CN108699153B - Pd-l1的结合成员 - Google Patents
Pd-l1的结合成员 Download PDFInfo
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- CN108699153B CN108699153B CN201780012727.3A CN201780012727A CN108699153B CN 108699153 B CN108699153 B CN 108699153B CN 201780012727 A CN201780012727 A CN 201780012727A CN 108699153 B CN108699153 B CN 108699153B
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Abstract
本发明涉及抗PD‑L1结合成员,并且具体地说涉及高度稳定且可溶的单价、高潜能PD‑L1结合抗体片段。这种结合成员能够用于治疗癌症和炎症性疾病以及用于诊断。还提供了相关核酸、载体、细胞和组合物。
Description
技术领域
提供了一种针对PD-L1的结合成员,例如人源化抗体片段,特别是适用于治疗和诊断用途的单价、高潜能且稳定的抗PD-L1scFv。还提供了一种编码这种结合成员的核酸分子,一种含有相应核酸分子的序列的载体,一种含有所述载体或相应核酸分子的核酸序列的宿主细胞,一种含有所述结合成员或核酸分子的药物和诊断组合物,以及其用途。
背景技术
程序性细胞死亡蛋白1(PD-1)是在激活的T细胞、B细胞和骨髓细胞上表达的细胞表面受体。PD-1结合两种配体,即PD-L1(Dong H等人,《自然医学(Nat Med.)》,1999年,第5卷,第1365到1369页)和PD-L2(Latchman Y.等人,《自然免疫学(Nat Immunol.)》,2001年,第2卷,第261到268页)。
在配体PD-L1或PD-L2与PD-1结合后,在T细胞内触发抑制性信号传导级联,其抑制TCR介导的IL-2生产和T细胞增殖的激活。PD-L1(程序性死亡-配体1)是1型跨膜蛋白质,其在大多数人癌细胞和抗原呈递细胞(APC)的表面上由IFNγ组成型表达或诱导。
进一步针对PD-1,PD-L1与CD80结合(Butte M.J.等人(2007年),第27卷,第111到122页),一种能够结合CD28和CTLA-4的膜受体。然而,PD-L1与PD-1的相互作用比与CD80的相互作用更强。与PD-1一样,CD80是在T细胞和B细胞上表达的膜受体。与PD-1或CD80结合的PD-L1将抑制信号传递给T淋巴细胞,从而抑制细胞毒性介质的T细胞迁移、增殖和分泌,并减少肿瘤细胞杀伤。然而,虽然PD-1/PD-L1相互作用驱动T细胞耗尽,但PD-L1/CD80相互作用驱动T细胞无能。这些是不同的过程,因为耗尽在数周或数月的时间内是进行性的并且取决于慢性抗原刺激,而无能是在没有适当的共刺激的情况下在抗原刺激后快速诱导的。
因此,PD-L1表达保护肿瘤细胞免受T细胞介导的破坏的影响(Haile S.T.等人(2011年),《免疫学杂志(J Immunol.)》,第186卷,第12期,第6822到6829页;Haile S.T.等人(2013年),《免疫学杂志(J Immunol.)》,第191卷,第5期,第2829到2836页)。上调的PD-L1水平与肿瘤侵袭性增加和死亡风险增加相关。动物研究表明,经由单克隆抗体阻断PD-L1:PD-1相互作用改善T细胞激活并减少肿瘤进展。此外,通过T细胞表达的CD80的PD-L1信号传导的抗体阻断阻止T细胞无能。
阻断PD-1或PD-L1的单克隆抗体在广泛的癌症亚型中表现出令人印象深刻的活性,即使在疾病的晚期和转移阶段也是如此(Maute等人(2015年),《美国科学院院报(PNAS)》,第112卷,第47期,第E6506到E6514页)。虽然早期的研究表明,在增加免疫力的同时最大限度地降低免疫病理学风险的方面,阻断PD-L1单独与PD-1或CD80的相互作用可能更有益(Butte MJ(2008年),《分子免疫学(Mol Immunol)》,第45卷,第13期,第3567到3572页),最近采用阻断PD-L1与PD-1和CD80二者的相互作用的单克隆抗体的临床试验在几种癌症中显示出显著的临床成功,并且它们的毒性低于传统化疗。尽管只有一部分患者对检查点阻断有响应,但由于免疫记忆引起的这种响应的持续时间显著,并且比任何其它难治性疾病药物的预期更长(Janakiram M等人(2016年),《免疫疗法(Immunotherapy)》,第8卷,第7期,第809到819页)。
阿特朱单抗(MPDL3280A,例如,描述于US 8,217,149中)是靶向PD-L1的人源化IgG1抗体,从而阻断与PD-1和CD80结合的受体。将抗体工程改造以具有降低的Fc效应子功能,并因此减少表达PD-L1的细胞的消耗。2016年10月,FDA批准了阿特朱单抗用于治疗患有转移性非小细胞肺癌(NSCLC)的患者,这些患者在含铂化疗期间或之后有疾病进展。如果肿瘤具有EGFR或ALK基因组畸变,则由于这些畸变,患者在接受抗体之前在FDA批准的治疗时应该有疾病进展。潜在的临床研究招募患者,无论其PD-L1状态如何,其包含鳞状和非鳞状疾病类型。
2016年5月,FDA批准了阿特朱单抗用于治疗患有局部晚期或转移性尿路上皮癌的患者,这些患者在含铂化疗期间或之后有疾病进展。
度伐鲁单抗(MEDI4736;参见例如US 8,779,108、WO2010077634)是人IgG1单克隆抗PD-L1抗体,其在PD-L1结合时阻断PD-1和CD80二者的相互作用。通过免疫IgG2和IgG4XenoMouse动物并把恒定结构域换成人IgG1三重突变结构域来生成抗体。该恒定结构域含有三个点突变,其减少与C1q和Fcγ受体的结合,导致抗体依赖性细胞毒性和补体依赖性细胞毒性降低。
所述抗体在临床试验中作为多种适应症的单一疗法,所述多种适应症包含局部晚期或转移性NSCLC、尿路上皮癌、头颈癌、宫颈癌、结肠直肠癌、食道癌、卵巢癌、乳腺癌、SCLC和胃癌以及复发性或转移性PD-L1-阳性头颈部鳞状细胞癌(SCCHN)。联合疗法临床试验正在进行中。
靶向PD-1并阻断PD-1和CD80二者与PD-L1的相互作用的另一种抗体是阿维单抗(MSB0010718C,描述于WO2013079174)。全人IgG1单克隆抗体保留天然的Fc区,因此可以诱导抗体依赖性细胞介导的细胞毒性(ADCC)。所述抗体处于实体瘤、胃癌、梅克尔细胞癌和NSCLC的临床试验。
仍然需要靶向免疫检查点抑制剂的改进化合物,并且需要提供安全有效的治疗方法来治疗免疫系统相关病症,例如癌症、免疫缺陷、自身免疫障碍、过敏症、炎性病症、移植排斥和其它病症。
发明内容
本发明提供了结合PD-L1的结合成员,包含编码这种结合成员的核酸和载体,表达这种结合成员的宿主细胞和含有这种结合成员的组合物,以及它们在治疗中的用途。
这种结合成员具有以下性质中的一种或多种:
(a)对PD-L1具有高亲和力,既可以是免疫球蛋白,也可以是单价抗体片段格式,如scFv。
(b)结合人PD-L1,其中结合解离平衡常数(KD)低于10pM,如通过动力学排斥测定在实例4中针对单价格式指定的条件下或在实例9中针对二价格式指定的条件下所测量的;
(c)结合到PD-L1上的表位,这阻碍人PD-L1与人PD-1和人CD80二者的相互作用;
(d)与猴PD-L1交叉反应;
(e)与猴PD-L1结合,其中对于猴PD-L1的结合亲和力至少与对于人PD-L1的结合亲和力一样强、更优选地至少两倍于对于人PD-L1的结合亲和力;
(f)不结合到人PD-L2或人B7-H3;
(g)抑制HCC827人肺癌模型中的肿瘤生长;和
(h)在37℃下在pH 7.2的PBS中以10mg/ml的浓度储存1周或2周后,以scFv格式形成少于3%的二聚体。
这种结合成员优选地包括(i)分别如SEQ ID NO:6、7和8中所阐述的可变重链CDR-H1、CDR-H2和CDR-H3序列中的至少一个;和/或
(ii)分别如SEQ ID NO:3、4和5中所阐述的可变轻链CDR-L1、CDR-L2和CDR-L3序列中的至少一个;或其变体。
这种结合成员可以用于癌症和炎性疾病的治疗以及诊断。还提供了相关的核酸、载体、细胞、组合物、方法和试剂盒。
附图说明
图1示出了scFv1在基于细胞的系统中阻断重组人(rh)PD-L1和rhPD-1介导的免疫检查点抑制信号。
图2示出了scFv1在ELISA中阻断rhPD-L1和rhPD-1之间的相互作用。在不存在scFv和PD-1的情况下确定背景水平。
图3示出了scFv1在ELISA中阻断rhPD-L1和rhCD80之间的相互作用。在不存在PD-L1的情况下确定背景水平。
图4示出了通过ELISA测量的scFv1结合rhPD-L1的能力在37℃下在人血清中储存后不受影响。
图5示出了scFv1在动力学排斥测定中与rhPD-L1结合。
图6示出了scFv1通过结合ELISA与重组人和猴PD-L1结合,但不与大鼠PD-L1结合。在不存在scFv的情况下示出背景水平,并且通过使用如实例5中所定义的阳性对照抗体来确认蛋白质的功能性。
图7示出了scFv1在动力学排斥测定中与重组猴PD-L1结合。
图8示出了scFv1在动力学排斥测定中与细胞表面上的人天然形式的PD-L1结合。
图9示出了由大肠杆菌包涵体产生或由CHO细胞分泌的scFv1在基于细胞的系统中表现出对PD-L1和PD-1之间相互作用的类似抑制。
图10示出了scFv1促进已经被给予人外周血单核细胞(PBMC)的裸小鼠中的HCC827人肺癌模型中的肿瘤收缩。A:如实例8中所定义的治疗(scFv1或阳性对照IgG)与对照(非结合scFv2)的比例。B:如实例8中所定义的肿瘤生长抑制(scFv1或阳性对照IgG与非结合scFv2相比)。
图11示出了IgG_1和IgG_2在抑制rhPD-L1和rhPD-1之间的相互作用方面比IgG_3和IgG_4更有效。在不存在IgG和PD-1的情况下确定背景水平。
图12示出了IgG_1(A)在IgG和PD-L1之间的相互作用中具有比IgG_2(B)更紧密的亲和力。
具体实施方式
为了更容易地理解本文公开的结合成员、核酸、载体、宿主细胞、组合物、方法和用途的解释,首先定义某些术语。
定义
除非另外定义,否则在说明书、附图和权利要求中使用的所有其它科学和技术术语具有本领域普通技术人员通常理解的普通含义。尽管与本文描述的那些相似或等同的方法和材料可以用于实践或测试本文公开的结合成员、核酸、载体、宿主细胞、组合物、方法和用途,但下文描述了合适的方法和材料。本文提及的所有出版物、专利申请、专利和其它参考文献都通过引用整体并入。如有冲突,以本说明书(包含定义)为准。材料、方法和实例仅是说明性的并不旨在是限制性的。
如本文使用,术语“给药”是指将物质转移、递送、引入或运输至受试者的任何模式,所述物质诸如化合物,例如药物化合物或其它药剂(如抗原)。给药方式包含但不限于肠胃外给药、口服给药、直肠给药、全身给药、静脉内给药、皮下给药、泌尿生殖器给药、局部给药、玻璃体内给药、眼内给药、耳部给药、鼻内给药、透皮给药、皮内给药、皮肤给药、腹膜内给药、肌肉内给药、舌下给药或口腔给药。与其它物质(一种或多种治疗剂)“联合”给药包含以任何顺序同时(simultaneous/concurrent)和连续给药。
如本文使用,术语“保守修饰”和“保守取代”是指分别在物理上、生物学上、化学上和/或功能上保持关于相应参考的性质的修饰和取代。包含具有保守取代的序列的分子例如具有相似的尺寸、形状、电荷、化学性质,包含形成共价键或氢键的相当能力和/或相当的极性。这种保守修饰包含但不限于一个或多个核碱基和氨基酸取代、添加和缺失。
例如,保守氨基酸取代包含其中氨基酸残基被具有相似侧链的氨基酸残基替换的氨基酸取代。例如,关于与抗原结合的非必需氨基酸残基可以用来自相同侧链家族的另一个氨基酸残基替换,例如,丝氨酸可以取代苏氨酸。氨基酸残基通常基于共同的、相似的侧链性质分为家族,例如:
1.非极性侧链(例如,甘氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、甲硫氨酸),
2.不带电荷的极性侧链(例如,天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸、脯氨酸、半胱氨酸、色氨酸),
3.碱性侧链(例如,赖氨酸、精氨酸、组氨酸、脯氨酸),
4.酸性侧链(例如,天冬氨酸、谷氨酸),
5.β-支化侧链(例如,苏氨酸、缬氨酸、异亮氨酸)和
6.芳族侧链(例如,酪氨酸、苯丙氨酸、色氨酸、组氨酸)。
保守取代可以被认为是上述六组中的一组中的第一氨基酸被六组中的同一组中的另一个氨基酸取代。优选的保守取代包含:
1.用缬氨酸(V)取代丙氨酸(A);
2.用赖氨酸(K)取代精氨酸(R);
3.用谷氨酰胺(Q)取代天冬酰胺(N);
4.用谷氨酸(E)取代天冬氨酸(D);
5.用丝氨酸(S)取代半胱氨酸(C);
6.用天冬氨酸(D)取代谷氨酸(E);
7.用丙氨酸(A)取代甘氨酸(G);
8.用精氨酸(R)或赖氨酸(K)取代组氨酸(H);
9.用亮氨酸(L)取代异亮氨酸(I);
10.用亮氨酸(L)取代甲硫氨酸(M);
11.用酪氨酸(Y)取代苯丙氨酸(F);
12.用苏氨酸(T)取代丝氨酸(S);
13.用酪氨酸(Y)取代色氨酸(W);
14.用色氨酸(W)取代苯丙氨酸(F);和/或
15.用亮氨酸(L)取代缬氨酸(V)
反之亦然。其它取代,例如丙氨酸(A)取代脯氨酸(P),也是允许的,并且可以凭经验确定或根据其它已知的保守或非保守取代确定。保守取代也可以涉及使用非天然氨基酸。
非保守取代,即将一个家族的成员与另一个家族的成员交换,可能导致实质性变化,例如,关于结合成员的电荷、偶极矩、尺寸、亲水性、疏水性或构象,这可能改变结合活性,特别是当与靶分子结合所必需的氨基酸受到影响时。非保守取代也可以涉及使用非天然氨基酸。
可以通过本领域已知的各种标准技术将保守和非保守修饰引入亲本结合成员,所述已知的各种标准技术例如组合化学、定点DNA诱变、PCR介导和/或盒式诱变、肽/蛋白质化学合成、将适当的修饰引入编码结合成员的新核酸序列或构建编码结合成员的新核酸序列、和/或特异性修饰亲本结合成员中的反应基团的化学反应。可以通过常规方法测试变体的化学、生物学、生物物理学和/或生物化学性质。优选地,保守氨基酸取代基本上不改变亲本序列的功能特性,并且通常也不改变亲本序列的结构特性。因此,包含保守取代的结合成员的结合特性至少基本上不改变。此外,保守氨基酸取代通常基本上不修饰或破坏亲本序列的二级结构。
术语“标记”在本文中用于指通过物理或化学手段直接或间接检测或测量的任何物质,其指示样本中存在选定的目标生物实体。有用的可检测标记的代表性实例包含但不限于可基于光吸收、荧光、反射率、光散射、磷光或发光性质直接或间接检测的分子或离子、可通过其放射性检测的分子或离子或可通过其核磁共振或顺磁性检测的分子或离子。在一些实施例中,标记可以是可以基于光吸收或荧光间接检测的分子,例如,引起适当底物转化(例如,从非光吸收分子转化为光吸收分子,或从非荧光分子转化为荧光分子)的各种酶。
一种物质(例如化合物,包含本文公开的结合成员)的“有效量”或“治疗有效量”是一定量,既可作为单次剂量,也可作为一系列剂量中的一部分,其以应用的给药方案产生所需的治疗效果,即达到某一治疗目标。治疗有效量通常是足以在相关病理情况的治疗或管理中提供治疗益处,或延缓或最小化与情况的存在相关的一种或多种症状的量。剂量将取决于各种因素,包含患者和临床因素(例如,年龄、体重、性别、患者的临床病史、病症的严重程度和/或对治疗的响应)、所治疗病症的性质、给予的特定组合物、给药途径和其它因素。
术语“基本上由……组成”应理解为允许样本或组合物中存在不影响样本或组合物性质的其它组分。作为一个说明性实例,如果医药组合物基本上由活性成分组成,则其可以包含赋形剂。
在本公开的范围内,术语“抗体”是指全长免疫球蛋白及其片段。这种全长免疫球蛋白可以是单克隆、多克隆、嵌合、人源化、镶饰(veneered)和/或人抗体。嵌合抗体可以例如包含不同种类和/或不同同种型的恒定区,或者可以是人工双特异性或多特异性构建体,例如,四源杂交瘤、柞臼结构(KIH)或CrossMab或DuoBody。所述术语还涵盖全长免疫球蛋白与抗体片段或非抗体支架融合的构建体。其示例性实例包含但不限于Bs1Ab、Bs2Ab、Bs3Ab、Bs4Ab、Ts1Ab和Ts2Ab,如Dimasi N.等人(2009年),《微生物学与生物技术杂志(JMB)》,第393卷,第672到692页所述。其它嵌合抗体包含DVD-Ig、IgG-scFab、scFab-dsscFv、Fv2-Fc、scFv-KIH、FynomAB或BiTE-KIH。在一些实施例中,本文公开的抗体可以是糖基化的,在其它实施例中,所述抗体不是糖基化的。
关于多肽(例如,抗体或蛋白质结合分子)的“片段”是指在相应多肽中存在的任何氨基酸序列,只要它比全长免疫球蛋白序列短并且只要它能够进行蛋白质的感兴趣的功能——在抗体与所需靶标(例如,抗原(如PD-L1))特异性结合的情况下。术语“抗体片段”是指抗体的一部分,通常是高变区和周围重链和轻链的部分,其表现出对特定靶标(通常是分子)的特异性结合亲和力。高变区是与多肽靶标物理结合的抗体的一部分。因此,抗体片段包含保留抗体靶向特异性的全长抗体的一个或多个部分或由其组成。例如,这种抗体片段可以至少部分地缺少全长抗体的恒定区(Fc区)。在一些实施例中,通过酶切全长抗体产生抗体片段。抗体片段也可以是含有抗体的一个或多个部分的合成或重组构建体(参见例如Holliger P和Hudson J.,《工程改造抗体片段和单结构域的兴起(Engineered antibodyfragments and the rise of single domains)》,《自然生物技术(NatureBiotechnol.)》,2005年,第23卷,第9期,第1126页)。抗体片段的实例包含但不限于scFv、Fab、Fv、Fab'、F(ab')2片段、scFab、dAb、VHH、纳米抗体、V(NAR)或所谓的最小识别单位、双抗体、单链双抗体(scDb)、串联scDb(Tandab)、线性二聚scDb(LD-scDb)、环状二聚scDb(CD-scDb)、BiTE(也称为双特异性T细胞衔接子、串联scFv或串联双scFv)、DART、串联三scFv、三(抗)体、双特异性Fab2、双微型抗体、四抗体、双-双抗体或scFab-dsscFv。
“单链可变片段”或“单链抗体”或“scFv”是一种类型的抗体片段的实例。scFv是融合蛋白,其包含通过接头连接的抗体的VH和VL结构域。因此,它缺少存在于全长抗体中的恒定Fc区。
如本文使用的“结合成员”是指蛋白质结合分子,其包括一个或多个CDR和任选的本文公开的可变轻链和/或重链。因此,术语“结合成员”包括抗体(即如上定义的全长免疫球蛋白和抗体片段)、蛋白质非抗体支架和/或其它结合化合物。在一些实施例中,非抗体支架包括一种或多种本文公开的CDR序列。这种结合成员可以是单价的或多价的,即具有一个或多个抗原结合位点。单价结合成员的非限制性实例包含scFv、Fab、scFab、dAb、VHH、V(NAR)(或所谓的最小识别单位)、DARPin、affilin和纳米抗体。多价结合成员可以具有两个、三个、四个或更多个抗原结合位点。全长免疫球蛋白、F(ab')2片段、双scFv(或串联scFv或BiTE)、DART、双抗体、scDb、DVD-Ig、IgG-scFab、scFab-Fc-scFab、IgG-scFv、scFv-Fc、scFv-fc-scFv、Fv2-Fc、FynomAB、四源杂交瘤(quadroma)、CrossMab、DuoBody、三抗体和四抗体是多价结合成员的非限制性实例;在示例性多价结合成员中,存在两个结合位点,即结合成员是二价的。在一些实施例中,多价结合成员是双特异性的,即结合成员针对一个靶分子上的两个不同靶标或两个不同靶位点。双特异性抗体例如在Muller D.和KontermannR.E.,《双特异性抗体(Bispecific antibodies)》,编辑人Dübel S.,魏因海姆:Wiley-VCH出版社,2007年,ISBN 3527314539,第345页中综述。在一些实施例中,多价结合成员包含两个以上不同的结合位点,例如分别针对于三个或四个不同抗原,包含三个或四个不同的结合位点。这种结合成员分别是多价和多特异性的,特别是三特异性的或四特异性的。
“非抗体支架”是抗原结合多肽,其例如描述于Fielder M.和Skerra A.,《非抗体支架(Non-antibody scaffolds)》,编辑人Dübel S.,魏因海姆:Wiley-VCH出版社,2007年,ISBN 3527314539,第467页;或者Gilbreth R.N.和Koide S.,《基于非抗体支架工程改造结合蛋白的结构见解(Structural insights for engineering binding proteins basedon non-antibody scaffolds)》,《结构生物学研究现状(Curr.Opin.Struct.Biol.)》,2012年,第22卷,第413页中。非限制性实例包含亲和体、affilin分子、AdNectin、基于脂质运载蛋白家族多肽的突变蛋白DARPin、打结素(Knottin)、Kunitz型结构域、高亲和性多聚体(Avimer)、fynomer、四连接素和反式体。高亲和性多聚体含有所谓的A结构域,其在几种细胞表面受体中作为多个结构域的串出现(Silverman J.等人,《自然生物技术(Nature Biotechnol.)》,2005年,第23卷,第1556页)。衍生自相应的人同源三聚蛋白的四连接素同样含有C型凝集素结构域中的环状区域,其可以被工程改造用于所需的结合(同上)。
如果需要,本文公开的结合成员可以是PEG化的或高糖基化的,也参见下文。在一些实施例中,结合成员是上述示例性蛋白质结合分子之一和白蛋白结合结构域(例如,链球菌蛋白G的白蛋白结合结构域)的融合蛋白。在一些实施例中,结合成员是抗体片段(例如,单链双抗体)和抗体结合结构域(例如,细菌抗体结合结构域)的融合蛋白。作为一个说明性实例,单链双抗体可以与葡萄球菌蛋白A的结构域B融合,如Unverdorben等人,(《蛋白质工程设计与选择(Protein Eng.,Design&Selection)》,2012年,第25卷,第81页)所述。
“IC50”或“半最大抑制浓度”是拮抗剂潜能的量度,并且定量地描述了化合物抑制生物学或生物化学功能的有效性。因此,该值表示需要多少某种物质(例如,结合成员)来抑制50%的某种生物学或生物化学过程或功能。虽然没有亲和力的直接指标,但IC50和Ki值是相关的并且可以经由Cheng-Prusoff方程(Cheng Y.和Prusoff W.H.,《导致酶促反应的50%抑制(IC50)的抑制剂的抑制常数(Ki)与抑制剂浓度之间的关系(Relationshipbetween the inhibition constant(Ki)and the concentration of inhibitor whichcauses 50per cent inhibition(IC50)of an enzymatic reaction)》,《生物化学药理学(Biochem.Pharmacol.)》,1973年,第22卷,第3099页;Rammes G.等人,《公共科学图书馆-综合(PLOS ONE)》,2009年,第4卷,第1到14页;Zhen J.等人,《在高亲和力放射性配体的修饰受体结合方案中重新检测受体和配体的浓度:[3H]螺哌隆与D2和D3多巴胺受体结合(Concentration of receptor and ligand revisited in a modified receptorbinding protocol for high-affinity radioligands:[3H]spiperone binding to D2andD3dopamine receptors)》,《神经科学方法杂志(J.Neurosci.Meth.)》,2010年,第188卷,第32页)来确定。
术语“框架”(FR)是指镶嵌相应的CDR的可变抗体结构域(可变轻链(VL)或可变重链(VH))的支架。VL和/或VH框架通常包含位于CDR区侧翼的四个框架部分,即FR1、FR2、FR3和FR4。因此,如本领域已知,VL具有通用结构:(FR-L1)-(CDR-L1)-(FR-L2)-(CDR-L2)-(FR-L3)-(CDR-L3)-(FR-L4),而VH具有通用结构:(FR-H1)-(CDR-H1)-(FR-H2)-(CDR-H2)-(FR-H3)-(CDR-H3)-(FR-H4)。
术语“CDR”是指抗体的高变区,其主要有助于抗原结合。通常,抗原结合位点包含嵌入框架支架中的六个CDR。在本文中,VL的CDR被称为CDR-L1、CDR-L2和CDR-L3,而VH的CDR被称为CDR-H1、CDR-H2和CDR-H3。这些可以被标识,如KABAT,E.A.等人,《免疫学相关蛋白质的序列(Sequences of Proteins of Immunological Interest)》第五版,由美国卫生和人类服务部编辑,NIH出版社,1991年,第91到3242页所述。然而,如本文使用的CDR-H1与Kabat定义的不同之处在于它从位置27开始并在位置36之前结束(AHo位置28到42,包含端值)。
如本文使用,用于标识抗体的VH和VL中的氨基酸残基位置的编号系统对应于Honegger A.和Plückthun A描述的“AHo”系统。另一种免疫球蛋白可变结构域的编号方案:自动建模和分析工具。《分子生物学杂志(J.Mol.Biol.)》,2001年,第309卷,第657页。该出版物进一步提供了AHo系统和Kabat系统之间的转换表(Kabat E.A.等人,《免疫学相关蛋白质的序列(Sequences of Proteins of Immunological Interest)》第五版,由美国卫生和人类服务部编辑,NIH出版社,1991年,第91到3242页)。
“人源化”抗体是指包含非人亲本抗体或其变体的一个或多个(通常全部六个)CDR区或合成CDR的抗体,并且其框架是例如(i)人框架,可能包含非人亲本抗体的一个或多个框架残基,或(ii)来自非人抗体的框架,其被修饰以增加与天然产生的人框架的相似性。人源化抗体的方法是本领域已知的,例如,Leger O.和Saldanha J.,《抗体药物发现(Antibody Drug Discovery.)》,编辑人Wood C.,伦敦:帝国理工学院出版社,2011年,ISBN1848166281,第1到23页。
术语“分离的”表示物质(例如,肽、核酸分子或细胞)已从其正常生理环境(例如,天然来源)中除去,或合成了肽或核酸。术语“分离的”的使用表明天然存在的序列已从其正常细胞(例如,染色体)环境中除去。因此,序列可以在无细胞溶液中或置于不同的细胞环境中。关于多肽或核酸分子的“分离的”是指彼此偶联的两个或更多个氨基酸或核苷酸的聚合物,包含从天然来源分离的多肽或核酸分子或合成的多肽或核酸分子。术语“分离的”并不意味着所述序列是存在的唯一氨基酸链或核苷酸链,而是它基本上不含例如分别天然与其相关的非氨基酸材料和/或非核酸材料。“分离细胞”是指与天然伴随细胞的分子和/或细胞组分分开的细胞。
如本文使用的术语“一致性”是指两种蛋白质或核酸之间的序列匹配。待比较的蛋白质或核酸序列在比较窗口上进行比对以获得最大对应性,例如使用生物信息学工具,如EMBOSS Needle(成对比对;可在www.ebi.ac.uk获得或通过手动比对和目视检查)。当待比较序列中的相同位置被相同的核碱基或氨基酸残基占据时,则各个分子在该位置是相同的。因此,“百分比一致性”是匹配位置数除以比较的位置数并乘以100%的函数。例如,如果10个序列位置中的6个是相同的,则一致性是60%。比对序列以获得最大对应性可能需要引入空位。两个蛋白质序列之间的一致性百分比可以例如使用Needleman和Wunsch算法(Needlemann S.B.和Wunsch C.D.,《一种适用于寻找两种蛋白质氨基酸序列相似性的一般方法(A general method applicable to the search for similarities in the aminoacid sequence of two proteins)》,《分子生物学杂志(J.Mol.Biol.)》,1970年,第48卷,第443页)来确定,其已被纳入EMBOSS Needle,使用BLOSUM62矩阵,“空位开放罚分”为10,“空位延伸罚分”为0.5,假“末端空位罚分”,“末端空位开放罚分”为“10”和“末端空位延伸罚分”为0.5,或者可以使用一种以最大化一致性的方式手动引入空位的序列比对方法。因此,在一个实施例中,通过以最大化序列一致性的方式手动引入空位来比对本文公开的序列。具有相同的一级氨基酸或核酸序列的两个分子是相同的,而与任何化学和/或生物学修饰无关。例如,按照该定义,具有相同的一级氨基酸序列但具有不同糖基化模式的两种抗体是相同的。在核酸的情况下,例如,按照该定义,具有相同序列但具有不同的连接组分的两个分子,例如硫代磷酸酯而非磷酸酯,是相同的。当在比较窗口上具有序列一致性时,一个序列可能比本文提供的任何序列更长,例如因为其包括几个可变结构域或一个或多个恒定结构域,但仍应与本文公开的参考序列相同。如本文使用的比较窗口包含所要求保护的整个序列。类似地,按照该定义,仅由于环外修饰而不同的核碱基,例如胞嘧啶和5-甲基-胞嘧啶,是相同的。
如本文使用的术语“核酸分子”是指任何可能构型(例如,单链、双链或其组合)的任何核酸。核酸的实例包含例如DNA分子、RNA分子、使用核苷酸类似物或使用核酸化学生成的DNA或RNA的类似物、锁核酸分子(LNA)、蛋白核酸分子(PNA)、烷基膦酸酯和烷基磷酸三酯核酸分子和tecto-RNA分子(例如,Fiu B.等人,《美国化学会志(J.Am.Chem.Soc.)》,2004年,第126卷,第4076页)。LNA具有修饰的RNA骨架,在C4'和O2'之间具有亚甲基桥,为相应的分子提供更高的双螺旋稳定性和核酸酶抗性。烷基膦酸酯和烷基磷酸三酯核酸分子可以被视为DNA或RNA分子,其中通过将核酸骨架中的磷酸根基团的P-OH基团分别与烷基和烷氧基基团交换来中和核酸骨架的磷酸根基团。DNA或RNA可以是基因组来源或合成来源的,并且可以是单链或双链的。这种核酸可以是例如mRNA、cRNA、合成RNA、基因组DNA、cDNA合成DNA、DNA和RNA的共聚物、寡核苷酸等。相应的核酸还可以含有非天然核苷酸类似物和/或可以与亲和标记物或标记连接。
许多核苷酸类似物是已知的,并且可以用于本说明书中公开的方法中使用的核酸。核苷酸类似物是在例如碱基、糖或磷酸根部分含有修饰的核苷酸。作为一个说明性实例,已知用2'F、2'O-Me或2'H残基取代siRNA的2'-OH残基可以改善相应RNA的体内稳定性。碱基部分的修饰可以是A、C、G和T/U,不同的嘌呤或嘧啶碱基,例如尿嘧啶-5-基、次黄嘌呤-9-基和2-氨基腺嘌呤-9-基,以及非嘌呤或非嘧啶核苷酸碱基的天然或合成修饰。其它核苷酸类似物用作通用碱基。通用碱基的实例包含3-硝基吡咯和5-硝基吲哚。通用碱基能够与任何其它碱基形成碱基对。碱基修饰通常可以与例如糖修饰相结合,例如2'-O-甲氧基乙基,例如以实现独特的性质,如增加的双螺旋稳定性。
如本文件中使用,表述“医药学上可接受的”是指那些在合理的医学判断范围内适合用于与人类和动物组织接触,没有过多毒性、刺激、过敏反应或其它问题或并发症,与合理的利益/风险比相称的活性化合物、材料、组合物、载剂和/或剂型。
在医学/生理学背景下,即在生理状态的背景下,术语“预防”是指降低生物体染上或患有异常病症的可能性。
“相似的”蛋白质序列是这样的蛋白质序列,当比对时,它们在待比较序列的相同位置具有相似的氨基酸残基,并且通常但非必须具有相同的氨基酸残基。相似的氨基酸残基按侧链的化学特性分组为家族。上文描述了这些家族针对于“保守氨基酸取代”。序列之间的“百分比相似性”是在待比较序列的相同序列位置含有相同或相似残基的位置数除以比较的位置总数并乘以100%。例如,如果10个序列位置中的6个具有相同的氨基酸残基,并且10个位置中的2个含有相似的残基,则序列具有80%的相似性。两个序列之间的相似性可以例如使用EMBOSS Needle来确定。当在比较窗口上具有序列相似性时,一个序列可能比本文提供的任何序列更长,例如因为其包括几个可变结构域或一个或多个恒定结构域,但仍应与本文公开的参考序列相似。如本文使用的比较窗口包含所要求保护的整个序列。
如本文件中使用的术语“特异性的”应理解为表示结合成员或结合化合物与定义的靶标(如PD-L1)结合,平衡结合常数KD<10-6摩尔。该常数可以例如使用Attana仪器中的石英晶体微天平(QCM)、BIACORE仪器中的表面等离子体共振(SPR)技术或动力学排斥测定中来确定。
如本文使用的术语“分层(stratifying/stratification)”表示根据与相应组匹配的特性(例如,响应本文公开的结合成员的相应概率)将个体分配给某个组。这些组可以用于例如对结合成员测试、开具处方、调整剂量、暂停或放弃。因此,在根据本发明的方法或用途的一些实施例中,受试者可以分层为治疗临床试验的亚组。
如本文使用的术语“受试者”也称为个体,是指人或非人动物,通常是哺乳动物。受试者可以是哺乳动物物种,例如兔子、小鼠、大鼠、豚鼠、仓鼠、狗、猫、猪、牛、山羊、绵羊、马、猴子、猿或人。因此,该文件中描述的方法、用途和组合物适用于人类疾病和兽医疾病。如下面更详细解释,样本可以从受试者获得。因此可以理解,从样本中的表达水平得出的结论和基于其的决定涉及从中采集样本的受试者。此外,虽然受试者通常是活生物体,但是本文件中描述的方法或用途也可以用于死后分析。如果受试者是接受针对疾病或疾症的医疗护理的活人,则其也被称为“患者”。
本文使用的术语“治疗(treatment/treating)”包含具有治疗效果和/或预防、减缓(减轻)或至少部分缓解或消除受试者体内的异常(包含病理)情况的预防措施(prophylactic/preventative)。根据本公开的治疗涉及将药学有效量的如本文所述的分子,即尤其是本文公开的结合成员(例如,抗体)、核酸、载体或细胞,给予有需要的受试者,以预防或治愈PD-L1相关病症的一种或多种症状、延缓其发作和/或进展、降低其严重度、使其稳定、对其进行调节、使其得到治愈或改善。通常,结合成员、核酸、载体或宿主细胞在包含本文所述的那些的医药组合物中提供。需要治疗的患者包括已患有病症的患者以及易患该病症的患者或需预防(prevented/prophylaxis)该病症的患者。通常,治疗会减少、稳定或抑制与疾病或病理情况的存在和/或进展相关的症状的进展。
如本文使用,“PD-L1”是指也称为“程序性细胞死亡配体1”、“分化簇274(即CD274)”或“B7同源物1(即B7-H1)”的蛋白质。天然蛋白质包括两个细胞外结构域、一个跨膜结构域和一个细胞质结构域。该术语涵盖全长和/或未加工的PD-L1以及由细胞中的加工产生的任何中间体。PD-L1可以作为跨膜蛋白质或作为可溶性蛋白质存在;因此,如本文使用的术语可以指蛋白质的全长或细胞外结构域。该术语还涵盖天然存在的PD-L1变体,例如剪接变体或等位基因变体。蛋白质可以另外含有标签,例如his标签或Fc标签。示例性人全长PD-L1蛋白的氨基酸序列可以例如在NCBI蛋白质数据库登录号NP_054862下找到。术语“hPD-L1”是指人PD-L1并且包括天然hPD-L1和重组人rhPD-L1。“rPD-L1”是指重组PD-L1。重组PD-L1可以具有或不具有氨基末端甲硫氨酸残基,这取决于其制备方法。“rhPD-L1”是指重组人PD-L1。同样地,PD-L1也可以通过从人来源或非人来源的生物样本中分离而获得。rhPD-L1可以例如从RnD Systems,USA,目录号156-B7或从Peprotech,USA,目录号310-35获得。“猴PD-L1”是指恒河猴(普通猕猴)的PD-L1。示例性猴PD-L1蛋白的氨基酸序列可以例如在NCBI蛋白质数据库登录号NP_001077358下找到。猴PD-L1可以例如从Sino Biological,China,目录号90251-C02H获得。“大鼠PD-L1”是指褐家鼠(挪威大鼠)的PD-L1。示例性大鼠PD-L1蛋白的氨基酸序列可以例如在NCBI蛋白质数据库登录号NP_001178883下找到。大鼠PD-L1可以例如从Sino Biological,China,目录号80450-R02H获得。“小鼠PD-L1”是指小家鼠的PD-L1。示例性小鼠PD-L1蛋白的氨基酸序列可以例如在NCBI蛋白质数据库登录号NP_068693下找到。小鼠PD-L1可以例如从Sino Biological,China,目录号50010-M03H或从RnDSystems,USA,目录号1019-B7-100获得。
“PD-1”是程序性细胞死亡蛋白1,也称为CD279,是PD-L1的细胞表面受体。PD-1结合两种配体PD-L1和PD-L2。PD-1是跨膜蛋白质,包含细胞外结构域,随后是跨膜区和细胞内结构域。该术语涵盖全长和/或未加工的PD-1以及由细胞中的加工产生的任何中间体。PD-1可以作为跨膜蛋白质或作为可溶性蛋白质存在;因此,如本文使用的术语可以指蛋白质的全长或细胞外结构域。该术语还涵盖天然存在的PD-1变体,例如剪接变体或等位基因变体。蛋白质可以另外含有标签,例如his标签或Fc标签。示例性人PD-1蛋白的氨基酸序列可以例如在NCBI蛋白质数据库登录号NP_005009下找到。术语“hPD-1”是指人PD-1并且包括其天然形式(hPD-1)以及重组人形式(rhPD-1)。“rPD-1”是指重组PD-1。
“CD80”是指分化簇80,也称为B7-1、B7.1、BB1、CD28LG、CD28LG1、LAB7。它是CD28和CTLA-4以及PD-L1的膜受体,并且包括细胞外结构域,随后是跨膜区和细胞内结构域。该术语涵盖全长和/或未加工的CD80以及由细胞中的加工产生的任何中间体。CD80可以作为跨膜蛋白质或作为可溶性蛋白质存在;因此,如本文使用的术语可以指蛋白质的全长或细胞外结构域。该术语还涵盖天然存在的CD80变体,例如剪接变体或等位基因变体。蛋白质可以另外含有标签,例如his标签或Fc标签。示例性人CD80蛋白的氨基酸序列可以例如在NCBI蛋白质数据库登录号NP_005182下找到。CD80可以例如从RnD Systems,USA,目录号9050-B1-100获得。术语“hCD80”是指人CD80并且包括其天然形式(hCD80)以及重组人形式(rhCD80)。“rCD80”是指重组CD80。
“PD-L2”是指也称为“程序性细胞死亡1配体2”、“B7-DC”或“CD273”(分化簇273)的蛋白质。如本文使用的术语涵盖全长和/或未加工的PD-L2以及由细胞中的加工产生的任何中间体。PD-L2可以作为跨膜蛋白质或作为可溶性蛋白质存在;因此,如本文使用的术语可以指蛋白质的全长或细胞外结构域。该术语还涵盖天然存在的PD-L2变体,例如剪接变体或等位基因变体。蛋白质可以另外含有标签,例如his标签或Fc标签。示例性人全长PD-L2蛋白的氨基酸序列可以例如在NCBI蛋白质数据库登录号NP_079515下找到。PD-L2可以例如从RnD Systems,USA,目录号1224-PL获得。术语“rhPD-L2”是指重组人PD-L2。
“B7-H3”是指也称为CD276(分化簇276)的蛋白质。如本文使用的术语涵盖全长和/或未加工的B7-H3以及由细胞中的加工产生的任何中间体。B7-H3可以作为跨膜蛋白质或作为可溶性蛋白质存在;因此,如本文使用的术语可以指蛋白质的全长或细胞外结构域。该术语还涵盖天然存在的B7-H3变体,例如剪接变体或等位基因变体。蛋白质可以另外含有标签,例如his标签或Fc标签。示例性人全长B7-H3蛋白的氨基酸序列可以例如在NCBI蛋白质数据库登录号NP_079516下找到。B7-H3可以例如从RnD Systems,USA,目录号1027-B3获得。术语“rhB7-H3”是指重组人B7-H3。
“变体”是指通过添加(包含插入)、缺失、修饰和/或取代一个或多个氨基酸残基或核碱基,同时保留本文公开的亲本序列的至少一种所需活性而与亲本序列不同的氨基酸或核酸序列。在抗体的情况下,这种所需活性可以包含特异性抗原结合。类似地,当通过一个或多个核碱基的添加、缺失和/或取代与亲本序列比较时,可以修饰变体核酸序列,但编码的抗体保留如上所述的所需活性。变体可以是天然存在的,例如等位基因变体或剪接变体,或者可以是人工构建的。
核酸杂交反应可以在不同严格条件下进行。“严格条件”在本领域中广为人知并公开。通常,在杂交反应期间,可以使用基于SSC的缓冲液,其中SSC是0.15M NaCl和pH为7.0的15mM柠檬酸盐缓冲液。升高缓冲液浓度和变性剂的存在增加了杂交步骤的严格性。例如,高严格杂交条件可以涉及使用(i)42℃下的50%(体积/体积)甲酰胺、5×SSC(0.75M NaCl,0.075M柠檬酸钠)、50mM磷酸钠(pH 6.8)、0.1%焦磷酸钠、5×邓哈特溶液、超声处理的鲑鱼精DNA(50mcg/ml)、0.1%SDS和10%硫酸葡聚糖以及42℃下的0.2×SSC和0.1%SDS中的洗涤液;(ii)42℃下的50%(体积/体积)甲酰胺以及0.1%牛血清白蛋白/0.1%聚蔗糖/0.1%聚乙烯吡咯烷酮/50mM磷酸钠缓冲液(pH 6.5)以及750mM氯化钠、75mM柠檬酸钠,或(iii)在55℃下的10%硫酸葡聚糖、2×SSC和50%甲酰胺,随后的在55℃下的由含EDTA的0.1%SSC组成的高严格洗涤液。另外或可替代地,在杂交方案中可以包含使用低离子强度和高温洗涤溶液的一个、两个或更多个洗涤步骤,使用例如50℃下的0.015M氯化钠/0.0015M柠檬酸钠/0.1%十二烷基硫酸钠。
任何术语使用的范围和含义将从使用该术语的特定上下文中显而易见。在具体实施方式的适当上下文中按需给出了本文件中使用的所选术语的某些进一步定义。
术语“包括”、“包含”、“含有”、“具有”等应当被广义或开放式理解而不受限制。除非上下文另有明确说明,否则诸如“一个(a/an)”或“所述(the)”的单数形式包含复数指代物。因此,例如,对一个“载体”的指代包含单个载体以及多个载体,其或者是相同的—例如,相同的操纵子—或者是不同的。同样地,对一个“细胞”的指代包含单个细胞以及多个细胞。除非另有说明,否则在一系列元素之前的术语“至少”应理解为指代系列中的每个元素。术语“至少一个”和“……中的至少一个”包含例如一个、两个、三个、四个或五个或更多个元素。还应理解,可以使用高于和低于所述范围的轻微变化来获得与该范围内的值基本相同的结果。而且,除非另有说明,否则范围的公开旨在作为包含最小值和最大值之间的每个值的连续范围。
本文具体和明确地叙述的任何实施例可以单独或与一个或多个其它实施例组合形成具体放弃的基础。
除非另外定义,否则本文使用的所有技术和科学术语具有与本文描述的发明所属领域的普通技术人员通常理解的含义相同的含义。本文提及的所有出版物和专利均以引用的方式整体并入本文,用于描述和公开例如在出版物中描述的构建体和方法的目的,这些出版物可以与当前描述的发明结合使用。
在以下小节中更详细地描述了本公开的各个方面。应理解,各个实施例、偏好和范围可以随意组合。
此外,取决于具体实施例,所选择的定义、实施例或范围可能不适用。
结合成员表征
本文提供的结合成员特异性结合PD-L1。可以使用本领域熟知的技术验证结合成员的结合特异性。在一些实施例中,PD-L1是人PD-L1。
结合成员与PD-L1的结合阻断PD-L1与PD-1和/或CD80的相互作用,优选与PD-1和CD80二者的相互作用。
在一些实施例中,本文提供的结合成员是二价的并且结合hPD-L1,其通过测量的KD低于10pM,优选低于5pM,更优选约3pM,例如2.9pM、2.8pM或2.7pM。在一些实施例中,这种二价结合成员是全长免疫球蛋白。在一个实施例中,所述二价结合成员的测量在室温下进行。在一个实施例中,结合成员是二价的,并且实例9中指定的条件用于测量。
在一些实施例中,本文提供的结合成员是单价的并且结合hPD-L1,其通过测量的KD低于50pM。所述KD优选低于10pM,例如约9pM,例如9.0pM、8.9pM、8.8pM或8.7pM。在一个实施例中,所述单价结合成员的测量在室温下进行。在一个实施例中,结合成员是单价的,并且实例4中指定的条件用于测量。
在一些实施例中,所述单价结合成员是scFv。在一些实施例中,所述单价结合成员是抗体片段,其分子量为约60kDa或更低,例如约55kDa、50kDa、45kDa、40kDa、35kDa、30kDa或27kDa或更低。在一个实施例中,结合成员的分子量为约26kDa,例如23kDa、24kDa、25kDa、26kDa或27kDa。特别是对于癌症治疗,当靶向PD-1:PD-L1信号传导途径时,抗体片段可能优于全长抗体(Maute等人(2015年),《美国科学院院报(PNAS)》,11月24日,第112卷,第47期:第E6506到E6514页)。由于其较小的尺寸,与全长抗体(其通常具有约150kDa的分子量)或具有相似分子量或更高的任何其它抗体格式的情况相比,认为抗体片段能更深地渗透到肿瘤中。与全长抗体(特别是IgG)相关的另一个缺点是它们通过其Fc区(例如,ADCC/ADCP或CDC)介导细胞毒性免疫应答的能力。当靶向PD-1:PD-L1轴时,这种抑制可能是不希望的,因为两种蛋白质都在抗肿瘤细胞毒性T细胞的表面上表达。因此,给予具有功能性Fc部分的全长单克隆抗体可能导致它们旨在激活的淋巴细胞的缺失。经发现,用抗PD-1抗体治疗与患者中较低的循环T细胞数相关。因此,具有小分子量(例如,60kDa或更低,例如约55kDa,50kDa,45kDa,40kDa,35kDa,30kDa或27kDa或更低)的抗体片段可以在癌症治疗中提供比全场抗体疗法更有效的替代方案。因此,在优选实施例中,结合成员是选自由Fab、Fab'、scFab、scFv、Fv片段、纳米抗体、VHH、dAb、最小识别单位、双抗体、单链双抗体(scDb)、BiTE或DART组成的组中的抗体片段。所述格式具有低于60kDa的分子量并且不包括Fc结构域。
结合成员的尺寸和/或构造对其半衰期有影响。为了减少治疗环境中的副作用,使用具有短半衰期的结合成员可能是有利的。这可以是例如通过使用缺少Fc部分或具有修饰的Fc部分的结合成员来实现。
在某些应用中,诱导细胞毒性免疫应答和/或激活补体可能是有利的,因此可能需要存在Fc结构域。因此,在一个实施例中,结合成员包括能够介导细胞毒性免疫应答的Fc结构域。包含Fc结构域的结合成员的非限制性实例是全长免疫球蛋白、DVD-Ig、scFv-Fc和scFv-Fc。scFv融合体、IgG-scFab、scFab-dsscFv、Fv2-Fc、IgG-scFv融合体(诸如例如,bsAb、Bs1Ab、Bs2Ab、Bs3Ab、Ts1Ab、Ts2Ab、柞臼结构(KiH)、DuoBody、CrossMab。
在一个实施例中,结合成员包括Fc结构域和/或铰链,其被修饰使得其不诱导细胞毒性免疫应答和/或不激活补体。这种失活的Fc结构域和/或铰链可以通过引入本领域认为的一个或多个取代来产生。在不介导细胞毒性免疫应答的情况下,与分子量低于60kDa的抗体片段相比,这种结合成员具有半衰期增加的优点。
在一个实施例中,结合成员衍生物缺少Fc结构域。缺少Fc结构域的示例性结合成员是Fab、Fab'、scFab、scFv、Fv片段、纳米抗体、VHH、最小识别单位、双抗体、单链双抗体(scDb)、串联scDb(Tandab)、线性二聚scDb(LD-scDb)、环状二聚scDb(CD-scDb)、BiTE(也称为串联双scFv或串联scFv)、串联三scFv、三(抗)体、双特异性Fab2、双微型抗体、双-双抗体、scFab-dsscFv或DART。
在一个实施例中,结合成员包括选自由人IgG1、IgG2、IgG3或IgG4同种型组成的群组的恒定区。
在一个实施例中,结合成员包括选自由鼠IgG1、IgG2A、IgG2B、IgG3同种型组成的群组的恒定区。
在一个方面,本发明提供了一种针对PD-L1的结合成员,其包括
(a)分别如SEQ ID NO:6、7和8中所阐述的VH CDR序列CDR-H1、CDR-H2或CDR-H3中的至少一个或其变体;和/或
(b)分别如SEQ ID NO:3、4和5中所阐述的VL CDR序列CDR-L1、CDR-L2或CDR-L3中的至少一个或其变体。在一些实施例中,结合成员包含至少SEQ ID NO:5的CDR-L3和/或SEQID NO:8的CDR-H3或其变体。在一些实施例中,结合成员包含选自由SEQ ID NO:6、7和8组成的群组的两个CDR序列或其变体。在一些实施例中,结合成员包含选自由SEQ ID NO:3、4和5组成的群组中的两个CDR序列或其变体。在一些实施例中,结合成员包括SEQ ID NO:6、7和8的所有三个CDR或其变体。在一些实施例中,结合成员包括SEQ ID NO:3、4和5的所有三个CDR或其变体。优选地,结合成员包含SEQ ID NO:3到8中所阐述的所有CDR或其变体。
本文提供的结合成员对人PD-L1具有强结合亲和力。例如,这种结合成员能够结合人PD-L1,其平衡结合常数KD低于100pM,优选低于75pM、50pM、25pM、15pM,最优选KD为约10pM或更低,例如约9pM(例如,9.0pM、8.9pM、8.8pM或8.7pM)、8pM、7pM、6pM、4pM、3pM(2.9pM、2.8pM或2.7pM)或更低。亲和力可以如下面的实例部分或本领域可用的其它方法中所述确定。在一个优选实施例中,亲和力通过动力学排斥测定在室温下确定,更优选在实例4中针对单价结合成员或在实例9针对二价结合成员指定的条件下确定。
本文描述的结合成员可以包含抗体(例如,全长免疫球蛋白)或抗体片段(例如,Fab、Fab'、F(ab')2、scFab、scFv、Fv片段、纳米抗体、VHH或最小识别单位)或非抗体支架或基本上由其组成。一些结合成员包含本文公开的可变轻链和/或可变重链的一个或多个拷贝,例如选自由串联scFv、双抗体或单链双抗体(scDb)、串联scDb、线性二聚scDb、环状二聚scDb、BiTE;串联三scFv、三(抗)体、双特异性Fab2、双微型抗体、IgG、三抗体、四抗体、scFv-Fc-scFv融合体、双-双抗体、DVD-Ig、IgG-scFab、scFab-dsscFv、Fv2-Fc或IgG-scFv融合体(包含但不限于Bs1Ab、Bs2Ab、Bs3Ab、Bs4Ab、Ts1Ab和Ts2Ab)、四源杂交瘤、柞臼结构(KIH)、双特异性抗体、CrossMab和DuoBody组成的群组的格式。
在一些实施例中,结合成员,特别是上述单价抗体片段,是scFv。VH和VL结构域可以通过柔性接头以任一取向(VL-接头-VH或VH-接头-VL)连接。在一个优选实施例中,取向是VL-接头-VH,即轻链可变区位于多肽的N-末端,重链可变区位于多肽的C-末端。
结合成员优选是人源化结合成员,例如人源化抗体,特别是人源化抗体片段,例如scFv。结合成员可以是单克隆的和/或嵌合的。
因此,在一些实施例中,结合成员包含亚型VH3的可变重链区和/或亚型Vkappa1的可变轻链区。
在一个优选实施例中,结合成员包括SEQ ID NO:2的VH序列或其变体。这种变体与SEQ ID NO:2具有至少85%,更优选至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或最优选100%的序列一致性。换句话说,在一个实施例中,结合成员包括VH序列,其与SEQ ID NO:2具有至少85%,更优选至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或最优选100%的序列一致性。
另外或可替代地,本文公开的结合成员包括SEQ ID NO:1的VL序列或其变体。这种变体与SEQ ID NO:1具有至少85%,更优选至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或最优选100%的序列一致性。换句话说,在一个实施例中,结合成员包括VL序列,其与SEQ ID NO:1具有至少85%,更优选至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或最优选100%的序列一致性。
在一个实施例中,这种结合成员包括VH序列,其与SEQ ID NO:2具有至少85%,更优选至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或最优选100%的序列相似性。另外或可替代地,结合成员包括VL序列,其与SEQ ID NO:1具有至少85%,更优选至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或最优选100%的序列相似性。
在一个更优选的实施例中,结合成员包括如SEQ ID NO:1中所阐述的VL和如SEQID NO:2中所阐述的VH。SEQ ID NO:1和SEQ ID NO:2二者的框架序列衍生自WO 03/097697A(ESBATech AG)中描述的人免疫球蛋白。其VH和VL框架序列已被修饰用于兔抗体的人源化和稳定化,参见例如WO2009/155726A(ESBATech,AN ALCON BIOMEDICAL RESEARCH UNITLLC);Borras,L.等人,《生物化学杂志(JBC)》,2010年,第285卷,第12期,第9054页。
在一些实施例中,结合成员包括一个或多个VL框架序列,优选所有VL框架序列,其选自由SEQ ID NO:12到15组成的组。
在一些实施例中,结合成员包括一个或多个VH框架序列,优选所有VH框架序列,其选自由SEQ ID NO:16到19组成的组。
结合成员,例如在scFv或双特异性分子(例如,串联scFv、双抗体或单链双抗体)的情况下,可以包括接头序列。在scFv的情况下,这种接头序列通常具有10到约25个氨基酸。通常,连接肽富含甘氨酸,其赋予柔韧性,以及丝氨酸和/或苏氨酸以提高溶解度。在一个优选实施例中,使用(GGGGS)4接头(SEQ ID NO:10)或其变体。也可以使用具有2到5个重复的所述模序的变体。其它合适的接头描述于例如Alfthan,K.,《蛋白质工程(Protein Eng)》,1995年,第8卷,第7期,第725页。
因此,在一个实施例中,这种结合成员包括或具有包含SEQ ID NO:9的氨基酸序列,或由其组成,或基本上由其组成。在一些实施例中,结合成员包括或具有包含SEQ IDNO:11的氨基酸序列,或由其组成,或基本上由其组成。
在某些实施例中,考虑了本文提供的结合成员的变体。例如,可能需要改善抗原结合、抗体依赖性细胞介导的细胞毒性(ADCC)、补体依赖性细胞毒性(CDC),以降低对蛋白质水解的敏感性和/或对氧化的敏感性,增加稳定性或溶解度,降低免疫原性和/或改变结合成员的其它生物学、生物化学或生物物理学性质。在一些实施例中,变体未表现出对亲本结合成员的任何改善。在一些实施例中,变体可以是蛋白质分子,其在其氨基酸序列的一个、两个、三个、四个、五个或更多个位置与给定的结合成员不同。这种差异可以例如是取代、添加、修饰或缺失。
本文提供的结合成员的变体可以通过蛋白质和/或化学工程将适当的修饰引入编码结合成员的核酸序列制备,或通过蛋白质/肽合成制备。可以对框架或CDR进行缺失、取代、添加、修饰和插入的任何组合,条件是所生成的结合成员具有可以使用适当方法筛选的所需特性。特别感兴趣的是取代,优选如上所述的保守取代。
本文所述的结合成员可以包括一个或多个,例如两个、三个、四个、五个、六个、七个、八个、九个、十个、十一个、十二个或更多个这种保守取代。非保守取代可能导致更大的变化,例如,关于多肽的电荷、偶极矩、尺寸、亲水性、疏水性或构象。在一个实施例中,结合成员包括一个或多个,例如两个、三个、四个、五个、六个、七个、八个、九个、十个、十一个、十二个或更多个这种非保守取代。
修饰可以存在于CDR和/或框架序列中。例如,本文提供的CDR可以包括一个、两个、三个、四个、五个或甚至更多个修饰。例如,作为整体取得的CDR-L1、CDR-L2和CDR-L3序列与本文提供的CDR(特别是与SEQ ID NO:3、4和5)具有至少75%,优选至少76%、77%、78%、79%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或更优选99%的一致性。另外或可替代地,作为整体取得的CDR-H1、CDR-H2和CDR-H3序列与本文提供的CDR(特别是与SEQ ID NO:6、7和8)具有至少80%,优选至少81%、82%、83%、84%、95%、90%、91%、92%、93%、94%、95%、96%、97%、98%或更优选99%的一致性。
在一个实施例中,作为整体取得的CDR-L1、CDR-L2、CDR-L3、CDR-H1、CDR-H2和CDR-H3与本文提供的CDR(特别是与SEQ ID NO:3、4和5)具有至少85%,优选至少90%、91%、92%、93%、94%、95%、96%、97%、98%或更优选99%的相似性。另外或可替代地,作为整体取得的CDR-L1、CDR-L2、CDR-L3、CDR-H1、CDR-H2和CDR-H3与本文提供的CDR(特别是与SEQID NO:6、7和8)具有至少85%,优选至少90%、91%、92%、93%、94%、95%、96%、97%、98%或更优选99%的相似性。
在一个实施例中,变体包括在序列SEQ ID NO:1到19的任一个中的一个、两个、三个或四个取代。在一个实施例中,变体包括在序列SEQ ID NO:1、2、9或11的任一个中的五个、六个、七个、八个、九个、十个、十一个或十二个取代。
特别优选类型的变体是其中一个或多个完整CDR被替换的变体。通常,CDR-H3和CDR-L3对抗原结合的贡献最大。例如,完整的CDR-L1、CDR-L2、CDR-H1和/或CDR-H2可以被天然或人工来源的不同CDR替换。在一些实施例中,一个或多个CDR被丙氨酸盒替换。
另外或可替代地,抗体的VH包括溶解度增强点突变。WO2009/155725(ESBATech,aNovartis Company)描述了一种模序,其已被证明可增加抗体的总体溶解度。残基被置于抗体的可变结构域和恒定结构域的交界面中的位置,并稳定在缺少恒定结构域的特定的抗体片段(例如scFv)中。在一些实施例中,在本文公开的结合成员的变体中,存在以下残基中的一个、两个或所有三个:
(i)重链氨基酸位置12处的丝氨酸(S)(根据AHo编号);
(ii)重链氨基酸位置103处的丝氨酸(S)或苏氨酸(T)(根据AHo编号);和/或
(iii)重链氨基酸位置144处的丝氨酸(S)或苏氨酸(T)(根据AHo编号)。在一个优选实施例中,这种变体具有VH位置12处的丝氨酸;VH位置处的丝氨酸103;和VH位置144处的苏氨酸(均根据AHo编号)。
另外或可替代地,变体可以包含EP2158315B1中要求保护的一个或多个点突变,其通过引用并入本文。
例如,变体可以包含WO2014/206561中描述的修饰,其通过引用并入本文,特别是包含WO2014/206561的VL框架序列SEQ ID NO:15到22。
优选地,如本文所述的变体结合成员
(i)保留与PD-L1的特异性结合,特别是与hPD-L1的特异性结合;和/或
(ii)通过测量的对人PD-L1的KD低于100pM,优选低于75pM、50pM、40pM、30pM、20pM,更优选低于10pM(测量优选使用实例4中针对单价结合成员描述的条件或实例9中针对二价结合成员描述的条件进行);和/或
(iii)不与小鼠PD-L1交叉反应;和/或;
(iv)与猴PD-L1交叉反应;和/或
(v)与本文公开的结合成员竞争以与PD-L1结合;和/或
(vi)与本文公开的序列具有至少80%,优选至少85%、90%、95%或97%的序列一致性。
变体也可以通过轻链和重链的链改组来制备。单个轻链可以与重链库组合以产生变体库。在一个实施例中,所述单个轻链选自上述VL序列的组和/或所述重链库包括上述VH序列中的一种或多种。同样地,单个重链可以与轻链库组合。优选地,所述单个重链选自上述VH序列的组和/或所述轻链库包括上述VL序列中的一种或多种。
结合成员可以包括上述任何VL和/或VH序列。具有单结构域格式的结合成员,例如纳米抗体或VHH,仅包括上述VL或VH序列中的一种,优选VH序列。
多价结合成员,特别是F(ab')2片段、双scFv(也称为串联scFv)、双抗体、scDb、三抗体或四抗体等,优选双特异性结合成员,可以包括上述VL序列中的一种或多种和/或上述VH序列中的一种或多种。
本发明的结合成员,优选单价抗体片段,更优选scFv,特别稳定。如本文使用,术语“稳定性”是指多肽在延时培养和/或在升温培养后在溶液中保持单体的生物物理性质。不稳定的多肽趋向二聚化或寡聚化甚至沉淀,从而降低保质期并变得不太适合药物应用。
本文提供的结合成员,特别是上述单价抗体片段,在4℃的温度下在pH7.2的PBS中以10mg/ml的浓度培养2周后,保持单体至少85%,优选至少90%、91%、92%、93%、94%,最优选95%;另外或可替代地,在22℃或37℃下在相同条件下培养时也是如此。在一些实施例中,结合成员,特别是上述单价抗体片段,在4℃的温度下在pH 7.2的PBS中以10mg/ml的浓度培养3周后,保持单体至少85%,优选至少90%、91%、92%、93%、94%、95%、96%,最优选97%;另外或可替代地,在22℃或37℃下在相同条件下培养时也是如此。
在一些实施例中,结合成员是scFv,并且在37℃下在pH 7.2的PBS中以10mg/ml的浓度储存1周或2周后形成少于3%的二聚体。
单体的程度可以例如通过SE-HPLC(尺寸排阻高效液相色谱法)确定。用于这种测试的合适的流动相是例如pH 7.2的PBS。单体含量可以通过蛋白质色谱法中测量的UV280信号的峰值积分来定量。合适的系统是例如由6.8软件控制的Dionex SummitHPLC,其也允许随后的色谱图分析和峰值定量。
结合成员,优选上述单价抗体片段,更优选scFv,可以具有4到10,优选4到9,最优选约7.6的理论等电点(pI)。例如,理论pI可以通过使用ExPASy服务器上的ProtParam工具计算得到(可从http://web.expasy.org/protparam/获得;另请参见GASTEIGER E.等人,《ExPASy服务器上的蛋白质标识和分析工具(Protein Identification and AnalysisToolson the ExPASy Server)》,(收录于)《蛋白质组学操作手册(TheProteomicsProtocols Handbook)》,编辑人Walker J.M.,托托瓦:胡马纳出版社,2005年,ISBN 9781588295934,第571到607页(中)。
结合成员可以与来自非人物种的PD-L1交叉反应,这对于在动物模型中测试结合成员具有优势。优选地,结合成员与猴PD-L1交叉反应。在一些实施例中,通过测量,在室温下scFv格式的单价结合成员对猴PD-L1的KD为约3.3pM。在一些实施例中,结合成员的对于猴PD-L1的亲和力至少与对于人PD-L1的亲和力一样强,更优选至少两倍于对于人PD-L1的亲和力。在一些实施例中,结合成员不与小鼠PD-L1交叉反应。通常,针对给定人靶标的抗体对啮齿动物直系同源物具有较低的亲和力,这使得啮齿动物体内动物数据的价值较低。由于本文公开的结合成员对于人PD-L1的KD值和对于猴PD-L1的KD值相当,因此预期体内动物数据更能反映人的疾病。另外,对猴子的交叉反应性使得猴子能够用作毒理学物种。
在优选实施例中,结合成员不与B7家族的其它成员交叉反应,例如PD-L2和/或B7-H3。两种蛋白质都与PD-L1具有高度的序列相似性,因此,与这些B7家族成员的结合会引起安全问题。
因此,在一些实施例中,提供了一种与PD-L1特异性结合的结合成员,其包括至少一个SEQ ID NO:1的可变轻链和至少一个SEQ ID NO:2的可变重链,其中所述结合成员对于人PD-L1的平衡结合常数KD低于10pM。优选地,在37℃下在PBS中以10mg/ml的浓度培养1周或2周后,所述结合成员以scFv格式保持单体至少95%。更优选地,所述结合成员不与小鼠PD-L1交叉反应。
本发明还提供了一种与本文公开的结合成员竞争以与人PD-L1结合的结合成员。例如,这种竞争(或交叉阻断)结合成员可以是中和的。优选地,这种竞争结合成员对于与人PD-L1结合的平衡结合常数(KD)为250pM或更低,例如低于约100pM、40pM、30pM、20pM、10pM或低于约5pM。因此,在一个实施例中,结合成员的KD小于约5pM。
如本文使用,术语“竞争”是指结合成员之间的与相同靶标结合的竞争。竞争可以通过竞争性结合测定来确定,其中感兴趣的结合成员阻止或抑制或降低本文公开的结合成员与共同抗原(此处分别为PD-L1或其片段)的特异性结合。这种竞争性结合测定是本领域已知的,包含但不限于固相直接或间接放射免疫测定(RIA)和固相直接或间接酶免疫测定(ELISA)。通常,这种测定涉及使用结合到固体表面的纯化抗原、待测试的结合成员和如本文所述的参考结合成员。通过确定以下量来测量竞争性抑制:(i)在待测试的结合成员存在下结合到固体表面的参考结合成员的量,或(ii)在参考结合成员存在下结合到固体表面的待测试的结合成员的量。竞争结合成员可以(i)与参考结合成员相同的表位结合,(ii)与重叠表位结合,或(iii)与相同靶分子上的不同表位结合,但在空间上阻碍参考结合成员与其靶标结合。
通常,当竞争结合成员过量存在时,它将降低本文所述的结合成员与PD-L1的特异性结合,即其交叉阻断结合至少40-45%、45-50%、50-55%、55-60%、60-65%、65-70%、70-75%或75%或更多。优选地,在竞争结合成员存在下本文所述的结合成员的结合降低至少80-85%、85-90%、90-95%、95-97%或97%或更多。
在一个实施例中,结合成员是单价的,例如scFv或Fab片段。在另一个实施例中,结合成员是多价的。这种多价分子可以是二价的(例如,全长抗体或F(ab')2片段)或包括至少三个靶结合位点。多价结合成员可以是双特异性抗体,诸如例如,双抗体、单链双抗体、双scFv或DART(参见例如Kontermann R.E.,《分子生物学方法(Methods in Mol.Biol.)》编辑人LO,B.,托托瓦,新泽西:胡马纳出版社,2004年,ISBN 1588290921,第227页)。
所述双特异性抗体可以使用比针对上述scFv描述的那些更短的接头,即仅具有SEQ ID NO:10的基本模序的一到三个重复序列(参见例如Holliger,P.等人,《美国科学院院报(PNAS)》,1993年,第90卷,第14期,第6444页)。在另一个实施例中,多价结合成员是三抗体、微型抗体或四抗体。多价结合成员的其它实例包含但不限于单链双抗体、串联scDb、线性二聚scDb、环状二聚scDb、BiTE、串联三scFv、三(抗)体、双特异性Fab2、双微型抗体、scFv-Fc-scFv融合体、双-双抗体、DVD-Ig、IgG-scFab、scFab-dsscFv、Fv2-Fc或IgG-scFv融合体(包含但不限于Bs1Ab、Bs2Ab、Bs3Ab、Bs4Ab、Ts1Ab和Ts2Ab、四源杂交瘤、柞臼结构(KIH)、双特异性抗体、CrossMab和DuoBody)。
在一些实施例中,根据本公开的结合成员可以包含捕获部分,例如链霉亲和素结合标签,例如描述于美国专利申请US 2003/0083474、美国专利5,506,121或6,103,493中的STREP-捕获部分的其它实例包含但不限于麦芽糖结合蛋白、谷胱甘肽-S-转移酶(GST)、钙调蛋白结合肽(CBP)、FLAG-肽(例如序列Asp-Tyr-Lys-Asp-Asp-Asp-Asp-Lys-Gly),T7表位(Ala-Ser-Met-Thr-Gly-Gly-Gln-Gln-Met-Gly)、麦芽糖结合蛋白(MBP)、单纯性疱疹病毒糖蛋白D的Gln-Pro-Glu-Leu-Ala-Pro-Glu-Asp-Pro-Glu-Asp序列的HSV表位、序列Tyr-Thr-Asp-Ile-Glu-Met-Asn-Arg-Leu-Gly-Lys的水疱性口炎病毒糖蛋白(VSV-G)表位、序列Tyr-Pro-Tyr-Asp-Val-Pro-Asp-Tyr-Ala的血凝素(HA)表位和序列Glu-Gln-Lys-Leu-Ile-Ser-Glu-Glu-Asp-Leu的转录因子c-myc的“myc”表位。
捕获部分的另一个实例是金属螯合剂,其能够结合金属离子。相应的捕获部分可以是乙二胺、乙二胺四乙酸(EDTA)、乙二醇四乙酸(EGTA)、二乙烯三胺五乙酸(DTPA)、N,N-双(羧甲基)甘氨酸(也称为次氮基三乙酸,NTA)、1,2-双(邻氨基苯氧基)乙烷-N,N,N',N'-四乙酸(BAPTA)、2,3-二巯基-1-丙醇(-二巯基丙醇)、卟吩或血红素。根据本领域中使用的固定化金属亲和色谱的标准方法,例如,寡聚组氨酸标签能够与铜(Cu2+)、镍(Ni2+)、钴(Co2 +)或锌(Zn2+)离子形成络合物,例如,可以通过螯合剂次氮基三乙酸(NTA)将其用于色谱目的。
在一些实施例中,本文公开的结合成员的免疫原性低于已知的针对PD-L1的结合成员。在一些实施例中,本文公开的结合成员与已知的针对PD-L1的结合成员结合不同的表位。在一些实施例中,本文公开的结合成员具有与已知的针对PD-L1的结合成员不同的清除率。在一些实施例中,与已知的针对PD-L1的结合成员相比,本文公开的结合成员对聚集和/或蛋白酶降解具有增加的抗性。在一些实施例中,与已知的针对PD-L1的结合成员相比,本文公开的结合成员具有改善的IC50和/或EC50。在一些实施例中,与已知的针对PD-L1的结合成员相比,本文公开的结合成员具有改善的结合参数,例如kon、koff或KD。在一些实施例中,本文公开的结合成员具有与已知的针对PD-L1的结合成员不同的物种交叉反应性模式。在一些实施例中,结合成员具有与已知的针对PD-L1的结合成员不同的pH稳定性。在一些实施例中,结合成员在指定温度下具有与已知的针对PD-L1的结合成员不同的长期稳定性。在一些实施例中,结合成员表现出与已知的针对PD-L1的结合成员不同的组织穿透能力。在一些实施例中,与已知的针对PD-L1的结合成员相比,结合成员具有不同的阻断PD-L1与其受体PD-1和/或CD80相互作用的效力。
还考虑了与本文公开的结合成员竞争以与PD-L1结合的结合成员。
核酸、载体、宿主细胞和生产方法
如本文所述的结合成员可以由单个核酸序列或多个核酸序列编码。在多个核酸序列的情况下,每个序列可以编码一个可变区。在一些实施例中,核酸序列可以编码两个或更多个可变区。通常,多个核酸序列编码结合成员的可变区。通常,每个可变区由一种不同的核酸序列编码。编码可变区的相应核酸序列可以包含在单个核酸分子中。在一些实施例中,编码可变区的两个或更多个核酸序列包含在单个核酸分子中。在一些实施例中,编码可变区的每个核酸序列包含在单个不同的核酸分子中。因此,可以使用多个核酸分子来生产结合成员,例如各自编码至少一个可变区。在一些实施例中,相应的核酸分子可以定义表达盒。如上所述,表达盒是能够指导特定核苷酸序列在合适的宿主细胞中表达的核酸分子。
表达盒包含与感兴趣的核苷酸序列可操作地连接的启动子,其与一个或多个终止信号可操作地连接。它还可以包含核苷酸序列适当翻译所需的序列。编码区可以编码感兴趣的多肽,并且还可以在正义或反义方向上编码感兴趣的功能性RNA,包含但不限于反义RNA或非翻译RNA。包括感兴趣的核苷酸序列的表达盒可以是嵌合的,意味着其至少一种组分相对于其至少一种其它组分是异源的。表达盒也可以是天然存在的,但是以可用于异源表达的重组形式获得。然而,在一些实施例中,表达盒相对于宿主是异源的;即,表达盒的特定核酸序列不是天然存在于宿主细胞中,而是通过转化事件引入宿主细胞或宿主细胞的始祖细胞。表达盒中核苷酸序列的表达可以在组成型启动子或诱导型启动子的控制下,该启动子仅在宿主细胞暴露于某些特定的外部刺激时才启动转录。在多细胞生物(如植物或动物)的情况下,启动子也可以对特定组织、器官或发育阶段具有特异性。
已知了结合成员或其部分的序列,编码多肽序列的cDNA可以通过本领域熟知的方法生成,例如,通过基因合成。可以通过标准克隆和诱变技术将这些cDNA克隆到合适的载体中,例如表达载体或克隆载体。任选地,抗体的可变轻链而非可变重链由单独载体编码。此外,可以将其它序列(诸如标签(例如,His标签))、用于产生Fab或全长抗体的恒定结构域、接头、第二结合特异性的编码序列或另一种功能性多肽(例如,生成融合构建体或双特异性分子的酶)包含在遗传构建体中。
基于所选择的克隆策略,遗传构建体可以生成在N-末端或C-末端具有一个或多个其它残基的结合成员。例如,衍生自起始密码子的N-末端甲硫氨酸或其它丙氨酸可以存在于表达的多肽中,除非它在翻译后被剪掉。因此,应理解本文公开的抗体包括所公开的序列而不是由其组成。因此,在一个实施例中,结合成员包括SEQ ID NO:9的序列。在另一个实施例中,结合成员包括SEQ ID NO:11的序列。如果结合成员是具有取向VH-接头-VL的scFv或VH位于N-末端的任何其它抗体片段,则分子的VH序列部分可以是N-末端甲基化的。因此,在一个实施例中,SEQ ID NO:2具有N-末端甲硫氨酸。
标准克隆、诱变和分子生物学技术的基本方案描述于例如《分子克隆,实验室手册(Molecular Cloning,A Laboratory Manual)》(Green M.和Sambrook,J.,《分子克隆,实验室手册(Molecular Cloning,a Laboratory Manual)》,第4版,冷泉港实验室,2012年,ISBN1936113422)。
进一步考虑了在严格条件下与本文所述核酸杂交的分离核酸。
还考虑了重组表达本文公开的结合成员的细胞。用于表达遗传构建体的合适宿主细胞可以是原核的或真核的。合适的原核宿主细胞是革兰氏阴性或革兰氏阳性细胞,包含埃希氏菌属、欧文氏菌属、肠杆菌属、克雷伯氏菌属、假单胞菌属或芽孢杆菌属的种。在一些实施例中,宿主细胞是大肠杆菌,例如大肠杆菌菌株BL21(DE3)(例如Invitrogen,USA,目录号C600003)和OrigamiTM 2(DE3)(例如Novagen,USA,目录号71345-3)中的一种或多种。
如果需要翻译后修饰(例如,糖基化或磷酸化),则使用真核宿主细胞可能是有利的。例如,真核微生物(例如,常用的酿酒酵母或毕赤酵母菌株)可以用作宿主细胞。宿主细胞的合适实例还包含植物或动物细胞,特别是昆虫或哺乳动物细胞。合适的哺乳动物细胞包含但不限于中国仓鼠卵巢细胞(CHO)、人胚肾细胞(HEK)、人脐静脉内皮细胞(HUVEC)或NS0骨髓瘤细胞。还报道了原核宿主细胞中的糖基化,参见例如JafféS.R.P.等人,《生物技术发展现状(Curr.Opin.Biotechnol.)》,2014年,第30卷,第205页。
结合成员可以通过在合适的宿主细胞中表达来产生。例如,通过标准技术(例如,电穿孔或化学转化)将上述表达载体引入宿主细胞中。然后在足以进行重组蛋白表达的条件下培养转化的细胞,通常在合适的营养培养基中,任选地进行修饰以诱导启动子、选择转化子或扩增感兴趣的编码序列。从培养物中回收结合成员,并任选地使用本领域的标准技术纯化。通过优化培养基和培养条件(例如,温度或氧气供应),可以提高重组蛋白的产量。在原核生物中,结合成员可以在周质中在细胞内作为包涵体产生或分泌到培养基中。动物细胞通常将结合成员分泌到培养基中。收获后,可以使用本领域熟知的方法纯化蛋白质,例如凝胶过滤、离子交换色谱、反相色谱、疏水相互作用、混合模式色谱和/或亲和色谱。
在一个实施例中,结合成员在无细胞系统中产生。这通常涉及体外转录,然后是编码如本文所述蛋白质的核酸产物模板的体外翻译,例如质粒DNA或PCR产物模板。例如,使用来自生长细胞的原始裂解物,从而提供必需的酶以及细胞蛋白质合成机制。可以从外源提供必要的构建块(例如,氨基酸或核碱基)以及能量递送分子等。无细胞表达系统可以例如基于裂解的兔网织红细胞(例如,兔网织红细胞裂解物系统,Promega,目录号L4540)、HeLa细胞(例如,1步法人体外翻译试剂盒,88881,Thermo Scientific)、昆虫细胞(例如,EasyXpress昆虫试剂盒II,32561,Qiagen)、小麦胚芽(例如,小麦胚芽提取物,L4380,Promega)或大肠杆菌细胞(例如,体外蛋白质合成试剂盒,E6800S,NEB)。此外,用于改善二硫键生成的优化的无细胞抗体表达系统可以用于生产。市售试剂盒包含昆虫细胞裂解物(例如,EasyXpress二硫昆虫试剂盒,32582,Qiagen)或大肠杆菌细胞裂解物(例如,EasyXpress二硫大肠杆菌试剂盒,32572,Qiagen)。无细胞蛋白质合成具有例如以下优点:快速,实现高产物产量,允许容易地改变反应条件,形成低程度的副产物或甚至没有副产物。无细胞蛋白质合成可以涉及不能在纯生物或化学生产系统中进行的生物和/或化学步骤。例如,非天然或化学修饰的氨基酸可以在所需位置掺入蛋白质中。已经在无细胞系统中成功地产生了ScFv-毒素融合蛋白(Nicholls,P.J.等人,《生物化学杂志(JBC)》,1993年,第268卷,第5302到5308页)。因此,在一个实施例中,提供了一种生产本文所述的结合成员的方法,其包含以下步骤:(a)提供无细胞系统,(b)提供编码上述结合成员的核酸产物模板,(c)允许核酸产物模板的转录和翻译;(d)回收;和任选地(e)分别纯化结合成员。
另外或可替代地,生产本文所述的结合成员的方法包括至少一个化学合成步骤。例如,该方法可以完全是化学的。在另一个实施例中,上述基于细胞的或无细胞的生产系统包含这样的至少一个化学合成步骤。
在一些实施例中,如本文所述的结合成员是在基于细胞的系统中使用表达载体在大肠杆菌中进行细胞内表达而产生的。表达后,多肽在宿主细胞内作为包涵体生成,其与其它细胞颗粒分离,然后在变性剂(例如,盐酸胍(GndHCl))中溶解,并通过本领域技术人员熟知的复性程序复性。
所需的结合成员也可以在转基因动物中产生。可以根据标准方法获得合适的转基因动物,标准方法例如包含以下步骤:(i)制作转基因胚胎,例如通过将包含结合成员的编码序列以及合适的控制序列的DNA构建体微注射到卵子中;(ii)将卵子转移到假怀孕的受体雌性;(iii)监测妊娠或怀孕;和(iv)选择表达所需抗体的后代。
应理解,上述核酸、载体、宿主细胞和生产方法也适用于本文所述的结合成员(只要它们是蛋白质)。
本文进一步考虑了表达嵌合抗原受体(CAR)的细胞。CAR表达细胞已在癌症治疗中得到充分利用。这些自体固有或同种异体来源的细胞经遗传修饰以表达CAR,例如通过用慢病毒载体转导细胞。细胞通常是T细胞,而NK细胞也有用。CAR通常具有几个部分,包括抗原结合结构域、间隔区、跨膜结构域、共刺激信号传导结构域和信号传导结构域。
细胞外抗原结合结构域特异性识别给定的靶蛋白,通常在癌细胞上。在与靶标结合后,CAR细胞被激活并且也保持在癌细胞附近。抗原结合结构域通过间隔区与跨膜结构域连接,跨膜结构域又与细胞内共刺激信号传导结构域连接。取决于抗原结合结构域及其靶蛋白的特性,可能必须优化间隔区的长度。靶标与癌细胞的结合触发了构象变化,其导致信号传导结构域(例如,CD3ζ信号传导结构域)的激活信号。共刺激信号传导结构域通常位于跨膜结构域和信号传导结构域之间,用于扩增激活信号。共刺激信号传导结构域的示例性实施例是CD28或4-1BB。
在一些实施例中,抗原结合结构域包括如本文所述的VL和/或VH序列。在一些实施例中,抗原结合结构域包括如本文所述的scFv。
在一些实施例中,CAR表达细胞是“铠装(armored)CAR”细胞,即分泌可溶性蛋白质以改变被给予CAR细胞的受试者的肿瘤微环境内的免疫应答的CAR表达细胞。在一些实施例中,这种细胞排泄如本文所述的结合成员,特别是scFv。
化学和/或生物修饰
在一个方面,本文公开的结合成员是化学和/或生物学修饰的。这种修饰可以包含但不限于糖基化、PEG化、HES化、白蛋白融合技术、PAS化,用染料和/或放射性同位素标记、与酶和/或毒素结合、磷酸化、羟基化和/或硫酸化。同样地,可以相应地修饰上述任何结合成员、核酸序列、载体和/或宿主细胞。
可以进行化学和/或生物学修饰以优化蛋白质的药效动力学或水溶性或降低其副作用。例如,可以应用PEG化、PAS化和/或HES化来减慢肾清除率,从而增加结合成员的血浆半衰期。另外或可替代地,修饰可以向蛋白质加入不同的功能性,例如,加入毒素以更有效地对抗癌细胞,或加入检测分子以用于诊断目的。
糖基化是指将糖类附着于蛋白质的过程。在生物系统中,该过程在细胞内酶促进行,作为共翻译和/或翻译后修饰的形式。蛋白质(此处是结合成员,例如抗体)也可以是化学糖基化的。通常但不限于,糖基化是(i)与天冬酰胺或精氨酸侧链的氮N连接;(ii)与丝氨酸、苏氨酸、酪氨酸、羟赖氨酸或羟脯氨酸侧链的羟基氧O连接;(iii)涉及木糖、岩藻糖、甘露糖和N-乙酰葡糖胺与磷酸丝氨酸的附接;或(iv)以C-甘露糖基化的形式,其中将甘露糖加入到特异性识别序列中发现的色氨酸残基中。糖基化模式可以例如通过选择合适的细胞系、培养基、蛋白质工程制造模式和加工策略来控制(HOSSLER,P.,《哺乳动物细胞培养中的最佳及一致的蛋白质糖基化(Optimal and consistent protein glycosylation inmammalian cell culture)》,《糖生物学(Glycobiology)》,2009年,第19卷,第9期,第936到949页)。在一些实施例中,修饰本文所述的结合成员的糖基化模式以增强ADCC和CDC效应子功能。
控制或改变糖基化模式的蛋白质工程可以涉及一个或多个糖基化位点的缺失和/或添加。通过将相应的酶识别序列引入结合成员的氨基酸序列或通过添加或取代上述氨基酸残基中的一个或多个,可以方便地实现糖基化位点的产生。
可能需要PEG化结合成员。PEG化可以改变蛋白质的药效动力学和药代动力学性质。适当分子量的聚乙二醇(PEG)共价附接到蛋白质骨架上(参见例如Pasut G.和VeroneseF.,《PEG化的最新技术:经四十年研究实现的巨大多功能性(State of the art inPEGylation:the great versatility achieved after forty years of research)》,《控制释放杂志(J.Control Release)》,2012年,第161卷,第2期,第461页)。PEG化还可以通过将PEG化蛋白质从免疫系统中屏蔽来降低免疫原性和/或通过例如增加结合成员的体内稳定性,保护其免受蛋白水解降解的影响,延长其半衰期并通过改变其生物分布来改变其药代动力学。
可以通过PEG模拟,例如使抗体HES化或PAS化,来实现类似的效果。HES化利用羟乙基淀粉(“HES”)衍生物,而在PAS化期间,抗体与构象紊乱的由氨基酸脯氨酸、丙氨酸和丝氨酸组成的多肽序列连接。这些PEG模拟和相关化合物例如描述于Binder U.和Skerra,A.,《通过遗传融合到重组PEG模拟的治疗性蛋白质的半衰期延长(Half-Life Extension ofTherapeutic Proteins via Genetic Fusion to Recombinant PEG Mimetics)》,收录于《治疗性蛋白质:调节其血浆半衰期的策略(Therapeutic Proteins:Strategies toModulate Their Plasma Half-Lives)》,编辑人Kontermann R.,魏因海姆,德国:Wiley-VCH出版社,2012年,ISBN:9783527328499,第63页中。
结合成员可以包含表位,例如挽救受体结合表位。这种挽救受体结合表位通常是指IgG分子的Fc区的表位(例如,IgG1、IgG2、IgG3或IgG4),并且具有增加分子的体内半衰期的作用。
另外或可替代地,结合成员用第二部分标记或与第二部分结合,该第二部分归属于靶结合后的辅助功能。第二部分可以例如具有其它免疫效应子功能,在药物靶向中有效或可用于检测,但不限于此。第二部分可以例如使用本领域已知的方法与结合成员化学连接或遗传融合。
可以用作第二部分的分子包含但不限于放射性核素(也称为放射性同位素)、脱辅酶、酶、辅助因子、肽部分(例如,HIS标签)、蛋白质、糖类(例如,甘露糖-6-磷酸标签)、荧光团(例如,异硫氰酸荧光素(FITC))、藻红蛋白、绿/蓝/红或其它荧光蛋白、别藻蓝蛋白(APC)、发色团、维生素(例如,生物素)、螯合剂,抗代谢物(例如,甲氨蝶呤)、脂质体、毒素(例如,细胞毒性药物)或放射性毒素。放射性核素的说明性实例是35S、32P、14C、18F和125I。合适的酶的实例包含但不限于碱性磷酸酶、辣根过氧化物酶、β-半乳糖苷酶和血管生成素。合适的蛋白质的说明性实例是凝集素。合适的细胞毒性药物的实例包含但不限于紫杉醇(taxol),短杆菌肽D和秋水仙碱。
标记的结合成员特别适用于体外和体内检测或诊断目的。例如,可以通过放射免疫测定(RIA)、酶联免疫吸附测定(ELISA)或基于流式细胞术的单细胞分析(例如,FACS分析)分别检测用合适的放射性同位素、酶、荧光团或发色团标记的结合成员。相似地,本文公开的核酸和/或载体可以用于检测或诊断目的,例如,使用其标记的片段作为杂交测定中的探针。标记方案可以例如在Johnson I.和Spence,M.T.Z.,《分子探针手册,荧光探针和标记技术指南(Molecular Probes Handbook,A Guide to Fluorescent Probes andLabelling Technologies)》,《生命技术(Life Technologies)》,2010年,ISBN:0982927916中找到。
组合物
可以在组合物中提供本文公开的结合成员、核酸序列和/或载体,所述组合物进一步包含合适的载剂、赋形剂或稀释剂。在典型的实施例中,相应的组合物包含本文所述的抗体。
这种组合物可以例如是诊断剂、化妆品或医药组合物。出于治疗或化妆目的,所述组合物是医药组合物,其包含医药学上可接受的载剂、赋形剂或稀释剂,即在所用剂量和浓度下无毒。
合适的“载剂”、“赋形剂”或“稀释剂”包含但不限于:(i)缓冲剂,例如磷酸盐、柠檬酸盐或其它有机酸;(ii)抗氧化剂,例如抗坏血酸和生育酚;(iii)防腐剂,例如3-戊醇、氯化六烃季铵、氯化苯甲烃铵、苯甲醇、对羟基苯甲酸烷基酯、儿茶酚或环己醇;(iv)氨基酸,例如组氨酸、精氨酸;(v)肽,优选多达10个残基,例如聚赖氨酸;(vi)蛋白质,例如牛或人血清白蛋白;(vii)亲水性聚合物,例如聚乙烯吡咯烷酮;(viii)单糖、二糖、多糖和/或其它糖类,包含葡萄糖、甘露糖、蔗糖、甘露糖醇、海藻糖、山梨糖醇、氨基葡聚糖或聚酰胺胺;(ix)螯合剂,例如EDTA;(x)成盐离子,例如钠、钾和/或氯离子;(xi)金属络合物(例如,Zn-蛋白质络合物);(xii)离子和非离子表面活性剂,例如TWEENTM、PLURONICSTM或聚乙二醇(PEG),和/或(xiii)冻存保护剂,例如二甲基亚砜(DMSO)。
许多示例性化合物具有不同的功能,并且可以例如充当载剂和稀释剂。还应理解,组合物可以包含每种载剂、稀释剂或赋形剂中不只一种。
可以在固定承载材料上提供结合成员、核酸序列或载体,所述固定承载材料例如珠粒、微粒或纳米颗粒。通常,结合成员分子通过共价键(任选地涉及接头)、非共价键或两者与这种承载体连接。珠粒和微粒可以包含例如淀粉、纤维素、聚丙烯酸酯、聚乙酸酯、聚乙醇酸酯、聚(丙交酯-共-乙交酯)、胶乳或葡聚糖。
在一个实施例中,提供了一种医药组合物,其包含如上所述的结合成员、核酸序列或载体。该组合物还可以包含治疗有效量的一种或多种其它治疗活性化合物。在一些实施例中,其它治疗活性化合物是针对PD-L1介导的疾病具有活性的化合物。
治疗应用
如本文所述的分子,特别是结合成员(例如,抗体)、核酸分子、宿主细胞或载体,可用作药物。通常,这种药物包含治疗有效量的本文提供的分子或细胞。因此,相应的分子或宿主细胞可以用于产生可用于治疗一种或多种PD-L1相关病症的药物。
在一个方面,提供了一种治疗PD-L1相关/PD-L1介导的病症的方法。该方法包含将药学有效量的如本文所述的分子或宿主细胞,特别是抗体或宿主细胞,给予有需要的受试者的步骤。在一个实施例中,将如上所述的医药组合物给予受试者,该医药组合物包含这种药学有效量的结合成员(例如,抗体)或宿主细胞。可以将上述药物给予受试者。
需要治疗的受试者可以是人或非人动物。通常,受试者是哺乳动物,例如小鼠、大鼠、兔子、仓鼠、狗、猫、猴子、猿、山羊、绵羊、马、鸡、豚鼠或猪。在典型的实施例中,受试者被诊断患有PD-L1相关病症或可能得上这种病症。在动物模型的情况下,可以对动物进行遗传工程改造以患有PD-L1相关病症。在动物模型中,动物也可以以某一方式进行遗传工程改造,使得其表现出PD-L1介导的疾病的特性。
已知多种PD-L1相关病症,其中PD-L1的拮抗剂已显示出以下方面的治疗效果,包含但不限于NSCLC(非小细胞肺癌)、尿路上皮癌、黑素瘤、肾细胞癌、霍奇金淋巴瘤、头颈部鳞状细胞癌、卵巢癌、胃肠癌、肝细胞癌、胶质瘤、乳腺癌、淋巴瘤、小细胞肺癌、骨髓增生异常综合征、前列腺癌、膀胱癌、宫颈癌、非透明细胞肾癌、结肠直肠癌、肉瘤、结肠癌、肾癌、肺癌、胰腺癌或胃癌、皮肤癌、子宫癌、成胶质细胞瘤、白血病、癌症、梅克尔细胞癌或肾细胞癌(RCC)、血癌、多发性骨髓瘤、淋巴细胞白血病(ALL)、B细胞白血病、慢性淋巴细胞白血病、非霍奇金淋巴瘤和卵巢癌;或其中所述疾病是全身性红斑狼疮。
PD-1途径也已显示参与败血症和相关病症(参见例如WO2015038538)。因此,在一个实施例中,PD-L1相关疾病是败血症、败血性休克、全身性炎性反应综合征或代偿性抗炎反应综合征。
Bodhankar等人((2015年),《中风(Stroke)》,第46卷,第10期:第2926到2934页)证明了在实验性中风的大脑中动脉闭塞小鼠模型中用抗PD-L1单克隆抗体治疗的有益治疗效果。
PD-1和PDL-1在原发性中枢神经系统淋巴瘤中是可免疫组织化学检测的,并且可能参与产生免疫抑制性微环境(Berghoff等人,(2014年),《临床神经病理学(ClinicalNeuropathology)》,第33卷,第1期,第42到49页)。对于该疾病的实验性治疗方法,可以考虑特异性免疫检查点抑制剂。
已经在小鼠和人中评估了PD-1/PD-L1相互作用对移植后环境中急性白血病的影响。Koestner等人((2011年),《血液(Blood)》,第117卷,第3期,第1030到1041页)在小鼠模型中观察到通过PD-L1阻断恢复移植物抗淋巴瘤效应而不触发移植物抗宿主病:移植造血干细胞后早期的基因修饰同种异体T细胞的过继转移提供了有效的移植物抗淋巴瘤效应而不引起移植物抗宿主病,而后期的过继转移只对并发的PD-L1阻断有效。将T细胞工程改造以表达针对受体白血病特异性抗原的T细胞受体(TCR)。
医药组合物可以通过各种合适的给药途径中的一种或多种给予。给药可以例如在肠胃外进行。在一些实施例中,给药在肌肉内进行。在一些实施例中,给药以推注或通过连续输注在静脉内进行。在一些实施例中,给药是在关节内、滑膜内、皮下、局部(例如,皮肤或眼睛)、肠胃外、直肠、皮内、皮下、透皮、经皮或局部进行。其它合适的给药方式包含但不限于例如脑内给药、脑脊髓内给药、鞘内给药、硬膜外给药、或腹膜内给药、口服给药、泌尿生殖器给药、玻璃体内给药、全身给药、静脉内给药、腹膜内给药、肌肉内给药、眼内给药、耳部给药、鼻内给药、吸入给药、舌下给药、颅内给药、肌肉内给药、腹膜内给药或口腔内给药。本文公开的结合成员、本文公开的核酸序列、载体或宿主细胞可以与一种或多种其它治疗有效化合物组合。在一些实施例中,这种化合物可以能够破坏通过PD-L1受体的信号传导。在一些实施例中,相应的化合物可以能够抑制一种或多种其它靶标,例如炎症反应的其它介质。这些化合物可以同时或依次给予。
对于治疗应用,结合成员也可以放射性标记或与毒素连接或与如上所述的另一种效应子功能连接。
通常,本文所述的结合成员的治疗用途可以与选自由以下组成的组中的一种或多种疗法组合:抗体疗法、化学疗法、细胞因子疗法、树突状细胞疗法、基因疗法、激素疗法、激光疗法、放射疗法或疫苗疗法。
在一些实施例中,结合成员与一种或多种不同的药物化合物组合给予。示例性实例包含CTLA-4抑制剂(例如,曲美单抗(tremelimumab)和/或伊匹单抗)、VEGF抑制剂(例如,贝伐单抗)、EGF受体抑制剂(例如,厄洛替尼)、细胞抑制剂(例如,顺铂、培美曲塞、卡铂和/或紫杉醇(paclitaxel))、IFN-g、癌症疫苗、可溶性CD80或其组合。在He J等人(2015年),《自然科学报告(Nature Scientific Reports)》,第5卷,第13110页,DOI:10.1038/srep13110中给出了涉及抗PD-L1抗体与一种或多种药物化合物组合的临床试验的综述。可以组合给予的化学治疗剂包含但不限于烷化剂、抗代谢物、抗肿瘤抗生素、生物碱、亚硝基脲剂、拓扑异构酶抑制剂、激素或其拮抗剂、芳香酶抑制剂、P-糖蛋白抑制剂和/或铂络合物衍生物。化学治疗剂的示例性实施例是吉西他滨、环磷酰胺、5-氟尿嘧啶、奥沙利铂,
Black等人(2016年),《肿瘤靶标(Oncotarget)》,第7卷,第9期,第10557到10567页,在表达PD-L1的人和小鼠乳腺癌和前列腺癌细胞系的图中示出PD-1/PD-L1免疫检查点的激活赋予肿瘤细胞化疗耐药性并增加了转移。他们还示出使用抗PD-1抗体抑制PD-1/PD-L1轴增强了阿霉素化学疗法以抑制转移性乳腺癌的同系乳腺原位小鼠模型中的转移。他们得出结论,化学疗法和免疫检查点阻断的组合可以限制化疗耐药性和向转移性疾病的进展。
在一个实施例中,将本文所述的抗体与疫苗组合给予患有持续性病毒感染的受试者。在小鼠模型中,显示出在耗竭CD8+T细胞上阻断PD-1/PD-L1抑制信号与治疗性疫苗接种相结合协同地增强了功能性CD8+T细胞应答并改善了病毒控制,即使在没有CD4(+)T细胞帮助的情况下也是如此(参见例如,Ha SJ等人,《实验医学学报(J Exp Med)》,2008年3月17日;第205卷,第3期,第543到555页和EP2079760B1)。受试者可以例如患有腺病毒、巨细胞病毒、人免疫缺陷病毒(HIV)、EB病毒、肝炎病毒、疱疹病毒、乳多空病毒、乳头瘤病毒、细小病毒、T细胞白血病病毒、嗜T淋巴病毒(HTLV)和/或水痘-带状疱疹病毒的持续性病毒感染。
还考虑了抑制肿瘤或肿瘤细胞生长的方法,其包括使肿瘤或肿瘤细胞与治疗有效量的本文公开的结合成员接触的步骤。在一个实施例中,给药引起肿瘤生长。在另一个实施例中,给药减小肿瘤尺寸。
诊断应用和/或检测目的
如本文公开的结合成员可以用于体内和/或体外检测或诊断目的。例如,涉及用于检测特异性细胞或组织中的表达的抗体的多种免疫测定是本领域技术人员已知的。同样地,可以如本部分详述相应地使用前文中描述的任何结合成员、核酸序列、载体和/或宿主细胞。
已经显示肿瘤PD-L1的表达状态在多种肿瘤类型(包含但不限于黑素瘤、肾细胞癌和非小细胞肺癌)中是预后的。PD-L1表达可以通过免疫组织化学(IHC)测量,其中抗-PD-L1抗体是必需的。
对于这种应用,本文公开的结合成员(例如,抗体)、核酸序列、载体或宿主细胞可以包含可检测标记。在一些实施例中,本文公开的结合成员、核酸序列、载体或宿主细胞不包含可检测标记。作为一个说明性实例,可以使用未标记的抗体,并通过在如本文所述的结合成员(例如,抗体)上与表位特异性结合的二级抗体检测。
在一些实施例中,结合成员、核酸序列、载体和/或宿主细胞与一种或多种可以被检测器物质识别的物质偶联。作为一个实例,结合成员可以与生物素共价连接,可以通过其与链霉亲和素结合的能力来检测。同样地,本文公开的核酸和/或载体可以用于检测或诊断目的,例如通过在杂交测定中使用其标记的片段作为探针。
在某些实施例中,本文提供的任何分子,特别是抗体,可用于检测样本(优选生物来源的样本)中PD-L1的存在。在本文中使用的术语“PD-L1”包含全长PD-L1,其片段和/或其前体。术语“检测”涵盖定量和/或定性检测。
在某些实施例中,生物样本包含来自人类患者的细胞或组织。生物样本的非限制性实例包含血液、尿液、脑脊髓液、活体组织切片、淋巴和/或非血液组织。
在某些实施例中,所述方法包含在允许抑制剂与其靶PD-L1(如果存在的话)结合的条件下使生物样本与如本文所述的PD-L1的结合成员(例如,抗PD-L1抗体)接触,并检测抑制剂-靶标复合物。这种方法可以是体外方法或体内方法。在一个实施例中,这种结合成员用于选择符合条件用本文所述的结合成员治疗的受试者,例如,其中PD-L1是用于选择患者的生物标志物。
在另一方面,结合成员(例如,抗体)用于化妆品应用,例如,用于改善皮肤的美观。
同样地,可以如以上详述相应地使用上述核酸序列、载体和/或宿主细胞。
制品
在另一方面,提供了一种制品(即试剂盒)。制品包含物质,例如材料,用于(i)治疗、预防PD-L1相关病症,或延缓其进展的目的;用于(ii)诊断目的;或用于(iii)化妆品目的。制品可以包含使用说明书和一个或多个容器。合适的容器包含例如瓶子、小瓶、注射器、药筒、板和试管,并且可以由多种材料制成,例如玻璃或塑料。至少一个容器容纳包含本文公开的结合成员的组合物。容器可以具有无菌进入孔。通常对相应的容器进行标记。
试剂通常以预定量的干粉提供,干粉通常是冻干的,包含赋形剂,其在溶解后将提供具有适当浓度的试剂溶液。还可以包含其它添加剂,例如稳定剂和/或缓冲剂。如果结合成员用酶进行标记,则试剂盒通常包含相应的底物和辅助因子。
使用说明书可以提供组合物用于治疗、预防所选病症和/或延缓其进展的指示;或进行检测或诊断测定的说明书。可以在标签和/或包装说明书上提供说明书。
参考序列
本文公开的序列是:
SEQ ID NO:1-scFv1的VL
SEQ ID NO:2-scFv1的VH
SEQ ID NO:3-scFv1的CDR-L1
SEQ ID NO:4-scFv1的CDR-L2
SEQ ID NO:5-scFv1的CDR-L3
SEQ ID NO:6-scFv1的CDR-H1
SEQ ID NO:7-scFv1的CDR-H2
SEQ ID NO:8-scFv1的CDR-H3
SEQ ID NO:9-scFv1
SEQ ID NO:10-接头
SEQ ID NO:11-甲基化scFv1
SEQ ID NO:12-FR-L1
SEQ ID NO:13-FR-L2
SEQ ID NO:14-FR-L3
SEQ ID NO:15-FR-L4
SEQ ID NO:16-FR-H1
SEQ ID NO:17-FR-H2
SEQ ID NO:18-FR-H3
SEQ ID NO:19-FR-H4
SEQ ID NO:20-IgG_1的重链
SEQ ID NO:21-IgG_2的重链
SEQ ID NO:22-IgG_3的重链
SEQ ID NO:23-IgG_4的重链
SEQ ID NO:24-IgG_1的轻链
SEQ ID NO:25-IgG_2的轻链
SEQ ID NO:26-IgG_3的轻链
SEQ ID NO:27-IgG_4的轻链
以下是说明本文公开的方法和组合物的实例。应当理解,在给出以上提供的一般描述的情况下,可以实践各个其它实施例。
实例
实例1-PD-L1结合scFv的标识
兔子的免疫:用重组人(rh)PD-L1Fc融合体(RnD Systems,USA,目录号156-B7)免疫兔子。最终增强后提取淋巴结,冷冻保存细胞。
PD-L1特异性的确认:通过结合ELISA进行兔血清对PD-L1的反应性的确认。简言之,PD-L1-Fc融合体(RnD Systems,USA,目录号156-B7)或PD-L1-His(BioVision,USA,目录号7429)在37℃下于Maxisorp 96孔微孔板上在PBS中以2mcg/mL的浓度包被1小时。用5%脱脂奶粉和1%BSA封闭后,加入递增浓度的兔血清,并用山羊抗兔IgG HRP(SouthernBiotech,USA,目录号4050-05)检测结合的IgG。用TMB ELISA底物溶液(eBioscience,USA,目录号00-4201-56)开发ELISA。
所有兔血清与Fc融合PD-L1和His标记PD-L1二者结合,表明免疫成功诱导针对PD-L1的B细胞应答。
兔B细胞的流式细胞术分选和培养:使用FACSAria III(BD Biosciences)将PD-L1特异性记忆B细胞作为单细胞分选到96孔微孔板中。在饲养细胞和含有10%胎牛血清(FCS)的条件培养基存在下培养单B细胞克隆。
对超过900个单B细胞克隆进行分选、培养,并通过ELISA分析细胞培养上清液中抗-PD-L1特异性IgG的存在。简言之,将rhPD-L1Fc融合体(RnD Systems,USA,目录号156-B7)在4℃下于Maxisorp 96孔微孔板上在PBS中以2mcg/mL的浓度包被过夜。用5%脱脂奶粉、1%BSA和0.05%吐温-20封闭后,加入细胞培养上清液。用抗兔IgG-HRP(SouthernBiotech,目录号4050-05)检测PD-L1特异性IgG。用TMB ELISA底物溶液(eBioscience,USA,目录号00-4201-56)开发ELISA。标识PD-L1特异性IgG产生B细胞克隆,并进一步分析IgG抗体的阻断PD-L1与PD-1相互作用的能力。简言之,将表达PD-L1的CHO细胞(Promega,USA,目录号CS187103)接种到96孔微孔板中。加入PD-L1特异性IgG,并将板在37℃,5%CO2下培养20分钟。加入表达PD-1的效应子Jurkat细胞(Promega,USA,目录号CS187105),并将板在37℃,5%CO2下再培养6小时。使用Bio-Glo荧光素酶测定系统(Promega,G7941)通过发光检测测量TCR/CD3激活。经发现,69个IgG产生B细胞克隆抑制PD-1和PD-L1的相互作用。
PD-L1中和IgG的测序:使用RNeasy迷你试剂盒(Qiagen,Germany,目录号74106)对产生中和抗PD-L1IgG抗体的所有兔B细胞克隆进行mRNA分离。根据制造商方案(一步法RT-PCR试剂盒,Qiagen,Germany,目录号210212),将mRNA用作逆转录模板。随后,进行使用寡核苷酸特异性扩增兔IgG重链和轻链编码序列的PCR反应(Biometra热循环仪T3)。对重链和轻链PCR片段进行独立测序(ABI,Sanger 3730x1;Microsynth AG,Balgach,Switzerland),并使用EMBOSS Transeq(http://www.ebi.ac.uk/Tools/st/)将获得的核苷酸序列翻译成氨基酸序列并使用CLUSTALW2(http://www.ebi.ac.uk/Tools/msa/clustalw2/)进行比对。
抗PD-L1scFv基因的构建和scFv蛋白表达:标识如上定义的可变轻链和可变重链的兔IgG CDR区,并将其移植到人轻链和重链受体框架上。在一些情况下,引入了点突变。生成编码scFv蛋白的细菌表达载体,其中N-末端可变轻链通过序列SEQ ID NO:10连接到C-末端可变重链。ScFv蛋白在大肠杆菌BL21(DE3)(Novagen,USA,目录号69450-3)中作为包涵体表达,将其分离、溶解,并复性蛋白质。通过尺寸排阻色谱法纯化复性scFv,并收集对应于约26kDa的单体峰值级分。
如上所述,通过ELISA分析人源化scFv的人PD-L1Fc融合体结合。通过该程序,在47种测试的scFv中,28种scFv被标识为人PD-L1的结合物。通过ELISA进一步分析人源化scFv与小鼠PD-L1的结合。简言之,小鼠PD-L1Fc融合体(Sino Biological,China,目录号50010-M03H或RnDSystems,USA,目录号1019-B7-100)在4℃下于Maxisorp 96孔微孔板上在PBS(pH7.2)中以5mcg/mL或1mcg/mL的浓度包被过夜。用1%BSA的PBS溶液(pH 7.2)或5%脱脂奶粉和1%BSA的PBS溶液(pH 7.2)封闭后,向孔中加入递增浓度的scFv(0.0016mcg/mL、0.008mcg/mL、0.04mcg/mL、0.2mcg/mL、1.0mcg/mL和5.0mcg/mL或0.02mcg/mL、0.06mcg/mL、0.19mcg/mL、0.56mcg/mL、1.67mcg/mL和5.0mcg/mL)。用小鼠PD-L1特异性抗体(SinoBiological,China,目录号50010-M08H)确认小鼠PD-L1Fc融合体的成功包被。尽管通过蛋白L-HRP(Sigma-Aldrich,USA,目录号P3226)检测到scFv,但是通过与HRP结合的山羊抗兔IgG(Southern Biotech,USA,目录号4050-05)检测到全长IgG对照抗体。用TMB ELISA底物溶液(eBioscience,USA,目录号00-4201-56)进行开发,并在450nm下测量吸光度。ScFv1不与小鼠PD-L1交叉反应,直到浓度为5mcg/mL。一种测试的scFv显示出对小鼠PD-L1的弱交叉反应性。人PD-L1结合scFv进一步表征为其中和人PD-L1活性的能力(如实例2中所示)、其稳定性(如实例3中所示)、其对人PD-L1的亲和力(如实例4中所示)以及其特异性(如实例5中所示)。scFv1进一步通过以下表征:与天然形式的人PD-L1的结合的分析(如实例6中所示),从细胞分泌的ScFv1的分析(如实例7中所示)以及体内效力的确定(如实例8中所示)。转化为IgG格式后,通过抑制人PD-L1与人PD-1之间相互作用的能力和通过分析对人PD-L1的亲和力(如实例9中所示)来进一步分析对应于scFv1的抗体。
实例2-人PD-L1的中和
在PD-1/PD-L1阻断测定中进一步测试26种scFv和一种非结合scFv(scFv2)的PD-L1中和能力。在该测定中,通过T细胞的活性促进荧光素酶活性。PD-L1与PD-L1的相互作用产生抑制信号并降低荧光素酶活性,这通过用PD-L1抑制剂处理细胞来克服。将表达PD-L1的CHO细胞(Promega,CS187103)接种到96孔微孔板中。加入递增浓度的scFv,并将板在37℃,5%CO2下培养20分钟。加入表达PD-1的效应子Jurkat细胞(Promega,CS187105),并将板在37℃,5%CO2下再培养6小时。使用Bio-Glo荧光素酶测定系统(Promega,G7941)通过发光检测测量TCR/CD3激活。绘制抑制曲线,并使用GraphPad 软件,版本6.05计算IC50值。scFv1和scFv2的结果显示在图1中。ScFv1有效阻断免疫检查点抑制信号,IC50为750pM。非结合scFv2对免疫检查点抑制信号没有显示出任何影响。ScFv1显示出所测试的27种scFv的最高效力。使用高达10mcg/mL的浓度范围无法确定最低效力scFv的IC50。
通过竞争ELISA测试scFv1、非结合scFv2和三种其它scFv抑制PD-L1与PD-1结合的能力。将rhPD-L1Fc融合体(RnD Systems,USA,目录号156-B7)在4℃下于Maxisorp 96孔微孔板上在PBS中以2mcg/mL的浓度包被过夜。用1%BSA和0.05%吐温-20的PBS溶液(pH 7.2)封闭板。制备scFv的系列稀释,其中11次1:3稀释以1mcg/mL开始,并加入板中。在室温下1小时后,除去一半scFv稀释,并用生物素化的PD-1Fc融合体(BPSBioscience,USA,目录号71109)替换,最终浓度为15ng/mL。用链霉亲和素-HRP(BD Pharmingen,USA,目录号554060)检测结合的PD-1Fc融合体。在不存在PD-1的情况下确定背景水平。用TMB ELISA底物溶液(eBioscience,USA,目录号00-4201-56)开发ELISA。在该测定中,PD-L1与PD-1相互作用的能力产生吸光度信号,其被scFv1但不被非结合scFv2有效地中和,如图2中所示。另外三种scFv也以与scFv1相当的程度中和了相互作用。
通过竞争ELISA测试scFv1和非结合scFv2抑制PD-L1与CD80结合的能力。将rhCD80-His(RnD Systems,USA,目录号9050-B1-100)在4℃下于Maxisorp 96孔微孔板上在PBS中以2mcg/mL的浓度包被过夜。用1%BSA和0.05%吐温-20的PBS溶液(pH 7.4)封闭板。用恒定浓度的50nM rhPD-L1Fc融合体(RnD Systems,USA,目录号156-B7)制备scFv的系列稀释,其中11次1:3scFv稀释以1mM开始。将该混合物与CD80包被的板在室温下培养2小时。通过在不存在任何PD-L1-Fc的情况下包含scFv1的稀释系列来确定对应于PD-L1不与CD80结合的背景水平。用山羊抗人IgGFc-HRP(Southern Biotech,USA,目录号2048-05)检测结合的PD-L1Fc融合体。用TMB ELISA底物溶液(eBioscience,USA,目录号00-4201-56)开发ELISA。在该测定中,PD-L1与CD80相互作用的能力产生吸光度信号,其被scFv1但不被非结合scFv2有效地中和到背景水平,如图3中所示。
总之,这些结果表明scFv1阻断PD-L1与PD-1和CD80二者的相互作用。
实例3-scFv的稳定性
可以观察到可能影响scFv稳定性的两种不同过程。首先,scFv可能易于二聚化,通常随后是寡聚化和进一步的聚集和沉淀。其次,随着时间的推移,可能发生scFv降解,从而导致更小的碎片。
在不同温度条件下储存后,研究了在PBS(pH 7.2)中配制的scFv1和4种其它scFv的稳定性。将scFv在4℃、22℃、37℃和-20℃下于1.5mL聚丙烯管中以10mg/mL浓度储存。通过SE-HPLC分析样本以确定单体、二聚体和高分子量寡聚体相对于总峰面积的水平(%):TOSOH TSKgel G2000SWXL柱,相二醇,L x I.D.30cm×7.8mm,5μm粒径(Sigma Aldrich,USA,目录号08540)。加载5μL10mg/mL的scFv。选择流动相PBS(pH 7.2)。
ScFv1是所测试的5种scFv中最稳定的。scFv1的SE-HPLC分析显示在上述实验条件下没有可检测的低分子量降解产物。在4℃、22℃和37℃下储存2周后,观察到只有少量的scFv1二聚化或形成高分子量分子。在37℃下储存1或2周后,ScFv1分别形成1.8%和2.7%的二聚体(表1)。
表1
还通过差示扫描荧光测定法(DSF)评估scFv1的热稳定性。将在PBS(pH 7.2)中配制的0.4mg/mL的scFv1在PBS(pH 7.2)中在20× Orange(Sigma-Aldrich,USA,目录号S5692,5000×)的存在下在实时PCR装置(Corbett,Rotor-Gene)中以1℃/5秒的扫描速率从30℃加热到95℃。在梯度运行期间测量荧光值(激发波长470nm;发射波长555nm)。使用Rotor-Gene 6000系列软件1.7计算的scFv1的中点熔解温度(Tm)是81.5℃。
蛋白质生物制剂可能在制造、储存和运输过程中暴露于冻/融应力,这可能导致聚集和降解。为了评估scFv1在冻/融循环期间的稳定性,将其于1.5mL聚丙烯管中在PBS(pH7.2)中以10mg/mL配制。将小瓶浸入液氮中1分钟,然后在室温下在水浴中培养5分钟。进行3、5、7或10次冻/融循环。将样本以16,100×g离心10分钟,弃去片状沉淀物。如上所述通过SE-HPLC分析上清液,并通过UV光谱确定蛋白质含量。在10次冻/融循环后,几乎100%的scFv1保持单体(表2),并且没有观察到蛋白质损失或沉淀。
表2
在37℃下在以10mcg/mL培养0小时、4小时和20小时后,通过ELISA评估scFv1在人血清(Sigma-Aldrich,USA,目录号H4522)中的稳定性。将结合信号与PBS(pH 7.4)中的scFv1进行比较,不进行培养。简言之,将rhPD-L1Fc融合体(RnD Systems,USA,目录号156-B7)在4℃下于Maxisorp 96孔微孔板上在PBS中以1mcg/mL的浓度包被过夜。用含有1%BSA和0.05%吐温-20的PBS(pH 7.4)封闭后,将一系列2.5mcg/ml到42ng/mL血清/scFv样本的1:3稀释一式两份加入ELISA板中。用蛋白L-HRP(Sigma-Aldrich,USA,目录号P3226)检测结合的scFv1。用TMB ELISA底物溶液(eBioscience,USA,目录号00-4201-56)开发ELISA。如图4中所示,在37℃下用人血清培养长达20小时后,scFv1的结合活性没有丧失。
实例4-与可溶性PD-L1的结合
scFv1和三种其它scFv对PD-L1-Fc融合体的亲和力使用包含自动进样器(Sapidyne Instruments,USA,5004)的KinExA 3200(Sapidyne Instruments,USA,目录号5001)通过动力学排斥测定来确定。测量溶液中未修饰分子之间的平衡结合亲和力和动力学。所述测量需要将一个相互作用配偶体固定在固相上,仅用作探针以确定溶液中相应结合配偶体的浓度。在此,将PD-L1Fc融合体(RnD Systems,USA,目录号156-B7)以30mcg/ml的浓度固定在聚(甲基丙烯酸甲酯)(PMMA)珠粒(440176,SapidyneInstruments Inc.)上。使用含有0.02%NaN3的PBS(pH 7.4)作为运行缓冲液。通常使用一组两条曲线确定scFv对PD-L1Fc融合体的亲和力,其中针对恒定量的scFv滴定2倍稀释系列的PD-L1Fc融合体。为每个数据点准备重复测量。对于scFv1,在第一曲线中,将20pM scFv1用11种不同的PD-L1Fc融合体浓度培养,以5nM PD-L1Fc融合体开始。将这些混合物培养5小时。在第二曲线中,将10pM scFv1用12种不同的PD-L1Fc融合体浓度培养,以2.5nM PD-L1Fc融合体开始。将这些混合物培养9小时。为了检测这些混合物中存在的未结合的scFv的量,将样本以0.25ml/分钟的流速暴露于含有固定化PD-L1Fc融合体的固相。然后通过注射0.5mL 250ng/ml生物素化蛋白-L(M00097,GenScript)并随后注射0.5mL 250ng/mL链霉亲和素DyLight 650结合物(Jackson ImmunoResearch)(每种流速为0.25ml/分钟)来检测捕获的scFv1。所有步骤均在室温下进行。将与平衡样本中的游离scFv1浓度成正比的荧光信号转换为电压信号。使用该电压信号来利用 Pro软件版本4.1.9或4.2.10(图5)的“n条曲线分析”使用选项“滴定剂作为分析浓度参考”计算scFv的KD值和活性。针对scFv1计算的KD值为8.8pM。针对其它scFv计算的KD值范围为12pM到92pM。
实例5-scFv的选择性
通过ELISA确定scFv1和scFv3与来自其它物种的PD-L1的交叉反应性。将来自人的PD-L1Fc融合体(RnD Systems,USA,目录号156-B7)、来自大鼠的PD-L1Fc融合体(SinoBiological,China,目录号80450-R02H)或来自猴子的PD-L1Fc融合体(Sino Biological,China,目录号90251-C02H)的PD-L1Fc融合体在4℃下于Maxisorp 96孔微孔板上在PBS(pH7.2)中以1mcg/mL的浓度包被过夜。用1%BSA和0.5%吐温-20的PBS溶液(pH 7.2)封闭板。制备浓度为1mcg/mL、333ng/mL和111ng/mL的scFv的系列稀释,并加入到板中。作为阴性对照,使用不含scFv的PBS,并且作为阳性对照,包含1mcg/mL小鼠抗人PD-L1抗体(BioLegend,USA,目录号329716)或生物素化rhPD-1Fc融合体(BPS Bioscience,USA,目录号71109)。用蛋白L-HRP(Sigma-Aldrich,USA,目录号P3226)检测结合的scFv,用山羊抗小鼠IgG-HRP(Southern Biotech,USA,目录号1033-01)检测结合的小鼠抗人PD-L1抗体,并用链霉亲和素-HRP(BD Pharmingen,USA,目录号554060)检测结合的生物素化的rhPD-1Fc融合体。用TMB ELISA底物溶液(eBioscience,USA,目录号00-4201-56)进行开发。结果表明scFv1和scFv3与人和猴PD-L1特异性结合,但不与大鼠PD-L1特异性结合(图6)。
通过ELISA确定scFv1与与PD-L1具有序列相似性的重组人蛋白的交叉反应性。将rhPD-L1Fc融合体(RnD Systems,USA,目录号156-B7)、rhPD-L2Fc融合体(RnD Systems,USA,目录号1224-PL)或rhB7-H3Fc融合体(RnD Systems,USA,目录号1027-B3)在4℃下于Maxisorp 96孔微孔板上在PBS(pH 7.2)中以1mcg/mL的浓度包被过夜。用1%BSA和0.5%吐温-20的PBS溶液(pH 7.2)封闭板。制备浓度为5mcg/mL、1mcg/mL和0.2mcg/mL的scFv的系列稀释并加入板中。作为阴性对照,使用非结合scFv2,并且作为阳性对照,包含5mcg/mL、1mcg/mL和0.2mcg/mL小鼠抗人B7-H3抗体(RnD Systems,USA,目录号MAB1027)或30ng/mL和15ng/mL生物素化的rhPD-1Fc融合体(BPS Bioscience,USA,目录号71109)。用蛋白L-HRP(Sigma-Aldrich,USA,目录号P3226)检测结合的scFv,用山羊抗小鼠IgG-HRP(SouthernBiotech,USA,目录号1033-01)检测结合的小鼠抗人B7-H3抗体,并用链霉亲和素-HRP(BDPharmingen,USA,目录号554060)检测结合的生物素化的rhPD-1Fc融合体。用TMBELISA底物溶液(eBioscience,USA,目录号00-4201-56)进行开发。结果表明scFv1与人PD-L1特异性结合,与人PD-L2或B7-H3无交叉反应性。
使用进一步研究scFv1与猴PD-L1的交叉反应性。所述方法如实例4中所述,只是PMMA珠粒用20mcg/ml的猴PD-L1Fc融合体(SinoBiological,China,目录号90251-C02H)包被,并且使用一组两条曲线确定亲和力,其中针对恒定量的scFv滴定2倍稀释系列的猴PD-L1Fc融合体。在第一曲线中,将50pM scFv1用12种不同的PD-L1Fc融合体浓度培养(重复测量),以2.5nM PD-L1Fc融合体开始。将这些混合物培养6小时。在第二曲线中,将10pM scFv1用12种不同的PD-L1Fc融合体浓度培养,以1nMPD-L1Fc融合体开始。将这些混合物培养16小时以检测这些混合物中存在的未结合的scFv的量,将样本以0.25ml/分钟的流速暴露于含有固定化PD-L1Fc融合体的固相。所有步骤均在室温下进行。针对scFv1利用 Pro软件版本4.2.10的“n条曲线分析”使用选项“滴定剂作为分析浓度参考”计算的KD值为3.3pM(图7)。结果证明scFv1与猴PD-L1结合的亲和力比与人PD-L1结合的亲和力大约2.7倍。
实例6-与天然形式的PD-L1的结合
通过细胞外FACS分析确定scFv1和非结合对照scFv、scFv2与肿瘤细胞表面上表达的天然形式的PD-L1结合的能力。将ES-2细胞(ATCC,USA,目录号CRL-1978)在冰上用5mcg/mL或1mcg/mL的scFv或抗人PD-L1小鼠IgG2(BioLegend,USA,目录号329716)染色30分钟。通过用生物素化的蛋白L(Pierce,目录号PI-29997)染色并随后染色链霉亲和素-藻红蛋白(BD Pharmingen,USA,目录号554061)检测结合的scFv。洗涤后,使用碘化丙啶排除死细胞,并在FACSAria III(BD Biosciences)上分析细胞。平均和中值荧光强度显示在表3中。结果证明scFv1能够特异性识别在ES-2细胞表面上表达的天然形式的PD-L1。
表3
样本 | 平均荧光强度 | 中值荧光强度 |
未染色的ES-2细胞 | 62 | 50 |
阳性对照IgG | 1172 | 948 |
scFv1,5mcg/mL | 2739 | 2478 |
scFv1,1mcg/mL | 2605 | 2338 |
scFv2,5mcg/mL | 93 | 78 |
使用进一步研究scFv1与细胞表面PD-L1的结合。所述方法如实例4中所述,只是使用12次ES-2细胞的2倍系列稀释确定亲和力(以2640万/mL开始),其针对恒定量的scFv1(50pM)一式两份滴定。将这些混合物培养5小时,以3800×g离心10分钟,并将上清液转移到新管中。为了检测scFv的量,将样本以0.25ml/分钟的流速暴露于含有固定化PD-L1Fc融合体的固相。所有步骤均在室温下进行。使用 Pro软件进行分析的结果是scFv1与细胞表面PD-L1结合的计算KD值为12.8pM(图8)。
结果证明scFv1结合在肿瘤细胞表面上表达的天然形式的PD-L1。
实例7-ScFv分泌
为了比较大肠杆菌细胞在包涵体中产生的scFv1的性质和从哺乳动物细胞分泌的scFv1的性质,在Evitria(苏黎世,瑞士)的悬浮适应的CHO K1细胞(最初从ATCC接收并适应于悬浮培养中的无血清生长)中产生scFv1。种子在化学成分确定的无动物成分的无血清培养基中生长。用定制的专有转染试剂转染细胞,并在无动物成分的无血清培养基中转染后使细胞生长。通过蛋白L亲和色谱随后通过尺寸排阻色谱纯化ScFv1。
在PD-1/PD-L1阻断测定中比较CHO细胞和大肠杆菌细胞表达的scFv1的PD-L1中和能力。在该测定中,通过T细胞的活性促进荧光素酶活性。PD-L1与PD-1的相互作用产生抑制信号并降低荧光素酶活性,这通过用PD-L1抑制剂处理细胞来克服。将表达PD-L1的CHO细胞(Promega,CS187103)接种到96孔微孔板中。加入递增浓度的scFv,并将板在37℃,5%CO2下培养20分钟。加入表达PD-1的效应子Jurkat细胞(Promega,CS187105),并将板在37℃,5%CO2下再培养6小时。使用Bio-Glo荧光素酶测定系统(Promega,G7941)通过发光检测测量TCR/CD3激活。绘制抑制曲线,并使用GraphPad 软件,版本7.02计算IC50值。CHO细胞表达的scFv1、大肠杆菌细胞表达的scFv1和scFv2的结果显示在图9中。CHO细胞表达的scFv1有效阻断PD-L1介导的抑制信号,IC50为602pM。大肠杆菌细胞表达的scFv1有效阻断免疫检查点抑制信号,IC50为874pM。非结合scFv2对免疫检查点抑制信号没有显示出任何影响。
实例8-体内活性
在5-6周龄雌性NOG小鼠(Vital River Laboratory Animal Technology Co.,Beijing,China)中使用HCC827人肺癌模型检查scFv1的体内功效。使用标准程序通过密度梯度离心从四个健康人供体的血液中分离外周血单核细胞(PBMC)。离心后,用PBS溶液洗涤细胞并重悬于PBS中。在HCC827肿瘤细胞接种3天前,通过i.p.注射0.1ml PBS(5×106个细胞)将来自每个供体的PBMC转移到小鼠。然后每只小鼠在右侧腹区皮下接种0.1ml PBS(5×106个HCC827肿瘤细胞)。肿瘤细胞接种日期表示为第0天。小鼠在第1天被随机分组并治疗每天两次,腹膜内(i.p.)注射15mg/kg scFv1或非结合scFv2,或每周两次,静脉内注射(i.v.)注射5mg/kg阳性对照IgG抗体(MPDL3280A的类似物)。肿瘤体积每周测量至少两次,并以mm3为单位表示,使用公式V=0.5a×b2,其中a和b分别是肿瘤的长度和宽度。肿瘤生长抑制(TGI)是抗肿瘤有效性的指示,并表示为TGI(%)=100×(1-(治疗组的平均肿瘤体积)/(scFv2组的平均肿瘤体积))。在第14天,选择具有显示最大肿瘤生长抑制的两个供体的PBMC的动物用于继续研究。在第21天,处死所有动物。每组供体的组大小为每组n=3,对于两组选择的供体,总组大小为n=6。治疗/对照比(T/C)被计算为scFv1或阳性对照IgG治疗组的中值肿瘤体积与非结合scFv2对照组的比率,使用公式T/C(%)=(治疗组的中值肿瘤体积/对照组的中值肿瘤体积)×100。
两组选择的供体(n=6)的T/C和TGI显示在图10中。在第21天评估scFv1和阳性对照IgG抗体的功效(表4)。六只scFv1治疗的小鼠中有三只没有肿瘤,scFv1治疗的动物的TGI是47%。T/C比为28%。根据国家癌症研究所标准的T/C%比的有效标准≤42%。总之,该数据证明了scFv1的体内功效。
表4
实例9–IgG格式的表征
将ScFv1重新格式化为IgG格式(IgG_1),具有重链SEQ ID NO:20和轻链SEQ IDNO:24。还制备了对应于以下公开序列的抗体:YW243.55.S70,如US2010/0203056中所述(IgG_2,具有重链SEQ ID NO:21和轻链SEQ ID NO:25);2.14H9OPT,如WO2011/066389/A1中所述(IgG_3,具有重链SEQ ID NO:22和轻链SEQ ID NO:26);和H2M8314N,如WO2015/112805A1中所述(IgG_4,具有重链SEQ ID NO:23和轻链SEQ ID NO:27)。由Evitria(苏黎世,瑞士)进行合成。最初从ATCC接收并适应于悬浮培养中无血清生长的悬浮适应的CHO K1细胞用于生产。通过蛋白A色谱随后通过尺寸排阻色谱纯化IgG抗体。
首先通过检查抗体抑制人PD-L1与人PD-1相互作用的能力来表征IgG抗体。将rhPD-L1Fc融合体(RnD Systems,USA,目录号156-B7)在4℃下于Maxisorp 96孔微孔板上在PBS中以2mcg/mL的浓度包被过夜。用1%BSA和0.05%吐温-20的PBS溶液(pH 7.4)封闭板。制备IgG的系列稀释,其中11次1:3稀释以1mcg/mL开始,并加入板中。在室温下30分钟后,除去一半的IgG稀释并用生物素化的PD-1Fc融合体(BPS Bioscience,USA,目录号71109)替换,最终终浓度为15ng/mL。用链霉亲和素-HRP(BD Pharmingen,USA,目录号554060)检测结合的PD-1Fc融合体。用TMB ELISA底物溶液(eBioscience,USA,目录号00-4201-56)开发ELISA。包含非结合scFv2作为对照。在该测定中,PD-L1与PD-1相互作用的能力产生吸光度信号,其被IgG1到4有效中和但不被非结合scFv2中和,如图11中所示。测试的抗体的抑制分布分为两组,其中较强潜能的IgG_1和IgG_2的IC50值分别为327pM和267pM。较弱潜能的IgG_3和IgG_4的IC50值分别为560pM和606pM。具有较强潜能的IgG被用于表征结合亲和力。
使用研究IgG_1和IgG_2与人PD-L1的结合。虽然公开的数据可用于IgG_2与人PD-L1的结合,但该数据通常基于涉及将一个相互作用配偶体固定在固体表面上的技术。这些方法可能无法反映溶液中的相互作用条件,并且在检查非常紧密的相互作用时也存在灵敏度问题。因此,选择基于溶液的方法来比较抗体的结合。选择不含Fc标签的PD-L1-His作为相互作用配偶体以避免测量亲合力。所述方法如实例4中所述,只是使用一组两条曲线确定亲和力,其中针对恒定量的scFv滴定2倍稀释系列的人PD-L1-His(BioVision,USA,目录号7429)。对于两种IgG,在第一曲线中,将100pM IgG用12种不同的PD-L1Fc融合体浓度培养(重复测量),以5nMPD-L1-His开始。将这些混合物培养5小时。将500微升每种样本注射到人PD-L1Fc融合体包被的珠粒上。对于IgG_1,在第二曲线中,将10pM IgG用12种不同的PD-L1-His浓度培养,以5nM PD-L1His开始。将这些混合物培养10小时。将5ml每种样本注射到PD-L1Fc融合体包被的PMMA珠粒上。对于IgG_2,在第二曲线中,将20pM IgG用12种不同的PD-L1-His浓度培养,以1.25nM PD-L1His开始。将这些混合物培养10小时。将5ml每种样本注射到PD-L1Fc融合体包被的PMMA珠粒上。针对IgG计算的KD值在表5中报告,并且n条曲线分析显示在图12中。
结果证明IgG_1(即,转化为IgG格式的scFv1)以比scFv1对PD-L1的亲和力大约三倍的亲和力结合PD-L1。与IgG_1相比,IgG_2对PD-L1的亲和力较弱。
表5
抗体 | K<sub>D</sub>(pM) |
IgG_1 | 2.77 |
IgG_2 | 10.06 |
尽管示出并描述了本发明的当前优选实施例,但是应该理解,本发明不限于此,而是可以在以下权利要求的范围内以其它方式不同地实施和实践。由于本发明的许多修改和替代实施例对于本领域技术人员而言将是显而易见的,因此该描述仅被解释为说明性的并且是为了教导本领域技术人员实现本发明的最佳模式的目的。因此,可以认为所有合适的修改和等同都落入以下权利要求的范围内。
序列表
<110> 细胞医学瑞士公司
<120> PD-L1的结合成员
<130> P1602WOF
<150> EP16020057.2
<151> 2016-02-25
<160> 27
<170> PatentIn版本3.5
<210> 1
<211> 114
<212> PRT
<213> 人工序列
<220>
<223> scFv1的VL
<400> 1
Glu Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ile Ile Thr Cys Gln Ala Ser Glu Asp Ile Tyr Ser Leu
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asp Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Ala Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gly Asn Tyr Gly Ser Ser Ser
85 90 95
Ser Ser Ser Tyr Gly Ala Val Phe Gly Gln Gly Thr Lys Leu Thr Val
100 105 110
Leu Gly
<210> 2
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> scFv1的VH
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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 Thr Val Ser Gly Ile Asp Leu Ser Ser Tyr
20 25 30
Thr Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Ile Ile Ser Ser Gly Gly Arg Thr Tyr Tyr Ala Ser Trp Ala Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Gly Arg Tyr Thr Gly Tyr Pro Tyr Tyr Phe Ala Leu Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 3
<211> 11
<212> PRT
<213> 穴兔
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Gln Ala Ser Glu Asp Ile Tyr Ser Leu Leu Ala
1 5 10
<210> 4
<211> 7
<212> PRT
<213> 穴兔
<400> 4
Asp Ala Ser Asp Leu Ala Ser
1 5
<210> 5
<211> 15
<212> PRT
<213> 穴兔
<400> 5
Gln Gly Asn Tyr Gly Ser Ser Ser Ser Ser Ser Tyr Gly Ala Val
1 5 10 15
<210> 6
<211> 9
<212> PRT
<213> 穴兔
<400> 6
Ile Asp Leu Ser Ser Tyr Thr Met Gly
1 5
<210> 7
<211> 16
<212> PRT
<213> 穴兔
<400> 7
Ile Ile Ser Ser Gly Gly Arg Thr Tyr Tyr Ala Ser Trp Ala Lys Gly
1 5 10 15
<210> 8
<211> 12
<212> PRT
<213> 穴兔
<400> 8
Gly Arg Tyr Thr Gly Tyr Pro Tyr Tyr Phe Ala Leu
1 5 10
<210> 9
<211> 254
<212> PRT
<213> 人工序列
<220>
<223> scFv1
<400> 9
Glu Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ile Ile Thr Cys Gln Ala Ser Glu Asp Ile Tyr Ser Leu
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asp Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Ala Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gly Asn Tyr Gly Ser Ser Ser
85 90 95
Ser Ser Ser Tyr Gly Ala Val Phe Gly Gln Gly Thr Lys Leu Thr Val
100 105 110
Leu Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly
130 135 140
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Thr Val Ser Gly
145 150 155 160
Ile Asp Leu Ser Ser Tyr Thr Met Gly Trp Val Arg Gln Ala Pro Gly
165 170 175
Lys Gly Leu Glu Trp Val Gly Ile Ile Ser Ser Gly Gly Arg Thr Tyr
180 185 190
Tyr Ala Ser Trp Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Thr Ser
195 200 205
Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr
210 215 220
Ala Val Tyr Tyr Cys Ala Arg Gly Arg Tyr Thr Gly Tyr Pro Tyr Tyr
225 230 235 240
Phe Ala Leu Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
245 250
<210> 10
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 接头
<400> 10
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser
20
<210> 11
<211> 255
<212> PRT
<213> 人工序列
<220>
<223> 甲基化scFv1
<400> 11
Met Glu Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val
1 5 10 15
Gly Asp Arg Val Ile Ile Thr Cys Gln Ala Ser Glu Asp Ile Tyr Ser
20 25 30
Leu Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Asp Ala Ser Asp Leu Ala Ser Gly Val Pro Ser Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Ala Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln
65 70 75 80
Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gly Asn Tyr Gly Ser Ser
85 90 95
Ser Ser Ser Ser Tyr Gly Ala Val Phe Gly Gln Gly Thr Lys Leu Thr
100 105 110
Val Leu Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
130 135 140
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Thr Val Ser
145 150 155 160
Gly Ile Asp Leu Ser Ser Tyr Thr Met Gly Trp Val Arg Gln Ala Pro
165 170 175
Gly Lys Gly Leu Glu Trp Val Gly Ile Ile Ser Ser Gly Gly Arg Thr
180 185 190
Tyr Tyr Ala Ser Trp Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Thr
195 200 205
Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
210 215 220
Thr Ala Val Tyr Tyr Cys Ala Arg Gly Arg Tyr Thr Gly Tyr Pro Tyr
225 230 235 240
Tyr Phe Ala Leu Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
245 250 255
<210> 12
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> VL FR1
<400> 12
Glu Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ile Ile Thr Cys
20
<210> 13
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> VL FR2
<400> 13
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr
1 5 10 15
<210> 14
<211> 32
<212> PRT
<213> 人工序列
<220>
<223> VL FR3
<400> 14
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Ala Glu Phe Thr
1 5 10 15
Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys
20 25 30
<210> 15
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> VL FR4
<400> 15
Phe Gly Gln Gly Thr Lys Leu Thr Val Leu Gly
1 5 10
<210> 16
<211> 26
<212> PRT
<213> 人工序列
<220>
<223> VH FR1
<400> 16
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 Thr Val Ser Gly
20 25
<210> 17
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> VH FR2
<400> 17
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Gly
1 5 10
<210> 18
<211> 32
<212> PRT
<213> 人工序列
<220>
<223> VH FR3
<400> 18
Arg Phe Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Val Tyr Leu Gln
1 5 10 15
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
20 25 30
<210> 19
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> VH FR4
<400> 19
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 20
<211> 450
<212> PRT
<213> 智人
<400> 20
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 Thr Val Ser Gly Ile Asp Leu Ser Ser Tyr
20 25 30
Thr Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Ile Ile Ser Ser Gly Gly Arg Thr Tyr Tyr Ala Ser Trp Ala Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Gly Arg Tyr Thr Gly Tyr Pro Tyr Tyr Phe Ala Leu Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 21
<211> 448
<212> PRT
<213> 智人
<400> 21
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 Thr Phe Ser Asp Ser
20 25 30
Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Trp Ile Ser Pro Tyr Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala 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 His Trp Pro Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 22
<211> 451
<212> PRT
<213> 智人
<400> 22
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 Thr Phe Ser Arg Tyr
20 25 30
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser 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 Glu Gly Gly Trp Phe Gly Glu Leu Ala Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 23
<211> 450
<212> PRT
<213> 小家鼠
<400> 23
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Arg Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Gly Met Thr Trp Val Arg Gln Ala Pro Gly Arg Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile His Trp His Gly Lys Arg Thr Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Lys Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Gly Glu Asp Thr Ala Leu Tyr His Cys
85 90 95
Val Arg Gly Gly Met Ser Thr Gly Asp Trp Phe Asp Pro Trp Gly Gln
100 105 110
Gly Thr Leu Val Ile Val Ser Ser Ala Lys Thr Thr Ala Pro Ser Val
115 120 125
Tyr Pro Leu Ala Pro Val Cys Gly Asp Thr Thr Gly Ser Ser Val Thr
130 135 140
Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu Thr
145 150 155 160
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Claims (41)
1.一种对PD-L1具有结合特异性的结合成员,所述结合成员包括(i)SEQ ID NO:6、7和8中所阐述的可变重链CDR-H1、CDR-H2和CDR-H3序列;和(ii)SEQ ID NO:3、4和5中所阐述的可变轻链CDR-L1、CDR-L2和CDR-L3序列。
2.根据权利要求1所述的结合成员,其是人源化的。
3.一种对PD-L1具有结合特异性的结合成员,所述结合成员包括(i)SEQ ID NO:6、7和8中所阐述的可变重链CDR-H1、CDR-H2和CDR-H3序列;和(ii)SEQ ID NO:3、4和5中所阐述的可变轻链CDR-L1、CDR-L2和CDR-L3序列,其中
所述可变轻链与SEQ ID NO:1具有至少90%的序列一致性;并且
所述可变重链与SEQ ID NO:2具有至少90%的序列一致性。
4.根据权利要求3所述的结合成员,其进一步包括接头序列,其中所述接头序列是SEQID NO:10中所阐述的序列。
5.根据权利要求4所述的结合成员,其包括SEQ ID NO:9或SEQ ID NO:11。
6.根据权利要求3所述的结合成员,包括
(i)抗体片段,选自Fab、Fab'、F(ab)'2、scFv、Fv片段、scFab、纳米抗体、VHH、和最小识别单位;或
(ii)全长抗体分子。
7.根据权利要求3所述的结合成员,包括非抗体支架,选自亲和体、affilin分子、AdNectin、脂质运载蛋白突变蛋白、DARPin、打结素(Knottin)、Kunitz型结构域、高亲和性多聚体(Avimer)、四连接素(Tetranectin)或反式体。
8.根据权利要求3所述的结合成员,其为多价的。
9.根据权利要求8所述的结合成员,其中所述结合成员是多特异性的、双特异性的、双抗体、单链双抗体、DART、BiTE或串联scFv。
10.根据权利要求3所述的结合成员,其包括Fc结构域。
11.根据权利要求10所述的结合成员,其中所述结合成员包括选自由人IgG1、IgG2、IgG3和IgG4同种型组成的群组的恒定区。
12.根据权利要求10所述的结合成员,其中所述结合成员包括选自由鼠IgG1、IgG2A、IgG2B、和IgG3同种型组成的群组的恒定区。
13.根据权利要求10所述的结合成员,其中所述Fc结构域被修饰成使得所述Fc结构域不诱导细胞毒性免疫应答。
14.根据权利要求3所述的结合成员,其是经化学修饰或生物修饰的。
15.根据权利要求14所述的结合成员,其被糖基化,用第二部分标记,或与第二部分结合。
16.根据权利要求15所述的结合成员,其中所述结合成员被PEG化或HES化。
17.一种分离的核酸分子,其包括对根据权利要求1到16中任一项所述的结合成员进行编码的序列。
18.一种载体,其包括根据权利要求17所述的核酸分子的所述序列。
19.根据权利要求18所述的载体,其是表达载体或克隆载体。
20.一种宿主细胞,其包括根据权利要求17所述的核酸分子或根据权利要求18或19所述的载体。
21.一种组合物,其包括根据权利要求1到16中任一项所述的结合成员、根据权利要求17所述的核酸分子、根据权利要求18或19所述的载体或根据权利要求20所述的宿主细胞;并且进一步包括合适的载剂、稀释剂或赋形剂。
22.根据权利要求21所述的组合物,其是化妆用组合物、诊断组合物或医药组合物。
23.根据权利要求22所述的组合物,其是医药组合物,并且所述载剂是医药学上可接受的载剂、稀释剂或赋形剂。
24.根据权利要求22或23所述的组合物,其采用适于肠胃外给药、口服给药、直肠给药、全身给药、静脉内给药、皮下给药、泌尿生殖器给药、局部给药、玻璃体内给药、眼内给药、耳部给药、鼻内给药、透皮给药、皮内给药、皮肤给药、舌下给药、颅内给药、肌肉内给药、腹膜内给药或口腔给药的形式。
25.根据权利要求1到16中任一项所述的结合成员、根据权利要求17所述的核酸分子、根据权利要求18或19所述的载体或根据权利要求20所述的宿主细胞在制备用于治疗、预防PD-L1介导的疾病或延缓其进展的药物中的应用。
26.根据权利要求25所述的应用,其中所述PD-L1介导的疾病是癌症;或者其中所述疾病是全身性红斑狼疮,或其中所述疾病是全身性红斑狼疮、败血症、中风、病原体感染或自身免疫障碍。
27.根据权利要求26所述的应用,其中所述癌症选自由以下组成的群组:NSCLC(非小细胞肺癌)、尿路上皮癌、黑素瘤、肾细胞癌、霍奇金淋巴瘤、头颈部鳞状细胞癌、卵巢癌、胃肠癌、肝细胞癌、胶质瘤、乳腺癌、淋巴瘤、小细胞肺癌、骨髓增生异常综合征、前列腺癌、膀胱癌、宫颈癌、非透明细胞肾癌、结肠直肠癌、肉瘤、结肠癌、肾癌、肺癌、胰腺癌或胃癌、皮肤癌、子宫癌、成胶质细胞瘤、白血病、癌症、梅克尔细胞癌或肾细胞癌(RCC)、血癌、多发性骨髓瘤、淋巴细胞白血病(ALL)、B细胞白血病、慢性淋巴细胞白血病、非霍奇金淋巴瘤和卵巢癌。
28.根据权利要求25到27中任一项所述的应用,其中所述结合成员与一种或多种疗法组合给予,所述一种或多种疗法选自由以下组成的群组:抗体疗法、化学疗法、细胞因子疗法、树突状细胞疗法、基因疗法、激素疗法、激光疗法、放射疗法和疫苗疗法。
29.根据权利要求1到16中任一项所述的结合成员、根据权利要求17所述的核酸分子、根据权利要求18或19所述的载体或根据权利要求20所述的宿主细胞在制备用于诊断或检测PD-L1介导的疾病的试剂中的应用。
30.一种抑制肿瘤或肿瘤细胞生长的体外方法,其包括使所述肿瘤或肿瘤细胞与治疗有效量的根据权利要求1到16中任一项所述的结合成员接触的步骤。
31.一种生产根据权利要求1到16中任一项所述的结合成员的方法,所述方法包括:
(i)培养根据权利要求20所述的宿主细胞;
(ii)允许所述结合成员得以表达;和
(iii)回收所述结合成员。
32.一种生产根据权利要求1到16中任一项所述的结合成员的方法,所述方法包括:
(a)使无细胞表达系统与核酸产物模板接触,所述核酸产物模板对根据权利要求1到16中任一项所述的结合成员进行编码;
(b)允许所述核酸产物模板的转录和翻译得以发生,从而允许反应混合物得以形成;以及
(c)从所述反应混合物中回收所述结合成员。
33.根据权利要求31或32所述的生产所述结合成员的方法,其中生产所述结合成员包括化学合成步骤。
34.一种检测生物样本中PD-L1的存在的用于非诊断目的的体外方法,所述方法包括:
(a)在允许根据权利要求1到16中任一项所述的结合成员与PD-L1特异性结合的条件下,使所述生物样本与所述结合成员接触,和
(b)检测所述结合成员与PD-L1之间是否形成复合物。
35.根据权利要求34所述的方法,其中所述生物样本是人来源的。
36.根据权利要求35所述的方法,其中所述生物样本是血液样本、尿液样本、脑脊髓液样本、活体组织切片样本、或淋巴样本中的至少一种。
37.一种抑制PD-L1与PD-1亚单位的受体复合物之间的相互作用的体外方法,其包括以下步骤:
(a)提供PD-L1以及所述受体复合物;和
(b)使PD-L1与根据权利要求1到16中任一项所述的结合成员接触。
38.一种抑制PD-L1生物活性的体外方法,其包括以下步骤:
(a)提供PD-L1;和
(b)使PD-L1与根据权利要求1到16中任一项所述的结合成员接触。
39.一种试剂盒,其包括根据权利要求1到16中任一项所述的结合成员以及试剂与说明书的包装组合。
40.根据权利要求31所述的方法,进一步包括纯化所述结合成员。
41.根据权利要求32所述的方法,进一步包括纯化所述结合成员。
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