据本公开使用的螯合基团的实例包含但不限于乙二胺四乙酸(EDTA)、二乙烯三胺五乙酸(DTPA)、DOTA、NOTA、NETA、TETA、卟啉、聚胺、冠醚、双缩氨基硫脲、聚肟以及类似基团。螯合物通常通过基团与PSMA抗体或功能抗体片段连接,所述基团使得能够在免疫反应性损失最小并且聚集和/或内部交联最小的情况下与分子形成键。当与本文所述的抗体和载剂一起使用时,与非放射性金属,如锰、铁和钆络合的相同螯合物可用于MRI。如NOTA、DOTA和TETA等大环螯合物与各种金属和放射性金属一起是有用的,所述各种金属和放射性金属分别包含但不限于镓、钇和铜的放射性核素。可以使用对于稳定结合核素所关注的其它环型螯合物,如大环聚醚,如用于RAIT的223Ra。在某些实施例中,螯合部分可以用于使如Al-18F络合物等PET显像剂附着到靶分子以用于PET分析。
“接触”根据其普通一般含义使用,并且是指允许至少两种不同的物种(例如,抗体和抗原)变得足够接近以发生反应、相互作用或物理接触的过程。然而,应当理解的是,所得反应产物可以由所添加的试剂之间的反应或由来自一种或多种所添加的试剂的中间体直接产生,所述中间体可以在反应混合物中产生。
术语“接触”可以包含允许两种物种发生反应、相互作用或物理接触,其中所述两种物种可以是例如本文所提供的药物组合物和细胞。在实施例中,接触包含例如允许如本文所描述的药物组合物与细胞相互作用。
如本文所使用的,“细胞”是指执行足以保持或复制其基因组DNA的代谢功能或其它功能的细胞。细胞可以通过本领域众所周知的方法来鉴定,包含例如完整膜的存在、通过特定染料进行的染色、产生子代的能力或在配子的情况下与第二配子组合以产生活的后代的能力。细胞可以包含原核细胞和真核细胞。原核细胞包含但不限于细菌。真核细胞包含但不限于酵母细胞和源自植物和动物的细胞,例如哺乳动物细胞、昆虫(例如,夜蛾(spodoptera))细胞和人细胞。
当关于例如细胞、核酸、蛋白质或载体使用时,术语“重组”表示细胞、核酸、蛋白质或载体已经通过引入异源核酸或蛋白质或改变天然核酸或蛋白质而被修饰,或者细胞源自如此修饰的细胞。因此,例如,重组细胞表达不存在于天然(非重组)形式的细胞内的基因,或表达以其它方式异常表达、表达不足或根本不表达的天然基因。转基因细胞和植物是通常由于重组方法而表达异源基因或编码序列的转基因细胞和植物。
当应用于核酸或蛋白质时,术语“分离的”表示所述核酸或蛋白质基本上不含在天然状态下与其缔合的其它细胞组分。例如,其可以处于均匀状态并且可以处于干燥或水溶液中。纯度和均匀性通常使用分析化学技术,如聚丙烯酰胺凝胶电泳或高效液相色谱法确定。作为制剂中存在的主要物种的蛋白质是基本上纯化的。
当关于核酸的部分使用时,术语“异源的”表明核酸包括在自然界中未发现彼此之间的相同关系的两个或更多个序列。例如,核酸通常是重组地产生的,具有来自不相关基因的布置成产生新的功能核酸的两个或更多个序列,例如来自一个来源的启动子和来自另一个来源的编码区。类似地,异源蛋白质指示蛋白质包括在自然界中未发现彼此之间的相同关系的两个或更多个子序列(例如,融合蛋白)。
术语“外源的”是指来源于给定细胞或生物体外部的分子或物质(例如,化合物,核酸或蛋白质)。例如,如本文所提及的,“外源启动子”是并不来源于其所表达的细胞或生物体的启动子。相反,术语“内源的”或“内源启动子”是指给定细胞或生物体原生的或来源于给定细胞或生物体内的分子或物质。
如本文所定义的,关于细胞增殖(例如,癌细胞增殖)的术语“抑制(inhibition)”、“抑制(inhibit)”、“抑制(inhibiting)”等意指负面地影响细胞(例如,减少增殖)或杀伤细胞。在一些实施例中,抑制是指疾病或疾病症状(例如,癌症、癌细胞增殖)的减少。因此,抑制至少部分地包含部分或完全阻断刺激、减少、阻止或延迟活化、脱敏或下调信号转导或酶活性或蛋白质的量。类似地,“抑制剂”是例如通过结合、部分或全部阻断、降低、预防、延迟、灭活、脱敏或下调活性(例如,受体活性或蛋白活性)来抑制受体或另一种蛋白质的化合物或蛋白质。
如本文所定义的,关于蛋白质-抑制剂相互作用的术语“抑制(inhibition)”“抑制(inhibit)”、“抑制(inhibiting)”等意指相对于在不存在抑制剂的情况下蛋白质的活性或功能,负面地影响(例如,降低)蛋白质的活性或功能。
因此,可互换的术语“抑制剂(inhibitor)”、“阻遏物(repressor)”或“拮抗剂(antagonist)”或“下调剂(downregulator)”是指能够可检测地降低给定基因或蛋白质的表达或活性的物质。相比于在不存在拮抗剂的情况下的对照,拮抗剂可以使蛋白质表达或活性降低10%、20%、30%、40%、50%、60%、70%、80%、90%或更多。在某些情况下,蛋白质表达或活性为不存在拮抗剂的情况下的表达或活性的1/1.5、1/2、1/3、1/4、1/5、1/10或甚至更低。
术语“表达”包含涉及多肽产生的任何步骤,包含但不限于转录、转录后修饰、翻译、翻译后修饰和分泌。可以使用用于检测蛋白质的常规技术(例如,ELISA、蛋白印迹、流式细胞术、免疫荧光、免疫组织化学等)来检测表达。
“生物样品”或“样品”是指获自或源自受试者或患者的材料。生物样品包含组织切片,如活检和尸检样品,以及提取用于组织学目的的冷冻切片。此类样品包含体液,如血液和血液级分或血液产物(例如,血清、血浆、血小板、红细胞等)、痰、组织、经培养的细胞(例如,原代培养物、外植体以及经转化的细胞)、粪便、尿、滑液、关节组织、滑膜组织、滑膜细胞、成纤维细胞样滑膜细胞、巨噬细胞样滑膜细胞、免疫细胞、造血细胞、成纤维细胞、巨噬细胞、T细胞等。生物样品通常获自真核生物体,如哺乳动物,如灵长类动物,例如黑猩猩或人;牛;狗;猫;啮齿动物,例如,豚鼠、大鼠、小鼠;兔子;或鸟;爬行动物;或鱼。
“对照”或“标准对照”是指用作参照物,通常是已知参照物,以与测试样品、测量结果或值进行比较的样品、测量结果或值。例如,测试样品可以取自疑似患有给定疾病(例如,癌症)的患者,并且可以与已知正常(未患病)个体(例如,标准对照受试者)进行比较。标准对照还可以表示从未患有给定疾病的类似个体(例如,标准对照受试者),例如,具有类似医疗背景、相同年龄、体重等的健康个体,的群体(即,标准对照群体)收集的平均测量结果或值。标准对照值还可以获自同一个体,例如在疾病发作之前从患者早前获得的样品。例如,可以设计对照,以基于药理学数据(例如,半衰期)或治疗量度(例如,副作用的比较)来比较治疗益处。对照对于确定数据的显著性也是有价值的。例如,如果对照中的给定参数的值广泛变化,那么测试样品中的变化将不被视为显著的。技术人员将认识到,可以设计标准对照用于评估任何数量的参数(例如,RNA水平、蛋白质水平、特定细胞类型、特定体液、特定组织等)。
本领域的技术人员将理解,在给定情形下哪种标准对照是最适合的,并且能够基于与标准对照值的比较来分析数据。标准对照对于确定数据的显著性(例如,统计显著性)也是有价值的。例如,如果标准对照中的给定参数的值广泛变化,那么测试样品中的变化将不被视为显著的。
“患者”或“有需要的受试者”是指患有或易于患上可以通过施用如本文所提供的组合物或药物组合物进行治疗的疾病或病状的活生物体。非限制性实例包含人、其它哺乳动物、牛、大鼠、小鼠、狗、猴、山羊、绵羊、牛、鹿和其它非哺乳动物。在一些实施例中,患者是人。
术语“疾病”或“病状”是指能够用本文所提供的化合物或方法治疗的患者或受试者所处的状态或健康状况。所述疾病可以是癌症。所述癌症可以是指实体瘤恶性肿瘤。实体瘤恶性肿瘤包含可能不含流体或囊肿的恶性肿瘤。例如,实体瘤恶性肿瘤可以包含乳腺癌、卵巢癌、胰腺癌、宫颈癌、胃癌、肾癌、头颈癌、骨癌、皮肤癌或前列腺癌。在一些另外的实例中,“癌症”是指人类癌症和癌、肉瘤、腺癌、淋巴瘤、白血病等,包含实体癌和淋巴癌、肾癌、乳腺癌、肺癌、膀胱癌、结肠癌、卵巢癌、前列腺癌、胰腺癌、胃癌、脑癌、头颈癌、皮肤癌、子宫癌、睾丸癌、神经胶质瘤、食道癌和肝癌(包含肝癌(hepatocarcinoma))、淋巴瘤,包含B急性淋巴母细胞淋巴瘤、非霍奇金氏淋巴瘤(Non-Hodgkin's Lymphoma)(例如,伯基特氏淋巴瘤(Burkitt's lymphoma)、小细胞淋巴瘤和大细胞淋巴瘤)、霍奇金氏淋巴瘤(Hodgkin'slymphoma)、白血病(包含急性髓系白血病(AML)、ALL和CML)或多发性骨髓瘤。
如本文所使用的,术语“癌症”是指在哺乳动物中发现的所有类型的癌症、赘生物或恶性肿瘤,包含白血病、淋巴瘤、黑色素瘤、神经内分泌肿瘤、癌和肉瘤。可以用本文提供的化合物、药物组合物或方法进行治疗的示例性癌症包含:淋巴瘤(例如,套细胞淋巴瘤、滤泡性淋巴瘤、弥漫大B细胞淋巴瘤、边缘带状淋巴瘤、伯基特氏淋巴瘤)、肉瘤、膀胱癌、骨癌、脑瘤、宫颈癌、结肠癌、食道癌、胃癌、头颈癌、肾癌、骨髓瘤、甲状腺癌、白血病、前列腺癌、乳腺癌(例如,三阴性、ER阳性、ER阴性、化学疗法抗性、赫塞汀(herceptin)抗性、HER2阳性、阿霉素抗性、他莫苷芬抗性、导管癌、小叶癌、原发性、转移性)、卵巢癌、胰腺癌、肝癌(例如,肝细胞癌)、肺癌(例如,非小细胞肺癌、鳞状细胞肺癌、腺癌、大细胞肺癌、小细胞肺癌、类癌、肉瘤)、多形性胶质母细胞瘤、神经胶质瘤、黑色素瘤、前列腺癌、去势抵抗性前列腺癌、乳腺癌、三阴性乳腺癌、胶质母细胞瘤、卵巢癌、肺癌、鳞状细胞癌(例如,头、颈或食管)、结肠直肠癌、白血病(例如,淋巴细胞白血病、慢性淋巴细胞白血病、毛细胞性白血病)、急性髓系白血病、淋巴瘤、B细胞淋巴瘤或多发性骨髓瘤。另外的实例包含甲状腺癌、内分泌系统癌、脑癌、乳癌、宫颈癌、结肠癌、头颈癌、食道癌、肝癌、肾癌、肺癌、非小细胞肺癌、黑色素瘤、间皮瘤、卵巢癌、肉瘤、胃癌、子宫癌或神经管胚细胞瘤、霍奇金氏病、非霍奇金氏淋巴瘤、多发性骨髓瘤、神经母细胞瘤、神经胶质瘤、多形性神经胶母细胞瘤、卵巢癌、横纹肌肉瘤、原发性血小板增多、原发性巨球蛋白血症、原发性脑瘤、癌症、恶性胰腺胰岛瘤、恶性类癌、尿膀胱癌、癌前皮肤病变、睾丸癌、淋巴瘤、甲状腺癌、神经母细胞瘤、食道癌、泌尿生殖道癌、恶性高钙血症、子宫内膜癌、肾上腺皮质癌、内分泌或外分泌胰腺赘生物、甲状腺髓样癌(medullary thyroid cancer)、甲状腺髓样癌(medullary thyroid carcinoma)、黑色素瘤、结肠直肠癌、乳头状甲状腺癌、肝细胞癌、乳头佩吉特氏病(Paget's Disease of theNipple)、叶状肿瘤、小叶癌、导管癌、胰腺星状细胞癌、肝星状细胞癌或前列腺癌。
术语“白血病”广义上是指血液形成器官的渐进性恶性疾病,并且通常特征在于白细胞以及其前体在血液和骨髓中的增殖和发育畸变。白血病通常在临床上基于以下进行分类:(1)急性病或慢性病的持续时间和特性;(2)所涉及的细胞的类型;髓系(骨髓性的)、淋巴样(淋巴性的)或单核细胞的;以及(3)血液-白血病性或非白血病性(亚白血病性)中的异常细胞数量的增加或非增加。可以用本文所提供的化合物或方法治疗的示例性白血病包含例如急性髓系白血病、急性非淋巴细胞白血病、慢性淋巴细胞白血病、急性粒细胞白血病、慢性粒细胞白血病、急性早幼粒细胞白血病、成人T细胞白血病、非白血性白血病(aleukemic leukemia)、白血病性白血病(leukocythemic leukemia)、嗜碱粒细胞白血病、母细胞白血病、牛白血病、慢性髓细胞性白血病、皮肤白血病、胚胎性白血病、嗜酸性粒细胞白血病、格罗氏白血病(Gross'leukemia)、毛细胞白血病、成血细胞性白血病(hemoblasticleukemia)、成血细胞性白血病(hemocytoblastic leukemia)、组织细胞性白血病、干细胞白血病、急性单核细胞白血病、白细胞减少性白血病、淋巴性白血病、成淋巴细胞性白血病、淋巴细胞性白血病、成淋巴性白血病(lymphogenous leukemia)、淋巴样白血病、淋巴肉瘤细胞白血病、肥大细胞白血病、巨核细胞性白血病、微成髓细胞性白血病(micromyeloblastic leukemia)、单核细胞性白血病、成髓细胞性白血病、髓细胞性白血病、髓系粒细胞性白血病、髓单核细胞白血病、内格利氏白血病(Naegeli leukemia)、浆细胞白血病、多发性骨髓瘤、浆细胞性白血病、早幼粒细胞白血病、里德尔氏细胞白血病(Rieder cell leukemia)、希林氏白血病(Schilling's leukemia)、干细胞白血病、亚白血病性白血病和未分化细胞白血病。
术语“肉瘤”通常是指由类似于胚胎结缔组织的物质构成并且通常由包埋在纤丝状或均质物质中的紧密压积细胞构成的肿瘤。可以用本文所提供的化合物或方法治疗的肉瘤包含软骨肉瘤、纤维肉瘤、淋巴肉瘤、黑色素肉瘤、粘液肉瘤、骨肉瘤、阿贝西氏肉瘤(Abemethy's sarcoma)、脂肉瘤、脂肪肉瘤、腺泡状软组织肉瘤、成釉细胞肉瘤、葡萄样肉瘤、绿色癌肉瘤、绒毛膜癌、胚胎肉瘤、威尔姆斯氏肿瘤肉瘤(Wilms'tumor sarcoma)、子宫内膜肉瘤、间质肉瘤、尤文氏肉瘤(Ewing's sarcoma)、筋膜肉瘤、成纤维细胞肉瘤、巨细胞肉瘤、粒细胞肉瘤、霍奇金氏肉瘤、特发性多发性色素沉着出血性肉瘤、B细胞的免疫母细胞肉瘤、淋巴瘤、T细胞的免疫母细胞肉瘤、詹恩逊氏肉瘤(Jensen's sarcoma)、卡波西氏肉瘤(Kaposi's sarcoma)、库普弗细胞肉瘤(Kupffer cell sarcoma)、血管肉瘤、白血病性肉瘤、恶性间质瘤肉瘤、骨膜外肉瘤、网状细胞肉瘤、劳斯氏肉瘤(Rous sarcoma)、浆液性囊肿肉瘤(serocystic sarcoma)、滑膜肉瘤或毛细血管扩张性肉瘤。
术语“黑色素瘤”意指由皮肤和其它器官的黑色素细胞系统引起的肿瘤。可以用本文所提供的化合物或方法治疗的黑色素瘤包含例如肢端雀斑样痣黑色素瘤、无黑色素性黑色素瘤、良性幼年黑色素瘤、克劳德曼氏黑色素瘤(Cloudman's melanoma)、S91黑色素瘤、哈丁-帕西黑色素瘤(Harding-Passey melanoma)、幼年黑色素瘤、恶性雀斑样痣黑色素瘤、恶性黑色素瘤、结节性黑色素瘤、甲下黑色素瘤或浅表扩散性黑色素瘤。
术语“癌”是指由上皮细胞构成的恶性新生长,所述上皮细胞倾向于浸润周围组织并引起转移。可以用本文所提供的化合物或方法治疗的示例性癌包含例如甲状腺髓样癌、家族性甲状腺髓样癌、腺泡癌、腺泡状癌、腺性囊性癌、腺样囊性癌、腺癌、肾上腺皮质癌、肺泡癌、肺泡细胞癌、基底细胞癌、基底样细胞瘤、基底细胞样癌、基底鳞状细胞癌、细支气管肺泡癌、细支气管癌、支气管癌、脑状癌、胆管细胞癌、绒毛膜癌、胶样癌、粉刺癌、子宫体癌、筛状癌、铠甲状癌、癌疮(carcinoma cutaneum)、柱状癌、柱状细胞癌、管癌、硬癌、胚胎性癌、髓样癌、表皮样癌、腺样上皮细胞癌、外植癌、溃疡性癌(carcinoma ex ulcere)、纤维癌、胶状癌(gelatiniforni carcinoma)、胶样癌(gelatinous carcinoma)、巨大细胞癌、巨细胞癌、腺癌、粒层细胞癌、发母质癌(hair-matrix carcinoma)、多血癌(hematoidcarcinoma)、肝细胞癌、许特尔氏细胞癌(Hurthle cell carcinoma)、玻质状癌(hyalinecarcinoma)、肾上腺样癌、幼稚型胚胎性癌、原位癌、表皮内癌、上皮内癌、克龙派切尔氏癌(Krompecher's carcinoma)、库尔奇茨基细胞癌(Kulchitzky-cell carcinoma)、大细胞癌、豆状癌(lenticular carcinoma)、豆状癌(carcinoma lenticulare)、脂肪瘤癌(lipomatous carcinoma)、淋巴上皮癌、髓样癌(carcinoma medullare)、髓样癌(medullary carcinoma)、黑色素癌、软癌、粘液癌、粘液性癌、粘液细胞癌(carcinomamucocellulare)、粘液表皮样癌、粘液质癌(carcinoma mucosum)、粘液样癌、粘液瘤样癌、鼻咽癌、燕麦细胞癌、骨化性癌(carcinoma ossificans)、骨样癌(osteoid carcinoma)、乳头状癌、门静脉周癌、浸润前癌、棘细胞癌、软糊状癌(pultaceous carcinoma)、肾脏肾细胞癌、储备细胞癌、肉瘤样癌、施奈德癌(schneiderian carcinoma)、硬癌、阴囊癌(carcinomascroti)、印戒细胞癌、单纯癌、小细胞癌、马铃薯状癌、球状细胞癌、梭形细胞癌、髓状癌(carcinoma spongiosum)、鳞状癌、鳞状细胞癌、绳捆癌、血管扩张性癌(carcinomatelangiectaticum)、毛细管扩张癌(carcinoma telangiectodes)、移行细胞癌、块状癌(carcinoma tuberosum)、结节性皮癌(tuberous carcinoma)、疣状癌或绒毛状癌。
如本文所使用的,术语“转移”、“转移性”和“转移性癌症”可互换使用,并且指代增殖性疾病或病症(例如,癌症)从一个器官向另一个不相邻器官或身体部分的扩散。癌症出现在起始部位,例如乳房,这一部位被称为原发性肿瘤,例如原发性乳腺癌。原发性肿瘤或起始部位中的一些癌细胞获得了穿透和渗透局部区域中的周围正常组织的能力和/或穿透通过系统循环到体内的其它部位和组织的淋巴系统或血管系统壁的能力。由原发性肿瘤的癌细胞形成的第二可临床检测到的肿瘤被称为转移性或继发性肿瘤。当癌细胞转移时,推测转移性肿瘤和其细胞与原发性肿瘤类似。因此,如果肺癌转移到乳房,则乳房部位处的继发性肿瘤由异常肺细胞而非异常乳腺细胞组成。乳房中的继发性肿瘤被称为转移性肺癌。因此,短语转移性癌症是指其中受试者患有或曾经患有原发性肿瘤并患有一种或多种继发性肿瘤的疾病。短语非转移性癌症或患有非转移性癌症的受试者是指其中受试者患有原发性肿瘤但不患有一种或多种继发性肿瘤的疾病。例如,转移性肺癌是指患有原发性肺肿瘤或有原发性肺肿瘤病史并且在第二位置或多个位置,例如,在乳腺中具有一种或多种继发性肿瘤的受试者的疾病。
在与疾病(例如,蛋白质相关疾病、与RKY活性相关的癌症、RKY相关的癌症、RKY相关的疾病(例如,癌症、炎性疾病、自身免疫性疾病或感染性疾病))相关的物质或物质活性或功能的上下文中,术语“相关”或“与……相关”意指疾病(例如,癌症、炎性疾病、自身免疫性疾病或感染性疾病)是由(全部或部分)物质或物质活性或功能引起的,或疾病症状是由(全部或部分)物质或物质活性或功能引起的。如本文所使用的,如果病原体可以是治疗疾病的靶标,则其被描述为与疾病相关。例如,与Ryk活性或功能相关的癌症或RKY相关的疾病(例如,癌症、炎性疾病、自身免疫性疾病或感染性疾病)可以用RKY调节剂或RKY抑制剂治疗,在这种情况下,RKY活性或功能增加(例如,信号传导通路活性)引起疾病(例如,癌症、炎性疾病、自身免疫性疾病或感染性疾病)。例如,与RKY活性或功能相关的炎性疾病或RKY相关的炎性疾病可以用RKY调节剂或RKY抑制剂治疗,在这种情况下,RKY活性或功能增加(例如,信号传导通路活性)引起疾病。
如本文所使用的,术语“信号传导通路”是指细胞组分与任选地细胞外组分(例如,蛋白质、核酸、小分子、离子、脂质)之间的一系列相互作用,所述相互作用将一种组分的变化传递到一种或多种其它组分,这进而可以将变化传递到另外的组分,所述变化任选地被传播到其它信号传导通路组分。
如本文所使用的,术语“异常”是指与正常不同。当用于描述酶促活性时,异常是指大于或小于正常对照或正常非患病对照样品的平均的活性。异常活性可以指代引起疾病的活性的量,其中使异常活性返回到正常或非疾病相关的量(例如,通过使用如本文所描述的方法)会导致疾病或一种或多种疾病症状减少。
如本文所提及的,“治疗剂”是可用于治疗或预防如癌症(例如,白血病)等疾病的组合物。在实施例中,治疗剂是抗癌剂。“抗癌剂”按照其普通一般含义使用,并且是指具有抗赘生物特性或抑制细胞生长或增殖的能力的组合物(例如,化合物、药物、拮抗剂、抑制剂、调节剂)。在实施例中,抗癌剂是化学治疗剂。在实施例中,抗癌剂是本文鉴定的在治疗癌症的方法中具有效用的药剂。在实施例中,抗癌剂是由FDA或除美国以外的国家的类似监管机构批准用于治疗癌症的药剂。
如本文所使用的,“抗癌剂”是指用于通过破坏或抑制癌细胞或组织来治疗癌症的分子(例如,化合物、肽、蛋白质、核酸、0103)。抗癌剂对于某些癌症或某些组织可以具有选择性。在实施例中,本文的抗癌剂可以包含表观遗传抑制剂和多激酶抑制“抗癌剂”,并且“抗癌剂”按照其普通一般含义使用,并且是指具有抗肿瘤特性或抑制细胞的生长或增殖的能力的组合物(例如,化合物、药物、拮抗剂、抑制剂、调节剂)。在一些实施例中,抗癌剂是化学治疗剂。在一些实施例中,抗癌剂是本文鉴定的在治疗癌症的方法中具有效用的药剂。在一些实施例中,抗癌剂是由FDA或除美国以外的其它国家的类似管理机构批准用于治疗癌症的药剂。抗癌剂的实例包含但不限于MEK(例如,MEK1、MEK2或MEK1和MEK2)抑制剂(例如,XL518、CI-1040、PD035901、司美替尼(selumetinib)/AZD6244、GSK1120212/曲美替尼(trametinib)、GDC-0973、ARRY-162、ARRY-300、AZD8330、PD0325901、U0126、PD98059、TAK-733、PD318088、AS703026、BAY 869766)、烷基化剂(例如,环磷酰胺、异环磷酰胺、苯丁酸氮芥(chlorambucil)、白消安(busulfan)、美法仑(melphalan)、甲氮芥(mechlorethamine)、尿喃唳氮芥(uramustine)、噻替哌(thiotepa)、亚硝基脲、氮芥(例如,氯乙胺、环磷酰胺、苯丁酸氮芥、美法仑)、亚乙基亚胺和甲基三聚氰胺(例如,六甲基三聚氰胺、噻替哌)、烷基磺酸盐(例如,白消安)、亚硝基脲(例如,卡莫司汀(carmustine)、洛美司汀(lomusitne)、司莫司汀(semustine)、链佐星(streptozocin))、三氮烯(达卡巴嗪(decarbazine))、抗代谢物(例如,5-硫唑嘌呤、亚叶酸、卡培他滨(capecitabine)、氟达拉滨(fludarabine)、吉西他滨(gemcitabine)、培美曲塞(pemetrexed)、雷替曲塞(raltitrexed)、叶酸类似物(例如,甲氨蝶呤)或嘧啶类似物(例如,氟尿嘧啶、氟尿苷(floxouridine)、阿糖胞苷)、嘌呤类似物(例如,巯基嘌呤、硫代鸟嘌呤、喷司他丁(pentostatin)等)、植物生物碱(例如,长春新碱(vincristine)、长春花碱(vinblastine)、长春瑞滨(vinorelbine)、长春地辛(vindesine)、鬼臼毒素(podophyllotoxin)、紫杉醇(paclitaxel)、多西他赛(docetaxel)等)、拓扑异构酶抑制剂(例如,伊立替康(irinotecan)、拓扑替康(topotecan)、安吖啶(amsacrine)、依托泊苷(etoposide)(VP16)、磷酸依托泊苷(etoposide phosphate)、替尼泊苷(teniposide)等)、抗肿瘤抗生素(例如,多柔比星(doxorubicin)、阿霉素(adriamycin)、柔红霉素(daunorubicin)、表柔比星(epirubicin)、放线菌素(actinomycin)、博来霉素(bleomycin)、丝裂霉素(mitomycin)、米托蒽醌(mitoxantrone)、普卡霉素(plicamycin)等)、铂基化合物(例如,顺铂(cisplatin)、奥沙利铂(oxaloplatin)、卡铂(carboplatin))、蒽醌(例如,米托蒽醌)、经取代的尿素(例如,羟基脲)、甲基肼衍生物(例如,丙卡巴肼(procarbazine))、肾上腺皮质激素抑制剂(例如,米托坦(mitotane)、氨鲁米特(aminoglutethimide))、表鬼臼毒素(epipodophyllotoxin)(例如,依托泊苷)、抗生素(例如,柔红霉素、多柔比星、博来霉素)、酶(例如,L-天冬酰胺酶)、促分裂原活化蛋白激酶信号传导的抑制剂(例如,U0126、PD98059、PD184352、PD0325901、ARRY-142886、SB239063、SP600125、BAY 43-9006、渥曼青霉素(wortmannin)或LY294002、Syk抑制剂、mTOR抑制剂、抗体(例如,利妥昔单抗(rituxan))、棉子酚(gossyphol)、更纳森(genasense)、多元酚E、氯夫辛(Chlorofusin)、全反式视黄酸(ATRA)、苔藓抑素、肿瘤坏死因子相关的凋亡诱导配体(TRAIL)、5-氮杂-2'-脱氧胞苷、全反式视黄酸、多柔比星、长春新碱、依托泊苷、吉西他滨、伊马替尼(imatinib)(Gleevec.RTM.)、格尔德霉素(geldanamycin)、17-N-烯丙基氨基-17-去甲氧基格尔德霉素(17-AAG)、夫拉平度(flavopiridol)、LY294002、硼替佐米(bortezomib)、曲妥珠单抗(trastuzumab)、BAY 11-7082、PKC412、PD184352、20-epi-1、25二羟维生素D3;或5-乙炔基尿嘧啶。
抗癌剂的进一步的实例包含但不限于阿比特龙(abiraterone);阿柔比星(aclarubicin);酰基富烯(acylfulvene);腺环戊醇;阿多来新(adozelesin);阿地白介素;ALL-TK拮抗剂;六甲蜜胺;氨莫司汀(ambamustine);阿米多克斯(amidox);氨磷汀;氨基丙酮酸;氨柔比星(amrubicin);安吖啶;阿那格雷(anagrelide);阿那曲唑(anastrozole);穿心莲内酯;血管生成抑制剂;拮抗剂D;拮抗剂G;安雷利克斯(antarelix);抗背侧化形态发生蛋白-1;抗雄激素;前列腺癌;抗雌激素;抗瘤酮;反义寡核苷酸;甘氨酸阿非迪霉素(aphidicolin glycinate);细胞凋亡基因调节剂;细胞凋亡调节剂;无嘌呤核酸;ara-CDP-DL-PTBA;精氨酸脱氨酶;阿宿拉克林(asulacrine);阿他美坦(atamestane);阿莫司汀(atrimustine);阿西那斯它汀1(axinastatin 1);阿西那斯它汀2;阿西那斯它汀3;阿扎西隆(azasetron);阿扎脱辛(azatoxin);重氮酪氨酸;浆果赤霉素III衍生物;巴拉诺尔(balanol);巴马司他(batimastat);BCR/ABL拮抗剂;苯唑氯辛;苯甲酰星形孢菌素;β内酰胺衍生物;β-阿列辛(beta-alethine);亚阿克拉霉素B;桦木酸;bFGF抑制剂;比卡鲁胺(bicalutamide);比生群(bisantrene);双吖丙啶基精胺;双萘法德(bisnafide);双脱汀尼A;比折来新(bizelesin);布赖氟雷(breflate);溴匹立明(bropirimine);布朵替坦(budotitane);丁胱亚磺酰亚胺;钙泊三醇;钙磷酸蛋白C;喜树碱衍生物;金丝雀痘IL-2;卡培他滨(capecitabine);甲酰胺基氨基三唑;羧基胺基三唑;CaRest M3;CARN 700;软骨源性抑制剂;卡折来新(carzelesin);酪蛋白激酶抑制剂(ICOS);粟树精胺;杀菌肽B;西曲瑞克(cetrorelix);卟吩;磺酰胺氯代喹喔啉;西卡前列素;顺卟啉;克拉屈滨(cladribine);氯米芬类似物;克霉唑;克林斯姆汀A(collismycin A);克林斯姆汀B;康普瑞汀A4(combretastatin A4);康普瑞汀类似物;康那格林(conagenin);克拉泊西汀816(crambescidin 816);克雷斯托(crisnatol);念珠藻素8;念珠藻素A衍生物;克由若辛A(curacin A);环戊蒽醌;环钼;噻泊米辛(cypemycin);阿糖胞苷烷磷酯;溶细胞因子;噻脱斯汀(cytostatin);达昔单抗;地西他滨(decitabine);脱水膜海鞘素B;德舍瑞林(deslorelin);地塞米松(dexamethasone);地西佛斯米(dexifosfamide);右雷佐生;右维拉帕米;地吖醌;膜海鞘素B;第多克斯(didox);二乙基去甲精胺;二氢-5-氮杂胞苷;9-二氧黄溶霉素;联苯螺莫司汀(diphenyl spiromustine);二十二醇;多拉司琼(dolasetron);去氧氟尿苷;屈洛昔芬(droloxifene);屈大麻酚;倍癌霉素SA(duocarmycin SA);依布硒啉(ebselen);依考莫司汀(ecomustine);依地福新(edelfosine);依决洛单抗;依氟鸟氨酸;榄香烯;乙嘧替氟(emitefur);表柔比星;爱普列特(epristeride);雌莫司汀类似物(estramustine analogue);雌激素激动剂;雌激素拮抗剂;依他硝唑(etanidazole);磷酸依托泊苷;或依西美坦(exemestane)。
抗癌剂的进一步实例包含但不限于法倔唑(fadrozole);法扎拉滨(fazarabine);芬维A胺;非格司亭(filgrastim);非那雄胺(finasteride);夫拉平度(flavopiridol);氟卓斯汀(flezelastine);氟甾酮(fluasterone);氟达拉滨(fludarabine);盐酸氟代柔红霉素(fluorodaunorunicin hydrochloride);福酚美克(forfenimex);福美司坦(formestane);福司曲星(fostriecin);福莫司汀(fotemustine);钆替沙林(gadoliniumtexaphyrin);硝酸镓;加洛他滨(galocitabine);加尼瑞克(ganirelix);白明胶酶抑制剂;吉西他滨;谷胱甘肽抑制剂;合普素凡(hepsulfam);调蛋白;六亚甲基双乙酰胺;金丝桃素;伊班膦酸(ibandronic acid);伊达比星(idarubicin);艾多昔芬(idoxifene);伊决孟酮(idramantone);伊莫福新(ilmofosine);伊洛马司他(ilomastat);咪唑并吖啶酮;咪喹莫特(imiquimod);免疫刺激肽;胰岛素样生长因子-1受体抑制剂;干扰素激动剂;干扰素;白介素;碘苄胍;碘多柔比星(iododoxorubicin);甘薯黑斑霉醇,4-;伊罗普拉(iroplact);伊索拉定(irsogladine);异本伽唑(isobengazole);异同软海绵素B(isohomohalicondrinB);伊他司琼(itasetron);亚普拉可诺林(jasplakinolide);卡哈拉莱F(kahalalide F);三乙酸片螺素N(lamellarin-N triacetate);兰瑞肽(lanreotide);雷拉霉素(leinamycin);来格司亭(lenograstim);香菇多糖硫酸酯(lentinan sulfate);莱普脱斯达汀(leptolstatin);来曲唑(letrozole);白血病抑制因子;白血球α干扰素;亮脯利特(leuprolide)+雌激素+孕酮;亮丙瑞林(leuprorelin);左旋咪唑(levamisole);利阿唑(liarozole);线性聚胺类似物;亲脂性二糖肽;亲脂性铂化合物;赖索林酰胺7(lissoclinamide 7);洛铂(lobaplatin);蚯蚓磷脂;洛美曲索(lometrexol);氯尼达明(lonidamine);洛索蒽醌(losoxantrone);洛伐他汀(lovastatin);洛索立宾(loxoribine);勒托替康(lurtotecan);镏替沙林(lutetium texaphyrin);力索啡林(lysofylline);裂解肽;美坦辛(maitansine);吗诺斯它汀A(mannostatin A);马立马司他(marimastat);马索罗酚(masoprocol);丝抑蛋白(maspin);基质分解素抑制剂(matrilysin inhibitor);基质金属蛋白酶抑制剂(matrix metalloproteinaseinhibitor);美诺立尔(menogaril);美巴隆(merbarone);美替瑞林(meterelin);甲硫氨酸酶(methioninase);胃复安(metoclopramide);MIF抑制剂;米非司酮(mifepristone);米替福星(miltefosine);米立司亭(mirimostim);错配的双链RNA;米托胍腙(mitoguazone);二溴卫矛醇(mitolactol);丝裂霉素类似物;米托萘胺(mitonafide);丝裂毒素成纤维细胞生长因子-皂草素(mitotoxin fibroblast growth factor-saporin);米托蒽醌(mitoxantrone);莫法罗汀(mofarotene);莫拉司亭(molgramostim);单克隆抗体,人绒毛膜促性腺激素;单磷酰脂质A+分枝杆菌细胞壁sk;莫哌达醇(mopidamol);多种耐药性基因抑制剂;基于多肿瘤抑制剂1的疗法;芥末抗癌剂;美卡普罗B(mycaperoxide B);分枝杆菌细胞壁提取物;迈普隆(myriaporone);N-乙酰地那林(N-acetyldinaline);N-取代的苯甲酰胺;那法瑞林(nafarelin);那瑞替喷(nagrestip);纳洛酮+喷他佐辛;纳帕林(napavin);纳啡特品(naphterpin);那托司亭(nartograstim);奈达铂(nedaplatin);奈莫柔比星(nemorubicin);奈立膦酸(neridronic acid);中性肽链内切酶(neutralendopeptidase);尼鲁米特(nilutamide);尼萨米辛(nisamycin);一氧化氮调节剂;硝基氧抗氧化剂;尼图林(nitrullyn);O6-苄基鸟嘌呤;奥曲肽(octreotide);奥可森诺(okicenone);寡核苷酸;奥那司酮(onapristone);昂丹司琼(ondansetron);昂丹司琼;奥罗新(oracin);口服细胞因子诱导剂;奥马铂(ormaplatin);奥沙特隆(osaterone);奥沙利铂(oxaliplatin);奥呷诺辛(oxaunomycin);帕劳胺(palauamine);棕榈酰根瘤菌素(palmitoylrhizoxin);帕米膦酸(pamidronic acid);人参炔三醇(panaxytriol);帕诺米芬(panomifene);帕拉巴汀(parabactin);帕泽普汀(pazelliptine);培门冬酶(pegaspargase);培得星(peldesine);戌聚糖聚硫钠(pentosan polysulfate sodium);喷司他丁(pentostatin);朋脱若唑(pentrozole);全氟溴烷(perflubron);培磷酰胺(perfosfamide);紫苏醇(perillyl alcohol);芬那兹诺辛(phenazinomycin);苯乙酸盐;磷酸酶抑制剂;毕西巴尼(picibanil);盐酸毛果芸香碱(pilocarpine hydrochloride);吡柔比星(pirarubicin);吡曲克辛(piritrexim);普莱斯汀A(placetin A);普莱斯汀B;纤溶酶原激活物抑制剂;铂络合物;铂化合物;铂-三胺络合物;卟吩姆钠(porfimer sodium);泊非霉素(porfiromycin);强的松(prednisone);丙基双吖啶酮(propyl bis-acridone);前列腺素J2;蛋白酶体抑制剂;基于蛋白A的免疫调节剂;蛋白激酶C抑制剂;蛋白激酶C抑制剂;微藻;蛋白酪氨酸磷酸酶抑制剂;嘌呤核苷磷酸化酶抑制剂;红紫素(purpurins);吡唑啉吖啶(pyrazoloacridine);或吡啶氧基化血红蛋白聚氧乙烯缀合物。
抗癌剂的进一步实例包含但不限于raf拮抗剂;雷替曲塞;雷莫司琼(ramosetron);ras法呢基蛋白转移酶抑制剂;ras抑制剂;ras-GAP抑制剂;脱甲基化瑞替普汀(retelliptine demethylated);依替膦酸铼Re 186(rhenium Re 186etidronate);根霉素;核酶;RII视黄酸酰胺;罗谷亚胺(rogletimide);罗希吐碱(rohitukine);罗莫肽(romurtide);罗喹美克(roquinimex);噜必吉诺B1(rubiginone B1);噜泊基(ruboxyl);沙芬戈(safingol);萨因脱匹(saintopin);SarCNU;肌肉叶绿醇A(sarcophytol A);沙格司亭(sargramostim);Sdi 1模拟物;司莫司汀;衰老源性抑制剂1;有义寡核苷酸;信号转导抑制剂;信号转导调节剂;单链抗原结合蛋白;西佐喃(sizofuran);索布佐生(sobuzoxane);硼卡钠(sodium borocaptate);苯基乙酸钠;索沃罗(solverol);生长调节素结合蛋白;索纳明(sonermin);膦门冬酸(sparfosic acid);螺旋霉素D(spicamycin D);螺莫司汀(spiromustine);斯耐潘定(splenopentin);海绵抑制素1(spongistatin 1);角鲨胺;干细胞抑制剂;干细胞分裂抑制剂;斯提酰胺(stipiamide);溶基质素抑制剂;素飞诺辛(sulfinosine);超活性血管活性肠肽拮抗剂;素若第斯它(suradista);苏拉明(suramin);苦马豆素(swainsonine);合成糖胺聚糖;他莫司汀(tallimustine);他莫昔芬甲碘化物(tamoxifen methiodide);牛磺莫司汀(tauromustine);他扎罗汀(tazarotene);替可加兰钠(tecogalan sodium);喃氟啶(tegafur);呔鲁拉利(tellurapyrylium);端粒酶抑制剂;替莫泊芬(temoporfin);替莫唑胺(temozolomide);替尼泊苷(teniposide);四氯十氧化物(tetrachlorodecaoxide);四唑胺(tetrazomine);塞利巴斯汀(thaliblastine);西奥考拉林(thiocoraline);促血小板生成素;促血小板生成素模拟物;胸腺法新(thymalfasin);促胸腺生成素受体激动剂;胸腺曲南(thymotrinan);促甲状腺激素;乙基初卟啉锡(tinethyl etiopurpurin);替拉扎明(tirapazamine);二氯二茂钛(titanocene bichloride);脱普森汀(topsentin);托瑞米芬(toremifene);全能干细胞因子;翻译抑制剂;维甲酸;三乙酰尿苷(triacetyluridine);曲西立滨(triciribine);三甲曲沙(trimetrexate);曲普瑞林(triptorelin);托烷司琼(tropisetron);妥罗雄脲(turosteride);酪氨酸激酶抑制剂;酪氨酸磷酸化抑制剂(tyrphostin);UBC抑制剂;乌苯美司(ubenimex);泌尿生殖窦源性生长抑制因子;尿激酶受体拮抗剂;伐普肽(vapreotide);瓦瑞奥林B(variolin B);载体系统;红细胞基因疗法;维拉雷琐(velaresol);藜芦胺(veramine);维尔丁(verdin);维替泊芬(verteporfin);长春瑞滨(vinorelbine);维西汀(vinxaltine);维他辛(vitaxin);伏氯唑(vorozole);扎诺特隆(zanoterone);折尼铂(zeniplatin);亚苄维C(zilascorb);净司他丁斯酯(zinostatin stimalamer);阿霉素(Adriamycin);更生霉素(Dactinomycin);博来霉素(Bleomycin);长春花碱(Vinblastine);顺铂;阿西维辛(acivicin);阿柔比星;盐酸阿可达佐(acodazole hydrochloride);阿克罗宁(acronine);阿多来新;阿地白介素;六甲蜜胺;安波霉素(ambomycin);醋酸阿美坦醌(ametantrone acetate);氨鲁米特(aminoglutethimide);安吖啶(amsacrine);阿那曲唑;蒽霉素(anthramycin);天冬酰胺酶;曲林菌素(asperlin);阿扎胞苷(azacitidine);阿扎替派(azetepa);阿佐霉素(azotomycin);巴马司他;苯佐替哌(benzodepa);比卡鲁胺(bicalutamide);盐酸必桑郡(bisantrene hydrochloride);二甲磺酸双奈法德(bisnafide dimesylate);比折来新;硫酸博莱霉素(bleomycin sulfate);布喹那钠(brequinar sodium);溴匹立明(bropirimine);白消安(busulfan);放线菌素;卡普睾酮(calusterone);卡醋胺(caracemide);卡贝替姆(carbetimer);卡铂;卡莫司汀;盐酸卡米诺霉素(carubicinhydrochloride);卡折来新;西地芬戈(cedefingol);苯丁酸氮芥(chlorambucil);西罗霉素(cirolemycin);克拉屈滨(cladribine);甲磺酸克立那托(crisnatol mesylate);环磷酰胺;阿糖胞苷。
抗癌剂的进一步实例包含但不限于达卡巴嗪(dacarbazine);盐酸柔红霉素(daunorubicin hydrochloride);地西他滨;右奥马铂(dexormaplatin);地扎胍宁(dezaguanine);甲磺酸地扎胍宁;地吖醌(diaziquone);多柔比星;盐酸多柔比星;屈洛昔芬;柠檬酸屈洛昔芬(droloxifene citrate);丙酸屈莫他酮(dromostanolonepropionate);达佐霉素(duazomycin);依达曲沙(edatrexate);盐酸依氟鸟氨酸(eflornithine hydrochloride);依沙芦星(elsamitrucin);恩洛铂(enloplatin);恩普氨酯(enpromate);依匹哌啶(epipropidine);盐酸表柔比星(epirubicin hydrochloride);厄布洛唑(erbulozole);盐酸依索比星(esorubicin hydrochloride);雌莫司汀(estramustine);雌莫司汀磷酸钠;依他硝唑(etanidazole);依托泊苷(etoposide);磷酸依托泊苷(etoposide phosphate);艾托卜宁(etoprine);盐酸法屈唑(fadrozolehydrochloride);法扎拉滨;芬维A胺;氟尿苷;磷酸氟达拉宾(fludarabine phosphate);氟尿嘧啶;氟环胞苷(fluorocitabine);磷喹酮(fosquidone);福司曲星钠(fostriecinsodium);吉西他滨;盐酸吉西他滨;羟基脲;盐酸伊达比星;异环磷酰胺;伊莫拉明(iimofosine);白介素I1(包含重组白介素II或rlL.sub.2);干扰素α-2a;干扰素α-2b;干扰素α-n1;干扰素α-n3;干扰素β-1a;干扰素γ-1b;异丙铂;盐酸伊立替康(irinotecanhydrochloride);醋酸兰瑞肽(lanreotide acetate);来曲唑(letrozole);醋酸亮丙瑞林;盐酸利阿唑(liarozole hydrochloride);洛美曲索钠(lometrexol sodium);洛莫司丁(lomustine);盐酸洛索蒽醌(losoxantrone hydrochloride);马索罗酚(masoprocol);美登素(maytansine);盐酸氮芥(mechlorethamine hydrochloride);醋酸甲地孕酮;醋酸美仑孕酮(melengestrol acetate);美法仑(melphalan);美诺立尔(menogaril);巯嘌呤;甲氨蝶呤;甲氨蝶呤钠;氯苯氨啶;美妥替哌(meturedepa);米丁度胺(mitindomide);米托卡星(mitocarcin);丝裂红素;米托洁林(mitogillin);米托马星(mitomalcin);丝裂霉素;米托司培(mitosper);米托坦(mitotane);盐酸米托蒽醌;霉酚酸;诺考达唑(nocodazoie);诺加霉素(nogalamycin);奥马铂;奥昔舒仑(oxisuran);培门冬酶(pegaspargase);佩里霉素(peliomycin);戊氮芥;硫酸培洛霉素(peplomycin sulfate);培磷酰胺(perfosfamide);哌泊溴烷(pipobroman);哌泊舒凡(piposulfan);盐酸吡罗蒽醌;普卡霉素(plicamycin);普洛美坦(plomestane);卟吩姆钠;甲基丝裂霉素;泼尼莫司汀(prednimustine);盐酸丙卡巴肼(procarbazine hydrochloride);嘌呤霉素;盐酸嘌呤霉素;吡唑霉素(pyrazofurin);利波腺苷(riboprine);罗谷亚胺;沙芬戈;盐酸沙芬戈;司莫司汀;辛曲秦(simtrazene);斯巴佛斯酸钠(sparfosate sodium);司帕霉素(sparsomycin);盐酸螺旋锗;螺莫司汀;螺铂;链黑菌素;链脲菌素;磺氯苯脲;他立霉素(talisomycin);替可加兰钠;喃氟啶;盐酸替洛蒽醌(teloxantrone hydrochloride);替莫泊芬;替尼泊苷;替罗昔隆(teroxirone);睾内酯;硫咪嘌呤(thiamiprine);硫鸟嘌呤(thioguanine);噻替哌;噻唑呋林;替拉扎明;柠檬酸托瑞米芬(toremifene citrate);醋酸曲托龙(trestolone acetate);磷酸曲西瑞宾(triciribine phosphate);三甲曲沙;葡萄糖醛酸三甲曲沙(trimetrexateglucuronate);曲普瑞林;盐酸妥布氯唑(tubulozole hydrochloride);乌拉莫司汀(uracil mustard);乌瑞替派(uredepa);伐普肽;维替泊芬;硫酸长春碱(vinblastinesulfate);硫酸长春新碱(vincristine sulfate);长春地辛;硫酸长春地辛(vindesinesulfate);硫酸长春匹定(vinepidine sulfate);硫酸长春甘酯(vinglycinate sulfate);硫酸长春罗新(vinleurosine sulfate);酒石酸长春瑞滨(vinorelbine tartrate);硫酸长春罗定(vinrosidine sulfate);硫酸长春利定(vinzolidine sulfate);伏氯唑;折尼铂;净司他丁;盐酸佐柔比星(zorubicin hydrochloride);将细胞阻滞在G2-M期和/或调节微管的形成或稳定性的药剂(例如,Taxol.TM(即,紫杉醇)、泰素帝.TM(Taxotere.TM)、包括紫杉烷骨架的化合物、厄布洛唑(erbulozole)(即,R-55104)、尾海兔素10(dolastatin 10)(即,DLS-10和NSC-376128));羟乙基磺酸米伏布林(Mivobulin isethionate)(即,为CI-980);长春新碱;NSC-639829;盘皮海绵内酯(discodermolide)(即,为NVP-XX-A-296);ABT-751(雅培公司(Abbott),即E-7010);或奥图来尔亭(Altorhyrtin)(例如,奥图来尔亭A和奥图来尔亭C)。
抗癌剂的进一步实例包含但不限于海绵抑制素(例如,海绵抑制素1、海绵抑制素2、海绵抑制素3、海绵抑制素4、海绵抑制素5、海绵抑制素6、海绵抑制素7、海绵抑制素8和海绵抑制素9)、盐酸西马多丁(Cemadotin hydrochloride)(即,LU-103793和NSC-D-669356)、埃博霉素(Epothilone)(例如,埃博霉素A、埃博霉素B、埃博霉素C(即,脱氧埃博霉素A或dEpoA)、埃博霉素D(即,KOS-862、dEpoB和脱氧埃博霉素B)、埃博霉素E、埃博霉素F、埃博霉素B N-氧化物、埃博霉素A N-氧化物、16-氮杂-埃博霉素B、21-氨基埃博霉素B(即,BMS-310705)、21-羟基埃博霉素D(即,脱氧埃博霉素F和dEpoF)、26-氟埃博霉素、澳瑞他汀PE(Auristati PE)(即,NSC-654663)、索利多亭(Soblidotin)(即,TZT-1027)、LS-4559-P(法玛西亚公司(Pharmacia),即,LS-4577)、LS-4578(法玛西亚公司,即,LS-477-P)、LS-4477(法玛西亚公司)、LS-4559(法玛西亚公司)、RPR-112378(安内特公司(Aventis))、硫酸长春新碱、DZ-3358(第一制药公司(Daiichi))、FR-182877(藤泽公司(Fujisawa),即,WS-9885B)、GS-164(武田公司(Takeda))、GS-198(武田公司)、KAR-2(匈牙利科学院(HungarianAcademy of Sciences))、BSF-223651(巴斯夫公司(BASF),即,ILX-651和LU-223651)、SAH-49960(礼来公司/诺华公司(Lilly/Novartis))、SDZ-268970(礼来公司/诺华公司)、AM-97(阿马德公司/协和发酵公司(Armad/Kyowa Hakko))、AM-132(阿马德公司)、AM-138(阿马德公司/协和发酵公司)、IDN-5005(意迪那公司(Indena))、念珠藻素52(即,LY-355703)、AC-7739(味之素公司(Ajinomoto),即,AVE-8063A和CS-39.HCl)、AC-7700(味之素公司,即,AVE-8062、AVE-8062A、CS-39-L-Ser.HCl和RPR-258062A)、维替乐维酰胺(Vitilevuamide)、妥布赖森A(Tubulysin A)、卡纳登索(Canadensol)、矢车菊黄素(Centaureidin)(即,NSC-106969)、T-138067(杜拉瑞克公司(Tularik),即,T-67、TL-138067和TI-138067)、COBRA-1(派克休斯研究所(Parker Hughes Institute),即,DDE-261和WHI-261)、H10(堪萨斯州立大学)、H16(堪萨斯州立大学)、奥克西丁A1(Oncocidin A1)(即,BTO-956和DIME)、DDE-313(派克休斯研究所)、斐吉诺莱B(Fijianolide B)、莱利霉素(Laulimalide)、SPA-2(派克休斯研究所)、SPA-1(派克休斯研究所,即,SPIKET-P)、3-IAABU(细胞骨架公司/西奈山伊坎医学院(Cytoskeleton/Mt.Sinai School of Medicine),即,MF-569)、纳可辛(Narcosine)(还被称为NSC-5366)、纳司卡滨(Nascapine)D-24851(爱斯达制药公司(Asta Medica))、A-105972(雅培公司)、哈米特林(Hemiasterlin)、3-BAABU(细胞骨架公司/西奈山伊坎医学院,即,MF-191)、TMPN(亚利桑那州立大学)、双钒乙酰丙酮(Vanadoceneacetylacetonate)、T-138026(杜拉瑞克公司)、莫那撒尔(Monsatrol)、依那斯纳(lnanocine)(即,NSC-698666)、3-IAABE(细胞骨架公司/西奈山伊坎医学院)、A-204197(雅培公司)、T-607(杜拉瑞克公司,即,T-900607)、RPR-115781(安内特公司)、伊斯罗宾(Eleutherobin)(如脱甲基伊斯罗宾(Desmethyleleutherobin)、脱乙酸基伊斯罗宾(Desaetyleleutherobin)、异伊斯罗宾(lsoeleutherobin)A和Z-伊斯罗宾)、卡巴斯德(Caribaeoside)、卡利贝林(Caribaeolin)、软海绵素B(Halichondrin B)、D-64131(爱斯达制药公司)、D-68144(爱斯达制药公司)、含氯环肽A(Diazonamide A)、A-293620(雅培公司)、NPI-2350(涅柔斯公司(Nereus))、根薯酮内酯A(Taccalonolide A)、TUB-245(安内特公司)、A-259754(雅培公司)、第在斯汀(Diozostatin)、(-)-苯基阿斯丁(Phenylahistin)(即,NSCL-96F037)、D-68838(爱斯达制药公司)、D-68836(爱斯达制药公司)、肌基质蛋白B(Myoseverin B)、D-43411(Zentaris公司,即,D-81862)、A-289099(雅培公司)、A-318315(雅培公司)、HTI-286(即,SPA-110,三氟乙酸盐(trifluoroacetate salt))(惠氏公司(Wyeth))、D-82317(Zentaris公司)、D-82318(Zentaris公司)、SC-12983(NCI)、瑞瓦斯汀磷酸钠(Resverastatin phosphate sodium)、BPR-OY-007(国立卫生研究院(National HealthResearch Institutes))和SSR-250411(赛诺菲公司(Sanofi)))、类固醇(例如,地塞米松)、非那雄胺(finasteride)、芳香酶抑制剂、如戈舍瑞林(goserelin)或亮丙瑞林等促性腺激素释放激素激动剂(GnRH)、肾上腺皮质类固醇(例如,强的松)、孕酮(例如,己酸羟孕酮(hydroxyprogesterone caproate)、醋酸甲地孕酮、醋酸甲羟孕酮(medroxyprogesteroneacetate))、雌激素(例如,二乙基己烯雌酚(diethlystilbestrol)、乙炔雌二醇(ethinylestradiol))、抗雌激素(例如,三苯氧胺(tamoxifen))、雄激素(例如,丙酸睾酮(testosterone propionate)、氟甲睾酮(fluoxymesterone))、抗雄激素(例如,氟他胺(flutamide))、免疫刺激剂(例如,卡介苗(Bacillus Calmette-Guérin,BCG)、左旋咪唑、白介素-2、α-干扰素等)、单克隆抗体(例如,抗CD20、抗HER2、抗CD52、抗HLA-DR和抗VEGF单克隆抗体)、免疫毒素(例如,抗CD33单克隆抗体-加利车霉素缀合物、抗CD22单克隆抗体-假单胞菌外毒素缀合物等)、放射免疫疗法(例如,与111In、90Y或131I等缀合的抗CD20单克隆抗体)、雷公藤甲素(triptolide)、高三尖杉酯碱(homoharringtonine)、更生霉素、多柔比星、表柔比星、拓扑替康、依曲康唑(itraconazole)、长春地辛、西立伐他汀(cerivastatin)、长春新碱、脱氧腺苷(deoxyadenosine)、舍曲林、匹伐他汀(pitavastatin)、伊立替康、氯法齐明(clofazimine)、5-壬氧基色胺、维莫非尼(vemurafenib)、达拉菲尼(dabrafenib)、埃罗替尼(erlotinib)、吉非替尼(gefitinib)、EGFR抑制剂、表皮生长因子受体(EGFR)靶向疗法或治疗剂(例如、吉非替尼(IressaTM)、埃罗替尼(TarcevaTM)、西妥昔单抗(cetuximab)(ErbituxTM)、拉帕替尼(lapatinib)(TykerbTM)、帕尼单抗(panitumumab)(VectibixTM)、凡德他尼(vandetanib)(CaprelsaTM)、阿法替尼(afatinib)/BIBW2992、CI-1033/卡奈替尼(canertinib)、来那替尼(neratinib)/HKI-272、CP-724714、TAK-285、AST-1306、ARRY334543、ARRY-380、AG-1478、达克替尼(dacomitinib)/PF299804、OSI-420/去甲基厄洛替尼(desmethyl erlotinib)、AZD8931、AEE788、培利替尼(pelitinib)/EKB-569、CUDC-101、WZ8040、WZ4002、WZ3146、AG-490、XL647、PD153035、BMS-599626)、索拉非尼(sorafenib)、伊马替尼(imatinib)、舒尼替尼(sunitinib)、达沙替尼(dasatinib)等。
如本文所使用的,“治疗(treating)”或“治疗(treatment of)”病状、疾病或病症或与病状、疾病或病症相关的症状是指用于获得有益或期望结果,包含临床结果的方法。有益或期望的临床结果可以包含但不限于减轻或改善一种或多种症状或病状;减轻病状、病症或疾病的程度;稳定病状、病症或疾病的状态;预防病状、病症或疾病的发展;预防病状、病症或疾病的传播;延缓或减缓病状、病症或疾病进展;延缓或减缓病状、病症或疾病发作;改善或缓和病状、病症或疾病状态;以及缓解,无论是部分的还是全部的。“治疗”还可以意指延长受试者的存活超过不存在治疗的情况下预期的存活。“治疗”还可以意指抑制病状、病症或疾病的进展,暂时减缓病状、病症或疾病的进展,但是在一些实例中,其涉及永久地停止病状、病症或疾病的进展。本文所使用的术语治疗(treatment、treat或treating)是指降低以蛋白酶表达为特征的疾病或病状的一种或多种症状或以蛋白酶表达为特征的疾病或病状的症状的影响的方法。因此,在所公开的方法中,治疗可以是指已确定的疾病、病状或疾病或病状的症状的严重程度降低10%、20%、30%、40%、50%、60%、70%、80%、90%或100%。例如,如果与对照相比,受试者的疾病的一种或多种症状减少10%,则用于治疗疾病的方法被视为是治疗。因此,与天然或对照水平相比,减少可以是10%、20%、30%、40%、50%、60%、70%、80%、90%、100%或介于10%与100%之间的任何百分比减少。应理解,治疗并不一定是指治愈或完全消除疾病、病状、或疾病或病状的症状。另外,如本文所使用的,与对照水平相比,提及降低、减少或抑制包含10%、20%、30%、40%、50%、60%、70%、80%、90%或更大的变化,并且这些术语可以包含但不一定包含完全消除。
术语“剂量(dose)”和“剂量(dosage)”在本文中可互换使用。剂量是指每次施用时给予个体的活性成分的量。剂量将根据许多因素而变化,所述因素包含给定疗法的正常剂量范围、施用频率;个体的大小和公差;病状的严重程度;副作用的风险;以及施用途径。技术人员将认识到,剂量可以取决于上述因素或基于治疗进展而修改。术语“剂型”是指药物或药物组合物的特定形式,并且取决于施用途径。例如,剂型可以呈用于雾化的液体形式,例如用于吸入剂,呈片剂或液体形式,例如用于口服递送,或盐溶液,例如用于注射。
如本文所使用的“治疗有效剂量或量”是指产生其所施用的效应的剂量(例如,治疗或预防疾病)。精确剂量和调配物将取决于治疗目的,并且将可由本领域的技术人员使用已知技术确定(参见例如,Lieberman,《医药剂型(Pharmaceutical Dosage Forms)》(第1-3卷,1992);Lloyd,《医药学配混的艺术、科学和技术(The Art,Science and Technology ofPharmaceutical Compounding)》(1999);《雷明顿:药学科学与实践(Remington:TheScience and Practice of Pharmacy)》,第20版,Gennaro编辑,(2003);以及Pickar,《剂量计算(Dosage Calculations)》(1999))。例如,对于给定参数,治疗有效量将显示出增加或降低至少5%、10%、15%、20%、25%、40%、50%、60%、75%、80%、90%或至少100%。治疗功效也可以表示为“倍数”增加或减少。例如,治疗有效量的效应可以是标准对照的效应的至少1.2倍、1.5倍、2倍、5倍或更多倍。治疗有效剂量或量可以改善疾病的一种或多种症状。当施用治疗有效剂量或量的效应是治疗有患上疾病的风险的人时,治疗有效剂量或量可以预防或延缓疾病或疾病的一种或多种症状的发作。
如本文所使用的,术语“施用”意指向受试者口服施用、以栓剂的形式施用、局部接触、静脉内、腹膜内、肌肉内、病灶内、鞘内、鼻内或皮下施用,或植入缓释装置,例如,微型渗透泵。通过任何途径进行施用,包含肠胃外和经粘膜(例如,颊、舌下、腭、牙龈、鼻、阴道、直肠或经皮)。肠胃外施用包含例如静脉内、肌肉内、动脉内、皮内、皮下、腹膜内、心室内和颅内施用。其它递送模式包含但不限于使用脂质体调配物、静脉内输注、经皮贴片等。“共施用”意指本文所描述的组合物在施用一种或多种另外疗法,例如,如化学疗法、激素疗法、放射疗法或免疫疗法等癌症疗法的同时、紧接着其之前或紧接着其之后施用。本发明的化合物可以单独施用或可以共施用于患者。共施用旨在包含化合物单独地或以组合形式(多于一种化合物)同时或依序施用。因此,制剂还可以在需要时与其它活性物质组合(例如,以减少代谢性降解)。本发明的组合物可以通过局部途径,调配成施涂棒、溶液、悬浮液、乳液、凝胶、乳膏、软膏、糊剂、果冻、油漆、粉剂和气雾剂,经皮递送。
适于口服施用的调配物可以由以下组成:(a)液体溶液,如悬浮在稀释剂,如水、盐水或PEG 400中的有效量的本文所提供的抗体;(b)胶囊、小袋或片剂,所述胶囊、小袋或片剂各自含有预定量的活性成分,如液体、固体、颗粒或明胶;(c)在适当液体中的悬浮液;以及(d)合适的乳液。片剂形式可以包含以下中的一种或多种:乳糖、蔗糖、甘露醇、山梨糖醇、磷酸钙、玉米淀粉、马铃薯淀粉、微晶纤维素、明胶、胶体二氧化硅、滑石、硬脂酸镁、硬脂酸和其它赋形剂、着色剂、填料、粘合剂、稀释剂、缓冲剂、润湿剂、防腐剂、调味剂、染料、崩解剂和药学上相容的载剂。锭剂形式可以包括呈调味剂,例如,蔗糖形式的活性成分,以及包括呈惰性基质形式的活性成分的糖锭,如除活性成分之外,含有本领域已知的载剂的明胶和甘油或蔗糖和金合欢乳液、凝胶等。
药物组合物还可以包含如蛋白质等大型缓慢代谢的大分子、如壳聚糖等多糖、聚乳酸、聚乙醇酸和共聚物(如乳胶官能化sepharose(TM)、琼脂糖、纤维素等)、聚合氨基酸、氨基酸共聚物以及脂质聚集体(如油滴或脂质体)。另外,这些载剂可以起到免疫刺激剂(即,佐剂)的作用。
适用于直肠施用的调配物包含例如由具有栓剂基质的经包装的核酸组成的栓剂。合适的栓剂基质包含天然或合成甘油三酯或链烷烃。另外,还可以使用明胶直肠胶囊,所述明胶直肠胶囊由所选择的化合物与基质,包含例如液体甘油三酯、聚乙二醇和链烷烃的组合组成。
适于肠胃外施用,例如通过关节内(在关节中)、静脉内、肌肉内、瘤内、皮内、腹膜内和皮下途径进行的肠胃外施用的调配物包含可以含有抗氧化剂、缓冲剂、抑菌剂的水性和非水性等渗无菌注射溶液和使调配物与预期接受者的血液等渗的溶质以及可以包含悬浮剂、增溶剂、增稠剂、稳定剂和防腐剂的水性和非水性无菌悬浮液。在本发明的实践中,组合物可以例如通过静脉内输注、口服地、局部地、腹膜内、膀胱内或鞘内施用。肠胃外施用、口服施用和静脉内施用是优选施用方法。化合物的调配物可以存在于单位剂量或多剂量密封容器中,如安瓿和小瓶中。
可以由前述种类的无菌粉剂、颗粒和片剂制备注射溶液和悬浮液。用于离体疗法的由核酸转导的细胞也可以如上文所描述的静脉内或肠胃外施用。
组合施用设想了使用单独调配物或单一药物调配物的共施用,以及任意顺序的连续施用,其中优选地,存在两种(或所有)活性剂同时发挥其生物活性的时间段。
本发明的组合物可以另外包含用于提供持续释放和/或舒适性的组分。此类组分包含高分子量、阴离子类粘液状聚合物、胶凝多糖和精细分散的药物载剂底物。这些组分在美国专利第4,911,920号;第5,403,841号;第5,212,162号;以及第4,861,760号中进行了更详细讨论。这些专利的全部内容出于所有目通过引用以其整体并入本文。本发明的组合物也可以以用于在体内缓慢释放的微球的形式递送。例如,微球可以如下施用:通过皮内注射含药物的微球,所述含药物的微球在皮下缓慢释放(参见Rao,《生物材料科学杂志聚合物版(J.Biomater Sci.Polym.Ed.)》7:623-645,1995;以可生物降解和可注射凝胶调配物的形式(参见例如,Gao《药学研究(Pharm.Res.)》12:857-863,1995);或以用于口服施用的微球的形式(参见例如,Eyles,《药学和药理学杂志(J.Pharm.Pharmacol.)》49:669-674,1997)。在实施例中,本发明的组合物的调配物可以通过使用与细胞膜融合或被内吞的脂质体来递送,即,通过使用附着到脂质体的受体配体,所述受体配体与细胞的表面膜蛋白受体结合从而导致内吞。通过使用脂质体,特别是在脂质体表面携带对靶细胞具有特异性或以其它方式优先针对特定器官的受体配体的情况下,可以集中将本发明的组合物在体内递送到靶细胞中。(参见例如,Al-Muhammed,《微包封杂志(J.Microencapsul.)》13:293-306,1996;Chonn,《生物技术当前述评(Curr.Opin.Biotechnol.)》6:698-708,(1995);Ostro,《美国医院药学杂志(Am.J.Hosp.Pharm.)》46:1576-1587,1989)。本发明的组合物也可以以纳米颗粒的形式递送。
如本文所使用的,术语“药学上可接受的”与“生理上可接受的”和“药理学上可接受的”同义地使用。药物组合物通常将包括用于缓冲和在储存中保存的药剂,并且可以包含用于适当递送的缓冲剂和载剂,这取决于施用途径。
“药学上可接受的赋形剂”和“药学上可接受的载剂”是指有助于向受试者施用活性剂并且有助于受试者吸收,并且可以包含在本发明的组合物中而不会对患者引起显著不良的毒性作用的物质。药学上可接受的赋形剂的非-限制性实例包含水、NaCl、生理盐水溶液、乳酸化林格氏液(Ringer's)、普通蔗糖、普通葡萄糖、粘合剂、填充剂、崩解剂、润滑剂、包衣、甜味剂、调味剂、盐溶液(如林格氏溶液)、醇、油、明胶、如乳糖、直链淀粉或淀粉等碳水化合物、脂肪酸酯、羧甲基纤维素、聚乙烯吡咯烷酮和颜料等。此类制剂可以进行灭菌,并且如果需要,可以与不与本发明的化合物有害地发生反应的助剂混合,所述助剂如润滑剂、防腐剂、稳定剂、润湿剂、乳化剂、用于影响渗透压的盐、缓冲剂、着色物质和/或芳香物质等。本领域的技术人员将认识到,其它药物赋形剂在本发明中是有用的。
术语“药学上可接受的盐”是指源自本领域公知的多种有机抗衡离子和无机抗衡离子的盐,并且包含,仅举例来说,钠、钾、钙、镁、铵和四烷基铵等,并且当分子含有碱性官能团时,包含有机酸或无机酸的盐,如盐酸盐、氢溴酸盐、酒石酸盐、甲磺酸盐、乙酸盐、马来酸盐、草酸盐等。
术语“制剂”旨在包含活性化合物与作为提供胶囊的载剂的封装材料的调配物,在所述胶囊中,具有或不具有其它载剂的活性组分被载剂包围,所述载剂由此与活性组分缔合。类似地,包含扁囊剂和锭剂。片剂、粉剂、胶囊、丸剂、扁囊剂以及锭剂可以用作适用于口服施用的固体剂型。
药物制剂任选地呈单位剂型的形式。在这种形式中,制剂被细分成含有适当量的活性组分的单位剂量。单位剂型可以是包装的制剂,所述包装含有离散量的制剂,如包装的片剂、胶囊、以及在小瓶或安瓿中的粉剂。同样,所述单位剂型可以是胶囊、片剂、扁囊剂、或锭剂本身,或其可以是适当数量的这些包装形式的任一种。单位剂型可以具有经冷冻的分散体。
应当理解,本文所描述的实例和实施例仅是出于说明性目的,并且根据其进行的各种修改或改变将启发本领域的技术人员并且将被包含在本申请的精神与权限范围内和所附权利要求书的范围内。本文所引用的所有出版物、专利和专利申请均出于所有目的特此通过引用以其整体并入。
抗RYK抗体
本文尤其提供了以高效率和特异性与人酪氨酸受体相关激酶(RYK)结合的抗体(例如,嵌合抗体、单克隆抗体、抗体片段(例如,scFv))。本文提供的抗体和抗体组合物包含例如新型轻链和重链结构域CDR以及框架区,并且尤其可用于诊断和治疗癌症和其它RYK相关疾病。在实施例中,本文提供的抗RYK抗体能够与人RYK蛋白结合,但是不能与小鼠RYK蛋白结合。
在一方面中提供了一种抗RYK抗体,其包含重链可变结构域和轻链可变结构域,其中所述重链可变结构域包含如SEQ ID NO:1中所示的CDR H1、如SEQ ID NO:2中所示的CDRH2以及如SEQ ID NO:3中所示的CDR H3;并且其中所述轻链可变结构域包含如SEQ ID NO:4中所示的CDR L1、如SEQ ID NO:5中所示的CDR L2以及如SEQ ID NO:6中所示的CDR L3。
在实施例中,重链可变结构域包含SEQ ID NO:15的序列。在实施例中,重链可变结构域为SEQ ID NO:15的序列。在实施例中,轻链可变结构域包含SEQ ID NO:16的序列。在实施例中,轻链可变结构域为SEQ ID NO:16的序列。在实施例中,重链可变结构域包含SEQ IDNO:15的序列,并且轻链可变结构域包含SEQ ID NO:16的序列。在实施例中,重链可变结构域为SEQ ID NO:15的序列,并且轻链可变结构域为SEQ ID NO:16的序列。
在实施例中,单克隆抗体以本段落中所述的平衡解离常数(KD)与RYK结合。在实施例中,抗RYK抗体的KD为约2pM至约2nM。在实施例中,抗RYK抗体的KD为约3pM至约2nM。在实施例中,抗RYK抗体的KD为约4pM至约2nM。在实施例中,抗RYK抗体的KD为约5pM至约2nM。在实施例中,抗RYK抗体的KD为约6pM至约2nM。在实施例中,抗RYK抗体的KD为约7pM至约2nM。在实施例中,抗RYK抗体的KD为约8pM至约2nM。在实施例中,抗RYK抗体的KD为约9pM至约2nM。在实施例中,抗RYK抗体的KD为约10pM至约2nM。在实施例中,抗RYK抗体的KD为约50pM至约2nM。在实施例中,抗RYK抗体的KD为约100pM至约2nM。在实施例中,抗RYK抗体的KD为约200pM至约2nM。在实施例中,抗RYK抗体的KD为约300pM至约2nM。在实施例中,抗RYK抗体的KD为约400pM至约2nM。在实施例中,抗RYK抗体的KD为约500pM至约2nM。在实施例中,抗RYK抗体的KD为约600pM至约2nM。在实施例中,抗RYK抗体的KD为约700pM至约2nM。在实施例中,抗RYK抗体的KD为约800pM至约2nM。在实施例中,抗RYK抗体的KD为约900pM至约2nM。在实施例中,抗RYK抗体的KD为约1nM至约2nM。
在实施例中,单克隆抗体以本段落中所述的平衡解离常数(KD)与RYK结合。在实施例中,抗RYK抗体的KD为约2pM至约1nM。在实施例中,抗RYK抗体的KD为约2pM至约900pM。在实施例中,抗RYK抗体的KD为约2pM至约800pM。在实施例中,抗RYK抗体的KD为约2pM至约700pM。在实施例中,抗RYK抗体的KD为约2pM至约600pM。在实施例中,抗RYK抗体的KD为约2pM至约500pM。在实施例中,抗RYK抗体的KD为约2pM至约400pM。在实施例中,抗RYK抗体的KD为约2pM至约300pM。在实施例中,抗RYK抗体的KD为约2pM至约200pM。在实施例中,抗RYK抗体的KD为约2pM至约100pM。在实施例中,抗RYK抗体的KD为约2pM至约50pM。在实施例中,抗RYK抗体的KD为约2pM至约10pM。在实施例中,抗RYK抗体的KD为约2pM至约9pM。在实施例中,抗RYK抗体的KD为约2pM至约8pM。在实施例中,抗RYK抗体的KD为约2pM至约7pM。在实施例中,抗RYK抗体的KD为约2pM至约6pM。在实施例中,抗RYK抗体的KD为约2pM至约5pM。在实施例中,抗RYK抗体的KD为约2pM至约4pM。在实施例中,抗RYK抗体的KD为约2pM至约3pM。
在实施例中,单克隆抗体以本段落中所述的平衡解离常数(KD)与RYK结合。在实施例中,抗RYK抗体的KD为2pM至2nM。在实施例中,抗RYK抗体的KD为3pM至2nM。在实施例中,抗RYK抗体的KD为4pM至2nM。在实施例中,抗RYK抗体的KD为5pM至2nM。在实施例中,抗RYK抗体的KD为6pM至2nM。在实施例中,抗RYK抗体的KD为7pM至2nM。在实施例中,抗RYK抗体的KD为8pM至2nM。在实施例中,抗RYK抗体的KD为9pM至2nM。在实施例中,抗RYK抗体的KD为10pM至2nM。在实施例中,抗RYK抗体的KD为50pM至2nM。在实施例中,抗RYK抗体的KD为100pM至2nM。在实施例中,抗RYK抗体的KD为200pM至2nM。在实施例中,抗RYK抗体的KD为300pM至2nM。在实施例中,抗RYK抗体的KD为400pM至2nM。在实施例中,抗RYK抗体的KD为500pM至2nM。在实施例中,抗RYK抗体的KD为600pM至2nM。在实施例中,抗RYK抗体的KD为700pM至2nM。在实施例中,抗RYK抗体的KD为800pM至2nM。在实施例中,抗RYK抗体的KD为900pM至2nM。在实施例中,抗RYK抗体的KD为1nM至2nM。
在实施例中,单克隆抗体以本段落中所述的平衡解离常数(KD)与RYK结合。在实施例中,抗RYK抗体的KD为2pM至1nM。在实施例中,抗RYK抗体的KD为2pM至900pM。在实施例中,抗RYK抗体的KD为2pM至800pM。在实施例中,抗RYK抗体的KD为2pM至700pM。在实施例中,抗RYK抗体的KD为2pM至600pM。在实施例中,抗RYK抗体的KD为2pM至500pM。在实施例中,抗RYK抗体的KD为2pM至400pM。在实施例中,抗RYK抗体的KD为2pM至300pM。在实施例中,抗RYK抗体的KD为2pM至200pM。在实施例中,抗RYK抗体的KD为2pM至100pM。在实施例中,抗RYK抗体的KD为2pM至50pM。在实施例中,抗RYK抗体的KD为2pM至10pM。在实施例中,抗RYK抗体的KD为2pM至9pM。在实施例中,抗RYK抗体的KD为2pM至8pM。在实施例中,抗RYK抗体的KD为2pM至7pM。在实施例中,抗RYK抗体的KD为2pM至6pM。在实施例中,抗RYK抗体的KD为2pM至5pM。在实施例中,抗RYK抗体的KD为2pM至4pM。在实施例中,抗RYK抗体的KD为2pM至3pM。在实施例中,抗RYK抗体的KD为约513pM。在实施例中,抗RYK抗体的KD为513pM。在实施例中,抗RYK抗体抗体在本文中被称为2-D11。
在另一方面中提供了一种抗RYK抗体,其包含重链可变结构域和轻链可变结构域,其中所述重链可变结构域包含如SEQ ID NO:17中所示的CDR H1、如SEQ ID NO:18中所示的CDR H2以及如SEQ ID NO:19中所示的CDR H3;并且其中所述轻链可变结构域包含如SEQ IDNO:20中所示的CDR L1、如SEQ ID NO:21中所示的CDR L2以及如SEQ ID NO:22中所示的CDRL3。
在实施例中,重链可变结构域包含SEQ ID NO:31的序列。在实施例中,重链可变结构域为SEQ ID NO:31的序列。在实施例中,轻链可变结构域包含SEQ ID NO:32的序列。在实施例中,轻链可变结构域为SEQ ID NO:32的序列。在实施例中,重链可变结构域包含SEQ IDNO:31的序列,并且轻链可变结构域包含SEQ ID NO:32的序列。在实施例中,重链可变结构域为SEQ ID NO:31的序列,并且轻链可变结构域为SEQ IDNO:32的序列。
在实施例中,单克隆抗体以本段落中所述的平衡解离常数(KD)与RYK结合。在实施例中,抗RYK抗体的KD为约6nM至约17nM。在实施例中,抗RYK抗体的KD为约7nM至约17nM。在实施例中,抗RYK抗体的KD为约8nM至约17nM。在实施例中,抗RYK抗体的KD为约9nM至约17nM。在实施例中,抗RYK抗体的KD为约10nM至约17nM。在实施例中,抗RYK抗体的KD为约11nM至约17nM。在实施例中,抗RYK抗体的KD为约12nM至约17nM。在实施例中,抗RYK抗体的KD为约13nM至约17nM。在实施例中,抗RYK抗体的KD为约14nM至约17nM。在实施例中,抗RYK抗体的KD为约15nM至约17nM。在实施例中,抗RYK抗体的KD为约16nM至约17nM。
在实施例中,单克隆抗体以本段落中所述的平衡解离常数(KD)与RYK结合。在实施例中,抗RYK抗体的KD为6nM至16nM。在实施例中,抗RYK抗体的KD为约6nM至约15nM。在实施例中,抗RYK抗体的KD为约6nM至约14nM。在实施例中,抗RYK抗体的KD为约6nM至约13nM。在实施例中,抗RYK抗体的KD为约6nM至约12nM。在实施例中,抗RYK抗体的KD为约6nM至约11nM。在实施例中,抗RYK抗体的KD为约6nM至约10nM。在实施例中,抗RYK抗体的KD为约6nM至约9nM。在实施例中,抗RYK抗体的KD为约6nM至约8nM。在实施例中,抗RYK抗体的KD为约6nM至约7nM。
在实施例中,单克隆抗体以本段落中所述的平衡解离常数(KD)与RYK结合。在实施例中,抗RYK抗体的KD为6nM至17nM。在实施例中,抗RYK抗体的KD为7nM至17nM。在实施例中,抗RYK抗体的KD为8nM至17nM。在实施例中,抗RYK抗体的KD为9nM至17nM。在实施例中,抗RYK抗体的KD为10nM至17nM。在实施例中,抗RYK抗体的KD为11nM至17nM。在实施例中,抗RYK抗体的KD为12nM至17nM。在实施例中,抗RYK抗体的KD为13nM至17nM。在实施例中,抗RYK抗体的KD为约14nM至约17nM。在实施例中,抗RYK抗体的KD为15nM至17nM。在实施例中,抗RYK抗体的KD为16nM至17nM。
在实施例中,单克隆抗体以本段落中所述的平衡解离常数(KD)与RYK结合。在实施例中,抗RYK抗体的KD为6nM至16nM。在实施例中,抗RYK抗体的KD为6nM至15nM。在实施例中,抗RYK抗体的KD为6nM至14nM。在实施例中,抗RYK抗体的KD为6nM至13nM。在实施例中,抗RYK抗体的KD为6nM至12nM。在实施例中,抗RYK抗体的KD为6nM至约11nM。在实施例中,抗RYK抗体的KD为6nM至10nM。在实施例中,抗RYK抗体的KD为6nM至9nM。在实施例中,抗RYK抗体的KD为6nM至8nM。在实施例中,抗RYK抗体的KD为约6nM至7nM。在实施例中,抗RYK抗体的KD为约10nM。在实施例中,抗RYK抗体的KD为10nM。在实施例中,抗RYK抗体抗体在本文中被称为7-D10。
在另一方面中提供了一种抗RYK抗体,其包含重链可变结构域和轻链可变结构域,其中所述重链可变结构域包含如SEQ ID NO:33中所示的CDR H1、如SEQ ID NO:34中所示的CDR H2以及如SEQ ID NO:35中所示的CDR H3;并且其中所述轻链可变结构域包含如SEQ IDNO:36中所示的CDR L1、如SEQ ID NO:37中所示的CDR L2以及如SEQ ID NO:38中所示的CDRL3。
在实施例中,重链可变结构域包含SEQ ID NO:47的序列。在实施例中,重链可变结构域为SEQ ID NO:47的序列。在实施例中,轻链可变结构域包含SEQ ID NO:48的序列。在实施例中,轻链可变结构域为SEQ ID NO:48的序列。在实施例中,重链可变结构域包含SEQ IDNO:47的序列,并且轻链可变结构域包含SEQ ID NO:48的序列。在实施例中,重链可变结构域为SEQ ID NO:47的序列,并且轻链可变结构域为SEQ ID NO:48的序列。在实施例中,抗RYK抗体抗体在本文中被称为11-E9。
在另一方面中提供了一种抗RYK抗体,其包含重链可变结构域和轻链可变结构域,其中所述重链可变结构域包含如SEQ ID NO:49中所示的CDR H1、如SEQ ID NO:50中所示的CDR H2以及如SEQ ID NO:51中所示的CDR H3;并且其中所述轻链可变结构域包含如SEQ IDNO:52中所示的CDR L1、如SEQ ID NO:53中所示的CDR L2以及如SEQ ID NO:54中所示的CDRL3。
在实施例中,重链可变结构域包含SEQ ID NO:63的序列。在实施例中,重链可变结构域为SEQ ID NO:63的序列。在实施例中,轻链可变结构域包含SEQ ID NO:64的序列。在实施例中,轻链可变结构域为SEQ ID NO:64的序列。在实施例中,重链可变结构域包含SEQ IDNO:63的序列,并且轻链可变结构域包含SEQ ID NO:64的序列。在实施例中,重链可变结构域为SEQ ID NO:63的序列,并且轻链可变结构域为SEQ ID NO:64的序列。在实施例中,抗RYK抗体抗体在本文中被称为3-C12。
在实施例中,抗RYK抗体为嵌合抗体。在实施例中,抗RYK抗体为Fab'片段。在实施例中,抗RYK抗体为IgG。在实施例中,轻链可变结构域和所述重链可变结构域形成scFv的一部分。
在实施例中,抗RYK抗体能够与RYK蛋白结合。在实施例中,抗RYK抗体与胞外RYK结构域结合。在实施例中,抗RYK抗体与人胞外RYK结构域结合。在实施例中,抗RYK抗体与包含SEQ ID NO:129的氨基酸序列的胞外RYK结构域结合。在实施例中,抗RYK抗体与为SEQ IDNO:129的氨基酸序列的胞外RYK结构域结合。在实施例中,抗RYK抗体与和SEQ ID NO:129的氨基酸残基48至57相对应的氨基酸序列结合。在实施例中,抗RYK抗体与RYK蛋白结合。在实施例中,RYK蛋白为人RYK蛋白。在实施例中,RYK蛋白包含SEQ ID NO:130的序列。在实施例中,RYK蛋白为SEQ ID NO:130的序列。在实施例中,RYK蛋白为SEQ ID NO:129的序列。在实施例中,RYK蛋白不与小鼠RYK蛋白结合。在实施例中,抗RYK抗体不与包含与SEQ ID NO:131的氨基酸残基32至41相对应的氨基酸序列的RYK蛋白结合。在实施例中,抗RYK抗体不与包含SEQ ID NO:131的序列的RYK蛋白结合。在实施例中,抗RYK抗体不与SEQ ID NO:131的RYK蛋白结合。在实施例中,抗RYK抗体不与小鼠胞外RYK结构域结合。在实施例中,RYK蛋白形成细胞的一部分。在实施例中,RYK蛋白在细胞的表面上表达。
在另一方面中提供了一种抗RYK抗体,其中所述抗RYK抗体与和包含以下的抗体相同的表位结合:重链可变结构域,所述重链可变结构域包含如SEQ ID NO:1中所示的CDRH1、如SEQ ID NO:2中所示的CDR H2以及如SEQ ID NO:3中所示的CDR H3;以及轻链可变结构域,所述轻链可变结构域包含如SEQ ID NO:4中所示的CDR L1、如SEQ ID NO:5中所示的CDR L2以及如SEQ ID NO:6中所示的CDR L3。
在另一方面中提供了一种抗RYK抗体,其中所述抗RYK抗体与和包含以下的抗体相同的表位结合:重链可变结构域,所述重链可变结构域包含如SEQ ID NO:17中所示的CDRH1、如SEQ ID NO:18中所示的CDR H2以及如SEQ ID NO:19中所示的CDR H3;以及轻链可变结构域,所述轻链可变结构域包含如SEQ ID NO:20中所示的CDR L1、如SEQ ID NO:21中所示的CDR L2以及如SEQ ID NO:22中所示的CDR L3。
在另一方面中提供了一种抗RYK抗体,其中所述抗RYK抗体与和包含以下的抗体相同的表位结合:重链可变结构域,所述重链可变结构域包含如SEQ ID NO:33中所示的CDRH1、如SEQ ID NO:34中所示的CDR H2以及如SEQ ID NO:35中所示的CDR H3;以及轻链可变结构域,所述轻链可变结构域包含如SEQ ID NO:36中所示的CDR L1、如SEQ ID NO:37中所示的CDR L2以及如SEQ ID NO:38中所示的CDR L3。
在另一方面中提供了一种抗RYK抗体,其中所述抗RYK抗体与和包含以下的抗体相同的表位结合:重链可变结构域,所述重链可变结构域包含如SEQ ID NO:49中所示的CDRH1、如SEQ ID NO:50中所示的CDR H2以及如SEQ ID NO:51中所示的CDR H3;以及轻链可变结构域,所述轻链可变结构域包含如SEQ ID NO:52中所示的CDRL1、如SEQ ID NO:53中所示的CDR L2以及如SEQ ID NO:54中所示的CDR L3。
在实施例中,抗RYK抗体附着到治疗或诊断部分。在实施例中,抗RYK抗体附着到治疗部分。在实施例中,抗RYK抗体附着到诊断部分。
核酸组合物
本文提供的组合物包含编码本文(包含其实施例)所提供的抗RYK抗体或其部分的核酸分子。贯穿本申请详细描述了由本文提供的分离的核酸编码的抗体(包含上文和实例部分中的描述)。因此,在一方面中提供了一种编码本文(包含其实施例)所提供的抗RYK抗体的分离的核酸。
抗体组合物
本文提供的抗体的轻链和重链尤其可以使用本领域公知的常规方法形成重组蛋白(例如,嵌合抗原受体(CAR)或双特异性抗体(BiTes))的一部分。通过募集效应细胞,本文提供的抗RYK抗体可以诱导RYK表达性细胞的细胞杀伤,并且因此在其单独使用或在CAR或BiTe的上下文中使用时可用于治疗目的。
细胞组合物
本文提供的组合物包含细胞组合物,所述细胞组合物包含本文(包含其实施例)所提供的抗RYK抗体。因此,在一方面中提供了一种细胞,其包括本文(包含其实施例)所提供的抗RYK抗体或本文(包含其实施例)所提供的核酸。
药物组合物
本文提供的组合物包含药物组合物,所述药物组合物包含本文(包含其实施例)所提供的抗RYK抗体。因此,在一方面中提供了一种药物组合物,其包括治疗有效量的本文(包含其实施例)所提供的抗体以及药学上可接受的赋形剂。
方法
在一方面中提供了一种形成能够与RYK蛋白结合的抗体的方法,所述方法包含用包含SEQ ID NO:129的序列的肽使哺乳动物免疫。
在另一方面中提供了一种检测RYK表达性细胞的方法,所述方法包含(i)使RYK表达性细胞与本文(包含其实施例)所提供的抗体接触;(ii)以及检测所述抗体与由所述细胞表达的RYK蛋白的结合。
在实施例中,抗体附着到可检测部分。在实施例中,生物样品为全血、血液级分或血液产物、组织或经培养的细胞。在实施例中,生物样品为全血。在实施例中,生物样品为血液级分或血液产物。在实施例中,生物样品为血液级分。在实施例中,生物样品为血液产物。在实施例中,生物样品为组织。在实施例中,生物样品为经培养的细胞。
在实施例中,RYK表达性细胞为癌细胞。在实施例中,癌细胞为膀胱癌细胞、脑癌细胞、乳腺癌细胞、慢性髓系白血病(CML)细胞、结肠癌细胞、尤文氏肉瘤细胞、肺癌细胞、套细胞淋巴瘤细胞、卵巢癌细胞、胰腺癌细胞、皮肤癌细胞或黑色素瘤细胞。在实施例中,癌细胞为膀胱癌细胞。在实施例中,癌细胞为脑癌细胞。在实施例中,癌细胞为乳腺癌细胞。在实施例中,癌细胞为慢性髓系白血病(CML)细胞。在实施例中,癌细胞为结肠癌细胞。在实施例中,癌细胞为尤文氏肉瘤细胞。在实施例中,癌细胞为肺癌细胞。在实施例中,癌细胞为套细胞淋巴瘤细胞。在实施例中,癌细胞为卵巢癌细胞。在实施例中,癌细胞为胰腺癌细胞。在实施例中,癌细胞为皮肤癌细胞。在实施例中,癌细胞为黑色素瘤细胞。
在另一方面中提供了一种治疗有需要的受试者的癌症的方法,所述方法包含向受试者施用治疗有效量的本文(包含其实施例)所提供的抗RYK抗体。
在实施例中,癌症为膀胱癌、脑癌、乳腺癌、慢性髓系白血病(CML)、结肠癌、尤文氏肉瘤、肺癌、套细胞淋巴瘤、卵巢癌、胰腺癌、皮肤癌或黑色素瘤。在实施例中,癌症为膀胱癌。在实施例中,癌症为脑癌。在实施例中,癌症为慢性髓系白血病(CML)。在实施例中,癌症为结肠癌。在实施例中,癌症为尤文氏肉瘤。在实施例中,癌症为肺癌。在实施例中,癌症为套细胞淋巴瘤。在实施例中,癌症为卵巢癌。在实施例中,癌症为胰腺癌。在实施例中,癌症为皮肤癌。在实施例中,癌症为黑色素瘤。
在另一方面中提供了一种鉴定抗RYK抗体的方法,所述方法包含:(i)使抗体与第一RYK多肽接触,所述第一RYK多肽包含与SEQ ID NO:129的氨基酸残基48至57相对应的氨基酸序列;(ii)检测与所述第一RYK多肽结合的所述抗体;(iii)使所述抗体与第二RYK多肽接触,所述第二RYK多肽不包含与SEQ ID NO:129的氨基酸残基48至57相对应的氨基酸序列;以及(iv)检测未与所述第二RYK多肽结合的所述抗体,由此鉴定抗RYK抗体。
在实施例中,抗体为嵌合抗体。在实施例中,抗体为Fab'片段。在实施例中,抗体为单链抗体。
应当理解,本文所描述的实例和实施例仅是出于说明性目的,并且根据其进行的各种修改或改变将启发本领域的技术人员并且将被包含在本申请的精神与权限范围内和所附权利要求书的范围内。本文所引用的所有出版物、专利和专利申请均出于所有目的特此通过引用以其整体并入。
实例
实例1:
申请人已经产生了对人Ryk的胞外结构域具有高度特异性、但不与高度同源的小鼠Ryk结合的mAb。这些mAb明显与存在于成熟人Ryk蛋白的氨基末端处的表位结合。此外,这些mAb对Ryk具有非常高的亲和力,并且令人惊讶地似乎不与正常人产后组织发生反应。例如,申请人发现这些mAb不与正常人脐带血或产后血、扁桃体、脾脏或骨髓中的造血细胞结合。然而,令人惊讶的是,这些mAb与源自多种不同实体瘤或血癌的癌细胞系发生反应。因为这些mAb不与源自同一组织类型的所有癌症发生反应,所以推测这些mAb不与源自所述组织类型的所有产后细胞发生反应。令人惊讶的是,申请人发现mAb与患有侵袭性癌症的患者的原发性肿瘤细胞,如三阴性转移性乳腺癌细胞非常强烈地发生反应。此外,申请人已经发现,这些mAb与恶性胸腔积液或腹水中的癌细胞强烈发生反应,并且可以与血液中的循环肿瘤细胞发生反应。初步研究还表明,这些mAb与具有癌症干细胞或间充质特征的癌细胞最强烈地发生反应,所述癌症干细胞或间充质特征与高转移轨迹和不良预后相关。
这些抗体可以用于与表达Ryk的癌细胞结合。因为Ryk在正常产后组织上明显具有低至可忽略的表达,所以这些mAb可以通过抗体依赖性细胞毒性(ADCC)或通过抑制Ryk的显著促进了癌细胞迁移、生长和/或癌干细胞更新的尚待定义的功能来靶向Ryk表达性癌细胞以进行破坏。另外,这些mAb可以与毒素连接,从而允许将抗Ryk mAb结合的毒素特异性递送到表达Ryk的肿瘤细胞。由于mAb的高亲和力,其可以被‘人源化’以同化人类抗体和/或用于产生与Ryk结合的单链Fv(scFv)结构域,所述结构域可以用于形成靶向Ryk的双特异性抗体以及另一种可以允许对针对Ryk表达性肿瘤细胞的抗肿瘤免疫应答进行细胞免疫活化的分子,如CD3。此外,这些抗Ryk scFv可以用于产生嵌合抗原受体(CAR)。抗Ryk CAR通过T细胞或NK细胞进行的表达可以允许针对Ryk表达性癌症的抗Ryk CAR T/NK细胞疗法。
如本文所描述的,申请人已经制备了抗Ryk抗体,并且已经测量了所述抗体对抗原的亲和力。此外,已经对Ryk结合位点进行测序,并且确定了两种所公开的抗Ryk mAb,即2-D11和7-H10(即将发表)的重链和轻链的氨基酸序列。已经在各种癌症的细胞系,包含三阴性乳腺癌的异种移植物中对所述抗体进行了测试。此外,已经使用了2-D11抗体以对源自各种癌症组织类型的癌细胞系,包含来自乳腺癌患者源性异种移植物(例如,三阴性转移性乳腺癌)的原代肿瘤细胞进行染色。
实例3:
由于数据表明在使用抗RYK抗血清的研究中,RYK在CLL细胞上表达,因此产生了用于与患有慢性淋巴细胞白血病(CLL)的患者的白血病细胞结合的抗RYK mAb。然而,在产生对RYK具有特异性的高亲和力mAb时,申请人惊讶地发现,抗RYK抗血清显然对CLL细胞具有虚假结合活性,所述CLL细胞被发现实际上不表达RYK,并且不与本文所述的所公开的抗RykmAb发生反应。申请人还发现,RYK不在所测试的所有非癌细胞上表达,但在许多不同人类癌症的赘生物细胞上表达。
实例3:
人Ryk的胞外蛋白质序列与小鼠RYK的胞外蛋白质序列高度同源(图1)。已经产生了与由图2中所示的氨基酸组成的人RYK的成熟胞外蛋白质结构域结合但不与由图3中所示的氨基酸组成的高度同源的小鼠RYK结合的抗人RYK mAb。
抗人RYK mAb,即2-D11和7-H10似乎对人Ryk的氨基末端表位(残基46-57)具有特异性,所述表位与小鼠Ryk中的表位不同(图3);这些mAb还与在人Ryk中在与高度同源的小鼠Ryk的位置不同的位置处含有氨基酸取代的Ryk的突变形式结合,以在取代位点处用如图3中所示的氨基酸序列同化小鼠Ryk,如通过人或小鼠或人Ryk的各种突变形式中的每种突变形式的重组胞外蛋白质的免疫印迹分析所示出的(图4)。为此,使用重组胞外RYK蛋白如符号说明中规定的那样对2-D11、7-H10或绵羊抗RYK mAb的结合进行评估。将每种重组蛋白转移到尼龙膜上,用2-D11、7-H10或绵羊抗RYK进行探测,并且用与辣根过氧化物酶缀合的抗小鼠IgG或驴抗绵羊抗体进行检测。黑色小点表示抗体结合的阳性信号。如图4中所看到的,绵羊抗Ryk与人或小鼠Ryk发生反应,而2-D11或7-H10各自与人Ryk发生反应,但不与小鼠Ryk发生反应。此外,2-D11或7-H10与在人Ryk序列与小鼠Ryk序列不同的特定位点处具有氨基酸取代的人Ryk的每种突变形式发生反应;这些重组蛋白中的每种重组蛋白的氨基酸序列在图3中提供。
上文提及的mAb 2-D11具有图5A中所示的重链可变区序列,并且2-D11的轻链可变区序列在图5B中提供。上文提及的mAb 7-H10具有图6A中所示的重链可变区序列,并且2-D11的轻链可变区序列在图6B中提供。在这些图中还分别呈现了在序列同源性上与2-D11或7-H10最接近的小鼠种系重链可变区基因(图5A、图6A)或小鼠种系轻链可变区基因(图5B、图6B)。
人Ryk的2-D11或7-H10的KinExA结合数据在图7中提供。人Ryk的2-D11的所计算的Kd为512.9pM;人Ryk的7-H10的所计算的Kd为10.56nM。
将2-D11 mAb与荧光染料(Alexa 647)缀合,并且将经缀合的mAb用于对所建立的肿瘤细胞系进行染色。开放直方图描绘了用具有不相关特异性的对照荧光染料缀合的mAb进行染色的细胞系的荧光强度(图8)。阴影直方图描绘了用2-D11荧光染料缀合的mAb进行染色的细胞的荧光度。提供了肿瘤细胞系的代表性染色,其示出了相对于用不与这些细胞结合的具有不相关特异性的荧光染料缀合的‘对照mAb’进行处理的细胞的染色,“++”染色(针对BT549)、“+”染色(针对HT29)或未染色或“阴性”(针对SK-MES-1)。这些对照mAb染色的细胞的荧光度与未经染色的细胞的荧光度相同。
表1提供了用荧光染料缀合的2-D11进行染色的各种癌细胞系的流式细胞术数据,如图8中描绘的。在第一列中列出了每个细胞系的名称,并且在第二列中列出了起源组织。通过流式细胞术染色对2-D11 mAb与人RYK的结合进行评估,并且分析通过使用5μg/ml 2-D11抗人RYK-Alexa647缀合的mAb或等量的同种型匹配的对照mAb在冰上染色20分钟、洗涤并分析。在中间列中列出了2-D11染色的细胞的中值荧光强度(MFI),并且在相邻列中列出了同种型对照染色的细胞的MFI。基于经染色的细胞的中值荧光强度(MFI)相对于同种型对照染色的细胞的MFI的比率(MFIR),将细胞系评分为“++”、“+”或阴性(未用“+”标记)系。
图9提供了关于对存在于如每列的顶部所指示的成人血液、脐带血(N=2)、扁桃体(N=2)或脾脏中的淋巴细胞进行的荧光染料缀合的2-D11染色的流式细胞术数据。开放直方图表示用具有不相关特异性的荧光染料缀合的mAb代替2-D11进行染色(对照染色)的细胞。阴影直方图为用2-D11进行染色的细胞。用与不同颜色的荧光染料缀合的对CD19或CD3具有特异性的mAb对细胞进行染色。顶部行提供了关于经门控的CD19+B细胞的数据,中间行提供了关于经门控的CD3+T细胞的数据,并且底部行提供了关于缺乏与对CD19或CD3具有特异性的mAb结合的细胞(NK细胞)的数据。如从这些数据中看到的,2-D11不与正常人淋巴细胞发生反应。
图10示出了原发性人乳腺癌细胞的2-D11的代表性染色。图10中的经染色的细胞是由患者源性异种移植物(PDX)制备的解离的单细胞,所述患者源性异种移植物是通过用从患有转移性乳腺癌的患者体内移除的三阴性(ER/PR-、HER2-)乳腺腺癌组织移植免疫缺陷而产生的。
表格
表1:对具有抗人RYK mAb的癌细胞系的流式细胞术染色分析。
在第一列中列出了每个细胞系的名称,并且在第二列中列出了起源组织。通过流式细胞术染色对2-D11 mAb与人RYK的结合进行评估并且分析通过使用5ug/ml 2-D11抗人RYK-Alexa647缀合的mAb或等量的同种型匹配的对照mAb在冰上染色20分钟、洗涤并分析。在中间列中列出了2-D11染色的细胞的中值荧光强度(MFI),并且在相邻列中列出了同种型对照染色的细胞的MFI。基于经染色的细胞的中值荧光强度(MFI)相对于同种型对照染色的细胞的MFI的比率(MFIR),将细胞系评分为“++”、“+”或阴性(未用“+”标记)系。
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参考文献
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非正式序列表
SEQ ID NO:1 2-D11 CDR H1
GFSLNDYG
SEQ ID NO:2 2-D11 CDR H2
IWGDGVT
SEQ ID NO:3 2-D11 CDR H3
QGSGVWFAH
SEQ ID NO:4 2-D11 CDR L1
QTIVHSNGNTY
SEQ ID NO:5 2-D11 CDR L2
KVS
SEQ ID NO:6 2-D11 CDR L3
FQGSHVPYT
SEQ ID NO:7 2-D11 FR H1
QVQLKESGPGLVAPSQSLSITCSVS
SEQ ID NO:8 2-D11 FR H2
VNWVRQPPGKDLEWLGM
SEQ ID NO:9 2-D11 FR H3
EYNSTLKSRLSISKDNSKSQVFLKMNNLQTEDTARYYCVR
SEQ ID NO:10 2-D11 FR H4
WGQGTLVSVSS
SEQ ID NO:11 2-D11 FR L1
DVLVTQTPLSLPVSLGDQASISCRSS
SEQ ID NO:12 2-D11 FR L2
LEWYLQKPGQSPKLLIY
SEQ ID NO:13 2-D11 FR L3
NRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGIYYC
SEQ ID NO:14 2-D11 FR L4
FGGGTKLEIK
SEQ ID NO:15 2-D11 VH
QVQLKESGPGLVAPSQSLSITCSVSGFSLNDYGVNWVRQPPGKDLEWLGMIWGDGVT
EYNSTLKSRLSISKDNSKSQVFLKMNNLQTEDTARYYCVRQGSGVWFAHWGQGTLVS
VSS
SEQ ID NO:16 2-D11 VL
DVLVTQTPLSLPVSLGDQASISCRSSQTIVHSNGNTYLEWYLQKPGQSPKLLIYKVSNR
FSGVPDRFSGSGSGTDFTLKISRVEAEDLGIYYCFQGSHVPYTFGGGTKLEIK
SEQ ID NO:17 7-H10 CDR H1
GYIFTNYD
SEQ ID NO:18 7-H10 CDR H2
IFPGDDST
SEQ ID NO:19 7-H10 CDR H3
YHYYGSSLGWSFDV
SEQ ID NO:20 7-H10 CDR L1
SRISSIN
SEQ ID NO:21 7-H10 CDR L2
GTS
SEQ ID NO:22 7-H10 CDR L3
QQWSSYPYT
SEQ ID NO:23 7-H10 FR H1
QVQLQQSGAELAKPGTSVKLSCKAS
SEQ ID NO:24 7-H10 FR H2
INWVRQRPEQGLEWIGW
SEQ ID NO:25 7-H10 FR H3
KYNEKFEGKAALTTDKSSNTAYIQLSRLTSGDSAVYFCTR
SEQ ID NO:26 7-H10 FR H4
WGAGTSVTVSS
SEQ ID NO:27 7-H10 FR L1
EIVLTQSPALMAASPGEKVTITCSVS
SEQ ID NO:28 7-H10 FR L2
LHWYQQKSETSPKTWIY
SEQ ID NO:29 7-H10 FR L3
NLASGVPSRFSGSGSGTSYSLTISNMEAEDAATYYC
SEQ ID NO:30 7-H10 FR L4
FGGGTKVEIK
SEQ ID NO:31 7-H10 VH
QVQLQQSGAELAKPGTSVKLSCKASGYIFTNYDINWVRQRPEQGLEWIGWIFPGDDST
KYNEKFEGKAALTTDKSSNTAYIQLSRLTSGDSAVYFCTRYHYYGSSLGWSFDVWGAG
TSVTVSS
SEQ ID NO:32 7-H10 VL
EIVLTQSPALMAASPGEKVTITCSVSSRISSINLHWYQQKSETSPKTWIYGTSNLASGVP
SRFSGSGSGTSYSLTISNMEAEDAATYYCQQWSSYPYTFGGGTKVEIK
SEQ ID NO:33 11-E9 CDR H1
GFSLNGYG
SEQ ID NO:34 11-E9 CDR H2
IWGDGIT
SEQ ID NO:35 11-E9 CDR H3
QGSGVWFAY
SEQ ID NO:36 11-E9 CDR L1
QTIVHSNGNTY
SEQ ID NO:37 11-E9 CDR L2
KVS
SEQ ID NO:38 11-E9 CDR L3
FQGSHVPYT
SEQ ID NO:39 11-E9 FR H1
QVQLKESGPGLVAPSQSLSITCTVS
SEQ ID NO:40 11-E9 FR H2
VNWVRQPPGKDLEWLGM
SEQ ID NO:41 11-E9 FR H3
EFNSALKSRLSISKDNSKSQVFLKMNSLQTEDTARYYCVR
SEQ ID NO:42 11-E9 FR H4
WGQGTLS
SEQ ID NO:43 11-E9 FR L1
DVLVTQTPLSLPVSLGDQASISCRSS
SEQ ID NO:44 11-E9 FR L2
LEWYLQKPGQSPKLLIY
SEQ ID NO:45 11-E9 FR L3
NRFCGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYC
SEQ ID NO:46 11-E9 FR L4
FGGGTKLEIK
SEQ ID NO:47 11-E9 VH
QVQLKESGPGLVAPSQSLSITCTVSGFSLNGYGVNWVRQPPGKDLEWLGMIWGDGITE
FNSALKSRLSISKDNSKSQVFLKMNSLQTEDTARYYCVRQGSGVWFAYWGQGTLS
SEQ ID NO:48 11-E9 VL
DVLVTQTPLSLPVSLGDQASISCRSSQTIVHSNGNTYLEWYLQKPGQSPKLLIYKVSNR
FCGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHVPYTFGGGTKLEIK
SEQ ID NO:49 3-C12 CDR H1
GFSLNGYG
SEQ ID NO:50 3-C12 CDR H2
IWGDGIT
SEQ ID NO:51 3-C12 CDR H3
QGSGVWFAY
SEQ ID NO:52 3-C12 CDR L1
QTIVHSNGNTY
SEQ ID NO:53 3-C12 CDR L2
KVS
SEQ ID NO:54 3-C12 CDR L3
FQGSHVPYT
SEQ ID NO:55 3-C12 FR H1
QVQLKESGPGLVAPSQSLSITCTVS
SEQ ID NO:56 3-C12 FR H2
VNWVRQPPGKDLEWLGM
SEQ ID NO:57 3-C12 FR H3
EFNSALKSRLSISKDNSKSQVFLKMNSLQTEDTARYYCVR
SEQ ID NO:58 3-C12 FR H4
WGQGTLVS
SEQ ID NO:59 3-C12 FR L1
DVLVTQTPLSLPVSLGDQASISCRSS
SEQ ID NO:60 3-C12 FR L2
LEWYLQKPGQSPKLLIY
SEQ ID NO:61 3-C12 FR L3
NRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYC
SEQ ID NO:62 3-C12 FR L4
FGGGTKLEIK
SEQ ID NO:63 3-C12 VH
QVQLKESGPGLVAPSQSLSITCTVSGFSLNGYGVNWVRQPPGKDLEWLGMIWGDGITE
FNSALKSRLSISKDNSKSQVFLKMNSLQTEDTARYYCVRQGSGVWFAYWGQGTLVSSEQ ID NO:643-C12 VL
DVLVTQTPLSLPVSLGDQASISCRSSQTIVHSNGNTYLEWYLQKPGQSPKLLIYKVSNR
FSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHVPYTFGGGTKLEIK
SEQ ID NO:65 2-D11 CDR H1核苷酸
GGGTTCTCATTAAACGACTATGGT
SEQ ID NO:66 2-D11 CDR H2核苷酸
ATTTGGGGTGATGGAGTCACA
SEQ ID NO:67 2-D11 CDR H3核苷酸
GTCAGACAGGGGTCTGGTGTCTGGTTTGCTCAC
SEQ ID NO:68 2-D11 CDR L1核苷酸
CAGACCATTGTACATAGTAATGGAAACACGTAT
SEQ ID NO:69 2-D11 CDR L2核苷酸
AAAGTTTCC
SEQ ID NO:70 2-D11 CDR L3核苷酸
TTTCAAGGTTCACATGTTCCGTACACG
SEQ ID NO:71 2-D11 FR H1核苷酸
CAGGTGCAGCTGAAGGAGTCAGGACCTGGCCTGGTGGCGCCCTCACAGAGCCTGT
CCATCACATGTTCCGTCTCA
SEQ ID NO:72 2-D11 FR H2核苷酸
GTAAATTGGGTTCGCCAGCCTCCAGGAAAGGATCTGGAGTGGCTGGGAATG
SEQ ID NO:73 2-D11 FR H3核苷酸
GAGTATAATTCAACTCTCAAATCCAGACTGAGCATCAGCAAGGACAACTCCAAGAG
CCAAGTTTTCTTAAAAATGAACAATCTGCAAACTGAAGACACAGCCAGGTACTACT
GT
SEQ ID NO:74 2-D11 FR H4核苷酸
TGGGGCCAAGGGACTCTGGTCAGTGTCTCTTCA
SEQ ID NO:75 2-D11 FR L1核苷酸
GATGTTTTGGTGACCCAAACTCCACTCTCCCTGCCTGTCAGTCTTGGAGATCAAGCC
TCCATCTCTTGCAGATCTAGT
SEQ ID NO:76 2-D11 FR L2核苷酸
TTAGAATGGTACCTGCAGAAACCAGGCCAGTCTCCAAAGCTCCTAATCTAC
SEQ ID NO:77 2-D11 FR L3核苷酸
AACCGATTTTCTGGGGTCCCAGACAGGTTCAGTGGCAGTGGATCAGGCACAGATTT
CACACTCAAGATCAGCAGAGTGGAGGCTGAGGATCTGGGAATTTATTACTGC
SEQ ID NO:78 2-D11 FR L4核苷酸
TTCGGAGGGGGGACCAAGCTGGAAATAAAA
SEQ ID NO:79 2-D11 VH核苷酸
CAGGTGCAGCTGAAGGAGTCAGGACCTGGCCTGGTGGCGCCCTCACAGAGCCTGT
CCATCACATGTTCCGTCTCAGGGTTCTCATTAAACGACTATGGTGTAAATTGGGTTCG
CCAGCCTCCAGGAAAGGATCTGGAGTGGCTGGGAATGATTTGGGGTGATGGAGTCA
CAGAGTATAATTCAACTCTCAAATCCAGACTGAGCATCAGCAAGGACAACTCCAAG
AGCCAAGTTTTCTTAAAAATGAACAATCTGCAAACTGAAGACACAGCCAGGTACTA
CTGTGTCAGACAGGGGTCTGGTGTCTGGTTTGCTCACTGGGGCCAAGGGACTCTGG
TCAGTGTCTCTTCA
SEQ ID NO:80 2-D11 VL核苷酸
GATGTTTTGGTGACCCAAACTCCACTCTCCCTGCCTGTCAGTCTTGGAGATCAAGCC
TCCATCTCTTGCAGATCTAGTCAGACCATTGTACATAGTAATGGAAACACGTATTTAG
AATGGTACCTGCAGAAACCAGGCCAGTCTCCAAAGCTCCTAATCTACAAAGTTTCC
AACCGATTTTCTGGGGTCCCAGACAGGTTCAGTGGCAGTGGATCAGGCACAGATTT
CACACTCAAGATCAGCAGAGTGGAGGCTGAGGATCTGGGAATTTATTACTGCTTTCA
AGGTTCACATGTTCCGTACACGTTCGGAGGGGGGACCAAGCTGGAAATAAAA
SEQ ID NO:81 7-H10 CDR H1核苷酸
GGCTACATCTTCACAAACTATGAT
SEQ ID NO:82 7-H10 CDR H2核苷酸
ATTTTTCCTGGAGATGATAGTACT
SEQ ID NO:83 7-H10 CDR H3核苷酸
ACAAGATATCATTACTACGGTAGTTCCTTGGGGTGGTCCTTCGATGTC
SEQ ID NO:84 7-H10 CDR L1核苷酸
TCAAGAATAAGTTCCATTAAC
SEQ ID NO:85 7-H10 CDR L2核苷酸
GGCACATCC
SEQ ID NO:86 7-H10 CDR L3核苷酸
CAACAGTGGAGTAGTTATCCGTACACG
SEQ ID NO:87 7-H10 FR H1核苷酸
CAGGTTCAGCTGCAGCAGTCTGGAGCTGAACTGGCAAAGCCTGGGACTTCAGTGA
AATTGTCCTGCAAGGCTTCT
SEQ ID NO:88 7-H10 FR H2核苷酸
ATAAACTGGGTGAGGCAGAGGCCTGAACAGGGACTTGAGTGGATTGGATGG
SEQ ID NO:89 7-H10 FR H3核苷酸
AAGTACAATGAGAAATTCGAGGGCAAGGCCGCACTGACTACAGACAAGTCCTCCA
ACACAGCCTACATACAACTCAGCAGACTGACATCTGGGGACTCAGCTGTCTATTTCT
GT
SEQ ID NO:90 7-H10 FR H4核苷酸
TGGGGCGCAGGGACCTCGGTCACCGTCTCCTCA
SEQ ID NO:91 7-H10 FR L1核苷酸
GAAATTGTGCTCACCCAGTCTCCAGCACTCATGGCTGCATCTCCAGGGGAGAAGGT
CACCATCACCTGCAGTGTCAGT
SEQ ID NO:92 7-H10 FR L2核苷酸
TTGCACTGGTACCAGCAGAAGTCAGAAACCTCCCCCAAAACCTGGATTTAT
SEQ ID NO:93 7-H10 FR L3核苷酸
AACCTGGCTTCTGGAGTCCCTAGTCGCTTCAGTGGCAGTGGATCTGGGACCTCTTAT
TCTCTCACAATCAGCAACATGGAGGCTGAAGATGCTGCCACTTATTACTGT
SEQ ID NO:94 7-H10 FR L4核苷酸
TTCGGAGGGGGGACCAAGGTGGAAATAAAA
SEQ ID NO:95 7-H10 VH核苷酸
CAGGTTCAGCTGCAGCAGTCTGGAGCTGAACTGGCAAAGCCTGGGACTTCAGTGA
AATTGTCCTGCAAGGCTTCTGGCTACATCTTCACAAACTATGATATAAACTGGGTGA
GGCAGAGGCCTGAACAGGGACTTGAGTGGATTGGATGGATTTTTCCTGGAGATGAT
AGTACTAAGTACAATGAGAAATTCGAGGGCAAGGCCGCACTGACTACAGACAAGTC
CTCCAACACAGCCTACATACAACTCAGCAGACTGACATCTGGGGACTCAGCTGTCT
ATTTCTGTACAAGATATCATTACTACGGTAGTTCCTTGGGGTGGTCCTTCGATGTCTG
GGGCGCAGGGACCTCGGTCACCGTCTCCTCA
SEQ ID NO:96 7-H10 VL核苷酸
GAAATTGTGCTCACCCAGTCTCCAGCACTCATGGCTGCATCTCCAGGGGAGAAGGT
CACCATCACCTGCAGTGTCAGTTCAAGAATAAGTTCCATTAACTTGCACTGGTACCA
GCAGAAGTCAGAAACCTCCCCCAAAACCTGGATTTATGGCACATCCAACCTGGCTT
CTGGAGTCCCTAGTCGCTTCAGTGGCAGTGGATCTGGGACCTCTTATTCTCTCACAA
TCAGCAACATGGAGGCTGAAGATGCTGCCACTTATTACTGTCAACAGTGGAGTAGTT
ATCCGTACACGTTCGGAGGGGGGACCAAGGTGGAAATAAAA
SEQ ID NO:97 11-E9 CDR H1核苷酸
GGGTTCTCATTAAACGGCTATGGT
SEQ ID NO:98:11-E9 CDR H2核苷酸
ATCTGGGGTGATGGAATCACA
SEQ ID NO:99 11-E9 CDR H3核苷酸
GTCAGACAGGGGTCTGGTGTCTGGTTTGCTTAC
SEQ ID NO:100 11-E9 CDR L1核苷酸
CAGACCATTGTACATAGTAATGGAAACACCTAT
SEQ ID NO:101 11-E9 CDR L2核苷酸
AAAGTTTCC
SEQ ID NO:102 11-E9 CDR L3核苷酸
TTTCAAGGTTCACATGTTCCGTACACG
SEQ ID NO:103 11-E9 FR H1核苷酸
CAGGTGCAGCTGAAGGAGTCAGGACCTGGCCTGGTGGCGCCCTCACAGAGCCTGT
CCATCACATGTACCGTCTCA
SEQ ID NO:104 11-E9 FR H2核苷酸
GTAAACTGGGTTCGCCAGCCTCCAGGAAAGGATCTGGAGTGGCTGGGAATG
SEQ ID NO:105 11-E9 FR H3核苷酸
GAGTTTAATTCAGCTCTCAAATCCAGACTGAGCATCAGCAAGGACAACTCCAAGAG
CCAAGTTTTCTTAAAAATGAACAGTCTGCAAACTGAAGACACAGCCAGGTACTACT
GT
SEQ ID NO:106 11-E9 FR H4核苷酸
TGGGGCCAAGGGACTCTGTCA
SEQ ID NO:107 11-E9 FR L1核苷酸
GATGTTTTGGTGACCCAAACTCCACTCTCCCTGCCTGTCAGTCTTGGAGATCAAGCC
TCCATCTCTTGCAGATCTAGT
SEQ ID NO:108 11-E9 FR L2核苷酸
TTAGAATGGTACCTGCAGAAACCAGGCCAGTCTCCAAAGCTCTTGATTTAC
SEQ ID NO:109 11-E9 FR L3核苷酸
AACCGATTTTGTGGGGTCCCAGACAGGTTCAGTGGCAGTGGATCAGGCACAGATTT
CACACTCAAGATCAGCAGAGTGGAGGCTGAGGATCTGGGAGTTTATTACTGC
SEQ ID NO:110 11-E9 FR L4核苷酸
TTCGGAGGGGGGACCAAGCTGGAAATAAAA
SEQ ID NO:111 11-E9 VH核苷酸
CAGGTGCAGCTGAAGGAGTCAGGACCTGGCCTGGTGGCGCCCTCACAGAGCCTGT
CCATCACATGTACCGTCTCAGGGTTCTCATTAAACGGCTATGGTGTAAACTGGGTTC
GCCAGCCTCCAGGAAAGGATCTGGAGTGGCTGGGAATGATCTGGGGTGATGGAATC
ACAGAGTTTAATTCAGCTCTCAAATCCAGACTGAGCATCAGCAAGGACAACTCCAA
GAGCCAAGTTTTCTTAAAAATGAACAGTCTGCAAACTGAAGACACAGCCAGGTACT
ACTGTGTCAGACAGGGGTCTGGTGTCTGGTTTGCTTACTGGGGCCAAGGGACTCTG
TCA
SEQ ID NO:112 11-E9 VL核苷酸
GATGTTTTGGTGACCCAAACTCCACTCTCCCTGCCTGTCAGTCTTGGAGATCAAGCC
TCCATCTCTTGCAGATCTAGTCAGACCATTGTACATAGTAATGGAAACACCTATTTAG
AATGGTACCTGCAGAAACCAGGCCAGTCTCCAAAGCTCTTGATTTACAAAGTTTCC
AACCGATTTTGTGGGGTCCCAGACAGGTTCAGTGGCAGTGGATCAGGCACAGATTT
CACACTCAAGATCAGCAGAGTGGAGGCTGAGGATCTGGGAGTTTATTACTGCTTTC
AAGGTTCACATGTTCCGTACACGTTCGGAGGGGGGACCAAGCTGGAAATAAAA
SEQ ID NO:113 3-C12 CDR H1核苷酸
GGGTTCTCATTAAACGGCTATGGT
SEQ ID NO:114 3-C12 CDR H2核苷酸
ATCTGGGGTGATGGAATCACA
SEQ ID NO:115 3-C12 CDR H3核苷酸
CAGGGGTCTGGTGTCTGGTTTGCTTAC
SEQ ID NO:116 3-C12 CDR L1核苷酸
CAGACCATTGTACATAGTAATGGAAACACCTAT
SEQ ID NO:117 3-C12 CDR L2核苷酸
AAAGTTTCC
SEQ ID NO:118 3-C12 CDR L3核苷酸
TTTCAAGGTTCACATGTTCCGTACACG
SEQ ID NO:119 3-C12 FR H1核苷酸
CAGGTGCAGCTGAAGGAGTCAGGACCTGGCCTGGTGGCGCCCTCACAGAGCCTGT
CCATCACATGTACCGTCTCA
SEQ ID NO:120 3-C12 FR H2核苷酸
GTAAACTGGGTTCGCCAGCCTCCAGGAAAGGATCTGGAGTGGCTGGGAATG
SEQ ID NO:121 3-C12 FR H3核苷酸
GAGTTTAATTCAGCTCTCAAATCCAGACTGAGCATCAGCAAGGACAACTCCAAGAG
CCAAGTTTTCTTAAAAATGAACAGTCTGCAAACTGAAGACACAGCCAGGTACTACT
GTGTCAGA
SEQ ID NO:122 3-C12 FR H4核苷酸
TGGGGCCAAGGGACTCTGGTCAGT
SEQ ID NO:123 3-C12 FR L1核苷酸
GATGTTTTGGTGACCCAAACTCCACTCTCCCTGCCTGTCAGTCTTGGAGATCAAGCC
TCCATCTCTTGCAGATCTAGT
SEQ ID NO:124 3-C12 FR L2核苷酸
TTAGAATGGTACCTGCAGAAACCAGGCCAGTCTCCAAAGCTCCTGATTTAC
SEQ ID NO:125 3-C12 FR L3核苷酸
AACCGATTTTCTGGGGTCCCAGACAGGTTCAGTGGCAGTGGATCAGGCACAGATTT
CACACTCAAGATCAGCAGAGTGGAGGCTGAGGATCTGGGAGTTTATTACTGC
SEQ ID NO:126 3-C12 FR L4核苷酸
TTCGGAGGGGGGACCAAGCTGGAAATAAAA
SEQ ID NO:127 3-C12 VH核苷酸
CAGGTGCAGCTGAAGGAGTCAGGACCTGGCCTGGTGGCGCCCTCACAGAGCCTGT
CCATCACATGTACCGTCTCAGGGTTCTCATTAAACGGCTATGGTGTAAACTGGGTTC
GCCAGCCTCCAGGAAAGGATCTGGAGTGGCTGGGAATGATCTGGGGTGATGGAATC
ACAGAGTTTAATTCAGCTCTCAAATCCAGACTGAGCATCAGCAAGGACAACTCCAA
GAGCCAAGTTTTCTTAAAAATGAACAGTCTGCAAACTGAAGACACAGCCAGGTACT
ACTGTGTCAGACAGGGGTCTGGTGTCTGGTTTGCTTACTGGGGCCAAGGGACTCTG
GTCAGT
SEQ ID NO:128 3-C12 VL核苷酸
GATGTTTTGGTGACCCAAACTCCACTCTCCCTGCCTGTCAGTCTTGGAGATCAAGCC
TCCATCTCTTGCAGATCTAGTCAGACCATTGTACATAGTAATGGAAACACCTATTTAG
AATGGTACCTGCAGAAACCAGGCCAGTCTCCAAAGCTCCTGATTTACAAAGTTTCC
AACCGATTTTCTGGGGTCCCAGACAGGTTCAGTGGCAGTGGATCAGGCACAGATTT
CACACTCAAGATCAGCAGAGTGGAGGCTGAGGATCTGGGAGTTTATTACTGCTTTC
AAGGTTCACATGTTCCGTACACGTTCGGAGGGGGGACCAAGCTGGAAATAAAA
SEQ ID NO:129人RYK胞外结构域的氨基酸1-181
MRGAARLGRPGRSCLPGARGLRAPPPPPLLLLLALLPLLPAPGAAAAPAPRPPELQSAS
AGPSVSLYLSEDEVRRLIGLDAELYYVRNDLISHYALSFSLLVPSETNFLHFTWHAKSKV
EYKLGFQVDNVLAMDMPQVNISVQGEVPRTLSVFRVELSCTGKVDSEVMILMQLNLT
VNSSK
SEQ ID NO:130人RYK胞外结构域的氨基酸48-57
PAPRPPELQS
SEQ ID NO:131小鼠RYK胞外结构域
MRAGRGGVPGSGGLRAPPPPLLLLLLAMLPAAAPRSPALAAAPAGPSVSLYLSEDEVRR
LLGLDAELYYVRNDLISHYALSFNLLVPSETNFLHFTWHAKSKVEYKLGFQVDNFVAM
GMPQVNISAQGEVPRTLSVFRVELSCTGKVDSEVMILMQLNLTVNSSKNFTVLNFKRR
KMCYKKLEEVKTSALDKNTSRTIYDPVHAAPTTSTRVFY
SEQ ID NO:132人RYK胞外结构域
MRGAARLGRPGRSCLPGARGLRAPPPPPLLLLLALLPLLPAPGAAAAPAPRPPELQSAS
AGPSVSLYLSEDEVRRLIGLDAELYYVRNDLISHYALSFSLLVPSETNFLHFTWHAKSKV
EYKLGFQVDNVLAMDMPQVNISVQGEVPRTLSVFRVELSCTGKVDSEVMILMQLNLT
VNSSKNFTVLNFKRRKMCYKKLEEVKTSALDKNTSRTIYDPVHAAPTTSTRVFY
SEQ ID NO:133小鼠IGHV2-6
QVQLKESGPGLVAPSQSLSITCTVSGFSLTGYGVNWVRQPPGKGLEWLGMIWGDGSTD
YNSALKSRLSISKDNSKSQVFLKMNSLQTDDTARYYCAR
SEQ ID NO:134小鼠IGKV1-117
DVLMTQTPLSLPVSLGDQASISCRSSQSIVHSNGNTYLEWYLQKPGQSPKLLIYKVSNR
FSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHVP
SEQ ID NO:135小鼠IGHV1-85
QVQLQQSGPELVKPGASVKLSCKASGYTFTSYDINWVKQRPGQGLEWIGWIYPRDGST
KYNEKFKGKATLTVDTSSSTAYMELHSLTSEDSAVYFCAR
SEQ ID NO:136小鼠IGKV4-53
EIVLTQSPALMAASPGEKVTITCSVSSSISSSNLHWYQQKSETSPKPWIYGTSNLASGVP
VRFSGSGSGTSYSLTISSMEAEDAATYYCQQWSSYPL
P实施例
P实施例1.一种抗受体相关酪氨酸激酶(Ryk)抗体,其包括重链可变结构域和轻链可变结构域,其中所述重链可变结构域包括:如SEQ ID NO:1中所示的CDR H1、如SEQ IDNO:2中所示的CDR H2以及如SEQ ID NO:3中所示的CDR H3;并且其中所述轻链可变结构域包括:如SEQ ID NO:4中所示的CDR L1、如SEQ ID NO:5中所示的CDR L2以及如SEQ ID NO:6中所示的CDR L3。
P实施例2.根据P实施例1所述的抗体,其中所述重链可变结构域包括SEQ ID NO:21的序列。
P实施例3.根据P实施例1或2所述的抗体,其中所述轻链可变结构域包括SEQ IDNO:22的序列。
P实施例4.一种抗受体相关酪氨酸激酶(Ryk)抗体,其包括重链可变结构域和轻链可变结构域,其中所述重链可变结构域包括:如SEQ ID NO:7中所示的CDR H1、如SEQ IDNO:8中所示的CDR H2以及如SEQ ID NO:9中所示的CDR H3;并且其中所述轻链可变结构域包括:如SEQ ID NO:10中所示的CDR L1、如SEQ ID NO:11中所示的CDR L2以及如SEQ IDNO:12中所示的CDR L3。
P实施例5.根据P实施例4所述的抗体,其中所述重链可变结构域包括SEQ ID NO:31的序列。
P实施例6.根据P实施例4或5所述的抗体,其中所述重链可变结构域包括SEQ IDNO:32的序列。
P实施例7.一种治疗有需要的受试者的癌症的方法,所述方法包括向受试者施用治疗有效量的根据P实施例1至6中任一项所述的抗体。
实施例
实施例1.一种抗RYK抗体,其包括轻链可变结构域和重链可变结构域,其中所述重链可变结构域包括如SEQ ID NO:1中所示的CDR H1、如SEQ ID NO:2中所示的CDR H2以及如SEQ ID NO:3中所示的CDR H3;并且其中所述轻链可变结构域包括如SEQ ID NO:4中所示的CDR L1、如SEQ ID NO:5中所示的CDR L2以及如SEQ ID NO:6中所示的CDR L3。
实施例2.根据实施例1所述的抗RYK抗体,其中所述重链可变结构域包括SEQ IDNO:15的序列。
实施例3.根据实施例1至2中任一项所述的抗RYK抗体,其中所述轻链可变结构域包括SEQ ID NO:16的序列。
实施例4.根据实施例1至3中任一项所述的抗RYK抗体,其中所述抗RYK抗体的KD为约2pM至约2nM。
实施例5.根据实施例1至4中任一项所述的抗RYK抗体,其中所述抗RYK抗体的KD为约513pM。
实施例6.一种抗RYK抗体,其包括轻链可变结构域和重链可变结构域,其中所述重链可变结构域包括如SEQ ID NO:17中所示的CDR H1、如SEQ ID NO:18中所示的CDR H2以及如SEQ ID NO:19中所示的CDR H3;并且其中所述轻链可变结构域包括如SEQ ID NO:20中所示的CDR L1、如SEQ ID NO:21中所示的CDR L2以及如SEQ ID NO:22中所示的CDR L3。
实施例7.根据实施例6所述的抗RYK抗体,其中所述重链可变结构域包括SEQ IDNO:31的序列。
实施例8.根据实施例6至7中任一项所述的抗RYK抗体,其中所述轻链可变结构域包括SEQ ID NO:32的序列。
实施例9.根据实施例6至8中任一项所述的抗RYK抗体,其中所述抗RYK抗体的KD为约6nM至约17nM。
实施例10.根据实施例6至9中任一项所述的抗RYK抗体,其中所述抗RYK抗体的KD为约10nM。
实施例11.一种抗RYK抗体,其包括轻链可变结构域和重链可变结构域,其中所述重链可变结构域包括如SEQ ID NO:33中所示的CDR H1、如SEQ ID NO:34中所示的CDR H2以及如SEQ ID NO:35中所示的CDR H3;并且其中所述轻链可变结构域包括如SEQ ID NO:36中所示的CDR L1、如SEQ ID NO:37中所示的CDR L2以及如SEQ ID NO:38中所示的CDR L3。
实施例12.根据实施例11所述的抗RYK抗体,其中所述重链可变结构域包括SEQ IDNO:47的序列。
实施例13.根据实施例11至12中任一项所述的抗RYK抗体,其中所述轻链可变结构域包括SEQ ID NO:48的序列。
实施例14.一种抗RYK抗体,其包括轻链可变结构域和重链可变结构域,其中所述重链可变结构域包括如SEQ ID NO:49中所示的CDR H1、如SEQ ID NO:50中所示的CDR H2以及如SEQ ID NO:51中所示的CDR H3;并且其中所述轻链可变结构域包括如SEQ ID NO:52中所示的CDR L1、如SEQ ID NO:53中所示的CDR L2以及如SEQ ID NO:54中所示的CDR L3。
实施例15.根据实施例14所述的抗RYK抗体,其中所述重链可变结构域包括SEQ IDNO:63的序列。
实施例16.根据实施例14至15中任一项所述的抗RYK抗体,其中所述轻链可变结构域包括SEQ ID NO:64的序列。
实施例17.根据实施例1至16中任一项所述的抗RYK抗体,其中所述抗RYK抗体为嵌合抗体。
实施例18.根据实施例1至17中任一项所述的抗RYK抗体,其中所述抗RYK抗体为Fab'片段。
实施例19.根据实施例1至18中任一项所述的抗RYK抗体,其中所述抗RYK抗体为IgG。
实施例20.根据实施例1至17中任一项所述的抗RYK抗体,其中所述轻链可变结构域和所述重链可变结构域形成scFv的一部分。
实施例21.根据实施例1至20中任一项所述的抗RYK抗体,其中所述抗RYK抗体能够与RYK蛋白结合。
实施例22.根据实施例1至21中任一项所述的抗RYK抗体,其中所述抗RYK抗体与胞外RYK结构域结合。
实施例23.根据实施例1至22中任一项所述的抗RYK抗体,其中所述抗RYK抗体与包括SEQ ID NO:129的氨基酸序列的胞外RYK结构域结合。
实施例24.根据实施例1至23中任一项所述的抗RYK抗体,其中所述抗RYK抗体与和SEQ ID NO:129的氨基酸残基48至57相对应的氨基酸序列结合。
实施例25.根据实施例1至21中任一项所述的抗RYK抗体,其中所述抗RYK抗体与RYK蛋白结合。
实施例26.根据实施例21至25中任一项所述的抗RYK抗体,其中所述RYK蛋白为人RYK蛋白。
实施例27.根据实施例21至26中任一项所述的抗RYK抗体,其中所述RYK蛋白包括SEQ ID NO:130的序列。
实施例28.根据实施例21至27中任一项所述的抗RYK抗体,其中所述RYK蛋白不与小鼠RYK蛋白结合。
实施例29.根据实施例21至28中任一项所述的抗RYK抗体,其中所述抗RYK抗体不与包括与SEQ ID NO:131的氨基酸残基32至41相对应的氨基酸序列的RYK蛋白结合。
实施例30.根据实施例25至28中任一项所述的抗RYK抗体,其中所述RYK蛋白形成细胞的一部分。
实施例31.根据实施例21至30中任一项所述的抗RYK抗体,其中所述RYK蛋白在细胞的表面上表达。
实施例32.一种抗RYK抗体,其中所述抗RYK抗体与和包括以下的抗体相同的表位结合:重链可变结构域,所述重链可变结构域包括如SEQ ID NO:1中所示的CDR H1、如SEQID NO:2中所示的CDR H2以及如SEQ ID NO:3中所示的CDR H3;以及轻链可变结构域,所述轻链可变结构域包括如SEQ ID NO:4中所示的CDR L1、如SEQ ID NO:5中所示的CDR L2以及如SEQ ID NO:6中所示的CDR L3。
实施例33.一种抗RYK抗体,其中所述抗RYK抗体与和包括以下的抗体相同的表位结合:重链可变结构域,所述重链可变结构域包括如SEQ ID NO:17中所示的CDR H1、如SEQID NO:18中所示的CDR H2以及如SEQ ID NO:19中所示的CDR H3;以及轻链可变结构域,所述轻链可变结构域包括如SEQ ID NO:20中所示的CDR L1、如SEQ ID NO:21中所示的CDR L2以及如SEQ ID NO:22中所示的CDR L3。
实施例34.一种抗RYK抗体,其中所述抗RYK抗体与和包括以下的抗体相同的表位结合:重链可变结构域,所述重链可变结构域包括如SEQ ID NO:33中所示的CDR H1、如SEQID NO:34中所示的CDR H2以及如SEQ ID NO:35中所示的CDR H3;以及轻链可变结构域,所述轻链可变结构域包括如SEQ ID NO:36中所示的CDR L1、如SEQ ID NO:37中所示的CDR L2以及如SEQ ID NO:38中所示的CDR L3。
实施例35.一种抗RYK抗体,其中所述抗RYK抗体与和包括以下的抗体相同的表位结合:重链可变结构域,所述重链可变结构域包括如SEQ ID NO:49中所示的CDR H1、如SEQID NO:50中所示的CDR H2以及如SEQ ID NO:51中所示的CDR H3;以及轻链可变结构域,所述轻链可变结构域包括如SEQ ID NO:52中所示的CDR L1、如SEQ ID NO:53中所示的CDR L2以及如SEQ ID NO:54中所示的CDR L3。
实施例36.根据实施例1至35中任一项所述的抗RYK抗体,其中所述抗RYK抗体附着到治疗或诊断部分。
实施例37.一种分离的核酸,其编码根据实施例1至36中任一项所述的抗RYK抗体。
实施例38.一种细胞,其包括根据实施例1至36中任一项所述的抗RYK抗体或根据实施例37所述的核酸。
实施例39.一种药物组合物,所述药物组合物包括治疗有效量的根据实施例1至36中任一项所述的抗体以及药学上可接受的赋形剂。
实施例40.一种形成能够与RYK蛋白结合的抗体的方法,所述方法包括用包括SEQID NO:129的序列的肽使哺乳动物免疫。
实施例41.一种检测RYK表达性细胞的方法,所述方法包括(i)使RYK表达性细胞与根据实施例1至36中任一项所述的抗体接触;(ii)以及检测所述抗体与由所述细胞表达的RYK蛋白的结合。
实施例42.根据实施例41所述的方法,其中所述抗体附着到可检测部分。
实施例43.根据实施例41或42所述的方法,其中所述RYK表达性细胞处于生物样品中。
实施例44.根据实施例41所述的方法,其中所述生物样品为全血、血液级分或血液产物、组织或经培养的细胞。
实施例45.根据实施例41至44中任一项所述的方法,其中所述RYK表达性细胞为癌细胞。
实施例46.根据实施例45所述的方法,其中所述癌细胞为膀胱癌细胞、脑癌细胞、乳腺癌细胞、慢性髓系白血病(CML)细胞、结肠癌细胞、尤文氏肉瘤细胞、肺癌细胞、套细胞淋巴瘤细胞、卵巢癌细胞、胰腺癌细胞、皮肤癌细胞或黑色素瘤细胞。
实施例47.一种治疗有需要的受试者的癌症的方法,所述方法包括向受试者施用治疗有效量的根据实施例1至36中任一项所述的抗RYK抗体。
实施例48.根据实施例47所述的方法,其中所述癌症为膀胱癌、脑癌、乳腺癌、慢性髓系白血病(CML)、结肠癌、尤文氏肉瘤、肺癌、套细胞淋巴瘤、卵巢癌、胰腺癌、皮肤癌或黑色素瘤。
实施例49.一种鉴定抗RYK抗体的方法,所述方法包括:(i)使抗体与第一RYK多肽接触,所述第一RYK多肽包括与SEQ ID NO:129的氨基酸残基48至57相对应的氨基酸序列;(ii)检测与所述第一RYK多肽结合的所述抗体;(iii)使所述抗体与第二RYK多肽接触,所述第二RYK多肽不包括与SEQ ID NO:129的氨基酸残基48至57相对应的氨基酸序列;以及(iv)检测不与所述第二RYK多肽结合的所述抗体,由此鉴定抗RYK抗体。
实施例50.根据实施例49所述的方法,其中所述抗体为嵌合抗体。
实施例51.根据实施例49或50所述的方法,其中所述抗体为Fab'片段。
实施例52.根据实施例49或50所述的方法,其中所述抗体为单链抗体。
Claims (52)
1.一种抗RYK抗体,其包括重链可变结构域和轻链可变结构域,其中所述重链可变结构域包括如SEQ ID NO:1中所示的CDR H1、如SEQ ID NO:2中所示的CDR H2以及如SEQ ID NO:3中所示的CDR H3;并且
其中所述轻链可变结构域包括如SEQ ID NO:4中所示的CDR L1、如SEQ ID NO:5中所示的CDR L2以及如SEQ ID NO:6中所示的CDR L3。
2.根据权利要求1所述的抗RYK抗体,其中所述重链可变结构域包括SEQ ID NO:15的序列。
3.根据权利要求1至2中任一项所述的抗RYK抗体,其中所述轻链可变结构域包括SEQID NO:16的序列。
4.根据权利要求1至3中任一项所述的抗RYK抗体,其中所述抗RYK抗体的KD为约2pM至约2nM。
5.根据权利要求1至4中任一项所述的抗RYK抗体,其中所述抗RYK抗体的KD为约513pM。
6.一种抗RYK抗体,其包括重链可变结构域和轻链可变结构域,其中所述重链可变结构域包括如SEQ ID NO:17中所示的CDR H1、如SEQ ID NO:18中所示的CDR H2以及如SEQ IDNO:19中所示的CDR H3;并且
其中所述轻链可变结构域包括如SEQ ID NO:20中所示的CDR L1、如SEQ ID NO:21中所示的CDR L2以及如SEQ ID NO:22中所示的CDR L3。
7.根据权利要求6所述的抗RYK抗体,其中所述重链可变结构域包括SEQ ID NO:31的序列。
8.根据权利要求6至7中任一项所述的抗RYK抗体,其中所述轻链可变结构域包括SEQID NO:32的序列。
9.根据权利要求6至8中任一项所述的抗RYK抗体,其中所述抗RYK抗体的KD为约6nM至约17nM。
10.根据权利要求6至9中任一项所述的抗RYK抗体,其中所述抗RYK抗体的KD为约10nM。
11.一种抗RYK抗体,其包括重链可变结构域和轻链可变结构域,其中所述重链可变结构域包括如SEQ ID NO:33中所示的CDR H1、如SEQ ID NO:34中所示的CDR H2以及如SEQ IDNO:35中所示的CDR H3;并且
其中所述轻链可变结构域包括如SEQ ID NO:36中所示的CDR L1、如SEQ ID NO:37中所示的CDR L2以及如SEQ ID NO:38中所示的CDR L3。
12.根据权利要求11所述的抗RYK抗体,其中所述重链可变结构域包括SEQ ID NO:47的序列。
13.根据权利要求11至12中任一项所述的抗RYK抗体,其中所述轻链可变结构域包括SEQ ID NO:48的序列。
14.一种抗RYK抗体,其包括重链可变结构域和轻链可变结构域,其中所述重链可变结构域包括如SEQ ID NO:49中所示的CDR H1、如SEQ ID NO:50中所示的CDR H2以及如SEQ IDNO:51中所示的CDR H3;并且
其中所述轻链可变结构域包括如SEQ ID NO:52中所示的CDR L1、如SEQ ID NO:53中所示的CDR L2以及如SEQ ID NO:54中所示的CDR L3。
15.根据权利要求14所述的抗RYK抗体,其中所述重链可变结构域包括SEQ ID NO:63的序列。
16.根据权利要求14至15中任一项所述的抗RYK抗体,其中所述轻链可变结构域包括SEQ ID NO:64的序列。
17.根据权利要求1至16中任一项所述的抗RYK抗体,其中所述抗RYK抗体为嵌合抗体。
18.根据权利要求1至17中任一项所述的抗RYK抗体,其中所述抗RYK抗体为Fab'片段。
19.根据权利要求1至18中任一项所述的抗RYK抗体,其中所述抗RYK抗体为IgG。
20.根据权利要求1至17中任一项所述的抗RYK抗体,其中所述轻链可变结构域和所述重链可变结构域形成scFv的一部分。
21.根据权利要求1至20中任一项所述的抗RYK抗体,其中所述抗RYK抗体能够与RYK蛋白结合。
22.根据权利要求1至21中任一项所述的抗RYK抗体,其中所述抗RYK抗体与胞外RYK结构域结合。
23.根据权利要求1至22中任一项所述的抗RYK抗体,其中所述抗RYK抗体与包括SEQ IDNO:129的氨基酸序列的胞外RYK结构域结合。
24.根据权利要求1至23中任一项所述的抗RYK抗体,其中所述抗RYK抗体与和SEQ IDNO:129的氨基酸残基48至57相对应的氨基酸序列结合。
25.根据权利要求1至21中任一项所述的抗RYK抗体,其中所述抗RYK抗体与RYK蛋白结合。
26.根据权利要求21至25中任一项所述的抗RYK抗体,其中所述RYK蛋白为人RYK蛋白。
27.根据权利要求21至26中任一项所述的抗RYK抗体,其中所述RYK蛋白包括SEQ IDNO:130的序列。
28.根据权利要求21至27中任一项所述的抗RYK抗体,其中所述RYK蛋白不与小鼠RYK蛋白结合。
29.根据权利要求21至28中任一项所述的抗RYK抗体,其中所述抗RYK抗体不与RYK蛋白结合,所述RYK蛋白包括与SEQ ID NO:131的氨基酸残基32至41相对应的氨基酸序列。
30.根据权利要求25至28中任一项所述的抗RYK抗体,其中所述RYK蛋白形成细胞的一部分。
31.根据权利要求21至30中任一项所述的抗RYK抗体,其中所述RYK蛋白在细胞的表面上表达。
32.一种抗RYK抗体,其中所述抗RYK抗体与和包括以下的抗体相同的表位结合:重链可变结构域,所述重链可变结构域包括如SEQ ID NO:1中所示的CDR H1、如SEQ ID NO:2中所示的CDR H2以及如SEQ ID NO:3中所示的CDR H3;以及轻链可变结构域,所述轻链可变结构域包括如SEQ ID NO:4中所示的CDR L1、如SEQ ID NO:5中所示的CDR L2以及如SEQ ID NO:6中所示的CDR L3。
33.一种抗RYK抗体,其中所述抗RYK抗体与和包括以下的抗体相同的表位结合:重链可变结构域,所述重链可变结构域包括如SEQ ID NO:17中所示的CDR H1、如SEQ ID NO:18中所示的CDR H2以及如SEQ ID NO:19中所示的CDR H3;以及轻链可变结构域,所述轻链可变结构域包括如SEQ ID NO:20中所示的CDR L1、如SEQ ID NO:21中所示的CDR L2以及如SEQID NO:22中所示的CDR L3。
34.一种抗RYK抗体,其中所述抗RYK抗体与和包括以下的抗体相同的表位结合:重链可变结构域,所述重链可变结构域包括如SEQ ID NO:33中所示的CDR H1、如SEQ ID NO:34中所示的CDR H2以及如SEQ ID NO:35中所示的CDR H3;以及轻链可变结构域,所述轻链可变结构域包括如SEQ ID NO:36中所示的CDR L1、如SEQ ID NO:37中所示的CDR L2以及如SEQID NO:38中所示的CDR L3。
35.一种抗RYK抗体,其中所述抗RYK抗体与和包括以下的抗体相同的表位结合:重链可变结构域,所述重链可变结构域包括如SEQ ID NO:49中所示的CDR H1、如SEQ ID NO:50中所示的CDR H2以及如SEQ ID NO:51中所示的CDR H3;以及轻链可变结构域,所述轻链可变结构域包括如SEQ ID NO:52中所示的CDR L1、如SEQ ID NO:53中所示的CDR L2以及如SEQID NO:54中所示的CDR L3。
36.根据权利要求1至35中任一项所述的抗RYK抗体,其中所述抗RYK抗体附着到治疗性或诊断性部分。
37.一种分离的核酸,其编码根据权利要求1至36中任一项所述的抗RYK抗体。
38.一种细胞,其包括根据权利要求1至36中任一项所述的抗RYK抗体或根据权利要求37所述的核酸。
39.一种药物组合物,其包括治疗有效量的根据权利要求1至36中任一项所述的抗体以及药学上可接受的赋形剂。
40.一种形成能够与RYK蛋白结合的抗体的方法,所述方法包括用包括SEQ ID NO:129的序列的肽使哺乳动物免疫。
41.一种检测RYK表达性细胞的方法,所述方法包括(i)使RYK表达性细胞与根据权利要求1至36中任一项所述的抗体接触;(ii)以及检测所述抗体与由所述细胞表达的RYK蛋白的结合。
42.根据权利要求41所述的方法,其中所述抗体附着到可检测部分。
43.根据权利要求41或42所述的方法,其中所述RYK表达性细胞处于生物样品中。
44.根据权利要求41所述的方法,其中所述生物样品为全血、血液级分或血液产物、组织或经培养的细胞。
45.根据权利要求41至44中任一项所述的方法,其中所述RYK表达性细胞为癌细胞。
46.根据权利要求45所述的方法,其中所述癌细胞为膀胱癌细胞、脑癌细胞、乳腺癌细胞、慢性髓系白血病(CML)细胞、结肠癌细胞、尤文氏肉瘤(Ewing's sarcoma)细胞、肺癌细胞、套细胞淋巴瘤细胞、卵巢癌细胞、胰腺癌细胞、皮肤癌细胞或黑色素瘤细胞。
47.一种治疗有需要的受试者的癌症的方法,所述方法包括向受试者施用治疗有效量的根据权利要求1至36中任一项所述的抗RYK抗体。
48.根据权利要求47所述的方法,其中所述癌症为膀胱癌、脑癌、乳腺癌、慢性髓系白血病(CML)、结肠癌、尤文氏肉瘤、肺癌、套细胞淋巴瘤、卵巢癌、胰腺癌、皮肤癌或黑色素瘤。
49.一种鉴定抗RYK抗体的方法,所述方法包括:
(i)使抗体与第一RYK多肽接触,所述第一RYK多肽包括与SEQ ID NO:129的氨基酸残基48至57相对应的氨基酸序列;
(ii)检测与所述第一RYK多肽结合的所述抗体;
(iii)使所述抗体与第二RYK多肽接触,所述第二RYK多肽不包括与SEQ ID NO:129的氨基酸残基48至57相对应的氨基酸序列;以及
(iv)检测未与所述第二RYK多肽结合的所述抗体,由此鉴定抗RYK抗体。
50.根据权利要求49所述的方法,其中所述抗体为嵌合抗体。
51.根据权利要求49或50所述的方法,其中所述抗体为Fab'片段。
52.根据权利要求49或50所述的方法,其中所述抗体为单链抗体。
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