CN104159921B - 针对人csf-1r的抗体及其用途 - Google Patents
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Abstract
本发明涉及针对人CSF‑1R的抗体(CSF‑1R抗体)、其生成方法、含有所述抗体的药物组合物、及其用途。
Description
本发明涉及针对人CSF-1R的抗体(CSF-1R抗体)、其生成方法、含有所述抗体的药物组合物、及其用途。
发明背景
CSF-1受体(CSF-1R;同义词:M-CSF受体,巨噬细胞集落刺激因子1受体,EC2.7.10.1,Fms原癌基因,c-fms,Swiss Prot P07333,CD115,(SEQ ID NO:23))自1986年以来是已知的(Coussens L.et al.,Nature320(1986)277-280)。CSF-1R是一种生长因子,并且由c-fms原癌基因编码(综述见例如Roth,P.and Stanley,E.R.,Curr.Top.Microbiol.Immunol.181(1992)141-67)。
CSF-1R是M-CSF(巨噬细胞集落刺激因子,又称作CSF-1)的受体,并且介导此细胞因子的生物学效应(Sherr,C.J.et al.,Cell41(1985)665-676)。集落刺激因子-1受体(又称作c-fms)的克隆第一次记载于Roussel,M.F.et al.,Nature325(1987)549-552。在该出版物中,显示了CSF-1R具有转化潜力,其依赖于蛋白质的C端尾部的变化,包含抑制性酪氨酸969磷酸化的丧失,其结合Cbl,并且由此调节受体下调(Lee,P.S.et al.,Embo J.18(1999)3616-3628)。
CSF-1R是一种单链、跨膜受体酪氨酸激酶(RTK)和以受体的胞外部分中的重复Ig域为特征的含有免疫球蛋白(Ig)基序的RTK家族的一名成员。胞内蛋白质酪氨酸激酶域以独特插入域中断,所述独特插入域也存在于包括血小板衍生的生长因子受体(PDGFR)、干细胞生长因子受体(c-Kit)和fins样细胞因子受体(FLT3)的其它相关RTK III类家族成员中。尽管此生长因子受体家族间有结构同源性,但是它们具有截然不同的组织特异性功能。CSF-1R主要在单核细胞谱系的细胞上及在女性生殖道和胎盘中表达。另外,已经在皮肤中的朗格汉斯细胞,即一种平滑肌细胞子集(Inaba,T.et al.,J.Biol.Chem.267(1992)5693-5699)、B细胞(Baker,A.H.et al.,Oncogene8(1993)371-378)和小胶质(Sawada,M.et al.,Brain Res.509(1990)119-124) 中报告了CSF-1R的表达。
CSF-1R信号传导的主要生物学效应是造血前体细胞向巨噬细胞谱系(包括破骨细胞)的分化、增殖、迁移、和存活。CSF-1R的激活由其配体M-CSF介导。M-CSF对CSF-1R的结合诱导同二聚体的形成和通过酪氨酸磷酸化实现的激酶活化(Stanley,E.R.et al.,Mol.Reprod.Dev.46(1997)4-10)。别的信号传导由分别连接PI3K/AKT和Ras/MAPK途径的PI3K的p85亚基和Grb2介导。这两种重要的信号传导途径可以调节增殖、存活和凋亡。结合CSF-1R的磷酸化的胞内域的其它信号传导分子包括STAT1、STAT3、PLCy、和Cbl(Bourette,R.P.and Rohrschneider,L.R.,Growth Factors17(2000)155-166)。
CSF-1R信号传导在免疫应答中、在骨重建(bone remodeling)中及在生殖系统中具有生理学作用。已经显示了M-CSF-1(Pollard,J.W.,Mol.Reprod.Dev.46(1997)54-61)或CSF-1R(Dai,X.M.et al.,Blood99(2002)111-120)的敲除动物具有与CSF-1R在相应细胞类型中的作用一致的骨硬化(osteopetrotic)、造血、组织巨噬细胞、和生殖表型。
Sherr,C.J.et al.,Blood73(1989)1786-1793涉及抑制CSF-1活性的一些针对CSF-1R的抗体(见Sherr,C.J.et al.,Blood73(1989)1786-1793)。Ashum,R.A.et al.,Blood73(1989)827-837涉及CSF-1R抗体。Lenda,D.et al.,Journal of immunology170(2003)3254-3262涉及CSF-1缺陷型小鼠中降低的巨噬细胞募集、增殖、和活化导致肾炎症期间降低的肾小管凋亡。Kitaura,H.et al.,Journal of dental research87(2008)396-400提及一种抑制口腔正畸牙移动的抗CSF-1抗体。WO2001/030381在仅披露CSF-1反义核苷酸的情况中提及包括反义核苷酸和抗体的CSF-1活性抑制剂。WO2004/045532涉及通过M-CSF拮抗剂(仅披露抗CSF-1抗体作为拮抗剂)对转移癌的转移和骨损失预防和治疗。WO2005/046657涉及通过抗CSF-1抗体治疗炎性肠病。US2002/0141994涉及集落刺激因子的抑制剂。WO2006/096489涉及通过抗CSF-1抗体治疗类风湿性关节炎。
发明概述
一方面,本发明包括一种结合人CSF-1R的抗体,其特征在于与保藏抗体DSMACC2920结合相同表位,用于在CSF-1配体依赖性和/或CSF-1配体不依赖性CSF-1-R表达细胞中抑制细胞增殖。
在一个实施方案中,所述CSF-1-R表达细胞为癌细胞。
在一个实施方案中,所述抗体特征在于作为重链可变域CDR3区包含SEQ ID NO:1或SEQ ID NO:9的CDR3区。
在一个实施方案中,所述抗体特征在于:
a)重链可变域包含SEQ ID NO:1的CDR3区、SEQ ID NO:2的CDR2区、和SEQ ID NO:3的CDR1区,且轻链可变域包含SEQ ID NO:4的CDR3区、SEQ ID NO:5的CDR2区、和SEQ ID NO:6的CDR1区,或
b)重链可变域包含SEQ ID NO:9的CDR3区、SEQ ID NO:10的CDR2区、和SEQ ID NO:11的CDR1区,且轻链可变域包含SEQ ID NO:12的CDR3区、SEQ ID NO:13的CDR2区、和SEQ IDNO:14的CDR1区,或
c)a)或b)所述抗体的CDR嫁接的、人源化的或T细胞表位消减的抗体变体。
如此,能够结合相同表位的依照本发明的抗体能够在CSF-1配体依赖性和CSF-1配体不依赖性细胞中抑制细胞增殖。
另一方面,本发明包括一种结合人CSF-1R的抗体,其特征在于与保藏抗体DSMACC2920结合相同表位。
另一方面,本发明包括一种结合人CSF-1R的抗体,其特征在于与保藏抗体DSMACC2920结合相同表位;
其中在体外竞争性结合抑制测定法中通过表面等离振子共振(SPR)于25℃测量对相同表位的结合;且
其中所述抗体具有下述特性:
a)于抗体浓度10μg/ml将NIH3T3–野生型CSF-1R重组细胞的生长抑制90%或更多;和
b)于抗体浓度10μg/ml将NIH3T3–突变型CSF-1R L301S Y969F重组细胞的生长抑制60%或更多。
在一个实施方案中,所述抗体特征在于作为重链可变域CDR3区包含SEQ ID NO:1或SEQ ID NO:9的CDR3区。
在一个实施方案中,所述抗体特征在于:
a)重链可变域包含SEQ ID NO:1的CDR3区、SEQ ID NO:2的CDR2区、和SEQ ID NO:3的CDR1区,且轻链可变域包含SEQ ID NO:4的CDR3区、SEQ ID NO:5的CDR2区、和SEQ ID NO:6的CDR1区,或
b)重链可变域包含SEQ ID NO:9的CDR3区、SEQ ID NO:10的CDR2区、和SEQ ID NO:11的CDR1区,且轻链可变域包含SEQ ID NO:12的CDR3区、 SEQ ID NO:13的CDR2区、和SEQID NO:14的CDR1区,或
c)a)或b)所述抗体的CDR嫁接的、人源化的或T细胞表位消减的抗体变体。
在一个实施方案中,所述抗体结合人CSF-1R,并且特征在于上文所提及的氨基酸序列和氨基酸序列片段是人IgG1亚类的或者是人IgG4亚类的。
本发明的又一个实施方案是包含依照本发明的抗体的药物组合物。
本发明进一步包括以包含结合人CSF-1R的抗体为特征的药物组合物,所述结合人CSF-1R的抗体特征在于上文所提及的表位结合特性或者备选地上文所提及的氨基酸序列和氨基酸序列片段。
本发明进一步包括以包含结合人CSF-1R的抗体为特征的抗体用于制造药物组合物的用途,所述结合人CSF-1R的抗体特征在于上文所提及的表位结合特性或者备选地上文所提及的氨基酸序列和氨基酸序列片段。
本发明进一步包括以包含结合人CSF-1R的抗体为特征的抗体用于治疗CSF-1R介导的疾病的用途,所述结合人CSF-1R的抗体特征在于上文所提及的表位结合特性或者备选地上文所提及的氨基酸序列和氨基酸序列片段。
本发明进一步包括以包含结合人CSF-1R的抗体为特征的抗体用于治疗癌症的用途,所述结合人CSF-1R的抗体特征在于上文所提及的表位结合特性或者备选地上文所提及的氨基酸序列和氨基酸序列片段。
本发明进一步包括以包含结合人CSF-1R的抗体为特征的抗体用于治疗骨损失的用途,所述结合人CSF-1R的抗体特征在于上文所提及的表位结合特性或者备选地上文所提及的氨基酸序列和氨基酸序列片段。
本发明进一步包括以包含结合人CSF-1R的抗体为特征的抗体用于预防或治疗转移的用途,所述结合人CSF-1R的抗体特征在于上文所提及的表位结合特性或者备选地上文所提及的氨基酸序列和氨基酸序列片段。
本发明进一步包括以包含结合人CSF-1R的抗体为特征的抗体用于治疗炎性疾病的用途,所述结合人CSF-1R的抗体特征在于上文所提及的表位结合特性或者备选地上文所提及的氨基酸序列和氨基酸序列片段。
所述抗体优选以至少10-8mol/l至10-12mol/l的亲和力结合人CSF-1R。
优选地,所述抗体是人源化抗体或人抗体。
本发明的又一个实施方案是编码依照本发明的抗体的重链可变域和/或轻链可变域的核酸。优选地,所述核酸编码结合人CSF-1R的抗体的重链,其特征在于作为重链CDR3区包含SEQ ID NO:1、SEQ ID NO:9、或SEQ ID NO: 17的CDR3区。
本发明的又一个实施方案是编码依照本发明的抗体的核酸,所述抗体特征在于:
a)重链可变域包含SEQ ID NO:1的CDR3区、SEQ ID NO:2的CDR2区、和SEQ ID NO:3的CDR1区,且轻链可变域包含SEQ ID NO:4的CDR3区、SEQ ID NO:5的CDR2区、和SEQ ID NO:6的CDR1区,或
b)重链可变域包含SEQ ID NO:9的CDR3区、SEQ ID NO:10的CDR2区、和SEQ ID NO:11的CDR1区,且轻链可变域包含SEQ ID NO:12的CDR3区、SEQ ID NO:13的CDR2区、和SEQ IDNO:14的CDR1区,或
c)a)或b)所述抗体的CDR嫁接的、人源化的或T细胞表位消减的抗体变体。
本发明进一步提供了含有依照本发明的核酸、能够在原核或真核宿主细胞中表达所述核酸的表达载体,和含有此类载体以重组生成此类抗体的宿主细胞。
本发明进一步包括包含依照本发明的载体的原核或真核宿主细胞。
本发明进一步包括用于生成依照本发明的重组人或人源化抗体的方法,其特征在于在原核或真核宿主细胞中表达依照本发明的核酸,并自所述细胞或细胞培养物上清液回收所述抗体。本发明进一步包括通过此类重组方法可获得的抗体。
依照本发明的抗体对需要CSF-1R靶向疗法的患者显示益处。依照本发明的抗体具有对患有肿瘤疾病,尤其是患有癌症的患者引起益处的、具有新颖性和创造性的特性。
本发明进一步提供了用于治疗患有癌症的患者的方法,包括对诊断为具有此类疾病(并且因此需要此类疗法)的患者施用有效量的依照本发明的结合人CSF-1R的抗体。优选地,在药物组合物中施用抗体。
本发明的又一个实施方案是用于治疗患有癌症的患者的方法,其特征在于对患者施用依照本发明的抗体。
本发明进一步包括依照本发明的抗体用于治疗患有癌症的患者及用于制造依照本发明的药物组合物的用途。另外,本发明包括用于制造依照本发明的药物组合物的方法。
本发明进一步包括包含依照本发明的抗体,任选地以及出于药用目的可用于配制抗体的缓冲液和/或佐剂的药物组合物。
本发明进一步提供了包含药学可接受载体中的依照本发明的抗体的药物组合物。在一个实施方案中,药物组合物可以包含在制品或试剂盒中。
附图简述
图1:在用10μg/ml浓度的不同抗CSF-1R单克隆抗体处理下对3D培养中BeWo肿瘤细胞的生长抑制。
X轴:与细胞的ATP含量对应的存活力均值相对光单位(RLU)(CellTiterGlo测定法)。
Y轴:测试探针:极限培养基(0.5%FBS)、小鼠IgG1(mIgG1,10μg/ml)、小鼠IgG2a(mIgG2a10μg/ml)、仅CSF-1、<CSF-1R>9D11.2E8、<CSF-1R>10H2.2F12、和SC-02、克隆2-4A5。用依照本发明的抗CSF-1R抗体观察到对CSF-1诱导的生长的最高抑制。
发明详述
本发明进一步包括一种结合人CSF-1R的抗体,其特征在于作为重链可变域CDR3区包含SEQ ID NO:1或SEQ ID NO:9的CDR3区。
本发明进一步包括所述抗体,其特征在于:
a)重链可变域包含SEQ ID NO:1的CDR3区、SEQ ID NO:2的CDR2区、和SEQ ID NO:3的CDR1区,且轻链可变域包含SEQ ID NO:4的CDR3区、SEQ ID NO:5的CDR2区、和SEQ ID NO:6的CDR1区,或
b)重链可变域包含SEQ ID NO:9的CDR3区、SEQ ID NO:10的CDR2区、和SEQ ID NO:11的CDR1区,且轻链可变域包含SEQ ID NO:12的CDR3区、SEQ ID NO:13的CDR2区、和SEQ IDNO:14的CDR1区,或
c)a)或b)所述抗体的CDR嫁接的、人源化的或T细胞表位消减的抗体变体。
术语“抗体”涵盖各种形式的抗体,包括但不限于全抗体、抗体片段、人源化抗体、嵌合抗体、T细胞表位消减的抗体、和别的遗传工程化抗体,只要依照本发明的特征性特性得到保留。
“抗体片段”包含全长抗体的一部分,优选地,其可变域,或至少其抗原结合位点。抗体片段的例子包括双抗体、单链抗体分子、和自抗体片段形成的多特异性抗体。例如,scFv抗体记载于Houston,J.S.,Methods in Enzymol.203(1991)46-88。另外,抗体片段包含具有结合CSF-1R的VH域或结合CSF-1R的VL域的特征(即能够与VL域或VH域一起装配成功能性抗原结合位点,并 且由此提供该特性)的单链多肽。
如本文中所使用的,术语“单克隆抗体”或“单克隆抗体组合物”指单一氨基酸组成的抗体分子的制备物。
术语“嵌合抗体”指通常通过重组DNA技术制备的,包含来自小鼠的可变区,即结合区和自不同来源或物种衍生的恒定区的至少一部分的单克隆抗体。包含小鼠可变区和人恒定区的嵌合抗体是特别优选的。此类大鼠/人嵌合抗体是包含编码大鼠免疫球蛋白可变区的DNA区段和编码人免疫球蛋白恒定区的DNA区段的所表达免疫球蛋白基因的产物。本发明所涵盖的“嵌合抗体”的其它形式是那些其中类或亚类已经自初始抗体的类或亚类修饰或改变的。此类“嵌合”抗体又称为“类转换抗体”。用于生成嵌合抗体的方法牵涉本领域现在公知的常规重组DNA和基因转染技术。参见例如Morrison,S.L.et al.,Proc.Natl.AcadSci.USA81(1984)6851-6855;US5,202,238和US5,204,244。
如本申请内所使用的,术语“CDR嫁接的变体”意指通常通过重组DNA技术制备的包含来自一种来源或物种的互补决定区(CDR或高变区)和来自不同来源或物种的框架区(FR)的抗体可变域。包含鼠CDR和人FR的可变域的CDR嫁接变体是优选的。
如本申请内所使用的,术语“T细胞表位消减的变体”意指通过除去人T细胞表位(可变域内具有结合MHC II类分子的能力的肽序列)修饰为消除或降低免疫原性的抗体可变域。通过此方法,鉴定可变域的氨基酸侧链与具有MHC II类结合沟的特定结合袋间的相互作用。将鉴定的免疫原性区突变以消除免疫原性。一般地,此类方法记载于例如WO98/52976。
如本申请内所使用的,术语“人源化变体”意指自非人起源,例如非人物种的互补决定区(CDR),和自人起源的框架区(FR)重建的,并且已经进一步修饰以重建或改善初始非人可变域的结合亲和力和特异性的抗体可变域。此类人源化变体通常通过重组DNA技术来制备。亲本非人可变域的亲和力和特异性的重建是至关重要的步骤,对此目前使用不同方法。在一种方法中,测定在非人CDR中及在人FR中引入突变,即所谓的回复突变是否是有益的。可以例如通过序列或同源性分析,通过选择人框架(固定的框架方法;同源性匹配或最佳拟合),通过使用共有序列,通过自几种不同人单抗选择FR,或者通过用存在于人单抗中的最常见的残基替换三维表面上的非人残基 (“表面重修”或“镶饰”)来鉴定此类回复突变的合适位置。
另外,依照本发明的抗体包括具有“保守序列修饰”,即不影响或改变依照本发明的抗体的上文所提及的特征的核苷酸和氨基酸序列修饰的此类抗体。可以通过本领域中已知的标准技术,诸如定点诱变和PCR介导的诱变引入修饰。保守氨基酸替代包括用具有相似侧链的氨基酸残基替换氨基酸残基的。本领域中已经限定具有相似侧链的氨基酸残基的家族。这些家族包括具有碱性侧链(例如,赖氨酸、精氨酸、组氨酸)、酸性侧链(例如,天冬氨酸、谷氨酸)、不带电荷的极性侧链(例如,甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸、半胱氨酸、色氨酸)、非极性侧链(例如,丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸)、β-分支的侧链(例如,苏氨酸、缬氨酸、异亮氨酸)和芳香族侧链(例如,酪氨酸、苯丙氨酸、色氨酸、组氨酸)的氨基酸。如此,优选地,可以将人抗CSF-1R抗体中预测的非必需氨基酸残基用来自同一侧链家族的另一种氨基酸残基替换。
可以基于分子建模通过诱变实施氨基酸替代,如Riechmann,L.et al.,Nature332(1988)323-327及Queen,C.et al.,Proc.Natl.Acad.Sci.USA86(1989)10029-10033所描述的。
CSF-1受体(CSF-1R;同义词:M-CSF受体,巨噬细胞集落刺激因子1受体,EC2.7.10.1,Fms原癌基因,c-fms,Swiss Prot P07333,CD115,(SEQ ID NO:23))自1986以来是已知的(Coussens L.et al.,Nature320(1986)277-280)。CSF-1R是一种生长因子,并且由c-fms原癌基因编码(综述见例如Roth,P.and Stanley,E.R.,Curr.Top.Microbiol.Immunol.181(1992)141-67)。
CSF-1R是M-CSF(巨噬细胞集落刺激因子,又称作CSF-1)的受体,并且介导此细胞因子的生物学效应(Sherr,C.J.et al.,Cell41(1985)665-676)。集落刺激因子-1受体(又称作c-fms)的克隆第一次记载于Roussel,M.F.et al.,Nature325(1987)549-552。在该出版物中,显示了CSF-1R具有转化潜力,其依赖于该蛋白质的C端尾部的变化,包括抑制性酪氨酸969磷酸化的丧失,其结合Cbl,并且由此调节受体下调(Lee,P.S.et al.,Embo J.18(1999)3616-3628)。
如本文中所使用的,“结合人CSF-1R”指特异性结合人CSF-1R抗原的抗 体。结合亲和力是于35℃的1.0x10-8mol/l或更低的KD值的,优选地,于35℃的1.0x10-9mol/l或更低的KD值的。于35℃用标准结合测定法,诸如表面等离振子共振技术测定结合亲和力(见实施例4)。
术语“表位”意指能够特异性结合抗体的蛋白质决定簇。表位通常由分子的化学活性表面聚集诸如氨基酸或糖侧链组成,并且通常表位具有特定的三维结构特征及特定的电荷特征。构象性和非构象性表位的区别之处在于在存在变性溶剂的情况中丧失对前一种,而不是对后一种的结合。优选地,依照本发明的抗体特异性结合天然的,而不是变性的CSF-1R。
如本文中所使用的,术语“与保藏抗体DSM ACC2920结合相同表位”指结合CSF-1R上抗体<CSF-1R>9D11.2E8(保藏号DSM ACC2920)结合的相同表位的本发明的抗CSF-1R抗体。可以使用本领域中已知的技术来测定本发明的抗CSF-1R抗体的表位结合特性。于25℃在体外竞争性结合抑制测定法中通过表面等离振子共振(SPR)测定测试抗体抑制抗体<CSF-1R>9D11.2E8(保藏号DSM ACC2920)结合CSF-1R的能力来测量CSF-1R抗体。这可以通过BIAcore测定法(Pharmacia Biosensor AB,Uppsala,Sweden)调查,如例如在实施例5中。在实施例5中,与结合的抗体<CSF-1R>9D11.2E8(保藏号DSM ACC2920)竞争的本发明的CSF-1R抗体的预期结合响应的百分比(%)通过“100*相对响应(大体_稳定性_早期)/rMax”计算,其中rMax通过“相对响应(大体_稳定性_晚期)*抗体分子量/抗原分子量”计算,如记载于Biacore测定法表位定位说明书的。还自相同抗体1和2的对计算最小限度结合响应(见实施例5)。其获得的最大值+50%设置为显著竞争并且如此显著结合相同表位的阈值(见实施例5,对于抗体<CSF-1R>9D11.2E8,计算的阈值是8+4=12)。如此,以“与<CSF-1R>9D11.2E8(保藏号DSM ACC2920)结合相同表位”为特征的结合人CSF-1R的抗体具有低于12的预期结合响应的百分比(%)(小于12的%预期结合响应)。
如本文中所使用的,“可变域”(轻链可变域(VL)、重链可变域(VH))意为直接牵涉抗体结合抗原的轻和重链域对之每种。可变轻和重链域具有相同的一般结构,并且每个域包含通过三个“高变区”(或互补决定区,CDR)连接的其序列广泛保守的四个框架(FR)区。框架区采用β-片层构象,而CDR可以形成连接β-片层结构的环。每条链中的CDR通过框架区保持其三维结构,并且与来自另一条链的CDR一起形成抗原结合位点。抗体的重和轻链 CDR3区在依照本发明的抗体的结合特异性/亲和力中发挥特别重要的作用,并且因此提供本发明的又一个目的。
术语“抗体的抗原结合部分”在本文中使用时指抗体中负责抗原结合的氨基酸残基。抗体的抗原结合部分包含来自“互补决定区”或“CDR”的氨基酸残基。“框架”或“FR”区是除了如本文中所限定的高变区残基外的那些可变域区。因此,抗体的轻和重链可变域从N至C端包含域FR1、CDR1、FR2、CDR2、FR3、CDR3、和FR4。特别地,重链的CDR3是对抗原结合贡献最大并且限定抗体特性的区域。CDR和FR区依照Kabat et al.,Sequences of Proteins ofImmunological Interest,5th ed.,Public Health Service,National Institutes ofHealth,Bethesda,MD(1991)的标准定义和/或来自“高变环”的那些残基确定。
如本文中所使用的,术语“核酸”或“核酸分子”意图包括DNA分子和RNA分子。核酸分子可以是单链或双链,但是优选的是双链DNA。
如本申请内所使用的,术语“氨基酸”意指天然存在的羧基α-氨基酸的组,包括丙氨酸(三字母代码:ala,单字母代码:A)、精氨酸(arg,R)、天冬酰胺(asn,N)、天冬氨酸(asp,D)、半胱氨酸(cys,C)、谷氨酰胺(gln,Q)、谷氨酸(glu,E)、甘氨酸(gly,G)、组氨酸(his,H)、异亮氨酸(ile,I)、亮氨酸(leu,L)、赖氨酸(lys,K)、甲硫氨酸(met,M)、苯丙氨酸(phe,F)、脯氨酸(pro,P)、丝氨酸(ser,S)、苏氨酸(thr,T)、色氨酸(trp,W)、酪氨酸(tyr,Y)、和缬氨酸(val,V)。
本发明的又一个实施方案是用于生成依照本发明的针对CSF-1R的抗体的方法,其特征在于将编码结合人CSF-1R的人IgG1类抗体的重链的核酸和编码所述抗体的轻链的核酸的序列插入表达载体中,在真核宿主细胞中插入所述载体,表达编码的蛋白质,并自宿主细胞或上清液回收。
优选地,通过重组手段来生成依照本发明的抗体。此类方法是现有技术中普遍已知的,并且包括在原核和真核细胞中表达蛋白质,随后分离抗体多肽,并且通常纯化至药学可接受纯度。对于蛋白质表达,通过标准的方法将编码轻和重链或其片段的核酸插入表达载体中。在合适的原核或真核宿主细胞,如CHO细胞、NS0细胞、SP2/0细胞、HEK293细胞、COS细胞、酵母、或大肠杆菌细胞中实施表达,并且自细胞(自上清液或在细胞裂解后)回收抗体。
通过本领域中已知的多种方法来制备编码抗CSF-1R抗体的氨基酸序列变体的核酸分子。这些方法包括但不限于自天然来源分离(在天然存在的氨基酸序列变体的情况中)或者通过对较早制备的变体或非变体型式的人源化抗CSF-1R抗体进行寡核苷酸介导的(或定点)诱变、PCR诱变、和盒式诱变来制备。
将依照本发明的重和轻链可变域与启动子、翻译起始、恒定区、3’非翻译区、多腺苷酸化、和转录终止的序列组合以形成表达载体构建体。可以将重和轻链表达构建体组合入单一载体中,共转染、连续转染、或分开转染入宿主细胞中,然后,将所述宿主细胞融合以形成表达这两条链的单一宿主细胞。
抗体的重组生成是现有技术中公知的,并且例如记载于综述文章Makrides,S.C.,Protein Expr.Purif.17(1999)183-202;Geisse,S.et al.,Protein Expr.Purif.8(1996)271-282;Kaufman,R.J.,Mol.Biotechnol.16(2000)151-161;Werner,R.G.,Drug Res.48(1998)870-880。
抗体可以存在于整个细胞中,在细胞溶胞物中,或者为部分纯化的或基本上纯的形式。通过标准的技术,包括碱/SDS处理、CsCl分带、柱层析、琼脂糖凝胶电泳、和本领域中公知的其它技术来实施纯化以消除其它细胞组分或其它污染物,例如其它细胞核酸或蛋白质。见Ausubel,F.et al.eds.Current Protocols in Molecular Biology,GreenePublishing and Wiley Interscience,New York(1987)。
NS0细胞中的表达由例如Barnes,L.M.et al.,Cytotechnology32(2000)109-123;Barnes,L.M.et al.,Biotech.Bioeng.73(2001)261-270描述。瞬时表达由例如Durocher,Y.et al.,Nucl.Acids.Res.30(2002)E9描述。可变域的克隆由Orlandi,R.et al.,Proc.Natl.Acad.Sci.USA86(1989)3833-3837;Carter,P.et al.,Proc.Natl.Acad.Sci.USA89(1992)4285-4289;Norderhaug,L.et al.,J.Immunol.Methods204(1997)77-87描述。一种优选的瞬时表达系统(HEK293)由Schlaeger,E.-J.,Christensen,K.,于Cytotechnology30(1999)71-83,及由Schlaeger,E.-J.,于J.Immunol.Methods194(1996)191-199描述。
适合于原核生物的控制序列例如包括启动子,任选地操纵基因序列,和核糖体结合位点。已知真核细胞利用启动子、增强子和多腺苷酸化信号。
在将核酸放置入与另一种核酸序列的功能性关系中时,它是“可操作连接的”。例如,若前序列或分泌前导的DNA以参与多肽分泌的前蛋白表达,则它与多肽的DNA可操作连接;若启动子或增强子影响序列的转录,则它与编码序列可操作连接;或者若核糖体结合位点定位为使得便于翻译,则它与编码序列可操作连接。一般而言,“可操作连接的”意指所连接的DNA序列是连续的,并且在分泌前导的情况中,是连续的且在读码框中。然而,增强子不必是连续的。通过在方便的限制性位点处的连接来实现连接。若不存在此类位点,则依照常规的实践使用合成的寡核苷酸衔接头或接头。
通过常规的免疫球蛋白纯化规程,诸如例如蛋白A-Sepharose、羟磷灰石层析、凝胶电泳、透析、或亲和层析自培养液适当地分离单克隆抗体。容易使用常规规程将编码单克隆抗体的DNA和RNA分离并测序。杂交瘤细胞可以充当此类DNA和RNA的来源。一旦分离,可以将DNA插入表达载体中,然后将所述表达载体转染入不另外生成免疫球蛋白蛋白质的宿主细胞诸如HEK293细胞、CHO细胞、或骨髓瘤细胞中,以获得重组单克隆抗体在宿主细胞中的合成。
如本文中所使用的,表述“细胞”、“细胞系”、和“细胞培养物”可互换使用,并且所有此类名称包括后代。如此,词语“转化体”和“经转化的细胞”包括原代主题细胞和自其衍生的培养物,而不管传递的次数。还应当理解,由于有意或无意的突变,所有后代在DNA内容上可以不是正好相同的。包括具有如在初始转化细胞中筛选的相同功能或生物学活性的变体后代。
抗体的“Fc部分”不直接牵涉抗体对抗原的结合,但是展现出各种效应器功能。“抗体的Fc部分”是熟练技术人员公知的术语,并且基于木瓜蛋白酶对抗体的切割限定。根据其重链恒定区的氨基酸序列,抗体或免疫球蛋白分成类:IgA、IgD、IgE、IgG和IgM,并且这些中的数种可以进一步分成亚类(同种型),例如IgG1、IgG2、IgG3、和IgG4、IgA1、和IgA2。依照重链恒定区,免疫球蛋白的不同类分别称作α、δ、ε、γ、和μ。抗体的Fc部分直接牵涉ADCC(抗体依赖性细胞介导的细胞毒性)和CDC(补体依赖性细胞毒性),其基于补体激活、C1q结合和Fc受体结合。补体激活(CDC)通过补体因子C1q与大多数IgG抗体亚类的Fc部分的结合来启动。虽然抗体对补体系统的影响依赖于某些条件,但是对C1q的结合是由Fc部分中的限定结合位点引起的。此类结合位点是现有技术中已知的,并且例如记载于Boackle,R.J. et al.,Nature282(1979)742-743;Lukas,T.J.et al.,J.Immunol.127(1981)2555-2560;Brunhouse,R.and Cebra,J.J.,Mol.Immunol.16(1979)907-917;Burton et al.,Nature288(1980)338-344;Thommesen,J.E.et al.,Mol.Immunol.37(2000)995-1004;Idusogie,E.E.et al.,J.Immunol.164(2000)4178-4184;Hezareh,M.et al.,J.Virology75(2001)12161-12168;Morgan,A.et al.,Immunology86(1995)319-324;EP0307434。此类结合位点是例如L234、L235、D270、N297、E318、K320、K322、P331和P329(依照Kabat,E.A.的EU索引的编号方式,参见下文)。亚类IgG1、IgG2和IgG3的抗体通常显示补体激活及C1q和C3结合,而IgG4不激活补体系统,而且不结合C1q和C3。
在一个实施方案中,依照本发明的抗体包含自人起源衍生的Fc部分,和优选地人恒定区的所有其它部分。如本文中所使用的,术语“自人起源衍生的Fc部分”意指如下的Fc部分,其作为IgG1、IgG2、IgG3或IgG4亚类的人抗体的Fc部分,优选地,来自人IgG1亚类的Fc部分、来自人IgG1亚类的突变Fc部分(优选地具有L234A+L235A方面的突变)、来自人IgG4亚类的Fc部分或来自人IgG4亚类的突变Fc部分(优选地具有S228P方面的突变)。通常优选的是SEQ ID NO:19(人IgG1亚类)、SEQ ID NO:20(具有突变L234A和L235A的人IgG1亚类)、SEQID NO:21(人IgG4亚类)、或SEQ ID NO:22(具有突变S228P的人IgG4亚类)的人重链恒定区。
在一个实施方案中,依照本发明的抗体的特征在于:恒定链是人起源的。此类恒定链是现有技术中公知的,并且例如由Kabat,E.A.(见例如Johnson,G.and Wu,T.T.,NucleicAcids Res.28(2000)214-218)描述。例如,一种有用的人重链恒定区包含氨基酸序列SEQID NO:17。例如,一种有用的人轻链恒定区包含κ轻链恒定区氨基酸序列SEQ ID NO:18。进一步优选的是,抗体是小鼠起源的,并且包含依照Kabat的小鼠抗体的抗体可变序列框。
本发明包括一种用于治疗需要治疗的患者的方法,其特征在于对患者施用治疗有效量的依照本发明的抗体。
本发明包括依照本发明的抗体用于治疗的用途。
如此,依照本发明的结合相同表位的抗体能够在CSF-1配体依赖性和CSF-1配体不依赖性细胞中抑制细胞增殖。尤其是,本发明的CSF-1R抗体用于治疗CSF-1配体依赖性和CSF-1配体不依赖性CSF-1R介导的疾病。这意味着CSF1-R介导的疾病依赖于CSF-1配体和相应的经由CSF-1R的信号传导和/ 或不依赖于CSF-1配体和相应的经由CSF-1R的信号传导。经由CSF-1R的信号传导有可能涉及肿瘤生长和转移。
本发明的一个实施方案是在治疗“CSF-1R介导的疾病”中使用的本发明的CSF-1R抗体或用于制造在治疗“CSF-1R介导的疾病”(其可以如下描述)中的药物的本发明的CSF-1R抗体。
存在着CSF-1R信号传导可能牵涉肿瘤生长和转移的3种独特的机制。第一种是已经在女性生殖系统(乳房、卵巢、子宫内膜、宫颈)中起源的肿瘤细胞中发现CSF配体和受体的表达(Scholl,S.M.et al.,J.Natl.Cancer Inst.86(1994)120-126;Kacinski,B.M.,Mol.Reprod.Dev.46(1997)71-74;Ngan,H.Y.et al.,Eur.J.Cancer35(1999)1546-1550;Kirma,N.et al.,Cancer Res67(2007)1918-1926),并且表达已经与乳腺癌异种移植物生长以及乳腺癌患者中不良预后联系起来。在一项研究中测试的约10-20%急性髓细胞性白血病、慢性髓细胞性白血病和脊髓发育不良患者中在CSF-1R中看到两处点突变,并且发现突变之一破坏受体周转(Ridge,S.A.et al.,Proc.Natl.Acad.Sci USA87(1990)1377-1380)。然而,突变的发生在后来的研究中未能得到确认(Abu-Duhier,F.M.et al.,Br.J.Haematol.120(2003)464-470)。还在肝细胞癌(Yang,D.H.et al.,HepatobiliaryPancreat.Dis.Int.3(2004)86-89)和特发性骨髓纤维化(Abu-Duhier,F.M.et al.,Br.J.Haematol.120(2003)464-470)的一些病例中发现突变。
色素沉着绒毛结节性滑膜炎(PVNS)和腱鞘滑膜巨大细胞肿瘤(TGCT)可以由于将M-CSF基因与胶原基因COL6A3融合,并导致M-CSF过表达的易位而发生(West,R.B.et al.,Proc.Natl.Acad.Sci.USA103(2006)690-695)。提出景观效应(landscape effect)造成所得的肿瘤块,其由被表达M-CSF的细胞吸引的单核细胞组成。TGCT是可以自它们通常发生的指相对容易地除去的较小肿瘤。PVNS由于它可以在大的关节中复发而更具攻击性,而且不同样容易用手术控制。
第二种机制基于阻断骨中转移部位经由M-CSF/CSF-1R的信号传导,其诱导破骨细胞发生(osteoclastogenesis)、骨吸收和溶骨性骨损伤。乳腺癌、多发性骨髓瘤和肺癌是已经发现转移至骨,并且引起溶骨性骨疾病,导致骨骼并发症的癌症的例子。由肿瘤细胞和基质释放的M-CSF与核因子κ-B配体的受体激活物RANKL协作诱导造血髓样单核细胞祖先分化成成熟的破骨细 胞。在此过程期间,M-CSF通过对破骨细胞给予存活信号充当允许因子(Tanaka,S.et al.,J.Clin.Invest.91(1993)257-263)。用抗CSF-1R抗体对破骨细胞分化和成熟期间CSF-1R活性的抑制有可能阻止引起溶骨性疾病和转移性疾病中有关的骨骼相关事件的破骨细胞的不平衡活性。鉴于乳腺、肺癌和多发性骨髓瘤通常导致溶骨性损伤,前列腺癌中的骨转移最初具有成骨细胞出现,其中升高的骨形成活性导致“编织骨”,其与正常骨的典型薄片状结构不同。在疾病进展期间,骨损伤展现出显著的溶骨性组分及骨吸收的高血清水平,并且提示了抗吸收疗法可以是有用的。已经显示了二膦酸盐类抑制溶骨性损伤的形成,并且仅在具有激素不应性转移性前列腺癌的男性中减少骨骼相关事件的数目,但是在这点上,其对成骨细胞损伤的影响是有争议的,并且二膦酸盐类至今在预防骨转移或激素响应性前列腺癌中尚不是有益的。抗吸收剂在混合性溶骨性/成骨细胞性前列腺癌中的效果在临床中仍在研究(Choueiri,M.B.et al.,Cancer Metastasis Rev.25(2006)601-609;Vessella,R.L.and Corey,E.,Clin.Cancer Res.12(20Pt2)(2006)6285s-6290s)。
第三种机制基于最近的观察结果,即存在于乳癌、前列腺、卵巢和宫颈癌的实体瘤中的肿瘤有关的巨噬细胞(TAM)与不良预后相关联(Bingle,L.et al.,J.Pathol.196(2002)254-265;Pollard,J.W.,Nat.Rev.Cancer4(2004)71-78)。巨噬细胞通过M-CSF和其它趋化因子募集至肿瘤。然后,巨噬细胞可以经由分泌血管生成因子、蛋白酶和其它生长因子和细胞因子促成肿瘤进展,并且可以通过抑制CSF-1R信号传导而阻断。最近,Zins等(Zins,K.et al.,Cancer Res.67(2007)1038-1045)显示了肿瘤坏死因子α(TNFα)、M-CSF或这两者的组合的siRNA的表达会在相应siRNA的肿瘤内注射后将小鼠异种移植物模型中的肿瘤生长降低34%-50%。靶向由人SW620细胞分泌的TNFα的siRNA降低小鼠M-CSF水平,并且导致肿瘤中的巨噬细胞减少。另外,用针对M-CSF的抗原结合片段处理MCF7肿瘤异种移植物确实导致40%肿瘤生长抑制,反转对化疗剂的抗性,而且在与化疗剂组合给予时改善小鼠的存活(Paulus,P.et al.,Cancer Res.66(2006)4349-4356)。
TAM是慢性炎症和癌症间新出现联系的唯一一个例子。炎症与癌症间的联系存在着别的证据,因为许多慢性疾病与升高的癌症风险有关,癌症在慢性炎症的部位出现,在许多癌症中找到炎症的化学介导物;删除炎症的细胞或化学介导物抑制实验性癌症的形成,并且抗炎剂的长期使用降低一些癌症 的风险。那些幽门螺杆菌(H.pylori)诱导的胃炎(对于胃癌)、血吸虫病(对于膀胱癌)、HHVX(对于卡波西(Kaposi)肉瘤)、子宫内膜异位症(endometriosis)(对于卵巢癌)和前列腺炎(对于前列腺癌)中的许多炎性状况存在与癌症的联系(Balkwill,F.et al.,Cancer Cell7(2005)211-217)。巨噬细胞是慢性炎症中的关键细胞,并且差别响应其微环境。存在着在功能性状态的连续区中被认为是极端的两类巨噬细胞:M1巨噬细胞牵涉1型反应。这些反应牵涉通过微生物产物的激活及随后杀死病原性微生物,这生成反应性氧中间体。极端的另一端是牵涉2型反应的M2巨噬细胞,所述2型反应促进细胞增殖、调整炎症和适应性免疫,而且促进组织重塑、血管发生和修复(Mantovani,A.et al.,Trends Immunol.25(2004)677-686)。导致建立的新生物形成的慢性炎症通常与M2巨噬细胞有关。介导炎性反应的一种枢要的细胞因子是TNFα,其名符其实在高剂量能刺激抗肿瘤免疫和出血性坏死,而且最近还已经发现了由肿瘤细胞表达,并且充当肿瘤促进物(Zins,K.et al.,Cancer Res.67(2007)1038-1045;Balkwill,F.,Cancer MetastasisRev.25(2006)409-416)。巨噬细胞就肿瘤而言的特定作用仍需要更好地了解,包括对其功能的潜在空间和时间依赖性和与特定肿瘤类型的相关性。
如此,本发明的一个实施方案是在治疗癌症中使用的本发明的CSF-1R抗体。如本文中所使用的,术语“癌症”可以例如是肺癌、非小细胞肺(NSCL)癌、细支气管肺泡细胞肺癌、骨癌、胰腺癌、皮肤癌、头或颈癌、皮肤或眼内黑素瘤、子宫癌、卵巢癌、直肠癌、肛区癌、胃癌(stomach cancer)、胃癌(gastric cancer)、结肠癌、乳腺癌、子宫癌、输卵管癌、子宫内膜癌、宫颈癌、阴道癌、外阴癌、何杰金(Hodgkin)氏病、食管癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、前列腺癌、膀胱癌、肾或输尿管癌、肾细胞癌、肾盂癌、间皮瘤、肝细胞癌、胆癌(biliary cancer)、中枢神经系统(CNS)新生物、脊柱轴肿瘤、脑干胶质瘤、多形性成胶质细胞瘤(glioblastoma multiforme)、星形细胞瘤、神经鞘瘤(schwanoma)、室鼓膜瘤(ependymona)、髓母细胞瘤、脑脊膜瘤、鳞状细胞癌、垂体腺瘤、淋巴瘤、淋巴细胞性白血病,包括任何上述癌症的顽固性型式、或一种或多种上述癌症的组合。优选地,此类癌症是乳腺癌、卵巢癌、宫颈癌、肺癌或前列腺癌。优选地,此类癌症的进一步特征在于CSF-1或CSF-1R表达或过表达。本发明的又一个实施方案是在原发性肿瘤和新的转 移的同时治疗中使用的本发明的CSF-1R抗体。
如此,本发明的另一个实施方案是在治疗牙周炎、组织细胞增多病X、骨质疏松、佩吉特(Paget)氏骨病(PDB)、由于癌症疗法所致的骨损失、假体周围骨质溶解、糖皮质素诱导的骨质疏松、类风湿性关节炎、银屑病关节炎(psioratic arthritis)、骨关节炎(osteoarthritis)、炎性关节炎(inflammatory arthridities)、和炎症中使用的本发明的CSF-1R抗体。
Rabello,D.et al.,Biochem.Biophys.Res.Commun.347(2006)791-796已经表明CSF1基因中的SNP展现出与攻击性牙周炎:即一种由于牙槽骨的吸收引起牙损失的牙周组织炎性疾病的正关联。
组织细胞增多病X(又称作朗格汉斯细胞组织细胞增多病,LCH)是一种表现为在骨和骨外LCH损伤中分化成破骨细胞的朗格汉斯树突细胞的增殖性疾病。朗格汉斯细胞自循环单核细胞衍生。发现在血清和损伤中测量到的升高的M-CSF水平与疾病严重性相关联(daCosta,C.E.et al.,J.Exp.Med.201(2005)687-693)。疾病主要在儿科患者群体中发生,并且在疾病变为系统性或者是复发性时不得不用化学疗法治疗。
骨质疏松的病理生理学是由形成骨的造骨细胞的损失和增加的破骨细胞依赖性骨吸收介导的。Cenci等已经描述了支持性数据,其显示了抗M-CSF抗体注射在切除卵巢的小鼠中保护骨密度并且抑制骨吸收(Cenci,S.et al.,J.Clin.Invest.105(2000)1279-1287)。最近,鉴定由于雌激素缺乏所致的绝经后骨损失间的潜在联系,并且发现了TNFα生成T细胞的存在影响骨代谢(Roggia,C.et al.,Minerva Med.95(2004)125-132)。一种可能的机制可能是TNFα在体内诱导M-CSF。通过阻断小鼠中TNFα诱导的骨质溶解的针对M-CSF的抗体的效果确认M-CSF在TNF-α诱导的破骨细胞发生中的重要作用,并且由此生成炎性关节炎的CSF-1R信号传导潜在的靶物的抑制剂(Kitaura,H.et al.,J.Clin.Invest.115(2005)3418-3427)。
佩吉特氏骨病(PDB)是骨质疏松后第二位最常见的骨代谢病症,其中骨周转升高的病灶性异常导致并发症诸如骨痛、畸形、病理性骨折和耳聋。已经鉴定出四种基因中的突变,其调节正常的破骨细胞功能,并且使个体易患PDB及相关病症:TNFRSF11A(其编码核因子(NF)κB的受体激活物(RANK),即破骨细胞功能的一种至关重要的调节物)中的插入突变、编码护骨蛋白(RANK配体的诱饵受体)的TNFRSF11B的失活突变、 Sequestosome1基因(SQSTM1)(其编码NFκB途径中的重要支架蛋白)的突变和含有缬酪肽的蛋白质(VCP)基因中的突变。此基因编码VCP,其在使NFκB抑制剂靶向蛋白酶体所致降解中具有作用(Daroszewska,A.and Ralston,S.H.,Nat.Clin.Pract.Rheumatol.2(2006)270-277)。靶向性CSF-1R抑制剂提供一个间接阻断RANKL信号传导脱调节的机会,并且对目前使用的二膦酸盐类添加额外的治疗选项。
癌症疗法诱导的骨损失(尤其在乳腺和前列腺癌患者中)是一种别的适应症,其中靶向性CSF-1R抑制剂可以预防骨损失(Lester,J.E.et al.,Br.J.Cancer94(2006)30-35)。随着早期乳腺癌的预后改善,辅助疗法的长期后果变得更加重要,因为一些疗法,包括化学疗法、放射、芳香酶抑制剂和卵巢切除通过降低骨矿物密度影响骨代谢,导致骨质疏松及有关的骨折的风险升高(Lester,J.E.et al.,Br.J.Cancer94(2006)30-35)。乳腺癌中的辅助芳香酶抑制剂疗法的等同方案是前列腺癌中的雄激素消融疗法,其导致骨矿物密度损失,而且显著增加骨质疏松相关骨折的风险(Stoch,S.A.et al.,J.Clin.Endocrinol.Metab.86(2001)2787-2791)。
对CSF-1R信号传导的靶向性抑制在靶定的细胞类型包括破骨细胞和巨噬细胞时在其它适应症中也可能是有益的,例如治疗响应关节置换术(由于类风湿性关节炎)的特定并发症。由于假体周围骨损失及随后的假体松弛所致的植入失败是关节置换术的一个主要并发症,并且需要重复手术,对于个体患者和健康护理系统造成高的社会经济负担。至今,没有用于预防或抑制假体周围骨质溶解的得到批准的药物疗法(Drees,P.et al.,Nat.Clin.Pract.Rheumatol.3(2007)165-171)。
糖皮质素诱导的骨质疏松(GIOP)是另一种适应症,其中CSF-1R抑制剂可以阻止由于那些慢性阻塞性肺疾病、哮喘和类风湿性关节炎的各种状况而给予的长期糖皮质类固醇使用后的骨损失(Guzman-Clark,J.R.et al.,Arthritis Rheum.57(2007)140-146;Feldstein,A.C.et al.,Osteoporos.Int.16(2005)2168-2174)。
类风湿性关节炎、银屑病关节炎和炎性关节炎本身是CSF-1R信号传导抑制剂的潜在适应症,因为它们由巨噬细胞组分和不同程度骨破坏组成(Ritchlin,C.T.et al.,J.Clin.Invest.111(2003)821-831)。骨关节炎和类风湿性关节炎是由巨噬细胞在结缔组织中积累和巨噬细胞浸润入滑液中(其 由M-CSF至少部分介导)引起的炎性自身免疫性疾病。Campbell,I.K.et al.,J.Leukoc.Biol.68(2000)144-150表明人-关节组织细胞(软骨细胞、滑膜成纤维细胞)在体外生成M-CSF,并且其存在于类风湿性关节炎患者的滑液中,提示了它促成与疾病的发病机制有关的巨噬细胞浸润和滑膜组织增殖。对CSF-1R信号传导的抑制有可能控制关节中巨噬细胞的数目,并且减轻来自有关的骨破坏的疼痛。为了使不利影响最小化并且为了进一步了解CSF-1R信号传导在这些适应症中的影响,一种方法是特异性抑制CSF-1R,而不靶向无数其它激酶,诸如Raf激酶。
最近的文献报告将增加的循环M-CSF与慢性冠状动脉疾病中的不良预后和动脉粥样硬化进展联系起来(Saitoh,T.et al.,J.Am.Coll.Cardiol.35(2000)655-665;Ikonomidis,I.et al.,Eur.Heart.J.26(2005)第1618-1624页);M-CSF通过帮助形成表达CSF-1R并且呈现初始斑块的泡沫细胞(具有摄取的氧化的LDL的巨噬细胞)影响动脉粥样硬化过程(Murayama,T.et al.,Circulation99(1999)1740-1746)。
在活化的小胶质中找到M-CSF和CSF-1R的表达和信号传导。小胶质(其是中枢神经系统的驻留巨噬细胞)可以通过多种损伤,包括感染和创伤性损伤活化。认为M-CSF是脑中炎性应答的一种关键调节物,并且M-CSF水平在HIV-1、脑炎、阿耳茨海默(Alzheimer)氏病(AD)和脑肿瘤中升高。由于M-CSF/CSF-1R的自分泌信号传导所致的小胶质细胞增生(microgliosis)导致诱导炎性细胞因子和一氧化氮释放,如通过例如使用实验性神经元损伤模型证明的(Hao,A.J.et al.,Neuroscience112(2002)889-900;Murphy,G.M.,Jr.etal.,J.Biol.Chem.273(1998)20967-20971)。发现具有升高的CSF-1R表达的小胶质在AD中及在AD的淀粉样前体蛋白V717F转基因小鼠模型中围绕斑块(Murphy,G.M.,Jr.et al.,Am.J.Pathol.157(2000)895-904)。另一方面,与正常对照相比,在脑中具有较少小胶质的op/op小鼠导致A-β的原纤维沉积和神经元损失,提示了小胶质在op/op小鼠中在AD缺乏的形成中确实具有神经保护性功能(Kaku,M.et al.,Brain Res.Brain Res.Protoc.12(2003)104-108)。
M-CSF和CSF-1R的表达和信号传导与炎性肠病(IBD)有关(WO2005/046657)。术语“炎性肠病”指以胃肠道中多个部位的慢性炎症为特征的严重的、慢性的肠道病症,并且明确包括溃疡性结肠炎(UC)和克罗恩 (Crohn)氏病。
本发明包括用于治疗癌症的抗体,其特征在于包括结合人CSF-1R的抗体,所述结合人CSF-1R的抗体特征在于上文所提及的表位结合特性或者备选地上文提及的氨基酸序列和氨基酸序列片段。
本发明包括用于治疗骨损失的抗体,其特征在于包括结合人CSF-1R的抗体,所述结合人CSF-1R的抗体特征在于上文所提及的表位结合特性或者备选地上文提及的氨基酸序列和氨基酸序列片段。
本发明包括用于预防或治疗转移的抗体,其特征在于包括结合人CSF-1R的抗体,所述结合人CSF-1R的抗体特征在于上文所提及的表位结合特性或者备选地上文提及的氨基酸序列和氨基酸序列片段。
本发明包括用于治疗炎性疾病的抗体,其特征在于包括结合人CSF-1R的抗体,所述结合人CSF-1R的抗体特征在于上文所提及的表位结合特性或者备选地上文提及的氨基酸序列和氨基酸序列片段。
本发明包括抗体用于治疗癌症或者备选地用于制造供治疗癌症用的药物的用途,所述抗体特征在于包括结合人CSF-1R的抗体,所述结合人CSF-1R的抗体特征在于上文所提及的表位结合特性或者备选地上文提及的氨基酸序列和氨基酸序列片段。
本发明包括抗体用于治疗骨损失或者备选地用于制造供治疗骨损失用的药物的用途,所述抗体特征在于包括结合人CSF-1R的抗体,所述结合人CSF-1R的抗体特征在于上文所提及的表位结合特性或者备选地上文提及的氨基酸序列和氨基酸序列片段。
本发明包括抗体用于预防或治疗转移或者备选地用于制造供预防或治疗转移用的药物的用途,所述抗体特征在于包括结合人CSF-1R的抗体,所述结合人CSF-1R的抗体特征在于上文所提及的表位结合特性或者备选地上文提及的氨基酸序列和氨基酸序列片段。
本发明包括抗体用于治疗炎性疾病或者备选地用于制造供治疗炎性疾病用的药物的用途,所述抗体特征在于包括结合人CSF-1R的抗体,所述结合人CSF-1R的抗体特征在于上文所提及的表位结合特性或者备选地上文提及的氨基酸序列和氨基酸序列片段。
在一个实施方案中,依照本发明的抗体具有一项或多项下述特性:
a)于抗体浓度10μg/ml将NIH3T3-野生型CSF-1R重组细胞的生长抑制 90%或更多(见实施例2);
b)于抗体浓度10μg/ml将NIH3T3-突变型CSF-1R L301S Y969F重组细胞的生长抑制60%或更多(例如见实施例2);
c)抑制CSF-1/CSF-1R相互作用(例如IC50值为15ng/ml或更低)(见实施例3);
d)在野生型NIH3T3-CSF-1R重组细胞中抑制CSF-1诱导的CSF-1R磷酸化(例如IC50值为80ng/ml或更低)(见实施例4);
e)抑制BeWo肿瘤细胞的生长(例如于抗体浓度10μg/ml抑制80%或更多)(见实施例7);
f)抑制巨噬细胞分化(例如IC50值为0.8nM或更低)(见实施例8)。
一方面,本发明包括一种结合人CSF-1R的抗体,其中所述抗体与保藏抗体DSMACC2920结合相同表位且其中所述抗体具有一项或多项下述特性:
a)于抗体浓度10μg/ml将NIH3T3-野生型CSF-1R重组细胞的生长抑制90%或更多(见实施例2);
b)于抗体浓度10μg/ml将NIH3T3-突变型CSF-1R L301S Y969F重组细胞的生长抑制60%或更多(例如见实施例2);
c)抑制CSF-1/CSF-1R相互作用(例如IC50值为15ng/ml或更低)(见实施例3);
d)在野生型NIH3T3-CSF-1R重组细胞中抑制CSF-1诱导的CSF-1R磷酸化(例如IC50值为80ng/ml或更低)(见实施例4);
e)抑制BeWo肿瘤细胞的生长(例如于抗体浓度10μg/ml抑制80%或更多)(见实施例7);
f)抑制巨噬细胞分化(例如IC50值为0.8nM或更低)(见实施例8)。
在另一方面,本发明提供了含有与药学可接受载体一起配制的一种或一组的本发明的单克隆抗体或其抗原结合部分的组合物,例如药物组合物。
如本文中所使用的,“药学可接受载体”包括生理学相容的任何和所有溶剂、分散介质、涂层材料、抗细菌剂和抗真菌剂、等张剂和吸收延迟剂、等等。优选地,载体适合于注射或输注。
可以通过本领域中已知的多种方法来施用本发明的组合物。如熟练技术人员会领会的,施用的路径和/或模式会随期望的结果而变化。
药学可接受载体包括无菌水溶液或分散体和供制备无菌可注射溶液或 分散体用的无菌粉剂。对药学活性物质使用此类介质和药剂是本领域中已知的。在水外,载体可以是例如等张缓冲盐水溶液。
不管选择的施用路径,通过本领域技术人员已知的常规方法来将本发明的化合物(其可以以合适的水合形式使用)和/或本发明的药物组合物配制成药学可接受剂量形式。
可以改变活性成分在本发明的药物组合物中的实际剂量水平,从而获得对于实现特定患者的期望的治疗响应、组成、和施用模式有效的,而对患者无毒的活性成分量(有效量)。选定的剂量水平会取决于多种药动学因素,包括所采用的本发明的特定组合物,或其酯、盐或酰胺的活性、施用路径、施用时间、所采用的特定化合物的排泄速率、与所采用的特定组合物组合使用的其它药物、化合物和/或材料、所治疗的患者的年龄、性别、重量、状况、一般健康和先前的医学史等医学领域公知的因素。
本发明包括依照本发明的抗体用于治疗患有癌症,尤其是结肠、肺或胰腺癌的患者的用途。
本发明还包括用于治疗患有此类疾病的患者的方法。
本发明进一步提供了用于制造包含有效量的依照本发明的抗体及药学可接受载体的药物组合物的方法和依照本发明的抗体用于此类方法的用途。
本发明进一步提供了有效量的依照本发明的抗体用于制造药剂(优选地与药学可接受载体一起)以治疗患有癌症的患者的用途。
本发明还提供了有效量的依照本发明的抗体用于制造药剂(优选地与药学可接受载体一起)以治疗患有癌症的患者的用途。
提供以下实施例和序列表来帮助理解本发明,其实际范围在所附权利要求书中列出。应当理解,可以在不背离本发明精神的前提下在所列的规程中做出修改。
抗体保藏
依照本发明优选的杂交瘤细胞系,杂交瘤细胞系<CSF-1R>9D11.2E,依照国际承认用于专利程序的微生物保藏布达佩斯条约于2008年6月10日保藏于德意志微生物和细胞培养物保藏中心(Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH,DSMZ,德国),登录号DSM ACC2920。
细胞系 | 保藏号 | 保藏日 |
<CSF-1R>9D11.2E8 | DSM ACC2920 | 2008年06月10日 |
自所述细胞系可获得的抗体是本发明的优选实施方案。
序列的描述
SEQ ID NO:1 重链CDR3,<CSF-1R>9D11.2E8
SEQ ID NO:2 重链CDR2,<CSF-1R>9D11.2E8
SEQ ID NO:3 重链CDR1,<CSF-1R>9D11.2E8
SEQ ID NO:4 轻链CDR3,<CSF-1R>9D11.2E8
SEQ ID NO:5 轻链CDR2,<CSF-1R>9D11.2E8
SEQ ID NO:6 轻链CDR1,<CSF-1R>9D11.2E8
SEQ ID NO:7 重链可变域,<CSF-1R>9D11.2E8
SEQ ID NO:8 轻链可变域,<CSF-1R>9D11.2E8
SEQ ID NO:9 重链CDR3,<CSF-1R>10H2.2F12
SEQ ID NO:10 重链CDR2,<CSF-1R>10H2.2F12
SEQ ID NO:11 重链CDR1,<CSF-1R>10H2.2F12
SEQ ID NO:12 轻链CDR3,<CSF-1R>10H2.2F12
SEQ ID NO:13 轻链CDR2,<CSF-1R>10H2.2F12
SEQ ID NO:14 轻链CDR1,<CSF-1R>10H2.2F12
SEQ ID NO:15 重链可变域,<CSF-1R>10H2.2F12
SEQ ID NO:16 轻链可变域,<CSF-1R>10H2.2F12
SEQ ID NO:17 γ1重链恒定区
SEQ ID NO:18 κ轻链恒定区
SEQ ID NO:19 自IgG1衍生的人重链恒定区
SEQ ID NO:20 在L234A和L235A上突变的自IgG1衍生的人重链恒定区
SEQ ID NO:21 自IgG4衍生的人重链恒定区
SEQ ID NO:22 在S228P上突变的自IgG4衍生的人重链恒定区
SEQ ID NO:23 野生型CSF-1R(wt CSF-1R)
SEQ ID NO:24 突变型CSF-1R L301S Y969F
提供以下实施例、序列表和图来帮助理解本发明,其实际范围在所附权利要求书中列出。应当理解,可以在不背离本发明精神的前提下在所列的规程中做出修改。
实施例1
生成抗CSF-1R抗体的杂交瘤细胞系的生成
NMRI小鼠的免疫规程
通过利用电穿孔用编码huCSF-1R的胞外域的表达载体pDisplayTM(Invitrogen,USA)免疫NMRI小鼠。用100μg DNA将每只小鼠免疫4次。在发现抗huCSF-1R的血清滴度足够时,在融合前4和3天用200μl PBS中50μg1:1混合物huCSF-1R ECD/huCSF-1R ECDhuFc嵌合物静脉内(i.v.)将小鼠额外加强一次。
抗原特异性ELISA
通过抗原特异性ELISA测定经免疫小鼠的血清中的抗CSF-1R滴度。
在具有0.1mg/ml生物素化的抗Fcγ(Jackson ImmunoResearch,产品目录编号109-066-098)的链霉亲合素板(MaxiSorb;MicroCoat,DE,产品目录编号11974998/MC1099)上捕获0.3μg/ml huCSF1R-huFc嵌合物(可溶性胞外域),并添加在PBS/0.05%Tween20/0.5%BSA中以1/800稀释的辣根过氧化物酶(HRP)缀合的F(ab’)2抗小鼠IgG(GEHealthcare,UK,产品目录编号NA9310V)。将来自所有抽液(tap)的血清在PBS/0.05%Tween20/0.5%BSA中以1/40稀释,并连续稀释,直至1/1638400。将稀释的血清添加至孔。抽液前血清作为阴性对照使用。使用自500ng/ml至0,25ng/ml的小鼠抗人CSF-IR单抗3291(R&D Systems,UK)的稀释系列作为阳性对照。将所有组分一起温育1.5小时。用PBST(PBS/0.2%Tween20)将孔清洗6次,并于RT用新鲜制备的溶液(1mg/ml)(ABTS:2,2’-连氮基二(3-乙基苯并噻唑啉-6-磺酸))显现测定法10分钟。于405nm测量吸光度。
杂交瘤生成
可以将小鼠淋巴细胞分离,并使用基于PEG的标准方案与小鼠骨髓瘤细胞系融合以生成杂交瘤。然后,对所得的杂交瘤筛选抗原特异性抗体的生成。例如,用50%PEG将来自经免疫小鼠的脾衍生淋巴细胞的单细胞悬浮液与Ag8非分泌性小鼠骨髓瘤细胞P3X63Ag8.653(ATCC,CRL-1580)融合。将细胞以约104个在平底96孔微量滴定板中分配,接着在选择性培养基中温育约2周。然后,通过ELISA对个别孔筛选人抗CSF-1R单克隆IgM和IgG抗体。一旦发生广泛的杂交瘤生长,将分泌抗体的杂交瘤再分配,再次筛选,并且若在人IgG方面仍呈阳性,可以通过FACS亚克隆抗CSF-1R单克隆抗体。然后,在体外培养稳定的亚克隆以在组织培养液中生成抗体以进行表征。
杂交瘤的培养
将生成的鼠单抗杂交瘤在补充有2mM L-谷氨酰胺(GIBCO-产品目录编号35050-038)、1mM丙酮酸钠(GIBCO-产品目录编号11360-039)、1xNEAA(GIBCO-产品目录编号11140-035)、10%FCS(PAA-产品目录编号A15-649)、1x Pen Strep(Roche-产品目录编号1074440)、1x Nutridoma CS(Roche-产品目录编号1363743)、50μM巯基乙醇(GIBCO-产品目录编号31350-010)和50U/ml IL6小鼠(Roche-产品目录编号1444581)的RPMI1640(PAN–产品目录编号PO4-17500)中于37℃和5%CO2培养。
实施例2
经由抗CSF-1R单克隆抗体处理下对3D培养中NIH3T3-CSF-1R(野生型CSF-1R或突变型CSF-1R L301S Y969F)重组细胞的生长抑制(CellTiterGlo测定法)来选择抗体
将用全长野生型CSF-1R(SEQ ID NO:23)或突变型CSF-1R L301S Y969F(SEQ IDNO:24)的表达载体以逆转录病毒感染的NIH3T3细胞(ATCC No.CRL-2795)在补充有2mM L-谷氨酰胺、2mM丙酮酸钠和非必需氨基酸和10%胎牛血清(Sigma,Taufkirchen,Germany)的DMEM高葡萄糖培养基(PAA,Pasching,Austria)中在经聚HEMA(聚(2-羟乙基甲基丙烯酸酯))(Polysciences,Warrington,PA,USA))包被(以防止对塑料表面的粘着)的皿上培养。将细胞在用5ng/ml亚硒酸钠、10mg/ml转铁蛋白、400μg/ml BSA和0.05mM2-巯基乙醇替换血清的培养基中接种。在用100ng/ml huCSF-1(Biomol,Hamburg,Germany)处理时,表达wtCSF-1R的细胞形成三维生长的密集球状体,即一种称作贴壁不依赖性的特性。这些球状体极其类似原位实体瘤的三维结构和组织。
突变型CSF-1R重组细胞能够不依赖于CSF-1配体形成球状体。将球状体培养物在存在10μg/ml抗体的情况中温育3天。使用CellTiterGlo测定法来通过测量细胞的ATP含量检测细胞存活力。
表1a:在CSF-1R抗体处理下表达野生型或突变型CSF-1R的细胞的存活
**15个不同实验的平均值,
***6个不同实验的平均值
表1b:对NIH3T3-野生型CSF-1R或突变型CSF-1R L301S Y969F重组细胞生长的抑制
**15个不同实验的平均值,
***6个不同实验的平均值
如此,依照本发明的结合相同表位的抗体能够在CSF-1配体依赖性和/或CSF-1配体不依赖性细胞中抑制细胞增殖。
在又一项实验中,对抗CSF-1R抗体1.2.SM1.19(WO2009/026303中记载的配体置换性CSF-1R抗体)、CXIIG6(WO2009/112245中记载的配体置换性CSF-1R抗体)、山羊多克隆抗CSF-1R抗体ab10676(abcam)调查它们抑制NIH3T3-突变型CSF-1R L301S Y969F生长的能力。将球状体培养物在存在不同浓度的抗体的情况中温育3天以测定IC30(细胞存活力抑制30%的浓度)。最大浓度为20μg/ml。使用CellTiterGlo测定法通过测量细胞的ATP含量来检测细胞存活力。
对于所有三种CSF-1R抗体(1.2.SM1.19,CXIIG6,和ab10676),即使在最高浓度20μg/ml,NIH3T3-突变型CSF-1R L301S Y969F重组细胞的生长抑制百分比为0%或甚至更低(这意味着1.2.SM1.19和CXIIG6不仅不能够抑制此类NIH3T3-突变型CSF-1R L301S Y969F重组细胞的细胞生长,反而它们甚至刺激此类细胞的生长(1.2.SM1.19在20μg/ml显示19%刺激,而CXIIG6在20μg/ml显示36%刺激))。
实施例3
对CSF-1/CSF-1R相互作用的抑制(ELISA)
在384孔微量滴定板(MicroCoat,DE,产品目录编号464718)上于RT实施测试。在每个温育步骤后,用PBST将板清洗3次。
开始时,用0.5mg/ml山羊F(ab’)2生物素化的抗Fcγ(Jackson ImmunoResearch.,产品目录编号109-006-170)将板包被1小时。
此后,用补充有0.2%和2%BSA的PBS(Roche Diagnostics GmbH,DE)将孔封闭0.5小时。将75ng/ml huCSF1R-huFc嵌合物(可溶性胞外域)固定化于板达1小时。然后,将纯化的抗体在PBS/0.05%Tween20/0.5%BSA中的稀释液温育1小时。在添加3ng/mlCSF-1(Biomol,DE,产品目录编号60530)、50ng/ml生物素化的抗CSF-1克隆BAF216(R&DSystems,UK)和1:5000稀释的链霉亲合素HRP(Roche Diagnostics GmbH,DE,产品目录编号11089153001)的混合物达1小时后,用PBST将板清洗6次。使用抗CSF-IR SC-02,克隆2-4A5(Santa Cruz Biotechnology,US)(其抑制配体-受体相互作用)作为阳性对照。用新鲜制备的BMPOD底物溶液(BM3,3’-5,5’-四甲基联苯胺,Roche Diagnostics GmbH,DE,产品目录编号11484281001)将板于RT显现30分钟。于370nm测量吸光度。所有抗CSF-1R抗体都显示对CSF-1结合CSF-1R的显著抑制(见表2)。使用抗CSF-IR SC-02,克隆2-4A5(Santa Cruz Biotechnology,US)(其抑制配体-受体相互作用)作为参照对照。
表2:抑制CSF-1/CSF-1R相互作用的计算IC50值
实施例4
对NIH3T3-CSF-1R重组细胞中CSF-1诱导的CSF-1R磷酸化的抑制
将4.5x103个用全长CSF-1R(SEQ ID NO:23)的表达载体以逆转录病毒感染的NIH3T3细胞在DMEM(PAA产品目录编号E15-011)、2mM L-谷氨酰胺(Sigma,产品目录编号G7513)、2mM丙酮酸钠、1x非必需氨基酸、10%FKS(PAA,产品目录编号A15-649)和100μg/mlPenStrep(Sigma,产品目录编号P4333[10mg/ml])中培养,直至它们达到汇合。此后,将细胞用补充有亚硒酸钠[5ng/ml](Sigma,产品目录编号S9133)、转铁蛋白[10μg/ml](Sigma,产品目录编号T8158)、BSA[400μg/ml](Roche Diagnostics GmbH,产品目录编号10735078)、4mM L-谷氨酰胺(Sigma,产品目录编号G7513)、 2mM丙酮酸钠(Gibco,产品目录编号11360)、1x非必需氨基酸(Gibco,产品目录编号:11140-035)、2-巯基乙醇[0,05mM](Merck,产品目录编号M7522)、100μg/ml和PenStrep(Sigma,产品目录编号P4333)的无血清DMEM培养基(PAA产品目录编号E15-011)清洗,并在30μl相同培养基中温育16小时以容许受体上调。对细胞添加10μl稀释的抗CSR-1R抗体达1.5小时。然后,用10μl100ng/ml huM-CSF-1(Biomol产品目录编号60530)将细胞刺激5分钟。温育后,除去上清液,将细胞用80μl冰冷的PBS清洗两次,并添加每10ml缓冲液50μl新鲜制备的冰冷的裂解缓冲液(150mM NaCl/20mMTris pH7.5/1mM EDTA/1mM EGTA/1%Triton X-100/1片蛋白酶抑制剂片(RocheDiagnostics GmbH产品目录编号1836170)/10μl/ml磷酸酶抑制剂混合物1(Sigma产品目录编号P-2850,100x储液)/10μl/ml蛋白酶抑制剂1(Sigma产品目录编号P-5726,100x储液)/10μl/ml1M NaF)。在冰上30分钟后,将板在摇板仪上有力摇动3分钟,然后,以2200rpm离心10分钟(Heraeus Megafuge10)。
用Elisa分析细胞裂解物中磷酸化的和总的CSF-1受体的存在。对于检测磷酸化的受体,依照供应商的用法说明书使用来自R&D Systems(产品目录编号DYC3268-2)的试剂盒。对于检测总的CSF-1R,通过使用试剂盒中含有的捕捉抗体将10μl裂解物固定化于板上。此后,添加1:750稀释的生物素化的抗CSF-1R抗体BAF329(R&D Systems)和1:1000稀释的链霉亲合素-HRP缀合物。在60分钟后,用新鲜制备的溶液将板显现,并检测吸光度。数据以没有抗体情况中的阳性对照%计算,并且表示比率值磷酸/总受体。在没有添加M-CSF-1的情况中限定阴性对照。使用抗CSF-1R SC-02,克隆2-4A5(Santa CruzBiotechnology,US,还可见Sherr,C.J.et al.,Cell41(1985)665-676)(其抑制配体-受体相互作用)作为参照对照。
表3:抑制CSF-1受体磷酸化的计算IC50值
实施例5
测定抗CSF-1R抗体对CSF-1R的亲和力
仪器: A100
芯片: CM5(Biacore BR-1006-68)
偶联: 胺偶联
缓冲液: PBS(Biacore BR-1006-72),pH7.4,35℃
对于亲和力测量,将36μg/ml抗小鼠Fcγ抗体(来自山羊,Jackson ImmunoResearch JIR115-005-071)与芯片表面偶联以捕捉针对CSF-1R的抗体。将CSF-1R ECD(R&D-Systems 329-MR或内部亚克隆的pCMV-presS-HisAvitag-hCSF-1R-ECD)在溶液中以多种浓度添加。通过于35℃注射CSF-1R1.5分钟测量结合;通过于35°用缓冲液清洗芯片表面10分钟测量解离。使用抗CSF-IR SC-02,克隆2-4A5(Santa Cruz Biotechnology,US;还可见Sherr,C.J.et al.,Cell41(1985)665-676)(其抑制配体-受体相互作用)作为参照对照。
对于动力学参数的计算,使用朗缪尔(Langmuir)1:1模型。
表4:于35℃通过SPR(A100)测量的亲和力数据
克隆 | KD(nM) | ka(1/Ms) | kd(1/s) | t1/2(分钟) |
<CSF-1R>9D11.2E8 | 0.77 | 4.7E+05 | 3.6E-04 | 32.00 |
<CSF-1R>10H2.2F12 | 0.78 | 5.2E+05 | 4.0E-04 | 28.60 |
SC-2-4A5 | 2.73 | 5.09E+05 | 1.39E-03 | 8.31 |
实施例6
通过利用SPR基于交叉竞争对抗CSF-1R单克隆抗体的表位定位
仪器: A100
芯片: CM5(Biacore BR-1006-68)
偶联: 胺偶联
缓冲液: PBS(Biacore BR-1006-72),pH7.4,25℃
对于经由交叉竞争的表位定位测定法,将36μg/ml抗小鼠Fcγ抗体或抗大鼠Fcγ抗体(来自山羊,Jackson Immuno Research产品目录编号115-005-071和产品目录编号112-005-071)与传感器芯片表面偶联以呈现针对CSF-1R的 抗体。在自5μg/ml抗CSF-1R单克隆抗体捕捉后,用250μg/ml小鼠或大鼠免疫球蛋白(Pierce产品目录编号31202和Pierce产品目录编号31233)封闭捕捉抗体的自由结合能力,接着注射12.5μg/ml CSF-1R(R&D-Systems产品目录编号329-MR)达2分钟。通过注射2分钟分析第二抗CSF-1R抗体的结合,通过用缓冲液清洗5分钟测量解离。于25℃进行测定法和测量。针对用相同芯片设置,但仅仅不注射CSF-1R的点比照第二抗CSF-1R抗体的特异性结合。已经以第二抗CSF-1R抗体的预期结合响应的百分比(%)计算交叉竞争数据。第二抗体结合的项“预期结合响应的百分比(%)”通过“100*相对响应(大体_稳定性_早期)/rMax”计算,其中rMax通过“相对响应(大体_稳定性_晚期)*抗体分子量/抗原分子量”计算,如记载于Biacore表位定位说明书(对于A100仪)的。
还自相同抗体1和2的对计算最小限度结合响应。其获得的最大值+50%设置为显著结合竞争的阈值(见表X,例如对于抗体<CSF-1R>9D11.2E8,计算的阈值是8+4=12)。如此,“与<CSF-1R>9D11.2E8结合相同表位的抗CSF-1R抗体”具有小于12的预期结合响应的百分比(%)。
使用抗CSF-1R SC-02,克隆2-4A5(Santa Cruz Biotechnology,US,还可见Sherr,C.J.et al.,Cell41(1985)665-676)(其抑制配体-受体相互作用)作为参照对照。
表5:抗CSF-1R抗体的经由交叉竞争数据的表位定位
结果指示抗体<CSF-1R>9D11.2E8和<CSF-1R>10H2.2F12均结合相同表位,而例如SC-2-4A5结合另一表位且不与依照本发明的抗体交叉反应(交叉竞争结合)。
还有,在又一项实验中对来自WO2011070024的抗CSF-1R抗体单抗2F11、2E10、2H7和1G10(它们能够抑制NIH3T3-野生型CSF-1R或突变型CSF-1R L301S Y969F重组细胞生长)测试它们是否与本发明的抗体结合相同 表位。这些表位作图(经由交叉竞争)结果清楚指示抗体<CSF-1R>9D11.2E8和<CSF-1R>10H2.2F12与来自WO2011070024的单抗2F11、2E10、2H7和1G10结合不同表位。
在又一项分开的实验(与WO2011070024实施例10中所述类似地进行)中,测定抗体<CSF-1R>9D11.2E8和<CSF-1R>10H2.2F12是否结合CSF1R胞外域的结构域D1-D3(CSF-1R-ECD(D1-D3))。这项测定导致下述发现,即抗体<CSF-1R>9D11.2E8和<CSF-1R>10H2.2F12不结合CSF-1R ECD(D1-D3)。如此,抗体<CSF-1R>9D11.2E8和<CSF-1R>10H2.2F12结合人CSF-1R胞外域(包含结构域D1至D5)且不结合人CSF-1R胞外域的结构域D1至D3。因此,抗体<CSF-1R>9D11.2E8和<CSF-1R>10H2.2F12结合人CSF-1R胞外域的(二聚化)结构域D4至D5。
实施例7
抗CSF-1R单克隆抗体处理下对3D培养中BeWo肿瘤细胞的生长抑制(CellTiterGlo测定法)
将BeWo绒毛膜癌细胞(ATCC CCL-98)在补充有10%FBS(Sigma)和2mM L-谷氨酰胺的F12K培养基(Sigma,Steinheim,Germany)中培养。将5x104个细胞/孔在含有补充有0.5%FBS和5%BSA的F12K培养基的96孔经聚HEMA(聚(2-羟乙基甲基丙烯酸酯))包被的板中接种。伴随地,添加200ng/ml huCSF-1和10μg/ml不同抗CSF-1R单克隆抗体,并温育6天。使用CellTiterGlo测定法来通过以相对光单位(RLU)测量细胞的ATP含量检测细胞存活力。在用不同抗CSF-1R抗体(10μg/ml)处理BeWo球状体培养物时,观察到对CSF-1诱导的生长的抑制。为了计算抗体介导的抑制,自所有样品减去未刺激的BeWo细胞的均值RLU数值。将经CSF-1刺激的细胞的均值RLU数值任意设置成100%。用CSF-1刺激并用抗CSF-1R抗体处理的细胞的均值RLU数值以CSF-1刺激的RLU的%计算。表6显示了计算的数据;图1描绘了均值RLU数值。每个均值数值自一式三份导出。
表6:
实施例8
抗CSF-1R单克隆抗体处理下对巨噬细胞分化的抑制(CellTiterGlo测定法)
使用RosetteSepTM人单核细胞富集混合物(StemCell Tech.–产品目录编号15028)自外周血分离单核细胞。将富集的单核细胞群于37℃和5%CO2在补充有10FCS(GIBCO-产品目录编号011-090014M)、4mM L-谷氨酰胺(GIBCO-产品目录编号25030)和1x PenStrep(Roche产品目录编号1074440)的100μl RPMI1640(Gibco-产品目录编号31870)中接种入96孔微量滴定板(2.5x104个细胞/孔)中。在对培养基添加150ng/ml huCSF-1时,可以观察到清楚的分化成粘附的巨噬细胞。此分化可以通过添加抗CSF-1R抗体抑制。而且,单核细胞存活受到影响,并且可以通过CellTiterGlo(CTG)分析来分析。自抗体处理对单核细胞存活的浓度依赖性抑制,计算IC50(见表7)。
表7:
克隆 | IC50[nM] |
<CSF-1R>9D11.2E8 | 0.7 |
<CSF-1R>10H2.2F12 | 0.6 |
SC-02,克隆2-4A5 | 2.4 |
在一项分开的实验中,于各5μg/ml抗体浓度在相同测定条件下测试自外周血分离(通过Ficoll分离,继以针对CD14的磁分选(Miltenyi Biotec产品目录130091097))的猕猴衍生单核细胞。<CSF-1R>9D11.2E8显示33%抑制,<CSF-1R>10H2.2F12显示18%抑制。(比较而言,WO2011/070024(A1)中记载的抗CSF-1R单抗2F11将猴单核细胞的存活抑制99%。)
Claims (9)
1.一种结合人CSF-1R的抗体,其特征在于:
a)重链可变域包含SEQ ID NO:1的CDR3区、SEQ ID NO:2的CDR2区、和SEQ ID NO:3的CDR1区,且轻链可变域包含SEQ ID NO:4的CDR3区、SEQ ID NO:5的CDR2区、和SEQ ID NO:6的CDR1区,或
b)重链可变域包含SEQ ID NO:9的CDR3区、SEQ ID NO:10的CDR2区、和SEQ ID NO:11的CDR1区,且轻链可变域包含SEQ ID NO:12的CDR3区、SEQ ID NO:13的CDR2区、和SEQ ID NO:14的CDR1区。
2.依照权利要求1的结合人CSF-1R的抗体,其特征在于与保藏抗体DSM ACC2920结合相同表位。
3.依照权利要求2的结合人CSF-1R的抗体,
其中在体外竞争性结合抑制测定法中通过表面等离振子共振(SPR)于25℃测量对相同表位的结合;且
其中所述结合人CSF-1R的抗体具有下述特性:
a)于抗体浓度10μg/ml将NIH3T3–野生型CSF-1R重组细胞的生长抑制90%或更多;和
b)于抗体浓度10μg/ml将NIH3T3–突变型CSF-1R L301S Y969F重组细胞的生长抑制60%或更多。
4.依照权利要求1至3中任一项的结合人CSF-1R的抗体,其特征在于所述结合人CSF-1R的抗体是人IgG4亚类的或者是人IgG1亚类的。
5.药物组合物,其特征在于包含依照权利要求1至4中任一项的结合人CSF-1R的抗体或其包含重链可变域和轻链可变域的片段。
6.编码依照权利要求1的结合人CSF-1R的抗体的重和轻链的核酸。
7.表达载体,其特征在于包含依照权利要求6的核酸以在原核或真核宿主细胞中表达结合人CSF-1R的抗体。
8.原核或真核宿主细胞,其包含依照权利要求7的载体。
9.用于生成依照权利要求1至4中任一项的结合人CSF-1R的抗体的方法,其特征在于在原核或真核宿主细胞中表达依照权利要求6的核酸,并自所述细胞或细胞培养物上清液回收所述结合人CSF-1R的抗体。
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BR112014012624A2 (pt) | 2018-10-09 |
MX356337B (es) | 2018-05-23 |
CA2853889A1 (en) | 2013-06-20 |
RU2658603C2 (ru) | 2018-06-21 |
EP2791174A1 (en) | 2014-10-22 |
EP2791174B1 (en) | 2018-02-28 |
US10023643B2 (en) | 2018-07-17 |
KR20140113683A (ko) | 2014-09-24 |
WO2013087699A1 (en) | 2013-06-20 |
HK1201282A1 (zh) | 2015-08-28 |
RU2014127438A (ru) | 2016-02-10 |
US20180346582A1 (en) | 2018-12-06 |
CN104159921A (zh) | 2014-11-19 |
MX2014007024A (es) | 2014-09-16 |
US20140336363A1 (en) | 2014-11-13 |
JP6242804B2 (ja) | 2017-12-06 |
US10336830B2 (en) | 2019-07-02 |
JP2015501823A (ja) | 2015-01-19 |
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