CN109096397B - 一种抗人csf-1r单克隆抗体及应用 - Google Patents
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Abstract
本发明涉及一种抗人CSF‑1R单克隆抗体及应用，同时提供了该抗体的编码核酸分子、表达载体、宿主细胞、以及用于表达该抗体的方法。还提供了包括本发明抗体的抗体免疫偶联缀合物、双特异性分子、嵌和抗原受体、药物组合物及用途。相对于现有技术，本发明具有以下优点：本发明的能特异识别人CSF‑1R的单克隆抗体，该抗体与人CSF‑1R结合的亲和力强于现有抗人CSF‑1R单克隆抗体，其序列新颖。
Description
技术领域
本发明涉及了一种高亲和力且具有功能性的抗人CSF1R的单克隆抗体或抗体片段。本发明同时提供了该抗体的编码核酸分子、表达载体、宿主细胞、以及用于表达该抗体的方法。还提供了包括本发明抗体的抗体免疫偶联缀合物、双特异性分子、嵌和抗原受体、药物组合物以及诊断和治疗方法。
背景技术
集落刺激因子1受体(CSF-1R)，属于III型的受体酪氨酸激酶家族，由原癌基因c-fms编码，蛋白结构包含胞内的激酶结构域和胞外由5个免疫球蛋白类似结构组成的配体结合区。CS1R表达在单核吞噬细胞表面，对单核吞噬细胞的存活、增殖、分化起关键作用(Felix,et al.,(2015)Structure 23,1621-1631)。并且CSF1R也高表达在许多种肿瘤细胞表面。例如，CSF1R表达与肿瘤组织大小和低存活密切相关(KLUGER,et al.(2004)Clinicalcancer research.vol.10,no.1,p.173-7；SCHOLL,et al.(1994)Journal of theNational Cancer Institute.vol.86,no.2,p.120-6.)。在卵巢癌和子宫内膜癌，northern杂交分析显示绝大多数肿瘤组织共表达CSF1和CSF1R，而正常的子宫内膜组织CSF1R表达很弱(，et al.(1991)Cancer，vol.67，no.4，p.990-6)。CSF1R也表达于肿瘤浸润性巨噬细胞表面(CHAMBERS,et al.(1997).Clinical Cancer Research.vol.3,no.6,p.999-1007)。
CSF1R的胞外区结合CSF-1后，引发CSF1R受体二聚化和其胞内的自身磷酸化，从而起始胞内信号传递。异常的受体酪氨酸激酶III信号传递导致大量炎症疾病和癌症发生提示胞内的RTK III型在先天和获得性免疫反应中起中心作用。例如，异常的CSF1R信号传递通常出现在诸如类风湿关节炎、动脉粥样硬化及肿瘤生长的多种人类疾病病理状态。(Chitu and Stanley,(2006),Curr.Opin.Immunol.18,39-48；Masteller and Wong,(2014),Drug Discov.Today,19,1212-1216；Pollard(2009),Nat.Rev.Immunol.9,259-270；Stanley and Chitu,(2014),Perspect.Biol.6,a021857；Verstraete and Savvides,(2012),Nat.Rev.Cancer.12,753-766)。
CSF1R信号也被证实在骨重塑中发挥生理作用。基因敲除CSF1或CSF1R的动物通常表现为骨硬化表型。长期以来，CSF1R抑制剂作为一种癌症、炎症性疾病或骨质疏松疾病的潜在疗法被深入研究。Pexidartinib，一种CSF1R的抑制剂，在治疗腱鞘巨细胞瘤的3期临床试验中展示出强劲的疗效。另外一种CSF1R抑制剂，Cabiralizumab,一种靶向肿瘤相关巨噬细胞的单克隆抗体，正进行转移性胰腺癌的早期临床试验。另一种处于临床II期的药物JNJ-40346527，一种口服的CSF1R抑制剂，作用机理为抑制巨噬细胞存活、增殖和分化，但对于疾病修复型抗风湿药难治性活动性类风湿关节炎(DMARD-refractory activerheumatoid arthritis)治疗无效果。
尽管CSF1R抗体已有开发，但对于治疗如上疾病的具备更高亲和力和其他药物关键性质的CSF1R抑制剂，特别是单克隆抗体还有待深入研究开发。
发明内容
为了克服上述缺陷，本发明的目的是提供一种抗人CSF-1R单克隆抗体及应用，该抗体具有高亲和力和功能性，其优于现有的抗人CSF-1R单克隆抗体。
为了达到上述目的，本发明提供一种抗人CSF-1R单克隆抗体，其特征在于，该抗体包含：重链和轻链；
所述的重链和轻链均包括可变区，该可变区包括互补决定区；
所述重链的互补决定区CDR1、CDR2和CDR3分别用CDR-H1、CDR-H2和CDR-H3表示；
所述轻链的互补决定区CDR1、CDR2和CDR3分别用CDR-L1、CDR-L2和CDR-L3表示；
所述的CDR-H1的氨基酸序列为SEQ ID NO：3所示；
所述的CDR-H2的氨基酸序列为SEQ ID NO：4所示；
所述的CDR-H3的氨基酸序列为SEQ ID NO：5所示；
所述的CDR-L1的氨基酸序列为SEQ ID NO：6所示；
所述的CDR-L2的氨基酸序列为SEQ ID NO：7所示；
所述的CDR-L3的氨基酸序列为SEQ ID NO：8所示。
重链可变区氨基酸序列为SEQ ID NO：1所示；轻链可变区氨基酸序列为SEQ IDNO：2所示。
一种核苷酸分子，该核苷酸分子编码所述的抗人CSF-1R单克隆抗体；
该核苷酸分子的序列选自SEQ ID NO：9和/或SEQ ID NO：10；
序列SEQ ID NO：9编码所述的抗体的重链可变区；
序列SEQ ID NO：10编码所述的抗体的轻链可变区。
一种表达载体，该表达载体含有所述的核苷酸分子。
一种宿主细胞，该宿主细胞含有所述的表达载体。
一种抗人CSF-1R单克隆抗体的制备方法，该制备方法包含如下步骤：
步骤1：制备含有表达所述的抗人CSF-1R单克隆抗体的核苷酸分子的表达载体；
步骤2：用步骤1的表达载体转染真核宿主细胞；
步骤3：培养步骤2转染的真核宿主细胞；
步骤4：分离纯化，获得所述的抗体。
本发明还涉及包括前述的抗人CSF-1R单克隆抗体的抗体免疫偶联缀合物、双特异性分子、嵌和抗原受体或药物组合物。
本发明还涉及抗人CSF-1R单克隆抗体在制备抗肿瘤药物、类风湿关节炎药物、动脉粥样硬化药物或骨重塑药物中的应用。
所述的重链和轻链都还包括恒定区，该恒定区为人IgG的恒定区，优选地为IgG1的恒定区。
相对于现有技术，本发明具有以下优点：本发明的能特异识别人CSF-1R的单克隆抗体，该抗体与人CSF-1R结合的亲和力强于现有抗人CSF-1R单克隆抗体，序列新颖。
具体实施方式
以下结合实施例对本发明的技术方案做进一步的说明。
一、抗体的获得：
实施例1通过融合杂交瘤技术获得特异性抗CSF1R的小鼠单克隆抗体
1.1动物免疫
根据文献中(E Harlow,D.Lane,Antibody:A Laboratory Manual,Cold SpringHarbor Laboratory Press,Cold Spring Harbor,N.Y.,1998)通用的方法免疫小鼠。免疫原为C端含有人IgG1Fc标签的重组人CSF1R(氨基酸区间I l e20-Glu 512)蛋白(Acrobiosystems,Cat#CSR-H5258)。使用重组人CSF1R带hi s标签的蛋白(Acro biosystems,cat#CSR-H5228)作为测定血清效价和杂交瘤筛选的检测抗原。简要地，取出适量的福氏佐剂到1.5ml EP管中，振荡器混匀。用PBS配制抗原蛋白溶液。按照需要量混匀佐剂和蛋白抗原溶液，通过注射器互推充分乳化抗原形成稳定油包水的溶液，而后进行动物注射。根据血清效价测定结果，首次免疫后通常需要进行2到3次加强免疫后才能达到良好的免疫效果。选择血清效价高的免疫小鼠行腹腔注射终免后进行细胞融合。
1.2杂交瘤融合和筛选
细胞融合前，培养小鼠骨髓瘤细胞(SP2/0-Ag14,ATCC#CRL-1581)处于对数生长期。处死免疫后小鼠无菌环境取脾，根据文献中方法使用PEG化学融合脾B淋巴细胞和SP2/0骨髓瘤细胞(E Harlow,D.Lane,Antibody:A Laboratory Manual,(Cold Spring HarborLaboratory Press,Cold Spring Harbor,N.Y.,1998)；Kohler G,and Milstein C,"Continuous cultures of fused cell secreting antibody of predefinedspecificity,"Nature,256:495-497(1975))。融合后的细胞铺板96孔细胞培养板，通常7到10天后显微镜下可观察到存活的杂交瘤细胞生长出来。细胞铺板两周后，收集各孔培养上清，以ELISA方法用人CSF1R-his蛋白抗原进行杂交瘤筛选。简述如下，用60ul 2ug/ml的人CSF1R-his抗原的PBS溶液包被酶标板，4度(本发明中的“度”指摄氏度)过夜。而后PBST洗板4次后，加入200μl/孔的5％脱脂奶粉的PBST溶液置于37度封闭2小时。再次洗板，加入60μl/孔的杂交瘤上清,37度孵育40分钟，而后洗板4次。以100μl/孔加入稀释的辣根过氧化物酶标记的羊抗小鼠二抗(Jackson Immuno research,cat#115-036-071),37度孵育40分钟，而后洗板4次,拍干。添加100μl/孔的TMB显色底物,室温显色5到15分钟，而后用1M的硫酸溶液终止,测定450纳米处各孔的吸光值。挑出ELISA显色阳性的杂交瘤孔细胞，转移到24孔板中，继续培养。并通过ELISA方法进行第二轮复筛，筛选出特异识别CSF1R抗原且能阻断CSF1R/CSF1结合的杂交瘤(结果见表1，其中1G7是本发明得到的杂交瘤，该杂交瘤表达本发明所制得的抗人CSF-1R单克隆抗体)，通过有限稀释法亚克隆，获得目标单克隆细胞株。而后通过无血清培养小量表达生产这些单克隆抗体，纯化抗体进行下一步的功能测评分析。
表1 CSF1R小鼠杂交瘤上清的ELISA测评
二、体外分析方法：
实施例2用于测定CSF1R单克隆抗体功能活性的体外分析方法
2.1基于捕获ELSIA测定抗体的结合能力用1xPBS配制羊抗小鼠IgG Fcr特异的二抗(Jackson Immuno Research,#115-006-071)，使其终浓度为2μg/ml,以100μl/孔加液于96孔酶标板，4度包被过夜。次日，用含0.05％的吐温20的PBS溶液(即1xPBST)洗板4次后，加入200μl/孔的5％脱脂奶粉的PBST溶液置于37度封闭2小时。再次洗板，加入100μl/孔的稀释抗体溶液或杂交瘤上清后,37度孵育40分钟，而后洗板4次。以100μl/孔加入配制的60nM生物素标记人CSF1R Fc蛋白溶液(在2.5％脱脂奶粉的PBST中),37度孵育40分钟，而后洗板4次。以100μl/孔加入1：10000稀释的辣根过氧化物酶标记的链霉亲和素(Jackson ImmunoResearch,#016-030-084),37度孵育40分钟，而后洗板4次,拍干。添加100μl/孔的ELISA显色底物TMB,室温显色5到15分钟，而后用1M的硫酸溶液终止显色,测定450纳米处各孔的吸光值。
2.2流式细胞术测评抗体结合细胞膜表面CSF1R抗原的结合能力收集处于对数生长期的膜表面过表达人CSF1R的293F细胞系，用PBS洗细胞2次后用FACS缓冲液(含2％胎牛血清的PBS溶液)重悬细胞。调节密度，以2x105个细胞/孔铺板于96孔U底板中，300g离心5分钟，倾去上清，添加已梯度稀释的CSF1R抗体溶液而后置于冰上孵育40分钟。洗细胞2次，添加100μL/孔藻红蛋白荧光标记的羊抗小鼠二抗(Jackson Immunoresearch,Cat#115-116-072，1：1000稀释)，4度避光孵育40分钟后，洗细胞3次，而后每孔加100μL的FACS缓冲液重悬，吹匀细胞后上机检测。使用BD公司Canto II型号流式细胞仪测定每孔细胞的荧光强度。使用Graphpad prism软件进行数据处理，得出抗体结合细胞的EC50浓度值(即达到该抗体最大荧光结合信号50％时对应的抗体浓度值)。
2.3竞争ELISA
2.3.1配体受体结合阻断ELISA
通过竞争ELISA方法测评CSF1R抗体对CSF1R/CSF1结合的阻断能力。简述如下，用1xPBS配制人的CSF1-his蛋白(BSI,cat#BS-TA1601154-96)，使其终浓度为2μg/ml,以100μl/孔加液于96孔酶标板，4度包被过夜。次日，用含0.05％的吐温20的PBS溶液(即PBST)洗板4次后，加入200μl/孔的5％脱脂奶粉的PBST溶液置于37度封闭2小时。再次洗板4次。
把CSF1R抗体或对照抗体梯度稀释在含有生物素标记的人CSF1R FC蛋白溶液中，配好后室温预孵40分钟。而后把已孵育的抗体和CSF1R Fc biotin的溶液以100μl/孔加到包被好CSF1-his的板上，37度孵育40分钟后，再次洗板4次。而后以100μl/孔加入辣根过氧化物酶标记的链霉亲和素,37度孵育40分钟后洗板4次,拍干。添加100μl/孔的TMB显色和50μl/孔的1M硫酸终止反应，测定450纳米处的吸收值。使用Graphpad prism软件进行数据处理，得出抗体阻断CSF1R/CSF1结合的IC50浓度值。
2.3.2参照抗体阻断ELISA
通过竞争ELISA方法测评CSF1R抗体阻断参照抗体/CSF1R抗原结合的阻断能力。简述如下，用1xPBS配制参照抗体(Cabiralizumab)，使其终浓度为1μg/ml,以100μl/孔加液于96孔酶标板，4度包被过夜。次日，用含0.05％的吐温20的PBS溶液(即PBST)洗板4次后，加入200μl/孔的5％脱脂奶粉的PBST溶液置于37度封闭2小时，再次洗板4次。
把CSF1R抗体或对照抗体梯度稀释在含有生物素标记的人CSF1R FC蛋白溶液(10nM)中，配好后室温预孵40分钟。而后把已孵育的抗体和CSF1R Fc biotin的溶液以100μl/孔加到包被好参照抗体的板上，37度孵育40分钟后，再次洗板4次。而后以100μl/孔加入辣根过氧化物酶标记的链霉亲和素,37度孵育40分钟后洗板4次,拍干。添加TMB显色和1M硫酸溶液终止反应，测定450纳米处的吸收值。使用Graphpad prism软件进行数据处理，得出抗体阻断参照抗体/CSF1R结合的IC50浓度值。
实施例3抗CSF1R小鼠单克隆抗体的结合活性
根据实施例2中描述的分析方法，测评CSF1R抗体的结合活性总结如下表2。其中Benchmark(Cabiralizumab)作为对照，是现有的未商业化的抗人CSF1R单克隆抗体。从表2可知，本发明的抗人CSF-1R单克隆抗体与人CSF1R抗原的结合活性明显优于Benchmark。
表2 CSF1R抗体的结合活性
实施例4功能性阻断实验(参照2.3的分析方法)，得到基于ELISA的抗体功能性实验测评数据
如下表3，汇总了抗CSF1R小鼠单克隆抗体的功能性测评结果。
表3纯化CSF1R小鼠单克隆抗体的功能性测评
表3中抗体对人CSF1/CSF1R的竞争ELISA实验表明，本发明的1G7抗体可特异阻断CSF1R结合其配体CSF1，其阻断能力明显优于Benchmark；同时抗体对benchmark/humanCSF1R的竞争ELISA实验表明，1G7抗体不阻断BM结合人CSF1R抗原,表明1G7结合的抗原表位不同于Benchmark抗体，为独特的抗原结合表位。
实施例5DNA克隆和测序,抗CSF1R小鼠单克隆抗体的可变区蛋白测序
使用Trizol试剂(Invitrogen,catalog#15596-018)从培养的小鼠单克隆细胞株中提取总RNA。过程简述如下，离心收集5x106的细胞到1.5ml离心管中，吸干上清。添加1ml的Trizol试剂并反复吹打数次后室温放置5分钟用于裂解细胞。紧接着，每管加入0.2ml的氯仿溶液，剧烈震荡15秒后室温放置3分钟。而后，离心管4度12000g离心10分钟，取出离心管，吸取上层水相溶液到新的1.5ml离心管中，再加入0.4ml的异丙醇用于从水相中沉淀RNA。手动混匀EP管并放置室温10min后，4度12000g离心10分钟，弃上清。加入1ml 75％的乙醇，再次4度7500rpm离心5min，弃上清。管底RNA沉淀于室温干燥10分钟后，加入30到50ul的无菌DEPC处理水溶解RNA样品。
紧接着，选用Taraka的逆转录cDNA试剂盒(catalog#6110A)把总RNA变为CDNA。实验体系配制如下，5μl的总RNA+0.5μl Oligo(dT)+8.5μl RNase-free水(共14ul)先置于65度5min预变性，而后放冰上2分钟。进一步加入4μl的5x缓冲液+1μl的dNTP混合物+0.5μl的RNase抑制剂+1μl逆转录酶(总共20.5ul体系)，配好后混匀，使用PCR仪运行40度50分钟，70度10min，完成cDNA合成。
cDNA进一步在3’端加Poly G，反应体系配制如下：5μl的cDNA样品+33.5μl的ddH2O+5μl的10xTdT缓冲液+5μl的CoCl2+1μl的dGTP+0.5μl的末端脱氧核苷酸转移酶(总体积50ul),配好后混匀，使用PCR仪运行37度30分钟，70度10min，完成Poly G加尾。
进一步，以加尾的cDNA为模板进行抗体可变区的基因扩增。对于扩增抗体重链可变区序列，配制PCR反应体系：10x Taq酶缓冲液5μl+通用poly C引物(正向引物)0.5μl+小鼠IgG1反向引物0.5μl+dNTP 1μl+Taq聚合酶1μl+cDNA 1μl+ddH2O 41μl。对于扩增抗体轻链可变区序列，配制PCR反应体系：10x Taq酶缓冲液5μl+通用poly C引物(正向引物)0.5μl+小鼠IgG kappa链反向引物0.5μl+dNTP 1μl+Taq聚合酶1ul+cDNA 1μl+ddH2O 41μl。抗体重链和轻链可变区PCR扩增的温度循环如下(其中步骤2到4，重复25个循环)：
1-预变性95℃.5min.
2-变性95℃.20sec.
3-退火56℃.20sec.
4-延伸72℃.30sec.
5-保存25℃.60min。
PCR产物经1％琼脂糖凝胶电泳分析，切出对应大小的DNA区段条带(VH的约600bp，Vkappa轻链约500bp)，用Qiagen的凝胶DNA回收试剂盒(catalog#28704)进行DNA的抽提。简述如下：凝胶称重，加3倍凝胶体积的QG缓冲液，而后50度孵育10分钟直到凝胶完全溶解。加入1倍胶体积的异丙醇混匀后，样品移至QIA纯化柱，离心13000rpm 1分钟。加入750ul的PE缓冲液到柱中，而后13000rpm离心1分钟。并再次13000rpm离心1分钟去除柱中液体残留。加入30ul的水洗脱柱离心1分钟，获得制备的DNA样品，纯化的PCR产物经测序获得抗体的可变区序列如表4所示，CSF1R小鼠单克隆抗体的氨基酸全长序列如表5所示，CSF1R小鼠单克隆抗体的核苷酸序列如表6所示。
表4 CSF1R小鼠单克隆抗体的可变区氨基酸序列和CDR区
表5 CSF1R小鼠单克隆抗体的氨基酸全长序列
表6 CSF1R小鼠单克隆抗体的DNA编码序列
综上所述，本发明的能特异识别人CSF-1R的单克隆抗体，该抗体与人CSF-1R结合的亲和力强，序列新颖，且结合独特的抗原表位。
尽管本发明的内容已经通过上述优选实施例作了详细介绍，但应当认识到上述的描述不应被认为是对本发明的限制。在本领域技术人员阅读了上述内容后，对于本发明的多种修改和替代都将是显而易见的。因此，本发明的保护范围应由所附的权利要求来限定。
序列表
<110> 博奥信生物技术(南京)有限公司
<120> 一种抗人CSF-1R单克隆抗体及应用
<130> xhx2018071805
<141> 2018-07-18
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Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu
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Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val Val Val Asp Ile Ser
130 135 140
Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu
145 150 155 160
Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr
165 170 175
Phe Arg Ser Val Ser Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn
180 185 190
Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro
195 200 205
Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln
210 215 220
Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val
225 230 235 240
Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val
245 250 255
Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln
260 265 270
Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn
275 280 285
Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val
290 295 300
Leu His Glu Gly Leu His Asn His His Thr Glu Lys Ser Leu Ser His
305 310 315 320
Ser Pro Gly Lys
<210> 14
<211> 107
<212> PRT
<213> Mus musculus
<400> 14
Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu
1 5 10 15
Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe
20 25 30
Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg
35 40 45
Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu
65 70 75 80
Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser
85 90 95
Pro Ile Val Lys Ser Phe Asn Arg Gly Glu Cys
100 105
Claims (9)
1.一种抗人CSF-1R单克隆抗体，其特征在于，该抗体包含：重链和轻链；
所述的重链和轻链均包括可变区，该可变区包括互补决定区；
所述重链的互补决定区CDR1、CDR2和CDR3分别用CDR-H1、CDR-H2和CDR-H3表示；
所述轻链的互补决定区CDR1、CDR2和CDR3分别用CDR-L1、CDR-L2和CDR-L3表示；
所述的CDR-H1的氨基酸序列为SEQ ID NO：3所示；
所述的CDR-H2的氨基酸序列为SEQ ID NO：4所示；
所述的CDR-H3的氨基酸序列为SEQ ID NO：5所示；
所述的CDR-L1的氨基酸序列为SEQ ID NO：6所示；
所述的CDR-L2的氨基酸序列为SEQ ID NO：7所示；
所述的CDR-L3的氨基酸序列为SEQ ID NO：8所示。
2.根据权利要求1所述的一种抗人CSF-1R单克隆抗体，其特征在于，重链可变区氨基酸序列为SEQ ID NO：1所示；轻链可变区氨基酸序列为SEQ ID NO：2所示。
3.一种核苷酸分子，其特征在于，该核苷酸分子编码如权利要求1或2所述的抗人CSF-1R单克隆抗体；
该核苷酸分子的序列选自SEQ ID NO：9和/或SEQ ID NO：10；
序列SEQ ID NO：9编码所述的抗体的重链可变区；
序列SEQ ID NO：10编码所述的抗体的轻链可变区。
4.一种表达载体，其特征在于，该表达载体含有如权利要求3所述的核苷酸分子。
5.一种宿主细胞，其特征在于，该宿主细胞含有如权利要求4所述的表达载体。
6.一种权利要求1或2所述的抗人CSF-1R单克隆抗体的制备方法，其特征在于，该制备方法包含如下步骤：
步骤1：制备含有表达权利要求1或2所述的抗人CSF-1R单克隆抗体的核苷酸分子的表达载体；
步骤2：用步骤1的表达载体转染真核宿主细胞；
步骤3：培养步骤2转染的真核宿主细胞；
步骤4：分离纯化，获得所述的抗体。
7.根据权利要求6所述的抗人CSF-1R单克隆抗体的制备方法，其特征在于，所述的表达载体含有选自SEQ ID NO：9和/或SEQ ID NO：10的核苷酸序列。
8.包括权利要求1或2所述的抗人CSF-1R单克隆抗体的抗体免疫偶联缀合物、双特异性分子、嵌和抗原受体或药物组合物。
9.权利要求1或2所述的抗人CSF-1R单克隆抗体在制备抗肿瘤药物、类风湿关节炎药物、动脉粥样硬化药物或骨重塑药物中的应用。
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