CN116782937A - 抗pd-1抗体及其用途 - Google Patents
抗pd-1抗体及其用途 Download PDFInfo
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- CN116782937A CN116782937A CN202180083724.5A CN202180083724A CN116782937A CN 116782937 A CN116782937 A CN 116782937A CN 202180083724 A CN202180083724 A CN 202180083724A CN 116782937 A CN116782937 A CN 116782937A
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Abstract
本发明涉及抗PD‑1(程序性细胞死亡蛋白‑1(Programmed cell death protein 1))抗体或其抗原结合片段、编码其的核酸、包含上述核酸的重组表达载体、由上述重组表达载体转染的宿主细胞、上述抗体或其抗原结合片段的制备方法、包含上述抗体或其抗原结合片段的双特异性或多特异性抗体、包含上述抗体的scFv及与免疫细胞激活抗原结合的抗体的scFv中的一个以上的免疫细胞参与的(immune cell engage)双特异性或多特异性抗体、上述抗体或其抗原结合片段与药物结合的抗体药物偶联物(ADC)、包含上述抗PD‑1抗体的scFv作为胞外结构域的抗原结合位点的嵌合抗原受体(CAR)、导入有上述嵌合抗原受体的免疫细胞、包含上述免疫细胞的联合治疗用组合物、包含上述抗体或其抗原结合片段的联合治疗用组合物、癌症治疗用组合物以及癌症治疗方法。
Description
技术领域
本发明涉及抗PD-1(程序性细胞死亡蛋白-1(Programmed cell death protein1))抗体或其抗原结合片段、编码其的核酸、包含上述核酸的重组表达载体、由上述重组表达载体转染的宿主细胞、上述抗体或其抗原结合片段的制备方法、包含上述抗体或其抗原结合片段的双特异性或多特异性抗体、包含上述抗体的scFv及与免疫细胞激活抗原结合的抗体的scFv中的一个以上的免疫细胞参与的(immune cell engage)双特异性或多特异性抗体、上述抗体或其抗原结合片段与药物结合的抗体药物偶联物(ADC)、包含上述抗PD-1抗体的scFv作为胞外结构域的抗原结合位点的嵌合抗原受体(CAR)、导入有上述嵌合抗原受体的免疫细胞、包含上述免疫细胞的联合治疗用组合物、包含上述抗体或其抗原结合片段的联合治疗用组合物、癌症治疗用组合物以及癌症治疗方法。
背景技术
已知PD-1在免疫调节及外周耐受的维持中起到重要作用。主要在激活的T细胞及B细胞上表达的作为免疫抑制受体的程序性细胞死亡受体1(Programmed Cell DeathReceptor 1:PD-1;程序性细胞死亡受体1、程序性细胞死亡蛋白1、CD279)为与CD28及细胞毒性T淋巴细胞相关蛋白-4(CTLA-4,CD152)相关的免疫球蛋白超家族的成员,PD-1为含有与配体结合的细胞外免疫球蛋白(Ig)可变型(V型)及与信号传导分子结合的细胞质尾部的I型跨膜糖蛋白。在T细胞、B细胞及自然杀伤(NK)T细胞上中等程度表达,在淋巴细胞、单核细胞及骨髓细胞上通过T/B细胞受体信号传导得到上调(Sharpe et al.,The function ofprogrammed cell death 1and its ligands in regulating autoimmunity andinfection.Nature Immunology(2007);8:239-245)。
PD-1在通过PD-L1(CD274,B7-H1)和/或PD-L2(CD273,B7-DC)结合时,弱化T细胞反应。这些配体对PD-1的结合传导抑制T细胞增殖、细胞因子生产及细胞裂解功能的信号。阻断PD-L1对PD-1的结合,提高肿瘤特异性CD8+T细胞免疫,从而使通过免疫系统的肿瘤细胞的清除更为容易。
对PD-1的配体PD-L1(CD274,B7-H1)和/或PD-L2(CD273,B7-DC)在人类多种组织中发生的癌症中表达。例如,在卵巢癌、肾癌、结肠直肠癌、胰腺癌、肝癌及黑色素瘤的大型样品集中,无关乎后续治疗,PD-L1的表达导致预后不良以及整体存活率的降低。
PD-L1表达肿瘤细胞与PD-1表达T细胞相互作用来减少T细胞的激活,逃避免疫监视,从而加重因肿瘤受损的免疫反应。
作为PD-1抑制抗体,市面上出售的有默克(Merck)公司开发的Keytruda(成分名:帕博利珠单抗(pembrolizumab))或百时美施贵宝(BMS)公司的Opdivo(成分名:纳武单抗(nivolumab))。然而,这些药物需要激活通过攻击肿瘤细胞来杀灭癌症的T淋巴细胞才能显出疗效,但具有表现出激活程度微乎其微等的问题。因此,需要开发用于激活在肿瘤或癌症的生长抑制中有效程度的T淋巴细胞的有别于现有抗体的新型抗PD-1抗体。
在这样的技术背景下,本发明人为开发新型抗PD-1抗体而几经努力的结果,确认到优秀的抗体特性及功效,确认到能够用在目标癌症的治疗中,从而完成本发明。
发明内容
技术问题
本发明的目的在于,提供对PD-1的新型抗体或其抗原结合片段。
本发明的再一目的在于,提供编码上述抗体或其抗原结合片段的核酸。
本发明的另一目的在于,提供包含上述核酸的重组表达载体或由上述重组表达载体转染的宿主细胞。
本发明的还有一目的在于,提供与PD-1特异性结合的抗体或其抗原结合片段的制备方法。
本发明的又一目的在于,提供包含上述抗体或其抗原结合片段的双特异性或多特异性抗体。
本发明的又一目的在于,提供包含上述抗体或其抗原结合片段的免疫细胞参与(immune cell engage)的双特异性或多特异性抗体。
本发明的又一目的在于,提供上述抗体或其抗原结合片段与药物结合的抗体药物偶联物(ADC)。
本发明的又一目的在于,提供包含上述抗PD-1抗体的scFv的胞外结构域的抗原结合位点的嵌合抗原受体、导入上述嵌合抗原受体的免疫细胞、包含上述免疫细胞的联合治疗用组合物。
本发明的又一目的在于,提供包含上述抗体或其抗原结合片段或上述免疫细胞参与的双特异性或多特异性抗体的联合治疗用组合物。
本发明的又一目的在于,提供抗体或其抗原结合片段、包含上述抗体或其抗原结合片段的双特异性或多特异性抗体、包含上述抗体或其抗原结合片段的抗体药物偶联物、包含上述抗体或其抗原结合片段的嵌合抗原受体、包含上述嵌合抗原受体的癌症治疗用组合物或癌症治疗方法。
技术方案
为了实现上述目的,本发明提供与PD-1特异性结合的抗体或其抗原结合片段,包含:重链CDR1,包含选自由序列1、序列8及序列14组成的组中的一种以上氨基酸序列;重链CDR2,包含选自由序列2、序列9及序列15组成的组中的一种以上氨基酸序列;重链CDR3,包含选自由序列3、序列4、序列10、序列16及序列56组成的组中的一种以上氨基酸序列;轻链CDR1,包含选自由序列5、序列11、序列17、序列57及序列58组成的组中的一种以上氨基酸序列;轻链CDR2,包含选自由序列6、序列12及序列18组成的组中的一种以上氨基酸序列;以及轻链CDR3,包含选自由序列7、序列13及序列19组成的组中的一种以上氨基酸序列。
本发明提供编码上述抗体或其抗原结合片段的核酸。
并且,本发明提供包含上述核酸的重组表达载体。
并且,本发明提供由上述重组表达载体转染的宿主细胞。
并且,本发明提供与PD-1特异性结合的抗体或其抗原结合片段的制备方法,包括:培养宿主细胞来生成抗体的步骤;以及分离纯化生成的抗体的步骤。
并且,本发明提供包含上述抗体或其抗原结合片段的双特异性或多特异性抗体。
并且,本发明提供免疫细胞参与的双特异性或多特异性抗体,包含一个以上的上述抗体的scFv及与免疫细胞激活抗原结合的抗体的scFv。
并且,本发明提供上述抗体或其抗原结合片段与药物结合的抗体药物偶联物。
并且,本发明提供嵌合抗原受体,其特在于,包含:包含抗原结合位点的胞外结构域;跨膜结构域;以及细胞内信号传导结构域。上述胞外结构域的抗原结合位点为上述抗体的scFv。
并且,本发明提供包含上述嵌合抗原受体的免疫细胞。
并且,本发明提供包含上述免疫细胞及除抗PD-1抗体以外的药物的联合治疗用组合物。
并且,本发明提供联合治疗用组合物,包含上述抗体或其抗原结合片段以及选自由如下成分组成的组中的一种以上:(i)免疫细胞;(ii)包含嵌合抗原受体的免疫细胞,所述嵌合抗原受体包含对除抗PD-1抗体以外的抗体的scFv作为胞外结构域;以及(iii)免疫检查点抑制剂(Immune checkpoint inhibitor)。
并且,本发明提供联合治疗用组合物,包含上述双特异性或多特异性抗体以及选自由如下成分组成的组中的一种以上:(i)免疫细胞;(ii)包含嵌合抗原受体的免疫细胞,所述嵌合抗原受体包含对除抗PD-1抗体以外的抗体的scFv作为胞外结构域;以及(iii)免疫检查点抑制剂(Immune checkpoint inhibitor)。
并且,本发明提供癌症治疗用组合物,包含上述抗体或其抗原结合片段;包含上述抗体或其抗原结合片段的双特异性或多特异性抗体;包含上述抗体或其抗原结合片段的抗体药物偶联物;包含上述抗体或其抗原结合片段的嵌合抗原受体;或者导入上述嵌合抗原受体的免疫细胞。
并且,本发明提供癌症治疗方法,包括给药上述抗体或其抗原结合片段、包含上述抗体或其抗原结合片段的双特异性或多特异性抗体、抗体药物偶联物、嵌合抗原受体、包含上述嵌合抗原受体的免疫细胞或双特异性免疫细胞结合物的步骤。
发明的效果
本发明的抗PD-1抗体或其抗原结合片段表现出对PD-1的优异的结合力,可以在目标肿瘤或癌症的预防或治疗中有效使用。
附图说明
图1示出免疫小鼠(immunized mice)筛选。分离互补脱氧核糖核酸(cDNA)与rh蛋白(rhprotein)的免疫接种(immunization)期间分离各个小鼠(mouse)的血清(serum)来确认PD-1抗体(antibody)的形成。在两次的互补脱氧核糖核酸疫苗接种(cDNA vaccination)后,确认到#2、#4小鼠中形成PD-1抗体,在蛋白质增强(protein boosting)后,在所有小鼠中确认到形成PD-1抗体。杂交瘤细胞发育(Hybidoma development)是利用#2、#4小鼠的脾脏(spleens)进行融合(Fusion)的。
图2示出通过酶联免疫吸附测定(ELISA)的杂交瘤细胞筛选(hybridomascreening)。在融合约2周左右时,形成了充分的杂交瘤细胞(hybridoma)克隆(clones),使用其上清液(supernatants)进行酶联免疫吸附测定筛选。结果,在#2小鼠的融合中选择(selection)12个克隆,在#4小鼠的融合中选择7个克隆,共选择19个阳性克隆(positiveclones),其中,OD=450值为1.0以上的克隆为11个。
图3示出通过定量酶联免疫吸附测定(Q-ELISA)的hPD-1抗体杂交瘤细胞筛选(hPD-1antibody hybridoma screening)。培养1×106个杂交瘤细胞24小时(hr)后,利用它们的上清液进行酶联免疫吸附测定以定量的方式比较抗体生产量来筛选各个克隆。结果,筛选出2-2B3、2-3C3、2-5F1、2-7C5、2-9A9以及4-8D4、4-8H11、4-9D12、4-9F10的9个克隆。
图4a至图4c示出hPD-1杂交瘤抗体(hybridoma antibodies)的特性。通过十二烷基硫酸钠聚丙烯酰胺凝胶电泳染色(SDS-PAGE stain)(图4a)、体积排阻高效液相色谱(SEC-HPLC)(图4b)、表面等离子体共振(SPR)(图4c)来分析纯化的抗体(Purifiedantibodies)的特性。8个克隆在与重组人类PD-1-His蛋白(recombinant human PD-1-Hisprotein,ECD)的结合力中示出相似的结合亲和力(binding affinity),其中,4-9D12、4-9F10示出略高的结合亲和力。
图5示出通过流式细胞术(flow cytometry)的hPD-1抗体与hPD-1表达细胞(Hpd-1expressing cells)之间的结合测试(Binding test)。在PD-1/PD-L1阻断测试(blockingassay)中利用所使用的PD-1表达效应细胞(expressing effector cells)的一部分通过流式细胞术分析对PD-1的抗体的结合效应(binding effect)的结果,确认到2-2B3(49.9%)、2-7C5(50.4%)、4-8D4(23.5%)。
图6示出对hPD-1杂交瘤抗体的hPD-1/PD-L1阻断功能测试(blocking functionalassay)。分析的原理为,在将两个基因工程细胞株(genetically engineered cell lines)与PD-1效应细胞(effector cells)和PD-L1人工抗原提呈细胞(aAPC cells)共培养(co-culture)时,PD-1/PD-L1的相互作用(interaction)抑制TCR介导的发光(TCR-mediatedluminescence)。与之相反,在通过筛选的抗体的作用下中断(disruption)PD-1/PD-L1的相互作用时,通过TCR的激活(activation)诱导发光(luminescence)。从5μg开始2倍连续稀释来确认PD-1/PD-L1共培养中筛选的抗体的阻断效应(blocking effect)的结果,在2-2B3、2-7C5、4-8D4抗体3个克隆中示出与对照组抗PD-1抗(control anti-PD-1抗体)相似的阻断效应。
图7a至图7c示出筛选的3个克隆抗体的人源化(humanization)。通过与Keytruda比较来分析抗体的特性,在筛选的抗体中,结合力低约2倍~8倍。在hPD-1表达(expressing中,示出人源化PD-1抗体的十二烷基硫酸钠聚丙烯酰胺电泳和定量酶联免疫吸附测定(SDS-PAGE&Q-ELISA)(图7a)、体积排阻高效液相色谱和表面等离子体共振(SEC-HPLC&SPR)(图7b)及结合效应的结果(图7c)。
图8a示出为分析本发明的人源化候选抗体的体内(In vivo)功效而分析肿瘤尺寸(tumor size)的结果。图8b示出本发明的人源化候选抗体的肝毒性测试结果。
图9a至图9c示出为增加各候选抗体对抗原的亲和度而进行基因工程(geneengineering)的结果。图9a为改善2B3W的亲和度的5个克隆的抗体,图9b为改善7C5的亲和度的5个克隆的抗体,图9c为改善8D4的亲和度的2个克隆的抗体,图9d示出通过与竞争公司抗体帕博利珠单抗(9nM)比较来筛选出亲和度更高的T14-05(5.8nM)和亲和度相似的T15-01(9.7nM)抗体的结果。
图10a示出为改善候选抗体的亲和度而通过流式细胞术分析筛选的抗体对过表达hPD-1的细胞的结合力的结果。图10b示出在从人类血液中分离的激活的(activated)hCD8T细胞中通过流式细胞术分析候选抗体的结合力的结果。
图11a示出在细胞水平上分析各个候选抗体能够抑制表达hPD-1的效应(effector)细胞与表达作为其受体(receptor)的hPD-L1的APC细胞的结合的功效的结果。图11b示出T14-05和T15-01抗体与作为阳性对照组的Keytruda比较的结果。
图12a示出筛选的2B3W候选抗体及改变其基因结构的克隆抗体的VH、VL及CDR区域(region)的序列的分析结果。图12b示出筛选的7C5候选抗体及其工程化的克隆抗体的VH、VL及CDR区域的序列的分析结果。图12c示出筛选的8D4候选抗体及其工程化的克隆抗体的VH、VL及CDR区域的序列的分析结果。图12d示出比较最终的候选抗体的序列与作为阳性对照组的keytruda的氨基酸序列的结果。
图13示出筛选的最终候选抗体的种间免疫交叉反应(Cross-Reactivity)的分析结果。
图14a至图14c示出最终候选抗体的体内(In vivo)功效分析结果。图14a示出给药抗体后各组的不同个体的肿瘤尺寸分析结果。图14b示出各组的肿瘤大小平均值的曲线化结果。图14c示出各组的CD4和CD8 T细胞的分布结果。
具体实施方式
若无其他定义,则本说明书中使用的所有技术及科学术语都具有本发明所属技术领域的普通技术人员通常理解的含义。通常,本说明书中使用的命名法为本发明所属技术领域中广为人知且通常使用的。
抗PD-1抗体
在利用Balb/c小鼠通过全长人类PD-1基因(full length human PD-1gene)的疫苗接种、重组人类PD-1蛋白的增强来免疫接种后,将其脾脏与小鼠骨髓瘤细胞(myelomacells)sp2/o融合。筛选(screening)生产抗hPD-1抗体的杂交瘤细胞进行克隆选择(clonesselection)。纯化(purification)选择的克隆(Selected clones)来分析其特性,筛选具有能够阻断(blocking)hPD-1/PD-L1结合的功能的杂交瘤抗体。对筛选的抗HPD-1抗体进行互补脱氧核糖核酸克隆(cDNA cloning)来开发嵌合PD-1抗体(chimeric PD-1antibodies)及最终开发出人源化的(humanized)PD-1抗体。
在本发明一实施方式涉及与PD-1特异性结合的抗体或其抗原结合片段,包含:重链CDR1,包含选自由序列1、序列8及序列14组成的组中的一种以上氨基酸序列;重链CDR2,包含选自由序列2、序列9及序列15组成的组中的一种以上氨基酸序列;重链CDR3,包含选自由序列3、序列4、序列10、序列16及序列56组成的组中的一种以上氨基酸序列;轻链CDR1,包含选自由序列5、序列11、序列17、序列57及序列58组成的组中的一种以上氨基酸序列;轻链CDR2,包含选自由序列6、序列12及序列18组成的组中的一种以上氨基酸序列;以及轻链CDR3,包含选自由序列7、序列13及序列19组成的组中的一种以上氨基酸序列。
本说明书中使用的术语“抗体(antibody)”是指与PD-1特异性结合的抗PD-1抗体。本发明的范围不仅包括与PD-1特异性结合的完整抗体形态,还包括上述抗体分子的抗原结合片段。
完整的抗体为具有2个全长的轻链及2个全长的重链的结构,各个轻链通过二硫键与重链连接。
本说明书中使用的术语“重链”是指包含含有具有用于赋予对抗原的特异性的充分的可变区序列的氨基酸序列的可变区结构域VH以及CH1、CH2及CH3的3个恒定区结构域的全长的重链及其片段。并且,本说明书中使用的术语“轻链”是指包含含有具有用于赋予对抗原的特异性的充分的可变区序列的氨基酸序列的可变区结构域VL以及恒定区结构域CL的全长的轻链及其片段。
上述全部抗体包括IgA、IgD、IgE、IgM及IgG的亚型(subtype),尤其,IgG包括IgG1、IgG2、IgG3及IgG4。重链恒定区有伽马(γ)、缪(μ)、阿尔法(α)、德尔塔(δ)及伊普西龙(ε)型,亚型有伽马1(γ1)、伽马2(γ2)、伽马3(γ3)、伽马4(γ4)、阿尔法1(α1)及阿尔法2(α2)。轻链的恒定区有卡帕(κ)及兰布达(λ)型。
抗体的抗原结合片段或抗体片段是指保有抗原结合功能的片段,包括Fab、F(ab')、F(ab')2及Fv等。在抗体片段中,Fab为具有轻链及重链的可变区与轻链的恒定区及重链的第一个恒定区(CH1)的结构,具有一个抗原结合位点。Fab'在重链CH1结构域的C-末端具有包含一个以上半胱氨酸残基的铰链区(hinge-region),这一点有别于Fab。F(ab')2通过Fab'的铰链区的半胱氨酸残基二硫键合来生成。
Fv为只具有重链可变区及轻链可变区的最小的抗体片段。双链Fv(two-chain Fv)通过非共价键连接重链可变区与轻链可变区,单链Fv(single-chain Fv,scFv)通常通过肽接头以共价键连接重链的可变区与轻链的可变区或者在C-末端直接连接,因此可以与双链Fv一样形成类似于二聚体的结构。这样的抗体片段可以利用蛋白质水解酶(例如,使用木瓜蛋白酶有限切割完整形态的抗体可以获得Fab,使用胃蛋白酶切割可以获得F(ab')2)或者基因重组技术来制备。
“Fv”片段为含有完整的抗体识别及结合部位的抗体片段。这样的区域为一个重链可变结构域与一个轻链可变结构域结合的二聚体。
“Fab”片段包含轻链的可变结构域及恒定结构域、重链的可变结构域及第一恒定结构域(CH1)。F(ab')2抗体片段通常包含通过存在于Fab'片段C-末端的铰链区的半胱氨酸以共价键连接的一对Fab'片段。
“单链Fv(scFv)”抗体片段为由包含抗体的VH及VL结构域的单多肽链形成的结构。为了与抗原结合,scFv可以在VH结构域与VL结构域之间追加包含多肽接头来形成所目标的结构。
在一实施例中,本发明的抗体包括单克隆抗体、多特异性抗体抗体、人类抗体、人源化抗体、嵌合抗体、scFv、Fab片段、F(ab')2片段、二硫键合Fvs(sdFv)及抗独特型(抗-Id)抗体或上述抗体的表位结合片段等,但不限定于此。
上述重链恒定区可以在伽马(γ)、缪(μ)、阿尔法(α)、德尔塔(δ)或伊普西龙(ε)中的任一亚型中选择。恒定区为伽马1(IgG1)、伽马2(IgG2)、伽马3(IgG3)或伽马4(IgG4)。轻链恒定区可以为卡帕或兰布达型。
上述单克隆抗体是指从实质上同质的抗体集团中获得的抗体,即,占据集团的每个抗体除可能以微量存在的天然发生的突变以外其余都相同。单克隆抗体为高度特异性,通过与单一抗体部位对抗来诱导。典型地,与包含对不同决定因子(表位)的不同抗体的通常的(多克隆)抗体相对照,各个单克隆抗体针对抗原上的单一决定因子。
“表位(epitope)”是指抗体能够特异性结合的蛋白质决定部位(determinant)。表位由通常在化学上具有活性的表面分子组,例如氨基酸或糖侧链构成,通常,不仅具有特定三维结构特征,还具有特定电荷特性。在变性溶剂的存在下,立体表位对电子的结合消失,但非立体表位对电子的结合不消失。
上述“人源化”形态的非人类(例如小鼠)抗体为含有来源于非人类免疫球蛋白的最小序列的嵌合抗体。在大部分情况下,人源化抗体为将接受者的超可变区的残基更换为保有所目标的特异性、亲和性及能力的非人种类(供与者抗体),例如小鼠、大鼠、兔或非人灵长类的超可变区的残基的人免疫球蛋白(接受者抗体)。
上述“人类抗体”为源自人类免疫球蛋白的分子,是指构成包含互补决定区、结构区域的抗体的氨基酸序列全部由人类的免疫球蛋白构成。
不仅包括重链和/或轻链的一部分源自特别的种类或与属于特别的抗体种类或亚类的抗体内的相应序列相同或与之具有同源性,而剩余链则与之相反,源自其他种类或与属于其他抗体种类或亚类的抗体内的相应序列同一或与之具有同源性的“嵌合”抗体(免疫球蛋白),还包括显出所目标的生物学活性的上述抗体的片段。
本发明中使用的抗体的“可变区”是指包含互补决定区(CDR;即,CDR1、CDR2以及CDR3)及骨架区(FR)的氨基酸序列的抗体分子的轻链及重链部分。VH是指重链的可变结构域。VL是指轻链的可变结构域。
“互补决定区(complement determining region,CDR)”是指作为与抗原结合的必需存在的抗体可变结构域的氨基酸残基。各个可变结构域典型地具有确认为CDR1、CDR2及CDR3的三个CDR区域。
例如,本发明的抗PD-1抗体或其抗原结合片段可以包含:(i)包含序列1的重链CDR1、序列2的重链CDR2及序列3的重链CDR3的重链可变区以及包含序列5的轻链CDR1、序列6的轻链CDR2及序列7的轻链CDR3的轻链可变区;(ii)包含序列1的重链CDR1、序列2的重链CDR2及序列4的重链CDR3的重链可变区以及包含序列5的轻链CDR1、序列6的轻链CDR2及序列7的轻链CDR3的轻链可变区;(iii)包含序列8的重链CDR1、序列9的重链CDR2及序列10的重链CDR3的重链可变区以及包含序列11的轻链CDR1、序列12的轻链CDR2及序列13的轻链CDR3的轻链可变区;(iv)包含序列14的重链CDR1、序列15的重链CDR2及序列16的重链CDR3的重链可变区以及包含序列17的轻链CDR1、序列18的轻链CDR2及序列19的轻链CDR3的轻链可变区;(v)包含序列1的重链CDR1、序列2的重链CDR2及序列56的重链CDR3的重链可变区以及包含序列57的轻链CDR1、序列6的轻链CDR2及序列7的轻链CDR3的轻链可变区;或者(vi)包含序列8的重链CDR1、序列9的重链CDR2及序列10的重链CDR3的重链可变区以及包含序列58的轻链CDR1、序列12的轻链CDR2及序列13的轻链CDR3的轻链可变区。
“骨架区(FR)”为CDR残基以外的可变结构域残基。典型地,各可变结构域具有FR1、FR2、FR3及FR4的4个FR。
抗PD-1抗体对PD-1的结合亲和性在10-5M至10-12M的范围内。例如,抗PD-1抗体对PD-1的结合亲和性为10-6M至10-12M、10-7M至10-12M、10-8M至10-12M、10-9M至10-12M、10-5M至10-11M、10-6M至10-11M、10-7M至10-11M、10-8M至10-11M、10-9M至10-11M、10-10M至10-11M、10-5M至10- 10M、10-6M至10-10M、10-7M至10-10M、10-8M至10-10M、10-9M至10-10M、10-5M至10-9M、10-6M至10-9M、10-7M至10-9M、10-8M至10-9M、10-5M至10-8M、10-6M至10-8M、10-7M至10-8M、10-5M至10-7M、10-6M至10-7M或10-5M至10-6M。
上述与PD-1结合的抗体或其抗原结合片段可以包含含有选自由序列20、序列21、序列23、序列25、序列27、序列28、序列30、序列32、序列48及序列50组成的组中的一个以上氨基酸序列的重链可变区。并且,上述与PD-1结合的抗体或其抗原结合片段可以包含含有选自由序列22、序列24、序列26、序列29、序列31、序列33、序列49、序列51、序列54及序列55组成的组中的一种以上氨基酸序列的轻链可变区。
在本发明的具体实施例中,可以包含:序列20的重链可变区及序列22的轻链可变区;序列21的重链可变区及序列22的轻链可变区;序列23的重链可变区及序列24的轻链可变区;序列25的重链可变区及序列26的轻链可变区;序列27的重链可变区及序列29的轻链可变区;序列28的重链可变区及序列29的轻链可变区;序列30的重链可变区及序列31的轻链可变区;序列32的重链可变区及序列33的轻链可变区;序列48的重链可变区及序列49的轻链可变区;序列50的重链可变区及序列51的轻链可变区;序列52的重链可变区及序列53的轻链可变区;或者序列54的重链可变区及序列55的轻链可变区.
scFv
scFv为由包含抗体的VH及VL结构域的单多肽链形成的结构体,为抗体片段。为了与抗原结合,scFv可以在VH结构域与VL结构域之间追加包含多肽接头来形成所目标的结构。
在一实施例中,包含抗体的VH及VL结构域的单链Fv(scFv)中的VH与VL结构域可以通过接头连接。包含选自由序列20、序列21、序列23、序列25、序列27、序列28、序列30、序列32、序列48及序列50组成的组中的一种以上氨基酸序列的重链可变区可以通过接头与包含选自由序列22、序列24、序列26、序列29、序列31、序列33、序列49、序列51、序列54及序列55组成的组中的一种以上氨基酸序列的轻链可变区连接。
本发明的在具体实施例中,可以包含:序列20的重链可变区及序列22的轻链可变区;序列21的重链可变区及序列22的轻链可变区;序列23的重链可变区及序列24的轻链可变区;序列25的重链可变区及序列26的轻链可变区;序列27的重链可变区及序列29的轻链可变区;序列28的重链可变区及序列29的轻链可变区;序列30的重链可变区及序列31的轻链可变区;序列32的重链可变区及序列33的轻链可变区;序列48的重链可变区及序列49的轻链可变区;序列50的重链可变区及序列51的轻链可变区;序列52的重链可变区及序列53的轻链可变区;或者序列54的重链可变区及序列55的轻链可变区。
上述接头可以为肽接头,可以具有约10aa-25aa的长度。例如,可以包含甘氨酸甘氨酸和/或丝氨酸等亲水性氨基酸,但不限定于此。
具体地,上述接头可以包含例如(GS)n、(GGS)n、(GSGGS)n或(GnS)m(n、m分别为1至10),例如,上述接头可以为(GnS)m(n、m分别为1至10)。具体地,上述接头可以包含GGGGS。
“噬菌体展示”是指在噬菌体上展示变异体多肽,例如在纤维状噬菌体粒子的表面上展示与外皮蛋白质的至少一部分融合的融合蛋白的技术。噬菌体展示技术的用处在于,能够以随机的蛋白质变异体的大文库为对象,迅速有效地分类与靶向抗原高亲和度地结合的序列。在噬菌体上展示肽及蛋白质文库的作用在于,为查明带有特异性结合特性的多肽而筛选数百万个多肽。
噬菌体展示技术为生产及筛选与特定配体(例如抗原)结合的新型蛋白质提供强力的工具。在使用噬菌体展示技术的情况下,可以在生成蛋白质变异体的大文库后,迅速分类与靶向抗原高亲和度地结合的序列。将编码变异体多肽的核酸与病毒性外皮蛋白质,例如,与编码基因III蛋白质或基因VIII蛋白质的核酸序列融合。开发了将编码蛋白质或多肽的核酸序列与编码基因III蛋白质的一部分的核酸序列融合的一价噬菌体展示系统。一价噬菌体展示系统低水平地表达基因融合物,也表达野生型基因III蛋白质,因此保持粒子感染性。
开发抗体噬菌体展示文库的重点在于,证明肽在纤维状噬菌体表面上的表达以及功能性抗体片段在大肠杆菌(E.coli)的周围细胞质中的表达。抗体或抗原结合性多肽的文库可以通过多种方式制备,例如,可以使用通过插入随机脱氧核糖核酸(DNA)序列来变更单一基因的方法或克隆相关基因系列的方法来制备。能够以文库为对象,与伴有所目标的特性的抗体或抗原结核性蛋白质的表达相关地来筛选。
与用来制备带有所目标的特征的抗体的通常的杂交瘤及重组方法相比,噬菌体展示技术具有几个优点。该技术可以在不使用动物的情况下,在短时间内生成具有多种序列的大的抗体文库。而杂交瘤的制备或人源化抗体的制备可能需要数个月的制备时间。并且,由于完全不需要免疫,因此噬菌体抗体文库也可以对毒性或抗原性低的抗原生成抗体。并且,还可以利用噬菌体抗体文库生产及确认新型的治疗性抗体。
可以使用噬菌体展示文库作为从免疫的、非免疫的人类、生殖细胞系统序列或不敏感的B细胞Ig库存(repertory)中生成人类抗体的技术。可以使用各种淋巴系统组织制备不敏感或非免疫抗原结合性文库。
能够从噬菌体展示文库中确认及分离高亲和性抗体的技术在新型抗体的分离中是重要的。从文库中分离高亲和性抗体可以被文库的大小、细菌性细胞中的生产效率及文库的多样性左右。文库的大小通过由抗体或抗原结合性蛋白质的不适当的折叠与终止密码子的存在引起的低效的生产而减小。在抗体或抗原结合性结构域不适当地折叠的情况下,细菌性细胞中的表达会受到抑制。可以通过在可变/恒定界面的表面或筛选的CDR残基中以替换残基的方式来引起突变来改善表达。在细菌性细胞中生成抗体噬菌体文库的情况下,骨架区的序列是用来提供适当的折叠的要素之一。
在高亲和性抗体的分离中,重点在于生成抗体或抗原结合性蛋白质的多种文库。已知CDR3区域在种种抗原结合中具有参与。重链上的CDR3区域在大小、序列及结构性立体形态方面具有相当的多样性,因此可以利用其制备多种文库。
并且,可以在各个位置都使用20种氨基酸使可变重链及重链及轻链的CDR区域随机化来产生多样性。若使用全部20种氨基酸,则可以多样性大的变异体抗体序列并增加确认到新型抗体的机会。
在能够特异性地识别PD-1的范围内,本发明的抗体或抗体片段不仅包括本说明书中记载的本发明的抗PD-1抗体的序列,还可以包括其生物学同等物。例如,为了进一步改善抗体的结合亲和度和/或其他生物学特性,可以给抗体的氨基酸序列追加的变化。这样的变形包括例如抗体的氨基酸序列残基的缺失、插入和/或取代。这样的氨基酸变异是基于氨基酸侧链取代物的例如疏水性、亲水性、电荷、大小等相对相似性来形成的。通过分析氨基酸侧链取代物的大小、形状及种类可知,精氨酸、赖氨酸及组氨酸都带有正电荷;丙氨酸、甘氨酸及丝氨酸具有相似的大小;苯丙氨酸、色氨酸及酪氨酸具有相似的形状。因此,基于这些考虑事项,可以将精氨酸、赖氨酸及组氨酸;丙氨酸、甘氨酸及丝氨酸;以及苯丙氨酸、色氨酸及酪氨酸在生物学上看做功能同等物。
若考虑上述在生物学上具有同等活性的变异,则本发明的抗体或编码其的核酸分子应解释为还包括与序列表中记载序列表现出实质同一性(substantial identity)的序列。上述实质同一性是指在将上述本发明的序列与任意其他序列以最大对应的方式对齐后,利用本发明所属技术领域中通常使用的算法分析对齐的序列时,表现出最少90%的同源性的序列,最优选地,为表现出最少95%的同源性、96%以上、97%以上、98%以上、99%以上的同源性的序列。用于序列比较的对齐方法是本发明所属技术领域中公知的。美国国家生物信息中心基于局部比对算法的搜索工具(NCBI Basic Local Alignment SearchTool,BLAST)在美国国家生物信息中心(NBCI)等处可以使用,可以在因特网上与blastp、blasm、blastx、tblastn及tblastx等序列分析软件联动来使用。BLAST可以在网址www.ncbi.nlm.nih.gov/BLAST/上访问。利用该软件的序列同源性比较方法可以在网址www.ncbi.nlm.nih.gov/BLAST/blast_help.html中确认。
基于此,本发明的抗体或其抗原结合片段可以为说明书中明确记载的序列或与它们整体比较后具有90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或以上的同源性的序列。这样的同源性可以由通过本发明所属技术领域中公知的方法的序列比较和/或排列来确定。例如,可以利用序列比较算法(即,BLAST或BLAST 2.0)、手动排列、肉眼检查来确定本发明的核酸或蛋白质的百分比序列同源性。
本发明的再一实施方式涉及编码上述抗体或其抗原结合片段的核酸。可以通过分离编码本发明抗体或其抗原结合片段的核酸来以重组的方式生产抗体或其抗原结合片段。
“核酸”具有包括脱氧核糖核酸(基因组脱氧核糖核酸(gDNA)及互补脱氧核糖核酸(cDNA))及核糖核酸(RNA)分子在内的含义,核酸的基本结构单位核苷酸不仅包括自然的核苷酸,还包括糖或碱基部位变形的类似物(analogue)。编码本发明的重链及轻链可变区的核酸的序列可以变形。上述变形包括核苷酸的追加、缺失、非保护性取代或保护性取代。
编码上述与PD-1结合的抗体或其抗原结合片段的核酸可以包含编码选自由序列34至序列47组成的组中的重链可变区或轻链可变区的核酸。
本发明的在具体实施例中,可以包含:编码序列34的重链可变区的核酸及编码序列36的轻链可变区的核酸;编码序列35的重链可变区的核酸及编码序列36的轻链可变区的核酸;编码序列37的重链可变区的核酸及编码序列38的轻链可变区的核酸;编码序列39的重链可变区的核酸及编码序列40的轻链可变区的核酸;编码序列41的重链可变区的核酸及编码序列43的轻链可变区的核酸;编码序列42的重链可变区的核酸及编码序列43的轻链可变区的核酸;编码序列44的重链可变区的核酸及编码序列45的轻链可变区的核酸;或者编码序列46的重链可变区的核酸及编码序列47的轻链可变区的核酸。
编码上述抗体的脱氧核糖核酸可以通过通常的分子生物学方法(例如使用使用能够与编码抗体、重链及轻链的脱氧核糖核酸特异性结合的寡核苷酸探针)轻易分离或合成,分离核酸后,将其插入可复制的载体内追加克隆(脱氧核糖核酸的扩增)或进一步表达。基于此,本发明的还一实施方式涉及包含上述核酸的重组表达载体。
本说明书中使用的术语“载体”为用于在宿主细胞中表达目标基因的工具,包括质粒载体、粘粒载体、噬菌体载体、腺病毒载体、逆转录病毒载体、腺相关病毒载体等病毒载体等。包含如下成分中的一种以上作为载体的成分:信号序列、复制起点、一个以上的耐抗生素标记物基因、增强子因素、启动子、转录终结序列,但不限定于此。编码抗体的核酸与启动子及转录终结序列等可操作连接。
“可操作连接”是指核酸表达调节序列(例如启动子、信号序列或转录调节因子结合部位的排列)与其他核酸序列之间的功能性结合,因此,上述调节序列调节上述其他核酸序列的转录和/或解读。
在以原核细胞为宿主的情况下,通常包含能够进行转录的强力的启动子(例如,tac启动子、lac启动子、lacUV5启动子、lpp启动子、pLλ启动子、pRλ启动子、rac5启动子、amp启动子、recA启动子、SP6启动子、trp启动子及T7启动子等)、用于开始解读的核糖体结合部位及转录/解读终结序列。并且,例如,在以真核细胞为宿主的情况下,可以利用源自哺乳动物的基因组的启动子(例如金属硫蛋白启动子、β肌动蛋白启动子、人血红蛋白启动子、及人肌肉肌酸启动子)或源自哺乳动物病毒的启动子(例如腺病毒后期启动子、牛痘病毒7.5K启动子、SV40启动子、巨细胞病毒(CMV)启动子、HSV的tk启动子、小鼠乳腺肿瘤病毒(MMTV)启动子、HIV的LTR启动子、莫洛尼病毒的启动子、EB病毒(EBV)的启动子及呼吸道合胞病毒(RSV)的启动子),通常具有聚腺苷酸化序列作为转录终结序列。
根据情况的不同,为了便于纯化载体中表达的抗体,载体还可以与其他序列融合。融合的序列有例如谷胱甘肽S-转移酶(法玛西亚公司(Pharmacia),美国(USA))、麦芽糖结合蛋白质(NEB公司,美国)、FLAG(IBI公司,美国)及6x His(6组氨酸(hexahistidine);快而精公司(Qiagen),美国)等。
上述载体包含本发明所属技术领域中通常使用的抗生素耐性基因作为选择标记,例如为对氨苄青霉素、庆大霉素、羧苄青霉素、氯霉素、链霉素、卡那霉素、遗传霉素、新霉素及四环素具有耐性的基因。
本发明的另一实施方式涉及由上述重组表达载体转染的宿主细胞。用来生成本发明的抗体的宿主细胞可以为原核生物、酵母或高等真核生物细胞,但不限定于此。
可以利用大肠杆菌(Escherichia coli)、枯草芽孢杆菌(Bacillus subtilus)及苏云金芽孢杆菌(Bacillus thuringiensis)等细菌属菌株,链霉菌(Streptomyces)、假单胞菌(Pseudomonas)(例如恶臭假单胞菌(Pseudomonas putida))、奇异变形杆菌(Proteusmirabilis)及葡萄球菌(Staphylococcus)(例如肉葡萄球菌(Staphylocus carnosus))等原核宿主细胞。
但更多关注动物细胞,有效的宿主细胞株的例可以为COS-7、BHK、CHO、CHOK1、DXB-11、DG-44、CHO/-DHFR、CV1、COS-7、HEK293、BHK、TM4、VERO、HELA、MDCK、BRL 3A、W138、HepG2、SK-Hep、MMT、TRI、MRC 5、FS4、3T3、RIN、A549、PC12、K562、PER.C6、SP2/0、NS-0、U20S或HT1080,但不限定于此。
本发明的又一实施方式涉及与PD-1特异性结合的抗体或其抗原结合片段的制备方法,包括:培养上述宿主细胞来生成抗体的步骤;以及分离及纯化生成的抗体的步骤。
上述宿主细胞可以在各种培养基中培养。市面上出售的培养基可以不受限制地用作培养基。能够以适当的浓度包含本发明所属技术领域中公知的所有必需的补充物。例如温度、pH等培养条件是与为表达而筛选的宿主细胞一同使用的,这对本发明所属技术领域的普通技术人员来说是显而易见的。
上述抗体或其抗原结合片段的回收可以通过例如通过离心分离或超滤去除杂质后,利用例如亲和层析等方法纯化其产物。其他的纯化技术还可以是用例如阴离子或阳离子交换层析、疏水性相互作用层析、羟基磷灰石层析等。
双特异性或多特异性抗体
本发明的又一实施方式涉及包含上述抗体或其抗原结合片段的双特异性或多特异性抗体。
双特异性抗体是指对一种以上的目标具有结合的能力或拮抗能力的抗体,是指对两个互不相同的目标具有结合能力或拮抗能力的抗体结合的形态或者对一个目标具有结合能力的抗体与对其他目标具有拮抗能力的物质结合的抗体。
多特异性抗体是指对三个以上不同抗原具有结合特异性的抗体。多特异性(multi-specific)抗体可以包括三特异性(Tri-specific)以上的抗体,例如三特异性(Tri-specific)抗体、四特异性(Tetra-specific)抗体或靶向四个以上目标的抗体。
属于双特异性或多特异性抗体的抗体可以区分为基于scFv的抗体、基于Fab的抗体及基于IgG的抗体等。在双特异性或多特异性抗体的情况下,可以同时抑制或扩增两个以上信号,因此能够比抑制/扩增一个信号的情况更为有效,与使用各自的信号抑制剂处理各信号的情况相比,能够以低剂量给药,可以在同一时间及空间中抑制/扩增两个以上的信号。
双特异性或多特异性抗体的制备方法广为人知。典型地,双特异性抗体的重组生产是在两个以上的重链具有不同的特异性的条件下以两个以上免疫球蛋白重链/轻链对的共同表达为基础的。
在基于scFv的双特异性或多特异性抗体的情况下,可以分别相互组合不同的scFv的VL与VH来将混合scFv制备为异二聚体(heterodimeric)形态,从而制备双特异抗体(diabody),可以相互连接不同的scFv来制备串联(tendem)ScFv,可以在各个scFv的末端表达Fab的CH1和CL来制备异二聚体微型抗体(miniantibody),可以通过取代作为Fc的同型二聚体(homodimeric)结构域的CH3结构域的一部分氨基酸来变更为“旋钮入孔(knob intohole)”形态的异二聚体结构,在各个scFv末端表达这些变更的CH3结构域来制备异二聚体scFv形态的微型抗体(minibody)。
在基于Fab的双特异性或多特异性抗体的情况下,可以利用二硫键合或媒介物使对特定抗原的单独Fab'相互组合来制备异二聚体Fab形态,可以通过在特定Fab的重链或轻链的末端表达对不同抗原的scFv来使抗原结合价(valency)为2个,或者在Fab与scFv之间放入铰链区(hinge region)制备同型二聚体形态以具有4个抗原结合价。并且,在Fab的轻链末端和重链末端融合对不同抗原的scFv来获得对抗原具有3个结合价的双靶向二聚体,在Fab的轻链末端和重链末端分别融合不同的scFv来获得具有对抗原的3个结合价的三靶向二聚体,可以通过化学方法使3个不同的Fab接合来获得。
在基于IgG的双特异性或多特异性抗体的情况下,已知通过特莱恩制药(TrionPharma)公司将小鼠与大鼠的杂交瘤重新杂交制备杂交杂交瘤,又称为四重杂交瘤(quadromas)来生产双特异性抗体的方法。并且,轻链部分共有,而对于不同的重链,将Fc的CH3同型二聚体结构域的一部分氨基酸变形来制备为异二聚体形态,从而能够以“孔与旋钮(Holes and Knob”形态来制备双特异性抗体。除异二聚体形态的双特异性抗体以外,可以将不同的2种scFv融合在IgG的轻链和重链的恒定(constant)结构域,而不是可变结构域,来制备同型二聚体形态的(scFv)4-IgG。并且,英克隆(ImClone)公司报告说,基于作为对人类VEGFR-2的嵌合单克隆抗体的IMC-1C11,在该抗体的轻链氨基末端只融合对小鼠血小板衍生生长因子受体α(Platelet-derived Growth Factor Receptor-α)的单可变结构域(single variable domain)来制备双特异性抗体。并且,可以通过利用蛋白激酶A(proteinkinase A,PKA)R亚型的二聚化及对接结构域(dimerization and docking domain(DDD))与蛋白激酶A锚定结构域(anchoring domain)的称为“对接和锁定(dock and lock(DNL))”的方法来制备具有对CD20的多个抗原结合价的抗体。
开发了非常多样的重组抗体格式,例如,二价以上、三价以上或四价以上的双特异性或多特异性抗体。例如,还包括国际专利申请公开第WO2001/077342号、第WO2009/080251号、第WO2009/080252号、第WO2009/080253号、第WO2009/080254号、第WO2010/112193号、第WO2010/115589号、第WO2010/136172号、第WO2010/145792号、第WO2010/145793号及第WO2011/117330号中记载的二价以上、三价以上或四价以上的抗体。二价以上、三价以上或四价以上的抗体分别表示抗体分子中存在2个以上的结合结构域、3个以上的结合结构域或4个以上的结合结构域。
在具体实施例中,本发明的双特异性或多特异性抗体可以包含上述抗PD-1抗体或抗原结合片段,具体地,可以包含IgG完整的抗体或其片段形态,例如,可以包含单链Fv、VH结构域和/或VL结构域、Fab或(Fab)2的形态。
并且,上述靶向PD-1的抗体和与其他目标结合的抗体或其抗原结合片段可以包含例如选自由FGFR3、TIGIT、PD-L1、BTLA、CTLA-4、VISTA、LAG3、TIM3、CD137(4-1BB)、VISTA、CD258(LIGHT)、MARCO、CD134(OX40)、CD28、CD278(ICOS)、CD27、CD154(CD40L)、CD357(GITR)、CD30、DR3、CD226(DNAM1)、CD96、CD200、CD200R、转铁蛋白受体(Transferrinreceptor)、c-Met、EGFR、HER2、KDR、PDGFRa、NRP1组成的组中的一种以上。具体地,上述抗体或其抗原结合片段可以包含IgG完整的抗体或其片段形态,例如,可以包含单链Fv、VH结构域和/或VL结构域、Fab或(Fab)2的形态。
除PD1以外,通过本发明的双特异性或多特异性抗体可以确保由其他目标诱导或介导的追加的结合特异性。
例如,本发明的双特异性抗体可以同时靶向PD-1与选自由FGFR3、TIGIT、PD-L1、BTLA、CTLA-4、VISTA、LAG3、TIM3、CD137(4-1BB)、VISTA、CD258(LIGHT)、MARCO、CD134(OX40)、CD28、CD278(ICOS)、CD27、CD154(CD40L)、CD357(GITR)、CD30、DR3、CD226(DNAM1)、CD96、CD200、CD200R、转铁蛋白受体、c-Met、EGFR、HER2、KDR、PDGFRa、NRP1组成的组中的一种以上。
例如,本发明的多特异性抗体可以同时靶向PD-1与先自由FGFR3、TIGIT、PD-L1、BTLA、CTLA-4、VISTA、LAG3、TIM3、CD137(4-1BB)、VISTA、CD258(LIGHT)、MARCO、CD134(OX40)、CD28、CD278(ICOS)、CD27、CD154(CD40L)、CD357(GITR)、CD30、DR3、CD226(DNAM1)、CD96、CD200、CD200R、转铁蛋白受体、c-Met、EGFR、HER2、KDR、PDGFRa、NRP1组成的组中的两种以上。
免疫细胞参与的双特异性或多特异性抗体
本发明的又一实施方式涉及包含一个以上抗体的scFv及与免疫细胞激活抗原结合的抗体的scFv的免疫细胞参与的双特异性或多特异性抗体。
通过上述免疫细胞参与的双特异性或多特异性抗体在细胞毒性T细胞与癌症靶向细胞之间一过性地诱导细胞裂解突触来释放毒性物质。
在一实施例中,与上述免疫细胞激活抗原结合的抗体或其抗原结合片段可以起到免疫细胞接合器(immune cell engager)的作用,上述免疫细胞激活抗原可以为例如选自由下述列举的抗原中:T细胞激活抗原为CD3、TCRα、TCRβ、TCRγ、TCRξ、ICOS、CD28、CD27、HVEM、LIGHT、CD40、4-1BB、OX40、DR3、GITR、CD30、TIM1、SLAM、CD2或CD226;自然杀伤(NK)细胞激活抗原为NKp30、NKp40、NKp44、NKp46、NKG2D、DNAM1、DAP10、CD16(e.g.、CD16a、CD16b)、CRTAM、CD27、PSGL1、CD96、CD100(SEMA4D)、NKp80、CD244(SLAMF4或2B4)、SLAMF6、SLAMF7、KIR2DS2、KIR2DS4、KIR3DS1、KIR2DS3、KIR2DS5、KIR2DS1、CD94、NKG2C、NKG2E或CD160;B细胞激活抗原为OX40、CD40或CD70;巨噬细胞激活抗原为CD2激动剂、CD40、CD70、TCR(Toll-likeReceptor)激动剂、CD47、STING或OX40L;或者树突细胞激活抗原为CD2激动剂、OX40、OX40L、41BB激动剂、TCR激动剂、CD47激动剂或STING激动剂。
免疫细胞接合器在美国专利申请公开第2017/0368169号中有具体记载,可以作为参照导入本发明中。
具体地,上述免疫细胞参与的双特异性或多特异性抗体包含串联scFv,可以与下述抗原及癌细胞上的表面抗原结合。上述癌细胞上的表面抗原为本发明的抗体所靶向的PD-1。上述抗原为:CD3、TCRα、TCRβ、TCRγ、TCRξ、ICOS、CD28、CD27、HVEM、LIGHT、CD40、4-1BB、OX40、DR3、GITR、CD30、TIM1、SLAM、CD2或CD226;NKp30、NKp40、NKp44、NKp46、NKG2D、DNAM1、DAP10、CD16(例如(e.g.,)CD16a、CD16b)、CRTAM、CD27、PSGL1、CD96、CD100(SEMA4D)、NKp80、CD244(SLAMF4或2B4)、SLAMF6、SLAMF7、KIR2DS2、KIR2DS4、KIR3DS1、KIR2DS3、KIR2DS5、KIR2DS1、CD94、NKG2C、NKG2E或CD160;OX40、CD40或CD70;CD2激动剂、CD40、CD70、TCR激动剂、CD47、STING或OX40L;或者CD2激动剂、OX40、OX40L、41BB激动剂、TCR激动剂、CD47激动剂或STING激动剂。
上述免疫细胞参与的双特异性或多特异性抗体可以包括例如VL(PD-1)-VH(PD-1)-VH(CD3或CD16A)-VL(CD3或CD16A)、VH(PD-1)-VL(PD-1)-VH(CD3或CD16A)-VL(CD3或CD16A)、VH(CD3或CD16A)-VL(CD3或CD16A)-VH(PD-1)-VL(PD-1)或VH(CD3或CD16A)-VL(CD3或CD16A)-VL(PD-1)-VH(PD-1)形态的结构。
上述scFv包含例如包含选自由序列20、序列21、序列23、序列25、序列27、序列28、序列30、序列32、序列48及序列50组成的组中的一种以上氨基酸序列的重链可变区与包含选自由序列22、序列24、序列26、序列29、序列31、序列33、序列49、序列51、序列54及序列55组成的组中的一种以上氨基酸序列的轻链可变区,上述重链可变区与轻链可变区可以通过接头连接。
上述接头可以为肽接头,可以具有约10aa-25aa的长度。例如,可以包含甘氨酸甘氨酸和/或丝氨酸等亲水性氨基酸。
具体地,上述接头可以包含例如(GS)n、(GGS)n、(GSGGS)n或(GnS)m(n、m分别为1至10),例如,上述接头可以为(GnS)m(n、m分别为1至10)。具体地,上述接头可以包含GGGGS。
上述免疫细胞参与的双特异性或多特异性抗体的例可以包括:与CD3及CD19结合的博纳吐单抗(blinatumomab)(安进公司(Amgen));与CD3及EpCAM结合的索利托单抗(solitomab)(安进公司);与CD3及CEA结合的MEDI 565(美国免疫公司(MedImmune)、安进公司);以及与CD3及PSMA结合的BAY2010112(拜耳公司(Bayer)、安吉公司)。例示性的DART可以包括:与CD3及CD123的MGD006(马可罗晋公司(Macrogenics));以及与CD3及gpA33结合的MGD007(马可罗晋公司)。例示性的TandAbs可以包括:与CD3及CD19结合的AFM11(阿芬医疗公司(Affimed Therapeutics));以及与CD30及CD16A结合的AFM13(阿芬医疗公司)。
抗体药物偶联物(ADC)
本发明的又一实施方式涉及上述抗体或其抗原结合片段与药物结合的抗体药物偶联物。
在将药物传递到靶向癌细胞之前,抗体药物偶联物的抗癌药物应与抗体稳定结合。传递到目标的药物应从抗体中游离出来诱导靶向细胞的凋亡。为此,药物应在与抗体稳定结合的同时具有在靶向细胞中游离时诱导靶向细胞凋亡的充分的细胞毒性。
在一实施例中,上述抗体可以通过接头与药物结合。上述接头应为在细胞内条件下在连接抗PD-1抗体与药物之间的部位可切割的形态,即,应能够在细胞内环境中从抗体释放药物,并且与抗体的长半衰期相应地使抗体在全身循环中保持稳定,接头与药物的结合不应给抗体的稳定性及药物动态带来影响。
上述接头可以包括可切割接头或不可切割接头。在可切割接头的情况下,应像肽接头一样,可以在细胞内通过肽酶或者溶酶体蛋白酶或内体蛋白酶等蛋白酶被切割,在不可切割接头的情况下,例如,硫醚接头可以在细胞内通过水解非选择性地分解后释放药物。
在一实施例中,上述可切割接头可以包括肽接头。上述肽接头具有2个以上的氨基酸长度。例如,可以包括Val-Cit、Val-Ala或Val-Cit等二肽或这Phe-Leu或Gly-Phe-Leu-Gly。接头的例示具体记录在国际专利申请公开第WO2004/010957号中,可以作为参照导入本发明中。
上述抗体药物偶联物的抗体区域与靶向癌细胞的抗原结合形成抗体药物偶联物-抗原复合物后,通过内体-溶酶体通路嵌套到癌细胞内部。在此情况下,可以通过内体/溶酶体的内部环境调节细胞毒性药物在细胞内的释放。
在一实施例中,上述可切割接头为pH敏感性,可以在特定pH值中对水解敏感。通常,pH敏感性接头在酸性条件下表现出可被水解。例如,可以为在溶酶体中被水解的酸不稳定接头,可以为例如腙、缩胺基硫脲、顺式乌头酰胺(cis-aconitic amide)、原酸酯、缩醛、缩酮等。
在再一实施例中,上述接头也可以在还原条件下被切割,例如,可以为二硫键接头。可以利用N-琥珀酰亚胺基-S-乙酰硫基乙酸酯(SATA,N-succinimidyl-S-acetylthioacetate)、N-琥珀酰亚胺-3-(2-吡啶二硫代)丙酸酯(SPDP,N-succinimidyl-3-(2-pyridyldithio)propionate)、N-琥珀酰亚胺-3-(2-吡啶二硫代)丁酸酯(SPDB,N-succinimidyl-3-(2-pyridyldithio)butyrate)及N-琥珀酰亚胺基-氧羰基-α-甲基-α-(2-吡啶基-二硫代)甲苯(SMPT,N-succinimidyl-oxycarbonyl-alpha-methyl-alpha-(2-pyridyl-dithio)toluene)来形成多种二硫键。这样的二硫键接头可以在细胞内通过谷胱甘肽的硫醇与二硫化取代被分解。
上述药物和/或药物-接头可以通过抗体的赖氨酸随机接合,或者可以通过还原二硫键链时露出的半胱氨酸来接合。根据情况的不同,可以通过利用遗传工程学制备的标签,例如通过存在于肽或蛋白质的半胱氨酸结合为接头-药物。上述肽或蛋白质等利用遗传工程制备的标签可以包括例如可以通过类异戊二烯转移酶识别的氨基酸基序。上述肽或蛋白质可以在肽或蛋白质的羧基末端具有缺失(deletion),或者在肽或蛋白质的羧基(C)末端具有通过间隔单元的共价键的附加。
上述肽或蛋白质可以通过共价键直接与氨基酸基序连接,或者通过与间隔单元共价键合来与氨基酸基序连接。其中,上述氨基酸间隔单元由1个至20个氨基酸构成,其中,甘氨酸(Glycine)单元为优选。
上述类异戊二烯转移酶可以为例如蛋白质脂肪酸转移酶(FTase,farnesylprotein transferase)或牻牛儿基牻牛儿基转移酶(GGTase,geranylgeranyltransferase),FTase及GGTase I可以识别前面提及的化学式1中的CAAX基序,GGTase II可以识别XXCC、XCXC或CXX基序(其中,C为半胱氨酸,A为脂肪族氨基酸,X为决定类异戊二烯转移酶的基质特异性的氨基酸)。
在还一实施例中,上述接头可以包括可以被大多存在于溶酶体中,或在几种肿瘤细胞中过表达的β-葡萄糖醛酸苷酶(β-glucuronidase)识别来水解的β葡萄糖苷酸接头。与肽接头不同,由于亲水性(hydrophilicity)大,因此具有在与疏水性质的药物结合时可以增加抗体药物偶联物的溶解度的优点。
与此相关地,可以使用国际专利申请公开第WO2015/182984号中公开的β葡萄糖苷酸接头,例如包含自毁基团(self-immolative group)的β葡萄糖苷酸接头,上述文献可以作为参照导入本发明。
例如,根据情况的不同,上述接头可以为不可切割接头,在细胞内只通过抗体水解的一个步骤来释放药物,例如,生产氨基酸-接头-药物复合物。这种类型的接头可以为硫醚基团或马来酰亚胺基己酰基团(maleimidocaproyl),可以保持血液内稳定性。
根据本发明的一实施例,可以通过在抗体的二硫键链被还原时露出的半胱氨酸随机结合为接头-药物,或者通过导入具有序列GGGGGGGCVIM的抗体末端结合态来结合为接头-药物。
上述药物(包括化学式(1)的D)可以作为表现出药理学效果的制剂来与抗体结合,具体地,可以为化疗制剂、毒素、微核糖核酸(miRNA)、小干扰核糖核酸(siRNA)、短发夹核糖核酸(shRNA)或放射性同位素。上述化疗制剂可以为例如细胞毒性制剂或免疫抑制剂。具体地,可以包括微管蛋白抑制剂、有丝分裂抑制剂、拓扑异构酶抑制剂或可以作为脱氧核糖核酸嵌入剂的化疗制剂。并且,还可以包括免疫调节化合物、抗病毒剂、抗细菌剂、抗真菌剂、驱虫剂或它们的组合。
上述药物可以为例如选自由美登醇、澳瑞他汀(包括MMAE、MMAF)、氨基蝶呤、放线菌素、博来霉素、泰莱霉素、喜树碱、N8-乙酰基亚精胺、1-(2氯乙基)-1,2-二甲基磺酰基肼、埃斯培拉霉素、依托泊苷、6-巯基嘌呤、多拉司他汀、单端孢霉烯、卡利奇霉素、泰素(taxol)、紫杉烷、紫杉醇(paclitaxel)、多西他赛(docetaxel)、甲氨蝶呤、长春新碱、长春碱、阿霉素、左旋苯丙氨酸氮芥、丝裂霉素A、丝裂霉素C、苯丁酸氮芥、多卡马嗪、左旋门冬酰胺酶(L-asparaginase)、巯基嘌呤(mercaptopurine)、硫鸟嘌呤(thioguanine)、硫酸羟脲(hydroxyurea)、阿糖胞苷(cytarabine)、环磷酰胺(cyclophosphamide)、异环磷酰胺(ifosfamide)、亚硝基脲(nitrosourea)、顺铂(cisplatin)、卡铂(carboplatin)、丝裂霉素(mitomycin)、达卡巴嗪(dacarbazine)、甲基苄肼(procarbazine)、托泊替康(topotecan)、氮芥(nitrogen mustard)、环磷酰胺(cytoxan)、依托泊苷(etoposide)、5-氟尿嘧啶(5-fluorouracil)、双氯乙基亚硝基脲(CNU,bischloroethylnitrosourea)、伊立替康(irinotecan)、喜树碱(camptothecin)、博来霉素(bleomycin)、伊达比星(idarubicin)、柔红霉素(daunorubicin)、放线菌素D(dactinomycin)、普卡霉素(plicamycin)、米托蒽醌(mitoxantrone)、门冬酰胺酶(asparaginase)、长春瑞滨(vinorelbine)、苯丁酸氮芥(chlorambucil)、马法兰(melphalan)、卡莫司汀(carmustine)、洛莫司汀(lomustine)、白消安(busuLfan)、苏消安(treosulfan)、达卡巴嗪(decarbazine)、依托泊苷(etoposide)、替尼泊甙(teniposide)、托泊替康(topotecan)、9-氨基喜树碱(9-aminocamptothecin)、克利那托(crisnatol)、丝裂霉素C(mitomycin C)、三甲曲沙(trimetrexate)、霉酚酸(mycophenolic acid)、噻唑呋啉(tiazofurin)、利巴韦林(ribavirin)、5-乙炔基-1-β-D-呋喃呋喃糖基咪唑-4-羧酰胺(EICAR,5-ethynyl-1-beta-Dribofuranosylimidazole-4-carboxamide)、硫酸羟脲(hydroxyurea)、去铁胺(deferoxamine)、5-氟脱氧尿苷(floxuridine)、去氧氟尿甙(doxifluridine)、雷替曲塞(raltitrexed)、阿糖胞苷(cytarabine(ara C))、胞嘧啶阿拉伯糖苷(cytosine arabinoside)、氟达拉滨(fludarabine)、他莫昔芬(tamoxifen)、雷洛昔芬(raloxifene)、甲地孕酮(megestrol)、戈舍瑞林(goserelin)、醋酸亮丙瑞林(leuprolide acetate)、氟他胺(flutamide)、比卡鲁胺(bicalutamide)、EB1089、CB1093、KH1060、维替泊芬(verteporfin)、酞菁(phthalocyanine)、光敏剂Pe4(photosensitizer Pe4)、去甲氧基竹红菌素A(demethoxy-hypocrellin A)、α干扰素(Interferon-α)、γ干扰素(Interferon-γ)、肿瘤坏死因子(tumor necrosis factor)、吉西他滨(Gemcitabine)、硼替佐米(velcade)、瑞复美(revamid)、THALAMID(thalamid)、洛伐他汀(lovastatin)、1-甲基4-苯基吡啶离子(1-methyl-4-phenylpyridiniumion)、星形孢菌素(staurosporine)、放线菌素D(actinomycinD)、放线菌素D(dactinomycin)、博来霉素A2(bleomycin A2)、博来霉素B2(bleomycinB2)、培洛霉素(peplomycin)、表阿霉素(epirubicin)、吡柔比星(pirarubicin)、佐柔比星(zorubicin)、米托蒽醌(mitoxantrone)、维拉帕米(verapamil)及毒胡萝卜素(thapsigargin)、核酸分解酶及源自细菌或动植物的毒素组成的组中的一种以上,但不限定于此。
根据情况的不同,上述药物可以包含用来通过反应与接头及接头试剂上的亲电子性基团形成共价键的选自由胺、硫醇、羟基、酰肼、肟、肼、缩胺基硫脲、羧酸肼以及芳基酰肼基组成的组中的一种以上亲核基团。
在本发明的具体实例中,通过MC-vc-PAB接头制备本发明的抗体或其抗原结合片段与例如澳瑞他汀(MMAE)的药物连接的抗体药物偶联物。确认到这样的抗体药物偶联物表现出所目标的细胞毒性。
嵌合抗原受体(CAR)
本发明的又一实施方式涉及嵌合抗原受体,包含:包含抗原结合位点的胞外结构域;跨膜结构域;以及细胞内信号传导结构域。上述胞外结构域的抗原结合位点为上述抗体的scFv。
嵌合抗原受体以能够诱导对靶向抗原及表达相关抗原的细胞诱导免疫反应的方式设计的结构。嵌合抗原受体包含胞外结构域、跨膜结构域以及细胞内信号传导结构域。可以通过向免疫细胞导入编码识别在癌细胞的表面特异性表达的癌细胞表面抗原的受体的基因来杀灭癌细胞。可以通过包含与癌细胞中特异性表达的抗原结合的受体的免疫细胞只靶向癌细胞来引起免疫反应。上述嵌合抗原受体包含本发明的抗PD-1抗体的scFv作为胞外结构域的抗原识别部位。
第一代嵌合抗原受体包含含有识别癌细胞中特异性表达的抗原识别部位的胞外结构域、跨膜结构域及细胞内信号传导结构域,只利用CD3ζ作为信号传导结构域,具有对癌症的治疗效果微乎其微,持续时间短的问题。这样的第一代嵌合抗原受体具体记录在美国授权专利第6319494号中,作为参照导入本发明。
为了提高对免疫细胞的反应性,制备了结合辅助刺激结构域(CD28或CD137/4-1BB)与CD3ζ的第二代嵌合抗原受体,与第一代嵌合抗原受体相比,体内残存的包含嵌合抗原受体的免疫细胞的数量显著增加。而与利用一种辅助刺激结构域的第二代嵌合抗原受体相反,第三代嵌合抗原受体利用两种以上辅助刺激结构域。可以为实现生物体内包含嵌合抗原受体的免疫细胞的扩张及持续性而使辅助刺激结构域与4-1BB、CD28或OX40等结合。第二代嵌合抗原受体具体记录在美国授权专利第7741465号、第7446190号或第9212229号中,第三代嵌合抗原受体具体记录在美国授权专利第8822647号中,作为参照导入本发明。
第四代嵌合抗原受体中还包含编码IL-12或IL-15等细胞因子的基因,可以追加表达基于细胞因子嵌合抗原受体的免疫蛋白,第五代嵌合抗原受体为强化免疫细胞还包含白细胞介素受体链,例如IL-2Rβ。第四代嵌合抗原受体具体记录在美国授权专利第10316102号中,第五代嵌合抗原受体具体记录在美国授权专利第10336810号中,作为参照导入本发明。
在一实施例中,上述胞外结构域的抗原结合位点为抗体的scFv。在包含抗体的VH及VL结构域的scFv中,VH与VL结构域可以通过接头连接。包含选自由序列20、序列21、序列23、序列25、序列27、序列28、序列30、序列32、序列48及序列50组成的组中的一种以上氨基酸序列的重链可变区可以通过接头与包含选自由序列22、序列24、序列26、序列29、序列31、序列33、序列49、序列51、序列54及序列55组成的组中的一种以上氨基酸序列的轻链可变区连接。
上述接头可以为肽接头,可以具有约10aa-25aa的长度。例如,可以包含甘氨酸甘氨酸和/或丝氨酸等亲水性氨基酸,但不限定于此。
具体地,上述接头可以包含例如(GS)n、(GGS)n、(GSGGS)n或(GnS)m(n、m分别为1至10),例如,上述接头可以为(GnS)m(n、m分别为1至10)。具体地,上述接头可以包含GGGGS。
上述跨膜结构域可以源自天然或合成供给源。在天然供给源的情况下,结构域可以源自任意结合有膜的蛋白质或跨膜蛋白。上述跨膜结构域可以包括T细胞受体、CD28、CD3ε、CD45、CD4、CD5、CD8、CD9、CD16、CD22、CD33、CD37、CD64、CD80、CD86、CD134、CD137、CD154以及ICOS的α、β或ζ链。在合成上述跨膜结构域的情况下,可以包含亮氨酸和缬氨酸等疏水性残基,或者可以在个末端包含含有苯丙氨酸、色氨酸及缬氨酸的肽。2个至10个氨基酸长度的短的寡肽或多肽接头可以在跨膜结构域与嵌合抗原受体的细胞质信号传导结构域之间形成结合。可以利用甘氨酸-丝氨酸肽作为接头。
上述信号传导结构域可以诱导激活位于嵌合抗原受体的免疫细胞正常官能团功能。例如,可以通过细胞因子的分泌诱导细胞裂解激活或辅助激活。上述信号传导结构域可以包含为充分转导官能团功能信号而切割的细胞内信号传导结构域的片段。
可以包含在通过上述信号传导结构域与抗原受体相关联后为开始信号传导而起协同作用的T细胞受体及共同-受体的细胞质。
已知单独通过T细胞受体生成的信号不足以完全激活T细胞,还需要共刺激信号。因此,T细胞的激活可以与通过T细胞受体开始抗原依赖性一次激活以及二次或以提供共刺激信号的抗原依赖性方式起作用相关。一次细胞质信号传导序列以刺激性方式或抑制性方式调节T细胞受体复合物的一次激活。以刺激性方式起作用的一次细胞质信号传导序列可以含有免疫受体基于酪氨酸的激活基序或公知为免疫受体酪氨酸激活基序(ITAM)的信号传导基序。含有一次细胞质信号传导序列的ITAM的例可以包括TCRζ、FcRγ、FcRβ、CD3γ、CD3δ、CD3ε、CD5、CD22、CD79a、CD79b以及CD66d。
根据情况的不同,嵌合抗原受体的细胞质结构域可以包含CD3ζ链部分及共刺激信号传导区。共刺激信号传导区是指包含共刺激分子的胞内结构域的嵌合抗原受体的一部分。例如,可以包括与CD27、CD28、4-1BB(CD137)、OX40、CD30、CD40、ICOS、与淋巴细胞功能相关的抗原-1(LFA-1)、CD2、CD7、LIGHT、NKG2C、B7-H3以及CD83特异性结合的配体等。嵌合抗原受体的细胞质信号传导部分内的细胞质信号传导序列可以通过例如甘氨酸-丝氨酸等包含2个至10个氨基酸的肽接头来连接。
本发明的又一实施方式涉及导入上述嵌合抗原受体(CAR)的免疫细胞。
上述免疫细胞可以通过诱导免疫来诱发所目标的癌症治疗效果,例如,可以选自由T细胞、自然杀伤(NK)细胞、细胞因子诱导的杀伤细胞(Cytokine Induced Killer cell,CIK)、激活的细胞毒性T淋巴细胞(Cytotoxic T Lymphocyte,CTL)、巨噬细胞、肿瘤浸润T细胞(Tumor-Infiltrating Lymphocytes,TIL)、树突细胞组成的组中,但不限定于此。
根据情况的不同,还可以导入包含对上述抗PD-1抗体以外的抗体的scFv作为胞外结构域的抗原结合位点的嵌合抗原受体。
上述抗PD-1抗体以外的抗体可以为例如靶向FGFR3、TIGIT、PD-L1、BTLA、CTLA-4、VISTA、LAG3、TIM3、CD137(4-1BB)、VISTA、CD258(LIGHT)、MARCO、CD134(OX40)、CD28、CD278(ICOS)、CD27、CD154(CD40L)、CD357(GITR)、CD30、DR3、CD226(DNAM1)、CD96、CD200、CD200R、转铁蛋白受体、c-Met、EGFR、HER2、KDR、PDGFRa或NRP1的抗体。
治疗用组合物
本发明涉及癌症治疗用组合物,包含:上述抗体或其抗原结合片段;包含上述抗体或其抗原结合片段的双特异性或多特异性抗体;包含上述抗体或其抗原结合片段的抗体药物偶联物;包含上述抗体或其抗原结合片段的嵌合抗原受体;或者包含上述嵌合抗原受体的免疫细胞。
例如,本发明可以为用于预防或治疗癌症的药物组合物,包含:(a)药剂学上有效量的如下物质:本发明的对PD-1的抗体或其抗原结合片段;包含上述抗体或其抗原结合片段的双特异性或多特异性抗体;包含上述抗体或其抗原结合片段的抗体药物偶联物;包含上述抗体或其抗原结合片段的嵌合抗原受体;或者包含上述嵌合抗原受体的免疫细胞的;以及(b)药剂学上可接受的载体。并且,本发明可以为癌症的预防或治疗方法,包括向癌症患者给药本发明的对PD-1的抗体或其抗原结合片段、包含上述抗体或其抗原结合片段的双特异性或多特异性抗体、包含上述抗体或其抗原结合片段的抗体药物偶联物、包含上述抗体或其抗原结合片段的嵌合抗原受体或者包含上述嵌合抗原受体的免疫细胞步骤。
“预防”是指通过给药本发明的组合物来抑制疾病的临床症状或延迟病程的所有行为,“治疗”是指抑制疾病的临床症状、减轻或消除疾病的临床症状。
上述癌症包括例如霍奇金淋巴瘤、非霍奇金淋巴瘤(例如B细胞淋巴瘤、弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤、慢性淋巴细胞白血病、套细胞淋巴瘤、边缘区B细胞淋巴瘤、伯基特淋巴瘤、淋巴浆细胞淋巴瘤、毛细胞白血病)、急性骨髓性白血病、慢性骨髓性白血病、骨髓增生异常综合征、多发性骨髓瘤或急性淋巴细胞白血病。
上述癌症包括例如卵巢癌、直肠癌、胃癌、睾丸癌、肛周癌、子宫癌、结肠癌、直肠癌、直肠癌、肾细胞癌、肝癌、肺的小细胞癌、小肠癌、食管癌、黑色素瘤、卡波氏肉瘤、内分泌系统癌症、甲状腺癌、甲状旁腺癌、肾上腺癌、骨癌、胰腺癌、皮肤癌、头颈部癌、皮肤或眼内恶性黑色素瘤、子宫癌、脑干胶质瘤、脑垂体腺癌、表皮样癌、子宫颈部扁平细胞癌、输卵管癌、子宫内膜癌、阴道癌、软组织肉瘤、尿道癌、外阴癌、阴茎癌、膀胱癌、肾癌或输尿管癌、肾盂肾癌、脊柱肿瘤、中枢神经系统(CNS)的新生物、原发性中枢神经系统淋巴瘤、肿瘤血管生成、上述癌症的转移病变或上述癌症的组合。
上述癌症可以为例如胶质母细胞瘤、肺癌、膀胱癌、口腔癌、头颈部扁平细胞癌、胆囊癌或宫颈癌。尤其,在胶质母细胞瘤的情况下,上述抗体或其抗原结合片段需要通过存在于脑组织及脊柱与周边循环系统之间的在脑的毛细血管内皮细胞膜内通过紧密结合(junction)形成的血脑屏障(blood-brain barrier)。可以通过与转运体结合使用来通过血脑屏障(BBB)。为了使药物通过血脑屏障,可以使用例如缓激肽或高密度聚焦超声波(HIFU,Hign density foucues ultrasound)等方法来瓦解血脑屏障的渗透压的方法。并且,可以包括使用细胞内存在的葡萄糖基氨基酸转运体、胰岛素或转铁蛋白的受体介导的穿胞作用或者阻断糖蛋白的活性外排转运体(efflux transporter)。
本发明的组合物中包含的药剂学上可接受的载体可以为配制时通常使用的载体,可以包括乳糖、蔗糖、葡萄糖、山梨糖醇、甘露醇、淀粉、阿拉伯胶、磷酸钙、海藻酸盐、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、水、糖浆、甲基纤维素、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁及矿物油等,但不限定于此。除上述成分外,本发明的组合物还可以包含润滑剂、湿润剂、甜味剂、香味剂、乳化剂、助悬剂、保存剂等。
本发明的药物组合物可以通过口服或胃肠外给药,在胃肠外给药的情况下,可以通过静脉内注射、皮下注射、肌肉注射、腹腔注射、内皮给药、病灶给药、鼻内给药、肺内给药及直肠内给药等方式来给药。
口服给药时,由于蛋白质或肽会被消化,因此口服用组合物应给活性药剂涂层或以保护不在胃里被分解的方式来剂型化。并且,药物组合物可以通过能够使活性物质向靶向细胞移动的任意装置给药。
本发明的组合物的适当给药量根据配制方法、给药方式、患者的年龄、体重、性别、疾病状态、饮食、给药时间、给药途径、代谢速度及反应敏感度等因素而不同,熟练的医生可以轻易确定及处方所希望在治疗或预防中有效的给药量。例如,本发明的药物组合物的1天给药量为0.0001mg/kg-100mg/kg。本说明书中的术语“药剂学上的有效量”是指用于预防或治疗癌症的充分的量。
根据本发明所属技术领域的普通技术人员易于实施的方法,本发明的药物组合物可以通过利用药剂学上可接受的载体和/或赋形剂配制来制备为单位剂量形式或制备为装入多剂量容器中的形式。在此情况下,剂型可以为油性或水性溶剂中的溶液、悬混液或乳化液形式,也可以为提取剂、散剂、栓剂、粉末剂、颗粒剂、片剂或胶囊剂形式,还可以包含分散剂或稳定剂。
联合治疗
本发明涉及包含免疫细胞及抗PD-1抗体以外的药物的联合治疗用组合物。
在一实施例中,上述抗PD-1抗体以外的药物可以包括化疗制剂或抗PD-1抗体以外的抗体。
上述药物可以为选自由美登醇、澳瑞他汀(包括MMAE、MMAF)、氨基蝶呤、放线菌素、博来霉素、泰莱霉素、喜树碱、N8-乙酰基亚精胺、1-(2氯乙基)-1,2-二甲基磺酰基肼、埃斯培拉霉素、依托泊苷、6-巯基嘌呤、多拉司他汀、单端孢霉烯、卡利奇霉素、泰素(taxol)、紫杉烷、紫杉醇、多西他赛、甲氨蝶呤、长春新碱、长春碱、阿霉素、左旋苯丙氨酸氮芥、丝裂霉素A、丝裂霉素C、苯丁酸氮芥、多卡马嗪、左旋门冬酰胺酶、巯基嘌呤、硫鸟嘌呤、硫酸羟脲、阿糖胞苷、环磷酰胺、异环磷酰胺、亚硝基脲、顺铂、卡铂、丝裂霉素、达卡巴嗪、甲基苄肼、托泊替康、氮芥、环磷酰胺、依托泊苷、5-氟尿嘧啶、双氯乙基亚硝基脲、伊立替康、喜树碱、博来霉素、伊达比星、柔红霉素、放线菌素D、普卡霉素、米托蒽醌、门冬酰胺酶、长春瑞滨、苯丁酸氮芥、马法兰、卡莫司汀、洛莫司汀、白消安、苏消安、达卡巴嗪、依托泊苷、替尼泊甙、托泊替康、9-氨基喜树碱、克利那托、丝裂霉素C、三甲曲沙、霉酚酸、噻唑呋啉、利巴韦林、5-乙炔基-1-β-D-呋喃呋喃糖基咪唑-4-羧酰胺、硫酸羟脲、去铁胺、5-氟脱氧尿苷、去氧氟尿甙、雷替曲塞、阿糖胞苷、胞嘧啶阿拉伯糖苷、氟达拉滨、他莫昔芬、雷洛昔芬、甲地孕酮、戈舍瑞林、醋酸亮丙瑞林、氟他胺、比卡鲁胺、EB1089、CB1093、KH1060、维替泊芬、酞菁、光敏剂Pe4、去甲氧基竹红菌素A、α干扰素、γ干扰素、肿瘤坏死因子、吉西他滨、硼替佐米、瑞复美、THALAMID、洛伐他汀、1-甲基4-苯基吡啶离子、星形孢菌素、放线菌素D、放线菌素D、博来霉素A2、博来霉素B2、培洛霉素、表阿霉素、吡柔比星、佐柔比星、米托蒽醌、维拉帕米及毒胡萝卜素、核酸分解酶及源自细菌或动植物的毒素组成的组中的一种以上。
在一实施例中,上述抗PD-1抗体以外的抗体可以为靶向选自由例如FGFR3、TIGIT、PD-L1、BTLA、CTLA-4、VISTA、LAG3、TIM3、CD137(4-1BB)、VISTA、CD258(LIGHT)、MARCO、CD134(OX40)、CD28、CD278(ICOS)、CD27、CD154(CD40L)、CD357(GITR)、CD30、DR3、CD226(DNAM1)、CD96、CD200、CD200R、转铁蛋白受体、c-Met、EGFR、HER2、KDR、PDGFRa、NRP1组成的组中的一种以上的抗体或其抗原结合片段。
本发明涉及联合治疗用组合物,包含上述抗体或其抗原结合片段以及选自由如下成分组成的组中的一种以上:(i)免疫细胞;(ii)包含嵌合抗原受体的免疫细胞,所述嵌合抗原受体包含对除抗PD-1抗体以外的抗体的scFv作为胞外结构域;以及(iii)免疫检查点抑制剂。
并且,本发明涉及联合治疗用组合物,包含上述免疫细胞参与的双特异性或多特异性抗体以及选自由如下成分组成的组中的一种以上:(i)免疫细胞;(ii)包含嵌合抗原受体的免疫细胞,所述嵌合抗原受体包含对除抗PD-1抗体以外的抗体的scFv作为胞外结构域;以及(iii)免疫检查点抑制剂。
上述免疫细胞可以诱发例如通过诱导免疫来治疗目标癌症的免疫治疗的效果,例如,可以选自由T细胞、自然杀伤细胞、细胞因子诱导的杀伤细胞、激活的细胞毒性T淋巴细胞、巨噬细胞、肿瘤浸润T细胞、树突细胞组成的组中的,但不限定于此。
上述抗PD-1抗体以外的抗体为以PD-1以外的目标为靶向的抗体,例如,可以为与FGFR3、TIGIT、PD-L1、BTLA、CTLA-4、VISTA、LAG3、TIM3、CD137(4-1BB)、VISTA、CD258(LIGHT)、MARCO、CD134(OX40)、CD28、CD278(ICOS)、CD27、CD154(CD40L)、CD357(GITR)、CD30、DR3、CD226(DNAM1)、CD96、CD200、CD200R、转铁蛋白受体、c-Met、EGFR、HER2、KDR、PDGFRa或NRP1结合的抗体或其抗原结合片段,但不限定于此。
上述免疫检查点抑制剂是指可以通过在抗原提呈细胞(APC,antigen presentingcell)和例如T细胞的免疫细胞相遇的部位阻断T细胞抑制信号来诱导T细胞激活的制剂。上述免疫检查点抑制剂可以为例如靶向TIGIT、PD-L1、BTLA、CTLA-4、VISTA、LAG3、TIM3、CD137(4-1BB)、CD258(LIGHT)、MARCO、CD134(OX40)、CD28、CD278(ICOS)、CD27、CD154(CD40L)、CD357(GITR)、CD30、DR3、CD226(DNAM1)、CD96、CD200或CD200R的药物,但不限定于此。
可以同时向上述联合给药对象给药第一成分及第二成分。并且,还可以间隔规定时间向上述联合给药对象单独给药第一成分及第二成分。可以在给药第一成分之前或之后向上述联合给药对象单独给药第二成分。
伴随诊断(Companion diagnostics,CDx)
伴随诊断为用于预测患者对特定药物治疗的反应性的分子诊断技术的一种,在药物的应用中,提出应用对象患者的选择标准,并考虑符合该标准的诊断、预后及预测生物标记物的特异性及敏感性,从而可以提出处理适合该患者的药物的标准。
在抗癌剂的情况下,虽然在显出反应的换这种观察到很高的效果,但有反应的患者的比例低,因此重点在于筛选显出效果的患者,可以通过伴随诊断筛选对抗癌剂有反应的患者,从而增大患者的治疗效果。
上述样品是指从患者的组织或体液中获得的生物学检材。组织样品的供给源可以包括:源自冷冻和/或保存的器官、组织样品、活检或吸入物等的固体组织;血液或任意血液成分(例如血清、血浆);骨髓或任意骨髓成分;尿液、脑脊髓液、全血液、血浆及血清等体液。样品可以包括非细胞成分(例如尿液、血浆、血清或其他非细胞体液)。样品可以包括体液,例如,可以包括血液(例如,全血液)。具体地,上述样品可以为从患者中获得的全血液样品、全骨髓样品、全外周血样品或全肿瘤样品。上述“全”样品是指实质上未从样品中清除或分离成分(例如细胞)的样品。上述样品,例如血液样品可以在使用前被稀释(例如通过生理兼容性缓冲液或培养基)。在其他具体例中,“全”样品,例如全组织样品或全肿瘤样品可以实质上保持起源组织来源的微环境,例如可以实质上保持肿瘤或免疫微环境的结构。具体地,样品,例如肿瘤样品可以加工为更小的碎片(例如研磨、碾压、混合、粉碎等)并被稀释(例如通过生理兼容性缓冲液或培养基)。
上述基因的表达确认为确认相关基因的存在与否以及表达程度的过程,可以通过聚合酶链式反应(PCR)进行,根据情况,可以使用逆转录聚合酶链式反应(Competitive RT-PCR)、实时逆转录聚合酶链式反应(Real-time RT-PCR)、核糖核酸酶保护试验(RPA;RNaseprotection assay)、北方印迹法(Northern blotting)、脱氧核糖核酸芯片来进行。
聚合酶链式反应可以利用引物通过基因扩增反应来进行。可以进行多重聚合酶链式反应、实时(real-time)聚合酶链式反应、差别显示聚合酶链式反应(differentialdisplay PCR:DD-PCR)、互补脱氧核糖核酸末端的迅速扩增(rapid amplification ofcDNA ends:RACE)、反聚合酶链式反应(inverse polymerase chain reaction:IPCR)、小载体(vectorette)聚合酶链式反应及热不对称聚合酶链式反应(TAIL-PCR,thermalasymmetric interlaced PCR)等。
也可以通过基因编码检测蛋白质的表达与否。就是确认通过上述基因表达的蛋白质的存在与否和表达程度的过程。可以利用与上述蛋白质特异性结合的抗体、寡肽、配体、肽核酸(PNA,Peptide nucleic acid)或适配体(aptamer)等来确认蛋白质的量。
为此的分析方法可以包括蛋白印迹法、酶联免疫吸附测定(enzyme linkedimmunosorbent assay,ELISA)、放射线免疫分析(RIA:Radioimmunoassay)、放射免疫扩散法(radioimmunodiffusion)、琼脂双向(Ouchterlony)免疫扩散法、火箭(rocket)免疫电泳、组织免疫染色、免疫沉淀分析(Immunoprecipitation Assay)、补体固定分析(Complement Fixation Assay)、流式细胞荧光分选技术(Fluorescence Activated CellSorter,FACS)、利用蛋白芯片(protein chip)的方法等。
实施例
以下,通过实施例更为详细地说明本发明。本发明所属技术领域的普通技术人员应该自明的是,这些实施例仅用于例示本发明,本发明的范围不限定于这些实施例。
实施例1.制备候选克隆及分析抗原结合力
如图1所示,将全长(full length)PD-1脱氧核糖核酸序列克隆到疫苗接种载体(vaccination vector)来用作脱氧核糖核酸疫苗接种,与重组人PD-1-His蛋白合并后免疫接种到小鼠,并且制备稳定表达人PD-1的293细胞株。在免疫接种之前和之后采血来确认免疫接种的程度。在二次脱氧核糖核酸免疫接种后,分离血清后与表达人PD-1的293细胞株结合来分析的结果,可以确认1号、2号、4号小鼠的血清中生成抗PD-1抗体。在第三次使用蛋白质免疫接种后,分离血清后与表达人PD-1的293细胞株结合来分析的结果,可以确认所有5只小鼠的血清中都生成抗PD-1抗体。然后,再分别进行一次脱氧核糖核酸疫苗接种和蛋白质免疫接种后,将2号、4号小鼠的脾脏与SP2/0骨髓细胞(myeloid cells)融合来生成杂交瘤细胞(hybridoma)克隆。
如图2所示,候选抗体是利用杂交瘤细胞培养液通过酶联免疫吸附测定一次筛选了11个对重组人PD-1-His蛋白具有结合力的克隆。
如图3所示,将1×106个细胞的11个杂交瘤细胞的各个克隆培养24小时后,使用它们的培养液进行酶联免疫吸附测定来以定量的方式比较抗体的结合力。酶联免疫吸附测定以如下方式进行:在4℃的温度下,在96孔酶标板(96-well ELISA plate)中O/N包被(coating)重组人PD-1-His蛋白后,使用5%的脱脂牛奶(non-fat skim milk)在常温(RT)下封闭(blocking)1小时(hr)。将各杂交瘤细胞培养液从100μl开始1/2连续稀释(serialdilution)来在常温下处理抗体2小时后,使用抗-mIgG-辣根过氧化物酶(anti-mIgG-HRP)进行探测(detection)。结果,在一次筛选的候选抗体中筛选2-2B3、2-3C3、2-5F1、2-7C5、2-9A9以及4-8D4、4-8H11、4-9D12、4-9F10的9个二次候选抗体。
实施例2.筛选的克隆的特性
如图4a至图4c所示,纯化从杂交瘤细胞的培养液中筛选的9个候选抗体后,分别通过十二烷基硫酸钠聚丙烯酰胺凝胶电泳(SDS-PAGE)(图4a)、体积排阻高效液相色谱(SEC-HPLC)(图4b)、表面等离子体共振(SPR)(图4c)分析特性。在与重组人PD-1-His蛋白的结合力中,9个克隆表现出相似的结合亲和力,其中,4-9D12、4-9F10克隆表现出相对较高的结合亲和力。
如图5及图6所示,通过流式细胞术方法分析使用PD-1/PD-L1阻断测试中使用的PD-1表达效应细胞的一部分纯化的候选抗体的结合力的结果,确认到2-2B3(49.9%)、2-7C5(50.4%)、4-8D4(23.5%)等结果。
如图6所示,为了分析纯化的候选抗体的体外(in vitro)功效,使用如下原理:当共同培养两种作为遗传工程细胞株(engineered cell lines)的表达PD-1的效应细胞(effector cells)与表达PD-L1的人工抗原提呈细胞时,PD-1与PD-L1的结合通过阻碍T细胞受体信号来抑制发光,相反,若通过候选抗体的功效阻断(block)PD-1与PD-L1的结合,则通过激活T细胞受体信号来诱导发光。从5μg开始2倍连续稀释(2-fold serial dilution)来确认筛选的抗体对PD-1与PD-L1的结合的阻断效果的结果,在2-2B3、2-7C5、4-8D4克隆中表现出与阳性对照组抗PD-1抗体(普洛麦格公司(Promega))相似的抑制效果。
因此,通过上述结果筛选3个候选抗体,为了筛选的抗体的互补脱氧核糖核酸克隆(cDNA cloning),从各杂交瘤细胞分离核糖核酸后合成互补脱氧核糖核酸。通过互补脱氧核糖核酸末端迅速扩增的聚合酶链式反应(RACE PCR)扩增作为各抗体的抗体片段(antibody fragments)的VH和VL后,将扩增的聚合酶链式反应产物(PCR product)在pGEM-Teasy载体(vector)中克隆后分析其序列。结果,筛选的3个克隆分别为具有不同的碱基序列、氨基酸序列的抗体,将这三个抗体人源化。
实施例3.分析筛选的各克隆的序列
在表1中整理了筛选的克隆的VH、VL及互补决定区(CDR region)序列的分析结果。在筛选的克隆中,将2-2B3的两个克隆以2-2B3W及2-2B3R表示。
在2-2B3W的情况下,包含序列20的重链可变区(VH)及序列22的轻链可变区(VL),其中,VH CDR1为GFVFSNYD(序列1),VH CDR2为ITIGGGTT(序列2),VH CDR3为ARWVYDPLYAMDY(序列3),VL CDR1为ESVDNYGISF(序列5),VL CDR2为AAS(序列6),VL CDR3为QQSKEVPWT(序列7)。
在2-2B3R的情况下,包含序列21的重链可变区(VH)及序列22的轻链可变区(VL),其中,VH CDR1为GFVFSNYD(序列1),VH CDR2为ITIGGGTT(序列2),VH CDR3为ARRVYDPLYAMDY(序列4),VL CDR1为ESVDNYGISF(序列5),VL CDR2为AAS(序列6),VL CDR3为QQSKEVPWT(序列7)。
在2-7C5的情况下,包含序列23的重链可变区(VH)及序列24的轻链可变区(VL),其中,VH CDR1为GFTFSSFG(序列8),VH CDR2为IYSNGDYT(序列9),VH CDR3为ARYYGNYGGYFDY(序列10),VL CDR1为QSVSNDVA(序列11),VL CDR2为YAS(序列12),VL CDR3为QQDYSSPPT(序列13)。
在4-8D4的情况下,包含序列25的重链可变区(VH)及序列26的轻链可变区(VL),其中,VH CDR1为GYTFTTYW(序列14),VH CDR2为INPTTGYT(序列15),VH CDR3为ARGVRYYFDY(序列16),VL CDR1为QSLLDSRTRKNY(序列17),VL CDR2为WAS(序列18),VL CDR3为KQSYNLIT(序列19)。
表1
抗体序列
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信号肽用斜体表示。各克隆的克隆的VH CDR区(region)及VL CDR区用加粗的字体表示。
表2
核酸序列
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实施例4.制备人源化抗体
从上述实施例1至实施例3的结果制备对于克隆2-2B3W、2-2B3R、2-7C5及4-8D4的人源化抗体2B3W、2B3R、7C5及8D4。分析制备的人源化抗体的序列的结果如表3所示。
在2B3W的情况下,包含序列27的重链可变区(VH)及序列29的轻链可变区(VL),其中,VH CDR1为GFVFSNYD(序列1),VH CDR2为ITIGGGTT(序列2),VH CDR3为ARWVYDPLYAMDY(序列3),VL CDR1为ESVDNYGISF(序列5),VL CDR2为AAS(序列6)及VL CDR3为QQSKEVPWT(序列7)。
在2B3R的情况下,包含序列28的重链可变区(VH)及序列29的轻链可变区(VL),其中,VH CDR1为GFVFSNYD(序列1),VH CDR2为ITIGGGTT(序列2),VH CDR3为ARRVYDPLYAMDY(序列4),VL CDR1为ESVDNYGISF(序列5),VL CDR2为AAS(序列6),VL CDR3为QQSKEVPWT(序列7)。
在7C5的情况下,包含序列30的重链可变区(VH)及序列31的轻链可变区(VL),其中VH CDR1为GFTFSSFG(序列8),VH CDR2为IYSNGDYT(序列9),VH CDR3为ARYYGNYGGYFDY(序列10),VL CDR1为QSVSNDVA(序列11),VL CDR2为YAS(序列12),VL CDR3为QQDYSSPPT(序列13)。
在8D4的情况下,包含序列32的重链可变区(VH)及序列33的轻链可变区(VL),其中,VH CDR1为GYTFTTYW(序列14),VH CDR2为INPTTGYT(序列15),VH CDR3为ARGVRYYFDY(序列16),VL CDR1为QSLLDSRTRKNY(序列17),VL CDR2为WAS(序列18),VL CDR3为KQSYNLIT(序列19)。
表3
人源化抗体序列
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各克隆的VH CDR区及VL CDR去以加粗的字体表示。克隆的工程化氨基酸残基以下划线表示。
表4
核酸序列
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实施例5.特性分析
如图7a至图7c所示,使用Expi293瞬时表达系统(transient expression system)生产及纯化3个人源化抗体,通过十二烷基硫酸钠聚丙烯酰胺凝胶电泳(7a)和酶联免疫吸附测定分析纯化的人源化抗体的定量结合力,其中,2B3R克隆没有表现出结合力。以与图3的实施例相似的方法实施酶联免疫吸附测定,从500ng浓度开始1/2连续稀释各抗体来处理。通过体积排阻高效液相色谱、表面等离子体共振(图7b)分析人源化候选抗体的纯度和结合力特性,将竞争公司的keytruda抗体用作阳性对照组来比较。并且,使纯化的各人源化抗体与表达人PD-1的293细胞结合后通过流式细胞术分析的结果,3个人源化抗体2B3W、7C5及8D4表现出高的结合力,选择它们作为用于之后体内(in vivo)抗癌功效分析的候选抗体。
实施例6.候选抗体的体内功效分析
本发明人分析了上述实施例5中筛选的人源化抗体2B3W、7C5及8D4候选抗体的体内功效。
简略叙述如下:为了分析人源化候选抗体的体内功效,使用表达hPD-L1的MC38癌细胞株(小鼠结肠癌(mouse colon cancer))将表达hPD-1的C57BL/6基因敲入小鼠(knock-in mice)制备为肿瘤模型,检测有关抗癌功效剂血清内肝毒性的标记物。以10mg/kg的浓度以间隔3天的方式给药5次人源化候选抗体2B3W、7C5、8D4,每个人源化抗体组为5只小鼠。
结果如图8a所示,在各组中测量每个个体的肿瘤大小(tumor size)时,所有候选抗体的给药都与竞争公司的抗体keytruda相似地显著抑制癌细胞的生长。将各组的结果值的平均值曲线化。由于肿瘤几乎被消除,因此无法分析肿瘤内的肿瘤浸润淋巴细胞(TIL,tumor infiltrated lymphocyte)。
并且,如图8b所示,在实验结束的同时从各组的动物中采集血液来分析肝毒性,在处理本发明的抗体的组中,未观察到肝毒性的症状。
通过上述数据不仅可以确认本发明的人源化候选抗体2B3W、7C5及8D4表现出卓越的抗癌效果,还因没有肝毒性而在生物体内安全。
实施例7.评估候选抗体的基因工程(gene engineering)
本发明人为了增加上述实施例5中筛选的人源化抗体2B3W、7C5及8D4候选抗体对抗原的亲和度进行了基因工程,从而获得各候选抗体。通过十二烷基硫酸钠聚丙烯酰胺凝胶电泳、体积排阻高效液相色谱及表面等离子体共振分析各选抗体的纯度和结合力特性,与作为阳性对照组的keytruda抗体进行比较。
结果如图9a所示,获得2B3W的亲和度得到改善的5个克隆抗体T14-01、T14-02、T14-03、T14-04及T14-05后,与作为阳性对照组的keytruda(9nM)比较时,从2B3W改善亲和度的T14-05(5.8nM)表现出比keytruda更高的抗原亲和度。
并且,如图9b所示,获得7C5的亲和度得到改善的5个克隆抗体T15-01、T15-02、T15-03、T15-04及T15-05后,与作为阳性对照组的keytruda(9nM)比较时,从7C5改善亲和度的T15-01(9.7nM)具有与keytruda相似的抗原结合力。
相反,如图9c所示,获得8D4的亲和度的得到改善的2个克隆抗体T16-01及T1-02后,与作为阳性对照组的keytruda(9nM)比较时,未表现出它们的抗原亲和度得到改善的迹象。
如上所述制备的人源化抗体的基因工程的抗体序列在上述表3中示出。
并且,如图9d所示,示出将亲和度得到改善的抗体中筛选的T14-05(5.8nM)和T15-01(9.7nM)抗体与竞争公司的抗体keytruda(9nM)进行最终比较的体积排阻高效液相色谱-纯度和表面等离子体共振-亲和度。
追加筛选通过上述结果判断为抗原亲和度高的克隆2B3W-T14-05(T14-05)及7C5-T15-01(T15-01)。
实施例8.评估候选抗体对目标细胞的结合力
本发明人通过流式细胞术分析上述实施例中筛选的人源化抗体2B3W、7C5、8D4、T14-05及T15-01对hPD-1过表达细胞的结合力。
结果,如图10a所示,所有候选抗体都对细胞表面表达的hPD-1表现出优秀的结合力。
并且,如图10b所示,在通过流式细胞术在从人类血液中分离的激活的(activated)hCD8 T细胞中分析候选抗体的结合力时,各克隆都表现出结合力的成比例的差异,其中,T14-05和T15-01抗体表现出相对较高的结合力。
实施例9.候选抗体基于PD-1/PD-L1细胞的阻滞测试(blockade assay)评估及序
列分析
本发明人在细胞水平中分析上述实施例中筛选的人源化抗体2B3W、7C5、8D4、T14-05及T15-01是否能够阻碍表达hPD-1的效应(effector)细胞与表达作为其受体(receptor)的hPD-L1的APC细胞的结合。
上述实验使用PD-1/PD-L1阻滞生物测定(Blockade Bioassay)(普洛麦格公司)试剂盒(kit),使用如下方法:当共培养(co-culture)表达人PD-1并具有荧光素酶报告基因(luciferase reporter)的Jurkat效应细胞与表达PD-L1的CHO-K1 aAPC时,处理候选抗体时若抗体与hPD-1结合来阻断与hPD-L1的结合,则T细胞受体信号(TCR signal)被激活,从而可以测定荧光素酶(luciferase)的表达程度。比较各候选抗体与亲和度得到改善的候选抗体。
结果如图11a及图11b所示,在对于PD-L1的候选抗体的PD-1的阻断功效(blockingeffect)中,确认到T14-05和T15-01抗体表现出与作为对照组的keytruda相似的功效。
于是,基于上述结果将克隆T14-05及T15-01筛选为最终候选抗体并测序。分析上述克隆T14-05及T15-01的序列的结果在上述表3中示出。
从2B3W中改善亲和度的T14-05(2B3W-T14-05)包含序列48的重链可变区(VH)及序列49的轻链可变区(VL),其中,VH CDR1为GFVFSNYD(序列1),VH CDR2为ITIGGGTT(序列2),VH CDR3为ARWRYDPLFAMDYW(序列56),VL CDR1为ESVTDYGISFMN(序列57),VL CDR2为AAS(序列6),VL CDR3为QQSKEVPWT(序列7)。
从7C5中改善亲和度的T15-01(7C5-T15-01)包含序列50的重链可变区(VH)及序列51的轻链可变区(VL),其中,VH CDR1为GFTFSSFG(序列8),VH CDR2为IYSNGDYT(序列9),VHCDR3为ARYYGNYGGYFDY(序列10),VL CDR1为QSVWDDLT(序列58),VL CDR2为YAS(序列12),VLCDR3为QQDYSSPPT(序列13)。
如图12a所示,各CDR区以粗体字体表示,为改善亲和度而序列工程(sequenceengineering)的序列以下划线来表示。更换2个氨基酸的候选抗体T14-05的VH的CDR3与T14-04的VH序列相同,VL在CDR1中更换2个氨基酸。
并且,如图12b所示,各CDR区以粗体字体表示,为改善亲和度而序列工程的序列以下划线来表示。候选抗体T15-01的VH序列(sequence)与7C5的VH序列相同,VL的CDR1中更换4个氨基酸。
并且,如图12c所示,各CDR区以粗体字体表示,为改善亲和度而序列工程的序列以下划线来表示,示出分析8D4、其克隆T16-01及T16-02序列的结果。
并且,如图12d所示,比较最终筛选的T14-05和T15-01的氨基酸序列与作为阳性对照组的keytruda的氨基酸序列的结果,确认到它们是具有包含各CDR区的互不相同序列的新型抗体。抗体将能够增加抗体结构稳定性的CPPCP氨基酸序列用作人IgG4同型(isotype)的铰链部分。
实施例10.分析候选抗体的种间免疫交叉反应(Cross-Reactivity)
本发明人利用各不同种的PD-1抗原通过酶联免疫吸附测定分析上述实施例中最终筛选的人源化抗体T14-05及T15-01在人(human)、猴(monkey)(猕猴(cynomolgus)、恒河猴(rhesus))、豚鼠(canine)、小鼠中的结合力。
结果如图13所示,最终筛选的T14-05与T15-01两种人源化候选抗体在猴中具有免疫交叉反应(Cross-Reactivity),在豚鼠和小鼠中不具有结合力。
实施例11.分析最终候选抗体的体内功效
本发明人利用上述实施例中确认亲和度得到改善的人源化候选抗体中亲和度比作为阳性对照组的keytruda(9nM)更高的T14-05(5.8nM)作为代表抗体来分析体内抗癌功效。
为了分析体内功效,向表达hPD-1的C57BL/6基因敲入小鼠(knock-in mice)给药1×106cells/小鼠的表达hPD-L1的小鼠结肠癌MC38细胞株来制备肿瘤模型,分析抗癌功效。以1mg/kg、3mg/kg以及5mg/kg的3种浓度间隔3天给药T14-05抗体(EU135-T14.05)6次,各抗体给药浓度组为6只小鼠。以5mg/kg的浓度给药竞争公司的抗体keytruda作为阳性对照组进行比较分析。从第一次给药开始,一周测量肿瘤大小2次。在100mm3~150mm3的小鼠肿瘤大小的范围内基于平均大小分组,在各个小鼠尾部标记数字标识来追踪随给药抗体的肿瘤大小变化。
结果如图14a所示,在各组中分析不同个体的肿瘤大小时,在所有抗体给药组中观察到肿瘤生长率从第二次抗体给药开始延迟,第三次给药后,开始肿瘤大小减少以及坏死现象,观察到癌细胞生长得到抑制的现象。这样的抗癌功效程度随抗体浓度的不同而不同。
并且,将各组中肿瘤大小的结果值的平均值曲线化。结果如图14b所示,与磷酸盐缓冲溶液(PBS)对照组的持续性的肿瘤生长相比,抗体给药组中表现出癌细胞生长的减少,尤其,以5mg/kg浓度给药的组中表现出比竞争公司的抗体keytruda更好的抗癌效果。并且,在T14-05给药组中表现出依赖抗体给药浓度的抗癌功效。
并且,在第三次给药后,采集各组的所有个体的血液来调查小鼠CD4和CD8 T细胞的分布率。以1∶1的比例向100μl的眼眶采血的血液中加入100μl的磷酸盐缓冲溶液来稀释,将其放在100μl的聚蔗糖(Ficoll)上离心分离,从而通过密度梯度分离出外周血单个核细胞(PBMC)。使用小鼠CD45、小鼠CD8以及小鼠CD4通过流式细胞术分析分离的外周血单个核细胞的比例。
结果如图14c所示,与磷酸盐缓冲溶液给药对照组(G1)相比,在给药抗体的所有组中,用于杀灭癌细胞的CD8 T细胞的比例增加,与之相反,小鼠CD4 T细胞的比例减少。
上述结果意味着抗体给药组中因免疫杀伤细胞CD8 T细胞的增加而表现出抗癌功效。
以上,详细记述了本发明内容的特定部分,但本发明所属技术领域的普通技术人员应该明白的是,这样具体的记述仅为本发明的优选实施方式,本发明的范围不受它们的限制。因此,本发明实质的范围应由随附的发明要求保护范围及其等价物来定义。
<110> 优特力克斯有限公司
<120> 抗PD-1抗体及其用途
<130> EUTILEX1-1P
<150> US 63/123705
<151> 2020-12-10
<160> 58
<170> PatentIn version 3.2
<210> 1
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> H-CDR1
<400> 1
Gly Phe Val Phe Ser Asn Tyr Asp
1 5
<210> 2
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> H-CDR2
<400> 2
Ile Thr Ile Gly Gly Gly Thr Thr
1 5
<210> 3
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> H-CDR3
<400> 3
Ala Arg Trp Val Tyr Asp Pro Leu Tyr Ala Met Asp Tyr
1 5 10
<210> 4
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> H-CDR3
<400> 4
Ala Arg Arg Val Tyr Asp Pro Leu Tyr Ala Met Asp Tyr
1 5 10
<210> 5
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> L-CDR1
<400> 5
Glu Ser Val Asp Asn Tyr Gly Ile Ser Phe
1 5 10
<210> 6
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> L-CDR2
<400> 6
Ala Ala Ser
1
<210> 7
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> L-CDR3
<400> 7
Gln Gln Ser Lys Glu Val Pro Trp Thr
1 5
<210> 8
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> H-CDR1
<400> 8
Gly Phe Thr Phe Ser Ser Phe Gly
1 5
<210> 9
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> H-CDR2
<400> 9
Ile Tyr Ser Asn Gly Asp Tyr Thr
1 5
<210> 10
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> H-CDR3
<400> 10
Ala Arg Tyr Tyr Gly Asn Tyr Gly Gly Tyr Phe Asp Tyr
1 5 10
<210> 11
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> L-CDR1
<400> 11
Gln Ser Val Ser Asn Asp Val Ala
1 5
<210> 12
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> L-CDR2
<400> 12
Tyr Ala Ser
1
<210> 13
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> L-CDR3
<400> 13
Gln Gln Asp Tyr Ser Ser Pro Pro Thr
1 5
<210> 14
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> H-CDR1
<400> 14
Gly Tyr Thr Phe Thr Thr Tyr Trp
1 5
<210> 15
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> H-CDR2
<400> 15
Ile Asn Pro Thr Thr Gly Tyr Thr
1 5
<210> 16
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> H-CDR3
<400> 16
Ala Arg Gly Val Arg Tyr Tyr Phe Asp Tyr
1 5 10
<210> 17
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> L-CDR1
<400> 17
Gln Ser Leu Leu Asp Ser Arg Thr Arg Lys Asn Tyr
1 5 10
<210> 18
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> L-CDR2
<400> 18
Trp Ala Ser
1
<210> 19
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> L-CDR3
<400> 19
Lys Gln Ser Tyr Asn Leu Ile Thr
1 5
<210> 20
<211> 139
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 20
Met Asp Ser Arg Leu Asn Leu Val Phe Leu Val Leu Thr Leu Lys Gly
1 5 10 15
Val Lys Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys
20 25 30
Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Val Phe
35 40 45
Ser Asn Tyr Asp Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu
50 55 60
Glu Trp Val Ala Tyr Ile Thr Ile Gly Gly Gly Thr Thr Tyr Tyr Pro
65 70 75 80
Asp Thr Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn
85 90 95
Thr Leu Tyr Leu Gln Met Asn Ser Leu Lys Ser Glu Asp Thr Ala Ile
100 105 110
Tyr Tyr Cys Ala Arg Trp Val Tyr Asp Pro Leu Tyr Ala Met Asp Tyr
115 120 125
Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser
130 135
<210> 21
<211> 139
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 21
Met Asp Ser Arg Leu Asn Leu Val Phe Leu Val Leu Thr Leu Lys Gly
1 5 10 15
Val Lys Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys
20 25 30
Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Val Phe
35 40 45
Ser Asn Tyr Asp Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu
50 55 60
Glu Trp Val Ala Tyr Ile Thr Ile Gly Gly Gly Thr Thr Tyr Tyr Pro
65 70 75 80
Asp Thr Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn
85 90 95
Thr Leu Tyr Leu Gln Met Asn Ser Leu Lys Ser Glu Asp Thr Ala Ile
100 105 110
Tyr Tyr Cys Ala Arg Arg Val Tyr Asp Pro Leu Tyr Ala Met Asp Tyr
115 120 125
Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser
130 135
<210> 22
<211> 131
<212> PRT
<213> 人工序列
<220>
<223> VL
<400> 22
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly Asp Ile Leu Leu Thr Gln Ser Pro Ala Ser Leu Ala
20 25 30
Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser
35 40 45
Val Asp Asn Tyr Gly Ile Ser Phe Met Asn Trp Phe Gln Gln Lys Pro
50 55 60
Gly Gln Pro Pro Lys Leu Leu Ile Tyr Ala Ala Ser Asn Gln Gly Ser
65 70 75 80
Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Ser
85 90 95
Leu Asn Ile His Pro Met Glu Glu Asp Asp Thr Ala Met Tyr Phe Cys
100 105 110
Gln Gln Ser Lys Glu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu
115 120 125
Glu Ile Lys
130
<210> 23
<211> 139
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 23
Met Asp Ser Arg Leu Asn Leu Val Phe Leu Ala Leu Ile Leu Lys Gly
1 5 10 15
Val Gln Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
20 25 30
Pro Val Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
35 40 45
Ser Ser Phe Gly Met Ser Trp Val Arg Gln Thr Pro Asp Lys Arg Leu
50 55 60
Glu Leu Val Ala Thr Ile Tyr Ser Asn Gly Asp Tyr Thr Tyr Tyr Pro
65 70 75 80
Asp Ser Val Lys Gly Arg Phe Thr Val Ser Arg Asp Asn Ala Lys Asn
85 90 95
Thr Leu Tyr Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Met
100 105 110
Tyr Tyr Cys Ala Arg Tyr Tyr Gly Asn Tyr Gly Gly Tyr Phe Asp Tyr
115 120 125
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser
130 135
<210> 24
<211> 127
<212> PRT
<213> 人工序列
<220>
<223> VL
<400> 24
Met Glu Ser Gln Thr Gln Val Phe Val Phe Leu Leu Leu Cys Val Ser
1 5 10 15
Gly Ala His Gly Ser Ile Val Met Thr Gln Thr Pro Lys Phe Leu Leu
20 25 30
Val Ser Ala Gly Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Ser
35 40 45
Val Ser Asn Asp Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro
50 55 60
Lys Leu Leu Ile Tyr Tyr Ala Ser Asn Arg Tyr Thr Gly Ala Pro Asp
65 70 75 80
Arg Phe Thr Gly Ser Gly Tyr Gly Thr Asp Phe Thr Phe Thr Ile Ser
85 90 95
Thr Val Gln Ala Glu Asp Leu Ala Val Tyr Phe Cys Gln Gln Asp Tyr
100 105 110
Ser Ser Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
115 120 125
<210> 25
<211> 136
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 25
Met Glu Cys Thr Trp Val Ile Leu Phe Leu Phe Ser Val Thr Ala Gly
1 5 10 15
Val His Ser Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Lys
20 25 30
Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Thr Tyr Trp Ile His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu
50 55 60
Glu Trp Ile Gly Tyr Ile Asn Pro Thr Thr Gly Tyr Thr Glu Tyr Asn
65 70 75 80
Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Asn
85 90 95
Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Gly Val Arg Tyr Tyr Phe Asp Tyr Trp Gly Lys
115 120 125
Gly Thr Thr Leu Thr Val Ser Ser
130 135
<210> 26
<211> 136
<212> PRT
<213> 人工序列
<220>
<223> VL
<400> 26
Met Gly Phe Lys Met Glu Ser Gln Ser Leu Val Leu Ile Leu Leu Leu
1 5 10 15
Leu Trp Val Ser Gly Ser Cys Gly Asp Ile Val Met Ser Gln Ser Pro
20 25 30
Ser Ser Leu Ala Val Ser Ala Gly Glu Lys Val Thr Met Ser Cys Lys
35 40 45
Ser Ser Gln Ser Leu Leu Asp Ser Arg Thr Arg Lys Asn Tyr Leu Ala
50 55 60
Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr Trp
65 70 75 80
Ala Ser Thr Arg Glu Ser Gly Val Pro Asp Arg Phe Thr Gly Ser Gly
85 90 95
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Val Lys Ala Glu Asp
100 105 110
Leu Ala Val Tyr Leu Cys Lys Gln Ser Tyr Asn Leu Ile Thr Phe Gly
115 120 125
Ala Gly Thr Lys Leu Glu Leu Lys
130 135
<210> 27
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 27
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Val Phe Ser Asn Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Tyr Ile Thr Ile Gly Gly Gly Thr Thr Tyr Tyr Pro Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Val Tyr Asp Pro Leu Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 28
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 28
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Val Phe Ser Asn Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Tyr Ile Thr Ile Gly Gly Gly Thr Thr Tyr Tyr Pro Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Val Tyr Asp Pro Leu Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 29
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> VL
<400> 29
Asp Ile Val Leu Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr
20 25 30
Gly Ile Ser Phe Met Asn Trp Phe Leu Gln Lys Pro Gly Gln Pro Pro
35 40 45
Gln Leu Leu Ile Tyr Ala Ala Ser Asn Gln Gly Ser Gly Val Pro Asp
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser
65 70 75 80
Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Gln Gln Ser Lys
85 90 95
Glu Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 30
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 30
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Leu Val
35 40 45
Ala Thr Ile Tyr Ser Asn Gly Asp Tyr Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Val Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Tyr Tyr Gly Asn Tyr Gly Gly Tyr Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 31
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> VL
<400> 31
Ala Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Ser Val Ser Asn Asp
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Ala Ser Asn Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Asp Tyr Ser Ser Pro Pro
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 32
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 32
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Thr Tyr
20 25 30
Trp Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Thr Thr Gly Tyr Thr Glu Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Ala Thr Leu Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Val Arg Tyr Tyr Phe Asp Tyr Trp Gly Lys Gly Thr Thr
100 105 110
Val Thr Val Ser Ser
115
<210> 33
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> VL
<400> 33
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser
20 25 30
Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Lys Gln
85 90 95
Ser Tyr Asn Leu Ile Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 34
<211> 417
<212> DNA
<213> 人工序列
<220>
<223> VH coding Sequence
<400> 34
atggactcca ggctcaattt agttttcctt gtccttactt taaaaggtgt gaagtgtgaa 60
gtgcagctgg tggagtctgg gggaggctta gtgaagcctg gagggtccct gaaactctcc 120
tgtgcagcct ctggattcgt tttcagtaac tatgacatgt cttgggttcg ccagactccg 180
gagaagaggc tggagtgggt cgcatacatt actattggtg gtggtaccac ctactatcca 240
gacactgtga agggccgatt caccatctcc agagacaatg ccaagaacac cctgtacctt 300
caaatgaaca gtctgaagtc tgaggacaca gccatatatt actgtgcaag gtgggtctat 360
gatcctctct atgctatgga ctactggggt caaggaacct cagtcaccgt ctcctca 417
<210> 35
<211> 417
<212> DNA
<213> 人工序列
<220>
<223> VH coding sequence
<400> 35
atggactcca ggctcaattt agttttcctt gtccttactt taaaaggtgt gaagtgtgaa 60
gtgcagctgg tggagtctgg gggaggctta gtgaagcctg gagggtccct gaaactctcc 120
tgtgcagcct ctggattcgt tttcagtaac tatgacatgt cttgggttcg ccagactccg 180
gagaagaggc tggagtgggt cgcatacatt actattggtg gtggtaccac ctactatcca 240
gacactgtga agggccgatt caccatctcc agagacaatg ccaagaacac cctgtacctt 300
caaatgaaca gtctgaagtc tgaggacaca gccatatatt actgtgcaag gcgggtctat 360
gatcctctct atgctatgga ctactggggt caaggaacct cagtcaccgt ctcctca 417
<210> 36
<211> 393
<212> DNA
<213> 人工序列
<220>
<223> VL coding sequence
<400> 36
atggagacag acacactcct gctatgggtc ctgcttctct gggttccagg ttccacaggt 60
gacattttgc tgacccaatc tccagcttct ttggctgtgt ctctagggca gagggccacc 120
atctcctgca gagccagcga aagtgttgat aattatggca ttagttttat gaactggttc 180
caacagaaac caggacagcc acccaaactc ctcatctatg ctgcatccaa ccaaggatcc 240
ggggtccctg ccaggtttag tggcagtggg tctgggacag acttcagcct caacatccat 300
cctatggagg aggatgatac tgcaatgtat ttctgtcagc aaagtaagga ggttccgtgg 360
acgttcggtg gaggcaccaa gctggaaatc aaa 393
<210> 37
<211> 417
<212> DNA
<213> 人工序列
<220>
<223> VH coding sequence
<400> 37
atggactcca ggctcaattt agttttcctt gcccttattt taaaaggtgt ccagtgtgag 60
gtgcagctgg tggagtctgg gggaggctta gtgcagcctg tagggtccct gaaactctcc 120
tgtgcagcct ctggattcac tttcagtagt tttggcatgt cttgggttcg ccagactcca 180
gacaagaggc tggagttggt cgcaaccatt tatagtaatg gtgattacac ctattatcca 240
gacagtgtga agggccgatt caccgtctcc agagacaatg ccaagaacac cctgtacctg 300
caaatgagca gtctgaagtc tgaggacaca gccatgtatt actgtgcaag gtactatggt 360
aactacgggg ggtactttga ctactggggc caaggcacca ctctcacagt ctcctca 417
<210> 38
<211> 381
<212> DNA
<213> 人工序列
<220>
<223> VL coding sequence
<400> 38
atggagtcac agacccaggt ctttgtattt ctactgctct gtgtgtctgg tgctcatggg 60
agtattgtga tgacccagac tcccaaattc ctgcttgtat cagcaggaga cagggttacc 120
ataacctgca aggccagtca gagtgtgagt aatgatgtag cttggtacca acagaagcca 180
gggcagtctc ctaaattgct gatatactat gcatccaatc gctacactgg agcccctgat 240
cgcttcactg gcagtggata tgggacggat ttcactttca ccatcagcac tgtgcaggct 300
gaagacctgg cagtttattt ctgtcagcag gattatagct ctcctccgac attcggtgga 360
ggcaccaagc tggaaatcaa a 381
<210> 39
<211> 408
<212> DNA
<213> 人工序列
<220>
<223> VH coding sequence
<400> 39
atggaatgca cctgggtcat tctcttcctg ttttcagtaa ctgcaggtgt ccactcccag 60
gtccagcttc agcagtctgg ggctgaactg gcaaaacctg gggcctcagt gaagatgtcc 120
tgcaaggctt ctggctacac ctttactacc tactggattc actgggtaaa acagaggcct 180
ggacagggac tggaatggat tggatacatt aatcctacca ctggttatac tgaatacaat 240
cagaagttca aggacaaggc cacattgact gcagacaaat cctccaacac agcctacatg 300
caactgagca gcctgacatc tgaggactct gcagtctatt actgtgcaag aggagtacgg 360
tactactttg actactgggg caaaggcacc actctcacag tctcctca 408
<210> 40
<211> 408
<212> DNA
<213> 人工序列
<220>
<223> VL coding sequence
<400> 40
atgggcttca agatggagtc acagtctctg gttcttatat tgctgctgct atgggtatct 60
ggttcctgtg gggacattgt gatgtcacag tctccatcct ccctggctgt gtcagcagga 120
gagaaggtca ctatgagctg caaatccagt cagagtctgc tcgacagtag aacccgaaag 180
aactacttgg cttggtacca gcagaaacca gggcagtctc ctaaactgct gatctactgg 240
gcatccacta gggaatctgg ggtccctgat cgcttcacag gcagtggatc tgggacagat 300
ttcactctca ccatcagcag tgtgaaggct gaagacctgg cagtttatct ctgcaagcaa 360
tcttataatc tgatcacgtt cggtgctggg accaagctgg agctgaaa 408
<210> 41
<211> 360
<212> DNA
<213> 人工序列
<220>
<223> VH coding sequence
<400> 41
gaggtgcagc tggtggagag cggcggcggc ctggtgcagc ccggcggcag cctgaggctg 60
agctgcgccg ccagcggctt cgtgttcagc aactacgaca tgagctgggt gaggcaggcc 120
cccggcaagg gcctggagtg ggtggcctac atcaccatcg gcggcggcac cacctactac 180
cccgacaccg tgaagggcag gttcaccatc agcagggaca acgccaagaa cagcctgtac 240
ctgcagatga acagcctgag ggccgaggac accgccgtgt actactgcgc caggtgggtg 300
tacgaccccc tgtacgccat ggactactgg ggccagggca ccaccgtgac cgtgagcagc 360
360
<210> 42
<211> 360
<212> DNA
<213> 人工序列
<220>
<223> VH coding sequence
<400> 42
gaggtgcagc tggtggagag cggcggcggc ctggtgcagc ccggcggcag cctgaggctg 60
agctgcgccg ccagcggctt cgtgttcagc aactacgaca tgagctgggt gaggcaggcc 120
cccggcaagg gcctggagtg ggtggcctac atcaccatcg gcggcggcac cacctactac 180
cccgacaccg tgaagggcag gttcaccatc agcagggaca acgccaagaa cagcctgtac 240
ctgcagatga acagcctgag ggccgaggac accgccgtgt actactgcgc caggagggtg 300
tacgaccccc tgtacgccat ggactactgg ggccagggca ccaccgtgac cgtgagcagc 360
360
<210> 43
<211> 333
<212> DNA
<213> 人工序列
<220>
<223> VL coding sequence
<400> 43
gacatcgtgc tgacccagac ccccctgagc ctgagcgtga cccccggcca gcccgccagc 60
atcagctgca gggccagcga gagcgtggac aactacggca tcagcttcat gaactggttc 120
ctgcagaagc ccggccagcc cccccagctg ctgatctacg ccgccagcaa ccagggcagc 180
ggcgtgcccg acaggttcag cggcagcggc agcggcaccg acttcaccct gaagatcagc 240
agggtggagg ccgaggacgt gggcgtgtac tactgccagc agagcaagga ggtgccctgg 300
accttcggcc agggcaccaa ggtggagatc aag 333
<210> 44
<211> 360
<212> DNA
<213> 人工序列
<220>
<223> VH coding sequence
<400> 44
gaggtgcagc tggtggagag cggcggcggc ctggtgaagc ccggcggcag cctgaggctg 60
agctgcgccg ccagcggctt caccttcagc agcttcggca tgagctgggt gaggcaggcc 120
cccggcaagg gcctggagct ggtggccacc atctacagca acggcgacta cacctactac 180
cccgacagcg tgaagggcag gttcaccgtg agcagggaca acgccaagaa cagcctgtac 240
ctgcagatga acagcctgag ggccgaggac accgccgtgt actactgcgc caggtactac 300
ggcaactacg gcggctactt cgactactgg ggccagggca ccctggtgac cgtgagcagc 360
360
<210> 45
<211> 321
<212> DNA
<213> 人工序列
<220>
<223> VL coding sequence
<400> 45
gccatccaga tgacccagag ccccagcagc ctgagcgcca gcgtgggcga cagggtgacc 60
atcacctgca aggccagcca gagcgtgagc aacgacgtgg cctggtacca gcagaagccc 120
ggcaaggccc ccaagctgct gatctactac gccagcaaca ggtacaccgg cgtgcccagc 180
aggttcagcg gcagcggcag cggcaccgac ttcaccctga ccatcagcag cctgcagccc 240
gaggacttcg ccacctacta ctgccagcag gactacagca gcccccccac cttcggcggc 300
ggcaccaagg tggagatcaa g 321
<210> 46
<211> 351
<212> DNA
<213> 人工序列
<220>
<223> VH coding sequence
<400> 46
caggtgcagc tggtgcagag cggcgccgag gtgaagaagc ccggcgccag cgtgaaggtg 60
agctgcaagg ccagcggcta caccttcacc acctactgga tccactgggt gaggcaggcc 120
cccggccagg gcctggagtg gatcggctac atcaacccca ccaccggcta caccgagtac 180
aaccagaagt tcaaggacag ggccaccctg accgccgaca agagcaccag caccgcctac 240
atggagctga gcagcctgag gagcgaggac accgccgtgt actactgcgc caggggcgtg 300
aggtactact tcgactactg gggcaagggc accaccgtga ccgtgagcag c 351
<210> 47
<211> 336
<212> DNA
<213> 人工序列
<220>
<223> VL coding sequence
<400> 47
gacatcgtga tgacccagag ccccgacagc ctggccgtga gcctgggcga gagggccacc 60
atcaactgca agagcagcca gagcctgctg gacagcagga ccaggaagaa ctacctggcc 120
tggtaccagc agaagcccgg ccagcccccc aagctgctga tctactgggc cagcaccagg 180
gagagcggcg tgcccgacag gttcagcggc agcggcagcg gcaccgactt caccctgacc 240
atcagcagcc tgcaggccga ggacgtggcc gtgtactact gcaagcagag ctacaacctg 300
atcaccttcg gccagggcac caagctggag atcaag 336
<210> 48
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 2B3W-T14-05 VH
<400> 48
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Val Phe Ser Asn Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Tyr Ile Thr Ile Gly Gly Gly Thr Thr Tyr Tyr Pro Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Arg Tyr Asp Pro Leu Phe Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 49
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 2B3W-T14-05 VL
<400> 49
Asp Ile Val Leu Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ala Ser Glu Ser Val Thr Asp Tyr
20 25 30
Gly Ile Ser Phe Met Asn Trp Phe Leu Gln Lys Pro Gly Gln Pro Pro
35 40 45
Gln Leu Leu Ile Tyr Ala Ala Ser Asn Gln Gly Ser Gly Val Pro Asp
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser
65 70 75 80
Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Gln Gln Ser Lys
85 90 95
Glu Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 50
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 7C5-T15-01 VH
<400> 50
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Leu Val
35 40 45
Ala Thr Ile Tyr Ser Asn Gly Asp Tyr Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Val Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Tyr Tyr Gly Asn Tyr Gly Gly Tyr Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 51
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 7C5-T15-01 VL
<400> 51
Ala Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Ser Val Trp Asp Asp
20 25 30
Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Ala Ser Asn Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Asp Tyr Ser Ser Pro Pro
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 52
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 8D4-T16-01 VH
<400> 52
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Thr Tyr
20 25 30
Trp Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Thr Thr Gly Tyr Thr Glu Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Ala Thr Leu Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Val Arg Tyr Tyr Phe Asp Tyr Trp Gly Lys Gly Thr Thr
100 105 110
Val Thr Val Ser Ser
115
<210> 53
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 8D4-T16-01 VL
<400> 53
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser
20 25 30
Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Lys Gln
85 90 95
Ser Tyr Asn Leu Ile Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 54
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 8D4-T16-02 VH
<400> 54
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Thr Tyr
20 25 30
Trp Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Thr Thr Gly Tyr Thr Glu Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Ala Thr Leu Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Val Arg Tyr Tyr Phe Asp Tyr Trp Gly Lys Gly Thr Thr
100 105 110
Val Thr Val Ser Ser
115
<210> 55
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> 8D4-T16-02 VL
<400> 55
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser
20 25 30
Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Gln Tyr Asp Pro Pro Ile Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 56
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> VH CDR3
<400> 56
Ala Arg Trp Arg Tyr Asp Pro Leu Phe Ala Met Asp Tyr Trp
1 5 10
<210> 57
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> VL CDR1
<400> 57
Glu Ser Val Thr Asp Tyr Gly Ile Ser Phe Met Asn
1 5 10
<210> 58
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> VL CDR1
<400> 58
Gln Ser Val Trp Asp Asp Leu Thr
1 5
Claims (37)
1.一种抗体或其抗原结合片段,上述抗体与PD-1特异性结合,其特征在于,包含:
重链CDR1,包含选自由序列1、序列8及序列14组成的组中的一种以上氨基酸序列;
重链CDR2,包含选自由序列2、序列9及序列15组成的组中的一种以上氨基酸序列;
重链CDR3,包含选自由序列3、序列4、序列10、序列16及序列56组成的组中的一种以上氨基酸序列;
轻链CDR1,包含选自由序列5、序列11、序列17、序列57及序列58组成的组中的一种以上氨基酸序列;
轻链CDR2,包含选自由序列6、序列12及序列18组成的组中的一种以上氨基酸序列;以及
轻链CDR3,包含选自由序列7、序列13及序列19组成的组中的一种以上氨基酸序列。
2.根据权利要求1所述的抗体或其抗原结合片段,其特征在于,上述抗体或其抗原结合片段包含:
(i)包含序列1的重链CDR1、序列2的重链CDR2及序列3的重链CDR3重链可变区以及包含序列5的轻链CDR1、序列6的轻链CDR2及序列7的轻链CDR3的轻链可变区;
(ii)包含序列1的重链CDR1、序列2的重链CDR2及序列4的重链CDR3的重链可变区以及包含序列5的轻链CDR1、序列6的轻链CDR2及序列7的轻链CDR3的轻链可变区;
(iii)包含序列8的重链CDR1、序列9的重链CDR2及序列10的重链CDR3的重链可变区以及包含序列11的轻链CDR1、序列12的轻链CDR2及序列13的轻链CDR3的轻链可变区;
(iv)包含序列14的重链CDR1、序列15的重链CDR2及序列16的重链CDR3的重链可变区以及包含序列17的轻链CDR1、序列18的轻链CDR2及序列19的轻链CDR3的轻链可变区;
(v)包含序列1的重链CDR1、序列2的重链CDR2及序列56的重链CDR3的重链可变区以及包含序列57的轻链CDR1、序列6的轻链CDR2及序列7的轻链CDR3的轻链可变区;或者
(vi)包含序列8的重链CDR1、序列9的重链CDR2及序列10的重链CDR3的重链可变区以及包含序列58的轻链CDR1、序列12的轻链CDR2及序列13的轻链CDR3的轻链可变区。
3.根据权利要求1所述的抗体或其抗原结合片段,其特征在于,
上述抗体或其抗原结合片段包含重链可变区,
上述重链可变区包含选自由序列20、序列21、序列23、序列25、序列27、序列28、序列30、序列32、序列48及序列50组成的组中的一种以上氨基酸序列。
4.根据权利要求1所述的抗体或其抗原结合片段,其特征在于,
上述抗体或其抗原结合片段包含轻链可变区,
上述轻链可变区包含选自由序列22、序列24、序列26、序列29、序列31、序列33、序列49、序列51、序列54及序列55组成的组中的一种以上氨基酸序列。
5.根据权利要求1所述的抗体或其抗原结合片段,其特征在于,上述抗体或其抗原结合片段包含:
序列20的重链可变区及序列22的轻链可变区;
序列21的重链可变区及序列22的轻链可变区;
序列23的重链可变区及序列24的轻链可变区;
序列25的重链可变区及序列26的轻链可变区;
序列27的重链可变区及序列29的轻链可变区;
序列28的重链可变区及序列29的轻链可变区;
序列30的重链可变区及序列31的轻链可变区;
序列32的重链可变区及序列33的轻链可变区;
序列48的重链可变区及序列49的轻链可变区;
序列50的重链可变区及序列51的轻链可变区;
序列52的重链可变区及序列53的轻链可变区;或者
序列54的重链可变区及序列55的轻链可变区。
6.根据权利要求1所述的抗体或其抗原结合片段,其特征在于,上述抗体或其抗原结合片段包括单链Fvs、单链抗体、Fab、F(ab')、二硫键连接的Fvs。
7.根据权利要求6所述的抗体或其抗原结合片段,其特征在于,上述单链Fvs的重链可变区与轻链可变区通过接头连接。
8.一种核酸,其特征在于,编码权利要求1至7中任一项所述的抗体或其抗原结合片段。
9.一种重组表达载体,其特征在于,包含权利要求8所述的核酸。
10.一种宿主细胞,其特征在于,由权利要求9所述的重组表达载体转染。
11.根据权利要求10所述的宿主细胞,其特征在于,上述宿主细胞为COS-7、BHK、CHO、CHOK1、DXB-11、DG-44、CHO/-DHFR、CV1、COS-7、HEK293、BHK、TM4、VERO、HELA、MDCK、BRL 3A、W138、Hep G2、SK-Hep、MMT、TRI、MRC 5、FS4、3T3、RIN、A549、PC12、K562、PER.C6、SP2/0、NS-0、U20S或HT1080。
12.一种抗体或其抗原结合片段的制备方法,上述抗体与PD-1特异性结合,其特征在于,包括:
培养权利要求10所述的宿主细胞来生成抗体的步骤;以及
分离及纯化生成的抗体的步骤。
13.一种双特异性或多特异性抗体,其特征在于,包含权利要求1至7中任一项所述的抗体或其抗原结合片段。
14.根据权利要求13所述的双特异性或多特异性抗体,其特征在于,包含与选自由FGFR3、TIGIT、PD-L1、BTLA、CTLA-4、VISTA、LAG3、TIM3、CD137、VISTA、CD258、MARCO、CD134、CD28、CD278、CD27、CD154、CD357、CD30、DR3、CD226、CD96、CD200、CD200R、转铁蛋白受体、c-Met、EGFR、HER2、KDR、PDGFRa、NRP1组成的组中的一种以上结合的抗体或其抗原结合片段作为配偶体。
15.一种免疫细胞参与的双特异性或多特异性抗体,其特征在于,包含一个以上权利要求1至7中任一项所述的抗体的scFv以及与免疫细胞激活抗原结合的抗体的scFv。
16.根据权利要求15所述的免疫细胞参与的双特异性或多特异性抗体,其特征在于,
在上述免疫细胞激活抗原中,
T细胞激活抗原为CD3、TCRα、TCRβ、TCRγ、TCRξ、ICOS、CD28、CD27、HVEM、LIGHT、CD40、4-1BB、OX40、DR3、GITR、CD30、TIM1、SLAM、CD2或CD226;
自然杀伤细胞激活抗原为NKp30、NKp40、NKp44、NKp46、NKG2D、DNAM1、DAP10、CD16、CRTAM、CD27、PSGL1、CD96、CD100、NKp80、CD244、SLAMF6、SLAMF7、KIR2DS2、KIR2DS4、KIR3DS1、KIR2DS3、KIR2DS5、KIR2DS1、CD94、NKG2C、NKG2E或CD160;
B细胞激活抗原为OX40、CD40或CD70;
巨噬细胞激活抗原为CD2激动剂、CD40、CD70、TCR激动剂、CD47、STING或OX40L;或者
树突细胞激活抗原为CD2激动剂、OX40、OX40L、41BB激动剂、TCR激动剂、CD47激动剂或STING激动剂。
17.一种抗体药物偶联物,其特征在于,药物与权利要求1至7中任一项所述的抗体或其抗原结合片段结合。
18.根据权利要求17所述的抗体药物偶联物,其特征在于,上述药物为选自由美登醇、包括澳瑞他汀E和澳瑞他汀F在内的澳瑞他汀、氨基蝶呤、放线菌素、博来霉素、泰莱霉素、喜树碱、N8-乙酰基亚精胺、1-(2氯乙基)-1,2-二甲基磺酰基肼、埃斯培拉霉素、依托泊苷、6-巯基嘌呤、多拉司他汀、单端孢霉烯、卡利奇霉素、泰素、紫杉烷、紫杉醇、多西他赛、甲氨蝶呤、长春新碱、长春碱、阿霉素、左旋苯丙氨酸氮芥、丝裂霉素A、丝裂霉素C、苯丁酸氮芥、多卡马嗪、左旋门冬酰胺酶、巯基嘌呤、硫鸟嘌呤、硫酸羟脲、阿糖胞苷、环磷酰胺、异环磷酰胺、亚硝基脲、顺铂、卡铂、丝裂霉素、达卡巴嗪、甲基苄肼、托泊替康、氮芥、环磷酰胺、依托泊苷、5-氟尿嘧啶、双氯乙基亚硝基脲、伊立替康、喜树碱、博来霉素、伊达比星、柔红霉素、放线菌素D、普卡霉素、米托蒽醌、门冬酰胺酶、长春瑞滨、苯丁酸氮芥、马法兰、卡莫司汀、洛莫司汀、白消安、苏消安、达卡巴嗪、依托泊苷、替尼泊甙、托泊替康、9-氨基喜树碱、克利那托、丝裂霉素C、三甲曲沙、霉酚酸、噻唑呋啉、利巴韦林、5-乙炔基-1-β-D-呋喃呋喃糖基咪唑-4-羧酰胺、硫酸羟脲、去铁胺、5-氟脱氧尿苷、去氧氟尿甙、雷替曲塞、阿糖胞苷、胞嘧啶阿拉伯糖苷、氟达拉滨、他莫昔芬、雷洛昔芬、甲地孕酮、戈舍瑞林、醋酸亮丙瑞林、氟他胺、比卡鲁胺、EB1089、CB1093、KH1060、维替泊芬、酞菁、光敏剂Pe4、去甲氧基竹红菌素A、α干扰素、γ干扰素、肿瘤坏死因子、吉西他滨、硼替佐米、瑞复美、THALAMID、洛伐他汀、1-甲基4-苯基吡啶离子、星形孢菌素、放线菌素D、放线菌素D、博来霉素A2、博来霉素B2、培洛霉素、表阿霉素、吡柔比星、佐柔比星、米托蒽醌、维拉帕米、毒胡萝卜素、核酸分解酶以及源自细菌或动植物的毒素组成的组中的一种以上。
19.根据权利要求17所述的抗体药物偶联物,其特征在于,上述抗体或其抗原结合片段通过接头与药物结合。
20.根据权利要求19所述的抗体药物偶联物,其特征在于,上述接头为可切割接头或不可切割接头。
21.根据权利要求20所述的抗体药物偶联物,其特征在于,上述可切割接头为酸不稳定接头、二硫键接头、肽接头或β葡萄糖苷酸接头,或者上述不可切割接头包含硫醚基团或马来酰亚胺基己酰基团。
22.根据权利要求19所述的抗体药物偶联物,其特征在于,上述接头与抗体的二硫键还原时暴露的半胱氨酸残基或存在于与抗体结合的标签上的半胱氨酸残基结合。
23.一种嵌合抗原受体,其特征在于,
包含:
包含抗原结合位点的胞外结构域;
跨膜结构域;以及
细胞内信号传导结构域,
上述胞外结构域的抗原结合位点为权利要求1至7中任一项所述的抗体的scFv。
24.一种免疫细胞,其特征在于,导入权利要求23所述的嵌合抗原受体。
25.根据权利要求24所述的免疫细胞,其特征在于,上述免疫细胞为选自由T细胞、自然杀伤细胞、细胞因子诱导的杀伤细胞、激活的细胞毒性T淋巴细胞、巨噬细胞、肿瘤浸润T细胞、树突细胞组成的组中的一种以上。
26.根据权利要求23所述的免疫细胞,其特征在于,还导入包含对除抗PD-1抗体以外的抗体的scFv作为胞外结构域的抗原结合位点的嵌合抗原受体。
27.根据权利要求26所述的免疫细胞,其特征在于,上述除抗PD-1抗体以外的抗体为靶向选自由FGFR3、TIGIT、PD-L1、BTLA、CTLA-4、VISTA、LAG3、TIM3、CD137、VISTA、CD258、MARCO、CD134、CD28、CD278、CD27、CD154、CD357、CD30、DR3、CD226、CD96、CD200、CD200R、转铁蛋白受体、c-Met、EGFR、HER2、KDR、PDGFRa、NRP1组成的组中的一种以上的抗体或其抗原结合片段。
28.一种联合治疗用组合物,其特征在于,包含权利要求24所述的免疫细胞以及除抗PD-1抗体以外的药物。
29.根据权利要求28所述的联合治疗用组合物,其特征在于,上述除抗PD-1抗体以外的药物为靶向选自由FGFR3、TIGIT、PD-L1、BTLA、CTLA-4、VISTA、LAG3、TIM3、CD137、VISTA、CD258、MARCO、CD134、CD28、CD278、CD27、CD154、CD357、CD30、DR3、CD226、CD96、CD200、CD200R、转铁蛋白受体、c-Met、EGFR、HER2、KDR、PDGFRa、NRP1组成的组中的一种以上的抗体或其抗原结合片段。
30.一种联合治疗用组合物,其特征在于,包含权利要求1至7中任一项所述的抗体或其抗原结合片段以及选自由如下成分组成的组中的一种以上:
(i)免疫细胞;
(ii)包含嵌合抗原受体的免疫细胞,所述嵌合抗原受体包含对除抗PD-1抗体以外的抗体的scFv作为胞外结构域;以及
(iii)免疫检查点抑制剂。
31.根据权利要求30所述的联合治疗用组合物,其特征在于,上述免疫细胞为选自由T细胞、自然杀伤细胞、细胞因子诱导的杀伤细胞、激活的细胞毒性T淋巴细胞、巨噬细胞、肿瘤浸润T细胞、树突细胞组成的组中的一种以上。
32.根据权利要求30所述的联合治疗用组合物,其特征在于,上述除抗PD-1抗体以外的抗体为靶向选自由FGFR3、TIGIT、PD-L1、BTLA、CTLA-4、VISTA、LAG3、TIM3、CD137、VISTA、CD258、MARCO、CD134、CD28、CD278、CD27、CD154、CD357、CD30、DR3、CD226、CD96、CD200、CD200R、转铁蛋白受体、c-Met、EGFR、HER2、KDR、PDGFRa、NRP1组成的组中的一种以上的抗体或其抗原结合片段。
33.根据权利要求30所述的联合治疗用组合物,其特征在于,上述免疫检查点抑制剂为靶向TIGIT、PD-L1、BTLA、CTLA-4、VISTA、LAG3、TIM3、CD137、CD258、MARCO、CD134、CD28、CD278、CD27、CD154、CD357、CD30、DR3、CD226、CD96、CD200或CD200R的药物。
34.一种联合治疗用组合物,其特征在于,包含权利要求13所述的双特异性或多特异性抗体以及选自由如下成分组成的组中的一种以上:
(i)免疫细胞;
(ii)包含嵌合抗原受体的免疫细胞,所述嵌合抗原受体包含对除抗PD-1抗体以外的抗体的scFv作为胞外结构域;以及
(iii)免疫检查点抑制剂。
35.根据权利要求34所述的联合治疗用组合物,其特征在于,上述除抗PD-1抗体以外的抗体为靶向选自由FGFR3、TIGIT、PD-L1、BTLA、CTLA-4、VISTA、LAG3、TIM3、CD137、VISTA、CD258、MARCO、CD134、CD28、CD278、CD27、CD154、CD357、CD30、DR3、CD226、CD96、CD200、CD200R、转铁蛋白受体、c-Met、EGFR、HER2、KDR、PDGFRa、NRP1组成的组中的一种以上的抗体或其抗原结合片段。
36.根据权利要求34所述的联合治疗用组合物,其特征在于,上述免疫检查点抑制剂为靶向TIGIT、PD-L1、BTLA、CTLA-4、VISTA、LAG3、TIM3、CD137、CD258、MARCO、CD134、CD28、CD278、CD27、CD154、CD357、CD30、DR3、CD226、CD96、CD200或CD200R的药物。
37.一种癌症治疗用组合物,其特征在于,包含:
权利要求1至7中任一项所述的抗体或其抗原结合片段;
包含上述抗体或其抗原结合片段的双特异性或多特异性抗体;
包含上述抗体或其抗原结合片段的抗体药物偶联物;
包含上述抗体或其抗原结合片段的嵌合抗原受体;或者
包含上述嵌合抗原受体的免疫细胞。
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WO2004010957A2 (en) | 2002-07-31 | 2004-02-05 | Seattle Genetics, Inc. | Drug conjugates and their use for treating cancer, an autoimmune disease or an infectious disease |
US20090162359A1 (en) | 2007-12-21 | 2009-06-25 | Christian Klein | Bivalent, bispecific antibodies |
US9266967B2 (en) | 2007-12-21 | 2016-02-23 | Hoffmann-La Roche, Inc. | Bivalent, bispecific antibodies |
US8242247B2 (en) | 2007-12-21 | 2012-08-14 | Hoffmann-La Roche Inc. | Bivalent, bispecific antibodies |
US8227577B2 (en) | 2007-12-21 | 2012-07-24 | Hoffman-La Roche Inc. | Bivalent, bispecific antibodies |
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BRPI1014089A2 (pt) | 2009-04-02 | 2016-04-19 | Roche Glycart Ag | anticorpos multiespecíficos que compreendem anticorpos de comprimento completo e fragmentos fab de cadeia simples |
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US9676845B2 (en) | 2009-06-16 | 2017-06-13 | Hoffmann-La Roche, Inc. | Bispecific antigen binding proteins |
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US10669338B2 (en) * | 2016-06-17 | 2020-06-02 | Immunomedics, Inc. | Anti-PD-1 checkpoint inhibitor antibodies that block binding of PD-L1 to PD-1 |
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