CN116249547A - 脑特异性血管生成抑制剂1(bai1)抗体及其用途 - Google Patents
脑特异性血管生成抑制剂1(bai1)抗体及其用途 Download PDFInfo
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Abstract
本公开提供了结合人粘附G蛋白偶联受体B1(BAI1)蛋白的抗体、包含所述抗体的组合物及其在检测方法、诊断方法和治疗方法中的用途。还提供了可变重链(VH)和可变轻链(VL)序列中的互补决定区(CDR)的序列以及VH和VL的氨基酸序列。
Description
序列表的引用
本申请包括以文本文件电子提交的序列表,其命名为18909900502SEQ,创建于2020年11月2日,大小为25千字节。该序列表通过引用并入本文。
技术领域
本公开涉及结合人脑特异性血管生成抑制剂1(BAI1)(也称为粘附G蛋白偶联受体B1(ADGRB1))蛋白的抗体及其片段、包含所述抗体及其片段的组合物及其在检测方法、细胞分离方法、耗竭方法、诊断方法和治疗方法中的用途。
背景技术
BAI1在单核细胞谱系的细胞、星形胶质细胞、神经元和Myo/Nog细胞中表达,这些细胞表达骨骼肌特异性转录因子MyoD和骨形态发生抑制剂noggin。BAI1+细胞参与先天免疫、伤口愈合、胚胎发育和神经保护。BAI1+细胞的伤口愈合特性部分反映了该分子通过它与磷脂酰丝氨酸的结合在吞噬凋亡细胞和革兰氏阴性菌中的作用。BAI1+细胞亚群在伤口愈合期间的另一功能是分化成肌成纤维细胞。虽然肌成纤维细胞收缩可以促进伤口闭合,但是它们也可以扰乱组织形态,并因此而扰乱功能。例如,继发性白内障或后囊膜浑浊(PCO)是白内障手术后在一些成人和大多数儿童中发展的损害视力的晶状体疾病。晶状体中的BAI1+细胞发育成肌成纤维细胞并在囊膜(包裹晶状体的厚基底膜)中产生皱纹。晶状体囊膜变形会影响视力。
除了它在吞噬中的作用之外,BAI1还代谢产生血管生成抑制剂,血管生成是血管从预先存在的血管发展而来的过程。在视网膜中,血管生成是糖尿病性视网膜病和湿性黄斑变性中威胁视力的组成部分。血管生成对于肿瘤的生长也至关重要,除非肿瘤获得额外生长,否则它们无法生长超过几毫米。BAI1+细胞存在于视网膜和肿瘤中。在一些癌症中,BAI1随着疾病进展而下调,从而有利于血管生成。然而,血管化对于化疗药物的分布也很重要,例如,那些附着于病毒上的药物。
发明内容
本公开提供了与人BAI1蛋白结合的抗体或其抗原结合片段,其中所述抗体或其抗原结合片段包含:可变重(VH)链中的第一互补决定区(CDR)(VH-CDR1),其包含根据SEQ IDNO:7的氨基酸序列或由所述氨基酸序列组成;所述VH链中的第二CDR(VH-CDR2),其包含根据SEQ ID NO:8的氨基酸序列或由所述氨基酸序列组成;所述VH链中的第三CDR(VH-CDR3),其包含根据SEQ ID NO:9的氨基酸序列或由所述氨基酸序列组成;可变轻(VL)链中的第一CDR(VL-CDR1),其包含根据SEQ ID NO:10的氨基酸序列或由所述氨基酸序列组成;所述VL链中的第二CDR(VL-CDR2),其包含根据SEQ ID NO:11的氨基酸序列或由所述氨基酸序列组成;和所述VL链中的第三CDR(VL-CDR3),其包含根据SEQ ID NO:12的氨基酸序列或由所述氨基酸序列组成。
本公开还提供了编码所述抗体或其抗原结合片段的重链的分离的核酸分子,其中所述核酸分子包含根据SEQ ID NO:2或SEQ ID NO:3的核苷酸序列或由所述核苷酸序列组成。
本公开还提供了编码所述抗体或其抗原结合片段的轻链的分离的核酸分子,其中所述核酸分子包含根据SEQ ID NO:5或SEQ ID NO:6的核苷酸序列或由所述核苷酸序列组成。
本公开还提供了检测表达BAI1的细胞的方法,所述方法包括使所述细胞与本文所述的抗体或其抗原结合片段接触,并检测所述抗体或其抗原结合片段。所述检测可以发生在固定组织、细胞培养物和活体动物中,用于细胞示踪和生物成像。
本公开还提供了纯化BAI1的方法,所述方法包括使所述分子与本文所述的抗体或其抗原结合片段接触。这些方法包括,例如,免疫沉淀和柱纯化。
本公开还提供了分离表达BAI1的活细胞的方法,所述方法包括使所述细胞与所述抗体或其抗原结合片段接触,并如本文所述将抗体或抗原结合片段结合的细胞与未结合的细胞分开。这些方法包括,例如,荧光激活细胞分选(FACS)和磁性细胞分选。
本公开还提供了分析BAI1功能的方法,所述方法包括使分子和体外和体内的活细胞与本文所述的抗体或其抗原结合片段接触。这些方法包括,例如,阻断受体及其片段用于酶联免疫吸附测定(ELISA)、免疫沉淀、蛋白质印迹和活细胞测定。
本公开还提供了杀伤体外和动物体内的表达BAI1的细胞以确定细胞功能,以及在有此需要的人患者中杀伤所述细胞的方法,所述方法包括施用本文所述的抗体或其抗原结合片段。
本公开还提供了治疗在细胞培养物中及在荷瘤动物和人中表达BAI1的癌症的方法,所述方法包括施用本文所述的抗体或其抗原结合片段。
本公开还提供了治疗后囊膜浑浊(PCO)的方法,所述方法包括向有此需要的组织培养物、动物和人患者施用本文所述的抗体或其抗原结合片段。
本公开还提供了治疗纤维化的方法,所述方法包括向有此需要的培养细胞、动物和人患者施用本文所述的抗体或其抗原结合片段。
本发明还提供了促进伤口愈合的方法,所述方法包括向有此需要的人患者施用本文所述的抗体或其抗原结合片段,或BAI1+细胞中的任一种至伤口。
附图说明
图1示出了使用膜蛋白质组阵列(MPA)平台的抗原鉴定工作流程。
图2A示出了HEK-293T细胞中G8批次3/21/13的免疫检测优化。每个点表示四次重复的平均值。基于信背比(S/B)计算和原始信号值筛选每种抗体的推荐工作浓度以红色突出显示。
图2B示出了HEK-293T细胞中G8批次PS30170160的免疫检测优化。每个点表示四次重复的平均值。基于信背比(S/B)计算和原始信号值筛选每种抗体的推荐工作浓度以红色突出显示。
图3A示出了G8批次3/21/13的膜蛋白结合靶标的鉴定。非特异性荧光经确定为高于噪声(虚线)3个标准差以下的任何值。示出抗体结合增加的靶标显示在虚线上方并用红色表示。
图3B示出了G8批次PS30170160的膜蛋白结合靶标的鉴定。非特异性荧光经确定为高于噪声(虚线)3个标准差以下的任何值。示出抗体结合增加的靶标显示在虚线上方并用红色表示。
图4A示出了G8批次3/21/13的结合的验证。每个点表示四次重复的平均值。
图4B示出了G8批次PS30170160的结合的验证。每个点表示四次重复的平均值。
图5示出了小鼠G8 IgM的重链和轻链的RACE鉴定的结果。
图6示出了G8 IgM(方框)和抗BAI1 IgG(圆圈;在本文中也称为“G8 IgG”)的ELISA测定的结果。
应理解,前面的概述和下面的详述都仅为示例性和说明性而非限制如本文所要求保护的实施方案。
具体实施方式
本文使用的术语仅仅是为了描述特定实施方案的目的,而非旨在为限制性。在整个说明书和权利要求书中使用与本公开的各方面有关的各种术语。除非另有说明,否则将对此类术语给予本领域中的普通含义。其它具体定义的术语应以与本文提供的定义一致的方式解释。
除非另有明确说明,否则决非旨在将本文阐述的任何方法或方面解释为要求其步骤以任何特定顺序执行。在方法权利要求没有在权利要求或说明书中特别说明将步骤限于特定顺序的情况下,其决非旨在在任何方面都可以推断出顺序。这适用于任何可能的非明确的解释基础,包括关于步骤安排或操作流程的逻辑问题,从语法组成或标点符号中得出的简单含义,或说明书中描述的各方面的数目或类型。
如本文所用,除非上下文另外明确指出,否则单数形式“一”、“一种(个)”和“所述(该)”包括多个指代物。
如本文所用,术语“约”意指所列举的数值是近似值并且小的变化不会显著影响所公开的实施方案的实践。在使用数值的情况下,除非上下文另有说明,否则“约”意指数值可以变化±10%并且仍然在所公开的实施方案的范围内。
如本文所用,术语“抗体”是指与特定抗原特异性结合或与特定抗原有免疫反应性的免疫球蛋白分子,并且包括其多克隆形式、单克隆形式、基因工程化形式和其它修饰形式,包括但不限于嵌合抗体、人源化抗体、异缀合抗体(例如,双特异性抗体、双链抗体、三链抗体和四链抗体)。
如本文所用,短语“其抗原结合片段”意指能够结合抗原的抗体片段。抗原结合片段包括但不限于Fab、Fab'、F(ab')2、Fv、scFv、scFv-Fc、双链抗体、双特异性双抗体、三特异性三链抗体、微抗体、单特异性Fab2、双特异性Fab2、三特异性Fab3、纳米抗体、IgNAR、V-NAR、hcIgG和VhH片段。
如本文所用,短语“嵌合抗体”是指具有源自非人免疫球蛋白(诸如大鼠或小鼠抗体)的可变序列以及通常选自人免疫球蛋白模板的人免疫球蛋白恒定区的抗体。
如本文所用,术语“Fv”片段是含有完整靶识别和结合位点的最小抗体片段。该区域由一个重链可变结构域和一个轻链可变结构域呈非共价缔合的二聚体(VH-VL二聚体)组成。正是在这种构型中,每个可变结构域的三个CDR相互作用以限定VH-VL二聚体表面上的靶结合位点。
如本文所用,短语“人抗体”指具有人免疫球蛋白的氨基酸序列的抗体并且包括从人免疫球蛋白文库或对于从一种或多种人免疫球蛋白为转基因且不表达内源性免疫球蛋白的动物中分离的抗体。
如本文所用,短语“人源化抗体”是指含有源自非人免疫球蛋白的最小序列的嵌合抗体或其抗原结合片段。一般而言,人源化抗体将包含至少一个且通常两个可变结构域的基本上全部,其中所有或基本上所有的CDR区对应于非人免疫球蛋白的那些CDR区,并且所有或基本上所有的框架(FR)区是人免疫球蛋白序列的那些FR区。人源化抗体还可包含免疫球蛋白恒定区(Fc),通常是人免疫球蛋白共有序列的恒定区的至少一部分。
如本文所用,短语“有此需要”意指已鉴定为对特定的方法、预防或治疗有需要的“受试者”或“患者”。在一些实施方案中,鉴定可以通过任何诊断手段进行。在本文所述的任何方法、预防和治疗中,“受试者”或“患者”可以是有此需要的。
如本文所用,“核酸分子”是任何长度的核苷酸的聚合形式,可以包含DNA和/或RNA,并且可以是单链、双链或多链。核酸的一条链也指它的互补链。
如本文所用,短语“灵长类化抗体”是指包含猴可变区和人恒定区的抗体。
如本文所用,短语“调控序列”旨在包括启动子、增强子和控制抗体链基因的转录或翻译的其它表达控制元件,诸如聚腺苷酸化信号。
如本文所用,术语“单链Fv”或“scFv”是指单链Fv抗体,其中来自传统抗体的重链和轻链可变结构域(VH和VL结构域)已经连接形成一条链。通常,Fv多肽还包含介于VH和VL结构域之间的多肽接头,该多肽接头使得scFv能够形成靶结合所需的结构。
如本文所用,术语“受试者”和“患者”可互换使用。受试者包括任何动物,包括哺乳动物。哺乳动物包括但不限于农场动物(例如,马、牛、猪)、伴侣动物(例如,狗、猫)、实验室动物(例如,小鼠、大鼠、兔)和非人灵长类动物(例如,猴)。在一些实施方案中,受试者或患者是人。
如本文所用,术语“VH”是指抗体的免疫球蛋白重链(包括例如Fv、scFv或Fab片段的重链)的可变区。
如本文所用,术语“VL”是指抗体的免疫球蛋白轻链(包括例如Fv、scFv、dsFv或Fab片段的轻链)的可变区。
本公开提供了与BAI1蛋白(也称为G8抗原)结合的抗体或其抗原结合片段。在一些实施方案中,BAI1蛋白包含以下氨基酸序列或由以下氨基酸序列组成:MRGQAAAPGPVWILAPLLLLL
LLLGRRARAAAGADAGPGPEPCATLVQGKFFGYFSAAAVFPANASRCSWTLRNPDPRRYTLYMKVAKAPVPCSGPGRVRTYQFDSFLESTRTYLGVESFDEVLRLCDPSAPLAFLQASKQFLQMRRQQPPQHDGLRPRAGPPGPTDDFSVEYLVVGNRNPSRAACQMLCRWLDACLAGSRSSHPCGIMQTPCACLGGEAGGPAAGPLAPRGDVCLRDAVAGGPENCLTSLTQDRGGHGATGGWKLWSLWGECTRDCGGGLQTRTRTCLPAPGVEGGGCEGVLEEGRQCNREACGPAGRTSSRSQSLRSTDARRREELGDELQQFGFPAPQTGDPAAEEWSPWSVCSSTCGEGWQTRTRFCVSSSYSTQCSGPLREQRLCNNSAVCPVHGAWDEWSPWSLCSSTCGRGFRDRTRTCRPPQFGGNPCEGPEKQTKFCNIALCPGRAVDGNWNEWSSWSACSASCSQGRQQRTRECNGPSYGGAECQGHWVETRDCFLQQCPVDGKWQAWASWGSCSVTCGAGSQRRERVCSGPFFGGAACQGPQDEYRQCGTQRCPEPHEICDEDNFGAVIWKETPAGEVAAVRCPRNATGLILRRCELDEEGIAYWEPPTYIRCVSIDYRNIQMMTREHLAKAQRGLPGEGVSEVIQTLVEISQDGTSYSGDLLSTIDVLRNMTEIFRRAYYSPTPGDVQNFVQILSNLLAEENRDKWEEAQLAGPNAKELFRLVEDFVDVIGFRMKDLRDAYQVTDNLVLSIHKLPASGATDISFPMKGWRATGDWAKVPEDRVTVSKSVFSTGLTEADEASVFVVGTVLYRNLGSFLALQRNTTVLNSKVISVTVKPPPRSLRTPLEIEFAHMYNGTTNQTCILWDETDVPSSSAPPQLGPWSWRGCRTVPLDALRTRCLCDRLSTFAILAQLSADANMEKATLPSVTLIVGCGVSSLTLLMLVIIYVSVWRYIRSERSVILINFCLSIISSNALILIGQTQTRNKVVCTLVAAFLHFFFLSSFCWVLTEAWQSYMAVTGHLRNRLIRKRFLCLGWGLPALVVAISVGFTKAKGYSTMNYCWLSLEGGLLYAFVGPAAAVVLVNMVIGILVFNKLVSKDGITDKKLKERAGASLWSSCVVLPLLALTWMSAVLAVTDRRSALFQILFAVFDSLEGFVIVMVHCILRREVQDAVKCRVVDRQEEGNGDSGGSFQNGHAQLMTDFEKDVDLACRSVLNKDIAACRTATITGTLKRPSLPEEEKLKLAHAKGPPTNFNSLPANVSKLHLHGSPRYPGGPLPDFPNHSLTLKRDKAPKSSFVGDGDIFKKLDSELSRAQEKALDTSYVILPTATATLRPKPKEEPKYSIHIDQMPQTRLIHLSTAPEASLPARSPPSRQPPSGGPPEAPPAQPPPPPPPPPPPPQQPLPPPPNLEPAPPSLGDPGEPAAHPGPSTGPSTKNENVATLSVSSLERRKSRYAELDFEKIMHTRKRHQDMFQDLNRKLQHAAEKDKEVLGPDSKPEKQQTPNKRPWESLRKAHGTPTWVKKELEPLQPSPLELRSVEWERSGATIPLVGQDIIDLQTEV(SEQ ID NO:15)。
在一些实施方案中,本文所述的抗体或其抗原结合片段与人BAI1蛋白内的表位结合,所述表位包含以下氨基酸或由以下氨基酸组成:Y83、F135、W415、W418、L420、T424、R432、R434、I458、W473、W476、R545、Y639和L776。在一些实施方案中,本文所述的抗体或其抗原结合片段所结合的人BAI1蛋白内的表位包含以下氨基酸或由以下氨基酸组成:这些氨基酸中的至少4至14个、至少4至13个、至少4至12个、至少4至11个、至少4至10个、至少4至9个、至少4至8个、至少4至7个或至少4至6个。在一些实施方案中,本文所述的抗体或其抗原结合片段所结合的人BAI1蛋白内的表位包含以下氨基酸或由以下氨基酸组成:这些氨基酸中的至少6至14个、至少6至13个、至少6至12个、至少6至11个、至少6至10个、至少6至9个或至少6至8个。在一些实施方案中,本文所述的抗体或其抗原结合片段所结合的人BAI1蛋白内的表位包含以下氨基酸或由以下氨基酸组成:这些氨基酸中的至少7至14个、至少7至13个、至少7至12个、至少7至11个、至少7至10个或至少7至9个。在一些实施方案中,本文所述的抗体或其抗原结合片段与人BAI1蛋白内的表位结合,所述表位包含以下氨基酸或由以下氨基酸组成:F135、W415、W418、L420、T424、R432、R434和I458。在一些实施方案中,本文所述的抗体或其抗原结合片段与人BAI1蛋白内的表位结合,所述表位包含以下氨基酸或由以下氨基酸组成:W415、W418、L420、T424、R432、R434和I458。在一些实施方案中,本文所述的抗体或其抗原结合片段与人BAI1蛋白内的表位结合,所述表位包含以下氨基酸或由以下氨基酸组成:T424、R432、R434和I458。
本公开还提供了与人BAI1蛋白结合的抗体或其抗原结合片段。在一些实施方案中,所述抗体或其抗原结合片段包含三个VH CDR和三个VL CDR。
在一些实施方案中,所述抗体或其抗原结合片段包含VH链中的第一CDR(VH-CDR1),其包含氨基酸序列GYSITSDY(SEQ ID NO:7)或由所述氨基酸序列组成。在一些实施方案中,该VH-CDR1可以包含一个、两个或三个保守氨基酸取代或由一个、两个或三个保守氨基酸取代组成。
在一些实施方案中,所述抗体或其抗原结合片段包含VH链中的第二CDR(VH-CDR2),其包含氨基酸序列SYSGS(SEQ ID NO:8)或由所述氨基酸序列组成。在一些实施方案中,该VH-CDR2可以包含一个或两个保守氨基酸取代或由一个或两个保守氨基酸取代组成。
在一些实施方案中,所述抗体或其抗原结合片段包含VH链中的第三CDR(VH-CDR3),其包含氨基酸序列AQGYAMDY(SEQ ID NO:9)或由所述氨基酸序列组成。在一些实施方案中,该VH-CDR3可以包含一个、两个或三个保守氨基酸取代或由一个、两个或三个保守氨基酸取代组成。
在一些实施方案中,所述抗体或其抗原结合片段包含VL链中的第一CDR(VL-CDR1),其包含氨基酸序列RASQSISDYLH(SEQ ID NO:10)或由所述氨基酸序列组成。在一些实施方案中,该VL-CDR1可以包含一个、两个、三个或四个保守氨基酸取代或由一个、两个、三个或四个保守氨基酸取代组成。
在一些实施方案中,所述抗体或其抗原结合片段包含VL链中的第二CDR(VL-CDR2),其包含氨基酸序列YASQSIS(SEQ ID NO:11)或由所述氨基酸序列组成。在一些实施方案中,该VL-CDR2可以包含一个或两个保守氨基酸取代或由一个或两个保守氨基酸取代组成。
在一些实施方案中,所述抗体或其抗原结合片段包含VL链中的第三CDR(VL-CDR3),其包含氨基酸序列QNGHSFPFT(SEQ ID NO:12)或由所述氨基酸序列组成。在一些实施方案中,该VL-CDR3可以包含一个、两个或三个保守氨基酸取代或由一个、两个或三个保守氨基酸取代组成。
在一些实施方案中,所述抗体或其抗原结合片段包含:VH链中的第一CDR(VH-CDR1),其包含氨基酸序列GYSITSDY(SEQ ID NO:7)或由所述氨基酸序列组成;VH链中的第二CDR(VH-CDR2),其包含氨基酸序列SYSGS(SEQ ID NO:8)或由所述氨基酸序列组成;VH链中的第三CDR(VH-CDR3),其包含氨基酸序列AQGYAMDY(SEQ ID NO:9)或由所述氨基酸序列组成;VL链中的第一CDR(VL-CDR1),其包含氨基酸序列RASQSISDYLH(SEQ ID NO:10)或由所述氨基酸序列组成;VL链中的第二CDR(VL-CDR2),其包含氨基酸序列YASQSIS(SEQ ID NO:11)或由所述氨基酸序列组成;和VL链中的第三CDR(VL-CDR3),其包含氨基酸序列QNGHSFPFT(SEQ ID NO:12)或由所述氨基酸序列组成。在一些实施方案中,CDR可以具有本文所述的保守性氨基酸取代。
在一些实施方案中,所述抗体或其抗原结合片段包含VH链,其包含以下氨基酸序列或由以下氨基酸序列组成:SDVQLQESGPG
LVKPSQSLSLTCTVTGYSITSDYAWNWIRQFPGNKLEWMGYISYSGSTSYNPSLKSRISITRDTSKNQFFLQLNSVTTEDTATYYCANAQGYAMDYWGQGTSVTVSS(SEQ ID NO:1)。在一些实施方案中,所述抗体或其抗原结合片段包含由根据SEQ ID NO:1的氨基酸序列组成的VH链。
在一些实施方案中,所述抗体或其抗原结合片段包含VH链,其包含与SEQ ID NO:1具有至少约85%、至少约90%、至少约92%、至少约94%、至少约96%或至少约98%序列同一性的氨基酸序列或由所述氨基酸序列组成。在一些实施方案中,所述抗体或其抗原结合片段包含VH链,其包含与SEQ ID NO:1具有至少约85%序列同一性的氨基酸序列或由所述氨基酸序列组成。在一些实施方案中,所述抗体或其抗原结合片段包含VH链,其包含与SEQID NO:1具有至少约90%序列同一性的氨基酸序列或由所述氨基酸序列组成。在一些实施方案中,所述抗体或其抗原结合片段包含VH链,其包含与SEQ ID NO:1具有至少约92%序列同一性的氨基酸序列或由所述氨基酸序列组成。在一些实施方案中,所述抗体或其抗原结合片段包含VH链,其包含与SEQ ID NO:1具有至少约94%序列同一性的氨基酸序列或由所述氨基酸序列组成。在一些实施方案中,所述抗体或其抗原结合片段包含VH链,其包含与SEQ ID NO:1具有至少约96%序列同一性的氨基酸序列或由所述氨基酸序列组成。在一些实施方案中,所述抗体或其抗原结合片段包含VH链,其包含与SEQ ID NO:1具有至少约98%序列同一性的氨基酸序列或由所述氨基酸序列组成。在一些实施方案中,VH链包含本文所述的任何VH CDR。在一些实施方案中,VH CDR包含根据SEQ ID NO:7、SEQ ID NO:8和SEQ IDNO:9的氨基酸序列。在一些实施方案中,VH链包含一个、两个、三个、四个、五个、六个、七个或八个保守性氨基酸取代或由一个、两个、三个、四个、五个、六个、七个或八个保守性氨基酸取代组成。在一些实施方案中,VH链包含在CDR外的一个、两个、三个、四个、五个、六个、七个或八个保守性氨基酸取代或由在CDR外的一个、两个、三个、四个、五个、六个、七个或八个保守性氨基酸取代组成。
在一些实施方案中,所述抗体或其抗原结合片段包含VL链,其包含以下氨基酸序列或由以下氨基酸序列组成:DIVMTQSPA
TLSVTPGDRVSLSCRASQSISDYLHWYQQKSHESPRLLIKYASQSISGIPSRFSGSGS
GSDFTLSINSVEPEDVGVYYCQNGHSFPFTFGSGTKLEIK(SEQ ID NO:4)。在一些实施方案中,所述抗体或其抗原结合片段包含由根据SEQ ID NO:4的氨基酸序列组成的VL链。
在一些实施方案中,所述抗体或其抗原结合片段包含VL链,其包含与SEQ ID NO:4具有至少约85%、至少约90%、至少约92%、至少约94%、至少约96%或至少约98%序列同一性的氨基酸序列或由所述氨基酸序列组成。在一些实施方案中,所述抗体或其抗原结合片段包含VL链,其包含与SEQ ID NO:4具有至少约85%序列同一性的氨基酸序列或由所述氨基酸序列组成。在一些实施方案中,所述抗体或其抗原结合片段包含VL链,其包含与SEQID NO:4具有至少约90%序列同一性的氨基酸序列或由所述氨基酸序列组成。在一些实施方案中,所述抗体或其抗原结合片段包含VL链,其包含与SEQ ID NO:4具有至少约92%序列同一性的氨基酸序列或由所述氨基酸序列组成。在一些实施方案中,所述抗体或其抗原结合片段包含VL链,其包含与SEQ ID NO:4具有至少约94%序列同一性的氨基酸序列或由所述氨基酸序列组成。在一些实施方案中,所述抗体或其抗原结合片段包含VL链,其包含与SEQ ID NO:4具有至少约96%序列同一性的氨基酸序列或由所述氨基酸序列组成。在一些实施方案中,所述抗体或其抗原结合片段包含VL链,其包含与SEQ ID NO:4具有至少约98%序列同一性的氨基酸序列或由所述氨基酸序列组成。在一些实施方案中,VL链包含本文所述的任何VL CDR。在一些实施方案中,VL CDR包含根据SEQ ID NO:10、SEQ ID NO:11和SEQID NO:12的氨基酸序列。在一些实施方案中,VL链包含一个、两个、三个、四个、五个、六个、七个或八个保守性氨基酸取代。在一些实施方案中,VL链包含在CDR外的一个、两个、三个、四个、五个、六个、七个或八个保守性氨基酸取代。
在一些实施方案中,所述抗体或其抗原结合片段包含含有根据SEQ ID NO:1的氨基酸序列的VH链和含有根据SEQ ID NO:4的氨基酸序列的VL链。在一些实施方案中,所述抗体或其抗原结合片段包含由根据SEQ ID NO:1的氨基酸序列组成的VH链和由根据SEQ IDNO:4的氨基酸序列组成的VL链。
在一些实施方案中,所述抗体或其抗原结合片段包含VH链和VL链,其分别包含与SEQ ID NO:1和SEQ ID NO:4具有至少约85%、至少约90%、至少约92%、至少约94%、至少约96%或至少约98%序列同一性的氨基酸序列或由所述氨基酸序列组成。在一些实施方案中,所述抗体或其抗原结合片段包含VH链和VL链,其分别包含与SEQ ID NO:1和SEQ ID NO:4具有至少约85%序列同一性的氨基酸序列或由所述氨基酸序列组成。在一些实施方案中,所述抗体或其抗原结合片段包含VH链和VL链,其分别包含与SEQ ID NO:1和SEQ ID NO:4具有至少约90%序列同一性的氨基酸序列或由所述氨基酸序列组成。在一些实施方案中,所述抗体或其抗原结合片段包含VH链和VL链,其分别包含与SEQ ID NO:1和SEQ ID NO:4具有至少约92%序列同一性的氨基酸序列或由所述氨基酸序列组成。在一些实施方案中,所述抗体或其抗原结合片段包含VH链和VL链,其分别包含与SEQ ID NO:1和SEQ ID NO:4具有至少约94%序列同一性的氨基酸序列或由所述氨基酸序列组成。在一些实施方案中,所述抗体或其抗原结合片段包含VH链和VL链,其分别包含与SEQ ID NO:1和SEQ ID NO:4具有至少约96%序列同一性的氨基酸序列或由所述氨基酸序列组成。在一些实施方案中,所述抗体或其抗原结合片段包含VH链和VL链,其分别包含与SEQ ID NO:1和SEQ ID NO:4具有至少约98%序列同一性的氨基酸序列或由所述氨基酸序列组成。在一些实施方案中,VH链和VL链包含本文所述的任何VH CDR和VL CDR。在一些实施方案中,VH CDR包含根据SEQ ID NO:7、SEQID NO:8和SEQ ID NO:9的氨基酸序列。在一些实施方案中,VL CDR包含根据SEQ ID NO:10、SEQ ID NO:11和SEQ ID NO:12的氨基酸序列或由所述氨基酸序列组成。在一些实施方案中,VH链和VL链各自可以包含一个、两个、三个、四个、五个、六个、七个或八个保守性氨基酸取代或由一个、两个、三个、四个、五个、六个、七个或八个保守性氨基酸取代组成。在一些实施方案中,VH链和VL链各自可以包含在CDR外的一个、两个、三个、四个、五个、六个、七个或八个保守性氨基酸取代或由在CDR外的一个、两个、三个、四个、五个、六个、七个或八个保守性氨基酸取代组成。
所述抗体或其抗原结合片段可以是任何同种型。在一些实施方案中,所述抗体是IgM或IgG抗体。在一些实施方案中,所述抗体是IgM抗体。在一些实施方案中,所述抗体是IgG抗体。在一些实施方案中,所述抗体是IgG1抗体。在一些实施方案中,所述IgG1抗体是IgG1 Glm1、Glm2、Glm3、Glm17、nGlmI、nGlm2或nGlm17同种异型抗体。在一些实施方案中,所述抗体是IgG1 Glm17同种异型抗体。
在一些实施方案中,变体IgG1重链与同种异型Km1、Km2或Km3的κ轻链配对。在一些实施方案中,变体IgG1重链与λ轻链配对。
在一些实施方案中,所述抗体或其抗原结合片段是人源化的并且是IgG。在一些实施方案中,所述抗体或其抗原结合片段是人源化的并且是IgG1。
在一些实施方案中,所述抗体或其抗原结合片段是嵌合抗体或其抗原结合片段。产生嵌合抗体的方法是本领域已知的(参见,Morrison,Science,1985,229,1202-1207;Oi等人,BioTechniques,1986,4,214-221;Gillies等人,J.Immunol.Methods,1985,125,191-202;以及美国专利号5,807,715、4,816,567和4,816,397)。
在一些实施方案中,所述嵌合抗体或其抗原结合片段是灵长类化的嵌合抗体或其抗原结合片段。产生灵长类化抗体的方法是本领域已知的(参见,美国专利号5,658,570、5,681,722和5,693,780)。
在一些实施方案中,所述嵌合抗体或其抗原结合片段是人源化抗体或其抗原结合片段。产生人源化抗体的方法是本领域已知的(参见,Riechmann等人,Nature,1988,332,323-327;Padlan,Mol.Immunol.,1991,28,489-498;Studnicka等人,Prot.Eng.,1994,7,805-814;Roguska等人,Proc.Natl.Acad.Sci.,1994,91,969-973;欧洲专利号EP239400、EP592106和EP519596;PCT公开WO 91/09967;以及美国专利号5,225,539、5,530,101、5,585,089、5,693,761、5,693,762、6,180,370和5,565,332)。
在一些实施方案中,所述人源化抗体或其抗原结合片段包含重链,其包含以下氨基酸序列或由以下氨基酸序列组成:VQLQESGPGLVKPSQSLSLTCTVTGYSITSDYAWNWIRQFPGNKLEWMGYISYSGST
SYNPSLKSRISITRDTSKNQFFLQLNSVTTEDTATYYCANAQGYAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(SEQ ID NO:13)。在一些实施方案中,所述人源化抗体或其抗原结合片段包含由根据SEQ ID NO:13的氨基酸序列组成的重链。
在一些实施方案中,所述人源化抗体或其抗原结合片段包含重链,其包含与SEQID NO:13具有至少约85%、至少约90%、至少约92%、至少约94%、至少约96%或至少约98%序列同一性的氨基酸序列或由所述氨基酸序列组成。在一些实施方案中,所述人源化抗体或其抗原结合片段包含重链,其包含与SEQ ID NO:13具有至少约85%序列同一性的氨基酸序列或由所述氨基酸序列组成。在一些实施方案中,所述人源化抗体或其抗原结合片段包含重链,其包含与SEQ ID NO:13具有至少约90%序列同一性的氨基酸序列或由所述氨基酸序列组成。在一些实施方案中,所述人源化抗体或其抗原结合片段包含重链,其包含与SEQ ID NO:13具有至少约92%序列同一性的氨基酸序列或由所述氨基酸序列组成。在一些实施方案中,所述人源化抗体或其抗原结合片段包含重链,其包含与SEQ ID NO:13具有至少约94%序列同一性的氨基酸序列或由所述氨基酸序列组成。在一些实施方案中,所述人源化抗体或其抗原结合片段包含重链,其包含与SEQ ID NO:13具有至少约96%序列同一性的氨基酸序列或由所述氨基酸序列组成。在一些实施方案中,所述人源化抗体或其抗原结合片段包含重链,其包含与SEQ ID NO:13具有至少约98%序列同一性的氨基酸序列或由所述氨基酸序列组成。在一些实施方案中,所述重链包含本文所述的任何VH CDR。在一些实施方案中,所述重链CDR包含根据SEQ ID NO:7、SEQ ID NO:8和SEQ ID NO:9的氨基酸序列。在一些实施方案中,所述重链包含一个、两个、三个、四个、五个、六个、七个、八个、九个或十个保守性氨基酸取代。在一些实施方案中,所述重链包含在CDR外的一个、两个、三个、四个、五个、六个、七个、八个、九个或十个保守性氨基酸取代。
在一些实施方案中,所述人源化抗体或其抗原结合片段包含轻链,其包含以下氨基酸序列或由以下氨基酸序列组成:DIVMTQSPATLSVTPGDRVSLSCRASQSISDYLHWYQQKSHESPRLLIKYASQSISGIP
SRFSGSGSGSDFTLSINSVEPEDVGVYYCQNGHSFPFTFGSGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:14)。在一些实施方案中,所述人源化抗体或其抗原结合片段包含由根据SEQ ID NO:14的氨基酸序列组成的轻链。
在一些实施方案中,所述人源化抗体或其抗原结合片段包含轻链,其包含与SEQID NO:14具有至少约85%、至少约90%、至少约92%、至少约94%、至少约96%或至少约98%序列同一性的氨基酸序列或由所述氨基酸序列组成。在一些实施方案中,所述人源化抗体或其抗原结合片段包含轻链,其包含与SEQ ID NO:14具有至少约85%序列同一性的氨基酸序列或由所述氨基酸序列组成。在一些实施方案中,所述人源化抗体或其抗原结合片段包含轻链,其包含与SEQ ID NO:14具有至少约90%序列同一性的氨基酸序列或由所述氨基酸序列组成。在一些实施方案中,所述人源化抗体或其抗原结合片段包含轻链,其包含与SEQ ID NO:14具有至少约92%序列同一性的氨基酸序列或由所述氨基酸序列组成。在一些实施方案中,所述人源化抗体或其抗原结合片段包含轻链,其包含与SEQ ID NO:14具有至少约94%序列同一性的氨基酸序列或由所述氨基酸序列组成。在一些实施方案中,所述人源化抗体或其抗原结合片段包含轻链,其包含与SEQ ID NO:14具有至少约96%序列同一性的氨基酸序列或由所述氨基酸序列组成。在一些实施方案中,所述人源化抗体或其抗原结合片段包含轻链,其包含与SEQ ID NO:14具有至少约98%序列同一性的氨基酸序列或由所述氨基酸序列组成。在一些实施方案中,所述轻链包含本文所述的任何VL CDR。在一些实施方案中,所述轻链CDR包含根据SEQ ID NO:10、SEQ ID NO:11和SEQ ID NO:12的氨基酸序列。在一些实施方案中,所述轻链包含一个、两个、三个、四个、五个、六个、七个、八个、九个或十个保守性氨基酸取代或由一个、两个、三个、四个、五个、六个、七个、八个、九个或十个保守性氨基酸取代组成。在一些实施方案中,所述轻链包含在CDR外的一个、两个、三个、四个、五个、六个、七个、八个、九个或十个保守性氨基酸取代或由在CDR外的一个、两个、三个、四个、五个、六个、七个、八个、九个或十个保守性氨基酸取代组成。
在一些实施方案中,所述人源化抗体或其抗原结合片段包含重链和轻链,其分别包含与SEQ ID NO:13和SEQ ID NO:14具有至少约85%、至少约90%、至少约92%、至少约94%、至少约96%或至少约98%序列同一性的氨基酸序列或由所述氨基酸序列组成。在一些实施方案中,所述人源化抗体或其抗原结合片段包含重链和轻链,其分别包含与SEQ IDNO:13和SEQ ID NO:14具有至少约85%序列同一性的氨基酸序列或由所述氨基酸序列组成。在一些实施方案中,所述人源化抗体或其抗原结合片段包含重链和轻链,其分别包含与SEQ ID NO:13和SEQ ID NO:14具有至少约90%序列同一性的氨基酸序列或由所述氨基酸序列组成。在一些实施方案中,所述人源化抗体或其抗原结合片段包含重链和轻链,其分别包含与SEQ ID NO:13和SEQ ID NO:14具有至少约92%序列同一性的氨基酸序列或由所述氨基酸序列组成。在一些实施方案中,所述人源化抗体或其抗原结合片段包含重链和轻链,其分别包含与SEQ ID NO:13和SEQ ID NO:14具有至少约94%序列同一性的氨基酸序列或由所述氨基酸序列组成。在一些实施方案中,所述人源化抗体或其抗原结合片段包含重链和轻链,其分别包含与SEQ ID NO:13和SEQ ID NO:14具有至少约96%序列同一性的氨基酸序列或由所述氨基酸序列组成。在一些实施方案中,所述人源化抗体或其抗原结合片段包含重链和轻链,其分别包含与SEQ ID NO:13和SEQ ID NO:14具有至少约98%序列同一性的氨基酸序列或由所述氨基酸序列组成。在一些实施方案中,所述重链和轻链包含本文所述的任何VH CDR和VL CDR。在一些实施方案中,VH CDR包含根据SEQ ID NO:7、SEQ ID NO:8和SEQ ID NO:9的氨基酸序列。在一些实施方案中,VL CDR包含根据SEQ ID NO:10、SEQ IDNO:11和SEQ ID NO:12的氨基酸序列或由所述氨基酸序列组成。在一些实施方案中,所述重链和轻链各自可以包含一个、两个、三个、四个、五个、六个、七个、八个、九个或十个保守性氨基酸取代或由一个、两个、三个、四个、五个、六个、七个、八个、九个或十个保守性氨基酸取代组成。在一些实施方案中,所述重链和轻链各自可以包含在CDR外的一个、两个、三个、四个、五个、六个、七个、八个、九个或十个保守性氨基酸取代或由在CDR外的一个、两个、三个、四个、五个、六个、七个、八个、九个或十个保守性氨基酸取代组成。
在一些实施方案中,所述抗体或其抗原结合片段是完全人源化的。完全“人”抗体对于人患者的治疗性治疗可能是理想的。用于产生完全人抗体的方法是本领域已知的,包括使用源自人免疫球蛋白序列的抗体文库的噬菌体展示方法(参见美国专利号4,444,887和4,716,111;和PCT公开WO 98/46645、WO 98/50433、WO 98/24893、WO 98/16654、WO 96/34096、WO 96/33735和WO 91/10741)。也可以使用不能表达功能性内源免疫球蛋白但可以表达人免疫球蛋白基因的转基因小鼠来产生人抗体(参见,PCT公开WO 98/24893、WO92/01047、WO 96/34096和WO 96/33735;以及美国专利号5,413,923、5,625,126、5,633,425、5,569,825、5,661,016、5,545,806、5,814,318、5,885,793、5,916,771和5,939,598)。识别所选表位的完全人抗体也可以使用称为“导向选择”的技术生成(参见,Jespers等人,Biotechnology,1988,12,899-903)。
在一些实施方案中,所述抗体或其抗原结合片段是双特异性抗体。双特异性抗体对至少两种不同的抗原具有结合特异性(即,一种结合特异性针对BAI1,另一种结合特异性针对任何其它抗原,诸如细胞表面蛋白、受体、受体亚基、组织特异性抗原、病毒来源的蛋白、病毒编码的包膜蛋白、细菌来源的蛋白或细菌表面蛋白等)。
在一些实施方案中,所述抗体或其抗原结合片段是衍生抗体。例如,衍生抗体可以是通过糖基化、乙酰化、聚乙二醇化、磷酸化、酰胺化、通过已知保护/封闭基团的衍生化、蛋白水解裂解、与细胞配体或其它蛋白的连接等修饰的抗体。许多化学修饰中的任何一种都可以通过已知技术进行,包括但不限于特定的化学裂解、乙酰化、甲酰化、衣霉素的代谢合成等。另外,衍生物可以含有一个或多个非天然氨基酸,诸如使用ambrx技术(参见,Wolfson,Chem.Biol.,2006,13,1011-1012)。
在一些实施方案中,所述抗体或其抗原结合片段通过糖基化而衍生。合适的双天线复合物可以由具有两个N-乙酰葡糖胺(GlcNAc)、三个甘露糖和两个GlcNAc残基的核心结构组成,所述两个GlcNAc残基β-1,2连接到α-6甘露糖和α-3甘露糖以形成两个天线。一个或多个岩藻糖(Fuc)、半乳糖(Gal)、高甘露聚糖Man-5或Man-9、二等分GlcNAc和唾液酸(包括N-乙酰神经氨酸(NANA)或N-乙醇酰神经氨酸(NGNA)残基)可以附接到核心上。N-连接的糖型可以包括G0(具有核心双天线糖基化结构的蛋白质)、G0F(岩藻糖基化G0)、G0F GlcNAc、G1(具有带一个半乳糖残基的核心糖基化结构的蛋白质)、G1F(岩藻糖基化G1)、G2(具有带两个半乳糖残基的核心糖基化结构的蛋白质)和/或G2F(岩藻糖基化G2)。在一些实施方案中,抗BAI1抗体具有G0F聚糖。
所述抗体或其抗原结合片段可通过在宿主细胞中重组表达免疫球蛋白轻链和重链基因来制备。为了重组表达抗体,用一种或多种携带编码抗体的免疫球蛋白轻链和重链的DNA片段的重组表达载体转染宿主细胞,使得轻链和重链在宿主细胞中表达,并且任选地分泌到培养宿主细胞的培养基中,可以从该培养基中回收抗体。标准重组DNA方法可用于获得抗体重链和轻链基因,将这些基因并入重组表达载体中并将载体引入宿主细胞中(参见,Molecular Cloning;A Laboratory Manual,第2版,Sambrook,Fritsch和Maniatis(编辑),Cold Spring Harbor,N.Y.,1989;Current Protocols in Molecular Biology,Ausubel等人编辑,Greene Publishing Associates,1989;和美国专利号4,816,397)。
在一些实施方案中,为了生成编码本文所述的抗体或其抗原结合片段的核酸分子,首先获得编码轻链和重链可变区的DNA片段。这些DNA可以通过扩增和修饰编码轻链和重链可变序列的种系DNA或cDNA获得,例如,使用聚合酶链式反应(PCR)。人重链和轻链可变区基因的种系DNA序列是本领域已知的(参见,“VBASE”人种系序列数据库;Kabat等人,1991,Sequences of Proteins of Immunological Interest,第5版,U.S.Department ofHealth and Human Services,NIH公开号91-3242;Tomlinson等人,J.Mol.Biol.,1992,22T,116-198;和Cox等人,Eur.J.Immunol.,1994,24,827-836)。可以合成编码重链或轻链可变区的DNA片段并将其用作诱变的模板,以使用常规诱变技术生成本文所述的变体;可替代地,可以直接合成编码该变体的DNA片段。
本公开提供了编码抗体或其抗原结合片段的VH链的分离的核酸分子,其中所述核酸分子包含以下核苷酸序列或由以下核苷酸序列组成:TCTGATGTGCAGCTTCAGGAGTCGG
GACCTGGCCTGGTGAAACCTTCTCAGTCTCTGTCCCTCACCTGCACTGTCACTGGCTACTCAATCACCAGTGATTATGCCTGGAACTGGATCCGGCAGTTTCCAGGAAACAAACTGGAGTGGATGGGCTACATAAGCTACAGTGGTAGCACTAGCTACAACCCATCTCTCAAAAGTCGAATCTCTATCACTCGAGACACATCCAAGAACCAGTTCTTCCTGCAGTTGAATTCTGTGACTACTGAGGACACAGCCACATATTACTGTGCCAATGCCCAGGGGTATGCTATGGACTACTGGGGTCAAGGAACCTCAGTCACCGTCTCCTCA(SEQ ID NO:2;DNA)或UCUGAUGUGCAGCUUCAGGAGUCGGGACCUGGCCUGGU
GAAACCUUCUCAGUCUCUGUCCCUCACCUGCACUGUCACUGGCUACUCAAUCACCAGUGAUUAUGCCUGGAACUGGAUCCGGCAGUUUCCAGGAAACAAACUGGAGUGGAUGGGCUACAUAAGCUACAGUGGUAGCACUAGCUACAACCCAUCUCUCAAAAGUCGAAUCUCUAUCACUCGAGACACAUCCAAGAACCAGUUCUUCCUGCAGUUGAAUUCUGUGACUACUGAGGACACAGCCACAUAUUACUGUGCCAAUGCCCAGGGGUAUGCUAUGGACUACUGGGGUCAAGGAACCUCAGUCACCGUCUCCUCA(SEQ ID NO:3;RNA)。
本公开还提供了编码抗体或其抗原结合片段的VL链的分离的核酸分子,其中所述核酸分子包含以下核苷酸序列或由以下核苷酸序列组成:GACATTGTGATGACTCAGT
CTCCAGCCACCCTGTCTGTGACTCCAGGAGATAGAGTCTCTCTTTCCTGCAGGGCCAGCCAGAGTATTAGCGACTACTTACACTGGTATCAACAAAAATCACATGAGTCTCCAAGGCTTCTCATCAAATATGCTTCCCAATCCATCTCTGGGATCCCCTCCAGGTTCAGTGGCAGTGGATCAGGGTCAGATTTCACTCTCAGTATCAACAGTGTGGAACCTGAAGATGTTGGAGTGTATTACTGTCAAAATGGTCACAGCTTTCCATTCACGTTCGGCTCGGGGACAAAGTTGGAAATAAAA(SEQ ID NO:5,DNA)或GACAUUGUGAUG
ACUCAGUCUCCAGCCACCCUGUCUGUGACUCCAGGAGAUAGAGUCUCUCUUUCCUGCAGGGCCAGCCAGAGUAUUAGCGACUACUUACACUGGUAUCAACAAAAAUCACAUGAGUCUCCAAGGCUUCUCAUCAAAUAUGCUUCCCAAUCCAUCUCUGGGAUCCCCUCCAGGUUCAGUGGCAGUGGAUCAGGGUCAGAUUUCACUCUCAGUAUCAACAGUGUGGAACCUGAAGAUGUUGGAGUGUAUUACUGUCAAAAUGGUCACAGCUUUCCAUUCACGUUCGGCUCGGGGACAAAGUUGGAAAUAAAA(SEQ ID NO:6,RNA)。
这些DNA片段可通过标准重组DNA技术进一步操纵,例如,以将可变区基因转化为全长抗体链基因、Fab片段基因或scFv基因。在这些操纵中,将编码VH或VL的DNA片段与编码另一种蛋白质(诸如抗体恒定区或柔性接头)的另一DNA片段可操作地连接。如该文本中所用,短语“可操作地连接”意指两个DNA片段连接,使得由所述两个DNA片段编码的氨基酸序列保持在框内。
可以通过将编码VH的DNA与编码重链恒定区(CH1、CH2、CH3和任选地CH4)的另一DNA分子可操作地地连接,将编码VH区的分离的DNA分子转化为全长重链基因。人重链恒定区基因的序列在本领域是已知的(参见,Kabat等人,1991,Sequences of Proteins ofImmunological Interest,第5版,U.S.Department of Health and Human Services,NIH公开号91-3242)并且涵盖这些区域的DNA片段可以通过标准PCR扩增获得。重链恒定区可以是IgG1、IgG2、IgG3、IgG4、IgA、IgE、IgM或IgD恒定区。在一些实施方案中,重链恒定区是IgG1或IgG4恒定区。对于Fab片段重链基因,编码VH的DNA可以与仅编码重链CH1恒定区的另一DNA分子可操作地连接。
可以通过将编码VL的DNA与编码轻链恒定区CL的另一DNA分子可操作地连接,来将编码VL区的分离的DNA转化为全长轻链基因(以及Fab轻链基因)。人轻链恒定区基因的序列在本领域是已知的(参见,Kabat等人,1991,Sequences of Proteins of ImmunologicalInterest,第5版(U.S.Department of Health and Human Services,NIH公开号91-3242))并且涵盖这些区域的DNA片段可以通过标准PCR扩增获得。轻链恒定区可以是κ或λ恒定区。在一些实施方案中,轻链恒定区是κ恒定区。为了产生scFv基因,将编码VH和VL的DNA片段与编码柔性接头,例如编码氨基酸序列(Gly4Ser)3的另一片段可操作地连接,使得VH和VL序列可以表达为连续的单链蛋白质,其中VH和VL区通过柔性接头连接(参见,Bird等人,Science,1988,242,423-426;Huston等人,Proc.Natl.Acad.Sci.USA,1988,85,5879-5883;和McCafferty等人,Nature,1990,348,552-554)。
为了表达本文所述的抗体或其抗原结合片段,可以将如本文所述获得的编码部分或全长轻链和重链的DNA分子插入表达载体中,使得基因与转录和翻译控制序列可操作地连接。在该上下文中,短语“可操作地连接”旨在意指将抗体基因连接到载体中,使得载体中的转录和翻译控制序列发挥其调控抗体基因的转录和翻译的预期功能。可以选择与所用表达宿主细胞相容的表达载体和表达控制序列。抗体轻链基因和抗体重链基因可以插入到单独的载体中,或者更典型地,两种基因插入到同一表达载体中。
抗体基因可以通过标准方法插入到表达载体中,例如抗体基因片段和载体上互补限制性位点的连接,或者如果不存在限制性位点,则进行平端连接。在轻链或重链序列插入之前,表达载体可能已经携带抗体恒定区序列。例如,将VH和VL序列转化为全长抗体基因的一种方法是将它们分别插入到已经编码重链恒定区和轻链恒定区的表达载体中,使得VH区段与载体内的CH区段可操作地连接,而VL区段与载体内的CL区段可操作地连接。另外或可替代地,重组表达载体可以编码促进抗体链从宿主细胞中分泌的信号肽。抗体链基因可以被克隆到载体中,使得信号肽框内连接到抗体链基因的氨基端。信号肽可以是免疫球蛋白信号肽或异源信号肽,诸如来自非免疫球蛋白的信号肽。
除了抗体链基因以外,重组表达载体可以携带控制抗体链基因在宿主细胞中的表达的调控序列。此类调控序列例如在Goeddel,Gene Expression Technology:Methods inEnzymology 185(Academic Press,San Diego,Calif.,1990)中有描述。本领域技术人员将认识到,表达载体的设计,包括调控序列的选择,可取决于诸如待转化的宿主细胞的选择,所需蛋白质的表达水平等因素。哺乳动物宿主细胞表达的合适调控序列包括指导哺乳动物细胞中的高水平蛋白质表达的病毒元件,诸如源自巨细胞病毒(CMV)(诸如CMV启动子/增强子)、猿猴病毒40(SV40)(诸如SV40启动子/增强子)、腺病毒(诸如腺病毒主要晚期启动子(AdMLP))和多瘤病毒的启动子和/或增强子。病毒调控元件及其序列是本领域已知的(参见,例如,美国专利号5,168,062、4,510,245和4,968,615)。
本公开的重组表达载体还可以携带另外的序列,诸如调控载体在宿主细胞中复制的序列(诸如复制起点)和选择标记基因。选择标记基因促进选择已向其中引入载体的宿主细胞(参见,美国专利号4,399,216、4,634,665和5,179,017)。例如,典型地,选择标记基因对已向其中引入载体的宿主细胞赋予对药物,诸如G418、嘌呤霉素、杀稻瘟素、潮霉素或甲氨蝶呤的抗性。合适的选择标记基因包括二氢叶酸还原酶(DHFR)基因(用于具有甲氨蝶呤选择/扩增的DHFR-宿主细胞中)和neo基因(用于G418选择)。为了表达轻链和重链,通过标准技术将编码重链和轻链的表达载体转染到宿主细胞中。术语“转染”的各种形式旨在涵盖多种常用于将外源DNA引入原核或真核宿主细胞中的技术,诸如电穿孔、脂转染、磷酸钙沉淀、DEAE-葡聚糖转染等。
所述抗体或其抗原结合片段可以在原核或真核宿主细胞中表达。在一些实施方案中,抗体或其抗原结合片段的表达可在真核细胞(诸如哺乳动物宿主细胞)中进行,以分泌正确折叠且具有免疫活性的抗体。用于表达本公开的重组抗体或其抗原结合片段的示例性哺乳动物宿主细胞包括中国仓鼠卵巢(CHO细胞)(包括DHFR CHO细胞(参见,Urlaub,Proc.Natl.Acad.Sci.USA,1980,77,4216-4220)(与DHFR选择标记一起使用(参见,Kaufman,Mol.Biol.,1982,159,601-621)))、NS0骨髓瘤细胞、COS细胞、293细胞和SP2/0细胞。当将编码抗体基因的重组表达载体引入到哺乳动物宿主细胞中时,通过培养宿主细胞一段时间来产生抗体,所述时间足以允许抗体在宿主细胞中表达或抗体分泌到宿主细胞生长的培养基中。可以使用标准的蛋白质纯化方法从培养基中回收抗体或其抗原结合片段。宿主细胞也可用于产生完整抗体的部分,诸如Fab片段或scFv分子。应当理解,上述程序的变化在本公开的范围内。例如,可能期望用编码本文所述的抗体或其抗原结合片段的轻链或重链(但不是两者)的DNA转染宿主细胞。
也可以使用重组DNA技术去除一些或所有编码对于与BAI1结合不必要的轻链和重链之一或两者的DNA。由此类截短的DNA分子表达的分子也涵盖在本文所述的抗体或其抗原结合片段中。
另外,可以通过标准化学交联方法将本公开的抗体与第二抗体交联来产生双功能抗体或其抗原结合片段,其中一条重链和一条轻链是本公开的抗体,而另一条重链和轻链对除BAI1以外的抗原具有特异性。双功能抗体也可以通过表达经工程改造为编码双功能抗体的核酸来制备。
对于本文所述的抗体或其抗原结合片段的重组表达,可以用本公开的两种表达载体共转染宿主细胞,第一载体编码重链来源多肽而第二载体编码轻链来源的多肽。通常,所述两种载体各自含有单独的选择标记。另选地,可以使用编码重链和轻链多肽两者的单一载体。
一旦生成编码具有所需CDR序列的抗体或其抗原结合片段的一个或多个部分的核酸,就可以向编码序列中引入进一步的改变,例如,以生成编码具有不同CDR序列的抗体、对Fc受体的亲和力降低的抗体或不同亚类的抗体的核酸。
本文所述的抗体或其抗原结合片段也可以通过化学合成产生(诸如通过SolidPhase Peptide Synthesis,第2版,1984The Pierce Che mical Co.,Rockford,Ill中描述的方法)。变体抗体或其抗原结合片段也可以使用无细胞平台生成(参见,Chu等人,Biochemia,2001,2)。
一旦通过重组表达产生了本文所述的抗体或其抗原结合片段,就可以通过本领域已知的用于免疫球蛋白分子纯化的任何方法对其进行纯化,例如,通过色谱法(诸如离子交换色谱法、亲和色谱法,特别是通过对蛋白A、蛋白G或蛋白L选择的亲和色谱法,以及施胶柱色谱法(sizing column chromatography))、离心、差异性溶解,或通过任何其它用于蛋白纯化的标准技术。此外,本文所述的抗体或其抗原结合片段可与本文所述或本领域另外已知的异源多肽序列融合,以利于纯化。
一旦分离,如果需要就可以进一步纯化所述抗体或其抗原结合片段,诸如通过高效液相色谱法(参见,Fisher,Laboratory Techniques In Biochemistry And MolecularBiology(Work和Burdon编辑,Elsevier,1980)),或通过SuperdexTM 75柱的凝胶过滤色谱法(Pharmacia Biotech AB,Uppsala,Sweden)。
本公开提供了包含本文所述的任何核酸分子的载体。本公开还提供了经载体转化的原核宿主细胞。本公开还提供了经载体转化的真核宿主细胞。在一些实施方案中,所述真核宿主细胞是哺乳动物宿主细胞。
在一些实施方案中,所述抗体或其抗原结合片段与效应部分缀合。在一些实施方案中,所述抗体或其抗原结合片段通过任何类型的分子与抗体或其抗原结合片段的共价附接而被修饰,使得共价附接不干扰与BAI1的结合。在一些实施方案中,所述效应部分是可检测的标记、细胞毒性剂、化学治疗剂或核酸分子。所述效应部分也可以是抗肿瘤剂、药物、毒素、生物活性蛋白(诸如酶)、另一种抗体或抗体片段、合成或天然存在的聚合物、核酸分子、放射性核素(诸如放射性碘化物)、放射性同位素、螯合金属、纳米颗粒或报告基团(诸如荧光化合物或者可通过NMR或ESR光谱法检测的化合物)。
在一些实施方案中,所述抗体或其抗原结合片段可与细胞毒性剂、放射性核素或药物部分缀合以改变特定的生物反应。所述效应部分可以是蛋白质或多肽,例如毒素(诸如相思子毒素、蓖麻毒素A、皂草素、假单胞菌外毒素、白喉毒素、溴乙锭或PE40、PE38、白树毒素、RNA酶、肽核酸(PNA)、核糖体失活蛋白(RIP)1型或2型、商陆抗病毒蛋白(PAP)、异株泻根毒蛋白(bryodin)、苦瓜蛋白、化学治疗剂和bouganin);信号传导分子(诸如α-干扰素、β-干扰素、神经生长因子、血小板衍生生长因子或组织纤溶酶原激活物);血栓形成剂或抗血管生成剂(诸如血管抑素或内皮抑素)或生物反应调节剂,诸如细胞因子或生长因子(诸如白细胞介素-1(IL-1)、白细胞介素-2(IL-2)、白细胞介素-6(IL-6)、粒细胞巨噬细胞集落刺激因子(GM-CSF)、粒细胞集落刺激因子(G-CSF)或神经生长因子(NGF))。
在一些实施方案中,细胞毒性剂是小分子、前药、美登木素生物碱(maytansinoid)或毒素。在一些实施方案中,所述抗体或其抗原结合片段在每个抗体或其抗原结合片段中包含3至5个美登木素生物碱分子。在一些实施方案中,美登木素生物碱通过选自N-琥珀酰亚胺-3-(2-吡啶基二硫代)丙酸酯、N-琥珀酰亚胺-4-(2-吡啶基硫代)戊酸酯(SPP)和琥珀酰亚胺-4-(N-马来酰亚胺甲基)环己烷-1-羧酸酯的化学接头与所述抗体或其抗原结合片段缀合。在一些实施方案中,细胞毒性剂是紫杉酚、细胞松弛素B、短杆菌肽D、溴乙锭、吐根碱、丝裂霉素、依托泊苷(etoposide)、替尼泊苷(tenoposide)、长春新碱、长春花碱、秋水仙素、阿霉素、柔红霉素、二羟基蒽二酮、米托蒽醌、光神霉素(mithramycin)、放线菌素D、
1-去氢睾酮、糖皮质激素、普鲁卡因(procaine)、丁卡因(tetracaine)、利多卡因(lidocaine)、普萘洛尔(propranolol)或嘌呤霉素。
在一些实施方案中,可检测标记是放射性化合物、荧光化合物、发色团、酶、显像剂、金属离子或底物。在一些实施方案中,荧光部分包括但不限于荧光素、异硫氰酸荧光素、罗丹明、5-二甲胺-1-萘磺酰氯、藻红蛋白等。有用的酶标记包括但不限于碱性磷酸酶、辣根过氧化物酶、葡萄糖氧化酶等。
在一些实施方案中,效应部分是抗代谢物(诸如,甲氨蝶呤、6-巯基嘌呤、6-硫鸟嘌呤、阿糖胞苷和5-氟尿嘧啶氨烯咪胺(decarbazine))、烷化剂(诸如,氮芥、噻替派(thioepa)苯丁酸氮芥(chlorambucil)、美法仑(melphalan)、卡莫司汀(carmustine)(BSNU)和洛莫司汀(lomustine)(CCNU)、环磷酰胺、白消安(busulfan)、二溴甘露醇、链脲菌素、丝裂霉素C5和顺二氯二胺铂(II)(DDP)顺铂(cisplatin))、蒽环类抗生素(诸如,柔红霉素(先前称道诺霉素)和阿霉素)、抗生素(诸如更生霉素(先前称放线菌素)、博来霉素(bleomycin)、光神霉素、氨茴霉素(AMC)、卡利奇霉素(calicheamicin)或倍癌霉素(duocarmycin))或抗有丝分裂剂(诸如长春新碱和长春花碱)。
在一些实施方案中,放射性核素是但不限于13N、18F、32P、64Cu、66Ga、67Ga、68Ga、67Cu、77Br、80mBr、82Rb、86Y、90Y、95Ru、97Ru、99mTc、103Ru、105Ru、111In、113mIn、113Sn、121mTe、122mTe、125mTe、123I、124I、125I、126I、131I、133I、165Tm、167Tm、168Tm、177Lu、186Re、188Re、195mHg、211At、212Bi、213Bi和225Ac。
在一些实施方案中,化学治疗剂是顺铂、卡铂(carboplatin)、奥沙利铂(oxaliplatin)、奈达铂(nedaplatin)、四硝酸三铂(triplatin tetranitrate)、菲铂(phenanthriplatin)、吡铂(picoplatin)、赛特铂(satraplatin)、甲氨蝶呤、长春新碱、阿霉素、衣霉素、寡霉素、硼替佐米(bortezomib)、MG132、
5-氟尿嘧啶、索拉非尼(sorafenib)、夫拉平度(flavopiridol)、吉西他滨(gemcitabine)、紫杉酚、巯基嘌呤、硫鸟嘌呤、羟基脲、阿糖胞苷、丝裂霉素、环磷酰胺、异环磷酰胺、亚硝基脲、达卡巴嗪(dacarbazine)、普鲁卡因、依托泊苷、喜树碱(campathecin)、博来霉素、伊达比星(idarubicin)、柔红霉素、放线菌素D(dactinomycin)、偏端霉素A(distamycin A)、依替丁(etidium)、纺锤菌素(netropsin)、澳瑞他汀(auristatin)、安吖啶(amsacrine)、灵菌红素(prodigiosin)、硼替佐米、匹苯济醇(pibenzimol)、托马霉素(tomaymycin)、倍癌霉素SA、普卡霉素(plicamycin)、米托蒽醌、天冬酰胺酶、长春花碱、长春瑞滨、紫杉醇、多西他赛(docetaxel)、CPT-11、格列卫(gleevec)、埃罗替尼(erlotinib)、吉非替尼(gefitinib)、依鲁替尼(ibrutinib)、克唑替尼(crizotinib)、塞瑞替尼(ceritinib)、拉帕替尼(lapatinib)、纳维托克(navitoclax)或瑞格菲尼(regorafenib)。
在一些实施方案中,核酸分子是单层核酸载剂、1.5层核酸载剂、双层核酸载剂、2.5层核酸载剂或三层核酸载剂(诸如在例如PCT公开WO 17/143156和WO 17/143171中公开的那些)。
将此类效应部分与抗体缀合的技术是本领域众所周知的(参见,Hellstrom等人,Controlled Drug Delivery,第2版,第623-53页(Robinson等人编辑,1987));Thorpe等人,Immunol.Rev.,1982,62,119-58;和Dubowchik等人,Pharmacology and Therapeutics,1999,83,67-123)。
在一些实施方案中,所述抗体或其抗原结合片段可以经由共价键(诸如肽键),通过抗体的N端或C端或在内部,融合至另一种蛋白质的氨基酸序列(或其部分;例如,所述蛋白质的至少10、20或50个氨基酸的部分)。所述抗体或其抗原结合片段可以在抗体恒定结构域的N端与另一种蛋白质连接。可以使用重组DNA程序产生此类融合体,例如,如PCT公开WO86/01533和欧洲专利EP0392745中所述。在一些实施方案中,效应部分可增加抗体的体内半衰期,和/或增强抗体穿过上皮屏障到免疫系统的递送。这种类型的合适效应部分的实例包括聚合物、白蛋白、白蛋白结合蛋白或白蛋白结合化合物,诸如PCT公开WO 2005/117984中描述的那些。
在一些实施方案中,所述抗体或其抗原结合片段可以与小分子毒素缀合。在一些实施方案中,所述抗体或其抗原结合片段可与尾海兔素或尾海兔素肽类似物或衍生物(诸如澳瑞他汀)缀合(参见,美国专利号5,635,483和5,780,588)。尾海兔素或澳瑞他汀药物部分可以通过其N端、C端或在内部附接到抗体上(参见,PCT公开WO 02/088172)。示例性澳瑞他汀实施方案包括N端连接的单甲基澳瑞他汀药物部分DE和DF,如美国专利号7,498,298中所公开的(公开了用于制备单甲基缬氨酸化合物的接头和方法,诸如与接头缀合的MMAE和MMAF)。
抗体或其抗原结合片段也可以缀合到脂质体上用于靶向递送(参见,Park等人,Adv.Pharmacol.,1997,40,399-435;和Marty等人,Methods Molec.Med.,2004,109,389-401)。
在一些实施方案中,所述抗体或其抗原结合片段可以附接到聚(乙二醇)(PEG)部分。在一些实施方案中,所述抗体或其抗原结合片段和PEG部分可以通过位于抗体或其抗原结合片段中的任何可用的氨基酸侧链或末端氨基酸官能团附接,例如任何游离氨基、亚氨基、硫醇、羟基或羧基基团。此类氨基酸可以天然存在于抗体或其抗原结合片段中,或者可以使用重组DNA方法工程改造到片段中(参见,美国专利号5,219,996)。多个位点可用于附接两个或更多个PEG部分。PEG部分可以通过位于所述抗体或其抗原结合片段中的至少一个半胱氨酸残基的硫醇基团共价连接。当硫醇基团用作附接点时,可以使用适当活化的效应部分,例如巯基选择性衍生物,诸如马来酰亚胺和半胱氨酸衍生物。
在一些实施方案中,所述抗体或其抗原结合片段可以包含聚乙二醇化的经修饰的Fab'片段。PEG部分可以附接到铰链区的半胱氨酸上。在一些实施方案中,PEG修饰的Fab'片段在经修饰的铰链区具有与单个硫醇基团共价连接的马来酰亚胺基团。赖氨酸残基可以共价连接到马来酰亚胺基团上,并且赖氨酸残基上的每个胺基可以附接到分子量为大约20,000Da的甲氧基聚(乙二醇)聚合物上。因此,与Fab'片段附接的PEG的总分子量为大约40,000Da。
在一些实施方案中,抗原结合片段可以是Fab、F(ab')2、Fv、scFv、scFv-Fc、双链抗体或微抗体片段。在一些实施方案中,抗原结合片段可以是Fab片段。在一些实施方案中,抗原结合片段可以是F(ab')2片段。在一些实施方案中,抗原结合片段可以是Fv片段。在一些实施方案中,抗原结合片段可以是scFv片段。在一些实施方案中,抗原结合片段可以是scFv-Fc片段。在一些实施方案中,抗原结合片段可以是双链抗体片段。在一些实施方案中,抗原结合片段可以是微抗体片段。
本公开还提供了包含本文所述的抗体或其抗原结合片段以及药学上可接受的载剂的药物组合物。在一些实施方案中,所述药物组合物还包含张力剂、表面活性剂、防腐剂和/或pH为约4.0至约8.0的缓冲系统。在一些实施方案中,所述药物组合物还包含一种或多种附加治疗剂,诸如本文所述的联合治疗剂。在一些实施方案中,所述药物组合物是液体药物组合物。
在一些实施方案中,所述药物组合物可以以单位剂量形式呈现,每剂含有预定量的本文所述的抗体或其抗原结合片段。用于药物组合物中的药学上可接受的载剂可以采取多种形式,这取决于待治疗的病状或施用途径。
包含本文所述的抗体或其抗原结合片段的药物组合物可通过将具有所需纯度的抗体或其抗原结合片段与本领域中通常采用的任选的药学上可接受的载剂、赋形剂或稳定剂(在本文中全部称为“载剂”),例如缓冲剂、稳定剂、防腐剂、等渗剂、非离子型洗涤剂、抗氧化剂和其它各种添加剂混合,制备成冻干制剂或水溶液以便储存。
缓冲剂有助于将pH值保持在接近生理条件的范围内。它们可以以约2mM至约50mM范围的浓度存在。用于本文所述的药物组合物中的合适的缓冲剂可包括有机酸和无机酸及其盐,诸如柠檬酸盐缓冲剂(诸如柠檬酸一钠-柠檬酸二钠混合物、柠檬酸-柠檬酸三钠混合物、柠檬酸-柠檬酸一钠混合物等)、琥珀酸盐缓冲剂(诸如琥珀酸琥珀酸一钠混合物、琥珀酸-氢氧化钠混合物、琥珀酸-琥珀酸二钠混合物等)、酒石酸盐缓冲剂(诸如酒石酸-酒石酸钠混合物、酒石酸-酒石酸钾混合物、酒石酸-氢氧化钠混合物等)、富马酸盐缓冲剂(诸如富马酸-富马酸一钠混合物、富马酸-富马酸二钠混合物、富马酸一钠-富马酸二钠混合物等)、葡萄糖酸盐缓冲剂(诸如葡萄糖酸-葡萄糖酸钠混合物、葡萄糖酸-氢氧化钠混合物、葡萄糖酸-葡萄糖酸钾混合物等)、草酸盐缓冲剂(诸如草酸-草酸钠混合物、草酸-氢氧化钠混合物、草酸-草酸钾混合物等)、乳酸缓冲剂(诸如乳酸-乳酸钠混合物、乳酸-氢氧化钠混合物、乳酸-乳酸钾混合物等)和乙酸盐缓冲剂(诸如,乙酸-乙酸钠混合物、乙酸-氢氧化钠混合物等)。另外,可以使用磷酸盐缓冲剂、组氨酸缓冲剂和三甲胺盐,诸如Tris。
可以向药物组合物中添加防腐剂以减少微生物生长,并且可以以约0.2%至约1%(w/v)范围的量添加。与本文所述的药物组合物一起使用的合适防腐剂包括但不限于苯酚、苯甲醇、间甲酚、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、氯化十八烷基二甲基苄基铵、苯扎卤铵(诸如氯化物、溴化物和碘化物)、氯化六甲双铵和对羟基苯甲酸烷基酯,诸如对羟基苯甲酸甲酯或对羟基苯甲酸丙酯、儿茶酚、间苯二酚、环己醇和3-戊醇。
可以添加有时称为“稳定剂”的等渗剂以确保液体组合物的等渗性,并且等渗剂包括多元糖醇,例如三元糖醇或高级糖醇,诸如甘油、赤藓糖醇、阿拉伯糖醇、木糖醇、山梨糖醇和甘露糖醇。稳定剂是指一大类赋形剂,其功能范围可从填充剂到溶解治疗剂或有助于防止变性或粘附于容器壁的添加剂。典型的稳定剂可以是多元糖醇(上面列举的);氨基酸,诸如精氨酸、赖氨酸、甘氨酸、谷氨酰胺、天冬酰胺、组氨酸、丙氨酸、鸟氨酸、L-亮氨酸、2-苯丙氨酸、谷氨酸、苏氨酸等;有机糖类或糖醇,诸如乳糖、海藻糖、水苏糖、甘露糖醇、山梨糖醇、木糖醇、核糖醇、肌醇、半乳糖醇、甘油等,包括环多醇诸如肌醇;聚乙二醇;氨基酸聚合物;含硫还原剂,诸如尿素、谷胱甘肽、硫辛酸、硫代乙醇酸钠、硫代甘油、α-单硫代甘油和硫代硫酸钠;低分子量多肽(诸如10个残基或更少残基的肽);蛋白质,诸如人血清白蛋白、牛血清白蛋白、明胶或免疫球蛋白;亲水聚合物,诸如聚乙烯吡咯烷酮单糖,诸如木糖、甘露糖、果糖、葡萄糖;二糖诸如乳糖、麦芽糖、蔗糖,和三糖诸如棉子糖;和多糖诸如葡聚糖。稳定剂可以以每重量份活性蛋白约0.1至约10,000重量份的范围存在。
还可以将非离子表面活性剂或洗涤剂(也称为“湿润剂”)添加到药物组合物中,帮助溶解抗体或其抗原结合片段,以及保护本文所述的抗体或其抗原结合片段免受搅拌诱发的聚集,这也容许制剂暴露于剪切表面应力而不引起蛋白质变性。合适的非离子表面活性剂包括聚山梨醇酯(20、80等)、泊洛沙姆(184、188等)、普朗尼克多元醇、聚氧乙烯脱水山梨醇单醚(TWEENTM-20、TWEENTM-80等)。非离子表面活性剂可以约0.05mg/mL至约1.0mg/mL的范围存在,例如约0.07mg/mL至约0.2mg/mL。
还可以向药物组合物中添加附加赋形剂,诸如填充剂(诸如淀粉)、螯合剂(诸如EDTA)、抗氧化剂(诸如抗坏血酸、蛋氨酸和维生素E)和助溶剂。
本公开还提供了含有本文所述的抗体或其抗原结合片段(包括抗体缀合物)的药物试剂盒。药物试剂盒可以是包含本文所述的抗体或其抗原结合片段(诸如,呈冻干形式或水溶液形式)和以下的一种或多种物质的包装:联合治疗剂、用于施用所述抗体或其抗原结合片段的装置,诸如笔、针和/或注射器;和用于重新悬浮抗体或其抗原结合片段(如果抗体是冻干形式)的药物级水或缓冲液。
在一些实施方案中,抗体或其抗原结合片段的每个单位剂量单独包装,并且试剂盒可以含有一个或多个单位剂量(诸如,两个单位剂量、三个单位剂量、四个单位剂量、五个单位剂量、八个单位剂量、十个单位剂量或更多个单位剂量)。在一些实施方案中,所述一个或多个单位剂量各自装在注射器或笔中。
本文还涵盖含有本文所述的抗体或其抗原结合片段(包括抗体缀合物)的诊断试剂盒。诊断试剂盒可以是包含本文所述的抗体或其抗原结合片段(诸如,呈冻干形式或水溶液形式)和一种或多种可用于进行诊断测定的试剂的包装。在所述抗体或其抗原结合片段用酶标记的情况下,所述试剂盒可以包括酶所需的底物和辅因子(诸如,提供可检测发色团或荧光团的底物前体)。另外,可以包括其它添加剂,诸如稳定剂、缓冲液(诸如,封闭缓冲液或裂解缓冲液)等。在一些实施方案中,诊断试剂盒中包括的抗体或其抗原结合片段可以固定在固体表面上,或者在诊断试剂盒中可以包括其上可以固定抗体或其抗原结合片段的固体表面(诸如载玻片或板)。可以改变各种试剂的相对量以提供溶液中大幅优化测定灵敏度的试剂浓度。在一些实施方案中,所述抗体或其抗原结合片段以及一种或多种试剂可以呈干粉形式(单独或组合)提供,通常是冻干的,包括在溶解时将提供具有适当浓度的试剂溶液的赋形剂。
本公开还提供了检测表达BAI1的细胞的方法,所述方法包括使所述细胞与本文所述的抗体或其抗原结合片段接触,并检测所述抗体或其抗原结合片段。在一些实施方案中,细胞存在于从人获得的生物样品中,并且细胞在体外与抗体或其抗原结合片段接触。在一些实施方案中,细胞存在于人中,并且细胞在体内与抗体或其抗原结合片段接触。
在一些实施方案中,本文所述的抗体或其抗原结合片段对BAI1具有高结合亲和力。在一些实施方案中,所述抗体或其抗原结合片段具有特定的缔合速率常数(kon或kA值)、解离速率常数(koff或kD值)、亲和常数(KA值)、解离常数(KD值)和/或IC50值。
在一些实施方案中,所述抗体或其抗原结合片段与BAI1结合,其KA(kon/koff)为至少约1010M-1、至少约4×1011M-1、至少约1011M-1、至少约4×1012M-1、至少约1012M-1、至少约4×1013M-1、至少约1013M-1、至少约4×1014M-1、至少约1014M-1、至少约4×1015M-1或至少约1015M-1,或其KA具有从任一对前述值到任一对前述值的任何范围(诸如,约4×1011M-1至约4×1013M-1或约4×1012M-1至约4×1015M-1)。
在一些实施方案中,所述抗体或其抗原结合片段与BAI1结合,其KD(koff/kon)为约10-10或更低、约4×10-11M或更低、约10-11M或更低、约4×10-12M或更低、约10-12M或更低、约4×1013M或更低、约10-13M或更低、约4×1014M或更低、约10-14M或更低、约4×10-15M或更低或约10-15M或更低,或其KD具有从任一对前述值到任一对前述值的任何范围(诸如,约4×10- 11M至约4×10-13M或约4×10-12M至约4×10-15M)。
在一些实施方案中,KD(koff/kon)值通过本领域众所周知的测定法来确定,诸如ELISA、等温滴定量热法(ITC)、荧光偏振测定法或任何其它生物传感器,诸如BIAcore。
在一些实施方案中,所述抗体或其抗原结合片段与BAI1结合并抑制BAI1与其配体的结合,其IC50小于约0.02nM、小于约0.01nM、小于约0.005nM、小于约0.002nM、小于约0.001nM、小于约5×10-4nM、小于约2×10-4nM、小于约
1×10-4nM、小于约5×10-5nM、小于约2×10-5nM、小于约1×10-4nM、小于约5×10- 6nM、小于约2×10-6nM、小于约1×10-6nM、小于约5×10-7nM、小于约2×10-7nM或小于约1×10-7nM,或其IC50从任一对前述值到任一对前述值的任何范围(诸如,约0.02nM至约2×10- 5nM或约5×10-5nM至约1×10-7nM)。IC50可以根据本领域众所周知的方法诸如ELISA来测量。
所述抗体或其抗原结合片段,包括那些已经修饰,诸如通过生物素化、辣根过氧化物酶或任何其它可检测部分(包括上述那些)修饰的抗体,可以用于诊断目的。
在一些实施方案中,所述抗体或其抗原结合片段可用于纯化或检测BAI1,包括体外和体内诊断方法。例如,所述抗体或其抗原结合片段可用于免疫测定,以定性和定量测量生物样品中的BAI1水平,或鉴定动物中BAI1的位置、数量、行为和/或类似性质。例如,使用本文所述的抗体或其抗原结合片段测量BAI1的水平可用于,例如:1)诊断或确定患者发展癌症的风险增加,2)确定患者的预后,包括肿瘤的分期和等级(特别是癌症是转移性的还是可能是转移性的)和/或其对BAI1疗法的潜在敏感性,3)确定肿瘤的起源,和/或4)确定患者治疗的功效。
在一些实施方案中,所述抗体或其抗原结合片段可以,例如,与化合物筛选测定结合,用于评价药剂对BAI1基因产物的表达和/或活性的影响。另外,所述抗体或其抗原结合片段可与基因治疗技术结合使用,以例如评价正常和/或工程化BAI1表达的转染是否成功。
本公开还提供了诊断神经系统疾病的方法,其包括检测在神经组织或与非CNS靶器官相关的任何组织,诸如肺、肝、肾、脾等中表达的BAI1的量或活性。诊断方法可以采用与诊断剂缀合的抗体或其抗原结合片段。所述抗体或其抗原结合片段可用于诊断,例如,检测特定细胞、组织或血清中BAI1的表达;或监测免疫反应的发展或进程,作为临床测试程序的一部分,以例如确定特定治疗方案的功效。通过将抗体或其抗原结合片段偶联到可检测物质上,可以促进检测。可检测物质的实例包括但不限于各种酶、辅基、荧光材料(诸如荧光素和罗丹明及其衍生物)、发光材料、生物发光材料、光学试剂(诸如卟啉、蒽醌、蒽吡唑、苝醌、呫吨、花青、吖啶、吩噁嗪和吩噻嗪的衍生物)、放射性材料、使用各种正电子发射断层摄影术的正电子发射金属以及非放射性顺磁性金属离子(诸如Gd(III)、Eu(III)、Dy(III)、Pr(III)、Pa(IV)、Mn(II)、Cr(III)、Co(III)、Fe(III)、Cu(II)、Ni(II)、Ti(III)和V(IV))。可检测物质可以与抗体或其抗原结合片段直接偶联或缀合,或者使用本领域已知的技术通过中间体(例如本领域已知的接头)间接偶联或缀合。酶标记的实例包括荧光素酶(诸如萤火虫荧光素酶和细菌荧光素酶;参见,美国专利号4,737,456)、萤光素、2,3-二氢酞嗪二酮、苹果酸脱氢酶、脲酶、过氧化物酶(诸如辣根过氧化物酶(HRPO))、碱性磷酸酶、β-半乳糖苷酶、乙酰胆碱酯酶、葡糖淀粉酶、溶菌酶、糖氧化酶(诸如葡萄糖氧化酶、半乳糖氧化酶和葡萄糖-6-磷酸脱氢酶)、杂环氧化酶(诸如尿酸酶和黄嘌呤氧化酶)、乳过氧化物酶、微过氧化物酶等。合适的辅基复合物的实例包括但不限于链霉亲和素/生物素和亲和素/生物素;合适的荧光材料的实例包括但不限于伞形酮、荧光素、异硫氰酸荧光素、罗丹明、二氯三嗪胺荧光素、丹磺酰氯或藻红蛋白;发光材料的实例包括鲁米诺(luminol);生物发光材料的实例包括但不限于荧光素酶、萤光素和水母发光蛋白;并且合适的放射性材料的实例包括但不限于125I、131I、111In或99Tc。
本公开还提供了用于检测细胞上BAI1的表达的方法,其包括使用本文所述的一种或多种抗体或其抗原结合片段(任选地与可检测部分缀合)接触来自患者的生物样品,并检测该样品是否为BAI1表达阳性,或者该样品与对照样品相比是否具有改变的(例如,减少的或增加的)表达。生物样品可以包括各种组织的活检,包括但不限于:皮肤、肌肉、乳房、前列腺、子宫颈、卵巢、脑、睾丸和肺部。生物样品的细胞实例包括肿瘤细胞、皮肤细胞、肌肉细胞、血细胞、卵巢细胞、脑细胞、前列腺细胞、乳腺细胞、睾丸细胞、子宫颈细胞和肺细胞。生物样品也可以是生物流体。
生物样品中表达BAI1的细胞的存在指示癌症的存在并且可以指示转移,特别是当其存在的数量大于正常健康受试者的数量时。随着时间的推移,患者(特别是正在接受治疗的患者)中表达BAI1的细胞的损失指示病情缓解(即,治疗成功),而正在接受治疗的患者中表达BAI1的细胞水平没有变化指示对该疗法有抗性,并指示可以采用不同的治疗策略。类似地,随着时间的推移,患者中表达BAI1的细胞增加可以指示复发。另外,本文所述的成像技术可用于监测肿瘤的大小,以确定治疗的功效。在一些实施方案中,可以进行其它癌症诊断测定以确认用本文所述的方法获得的结果。
在一些实施方案中,可以从受试者中获得生物样品(诸如,肿瘤样品)并确定表达BAI1的细胞的存在。表达BAI1的细胞的数目可以与肿瘤分级相关。在一些实施方案中,将生物样品中表达BAI1的细胞的数目与来自健康个体的相应生物样品中表达BAI1的细胞的数目进行比较,以确定肿瘤中表达BAI1的细胞的调节。可以用药剂治疗含肿瘤的受试者,以将表达BAI1的细胞的活性调节至正常、健康的水平。
可以用本发明方法诊断的疾病包括但不限于神经系统癌症,诸如原发性脑肿瘤,包括神经胶质瘤(胶质母细胞瘤)、脑膜瘤、神经鞘瘤、垂体腺瘤、髓母细胞瘤、颅咽管瘤、血管瘤、表皮样瘤、肉瘤和来自其它肿瘤来源的颅内转移瘤。在一些实施方案中,本文所述的抗体或其抗原结合片段可用于诊断多形性胶质母细胞瘤(GBM)。
本公开还提供了治疗表达BAI1的癌症的方法,所述方法包括向有此需要的人患者施用本文所述的抗体或其抗原结合片段。在一些实施方案中,所述方法涉及向患有实体瘤的人患者施用一定量的本文所述的抗体或其抗原结合片段,以提供治疗益处。
在一些实施方案中,本文所述的抗体或其抗原结合片段可以通过多种途径施用给患者,诸如口服、经皮、皮下、鼻内、静脉内、动脉内、肌内、眼内、外用、局部、鞘内、脑室内、脊髓内和颅内。在任何给定的情况下,最合适的施用途径将取决于特定的抗体、受试者、疾病的性质和严重程度以及受试者的身体状况。在一些实施方案中,所述抗体或其抗原结合片段可以配制成水溶液。在一些实施方案中,所述抗体或其抗原结合片段经静脉内或颅内施用。
本文所述的抗体或其抗原结合片段可用于治疗各种表达BAI1的赘生物。在一些实施方案中,本文所述的抗体或其抗原结合片段可用于治疗表达BAI1的癌症,诸如具有骨骼肌特性的肉瘤和皮肤肿瘤。在一些实施方案中,本文所述的抗体或其抗原结合片段可用于治疗患者中表达BAI1的神经系统癌症,诸如脑肿瘤或小的脑病变,诸如微小转移。在一些实施方案中,表达BAI1的癌症是神经系统癌症。在一些实施方案中,神经系统癌症是原发性脑肿瘤、胶质母细胞瘤、神经胶质瘤、脑膜瘤、神经鞘瘤、垂体腺瘤、髓母细胞瘤、颅咽管瘤、血管瘤、表皮样瘤、肉瘤或来自其它肿瘤来源的颅内转移瘤。在一些实施方案中,神经系统癌症是胶质母细胞瘤。在一些实施方案中,胶质母细胞瘤是多形性胶质母细胞瘤(GBM)。
在一些实施方案中,表达BAI1的脑肿瘤是含有GBM肿瘤起始细胞的GBM肿瘤。在一些实施方案中,用本文所述的抗体或其抗原结合片段治疗引起对GBM肿瘤起始细胞增殖的抑制。在一些实施方案中,所述抗体或其抗原结合片段还抑制GBM肿瘤起始细胞的自我更新。抑制细胞增殖和/或自我更新可以导致疾病的体征或症状的改善。例如,此类疗法可以引起存活期(总存活期和/或无进展存活期)的提高和/或可以引起客观的临床反应(部分或完全)。在一些实施方案中,所述抗体或其抗原结合片段被GBM肿瘤细胞内化,引起抗体或其抗原结合片段在杀伤与其结合的GBM肿瘤细胞中的治疗功效增加。在一些实施方案中,所述抗体或其抗原结合片段充当BAI1生物活性的拮抗剂,并且可另外用作抑制异常BAI1活性的方法。
在一些实施方案中,所述抗体或其抗原结合片段可用于治疗非神经系统的表达BAI1的肿瘤,包括癌症和良性肿瘤。易于通过本文所述的抗体或其抗原结合片段治疗的癌症包括过表达BAI1的癌症。在一些实施方案中,易于通过本文所述的抗体或其抗原结合片段治疗的癌症包括上皮细胞癌。在一些实施方案中,易于通过本文所述的抗体或其抗原结合片段治疗的癌症包括但不限于乳腺癌、卵巢癌、肺癌、结直肠癌、肛门癌、前列腺癌、肾癌、膀胱癌、头颈癌、卵巢癌、胰腺癌、皮肤癌、口腔癌、食道癌、阴道癌、宫颈癌、脾癌、睾丸癌、胸腺癌、头颈癌和结直肠癌。癌症可以是新诊断的未治疗的,或者可以是复发的、难治性的、或复发且难治性的,或者是实体瘤的转移形式。
在一些实施方案中,本文所述的抗体或其抗原结合片段可用于治疗表达BAI1的血液恶性肿瘤,包括但不限于骨髓瘤(诸如多发性骨髓瘤)、淋巴瘤(诸如霍奇金淋巴瘤(Hodgkin’s lymphoma)、非霍奇金淋巴瘤、瓦尔登斯特伦巨球蛋白血症(macroglobulinemia)和套细胞淋巴瘤)、白血病(诸如慢性淋巴细胞性白血病、急性髓细胞性白血病和急性淋巴细胞性白血病)和骨髓增生异常综合征。在一些实施方案中,所述方法包括向患有血液恶性肿瘤的人患者施用本文所述的抗体或其抗原结合片段,以提供治疗益处。
在一些实施方案中,本文所述的抗体或其抗原结合片段的施用在一天、两天、三天、五天、一周、两周、三周、一个月、五周、六周、七周、八周、两个月或三个月后重复。重复施用可以是以相同剂量或以不同剂量。施用可以重复一次、两次、三次、四次、五次、六次、七次、八次、九次、十次或更多次。例如,根据某些剂量方案,患者可以接受长时间的抗BAI1疗法,诸如6个月、1年或更长时间。施用给患者的本文所述的抗体或其抗原结合片段的量是治疗有效量。如本文所用,本文所述的抗体或其抗原结合片段的“治疗有效”量可以作为单剂量施用或在治疗方案过程中,诸如在一周、两周、三周、一个月、三个月、六个月、一年或更长时间的过程中施用。本文进一步描述了示例性的治疗方案。疾病的治疗涵盖对已经诊断为患有任何临床分期或表现的任何形式的疾病的患者的治疗;疾病症状或体征的发作或演变或加重或恶化的延迟;和/或预防和/或减轻疾病的严重程度。
使用本文所述的抗体或其抗原结合片段来治疗患者的癌症,与不进行治疗(适当时)或与已知的护理标准相比,可产生任何经证明的临床益处。临床益处可以通过本领域普通技术人员已知的任何方法来评估。在一些实施方案中,基于客观反应率(ORR)(使用RECIST 1.1版确定)、反应持续时间(DOR)、无进展存活期(PFS)和/或总存活期(OS)来评估临床益处。在一些实施方案中,完全反应指示治疗益处。在一些实施方案中,部分反应指示治疗益处。在一些实施方案中,稳定的疾病指示治疗益处。在一些实施方案中,总存活期增加指示治疗益处。在一些实施方案中,治疗益处可以包括疾病进展时间的改善和/或症状或生活质量的改善。在一些实施方案中,治疗益处可能不会转化为疾病控制期的增加,而是显著减轻症状负担,从而引起生活质量提高。正如对本领域技术人员来说将显而易见的,单独使用本文所述的抗体或其抗原结合片段(单一疗法)或与其它抗癌疗法和/或靶向或非靶向抗癌剂辅助或一起使用,可以观察到治疗益处。
在一些实施方案中,可以使用设计用于测量对癌症新治疗的反应的标准临床试验来评估治疗益处。为了评估本文所述的抗体或其抗原结合片段的治疗益处,可以使用以下试验中的一种或组合:1)实体瘤反应评价标准(RECIST)1.1版;2)免疫相关RECIST(irRECIST);3)东部肿瘤协作组(ECOG)活动状态;4)免疫相关反应标准(irRC);5)通过评估肿瘤抗原可评价的疾病;6)经过验证的患者报告的结果量表;和/或7)总存活期和无进展存活期的Kaplan-Meier估计。
本公开还提供了联合治疗方法,其包括向患者施用至少两种试剂,第一种试剂是本文所述的抗体或其抗原结合片段,第二种试剂是联合治疗剂。本文所述的抗体或其抗原结合片段和联合治疗剂可以同时、依次或单独施用。联合治疗方法可以产生大于累加的效应。
在本发明方法中,本文所述的抗体或其抗原结合片段和联合治疗剂可以并发、同时或相继施用。本文所述的抗体或其抗原结合片段和联合治疗剂如果在同一天(例如,在患者同一就诊期间)向患者施用,则它们是相继施用的。相继施用可以间隔1、2、3、4、5、6、7或8小时进行。相对来说,本文所述的抗体或其抗原结合片段和联合治疗剂如果在不同的日子向患者施用,则它们是单独施用的,例如,所述抗体或其抗原结合片段和联合治疗剂可以1天、2天或3天、1周、2周或每月的间隔施用。在本公开的方法中,本文所述的抗体或其抗原结合片段的施用可以在联合治疗剂施用之前或之后。在一些实施方案中,本文所述的抗体或其抗原结合片段和联合治疗剂可以并发施用一段时间,接着在第二段时间内交替施用所述抗体或其抗原结合片段和联合治疗剂。
在一些实施方案中,联合治疗剂是化学治疗剂、抗血管生成剂、抗风湿性药物、抗炎剂、放射治疗剂、免疫抑制剂或细胞毒性药物。本文所述的抗体或其抗原结合片段可与常规癌症疗法诸如手术、放疗、化疗或其组合联合使用。在一些实施方案中,所述方法还包括手术切除肿瘤细胞和/或施用放射疗法中的一种或两种。在一些实施方案中,可用于与本文所述的抗体或其抗原结合片段进行联合肿瘤疗法的其它治疗剂包括参与肿瘤生长的其它因子(诸如HER2、HER3、HER4、VEGF或TNF-α)的拮抗剂,诸如抗体。在一些实施方案中,对于癌症的治疗,还向患者施用一种或多种细胞因子可能是有益的。在一些实施方案中,本文所述的抗体或其抗原结合片段与生长抑制剂共同施用。
对于癌症的治疗,抗炎剂可以适当地与本文所述的抗体或其抗原结合片段联合使用。抗炎剂包括但不限于对乙酰氨基酚、苯海拉明、哌替啶(meperidine)、地塞米松、颇得斯安(pentasa)、美沙拉秦(mesalazine)、美沙拉嗪(asacol)、磷酸可待因、贝诺酯(benorylate)、芬布芬(fenbufen)、萘普生(naprosyn)、双氯芬酸(diclofenac)、依托度酸(etodolac)和吲哚美辛(indomethacin)、阿司匹林(aspirin)和布洛芬(ibuprofen)。
对于癌症的治疗,化学治疗剂可以与本文所述的抗体或其抗原结合片段联合使用。化学治疗剂包括但不限于放射性分子、毒素(诸如细胞毒素或细胞毒性剂),包括任何对细胞活力有害的剂、含有化疗化合物的剂和脂质体或其它囊泡。合适的化学治疗剂的实例包括但不限于,1-脱氢睾酮、
5-氟尿嘧啶氨烯咪胺、6-巯基嘌呤、6-硫鸟嘌呤、放线菌素D、阿霉素、阿地白介素、抗α5β1整联蛋白抗体、烷化剂、别嘌呤醇钠、六甲蜜胺、氨磷汀、阿那曲唑、氨茴霉素(AMC))、抗有丝分裂剂、顺二氯二胺铂(II)(DDP)顺铂、二氨基二氯铂、蒽环类抗生素、抗生素、抗代谢物、天冬酰胺酶、活卡介苗(BCG)(膀胱内)、倍他米松磷酸钠和醋酸倍他米松、比卡鲁胺、硫酸博来霉素、白消安、甲酰四氢叶酸钙(calcium leucouorin)、卡利奇霉素、卡培他滨、卡铂、洛莫司汀(CCNU)、卡莫司汀(BSNU)、苯丁酸氮芥、顺铂、克拉屈滨、秋水仙碱、缀合雌激素、环磷酰胺、环硫酰胺、阿糖胞苷、阿糖胞苷、细胞松弛素B、癌得星(cytoxan)、达卡巴嗪、放线菌素D、放线菌素D(先前称放线菌素)、柔红霉素、柠檬酸道诺霉素、地尼白介素(denileukin diftitox)、右雷佐生(dexrazoxane)、二溴甘露醇、二羟基蒽二酮(dihydroxyanthracin dione)、多西他赛、甲磺酸多拉司琼(dolasetron mesylate)、阿霉素、屈大麻酚(dronabinol)、大肠杆菌L-天冬酰胺酶、依洛西单抗(eolociximab)、吐根碱(emetine)、依泊汀-α(epoetin-α)、欧文氏菌L-天冬酰胺酶(Erwinia Lasparaginase)、酯化雌激素、雌二醇、雌莫司汀磷酸钠、溴乙锭、乙炔雌二醇、依替膦酸盐(etidronate)、依托泊苷嗜橙菌因子(etoposide citrororum factor)、磷酸依托泊苷、非格司亭(filgrastim)、氟尿苷(floxuridine)、氟康唑(fluconazole)、磷酸氟达拉滨、氟尿嘧啶、氟他胺(flutamide)、亚叶酸、吉西他滨、糖皮质激素、醋酸戈舍瑞林、短杆菌肽D、格拉司琼(granisetron)、羟基脲(hydroxyurea)、伊达比星(idarubicin)、异环磷酰胺、干扰素α-2b、伊立替康、来曲唑、甲酰四氢叶酸钙、醋酸亮丙瑞林(leuprolide acetate)、左旋咪唑(levamisole)、利多卡因(lidocaine)、洛莫司汀(lomustine)、美登木素生物碱、二氯甲基二乙胺、醋酸甲羟孕酮、醋酸甲地孕酮、美法仑、巯基嘌呤、美司那(mesna)、甲氨蝶呤、甲基睾酮、光神霉素、丝裂霉素C、米托坦、米托蒽醌、尼鲁米特、醋酸奥曲肽、昂丹司琼(ondansetron)、紫杉醇、帕米膦酸二钠、喷司他丁(pentostatin)、匹鲁卡品(pilocarpine)、皮利霉素(plimycin)、具有卡莫司汀植入物的聚苯丙生20、卟吩姆钠、普鲁卡因、丙卡巴肼、普萘洛尔(propranolol)、利妥昔单抗(rituximab)、沙格司亭(sargramostim)、链脲佐菌素、他莫昔芬(tamoxifen)、紫杉酚、替尼泊苷(teniposide)、替尼泊苷、睾内酯(testolactone)、丁卡因(tetracaine)、噻替派苯丁酸氮芥、硫鸟嘌呤、噻替派、拓扑替康、柠檬酸托瑞米芬、曲妥珠单抗(trastuzumab)、维甲酸(tretinoin)、戊柔比星(valrubicin)、硫酸长春花碱、硫酸长春新碱和酒石酸长春瑞滨或它们的任何盐。在一些实施方案中,所述方法包括向患者施用至少一种化学治疗剂。
任何抗血管生成剂都可以连同本文所述的抗体或其抗原结合片段一起使用。在一些实施方案中,抗血管生成剂是VEGF拮抗剂或另一种VEGF受体拮抗剂,诸如VEGF变体、可溶性VEGF受体片段、能够阻断VEGF或VEGFR的适体、中和性抗VEGFR抗体、VEGFR酪氨酸激酶的低分子量抑制剂及它们的任何组合。可替代地,或另外,抗VEGF抗体可以共同向患者施用。
向给患施用的治疗方案可以根据患者的年龄、体重和疾病状况而变化。治疗方案可以持续2周到无限期。在一些实施方案中,治疗方案持续约2周至约6个月、约3个月至约5年、约6个月至约1年或约2年、约8个月至约18个月等。治疗方案可以是非可变剂量方案或多可变剂量方案。
本文所述的抗体或其抗原结合片段的施用量可取决于多种因素,包括但不限于所治疗的实体瘤的具体类型、所治疗的实体瘤的分期、施用方式、施用频率、所需的治疗益处以及其它参数,诸如患者的年龄、体重和其它特征。对于特定的施用方式和频率,有效提供治疗益处的剂量的确定在本领域技术人员的能力范围内。提供治疗益处的有效剂量可以从动物体内模型或临床试验中初步估计。适用于多种疾病的动物模型是本领域已知的。本文所述的抗体或其抗原结合片段可以通过适于待治疗的病症的任何途径施用。
在一些实施方案中,本文所述的抗体或其抗原结合片段作为冻干粉在小瓶中提供。小瓶可以含有约100mg、约125mg、约150mg、约200mg、约250mg、约300mg或约400mg的抗体或其抗原结合片段。在施用前,冻干粉可以用无菌注射用水(SWFI)或其它合适的介质复原,以提供含有本文所述抗体或其抗原结合片段的溶液。在一些实施方案中,将所得复原溶液进一步用盐水或其它适合输注的介质稀释,并经由例如IV输注来施用,每7天两次、每7天一次、每14天一次、每21天一次、每28天一次、每35天一次、每42天一次、每49天一次或每56天一次。在一些实施方案中,对于第一周期,输注发生在90分钟内。在一些实施方案中,后续输注在60分钟内。
在一些实施方案中,本文所述的抗体或其抗原结合片段以约0.1mg/kg、约0.5mg/kg、约1.0mg/kg、约2.0mg/kg、约3.0mg/kg、约4.0mg/kg、约5.0mg/kg、约6.0mg/kg、约8.0mg/kg或约10.0mg/kg作为IV输注每7天施用一次。在一些实施方案中,本文所述的抗体或其抗原结合片段以约0.1mg/kg、约0.5mg/kg、约1.0mg/kg、约2.0mg/kg、约3.0mg/kg、约4.0mg/kg、约5.0mg/kg、约6.0mg/kg、约8.0mg/kg或约10.0mg/kg作为IV输注每14天施用一次。在一些实施方案中,本文所述的抗体或其抗原结合片段以约0.1mg/kg、约0.5mg/kg、约1.0mg/kg、约2.0mg/kg、约3.0mg/kg、约4.0mg/kg、约5.0mg/kg、约6.0mg/kg、约8.0mg/kg或约10.0mg/kg作为IV输注每21天施用一次。在一些实施方案中,本文所述的抗体或其抗原结合片段以约0.1mg/kg、约0.5mg/kg、约1.0mg/kg、约2.0mg/kg、约3.0mg/kg、约4.0mg/kg、约5.0mg/kg、约6.0mg/kg、约8.0mg/kg或约10.0mg/kg作为IV输注每28天施用一次。
当与其它试剂(诸如其它化学治疗剂)辅助或一起使用时,本文所述的抗体或其抗原结合片段可以以与其它剂相同的日程表或以不同的日程表施用。当以相同的日程表施用时,本文所述的抗体或其抗原结合片段可以在另一种剂之前、之后或并发施用。在一些实施方案中,在本文所述的抗体或其抗原结合片段与标准护理辅助或一起使用的情况下,所述抗体或其抗原结合片段可在标准护理治疗开始之前启动,例如在标准护理治疗开始之前一天、几天、一周、几周、一个月或甚至几个月启动。在一些实施方案中,在本文所述的抗体或其抗原结合片段与标准护理辅助或一起使用的情况下,本文所述的抗体或其抗原结合片段可在标准治疗开始之后启动,例如在标准护理治疗开始之后一天、几天、一周、几周、一个月或甚至几个月启动。
皮下施用的给药方案可以从每六个月一次到每天一次变化,这取决于许多临床因素,包括疾病的类型、疾病的严重程度以及患者对本文所述的抗体或其抗原结合片段的敏感性。
本公开还提供了治疗后囊膜浑浊(PCO)的方法,所述方法包括向有此需要的人患者施用本文所述的抗体或其抗原结合片段。在一些实施方案中,将所述抗体或其抗原结合片段施用于眼部。
本公开还提供了治疗纤维化的方法,所述方法包括向有此需要的人患者施用本文所述的抗体或其抗原结合片段。在一些实施方案中,将所述抗体或其抗原结合片段施用于器官。在一些实施方案中,所述器官是肾或肺。
在一些实施方案中,本文所述的抗体或其抗原结合片段可用于通过分选与之结合的细胞来分离和/或纯化细胞(例如肌成纤维细胞祖细胞)的方法中。此类细胞可以快速迁移到皮肤、晶状体、视网膜和脑部中的伤口,从而有助于伤口愈合。此类细胞具有发展成收缩性肌成纤维细胞的潜力。人脂肪组织是此类细胞(即,BAI1+细胞)的一个来源(未公开的结果)。可以将分离的BAI1+细胞施用于人体或植入缓慢愈合或未愈合的伤口,诸如糖尿病和褥疮性溃疡以及严重的手术切口,以促进伤口愈合。
在一些实施方案中,本文所述的抗体或其抗原结合片段可用于通过分选与之结合的细胞来分离神经保护细胞的方法中。响应于视网膜和脑部的损伤,表达BAI1的细胞数目增加。可将此类细胞施用于视网膜和脑部,以减少神经元的死亡。损伤后,可将BAI1+细胞和/或它们产生的分子注射到眼部的玻璃体或脑部的脉管系统中。
提供了以下代表性实施方案:
实施方案1.一种与人粘附G蛋白偶联受体B1(BAI1)蛋白结合的抗体或其抗原结合片段,其中所述抗体或其抗原结合片段包含:可变重(VH)链中的第一互补决定区(CDR)(VH-CDR1),其包含根据SEQ ID NO:7的氨基酸序列;所述VH链中的第二CDR(VH-CDR2),其包含根据SEQ ID NO:8的氨基酸序列;所述VH链中的第三CDR(VH-CDR3),其包含根据SEQ ID NO:9的氨基酸序列;可变轻(VL)链中的第一CDR(VL-CDR1),其包含根据SEQ ID NO:10的氨基酸序列;所述VL链中的第二CDR(VL-CDR2),其包含根据SEQ ID NO:11的氨基酸序列;和所述VL链中的第三CDR(VL-CDR3),其包含根据SEQ ID NO:12的氨基酸序列。
实施方案2.根据实施方案1所述的抗体或其抗原结合片段,其中所述抗体或其抗原结合片段包含VH链,所述VH链包含根据SEQ ID NO:1的氨基酸序列。
实施方案3.根据实施方案1所述的抗体或其抗原结合片段,其中所述抗体或其抗原结合片段包含VL链,所述VL链包含根据SEQ ID NO:4的氨基酸序列。
实施方案4.根据实施方案1所述的抗体或其抗原结合片段,其中所述抗体或其抗原结合片段包含含有根据SEQ ID NO:1的氨基酸序列的VH链和含有根据SEQ ID NO:4的氨基酸序列的VL链。
实施方案5.根据实施方案1至4中任一项所述的抗体或其抗原结合片段,其中所述抗体是IgM或IgG抗体。
实施方案6.根据实施方案1至4中任一项所述的抗体或其抗原结合片段,其中所述抗体是IgM抗体。
实施方案7.根据实施方案1至4中任一项所述的抗体或其抗原结合片段,其中所述抗体是IgG抗体。
实施方案8.根据实施方案7所述的抗体或其抗原结合片段,其中所述抗体是IgG1抗体。
实施方案9.根据实施方案7所述的抗体或其抗原结合片段,其中所述抗体是IgG1G1m17同种异型抗体。
实施方案10.根据实施方案1至9中任一项所述的抗体或其抗原结合片段,其中所述抗体或其抗原结合片段是人源化的。
实施方案11.根据实施方案10所述的人源化抗体或其抗原结合片段,其中所述人源化抗体或其抗原结合片段包含重链,所述重链包含根据SEQ ID NO:13的氨基酸序列。
实施方案12.根据实施方案10所述的人源化抗体或其抗原结合片段,其中所述人源化抗体或其抗原结合片段包含轻链,所述轻链包含根据SEQ ID NO:14的氨基酸序列。
实施方案13.根据实施方案10所述的人源化抗体或其抗原结合片段,其中所述人源化抗体或其抗原结合片段包含含有根据SEQ ID NO:13的氨基酸序列的重链和含有根据SEQ ID NO:14的氨基酸序列的轻链。
实施方案14.根据实施方案1至13中任一项所述的抗体或其抗原结合片段,其中所述抗体或其抗原结合片段与效应部分缀合。
实施方案15.根据实施方案14所述的抗体或其抗原结合片段,其中所述效应部分是可检测标记、细胞毒性剂、化学治疗剂或核酸分子。
实施方案16.根据实施方案15所述的抗体或其抗原结合片段,其中所述可检测标记是放射性化合物、荧光化合物、发色团、酶、显像剂、金属离子或底物。
实施方案17.根据实施方案15所述的抗体或其抗原结合片段,其中所述细胞毒性剂是小分子、前药、美登木素生物碱或毒素。
实施方案18.根据实施方案15所述的抗体或其抗原结合片段,其中所述抗体或其抗原结合片段在每个抗体或其抗原结合片段中包含3至5个美登木素生物碱分子。
实施方案19.根据实施方案18所述的抗体或其抗原结合片段,其中所述美登木素生物碱通过选自N-琥珀酰亚胺-3-(2-吡啶基二硫代)丙酸酯、N-琥珀酰亚胺-4-(2-吡啶基硫代)戊酸酯(SPP)和琥珀酰亚胺-4-(N-马来酰亚胺甲基)环己烷-1-羧酸酯的化学接头与所述抗体或其抗原结合片段缀合。
实施方案20.根据实施方案15所述的抗体或其抗原结合片段,其中所述细胞毒性剂是紫杉酚、细胞松弛素B、短杆菌肽D、溴乙锭、吐根碱、丝裂霉素、依托泊苷、替尼泊苷、长春新碱、长春花碱、秋水仙素、阿霉素、柔红霉素、二羟基蒽二酮、米托蒽醌、光霉素、放线菌素D、1-脱氢睾酮、糖皮质激素、普鲁卡因、丁卡因、利多卡因、普萘洛尔或嘌呤霉素。
实施方案21.根据实施方案15所述的抗体或其抗原结合片段,其中所述化学治疗剂是顺铂、卡铂、奥沙利铂、奈达铂、四硝酸三铂、菲铂、吡铂、赛特铂、甲氨蝶呤、长春新碱、阿霉素、衣霉素、寡霉素、硼替佐米、MG132、5-氟尿嘧啶、索拉非尼、夫拉平度、吉西他滨、紫杉醇、巯基嘌呤、硫鸟嘌呤、羟基脲、阿糖胞苷、丝裂霉素、环磷酰胺、异环磷酰胺、亚硝基脲、达卡巴嗪、普鲁卡因、依托泊苷、喜树碱、博来霉素、伊达比星、柔红霉素、放线菌素D、偏端霉素A、依替丁、纺锤菌素、澳瑞他汀、安吖啶、灵菌红素、硼替佐米、匹苯济醇、托马霉素、倍癌霉素SA、普卡霉素、米托蒽醌、天冬酰胺酶、长春花碱、长春瑞滨、紫杉醇、多西他赛、CPT-11、格列卫、埃罗替尼、吉非替尼、依鲁替尼、克唑替尼、塞瑞替尼、拉帕替尼、纳维托克或瑞格菲尼。
实施方案22.根据实施方案15所述的抗体或其抗原结合片段,其中所述核酸分子是单层核酸载剂、1.5层核酸载剂、双层核酸载剂、2.5层核酸载剂或三层核酸载剂。
实施方案23.根据实施方案1至22中任一项所述的抗体或其抗原结合片段,其中所述抗原结合片段是Fab、F(ab')2、Fv、scFv、scFv-Fc、双链抗体或微抗体片段。
实施方案24.一种药物组合物,其包含根据实施方案1至23中任一权利要求所述的抗体或其抗原结合片段以及药学上可接受的载剂。
实施方案25.根据实施方案24所述的药物组合物,其中所述药物组合物是液体药物组合物。
实施方案26.根据实施方案24或实施方案25所述的药物组合物,其还包含张力剂、表面活性剂、防腐剂和/或pH为约4.0至约8.0的缓冲系统。
实施方案27.一种分离的核酸分子,其编码根据实施方案1至9中任一项所述的抗体或其抗原结合片段的VH链,其中所述核酸分子包含根据SEQ ID NO:2或SEQ ID NO:3的核苷酸序列。
实施方案28.一种分离的核酸分子,其编码根据实施方案1至9中任一项所述的抗体或其抗原结合片段的VL链,其中所述核酸分子包含根据SEQ ID NO:5或SEQ ID NO:6的核苷酸序列。
实施方案29.一种载体,其包含根据实施方案27或实施方案28所述的核酸分子。
实施方案30.一种用根据实施方案29所述的载体转化的原核宿主细胞。
实施方案31.一种用根据实施方案29所述的载体转化的真核宿主细胞。
实施方案32.根据实施方案31所述的真核宿主细胞,其是哺乳动物宿主细胞。
实施方案33.一种检测表达BAI1的细胞的方法,所述方法包括使所述细胞与根据实施方案1至23中任一项所述的抗体或其抗原结合片段接触,并检测所述抗体或其抗原结合片段。
实施方案34.根据实施方案33所述的方法,其中所述细胞存在于从人获得的生物样品中,并且细胞在体外与抗体或其抗原结合片段接触。
实施方案35.根据实施方案33所述的方法,其中所述细胞存在于人中,并且细胞在体内与抗体或其抗原结合片段接触。
实施方案36.一种治疗表达BAI1的癌症的方法,所述方法包括向有此需要的人患者施用根据实施方案1至23中任一项所述的抗体或其抗原结合片段。
实施方案37.根据实施方案36所述的方法,其中所述表达BAI1的癌症是神经系统癌症。
实施方案38.根据实施方案中37所述的方法,其中所述神经系统癌症是原发性脑肿瘤、胶质母细胞瘤、神经胶质瘤、脑膜瘤、神经鞘瘤、垂体腺瘤、髓母细胞瘤、颅咽管瘤、血管瘤、表皮样瘤、肉瘤或来自其它肿瘤来源的颅内转移瘤。
实施方案39.根据实施方案38所述的方法,其中所述神经系统癌症是胶质母细胞瘤。
实施方案40.根据实施方案36至39中任一项所述的方法,其中所述抗体或其抗原结合片段经静脉内或颅内施用。
实施方案41.根据实施方案36至40中任一项所述的方法,其还包括向患者施用至少一种化学治疗剂。
实施方案42.根据实施方案36至41中任一项所述的方法,其还包括手术切除肿瘤细胞和/或施用放射疗法中的一种或两种。
实施方案43.一种治疗后囊膜浑浊(PCO)的方法,所述方法包括向有此需要的人患者施用根据实施方案1至23中任一项所述的抗体或其抗原结合片段。
实施方案44.根据实施方案43所述的方法,其中将所述抗体或其抗原结合片段施用于眼部。
实施方案45.一种治疗纤维化的方法,所述方法包括向有此需要的人患者施用根据实施方案1至23中任一项所述的抗体或其抗原结合片段。
实施方案46.根据实施方案45所述的方法,其中将所述抗体或其抗原结合片段施用于器官。
实施方案47.根据实施方案46所述的方法,其中所述器官是肾或肺。
实施方案48.一种促进伤口愈合的方法,所述方法包括向有此需要的人患者施用根据实施方案1至23中任一项所述的抗体或其抗原结合片段。
实施方案49.根据实施方案48所述的方法,其中所述伤口存在于所述皮肤、晶状体、视网膜或脑部中。
实施方案50.根据实施方案48所述的方法,其中所述伤口是糖尿病性溃疡或褥疮性溃疡。
实施方案51.一种促进伤口愈合的方法,所述方法包括向有此需要的人患者施用表达BAI1的细胞。
为了更有效地理解本文公开的主题,下面提供了实施例。应当理解,这些实施例仅用于说明目的,而不应被解释为以任何方式限制所要求保护的主题。在所有这些实施例中,除非另有说明,否则分子克隆反应和其它标准重组DNA技术都是根据Maniatis等人,Molecular Cloning-A Laboratory Manual,第2版,Cold Spring Harbor Press(1989)中描述的方法,使用市售试剂进行的。如本文所用,除非另有说明,否则免疫球蛋白氨基酸残基的编号是根据Kabat等人的免疫球蛋白氨基酸残基编号系统进行的。
实施例
实施例1:G8(BAI1)抗原的鉴定
膜蛋白质组阵列(MPA)是用于分析靶向人膜蛋白的抗体和其它配体的特异性的平台。MPA可用于确定抗体靶特异性、去卷积孤儿抗体靶,以及表征生物相似候选物的靶谱。流式细胞术用于直接检测与真核细胞(诸如人HEK-293细胞)中表达的膜蛋白结合的抗体。因此,将所有MPA靶标都设计成具有天然构象和适当的翻译后修饰。该工艺的工作流程如图1所示。测试G8抗体对超过4,500种人膜蛋白的MPA文库(包括GPCR、离子通道和转运蛋白)的反应性。在二次筛选中验证已鉴定的靶标,以确认反应性。
为了确定最佳抗体浓度并且使背景反应性最小化,使用表达单独蛋白A和蛋白G构建体或载体的HEK-293T(人)细胞检查不同浓度的G8批次3/21/13和G8批次PS30170160。这些实验以384孔格式,使用二抗的单一稀释液进行(图2A和图2B;表1)。来自测定设置实验的数据用于确定高通量免疫检测的最佳筛选条件(表2)。简言之,为了优化抗体检测的条件,以384孔格式用单独的蛋白A和G表达构建体(MAb结合的阳性对照)或载体(阴性对照)转染细胞,接着使用高通量免疫荧光流式细胞术测定法检测细胞表达。检查每种试验和对照MAb的连续稀释液(从4μg/ml开始)针对表达单独蛋白A和G或载体的细胞的免疫反应性。发现IgM不与阳性对照构建体发生强烈反应。因而,这些实验用于确定显示低背景反应性的条件。低背景反应性指示在高浓度下检测是可能的,不会掩盖潜在命中。
表1:筛选条件
表2:高通量免疫检测的实验参数
抗体结合靶标的确定
为了鉴定抗体结合靶标,在384孔板中排列的各个孔的HEK-293T细胞中各自表达5,300种不同的膜蛋白。然后,通过汇集每张384孔板的各列和各行,将细胞矩阵化。用浓度为30μg/ml的G8批次3/21/13和G8批次PS30170160探测所得MPA矩阵,接着使用荧光标记的二抗进行检测。使用阳性(表达已知靶标的构建体)和阴性(空载体)对照验证每张实验板的荧光读数。每个单独的膜蛋白靶标被赋予与其独特的行和列集合的结合值相对应的值。将所得结合值(包括行和列组成部分)归一化并转换,以给出抗体与每种靶蛋白结合的单一数值(归一化靶标结合)。然后通过检测抗体与出自同张板的重叠的列和行集合的结合来鉴定靶标,从而允许特异性去卷积(图3A和图3B;表3)。使用荧光二抗通过流式细胞术检测抗体结合。
表3:G8批次:3/21/13和批次:PS30170160膜蛋白靶标
抗体 | 靶基因(HGNC) | Uniprot |
G8批次3/21/13 | BAI1 | E5RG74 |
G8批次PS30170160 | BAI1 | E5RG74 |
该筛选产生了结合靶标,所述结合靶标在二次流式细胞术测定中使用连续抗体稀释液得到证实(图4A和图4B)。为此,用表达单独靶标或载体的质粒构建体转染HEK-293T细胞。测试每种MAb的连续稀释液对表达单独靶蛋白或载体的细胞的免疫反应性。最后,通过测序重新验证所有靶标的身份。
实施例2:G8重链和轻链的RACE鉴定
为了鉴定编码G8抗体的重链和轻链的核酸分子,进行cDNA末端快速扩增(RACE)反应。在琼脂糖凝胶上分析RACE PCR反应样品,以使扩增的DNA片段可见。扩增大小在500-700个碱基对之间的正确抗体可变区DNA片段(图5)。
从琼脂糖凝胶中回收来自24个克隆的PCR扩增的DNA片段,并测序。使用VBASE2工具鉴定CDR。
实施例3:人源化抗BAI1 IgG的构建、产生和表征
将G8 IgG的表达构建体克隆到高表达哺乳动物载体中。将G8IgG的每个DNA构建体放大用于转染,并确认序列。在HEK293细胞中完成0.03升的瞬时生产(Tuna293TM工艺)。收获来自瞬时生产运行的条件培养基,并通过离心和过滤进行澄清。将上清液上样到用结合缓冲液预先平衡的蛋白A柱上。使洗涤缓冲液通过该柱,直到测得OD280值(NanoDrop,ThermoScientific)为零。用低pH缓冲液洗脱靶蛋白,收集级分,并记录每个级分的OD280值。将含有靶蛋白的级分合并,并通过0.2μm滤膜过滤器过滤。由OD280值和计算的消光系数计算蛋白质浓度,并获得2.92mg的G8 IgG。数据汇总在表4最终蛋白质产量、等分试样和分析中。
表4
表4(续)
随后,使用LabChip GXII(Perkin Elmer)进行CE-SDS分析。使用显色鲎变形细胞溶解物法(Endosafe-MCS,Charles River)对纯化产物的样品进行内毒素测量。样品一式两份运行。实验确认所有样品都符合<1EU/mg的要求(表4)。进行SE-UPLC分析,其中SEC标准(MEDNA,目录号Y3101)作为蛋白质大小的参考运行。观察到所有蛋白质含有>99%的单体。通过质谱法进行完整质量QC,并且观察到的IgG分子量在预期范围内。
为了测量G8 IgM和抗BAI1 IgG(在本文中也称为“G8 IgG”)的相对亲和力,对G8IgG和G8 IgM进行ELISA测定。简言之,将板在4℃下用2μg/ml的人BAI1包被过夜,在室温下用在PBS中的1%BSA封闭1小时。在室温下用G8 IgM的连续1:2稀释液(从20μg/ml开始)或G8IgG(抗BAI1 IgG)的连续1:2稀释液(从100μg/ml开始)进行初步孵育1小时。在室温下用HRP缀合的抗小鼠IgM Fc(G8 IgM)或HRP缀合的抗人Fc(G8 IgG)进行二次孵育1小时。经由与3,3',5,5'-四甲基联苯胺(TMB)一起孵育15分钟来进行测定,并用1M HCl终止测定。所有测定一式两份地进行。结果示于图6中。G8 IgG和G8 IgM对照样品在ELISA上都显示阳性信号。
根据前面的描述,除了本文描述的那些以外,对所描述的主题的各种修改对于本领域技术人员来说将是显而易见的。此类修改也旨在落入所附权利要求书的范围内。本申请中引用的每篇参考文献(包括但不限于,期刊论文、美国专利和非美国专利、专利申请公开、国际专利申请公开、基因库登录号等)通过引用整体并入本文。
序列表
<110> 詹尼斯费尔有限责任公司(Genisphere, LLC)
R·盖茨(Getts, Robert)
J·保尔斯(Bowers, Jessica)
M·E·乔治-温斯坦(George-Weinstein, Mindy Ellen)
J·格哈特(Gerhart, Jacquelyn)
<120> 脑特异性血管生成抑制剂1(BAI1)抗体及其用途
<130> 189099.00502 (3035)
<150> 62/929,986
<151> 2019-11-04
<160> 15
<170> PatentIn version 3.5
<210> 1
<211> 118
<212> PRT
<213> 智人(homo sapien)
<400> 1
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Trp Met Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Ser Tyr Asn Pro Ser
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Leu Lys Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Phe Leu Gln Leu Asn Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr
85 90 95
Cys Ala Asn Ala Gln Gly Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Ser Val Thr Val Ser Ser
115
<210> 2
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<212> DNA
<213> 智人(homo sapien)
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cagtttccag gaaacaaact ggagtggatg ggctacataa gctacagtgg tagcactagc 180
tacaacccat ctctcaaaag tcgaatctct atcactcgag acacatccaa gaaccagttc 240
ttcctgcagt tgaattctgt gactactgag gacacagcca catattactg tgccaatgcc 300
caggggtatg ctatggacta ctggggtcaa ggaacctcag tcaccgtctc ctca 354
<210> 3
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<213> 智人(homo sapien)
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caguuuccag gaaacaaacu ggaguggaug ggcuacauaa gcuacagugg uagcacuagc 180
uacaacccau cucucaaaag ucgaaucucu aucacucgag acacauccaa gaaccaguuc 240
uuccugcagu ugaauucugu gacuacugag gacacagcca cauauuacug ugccaaugcc 300
cagggguaug cuauggacua cuggggucaa ggaaccucag ucaccgucuc cuca 354
<210> 4
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<212> PRT
<213> 智人(homo sapien)
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aggttcagtg gcagtggatc agggtcagat ttcactctca gtatcaacag tgtggaacct 240
gaagatgttg gagtgtatta ctgtcaaaat ggtcacagct ttccattcac gttcggctcg 300
gggacaaagt tggaaataaa a 321
<210> 6
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<213> 智人(homo sapien)
<400> 6
gacauuguga ugacucaguc uccagccacc cugucuguga cuccaggaga uagagucucu 60
cuuuccugca gggccagcca gaguauuagc gacuacuuac acugguauca acaaaaauca 120
caugagucuc caaggcuucu caucaaauau gcuucccaau ccaucucugg gauccccucc 180
agguucagug gcaguggauc agggucagau uucacucuca guaucaacag uguggaaccu 240
gaagauguug gaguguauua cugucaaaau ggucacagcu uuccauucac guucggcucg 300
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<210> 7
<211> 8
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<213> 智人(homo sapien)
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<210> 8
<211> 5
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<213> 智人(homo sapien)
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<210> 9
<211> 8
<212> PRT
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Ala Gln Gly Tyr Ala Met Asp Tyr
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<210> 10
<211> 11
<212> PRT
<213> 智人(homo sapien)
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Arg Ala Ser Gln Ser Ile Ser Asp Tyr Leu His
1 5 10
<210> 11
<211> 7
<212> PRT
<213> 智人(homo sapien)
<400> 11
Tyr Ala Ser Gln Ser Ile Ser
1 5
<210> 12
<211> 9
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<213> 智人(homo sapien)
<400> 12
Gln Asn Gly His Ser Phe Pro Phe Thr
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<210> 13
<211> 445
<212> PRT
<213> 智人(homo sapien)
<400> 13
Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln Ser
1 5 10 15
Leu Ser Leu Thr Cys Thr Val Thr Gly Tyr Ser Ile Thr Ser Asp Tyr
20 25 30
Ala Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp Met
35 40 45
Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Ser Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe Leu
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Gln Leu Asn Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys Ala
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Asn Ala Gln Gly Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val
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Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
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Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
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Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
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Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
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Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
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Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
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<210> 14
<211> 214
<212> PRT
<213> 智人(homo sapien)
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Asp Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Thr Pro Gly
1 5 10 15
Asp Arg Val Ser Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Asp Tyr
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Leu His Trp Tyr Gln Gln Lys Ser His Glu Ser Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Ala Ser Gln Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
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Ser Gly Ser Gly Ser Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Pro
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Glu Asp Val Gly Val Tyr Tyr Cys Gln Asn Gly His Ser Phe Pro Phe
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Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
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Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
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Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
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Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
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Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
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Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 15
<211> 1584
<212> PRT
<213> 智人(homo sapien)
<400> 15
Met Arg Gly Gln Ala Ala Ala Pro Gly Pro Val Trp Ile Leu Ala Pro
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Leu Leu Leu Leu Leu Leu Leu Leu Gly Arg Arg Ala Arg Ala Ala Ala
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Gly Ala Asp Ala Gly Pro Gly Pro Glu Pro Cys Ala Thr Leu Val Gln
35 40 45
Gly Lys Phe Phe Gly Tyr Phe Ser Ala Ala Ala Val Phe Pro Ala Asn
50 55 60
Ala Ser Arg Cys Ser Trp Thr Leu Arg Asn Pro Asp Pro Arg Arg Tyr
65 70 75 80
Thr Leu Tyr Met Lys Val Ala Lys Ala Pro Val Pro Cys Ser Gly Pro
85 90 95
Gly Arg Val Arg Thr Tyr Gln Phe Asp Ser Phe Leu Glu Ser Thr Arg
100 105 110
Thr Tyr Leu Gly Val Glu Ser Phe Asp Glu Val Leu Arg Leu Cys Asp
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Pro Ser Ala Pro Leu Ala Phe Leu Gln Ala Ser Lys Gln Phe Leu Gln
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Met Arg Arg Gln Gln Pro Pro Gln His Asp Gly Leu Arg Pro Arg Ala
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Gly Pro Pro Gly Pro Thr Asp Asp Phe Ser Val Glu Tyr Leu Val Val
165 170 175
Gly Asn Arg Asn Pro Ser Arg Ala Ala Cys Gln Met Leu Cys Arg Trp
180 185 190
Leu Asp Ala Cys Leu Ala Gly Ser Arg Ser Ser His Pro Cys Gly Ile
195 200 205
Met Gln Thr Pro Cys Ala Cys Leu Gly Gly Glu Ala Gly Gly Pro Ala
210 215 220
Ala Gly Pro Leu Ala Pro Arg Gly Asp Val Cys Leu Arg Asp Ala Val
225 230 235 240
Ala Gly Gly Pro Glu Asn Cys Leu Thr Ser Leu Thr Gln Asp Arg Gly
245 250 255
Gly His Gly Ala Thr Gly Gly Trp Lys Leu Trp Ser Leu Trp Gly Glu
260 265 270
Cys Thr Arg Asp Cys Gly Gly Gly Leu Gln Thr Arg Thr Arg Thr Cys
275 280 285
Leu Pro Ala Pro Gly Val Glu Gly Gly Gly Cys Glu Gly Val Leu Glu
290 295 300
Glu Gly Arg Gln Cys Asn Arg Glu Ala Cys Gly Pro Ala Gly Arg Thr
305 310 315 320
Ser Ser Arg Ser Gln Ser Leu Arg Ser Thr Asp Ala Arg Arg Arg Glu
325 330 335
Glu Leu Gly Asp Glu Leu Gln Gln Phe Gly Phe Pro Ala Pro Gln Thr
340 345 350
Gly Asp Pro Ala Ala Glu Glu Trp Ser Pro Trp Ser Val Cys Ser Ser
355 360 365
Thr Cys Gly Glu Gly Trp Gln Thr Arg Thr Arg Phe Cys Val Ser Ser
370 375 380
Ser Tyr Ser Thr Gln Cys Ser Gly Pro Leu Arg Glu Gln Arg Leu Cys
385 390 395 400
Asn Asn Ser Ala Val Cys Pro Val His Gly Ala Trp Asp Glu Trp Ser
405 410 415
Pro Trp Ser Leu Cys Ser Ser Thr Cys Gly Arg Gly Phe Arg Asp Arg
420 425 430
Thr Arg Thr Cys Arg Pro Pro Gln Phe Gly Gly Asn Pro Cys Glu Gly
435 440 445
Pro Glu Lys Gln Thr Lys Phe Cys Asn Ile Ala Leu Cys Pro Gly Arg
450 455 460
Ala Val Asp Gly Asn Trp Asn Glu Trp Ser Ser Trp Ser Ala Cys Ser
465 470 475 480
Ala Ser Cys Ser Gln Gly Arg Gln Gln Arg Thr Arg Glu Cys Asn Gly
485 490 495
Pro Ser Tyr Gly Gly Ala Glu Cys Gln Gly His Trp Val Glu Thr Arg
500 505 510
Asp Cys Phe Leu Gln Gln Cys Pro Val Asp Gly Lys Trp Gln Ala Trp
515 520 525
Ala Ser Trp Gly Ser Cys Ser Val Thr Cys Gly Ala Gly Ser Gln Arg
530 535 540
Arg Glu Arg Val Cys Ser Gly Pro Phe Phe Gly Gly Ala Ala Cys Gln
545 550 555 560
Gly Pro Gln Asp Glu Tyr Arg Gln Cys Gly Thr Gln Arg Cys Pro Glu
565 570 575
Pro His Glu Ile Cys Asp Glu Asp Asn Phe Gly Ala Val Ile Trp Lys
580 585 590
Glu Thr Pro Ala Gly Glu Val Ala Ala Val Arg Cys Pro Arg Asn Ala
595 600 605
Thr Gly Leu Ile Leu Arg Arg Cys Glu Leu Asp Glu Glu Gly Ile Ala
610 615 620
Tyr Trp Glu Pro Pro Thr Tyr Ile Arg Cys Val Ser Ile Asp Tyr Arg
625 630 635 640
Asn Ile Gln Met Met Thr Arg Glu His Leu Ala Lys Ala Gln Arg Gly
645 650 655
Leu Pro Gly Glu Gly Val Ser Glu Val Ile Gln Thr Leu Val Glu Ile
660 665 670
Ser Gln Asp Gly Thr Ser Tyr Ser Gly Asp Leu Leu Ser Thr Ile Asp
675 680 685
Val Leu Arg Asn Met Thr Glu Ile Phe Arg Arg Ala Tyr Tyr Ser Pro
690 695 700
Thr Pro Gly Asp Val Gln Asn Phe Val Gln Ile Leu Ser Asn Leu Leu
705 710 715 720
Ala Glu Glu Asn Arg Asp Lys Trp Glu Glu Ala Gln Leu Ala Gly Pro
725 730 735
Asn Ala Lys Glu Leu Phe Arg Leu Val Glu Asp Phe Val Asp Val Ile
740 745 750
Gly Phe Arg Met Lys Asp Leu Arg Asp Ala Tyr Gln Val Thr Asp Asn
755 760 765
Leu Val Leu Ser Ile His Lys Leu Pro Ala Ser Gly Ala Thr Asp Ile
770 775 780
Ser Phe Pro Met Lys Gly Trp Arg Ala Thr Gly Asp Trp Ala Lys Val
785 790 795 800
Pro Glu Asp Arg Val Thr Val Ser Lys Ser Val Phe Ser Thr Gly Leu
805 810 815
Thr Glu Ala Asp Glu Ala Ser Val Phe Val Val Gly Thr Val Leu Tyr
820 825 830
Arg Asn Leu Gly Ser Phe Leu Ala Leu Gln Arg Asn Thr Thr Val Leu
835 840 845
Asn Ser Lys Val Ile Ser Val Thr Val Lys Pro Pro Pro Arg Ser Leu
850 855 860
Arg Thr Pro Leu Glu Ile Glu Phe Ala His Met Tyr Asn Gly Thr Thr
865 870 875 880
Asn Gln Thr Cys Ile Leu Trp Asp Glu Thr Asp Val Pro Ser Ser Ser
885 890 895
Ala Pro Pro Gln Leu Gly Pro Trp Ser Trp Arg Gly Cys Arg Thr Val
900 905 910
Pro Leu Asp Ala Leu Arg Thr Arg Cys Leu Cys Asp Arg Leu Ser Thr
915 920 925
Phe Ala Ile Leu Ala Gln Leu Ser Ala Asp Ala Asn Met Glu Lys Ala
930 935 940
Thr Leu Pro Ser Val Thr Leu Ile Val Gly Cys Gly Val Ser Ser Leu
945 950 955 960
Thr Leu Leu Met Leu Val Ile Ile Tyr Val Ser Val Trp Arg Tyr Ile
965 970 975
Arg Ser Glu Arg Ser Val Ile Leu Ile Asn Phe Cys Leu Ser Ile Ile
980 985 990
Ser Ser Asn Ala Leu Ile Leu Ile Gly Gln Thr Gln Thr Arg Asn Lys
995 1000 1005
Val Val Cys Thr Leu Val Ala Ala Phe Leu His Phe Phe Phe Leu
1010 1015 1020
Ser Ser Phe Cys Trp Val Leu Thr Glu Ala Trp Gln Ser Tyr Met
1025 1030 1035
Ala Val Thr Gly His Leu Arg Asn Arg Leu Ile Arg Lys Arg Phe
1040 1045 1050
Leu Cys Leu Gly Trp Gly Leu Pro Ala Leu Val Val Ala Ile Ser
1055 1060 1065
Val Gly Phe Thr Lys Ala Lys Gly Tyr Ser Thr Met Asn Tyr Cys
1070 1075 1080
Trp Leu Ser Leu Glu Gly Gly Leu Leu Tyr Ala Phe Val Gly Pro
1085 1090 1095
Ala Ala Ala Val Val Leu Val Asn Met Val Ile Gly Ile Leu Val
1100 1105 1110
Phe Asn Lys Leu Val Ser Lys Asp Gly Ile Thr Asp Lys Lys Leu
1115 1120 1125
Lys Glu Arg Ala Gly Ala Ser Leu Trp Ser Ser Cys Val Val Leu
1130 1135 1140
Pro Leu Leu Ala Leu Thr Trp Met Ser Ala Val Leu Ala Val Thr
1145 1150 1155
Asp Arg Arg Ser Ala Leu Phe Gln Ile Leu Phe Ala Val Phe Asp
1160 1165 1170
Ser Leu Glu Gly Phe Val Ile Val Met Val His Cys Ile Leu Arg
1175 1180 1185
Arg Glu Val Gln Asp Ala Val Lys Cys Arg Val Val Asp Arg Gln
1190 1195 1200
Glu Glu Gly Asn Gly Asp Ser Gly Gly Ser Phe Gln Asn Gly His
1205 1210 1215
Ala Gln Leu Met Thr Asp Phe Glu Lys Asp Val Asp Leu Ala Cys
1220 1225 1230
Arg Ser Val Leu Asn Lys Asp Ile Ala Ala Cys Arg Thr Ala Thr
1235 1240 1245
Ile Thr Gly Thr Leu Lys Arg Pro Ser Leu Pro Glu Glu Glu Lys
1250 1255 1260
Leu Lys Leu Ala His Ala Lys Gly Pro Pro Thr Asn Phe Asn Ser
1265 1270 1275
Leu Pro Ala Asn Val Ser Lys Leu His Leu His Gly Ser Pro Arg
1280 1285 1290
Tyr Pro Gly Gly Pro Leu Pro Asp Phe Pro Asn His Ser Leu Thr
1295 1300 1305
Leu Lys Arg Asp Lys Ala Pro Lys Ser Ser Phe Val Gly Asp Gly
1310 1315 1320
Asp Ile Phe Lys Lys Leu Asp Ser Glu Leu Ser Arg Ala Gln Glu
1325 1330 1335
Lys Ala Leu Asp Thr Ser Tyr Val Ile Leu Pro Thr Ala Thr Ala
1340 1345 1350
Thr Leu Arg Pro Lys Pro Lys Glu Glu Pro Lys Tyr Ser Ile His
1355 1360 1365
Ile Asp Gln Met Pro Gln Thr Arg Leu Ile His Leu Ser Thr Ala
1370 1375 1380
Pro Glu Ala Ser Leu Pro Ala Arg Ser Pro Pro Ser Arg Gln Pro
1385 1390 1395
Pro Ser Gly Gly Pro Pro Glu Ala Pro Pro Ala Gln Pro Pro Pro
1400 1405 1410
Pro Pro Pro Pro Pro Pro Pro Pro Pro Gln Gln Pro Leu Pro Pro
1415 1420 1425
Pro Pro Asn Leu Glu Pro Ala Pro Pro Ser Leu Gly Asp Pro Gly
1430 1435 1440
Glu Pro Ala Ala His Pro Gly Pro Ser Thr Gly Pro Ser Thr Lys
1445 1450 1455
Asn Glu Asn Val Ala Thr Leu Ser Val Ser Ser Leu Glu Arg Arg
1460 1465 1470
Lys Ser Arg Tyr Ala Glu Leu Asp Phe Glu Lys Ile Met His Thr
1475 1480 1485
Arg Lys Arg His Gln Asp Met Phe Gln Asp Leu Asn Arg Lys Leu
1490 1495 1500
Gln His Ala Ala Glu Lys Asp Lys Glu Val Leu Gly Pro Asp Ser
1505 1510 1515
Lys Pro Glu Lys Gln Gln Thr Pro Asn Lys Arg Pro Trp Glu Ser
1520 1525 1530
Leu Arg Lys Ala His Gly Thr Pro Thr Trp Val Lys Lys Glu Leu
1535 1540 1545
Glu Pro Leu Gln Pro Ser Pro Leu Glu Leu Arg Ser Val Glu Trp
1550 1555 1560
Glu Arg Ser Gly Ala Thr Ile Pro Leu Val Gly Gln Asp Ile Ile
1565 1570 1575
Asp Leu Gln Thr Glu Val
1580
Claims (23)
1.一种与人粘附G蛋白偶联受体B1(BAI1)蛋白结合的抗体或其抗原结合片段,其中所述抗体或其抗原结合片段包含:
可变重(VH)链中的第一互补决定区(CDR)(VH-CDR1),其包含根据SEQ ID NO:7的氨基酸序列;
所述VH链中的第二CDR(VH-CDR2),其包含根据SEQ ID NO:8的氨基酸序列;
所述VH链中的第三CDR(VH-CDR3),其包含根据SEQ ID NO:9的氨基酸序列;
可变轻(VL)链中的第一CDR(VL-CDR1),其包含根据SEQ ID NO:10的氨基酸序列;
所述VL链中的第二CDR(VL-CDR2),其包含根据SEQ ID NO:11的氨基酸序列;以及
所述VL链中的第三CDR(VL-CDR3),其包含根据SEQ ID NO:12的氨基酸序列。
2.根据权利要求1所述的抗体或其抗原结合片段,其中所述抗体或其抗原结合片段包含VH链,所述VH链包含根据SEQ ID NO:1的氨基酸序列。
3.根据权利要求1或权利要求2所述的抗体或其抗原结合片段,其中所述抗体或其抗原结合片段包含VL链,所述VL链包含根据SEQ ID NO:4的氨基酸序列。
4.根据权利要求1至3中任一项所述的抗体或其抗原结合片段,其中所述抗体是IgM或IgG抗体。
5.根据权利要求1至4中任一项所述的抗体或其抗原结合片段,其中所述抗体或其抗原结合片段是人源化的。
6.根据权利要求5所述的人源化抗体或其抗原结合片段,其中所述人源化抗体或其抗原结合片段包含重链,所述重链包含根据SEQ ID NO:13的氨基酸序列。
7.根据权利要求5或权利要求6所述的人源化抗体或其抗原结合片段,其中所述人源化抗体或其抗原结合片段包含轻链,所述轻链包含根据SEQ ID NO:14的氨基酸序列。
8.根据权利要求1至7中任一项所述的抗体或其抗原结合片段,其中所述抗体或其抗原结合片段与效应部分缀合。
9.根据权利要求8所述的抗体或其抗原结合片段,其中所述效应部分是可检测标记、细胞毒性剂、化学治疗剂或核酸分子。
10.根据权利要求9所述的抗体或其抗原结合片段,其中所述抗体或其抗原结合片段在每个抗体或其抗原结合片段中包含3至5个美登木素生物碱分子。
11.根据权利要求9所述的抗体或其抗原结合片段,其中所述核酸分子是单层核酸载剂、1.5层核酸载剂、双层核酸载剂、2.5层核酸载剂或三层核酸载剂。
12.根据权利要求1至11中任一项所述的抗体或其抗原结合片段,其中所述抗原结合片段是Fab、F(ab')2、Fv、scFv、scFv-Fc、双链抗体或微抗体片段。
13.一种药物组合物,其包含根据权利要求1至12中任一项所述的抗体或其抗原结合片段以及药学上可接受的载剂。
14.一种分离的核酸分子,其编码根据权利要求1至4中任一项所述的抗体或其抗原结合片段的VH链,其中所述核酸分子包含根据SEQ ID NO:2或SEQ ID NO:3的核苷酸序列。
15.一种分离的核酸分子,其编码根据权利要求1至4中任一项所述的抗体或其抗原结合片段的VL链,其中所述核酸分子包含根据SEQ ID NO:5或SEQ ID NO:6的核苷酸序列。
16.一种载体,其包含根据权利要求14或权利要求15所述的核酸分子。
17.一种宿主细胞,其用根据权利要求16所述的载体转化。
18.一种检测表达BAI1的细胞的方法,所述方法包括使所述细胞与根据权利要求1至12中任一项所述的抗体或其抗原结合片段接触,并检测所述抗体或其抗原结合片段。
19.一种治疗表达BAI1的癌症的方法,所述方法包括向有此需要的人患者施用根据权利要求1至12中任一项所述的抗体或其抗原结合片段。
20.一种治疗后囊膜浑浊(PCO)的方法,所述方法包括向有此需要的人患者施用根据权利要求1至12中任一项所述的抗体或其抗原结合片段。
21.一种治疗纤维化的方法,所述方法包括向有此需要的人患者施用根据权利要求1至12中任一项所述的抗体或其抗原结合片段。
22.一种促进伤口愈合的方法,所述方法包括向有此需要的人患者施用根据权利要求1至12中任一项所述的抗体或其抗原结合片段。
23.一种促进伤口愈合的方法,所述方法包括向有此需要的人患者施用表达BAI1的细胞。
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