CN108101991A - 结合淋巴细胞活化基因-3(lag-3)的抗体的优化及该抗体的用途 - Google Patents
结合淋巴细胞活化基因-3(lag-3)的抗体的优化及该抗体的用途 Download PDFInfo
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Abstract
本申请提供结合淋巴细胞活化基因‑3(LAG‑3)的抗体的优化及该抗体的用途,具体提供分离的单克隆抗体,其特异性结合LAG‑3且与先前描述的抗LAG‑3抗体(例如抗体25F7(US 2011/0150892 A1))相比具有优化的功能特性。
Description
本申请是2013年7月2日提交的申请号为201380035443.8(PCT申请号为PCT/US2013/048999)、发明名称为“结合淋巴细胞活化基因-3(LAG-3)的抗体的优化及该抗体的用途”的发明专利申请的分案申请。
发明背景
治疗性抗体是医药产业中最快发展的部分之一。为维持效力(即活性)并使免疫原性最小化,在制造及储存期间必须防止抗体及其他蛋白质药物发生物理和化学降解。实际上,在研发抗体治疗物中的一个主要困难是在对受试者施用时的潜在免疫原性反应,其可导致快速清除或甚至诱导危及生命的副作用(包括过敏性休克)。许多因素影响抗体的免疫原性,例如其生理化学特性(例如纯度、稳定性或溶解性)、临床因素(例如剂量、施用路径、疾病异质性或患者特征)、及其他药剂的伴随治疗(Swann等人(2008)Curr Opinion Immuol20:493-499)。
抗体的免疫原性和/或抗体活性的损失通常是由去酰胺化所致。去酰胺化是自发性发生于蛋白质(例如抗体)中的化学降解过程。去酰胺化自氨基酸残基(例如天冬酰胺及谷氨酰胺)去除酰胺官能团,由此破坏其含酰胺的侧链。这继而在整个蛋白质中引起结构及生物学变化,由此创建出抗体的异质性形式。去酰胺化是在重组产生的治疗性抗体中发生的最常见的翻译后修饰之一。
举例而言,Tsai等人(Pharm Res 10(11):1580(1993))报导了单克隆抗体h1B4(人源化抗CD18抗体)的重链中因细胞培养期间的去酰胺化而产生异质性。此外,由去酰胺化所致的生物活性的减小/损失已成为公认问题。例如,Kroon等人表征了治疗性抗体OKT3中的几个去酰胺化位点,并报导OKT3生产批次的样品(出厂14个月至3年)已降至低于75%活性(Pharm Res 9(11):1386(1992),第1389页,第二栏)。此外,在图谱中展示大量氧化肽的OKT3样品在抗原结合效力测定中具有显著降低的活性(第1390页,第一栏)。作者总结得出,在储存OKT3时发生的化学修饰的特定位点可通过肽图谱法进行鉴别且与抗体的化学分析及生物测定中所观察到的变化相关(第1392页,第一栏)。对于多种其他去酰胺化的治疗性蛋白亦已报导生物活性损失,包括重组人DNase(Cacia等人(1993)J.Chromatogr.634:229-239)和重组可溶性CD4(Teshima等人(1991)Biochemistry 30:3916-3922)。
总之,去酰胺化在医药产业中引起重要且不可预测的问题。具体地,与监测由抗体治疗物内的去酰胺化引起的变化性有关的工作以及与此变化性有关的FDA关注增加成本且延迟临床试验。另外,用于解决此问题的改良,包括改变与易受去酰胺化影响的氨基酸的重组产生和/或改变(例如定点诱变)有关的条件(例如温度、pH和细胞类型),可负面影响稳定性及活性,尤其当在抗体的互补决定区(CDR)内作出改变时。因此,需要治疗性抗体的更稳定形式。
发明概述
本发明提供分离的单克隆抗体(例如人单克隆抗体),其结合LAG-3(例如人LAG-3)且与先前所描述的抗LAG-3抗体相比具有优化的物理稳定性。具体地,本发明涉及抗体25F7(US 2011/0150892 A1)的经修饰形式,其与未修饰抗体相比展现显著改良的热稳定性及化学稳定性。特定地,通过改变抗体25F7的重链CDR2域的关键结合区,展示经修饰的抗体展现出显著较高的物理和热稳定性、降低的去酰胺化、更高的热可逆性和更低的聚集。同时,出人意料地观察到,经修饰的抗体保留与未修饰抗体同样高的对人LAG-3的结合亲和力和功能活性,包括抑制LAG-3对主要组织相容性(MHC)II类分子的结合并刺激抗原特异性T细胞反应的能力。经修饰抗体在稳定性和结合/生物活性保留上的组合的实质性提高是令人惊讶的,尤其是考虑到CDR区对于抗体功能的关键性。
本发明的抗体可用于各种应用,包括检测LAG-3蛋白和刺激带肿瘤或携带病毒的受试者中的抗原特异性T细胞反应。
因此,在一个方面,本发明涉及一种分离的单克隆抗体(例如人抗体)或其抗原结合部分,其具有包含SEQ ID NO:12的氨基酸序列的重链可变区。在另一个实施方案中,所述抗体进一步包含轻链可变区,其包含SEQ ID NO:14的氨基酸序列。在另一个实施方案中,抗体或其抗原结合部分包含含有SEQ ID NO:12的氨基酸序列的重链可变区的CDR1、CDR2及CDR3区(例如分别为SEQ ID NO:15、16及17)。在另一个实施方案中,所述抗体进一步包含含有SEQ ID NO:12的氨基酸序列的轻链可变区的CDR1、CDR2及CDR3区(例如分别为SEQ IDNO:18、19及20)。
在一个优选的实施方案中,与抗体25F7相比,所述抗体展现增加的物理特性(即热稳定性及化学稳定性),同时仍保留至少与25F7相同的对人LAG-3的结合亲和力。举例而言,与抗体25F7相比,所述抗体在重链CDR2区中展现降低的由去酰胺化所致的序列可变性,例如在4℃12周后(即在如本文描述的“实时”稳定性研究下)氨基酸序列中约2.5%或更少的修饰和/或在40℃12周后(即在如本文描述的加速应激条件下)氨基酸序列中约12.0%或更少的修饰,同时仍保留约至少1x 10-7M或更小的KD(更优选地,1x 10-8M或更小的KD、5x 10-9M或更小的KD或1x 10-9M或更小的KD)的对人LAG-3的结合亲和力。在另一个实施方案中,所述抗体在pH8.0于PBS中展现至少约40%的热可逆性。
在另一个实施方案中,与未修饰抗体相比,所述抗体拥有较高熔解温度(指示体内更高的总体稳定性)(Krishnamurthy R及Manning MC(2002)Curr Pharm Biotechnol 3:361-71)。在一个实施方案中,所述抗体展现大于60℃(例如大于65℃或大于70℃)的TM1(初始解折叠温度)。可使用差示扫描量热法(Chen等人(2003)Pharm Res 20:1952-60;Ghirlando等人(1999)Immunol Lett 68:47-52)或圆二色性(Murray等人,(2002)J.Chromatogr Sci 40:343-9)来测量抗体的熔点。
在另一个实施方案中,抗体的特征在于其对快速降解的抗性。可使用毛细管电泳(CE)及MALDI-MS测量抗体降解(Alexander AJ和Hughes DE(1995)Anal Chem 67:3626-32)。
在另一个实施方案中,所述抗体展现最小聚集效应,例如25%或更小(例如20%或更小、15%或更小、10%或更小、5%或更小、或4%或更小)的聚集。聚集可导致触发不期望的免疫反应和/或改变或不利的药物动力学特性,可通过几种技术(包括大小排阻柱(SEC)、高效液相层析(HPLC)及光散射)来测量聚集。
在另一个实施方案中,所述抗体还展现至少一种以下特性:
(a)结合猴LAG-3;
(b)缺少对小鼠LAG-3的结合;
(c)抑制LAG-3对主要组织相容性(MHC)II类分子的结合;和
(d)刺激免疫反应,特定而言抗原特异性T细胞反应。
优选地,所述抗体展现特性(a)、(b)、(c)及(d)中的至少两种。更优选地,所述抗体展现特性(a)、(b)、(c)及(d)中的至少三种。甚至更优选地,所述抗体展现特性(a)、(b)、(c)及(d)中的所有四种特性。
在另一个实施方案中,所述抗体刺激抗原特异性T细胞反应,例如抗原特异性T细胞反应中的白介素-2(IL-2)产生。在其他实施方案中,抗体刺激免疫反应,例如抗肿瘤反应(例如抑制体内肿瘤移植物模型中的肿瘤生长)或自体免疫反应(例如在NOD小鼠中发生糖尿病)。
在另一个实施方案中,所述抗体结合包括氨基酸序列PGHPLAPG(SEQ ID NO:21)的人LAG-3的表位。在另一个实施方案中,所述抗体结合包括氨基酸序列HPAAPSSW(SEQ IDNO:22)或PAAPSSWG(SEQ ID NO:23)的人LAG-3的表位。
在其他实施方案中,所述抗体通过免疫组织化学将垂体组织染色,或通过免疫组织化学不会将垂体组织染色。
本发明的抗体可为全长抗体(例如IgG1、IgG2或IgG4同种型的全长抗体),任选地在重链恒定区铰链区中具有丝氨酸至脯氨酸突变(在对应于位置241的位置处,如在Angal等人(1993)Mol.Immunol.30:105-108中描述的),从而减小或消除重链间二硫键的异质性。在一个方面,恒定区同种型是在氨基酸残基228处具有突变(例如S228P)的IgG4。或者,所述抗体可为抗体片段(例如Fab、Fab’或Fab’2片段)或单链抗体。
在本发明的另一方面,抗体(或其抗原结合部分)是免疫缀合物的一部分,所述免疫缀合物包含连接于该抗体的治疗剂(例如细胞毒素或放射性同位素)。在另一方面,抗体是双特异性分子的一部分,所述双特异性分子包含具有不同于该抗体或其抗原结合部分的结合特异性的第二功能模块(例如第二抗体)。
亦提供组合物,其包含本发明的抗体或其抗原结合部分、免疫缀合物或双特异性分子,任选地在药学可接受的载体中配制。
亦提供编码本发明的抗体或其抗原结合部分(例如可变区和/或CDR)的核酸分子、以及包含这类核酸的表达载体及包含这类表达载体的宿主细胞。亦提供使用包含这类表达载体的宿主细胞制备抗LAG-3抗体的方法,且可包含以下步骤:(i)在宿主细胞中表达该抗体及(ii)自宿主细胞分离抗体。
在另一方面,本发明提供使用本发明的抗LAG-3抗体刺激免疫反应的方法。在一个实施方案中,该方法涉及通过使T细胞与本发明抗体接触来刺激抗原特异性T细胞反应,从而刺激抗原特异性T细胞反应。在一个优选的实施方案中,刺激通过抗原特异性T细胞的白介素-2产生。在另一个实施方案中,受试者是具肿瘤的受试者且刺激对肿瘤的免疫反应。在另一个实施方案中,受试者是携带病毒的受试者且刺激针对病毒的免疫反应。
在又一实施方案中,本发明提供一种用于抑制受试者中的肿瘤细胞生长的方法,包括对受试者施用本发明抗体或其抗原结合部分,从而抑制受试者中的肿瘤生长。在再一实施例中,本发明提供治疗受试者的病毒感染的方法,其包括向受试者施用本发明抗体或其抗原结合部分,从而治疗受试者的病毒感染。在另一个实施方案中,该等方法包括施用本发明的组合物、双特异性分子或免疫缀合物。
在又一实施方案中,本发明提供一种用于刺激受试者中的免疫反应的方法,其包括对受试者施用本发明的抗体或其抗原结合部分及至少一种另外的免疫刺激性抗体(例如抗PD-1抗体、抗PD-L1抗体和/或抗CTLA-4抗体),从而刺激受试者中的免疫反应(例如抑制肿瘤生长或刺激抗病毒反应)。在一个实施方案中,另外的免疫刺激性抗体是抗PD-1抗体。在另一个实施方案中,另外的免疫刺激剂是抗PD-L1抗体。在又一实施方案中,另外的免疫刺激剂是抗CTLA-4抗体。在又一实施方案中,将本发明的抗体或其抗原结合部分与细胞因子(例如IL-2和/或IL-21)或共刺激性抗体(例如抗CD137和/或抗GITR抗体)一起施用。抗体可为例如人抗体、嵌合抗体或人源化抗体。
在另一方面,本发明提供用于前述方法或用于制造供在前述方法中使用(例如用于治疗)的药物的本发明的抗LAG-3抗体及组合物。
本公开的其他特征及优点自下列详细说明及实例是显而易见的,其不应理解为限制性的。在本申请案通篇中所引用的所有参考文献、GenBank条目、专利及公开专利申请的内容皆通过提述明确并入本文中。
具体而言,本申请提供:
1.一种分离的单克隆抗体或其抗原结合部分,其结合人LAG-3且包含重链和轻链可变区,其中所述重链可变区包含来自SEQ ID NO:12的重链可变区的CDR1、CDR2和CDR3区。
2.项1的抗体或其抗原结合部分,其中所述重链CDR1、CDR2和CDR3区分别包括SEQID NO:15、16和17的氨基酸序列。
3.项1的抗体或其抗原结合部分,其中所述轻链可变区包含来自SEQ ID NO:14的轻链可变区的CDR1、CDR2和CDR3区。
4.项3的抗体或其抗原结合部分,其中所述轻链CDR1、CDR2和CDR3区分别包含SEQID NO:18、19和20的氨基酸序列。
5.项1或3的抗体或其抗原结合部分,其中所述重链可变区包含SEQ ID NO:12的氨基酸序列。
6.前述项中任一项的抗体或其抗原结合部分,其中所述轻链可变区包含SEQ IDNO:14的氨基酸序列。
7.一种分离的单克隆抗体或其抗原结合部分,其结合人LAG-3且包含重链和轻链CDR1、CDR2和CDR3区,所述重链CDR1、CDR2和CDR3区分别包含SEQ ID NO:15、16、17的氨基酸序列,所述轻链CDR1、CDR2和CDR3区分别包含SEQ ID NO:18、19和20的氨基酸序列。
8.一种分离的单克隆抗体或其抗原结合部分,其结合人LAG-3且包含重链和轻链可变区,所述重链和轻链可变区分别包含SEQ ID NO:12和14的氨基酸序列。
9.前述项中任一项的抗体或其抗原结合部分,其展现下列特性的一种或组合:
(a)结合猴LAG-3;
(b)缺少对小鼠LAG-3的结合;
(c)结合LAG-3主要组织相容性(MHC)II类分子;
(d)抑制LAG-3对主要组织相容性(MHC)II类分子的结合;或
(e)刺激免疫反应。
10.前述项中任一项的抗体或其抗原结合部分,其刺激抗原特异性T细胞反应中的白介素-2(IL-2)产生。
11.前述项中任一项的抗体或其抗原结合部分,其刺激抗肿瘤免疫反应。
12.前述项中任一项的抗体或其抗原结合部分,其结合人LAG-3的表位,所述表位包含氨基酸序列PGHPLAPG(SEQ ID NO:21)。
13.前述项中任一项的抗体或其抗原结合部分,其结合人LAG-3的表位,所述表位包含氨基酸序列HPAAPSSW(SEQ ID NO:22)或PAAPSSWG(SEQ ID NO:23)。
14.前述项中任一项的抗体或其抗原结合部分,其以0.27x 10-9M或更小的KD结合人LAG-3。
15.前述项中任一项的抗体或其抗原结合部分,其是人抗体、人源化抗体或嵌合抗体。
16.前述项中任一项的抗体或其抗原结合部分,其为IgG1、IgG2或IgG4同种型。
17.前述项中任一项的抗体或其抗原结合部分,其为抗体片段或单链抗体。
18.一种双特异性分子,其包含前述项中任一项的抗体或其抗原结合部分,和第二抗体或其抗原结合部分。
19.一种免疫缀合物,其包含连接于治疗剂的项1-17中任一项的抗体或其抗原结合部分。
20.项19的免疫缀合物,其中所述治疗剂是细胞毒素或放射性同位素。
21.一种组合物,其包含项1至17中任一项的抗体或其抗原结合部分、项18的双特异性分子、或项19或20的免疫缀合物、和药学可接受的载体。
22.项21的组合物,其还包含抗癌剂。
23.项22的组合物,其中所述抗癌剂是抗体或化学治疗剂。
24.一种分离的核酸,其编码项1至8中任一项的抗体或其抗原结合部分的重链和/或轻链可变区。
25.一种表达载体,其包括项24的核酸。
26.一种宿主细胞,其包括项25的表达载体。
27.一种用于制备抗LAG-3抗体的方法,包括在项26的宿主细胞中表达该抗体,并自该宿主细胞分离该抗体。
28.一种刺激受试者中的免疫反应的方法,包括对所述受试者施用项1至17中任一项的抗体或其抗原结合部分、项18的双特异性分子、或项19或20的免疫缀合物,从而刺激所述受试者中的免疫反应。
29.项28的方法,其中所述受试者是携带肿瘤的受试者且刺激针对所述肿瘤的免疫反应。
30.项28的方法,其中所述受试者是携带病毒的受试者且刺激针对该病毒的免疫反应。
31.项28的方法,其中所述免疫反应是抗原特异性T细胞反应,从而刺激了抗原特异性T细胞反应。
32.项31的方法,其中所述抗原特异性T细胞的白介素-2生成被刺激。
33.一种用于抑制受试者中的肿瘤细胞的生长的方法,包括对所述受试者施用项1至17中任一项的抗体或其抗原结合部分、项18的双特异性分子、或项19或20的免疫缀合物,从而在所述受试者中抑制肿瘤生长。
34.一种用于治疗受试者的病毒感染的方法,包括对所述受试者施用项1至17中任一项的抗体或其抗原结合部分、项18的双特异性分子、或项19或20的免疫缀合物,从而在所述受试者中治疗病毒感染。
35.项30的方法,其进一步包括施用至少一种另外的免疫刺激性抗体。
36.项35的方法,其中所述至少一种另外的免疫刺激性抗体是抗PD-1抗体。
37.项36的方法,其中所述至少一种另外的免疫刺激性抗体是抗PD-L1抗体。
38.项36的方法,其中所述至少一种另外的免疫刺激性抗体是抗CTLA-4抗体。
39.项1至17中任一项的抗体或其抗原结合部分、项18的双特异性分子、或项19或20的免疫缀合物在受试者中刺激免疫反应或抑制肿瘤细胞生长或治疗病毒感染的用途,其中所述免疫反应任选为抗原特异性T细胞反应。
40.项1至17中任一项的抗体或其抗原结合部分、项18的双特异性分子、或项19或20的免疫缀合物在制备用于在受试者中刺激免疫反应或抑制肿瘤细胞生长或治疗病毒感染的药物中的用途,其中所述免疫反应任选为抗原特异性T细胞反应。
附图简述
图1A展示25F7人单克隆抗体的重链可变区的核苷酸序列(SEQ ID NO:1)及氨基酸序列(SEQ ID NO:2)。CDR1(SEQ ID NO:5)、CDR2(SEQ ID NO:6)及CDR3(SEQ ID NO:7)区划线且指示V、D及J种系衍生。使用Kabat系统对CDR区划线(Kabat等人(1991)Sequences ofProteins of Immunological Interest,第5版,U.S.Department of Health and HumanServices,NIH公开案第91-3242号)。
图1B展示25F7人单克隆抗体的κ轻链可变区的核苷酸序列(SEQ ID NO:3)及氨基酸序列(SEQ ID NO:4)。CDR1(SEQ ID NO:8)、CDR2(SEQ ID NO:9)及CDR3(SEQ ID NO:10)区划线且指示V及J种系衍生。抗体25F7的全长重链及轻链氨基酸序列分别展示于SEQ ID NO:32及34中。
图2A展示LAG3.5单克隆抗体的重链可变区的氨基酸序列(SEQ ID NO:12)。CDR1(SEQ ID NO:15)、CDR2(SEQ ID NO:16)及CDR3(SEQ ID NO:17)区划线。抗体LAG3.5的全长重链及轻链氨基酸序列分别展示于SEQ ID NO:35及37中。
图2B展示LAG3.5单克隆抗体的κ轻链可变区的核苷酸序列(SEQ ID NO:13)及氨基酸序列(SEQ ID NO:14)。CDR1(SEQ ID NO:18)、CDR2(SEQ ID NO:19)及CDR3(SEQ ID NO:20)区划线。
图3展示LAG-3变体LAG3.5(SEQ ID NO:16)、LAG3.6(SEQ ID NO:24)、LAG3.7(SEQID NO:25)及LAG3.8(SEQ ID NO:26)的CDR2重链可变区序列的氨基酸序列,将其与抗体25F7(LAG3.1)(SEQ ID NO:6)的CDR2重链可变区序列的氨基酸序列及相应人种系序列(SEQID NO:27)进行比较。LAG3.5的CDR2重链可变区与25F7的CDR2重链可变区的不同之处在于54位处的精氨酸(R)(相对于天冬酰胺(N))及56位处的丝氨酸(S)(相对于天冬酰胺(N))。LAG3.5与25F7的其余CDR相同。
图4A及4B是展示抗体LAG3.1(25F7)、LAG3.2、LAG3.5、LAG3.6、LAG3.7及LAG3.8对活化的人CD4+T细胞的结合活性(分别为EC50及亲和力)的图形。
图5A、5B、5C、5D及5E是分别展示抗体LAG3.1(25F7)、LAG3.5、LAG3.6、LAG3.7及LAG3.8的热熔解曲线(即热稳定性)的图形。
图6A、6B、6C、6D及6E是分别展示抗体LAG3.1(25F7)、LAG3.5、LAG3.6、LAG3.7及LAG3.8的热可逆性曲线(即热稳定性)的图形。
图7是展示抗体LAG3.1(25F7)及LAG3.5对活化的人CD4+T细胞的结合活性及抗原结合(Biacore)的图形。
图8展示使用质谱术对抗体LAG3.1(25F7)及LAG3.5实施肽图谱法的结果(化学修饰/分子稳定性),其反映了在如本文所阐述的加速应激条件下温育5天后的去酰胺化及异构化。
图9是比较抗体LAG3.1(25F7)及LAG3.5的亲水性概况(profile)的图形。
图10A、10B、10C及10D是比较抗体LAG3.1及LAG3.5在4℃及40℃(即如本文所阐述的两种加速应激条件和“实时”稳定性研究)的亲和力及物理稳定性(即热稳定性及化学稳定性)的图形。
图11A及11B是比较抗体LAG3.1及LAG3.5在4℃及40℃的氨基酸序列的百分比修饰的图形。
发明详述
为可更易于理解本揭示内容,首先定义某些术语。其他定义阐述于整个详细说明中。
术语“25F7”、“抗体25F7”、“抗体LAG3.1”及“LAG3.1”指US2011/0150892A1中所阐述的抗人LAG-3抗体。编码25F7(LAG3.1)的重链可变区的核苷酸序列(SEQ ID NO:1)及相应氨基酸序列(SEQ ID NO:2)展示于图1A中(其中CDR序列分别称为SEQ ID NO:4、5及7)。编码25F7(LAG3.1)的轻链可变区的核苷酸序列(SEQ ID NO:3)及相应氨基酸序列(SEQ ID NO:4)展示于图1B中(其中CDR序列分别称为SEQ ID NO:8、9及10)。
术语“LAG-3”是指淋巴细胞活化基因-3。术语“LAG-3”包含变体、同等型(isoform)、同源物、直系同源体(ortholog)及旁系同源体(paralog)。举例而言,在某些情形下,人LAG-3蛋白的特异性抗体可与来自人外的物种的LAG-3蛋白交叉反应。在其他实施方案中,人LAG-3蛋白的特异性抗体可对人LAG-3蛋白具有完全特异性且不展现物种或其他类型的交叉反应性,或可与来自某些其他物种(但并非所有其他物种)的LAG-3交叉反应(例如与猴LAG-3交叉反应但不与小鼠LAG-3交叉反应)。术语“人LAG-3”指人序列LAG-3,例如人LAG-3的具有Genbank登录编号:NP_002277的完整氨基酸序列(SEQ ID NO:29)。术语“小鼠LAG-3”指小鼠序列LAG-3,例如小鼠LAG-3的具有Genbank登录编号:NP_032505的完整氨基酸序列。本领域中亦已知LAG-3,例如CD223。人LAG-3序列与Genbank登录编号:NP_002277的人LAG-3的不同之处可在于具有例如保守突变或在非保守区中的突变,且LAG-3与Genbank登录编号:NP_002277的人LAG-3具有实质上相同的生物功能。举例而言,人LAG-3的生物功能是在LAG-3的胞外域中具有表位,该表位被本公开的抗体特异性结合,或人LAG-3的生物功能是结合MHC II类分子。
术语“猴LAG-3”意图涵盖由旧大陆猴(Old World monkey)及新大陆猴(New Worldmonkey)表达的LAG-3蛋白(包含但不限于猕猴LAG-3及恒河猴LAG-3)。猴LAG-3的代表性氨基酸序列是恒河猴LAG-3氨基酸序列,其亦存放为Genbank登录编号:XM_001108923。猴LAG-3的另一代表性氨基酸序列是克隆pa23-5的备选恒河猴序列,如US 2011/0150892 A1中所阐述的。与Genbank存放的序列相比,这一备选的恒河猴序列在419位处展现单氨基酸差异。
特定人LAG-3序列在氨基酸序列中通常与Genbank登录编号:NP_002277的人LAG-3至少90%相同,且含有在与其他物种(例如鼠类)的LAG-3氨基酸序列相比时鉴别为人氨基酸序列的氨基酸残基。在某些情形下,人LAG-3在氨基酸序列中可与Genbank登录编号:NP_002277的LAG-3至少95%或甚至至少96%、97%、98%或99%相同。在某些实施方案中,人LAG-3序列较Genbank登录编号:NP_002277的LAG-3序列显示不超过10个氨基酸差异。在某些实施方案中,人LAG-3可较Genbank登录编号:NP_002277的LAG-3序列显示不超过5或甚至不超过4、3、2或1个氨基酸差异。可如本文所阐述的测定百分比同一性。
术语“免疫反应”指例如淋巴细胞、抗原呈现细胞、吞噬细胞、粒细胞及由上述细胞或肝产生的可溶性大分子(包含抗体、细胞因子及补体)的作用,该作用可使得选择性损害、破坏或从人体消除侵入的病原体、感染病原体的细胞或组织、癌细胞或(在自体免疫性或病理学验证的情形下)正常人细胞或组织。
“抗原特异性T细胞反应”是指源于使用T细胞特异性抗原刺激T细胞的T细胞反应。在抗原特异性刺激后的T细胞反应的非限制性实例包含增殖及细胞因子产生(例如IL-2产生)。
如本文所提及的术语“抗体”包含全抗体及其任一抗原结合片段(即“抗原结合部分”)或单链。全抗体是包括通过二硫键互连的至少两条重(H)链及两条轻(L)链的糖蛋白。每一重链包括重链可变区(本文缩写为VH)及重链恒定区。重链恒定区包括三个域:CH1、CH2及CH3。每一轻链包括轻链可变区(本文缩写为VL)及轻链恒定区。轻链恒定区包括一个域CL。可将VH及VL区进一步细分成高可变区(称为互补决定区(CDR))及较为保守的区(称为框架区(FR)),二者间杂排列。每一VH及VL由三个CDR及四个FR构成,其自氨基末端至羧基末端按下列顺序排列:FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。重链及轻链的可变区含有与抗原相互作用的结合域。抗体的恒定区可介导免疫球蛋白对宿主组织或因子(包括免疫系统的各种细胞(例如效应器细胞)及经典补体系统的第一组分(Clq))的结合。
本文所用的术语抗体的“抗原结合部分”(或简称为“抗体部分”)是指保留特异性结合至抗原(例如LAG-3蛋白)的能力的一或多个抗体片段。已展示,抗体的抗原结合功能可由全长抗体的片段来实施。涵盖于术语抗体的“抗原结合部分”内的结合片段的实例包含(i)Fab片段,其是由VL、VH、CL及CH1域组成的单价片段;(ii)F(ab')2片段,其是包含两个通过铰链区处的二硫键连接的Fab片段的二价片段;(iii)由VH及CH1域组成的Fd片段;(iv)由VH及CH1域组成的Fv片段;(v)由抗体单臂的VL及VH域组成的Fv片段;(vi)dAb片段(Ward等人,(1989)Nature 341:544-546),其由VH域组成;(vii)分离的互补决定区(CDR);及(viii)纳米抗体(nanobody),其是含有单一可变域及两个恒定域的重链可变区。另外,尽管Fv片段的两个域(VL及VH)是由分开的基因编码,但可使用重组方法通过合成接头将此两个域连接在一起,此合成接头使其能够以单一蛋白质链制备,其中VL及VH区配对形成单价分子(称为单链Fv(scFv);例如参见Bird等人(1988)Science 242:423-426;及Huston等人(1988)Proc.Natl.Acad.Sci.USA 85:5879-5883)。这类单链抗体亦意图涵盖于术语抗体的“抗原结合部分”内。使用本领域技术人员已知的常见技术获得这些抗体片段,并以与完整抗体相同的方式筛选片段以供使用。
本文所用的“分离的抗体”意图指实质上不含具有不同抗原特异性的其他抗体的抗体(举例而言,与LAG-3蛋白特异性结合的分离的抗体实质上没有特异性结合除LAG-3蛋白外的抗原的抗体)。然而,特异性结合人LAG-3蛋白的分离的抗体可与其他抗原(例如来自其他物种的LAG-3蛋白)具有交叉反应性。另外,分离的抗体可实质上没有其他细胞材料和/或化学物。
本文所用的术语“单克隆抗体”或“单克隆抗体组合物”是指具有单一分子组成的抗体分子制备物。单克隆抗体组合物对于特定表位显示单一结合特异性及亲和力。
本文所用的术语“人抗体”意图包含具有其中框架及CDR区两者衍生自人种系免疫球蛋白序列的可变区的抗体。另外,若抗体含有恒定区,则恒定区亦衍生自人种系免疫球蛋白序列。本发明的人抗体可包含并非由人种系免疫球蛋白序列编码的氨基酸残基(例如通过体外随机随机或定点诱变或通过体内体细胞突变引入的突变)。然而,本文所用的术语“人抗体”不意图包含其中将衍生自另一哺乳动物物种(例如小鼠)种系的CDR序列移植到人框架序列上的抗体。
术语“人单克隆抗体”是指显示单一结合特异性的抗体,其具有其中框架及CDR区皆衍生自人种系免疫球蛋白序列的可变区。在一个实施方案中,人单克隆抗体可通过杂交瘤产生,该杂交瘤包含自转基因非人动物(例如转基因小鼠)获得的B细胞,其具有包含人重链转基因及轻链转基因的基因组,所述B细胞融合至永生化细胞。
本文所用的术语“重组人抗体”包含通过重组方式制备、表现、创建或分离的所有人抗体,例如(a)自对于人免疫球蛋白基因转基因或转染色体的动物(例如小鼠)或从其制备的杂交瘤分离的抗体(进一步阐述于下文中);(b)自经转化以表达人抗体的宿主细胞(例如自转染瘤)分离的抗体;(c)自重组、组合人抗体文库分离的抗体;和(d)及通过涉及将人免疫球蛋白基因序列剪接至其他DNA序列的任何其他手段所制备、表达、创建或分离的抗体。这类重组人抗体具有其中框架及CDR区衍生自人种系免疫球蛋白序列的可变区。然而,在某些实施方案中,这类重组人抗体可经受体外诱变(或在使用对于人Ig序列转基因的动物时经受体内体细胞诱变),且由此重组抗体的VH及VL区的氨基酸序列尽管源自人种系VH及VL序列并与其相关,但其是不可天然存在于体内人抗体种系储库中的序列。
术语“同种型”是指由重链恒定区基因编码的抗体种类(例如IgM或IgG1)。
短语“识别抗原的抗体”及“抗原特异性抗体”在本文中可与术语“特异性结合抗原的抗体”互换使用。
术语“人抗体衍生物”是指人抗体的任一修饰形式,例如抗体与另一药剂或抗体的缀合物。
术语“人源化抗体”意图指其中将衍生自另一哺乳动物物种(例如小鼠)种系的CDR序列移植到人框架序列上的抗体。可在人框架序列内作出其他框架区修饰。
术语“嵌合抗体”意图指其中可变区序列衍生自一种物种且恒定区序列衍生自另一物种的抗体,例如其中可变区序列衍生自小鼠抗体且恒定区序列衍生自人抗体的抗体。
如本文中所使用,“特异性结合人LAG-3”的抗体意图指结合人LAG-3蛋白(及可能的来自一或多种非人物种的LAG-3蛋白)但不实质性结合非LAG-3蛋白的抗体。优选地,抗体以“高亲和力”结合人LAG-3蛋白,即KD为1×10-7M或更小、更优选地1×10-8M或更小、更优选地5×10-9M或更小、更优选地1×10-9M或更小。
本文所用的术语“不实质性结合”蛋白质或细胞意指不结合或不以高亲和力结合蛋白质或细胞,即以以下KD结合蛋白质或细胞:1×10-6M或更高、更优选地1×10-5M或更高、更优选地1×10-4M或更高、更优选地1×10-3M或更高、甚至更优选地1×10-2M或更高。
本文所用的术语“Kassoc”或“Ka”意图指特定抗体-抗原相互作用的缔合速率,而本文所用的术语“Kdis”或“Kd”意图指特定抗体-抗原相互作用的解离速率。本文所用的术语“KD”意图指解离常数,其是自Kd对Ka的比率(即Kd/Ka)获得且表示为摩尔浓度(M)。可使用本领域中充分确立的方法测定抗体的KD值。测定抗体的KD的优选方法是通过使用表面等离振子共振,优选地使用生物传感器系统(例如系统)。
术语“高亲和力”对于IgG抗体是指抗体对于靶抗原具有以下KD:1×10-7M或更小、更优选地5×10-8M或更小、甚至更优选地1×10-8M或更小、甚至更优选地5×10-9M或更小及甚至更优选地1×10-9M或更小。然而,对于其他抗体同种型而言,“高亲和力”结合可有所变化。举例而言,IgM同种型的“高亲和力”结合是指抗体具有10-6M或更小、更优选地10-7M或更小、甚至更优选地10-8M或更小的KD。
术语“去酰胺化”是指自发性发生于蛋白质(例如抗体)中的化学降解过程。去酰胺化自氨基酸残基(例如天冬酰胺及谷氨酰胺)去除酰胺官能团,由此破坏其含有酰胺的侧链。具体而言,天冬酰胺的侧链攻击毗邻肽基团,从而形成对称的琥珀酰亚胺中间体。中间体的对称性产生两种水解产物,即天冬氨酸或异天冬氨酸。类似反应亦可发生于天冬氨酸侧链中,从而使得部分转化成异天冬氨酸。在谷氨酰胺的情形下,去酰胺化速率通常比天冬酰胺小10倍,然而,机制基本相同,从而仅需水分子即可进行。
术语“受试者”包含任一人或非人动物。术语“非人动物”包含所有脊椎动物,例如哺乳动物及非哺乳动物,例如非人灵长类、绵羊、犬、猫、牛、马、鸡、两栖动物及爬行类,但优选哺乳动物,例如非人灵长类、绵羊、犬、猫、牛及马。
本发明的多个方面进一步详细阐述于下列小节中。
具有增加的稳定性及有利功能特性的抗LAG-3抗体
本发明的抗体特异性结合人LAG-3且与先前所阐述抗LAG-3抗体相比,尤其是与抗体25F7(LAG3.1)相比具有优化的稳定性。此优化包括降低的去酰胺化(例如增加的化学稳定性)及增加的热重折叠(例如增加的物理稳定性),同时仍保留对人LAG-3的高亲和力结合。
用于鉴别去酰胺化位点的方法是本领域中已知的(例如参见离子交换、反相和疏水性相互作用层析、和蛋白水解消化的肽图谱法(LC-MS))。用于测量物理稳定性的适宜测定法包括,例如熔点分析和/或在变性后抗体结构的重折叠(例如如记载于例如实施例3第3部分中的百分比可逆性)。
可使用一或多种亦在本领域中充分确立的技术来评价对人LAG-3的结合。举例而言,可通过流式细胞术分析来测试抗体,其中使抗体与表达人LAG-3的细胞系(例如经转染以在其细胞表面上表达LAG-3(例如人LAG-3或猴LAG-3(例如恒河猴或猕猴)或小鼠LAG-3)的CHO细胞)进行反应。适用于流式细胞术测定的其他细胞包括抗CD3刺激的CD4+活化T细胞,其表达天然LAG-3。另外或备选地,可在BIAcore测定法中测试抗体结合(包含结合动力学(例如KD值))。其他适宜的结合测定法包括例如使用重组LAG-3蛋白的ELISA测定法。
本发明的抗体优选地以以下KD结合人LAG-3蛋白:1×10-7M或更小及更优选地1×10-8M或更小、5×10-9M或更小或1×10-9M或更小。
通常,抗体结合淋巴组织(例如扁桃体、脾或胸腺)中的LAG-3,这可以通过免疫组织化学进行检测。在一个实施方案中,所述抗体将垂体组织染色(例如保留于垂体中),如通过免疫组织化学所测量的。在另一个实施方案中,所述抗体不将垂体组织染色(即不保留于垂体中),如通过免疫组织化学所测量的。
其他功能特性包括与来自其他物种的LAG-3的交叉反应性。举例而言,抗体可结合猴LAG-3(例如猕猴、恒河猴),但不实质性结合至来自小鼠LAG-3的LAG-3。优选地,本发明抗体以高亲和力结合人LAG-3。
其他功能特性包括抗体能够刺激免疫反应,例如抗原特异性T细胞反应的能力。这可以例如通过评价抗体刺激抗原特异性T细胞反应中的白介素-2(IL-2)产生的能力进行测试。在某些实施方案中,抗体结合人LAG-3且刺激抗原特异性T细胞反应。在其他实施方案中,抗体结合人LAG-3但不刺激抗原特异性T细胞反应。用于评估抗体刺激免疫反应的能力的其他手段包括测试其抑制肿瘤生长的能力,如在体内肿瘤移植物模型中(例如见实施例6),或刺激自体免疫反应的能力,如促进自体免疫模型中的自体免疫疾病形成的能力,例如促进NOD小鼠模型中的糖尿病形成的能力。
本发明的优选抗体是人单克隆抗体。另外或备选地,所述抗体可为例如嵌合或人源化单克隆抗体。
单克隆抗体LAG3.5
本发明的优选抗体是人单克隆抗体LAG3.5,其结构及化学表征如下文及下列实施例中所阐述。LAG3.5的VH氨基酸序列展示于SEQ ID NO:12中(图2A)。LAG3.5的VL氨基酸序列展示于SEQ ID NO:14中(图2B)。
结合人LAG-3的其他抗LAG-3抗体的VH及VL序列(或CDR序列)可与抗体LAG3.5的VH及VL序列(或CDR序列)“混合且匹配”。优选地,在VH及VL链(或这类链内的CDR)混合且匹配时,使用结构类似的VH序列代替来自特定VH/VL配对的VH序列。同样,优选地,使用结构类似的VL序列代替来自特定VH/VL配对的VL序列。
因此,在一个实施方案中,本发明的抗体或其抗原结合部分包含:
(a)包含氨基酸序列SEQ ID NO:12的重链可变区(即LAG3.5的VH);及
(b)包含氨基酸序列SEQ ID NO:14的轻链可变区(即LAG3.5的VL)或另一抗LAG3抗体(即其不同于LAG3.5)的VL;
其中所述抗体特异性结合人LAG-3。
在另一个实施方案中,本发明的抗体或其抗原结合部分包含:
(a)包含氨基酸序列SEQ ID NO:12的重链可变区的CDR1、CDR2及CDR3区(即分别为LAG3.5的CDR序列SEQ ID NO:15、16及17);及
(b)包含氨基酸序列SEQ ID NO:14的轻链可变区的CDR1、CDR2及CDR3区(即分别为LAG3.5的CDR序列SEQ ID NO:18、19及20)或另一抗LAG3抗体(即其不同于LAG3.5)的CDR;
其中所述抗体特异性结合人LAG-3。
在又一实施方案中,所述抗体或其抗原结合部分包含与结合人LAG-3的其他抗体的CDR(例如不同的抗LAG-3抗体的重链可变区的CDR1和/或CDR3,和/或轻链可变区的CDR1、CDR2和/或CDR3)组合的LAG3.5的重链可变CDR2区。
此外,在本领域中已众所周知,CDR3域(独立于CDR1和/或CDR2域)单独即可决定抗体对于同类抗原的结合特异性,且基于共同CDR3序列可以可预测地生成具有相同结合特异性的多种抗体。例如参见Klimka等人,British J.of Cancer 83(2):252-260(2000);Beiboer等人,J.Mol.Biol.296:833-849(2000);Rader等人,Proc.Natl.Acad.Sci.U.S.A.95:8910-8915(1998);Barbas等人,J.Am.Chem.Soc.116:2161-2162(1994);Barbas等人,Proc.Natl.Acad.Sci.U.S.A.92:2529-2533(1995);Ditzel等人,J.Immunol.157:739-749(1996);Berezov等人,BIAjournal 8:Scientific Review 8(2001);Igarashi等人,J.Biochem(Tokyo)117:452-7(1995);Bourgeois等人,J.Virol 72:807-10(1998);Levi等人,Proc.Natl.Acad.Sci.U.S.A.90:4374-8(1993);Polymenis及Stoller,J.Immunol.152:5218-5329(1994)以及Xu及Davis,Immunity 13:37-45(2000)。亦参见美国专利第6,951,646号、第6,914,128号、第6,090,382号、第6,818,216号、第6,156,313号、第6,827,925号、第5,833,943号、第5,762,905号及第5,760,185号。这类参考文献中的每一篇均通过提述完整并入本文。
因此,在另一个实施方案中,本发明的抗体包含LAG3.5的重链可变区的CDR2和至少LAG3.5的重链和/或轻链可变区的CDR3(SEQ ID NO:17和/或20),或另一LAG-3抗体的重链和/或轻链可变区的CDR3,其中所述抗体能够特异性结合人LAG-3。这些抗体优选地与LAG3.5(a)竞争结合;(b)保留功能特征;(c)结合相同表位;和/或(d)具有类似的结合亲和力。在又一实施方案中,所述抗体进一步可包含LAG3.5的轻链可变区的CDR2(SEQ ID NO:17和/或20),或另一LAG-3抗体的轻链可变区的CDR2,其中该抗体能够特异性结合人LAG-3。在另一个实施方案中,本发明的抗体还可包含LAG3.5的重链和/或轻链可变区的CDR1(SEQ IDNO:17和/或20),或另一LAG-3抗体的重链和/或轻链可变区的CDR1,其中该抗体能够特异性结合人LAG-3。
保守修饰
在另一个实施方案中,本发明的抗体包含具有CDR1、CDR2及CDR3序列的重链和/或轻链可变区序列,其与LAG3.5的那些序列的不同之处在于一或多种保守修饰。然而,在一个优选的实施方案中,VH CDR2的残基54及56分别保持为精氨酸及丝氨酸(即并未突变)。在本领域中应理解,可进行某些保守序列修饰,其不消除抗原结合。例如参见Brummell等人(1993)Biochem32:1180-8;de Wildt等人(1997)Prot.Eng.10:835-41;Komissarov等人(1997)J.Biol.Chem.272:26864-26870;Hall等人(1992)J.Immunol.149:1605-12;Kelley及O’Connell(1993)Biochem.32:6862-35;Adib-Conquy等人(1998)Int.Immunol.10:341-6及Beers等人(2000)Clin.Can.Res.6:2835-43。因此,在一个实施方案中,所述抗体包含含有CDR1、CDR2及CDR3序列的重链可变区和/或含有CDR1、CDR2及CDR3序列的轻链可变区,其中:
(a)重链可变区CDR1序列包括SEQ ID NO:15和/或其保守修饰(54及56位除外);且/或
(b)重链可变区CDR3序列包括SEQ ID NO:17及其保守修饰;且/或
(c)轻链可变区CDR1和/或CDR2和/或CDR3序列包含SEQ ID NO:18和/或SEQ IDNO:19和/或SEQ ID NO:20和/或其保守修饰;且
(d)抗体特异性结合人LAG-3。
另外或备选地,所述抗体可拥有诸如下列上述功能特性中的一或多种,如以高亲和力结合人LAG-3、结合猴LAG-3、缺少对小鼠LAG-3的结合、抑制LAG-3对MHC II类分子的结合的能力和/或刺激抗原特异性T细胞反应的能力。
在各种实施方案中,抗体可为例如人抗体、人源化抗体或嵌合抗体。
如本文中所使用,术语“保守序列修饰”意图指不显著影响或改变含有氨基酸序列的抗体的结合特征的氨基酸修饰。这类保守修饰包含氨基酸取代、添加及缺失。可通过本领域中已知的标准技术(例如定点诱变及PCR介导的诱变)将修饰引入本发明抗体中。保守氨基酸取代是使用具有类似侧链的氨基酸残基代替氨基酸残基。本领域中已定义具有类似侧链的氨基酸残基的家族。这些家族包含具有以下侧链的氨基酸:碱性侧链(例如赖氨酸、精氨酸、组胺酸)、酸性侧链(例如天冬氨酸、谷氨酸)、不带电荷的极性侧链(例如甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸、半胱氨酸、色氨酸)、非极性侧链(例如丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸)、β-支链侧链(例如苏氨酸、缬氨酸、异亮氨酸)及芳族侧链(例如酪氨酸、苯丙氨酸、色氨酸、组氨酸)。因此,本发明抗体的CDR区内的一或多个氨基酸残基可经来自相同侧链家族的其他氨基酸残基代替,且可使用本文所阐述的功能测定法测试经改变抗体的保留功能(即上文所述的功能)。
工程化和经修饰的抗体
可使用具有LAG3.5的一个或多个VH和/或VL序列的抗体作为起始材料来工程化改造经修饰的抗体以制备本发明抗体。可通过对一个或两个可变区(即VH和/或VL)内(例如一或多个CDR区内和/或一或多个框架区内)的一或多个残基进行修饰来工程化抗体。另外或备选地,可通过对恒定区内的残基进行修饰来工程化抗体以例如改变抗体的效应器功能。
在某些实施方案中,可利用CDR嫁接来工程化抗体的可变区。抗体与靶抗原主要经由位于6个重链及轻链互补决定区(CDR)中的氨基酸残基发生相互作用。出于此原因,CDR内的氨基酸序列较CDR外侧的序列在各抗体之间更为不同。由于CDR序列负责大部分抗体-抗原相互作用,所以可以表达模拟特定天然存在抗体的特性的重组抗体,其通过构建包含来自特定天然存在抗体的CDR序列嫁接到来自具有不同特性的不同抗体的框架序列上的表达载体(例如参见Riechmann等人(1998)Nature 332:323-327;Jones等人(1986)Nature 321:522-525;Queen等人(1989)Proc.Natl.Acad.参见.U.S.A.86:10029-10033;美国专利第5,225,539号、第5,530,101号、第5,585,089号、第5,693,762号及第6,180,370号)。
因此,本发明的另一实施方案是关于一种分离的单克隆抗体或其抗原结合部分,其包含重链可变区(包括分别包含SEQ ID NO:15、16、17的CDR1、CDR2及CDR3序列)和/或轻链可变区(包括分别包含SEQ ID NO:18、19、20的CDR1、CDR2及CDR3序列)(即LAG3.5的CDR)。尽管这些抗体含有单克隆抗体LAG3.5的VH及VL CDR序列,但其可含有不同框架序列。
这类框架序列可自包含种系抗体基因序列的公开DNA数据库或公开参考文献获得。举例而言,人重链及轻链可变区基因的种系DNA序列可见于“VBase”人种系序列数据库(可在因特网上于www.mrc-cpe.cam.ac.uk/vbase处获得)以及Kabat等人(1991)(引用于上文中);Tomlinson等人(1992)“The Repertoire of Human Germline VH SequencesReveals about Fifty Groups of VH Segments with Different Hypervariable Loops”J.Mol.Biol.227:776-798;及Cox等人(1994)“A Directory of Human Germ-line VHSegments Reveals a Strong Bias in their Usage”Eur.J.Immunol.24:827-836;其中每篇的内容均通过提述明确并入本文。作为另一个例子,人重链及轻链可变区基因的种系DNA序列可见于Genbank数据库。举例而言,在HCo7HuMAb小鼠中发现的下列重链种系序列可以随附Genbank登录编号获得:1-69(NG_0010109、NT_024637及BC070333)、3-33(NG_0010109及NT_024637)及3-7(NG_0010109及NT_024637)。根据另一例子,在HCo12HuMAb小鼠中发现的下列重链种系序列可以随附Genbank登录编号获得:1-69(NG_0010109、NT_024637及BC070333)、5-51(NG_0010109及NT_024637)、4-34(NG_0010109及NT_024637)、3-30.3(CAJ556644)及3-23(AJ406678)。
使用称为Gapped BLAST(Altschul等人(1997),参见上文)且为本领域技术人员熟知的序列类似性搜寻方法之一来将抗体蛋白序列与经编译蛋白质序列数据库比较。
用于本发明抗体的优选框架序列是那些在结构上类似于本发明所选抗体所使用的框架序列的(例如类似于本发明的优选单克隆抗体所使用的VH4-34框架序列和/或VK L6框架序列)。可将VH CDR1、CDR2及CDR3序列及VK CDR1、CDR2及CDR3序列嫁接到与在衍生框架序列的种系免疫球蛋白基因中所发现序列具有相同序列的框架区上,或可将CDR序列嫁接到与种系序列相比含有一或多个突变的框架区上。举例而言,已发现在某些情况下,可有益地使框架区内的残基突变以维持或增强抗体的抗原结合能力(例如参见美国专利第5,530,101号、第5,585,089号、第5,693,762号及第6,180,370号)。
另一类型的可变区修饰是使VH和/或VL CDR1、CDR2和/或CDR3区内的氨基酸残基突变以由此改进目的抗体的一或多种结合特性(例如亲和力)。可实施定点诱变或PCR介导的诱变以引入突变,并且可在体外或体内测定法(如本文所阐述且提供于实施例中)中评估对于抗体结合或感兴趣的其他功能特性的影响。优选地,引入保守修饰(如上文所论述)。所述突变可为氨基酸取代、添加或缺失,但优选地是取代。另外,通常改变CDR区内的不超过一处、两处、三处、四处或五处残基。
因此,在另一个实施方案中,本发明提供分离的抗LAG-3单克隆抗体或其抗原结合部分,其包含含有以下的重链可变区:(a)VH CDR1区,其包含SEQ ID NO:15或与SEQ ID NO:15相比具有一处、两处、三处、四处或五处氨基酸取代、缺失或添加的氨基酸序列;(b)VHCDR2区,其包含SEQ ID NO:16或与SEQ ID NO:16相比具有一处、两处、三处、四处或五处氨基酸取代、缺失或添加的氨基酸序列(优选地其中54及56位与SEQ ID NO:16相同);(c)VHCDR3区,其包含SEQ ID NO:17或与SEQ ID NO:17相比具有一处、两处、三处、四处或五处氨基酸取代、缺失或添加的氨基酸序列;(d)VL CDR1区,其包含SEQ ID NO:18或与SEQ ID NO:18相比具有一处、两处、三处、四处或五处氨基酸取代、缺失或添加的氨基酸序列;(e)VLCDR2区,其包含SEQ ID NO:19或与SEQ ID NO:19相比具有一处、两处、三处、四处或五处氨基酸取代、缺失或添加的氨基酸序列;及(f)VL CDR3区,其包含SEQ ID NO:20或与SEQ IDNO:20相比具有一处、两处、三处、四处或五处氨基酸取代、缺失或添加的氨基酸序列。
本发明的工程化抗体包括其中已对VH和/或VL内的框架残基实施修饰以例如改进抗体的特性那些抗体。通常,实施这类框架修饰以降低抗体的免疫原性。举例而言,一种方式是将一或多种框架残基“回复突变”至相应的种系序列。更具体而言,发生体细胞突变的抗体可含有与衍生该抗体的种系序列不同的框架残基。可通过比较抗体框架序列与衍生该抗体的种系序列来鉴别这类残基。
另一类型的框架修饰涉及使框架区内或甚至一或多个CDR区内的一或多种残基发生突变以去除T细胞表位,由此减小抗体的潜在免疫原性。此办法亦称为“去免疫化”且进一步详细阐述于美国专利公开案第20030153043号中。
在框架或CDR区内做出的修饰外或作为该修饰的替代方式,可工程化本发明抗体以包含Fc区内的修饰,从而通常改变抗体的一或多种功能特性,例如血清半衰期、补体固定、Fc受体结合和/或抗原依赖性细胞性细胞毒性。另外,可以化学方式对本发明抗体实施修饰(例如可将一或多个化学模块附接至抗体)或经修饰以改变其糖基化,从而也去改变抗体的一或多种功能特性。这类实施方案中的每一种进一步详细阐述于下文中。Fc区中的残基编号是Kabat的EU索引中的编号。
在一个优选的实施方案中,所述抗体是IgG4同种型抗体,其在重链恒定区的铰链区中对应于228位的位置处包括丝氨酸至脯氨酸的突变(S228P;EU索引)。已报导,此突变可消除铰链区中的重链间二硫键的异质性(Angal等人,参见上文;241位是基于Kabat编号系统)。
在一个实施方案中,对CH1的铰链区实施修饰,从而改变(例如增加或降低)铰链区中的半胱氨酸残基的数目。此办法进一步阐述于美国专利第5,677,425号中。改变CH1的铰链区中半胱氨酸残基的数目以例如促进轻链及重链的装配或增加或降低抗体的稳定性。
在另一个实施方案中,使抗体的Fc铰链区突变以降低抗体的生物半衰期。更具体而言,将一或多种氨基酸突变引入Fc铰链片段的CH2-CH3域界面区中,从而使该抗体相对于天然的Fc铰链域葡萄球菌蛋白A(SpA)结合具有受损的SpA结合。此办法进一步详细阐述于美国专利第6,165,745号中。
在另一个实施方案中,对抗体实施修饰以增加其生物半衰期。各种办法皆是可行的。举例而言,可引入下列突变中的一或多者:T252L、T254S、T256F,如美国专利第6,277,375号中所阐述。备选地,为增加生物半衰期,抗体可在CH1或CL区内改变以含有自IgG的Fc区中CH2域的两个环获取的补救受体结合表位,如美国专利第5,869,046号及第6,121,022号中所阐述。
在其他实施方案中,通过使用不同氨基酸残基代替至少一种氨基酸残基来改变Fc区以改变抗体的效应器功能。举例而言,可使用不同氨基酸残基代替一或多种选自氨基酸残基234、235、236、237、297、318、320及322的氨基酸,从而抗体对效应器配体具有改变的亲和力但保留亲本抗体的抗原结合能力。对其亲和力发生改变的效应器配体可为例如Fc受体或补体的C1组分。此办法进一步详细阐述于美国专利第5,624,821号及第5,648,260号中。
在另一例子中,可使用不同氨基酸残基代替一或多种选自氨基酸残基329、331及322的氨基酸,从而抗体具有改变的C1q结合和/或降低或消除的补体依赖性细胞毒性(CDC)。此办法进一步详细阐述于美国专利第6,194,551号中。
在另一例子中,改变第231及239处氨基酸位置内的一或多种氨基酸残基以由此改变抗体固定补体的能力。此办法进一步阐述于PCT公开文本WO94/29351中。
在又一例子中,通过对下列位置处的一或多种氨基酸进行修饰来对Fc区实施修饰以增加抗体介导抗体依赖性细胞毒性(ADCC)的能力和/或增加抗体对Fcγ受体的亲和力:238、239、248、249、252、254、255、256、258、265、267、268、269、270、272、276、278、280、283、285、286、289、290、292、293、294、295、296、298、301、303、305、307、309、312、315、320、322、324、326、327、329、330、331、333、334、335、337、338、340、360、373、376、378、382、388、389、398、414、416、419、430、434、435、437、438或439。此办法进一步阐述于PCT公开文本WO 00/42072中。另外,已定位人IgG1上对FcγR1、FcγRII、FcγRIII及FcRn的结合位点且已阐述具有改进的结合的变体(参见Shields等人(2001)J.Biol.Chem.276:6591-6604)。在256、290、298、333、334及339位处的特定突变已展示可改进对FcγRIII的结合。另外,显示下列组合突变体改进FcγRIII结合:T256A/S298A、S298A/E333A、S298A/K224A及S298A/E333A/K334A。
在再一实施方案中,对抗体的糖基化实施修饰。举例而言,可制备无糖基化抗体(即抗体缺少糖基化)。可改变糖基化以例如增加抗体对抗原的亲和力。可通过例如改变抗体序列内的一或多个糖基化位点来完成这类糖类修饰。举例而言,可实施一或多种氨基酸取代以消除一或多个可变区框架糖基化位点,由此消除该位点处的糖基化。这类无糖基化可增加抗体对抗原的亲和力。例如参见美国专利第5,714,350号及第6,350,861号。
另外或备选地,可制备具有改变类型的糖基化的抗体,例如具有减小量的岩藻糖基残基的低岩藻糖化抗体或具有增加的等分GlcNac结构的抗体。这类改变的糖基化模式已显示可增加抗体的ADCC能力。可通过例如在具有改变的糖基化体系的宿主细胞中表现抗体来实现这类糖类修饰。具有改变的糖基化体系的细胞已在本领域中阐述,且可用作其中表达本发明的重组抗体以由此产生具有改变的糖基化的抗体的宿主细胞。举例而言,细胞系Ms704、Ms705及Ms709缺乏岩藻糖基转移酶基因FUT8(α(1,6)-岩藻糖基转移酶),从而在Ms704、Ms705及Ms709细胞系中表达的抗体在其糖类上缺乏岩藻糖。通过使用两种代替载体靶向破坏CHO/DG44细胞中的FUT8基因来创建Ms704、Ms705及Ms709FUT8-/-细胞系(参见美国专利公开案第20040110704号及Yamane-Ohnuki等人(2004)Biotechnol Bioeng 87:614-22)。根据另一例子,EP 1,176,195描述了具有功能受破坏的编码岩藻糖基转移酶的FUT8基因的细胞系,从而在这类细胞系中表达的抗体通过减少或消除α-1,6键相关酶来展现低岩藻糖化。EP 1,176,195还描述了具有向结合抗体Fc区的N-乙酰葡糖胺添加岩藻糖的低酶活性或不具有该酶活性的细胞系,例如大鼠骨髓瘤细胞系YB2/0(ATCC CRL 1662)。PCT公开文本WO 03/035835描述了一种变体CHO细胞系Lec13细胞,其中使岩藻糖附接至Asn(297)-连接的糖类的能力降低,从而亦导致在该宿主细胞中表达的抗体的低岩藻糖化(亦参见Shields等人(2002)J.Biol.Chem.277:26733-26740)。具有经修饰的糖基化概况的抗体亦可产生于鸡蛋中,如PCT公开文本WO 06/089231中所阐述。备选地,具有经修饰的糖基化概况的抗体可产生于植物细胞(例如青萍(Lemna))中。在植物系统中产生抗体的方法公开在对应于Alston及Bird LLP代理档案号:040989/314911的2006年8月11日提出申请的美国专利申请案中。PCT公开文本WO 99/54342描述了经工程化以表达糖蛋白修饰糖基转移酶(例如β(1,4)-N-乙酰葡糖胺基转移酶III(GnTIII))的细胞系,从而在该工程化细胞系中表达的抗体展现增加的等分GlcNac结构,其导致增加的抗体的ADCC活性(亦参见Umana等人(1999)Nat.Biotech.17:176-180)。备选地,可使用岩藻糖苷酶切除抗体的岩藻糖残基;举例而言,岩藻糖苷酶α-L-岩藻糖苷酶自抗体去除岩藻糖基残基(Tarentino等人(1975)Biochem.14:5516-23)。
本公开所涵盖的另一种对本文抗体的修饰是聚乙二醇化(pegylation)。可对抗体实施聚乙二醇化以例如增加抗体的生物(例如血清)半衰期。为将抗体乙二醇化,通常使抗体或其片段与聚乙二醇(PEG)(例如PEG的反应性酯或醛衍生物)在其中一或多个PEG基团变得附接至抗体或抗体片段的条件下发生反应。优选地,经由使用反应性PEG分子(或类似反应性水溶性聚合物)进行酰化反应或烷基化反应来实施聚乙二醇化。如本文中所使用,术语“聚乙二醇”意图涵盖已用于衍生化其他蛋白质的PEG的任一形式,例如单(C1-C10)烷氧基-或芳氧基聚乙二醇或聚乙二醇-马来酰亚胺。在某些实施方案中,要聚乙二醇化的抗体是无糖基化抗体。本领域中已知的使蛋白质聚乙二醇化的方法且可应用于本发明的抗体。例如参见EP 0 154 316及EP 0 401 384。
抗体物理特性
可通过各种物理特性来表征本发明抗体,从而检测和/或区分其不同种类。
举例而言,抗体可在轻链或重链可变区中含有一或多个糖基化位点。这类糖基化位点可使得增加抗体的免疫原性或改变抗体的pK(因抗原结合有所改变)(Marshall等人(1972)Annu Rev Biochem 41:673-702;Gala及Morrison(2004)J Immunol 172:5489-94;Wallick等人(1988)J Exp Med 168:1099-109;Spiro(2002)Glycobiology 12:43R-56R;Parekh等人(1985)Nature 316:452-7;Mimura等人(2000)Mol Immunol 37:697-706)。已知糖基化发生于含有N-X-S/T序列的基序处。在一些情况下,优选地,抗LAG-3抗体不含有可变区糖基化。此可通过选择在可变区中不含有糖基化基序的抗体或通过使糖基化区内的残基发生突变来达成。
在一个优选的实施方案中,所述抗体不含有天冬酰胺异构位点。天冬酰胺的去酰胺化可发生于N-G或D-G序列上且使得产生异天冬氨酸残基,该异天冬氨酸残基在多肽链中引入纽结(kink)并降低其稳定性(异天冬氨酸效应)。
每种抗体均具有独特的等电点(pI),其通常在6至9.5的pH范围内。IgG1抗体的pI通常在7-9.5的pH范围内且IgG4抗体的pI通常在6-8的pH范围内。据推测,pI在正常范围以外的抗体体内条件下可能具有一定解折叠和不稳定性。因此,优选地,抗LAG-3抗体含有在正常范围内的pI值。此可通过选择pI在正常范围内的抗体或通过使带电荷的表面残基突变来达成。
编码本发明抗体的核酸分子
在另一方面,本发明提供编码本发明抗体的重链和/或轻链可变区或CDR的核酸分子。核酸可存在于全细胞、细胞裂解物或部分纯化或实质性纯的形式中。在通过标准技术(包含碱性/SDS处理、CsCl显带、柱层析、琼脂糖凝胶电泳及本领域中熟知的其他技术)自其他细胞组分或其他污染物(例如其他细胞核酸或蛋白质)纯化时,核酸是“分离的”或“达成实质性纯”的核酸。参见Ausubel等人编辑,(1987)Current Protocols in MolecularBiology,Greene Publishing and Wiley Interscience,New York。本发明核酸可为例如DNA或RNA,且可含有或不含有内含子序列。在一个优选的实施方案中,核酸是cDNA分子。
可使用标准分子生物学技术获得本发明核酸。对于由杂交瘤(例如自携载人免疫球蛋白基因的转基因小鼠制得的杂交瘤,如下文进一步所阐述)表达的抗体而言,可通过标准PCR扩增或cDNA克隆技术获得编码由该杂交瘤制得的抗体的轻链及重链的cDNA。对于自免疫球蛋白基因文库获得的抗体而言(例如使用噬菌体显示技术),可自基因文库回收编码这类抗体的核酸。
本发明的优选核酸分子包含那些编码LAG3.5单克隆抗体的VH及VL序列(分别为SEQID NO:12及14)或CDR的。在获得编码VH及VL区段的DNA片段后,可进一步通过标准重组DNA技术操作这些DNA片段以例如将可变区基因转化成全长抗体链基因、Fab片段基因或scFv基因。在这些操作中,编码VL或VH的DNA片段可操作连接至编码另一蛋白质(例如抗体恒定区或柔性接头)的另一DNA片段。此背景中所用的术语“可操作连接”意图意指连接两个DNA片段,从而使得由这两个DNA片段编码的氨基酸序列保持为符合阅读框(in-frame)。
可通过使编码VH的DNA可操作连接至另一编码重链恒定区(CH1、CH2及CH3)的DNA分子来将编码VH区的分离的DNA转化成全长重链基因。本领域中已知人重链恒定区基因的序列(例如参见Kabat等人(1991),参见上文)且可通过标准PCR扩增获得涵盖这些区的DNA片段。重链恒定区可为IgG1、IgG2、IgG3、IgG4、IgA、IgE、IgM或IgD恒定区,但最优选地是IgG1或IgG4恒定区。对于Fab片段重链基因而言,可将编码VH的DNA可操作连接至另一仅编码重链CH1恒定区的DNA分子。
可通过使编码VL的DNA可操作连接至另一编码轻链恒定区CL的DNA分子来将编码VL区的分离的DNA转化成全长轻链基因(以及Fab轻链基因)。本领域中已知人轻链恒定区基因的序列(例如参见Kabat等人的参考文献,参见上文)且可通过标准PCR扩增获得涵盖这些区的DNA片段。在优选的实施方案中,轻链恒定区可为κ或λ恒定区。
为创建scFv基因,将编码VH及VL的DNA片段可操作地连接于另一编码柔性接头(例如编码氨基酸序列(Gly4-Ser)3)的片段,从而VH及VL序列可表达为邻接的单链蛋白,其中VL区及VH区由柔性接头连接(例如参见Bird等人(1988)Science 242:423-426;Huston等人(1988)Proc.Natl.Acad.Sci.USA85:5879-5883;McCafferty等人,(1990)Nature 348:552-554)。
本发明的单克隆抗体的产生
可使用Kohler及Milstein(1975)Nature 256:495中的公知的体细胞杂交(杂交瘤)技术产生本发明的单克隆抗体(mAb)。产生单克隆抗体的其他实施方案包含B淋巴细胞的病毒或致癌性转化及噬菌体展示技术。嵌合或人源化抗体亦在本领域中众所周知。例如参见美国专利第4,816,567号、第5,225,539号、第5,530,101号、第5,585,089号、第5,693,762号及第6,180,370号,其内容通过提述完整特定地并入本文。
在一个优选的实施方案中,本发明的抗体是人单克隆抗体。可使用携载人免疫系统而非小鼠系统的部分的转基因或转染色体小鼠来生成这类针对人LAG-3的人单克隆抗体。这些转基因及转染色体小鼠包含在本文中分别称为及的小鼠,且在本文中统称为“人Ig小鼠”。
(公司)含有人免疫球蛋白基因微卫星基因座(miniloci)(其编码未重排的人重链(μ及γ)及κ轻链免疫球蛋白序列)以及靶向突变(其使内源性μ及κ链基因座失活)(例如参见Lonberg等人(1994)Nature 368(6474):856-859)。因此,小鼠展现降低的小鼠IgM或κ表达,且引入的人重链及轻链转基因应答免疫发生类转换及体细胞突变以生成高亲和力人IgGκ单克隆抗体(Lonberg等人(1994),参见上文;参见Lonberg(1994)Handbook of Experimental Pharmacology 113:49-101;Lonberg,N.及Huszar,D.(1995)Intern.Rev.Immunol.13:65-93以及Harding及Lonberg(1995)Ann.N.Y.Acad.Sci.764:536-546)。的制备及应用及由这类小鼠携载的基因组修饰进一步阐述于以下参考文献中:Taylor等人(1992)Nucleic Acids Research 20:6287-6295;Chen等人(1993)International Immunology 5:647-656;Tuaillon等人(1993)Proc.Natl.Acad.Sci.USA 90:3720-3724;Choi等人(1993)Nature Genetics 4:117-123;Chen等人(1993)EMBO J.12:821-830;Tuaillon等人(1994)J.Immunol.152:2912-2920;Taylor等人(1994)International Immunology 6:579-591;及Fishwild等人(1996)NatureBiotechnology 14:845-851,其内容通过提述完整明确并入本文中。进一步参见美国专利第5,545,806号、第5,569,825号、第5,625,126号、第5,633,425号、第5,789,650号、第5,877,397号、第5,661,016号、第5,814,318号、第5,874,299号、第5,770,429号及第5,545,807号、PCT公开文本第WO 92/03918号、第WO 93/12227号、第WO 94/25585号、第WO 97/13852号、第WO 98/24884号、第WO 99/45962号及第WO 01/14424号,其内容通过提述完整并入本文中。
在另一个实施方案中,可使用在转基因及转染色体上携载人免疫球蛋白序列的小鼠(例如携载人重链转基因及人轻链转染色体的小鼠)来产生本发明的人抗体。此小鼠在本文中称为且详细阐述于PCT公开文本WO 02/43478中。此小鼠的修饰形式(其进一步包括内源性FcγRIIB受体基因的纯合性破坏)亦阐述于PCT公开文本WO 02/43478中且在本文中称为此外,可使用具有HCo7或Co12重链转基因或二者的小鼠。
其他转基因动物实施方案包括Xenomouse(Abgenix公司,美国专利第5,939,598号、第6,075,181号、第6,114,598号、第6,150,584号及第6,162,963号)。其他实施方案包括“TC小鼠”(Tomizuka等人(2000)Proc.Natl.Acad.Sci.USA 97:722-727)及携载人重链及轻链转染色体的牛(Kuroiwa等人(2002)Nature Biotechnology 20:889-894;PCT公开文本WO02/092812)。这些专利及公开文本的内容通过提述完整明确并入本文中。
在一个实施方案中,使用用于筛选人免疫球蛋白基因文库的噬菌体显示方法来制备本发明的人单克隆抗体。例如参见美国专利第5,223,409号、第5,403,484号、第5,571,698号、第5,427,908号、第5,580,717号、第5,969,108号、第6,172,197号、第5,885,793号、第6,521,404号、第6,544,731号、第6,555,313号、第6,582,915号及第6,593,081号,其内容通过提述完整并入本文中。
本发明的人单克隆抗体亦可使用SCID小鼠来制备,其中人免疫细胞已经重构以便可在实施免疫后生成人抗体反应。例如参见美国专利第5,476,996号及第5,698,767号,其内容通过提述完整并入本文中。
在另一个实施方案中,使用噬菌体展示来制备人抗LAG-3抗体,其中所述噬菌体包含编码在先前使用LAG-3免疫的转基因动物中所生成抗体的核酸。在一个优选的实施方案中,所述转基因动物是HuMab、KM或Kirin小鼠。例如参见美国专利第6,794,132号,其内容通过提述完整并入本文中。
人Ig小鼠的免疫
在本发明的一实施方案中,使用LAG-3抗原的纯化或富集配制物、重组LAG-3蛋白、或表达LAG-3蛋白的细胞对人Ig小鼠实施免疫。例如参见Lonberg等人(1994),参见上文;Fishwild等人(1996),参见上文;PCT公开文本WO 98/24884或WO 01/14424,其内容通过提述完整并入本文中。在一个优选的实施方案中,使用5-50μg LAG-3蛋白对6-16周龄小鼠实施免疫。或者,使用融合至非LAG-3多肽的LAG-3的部分。
在一个实施方案中,在腹膜内(IP)或静脉内(IV)使用在完全弗氏佐剂(completeFreund's adjuvant)中的LAG-3抗原对转基因小鼠实施免疫,随后使用在不完全弗氏佐剂中的抗原实施后续IP或IV免疫。在其他实施方案中,使用除弗氏佐剂外的佐剂或在不存在佐剂的全细胞。可通过ELISA筛选血浆且可使用来自小鼠的具有足够抗LAG-3人免疫球蛋白效价的细胞进行融合。
产生本发明的人单克隆抗体的杂交瘤的生成
为生成产生本发明的人单克隆抗体的杂交瘤,可分离来自经免疫小鼠的脾细胞和/或淋巴结细胞且融合至适宜的永生化细胞系(例如小鼠黑素瘤细胞系)。可筛选所得杂交瘤以用于产生抗原特异性抗体。杂交瘤的生成在本领域中已众所周知。例如参见Harlow及Lane(1988)Antibodies,A Laboratory Manual,冷Spring Harbor Publications,NewYork。
产生本发明的单克隆抗体的转染瘤的生成
亦可在宿主细胞转染瘤中使用例如本领域中熟知的重组DNA技术及基因转染方法的组合来产生本发明抗体(例如Morrison,S.(1985)Science 229:1202)。在一个实施方案中,将通过标准分子生物技术获得的编码部分或全长轻链及重链的DNA插入一或多种表达载体中,从而使该基因可操作连接于转录和翻译调控序列。在此背景中,术语“可操作连接”意图指使抗体基因连接于载体以便使该载体内的转录及翻译控制序列发挥其调控抗体基因的转录及翻译的预期功能。
术语“调控序列”意图包含控制抗体链基因转录或翻译的启动子、增强子及其他表达控制元件(例如聚腺苷酸化信号)。这类调控序列阐述于(例如)Goeddel(GeneExpression Technology.Methods in Enzymology 185,Academic Press,San Diego,CA(1990))中。用于哺乳动物宿主细胞表达的优选调控序列包括在哺乳动物细胞中指导高水平的蛋白质表达的病毒元件,例如衍生自巨细胞病毒(CMV)、猿病毒40(SV40)、腺病毒(例如腺病毒主要晚期启动子(AdMLP))及多瘤病毒的启动子和/或增强子。或者,可使用非病毒调控序列,例如泛素启动子或β-球蛋白启动子。另外,调控元件是由来自不同来源的序列构成,例如SRα启动子系统,其含有来自SV40早期启动子及1型人T细胞白血病病毒的长末端重复的序列(Takebe等人(1988)Mol.Cell.Biol.8:466-472)。选择与所用表达宿主细胞相容的表达载体及表达控制序列。
可将抗体轻链基因及抗体重链基因插入相同或分别的表达载体中。在优选实施方案中,使用可变区通过以下方式产生任一抗体同种型的全长抗体基因:将其插入已编码期望同种型的重链恒定区及轻链恒定区的表达载体中,从而使得VH区段可操作连接于载体内的CH区段且VL区段可操作连接于载体内的CL区段。另外或备选地,重组表达载体可编码促进抗体链从宿主细胞分泌的信号肽。可将抗体链基因克隆至载体中,从而信号肽符合阅读框地连接至抗体链基因的氨基末端。所述信号肽可为免疫球蛋白信号肽或异源信号肽(即来自非免疫球蛋白的信号肽)。
除抗体链基因及调控序列外,本发明的重组表达载体可携载其他序列,例如调控宿主细胞中的载体复制的序列(例如复制起点)及可选标记物基因。可选标记物基因促进了引入载体的宿主细胞的选择(例如参见美国专利第4,399,216号、第4,634,665号及第5,179,017号)。举例而言,可选标记物基因通常赋予已引入载体的宿主细胞对药物(例如G418、潮霉素或甲氨蝶呤(methotrexate))的抗性。优选的可选标记物基因包括二氢叶酸还原酶(DHFR)基因(用于经甲氨蝶呤选择/扩增的dhfr-宿主细胞)及neo基因(用于G418选择)。
为表达轻链及重链,通过标准技术将编码重链及轻链的表达载体转染至宿主细胞中。术语“转染”的各种形式意图涵盖众多种通常用于将外源性DNA引入原核或真核宿主细胞中的很多种技术,例如电穿孔、磷酸钙沈淀、DEAE-右旋糖酐转染及诸如此类。尽管理论上可在原核或真核宿主细胞中表达本发明的抗体,但在真核细胞,且最优选地在哺乳动物宿主细胞中表达抗体是最优选的,因为这类真核细胞特别是哺乳动物细胞比原核细胞更有可能装配并分泌经适当折叠且具有免疫活性的抗体。
用于表达本发明的重组抗体的优选哺乳动物宿主细胞包括中国仓鼠卵巢(CHO细胞)(包括dhfr-CHO细胞,阐述于Urlaub及Chasin,(1980)Proc.Natl.Acad.Sci.USA 77:4216-4220中且与DHFR可选标记物(例如,如R.J.Kaufman及P.A.Sharp(1982)J.Mol.Biol.159:601-621中所阐述)一起使用)、NSO黑素瘤细胞、COS细胞及SP2细胞。具体地,对于与NSO黑素瘤细胞一起使用,另一优选的表达系统是披露于WO 87/04462、WO 89/01036及EP 338,841中的GS基因表达系统。在将编码抗体基因的重组表达载体引入哺乳动物宿主细胞中时,通过将宿主细胞培养一定时间段以足以在宿主细胞中表达抗体或更优选地将抗体分泌至生长宿主细胞的培养基中来产生抗体。可使用标准蛋白质纯化方法自培养基回收抗体。
免疫缀合物
可将本发明抗体缀合至治疗剂以形成免疫缀合物,例如抗体-药物缀合物(ADC)。适宜的治疗剂包含抗代谢物、烷化剂、DNA小沟结合剂、DNA嵌入剂、DNA交联剂、组蛋白去乙酰基酶抑制剂、核输出抑制剂、蛋白酶体抑制剂、拓扑异构酶I或II抑制剂、热激蛋白抑制剂、酪氨酸激酶抑制剂、抗生素及抗有丝分裂剂。在ADC中,抗体及治疗剂优选地经由可裂解的接头(例如肽基、二硫化物或腙接头)进行缀合。更优选地,所述接头是肽基接头,例如Val-Cit、Ala-Val、Val-Ala-Val、Lys-Lys、Pro-Val-Gly-Val-Val(SEQ ID NO:15)、Ala-Asn-Val、Val-Leu-Lys、Ala-Ala-Asn、Cit-Cit、Val-Lys、Lys、Cit、Ser或Glu。可如以下案件中所阐述的来制备ADC:美国专利第7,087,600号、第6,989,452号及第7,129,261号、PCT公开文本WO 02/096910、WO 07/038658、WO 07/051081、WO 07/059404、WO 08/083312及WO08/103693、美国专利公开案20060024317、20060004081及20060247295;其公开内容通过提述并入本文中。
双特异性分子
在另一方面,本公开的特征是双特异性分子,其包含一或多种连接至至少一种另外的功能分子(例如另一肽或蛋白质(例如用于受体的另一抗体或配体))的本发明抗体,从而生成结合至少两种不同结合位点或靶分子的双特异性分子。因此,如本文所使用,“双特异性分子”包含具有三种或更多种特异性的分子。在一个优选的实施方案中,双特异性分子包含用于LAG-3的第一结合特异性及用于触发分子(其募集可杀伤表达LAG-3的靶细胞的细胞毒性效应器细胞)的第二结合特异性。适宜的触发分子的例子是CD64、CD89、CD16及CD3。例如参见Kufer等人,TRENDS in Biotechnology,22(5),238-244(2004)。
在一个实施方案中,除抗Fc结合特异性及抗LAG-3结合特异性外,所述双特异性分子还具有第三特异性。第三特异性可针对抗增强因子(EF),例如结合涉及细胞毒性活性的表面蛋白且由此增加对靶细胞的免疫反应的分子。举例而言,抗增强因子可结合细胞毒性T细胞(例如经由CD2、CD3、CD8、CD28、CD4、CD40或ICAM-1)或其他免疫细胞,从而增加对靶细胞的免疫反应。
双特异性分子可具有许多不同形式和大小。在大小谱的一端,双特异性分子保留传统的抗体形式,只是其具有两个各自具有不同特异性的结合臂而非具有两个具有相同特异性的结合臂。在另一端是由通过肽链连接的两个单链抗体片段(scFv)组成的双特异性分子,即所谓的Bs(scFv)2构筑体。中间大小的双特异性分子包含两个由肽基接头连接的不同F(ab)片段。可通过基因工程、体细胞杂交或化学方法来制备这些和其他格式的双特异性分子。例如参见Kufer等人,参见上文所引用;Cao及Suresh,Bioconjugate Chemistry,9(6),635-644(1998);及van Spriel等人,Immunology Today,21(8),391-397(2000)及其中所引用的参考文献。
药物组合物
在另一方面,本公开提供一种药物组合物,其包括与药学可接受的载体一起配制的一或多种本发明的抗体。所述组合物任选地可含有一或多种其他药学活性成份,例如另一抗体或药物。本发明的药物组合物亦可以组合疗法与例如另一免疫刺激剂、抗癌剂、抗病毒剂或疫苗一起施用,从而使得抗LAG-3抗体增强对疫苗的免疫反应。
所述药物组合物可包括任意数量的赋形剂。可使用的赋形剂包含载体、表面活性剂、增稠剂或乳化剂、固体黏合剂、分散剂或悬浮助剂、增溶剂、染色剂、增味剂、涂层、崩解剂、润滑剂、甜味剂、防腐剂、等渗剂及其组合。适宜赋形剂的选择及应用教示于Gennaro编辑,Remington:The Science and Practice of Pharmacy,第20版(Lippincott Williams&Wilkins 2003)中,其公开通过提述并入本文中。
优选地,所述药物组合物适于静脉内施用、肌内施用、皮下施用、胃肠外施用、脊椎或表皮施用(例如通过注射或输注)。根据施用路径,可将活性化合物涂覆于一定材料中以保护其免受酸作用及其他可将其钝化的天然条件影响。本文所用的短语“胃肠外施用”意指除经肠及局部施用外的施用模式,通常是通过注射且包括但不限于静脉内、肌内、动脉内、鞘内、囊内、眼窝内、心内、真皮内、腹膜内、经气管、皮下、表皮下、关节内、囊下、蛛网膜下、经脊柱内、经硬膜外及经胸骨内注射及输注。或者,本发明的抗体可经由非胃肠外路径(例如局部、表皮)或黏膜施用途径(例如经鼻内、经口、经阴道、经直肠、经舌下或局部)施用。
本发明的药物组合物可包含药学接受的盐。“药学可接受的盐”是指保留母体化合物的期望生物活性且不赋予任何不期望的毒理学效应的盐。这类盐的实例包括酸加成盐及碱加成盐。酸加成盐包含那些衍生自以下酸的:无毒无机酸,例如盐酸、硝酸、磷酸、硫酸、氢溴酸、氢碘酸、亚磷酸及诸如此类;以及无毒有机酸,例如脂肪族单羧酸及二羧酸、经苯基取代的链烷酸、羟基链烷酸、芳族酸、脂肪族及芳族磺酸及诸如此类。碱加成盐包含那些衍生自以下物质的:碱土金属,例如钠、钾、镁、钙及诸如此类;以及无毒有机胺,例如N,N'-二苄基乙二胺、N-甲基葡糖胺、氯普鲁卡因(chloroprocaine)、胆碱、二乙醇胺、乙二胺、普鲁卡因(procaine)及诸如此类。
药物组合物可呈无菌水溶液或分散物的形式。其亦可配制于微乳液、脂质体或其他适用于高药物浓度的有序结构中。
可与载体材料组合产生单一剂量形式的活性成份的量将随所治疗受试者及特定施用模式而有所变化,且通常是产生治疗效应的组合物量。通常,在100个百分比中,此量的范围为约0.01%至约99%活性成份、优选地约0.1%至约70%活性成份、最佳地约1%至约30%活性成份(与药学可接受的载体组合)。
调节剂量方案以提供最佳期望反应(例如治疗性反应)。举例而言,可施用单一推注,可在一段时间内施用数个细分剂量或可如治疗状况紧急程度指示的按比例减小或增加剂量。以剂量单元形式来配制胃肠外组合物特别有利于方便施用及达成剂量一致性。本文所用的剂量单位形式是指适合作为单位剂量供拟治疗受试者使用的物理分散单位;每一单位含有预定量的活性化合物,此预定量经计算可与所需的药学载体一起产生期望的治疗效应。或者,可以持续释放制剂形式施用抗体,在该情形下需要更小的施用频率。
对于抗体施用而言,剂量范围为约0.0001mg/kg至100mg/kg宿主体重,更通常而言0.01mg/kg至5mg/kg宿主体重。举例而言,剂量可为0.3mg/kg体重、1mg/kg体重、3mg/kg体重、5mg/kg体重或10mg/kg体重、或在1-10mg/kg范围内。例示性治疗方案需要以以下方式施用:每周一次、每两周一次、每三周一次、每四周一次、每月一次、每3个月一次或每3至6个月一次。本发明的抗LAG-3抗体的优选剂量方案包含经由静脉内施用来施用1mg/kg体重或3mg/kg体重,其中使用下列给药时间表中的一种来给予抗体:(i)每四周给予6个剂量,然后每三个月一次;(ii)每三周一次;(iii)每三周给予一次3mg/kg体重随后给予1mg/kg体重。在一些方法中,调整剂量以达成约1-1000μg/ml及在一些方法中约25-300μg/ml的血浆抗体浓度。
本发明的抗LAG-3抗体的“治疗有效剂量”优选地使得可降低疾病症状的严重程度,增加疾病无症状期的频率及持续时间,或预防由染病所致的损伤或失能。举例而言,为治疗带肿瘤的受试者,相对于未治疗受试者,“治疗有效剂量”优选地将肿瘤生长抑制至少约20%、更优选地至少约40%、甚至更优选地至少约60%及更优选地至少约80%。治疗有效量的治疗性化合物可减小肿瘤大小,或以其他方式改善受试者(其通常是人或可为另一哺乳动物)中的症状。
药物组合物可为受控释放的制剂,包含植入物、经皮贴片及微胶囊化的递送系统。可使用生物可降解的生物相容的聚合物,例如乙烯基乙酸乙烯酯、聚酐、聚乙醇酸、胶原、聚原酸酯及聚乳酸。例如参见Sustained and Controlled Release Drug DeliverySystems,J.R.Robinson编辑,Marcel Dekker公司,New York,1978。
可经由医学装置施用治疗性组合物,例如(1)无针皮下注射装置(例如US 5,399,163、5,383,851、5,312,335、5,064,413、4,941,880、4,790,824及4,596,556);(2)微输注泵(US 4,487,603);(3)经皮装置(US 4,486,194);(4)输注装置(US 4,447,233及4,447,224);及(5)渗透装置(US 4,439,196及4,475,196);其公开内容以引用方式并入本文中。
在某些实施方案中,可将本发明的人单克隆抗体配制为确保在体内合理分布。举例而言,为确保本发明的治疗性化合物穿过血-脑屏障,可将其配制在脂质体中,所述脂质体可另外包括靶向性模块以增强至特定细胞或器官的选择性运输。例如参见US 4,522,811;5,374,548;5,416,016;及5,399,331;V.V.Ranade(1989)J.Clin.Pharmacol.29:685;Umezawa等人,(1988)Biochem.Biophys.Res.Commun.153:1038;Bloeman等人(1995)FEBSLett.357:140;M.Owais等人(1995)Antimicrob.Agents Chemother.39:180;Briscoe等人(1995)Am.J.Physiol.1233:134;Schreier等人(1994)J.Biol.Chem.269:9090;Keinanen及LAukkanen(1994)FEBS Lett.346:123;及Killion及Fidler(1994)Immunomethods 4:273。
本发明的用途及方法
本发明的抗体(组合物、双特异性分子及免疫缀合物)具有多种涉及(例如)检测LAG-3或通过阻断LAG-3来增强免疫反应的体外及体内用途。在一个优选的实施方案中,所述抗体是人抗体。可将这类抗体施用到体外或离体培养的细胞中或对人受试者(例如体内)施用以增强各种情形下的免疫性。因此,在一个方面,本发明提供对受试者中的免疫反应实施修改的方法,其包括向该受试者施用本发明的抗体或其抗原结合部分,从而对受试者中的免疫反应实施修改。优选地,反应得以增强、刺激或上调。
优选的受试者包含需要增强免疫反应的人患者。所述方法尤其适于治疗患有可通过增大免疫反应(例如T细胞介导的免疫反应)来治疗的病症的人患者。在一具体的实施方案中,所述方法尤其适于治疗体内癌症。为实现免疫性的抗原特异性增强,可将抗LAG-3抗体与感兴趣的抗原一起施用或该抗原可已存在于拟治疗的受试者(例如带肿瘤或携带病毒的受试者)中。在将LAG-3抗体与另一药剂一起施用时,二者可以任一顺序或同时施用。
本发明进一步提供检测样品中人LAG-3抗原的存在、或测量人LAG-3抗原的量的方法,其包括使样品及对照样品与人单克隆抗体或其抗原结合部分(其特异性结合至人LAG-3)在容许在抗体或其部分与人LAG-3之间形成复合物的条件下接触。然后检测复合物的形成,其中样品与对照样品之间复合物形成的差异可指示样品中人LAG-3抗原的存在。另外,可使用本发明的抗LAG-3抗体经由免疫亲和纯化来纯化人LAG-3。
鉴于本发明的抗LAG-3抗体能够抑制LAG-3对MHC II类分子的结合并刺激抗原特异性T细胞反应,本发明亦提供使用该抗体来刺激、增强或上调抗原特异性T细胞反应的体外及体内方法。举例而言,本发明提供刺激抗原特异性T细胞反应的方法,其包括使所述T细胞与本发明的抗体接触,从而刺激抗原特异性T细胞反应。可使用抗原特异性T细胞反应的任一适宜指示物来测量抗原特异性T细胞反应。这类适宜指示物的非限制性例子包含在抗体存在下增加的T细胞增殖和/或在抗体存在下增加细胞因子产生。在一个优选的实施方案中,刺激通过抗原特异性T细胞来产生白介素-2。
本发明亦提供刺激受试者中的免疫反应(例如抗原特异性T细胞反应)的方法,其包括向受试者施用本发明抗体,从而刺激受试者中的免疫反应(例如抗原特异性T细胞反应)。在一个优选的实施方案中,受试者是带肿瘤受试者且刺激对肿瘤的免疫反应。在另一优选实施方案中,受试者是带病毒的受试者且刺激对病毒的免疫反应。
在另一个实施方案中,本发明提供抑制受试者中的肿瘤细胞生长的方法,其包括向受试者施用本发明抗体,从而抑制受试者中的肿瘤生长。在又一实施方案中,本发明提供治疗受试者的病毒感染的方法,其包括向受试者施用本发明抗体,从而治疗受试者的病毒感染。
本发明的这类及其他方法进一步详细论述于下文中。
癌症
通过抗体阻断LAG-3可增强患者对癌细胞的免疫反应。在一个方面,本发明涉及使用抗LAG-3抗体在体内治疗受试者,从而抑制癌症性肿瘤的生长。可单独使用抗LAG-3抗体来抑制癌症性肿瘤的生长。或者,抗LAG-3抗体可与其他免疫原性剂、标准癌症治疗或其他抗体结合使用,如下文所描述的。
因此,在一个实施方案中,本发明提供抑制受试者中肿瘤细胞的生长的方法,其包括向受试者施用治疗有效量的抗LAG-3抗体或其抗原结合部分。优选地,所述抗体是人抗LAG-3抗体(例如本文所阐述的人的抗人LAG-3抗体中的任一者)。另外或备选地,所述抗体可为嵌合或人源化抗LAG-3抗体。
可使用本发明抗体抑制生长的优选癌症包括通常对免疫疗法具有反应的癌症。用于治疗的优选癌症的非限制性实例包含黑素瘤(例如转移性恶性黑素瘤)、肾癌(例如透明细胞癌瘤)、前列腺癌(例如激素难治性前列腺腺癌)、乳腺癌、结肠癌及肺癌(例如非小细胞肺癌)。另外,本发明包括可使用本发明抗体抑制生长的难治性或复发性恶性肿瘤。
可使用本发明方法治疗的其他癌症的实例包含骨癌、胰腺癌、皮肤癌、头和颈癌、皮肤或眼内恶性黑素瘤、子宫癌、卵巢癌、直肠癌、肛门区癌、胃癌、睾丸癌、输卵管癌、子宫内膜癌、宫颈癌、阴道癌、外阴癌、霍奇金氏病(Hodgkin's Disease)、非霍奇金氏淋巴瘤(non-Hodgkin's lymphoma)、食道癌、小肠癌、内分泌系统癌、甲状腺癌、副甲状腺癌症、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、慢性或急性白血病(包含急性骨髓性白血病、慢性骨髓性白血病、急性淋巴母细胞性白血病、慢性淋巴细胞性白血病)、儿童实体肿瘤、淋巴细胞性淋巴瘤、膀胱癌、肾或输尿管癌、肾盂癌、中枢神经系统(CNS)赘瘤、原发性CNS淋巴瘤、肿瘤血管生成、脊柱瘤、脑干胶质瘤、垂体腺瘤、卡波西氏肉瘤(Kaposi's sarcoma)、表皮样癌、鳞状细胞癌、T细胞淋巴瘤、环境诱导的癌症(包含那些由石棉诱导的者)及所述癌症的组合。本发明亦可用于治疗转移性癌症,尤其表达PD-L1的转移性癌症(Iwai等人(2005)Int.Immunol.17:133-144)。
任选地,可将LAG-3抗体与免疫原性剂(例如癌细胞、经纯化肿瘤抗原(包含重组蛋白、肽及碳水化合物分子)、细胞及经编码免疫刺激细胞因子的基因转染的细胞)组合(He等人(2004)J.Immunol.173:4919-28)。可使用的肿瘤疫苗的非限制性实例包括黑素瘤抗原的肽(例如gp100、MAGE抗原、Trp-2、MART1和/或酪氨酸酶的肽)或经转染以表达细胞因子GM-CSF的肿瘤细胞(进一步论述于下文中)。
在人中,已展示一些肿瘤具有免疫原性,例如黑素瘤。通过以LAG-3阻断提高T细胞活化的临限值,可活化宿主中的肿瘤反应。
在与疫苗接种方案组合时,LAG-3阻断很可能更为有效。已设计用于对肿瘤进行疫苗接种的许多实验策略(参见Rosenberg,S.,2000,Development of Cancer Vaccines,ASCO Educational Book Spring:60-62;Logothetis,C.,2000,ASCO Educational BookSpring:300-302;Khayat,D.2000,ASCO Educational Book Spring:414-428;Foon,K.2000,ASCO Educational Book Spring:730-738;亦参见Restifo,N.及Sznol,M.,CancerVaccines,第61章,第3023-3043页,DeVita等人(编辑),1997,Cancer:Principles andPractice of Oncology,第5版)。在其中一种策略中,使用自体或同种异体肿瘤细胞制备疫苗。这些细胞疫苗已展示在转导肿瘤细胞以表达GM-CSF时最有效。已展示GM-CSF是用于肿瘤疫苗接种的抗原呈现的强力活化剂(Dranoff等人(1993)Proc.Natl.Acad.SciU.S.A.90:3539-43)。
在各种肿瘤中对于基因表达及大规模基因表达模式的研究已定义了所谓的肿瘤特异性抗原(Rosenberg,SA(1999)Immunity 10:281-7)。在许多情形下,这类肿瘤特异性抗原是表达于肿瘤及发生肿瘤的细胞中的分化抗原,例如黑素细胞抗原gp100、MAGE抗原及Trp-2。更重要的是,许多这些抗原可显示为是在宿主中发现的肿瘤特异性T细胞的靶物。可将LAG-3阻断与表达于肿瘤中的重组蛋白和/或肽的集合组合以生成对这类蛋白质的免疫反应。这些蛋白质通常被免疫系统视为自体抗原且由此对其耐受。肿瘤抗原可包括蛋白质端粒末端转移酶,其是合成染色体的端粒所需且表达于超过85%的人癌症中及仅有限数量的体细胞组织中(Kim等人(1994)Science 266:2011-2013)。(可通过各种方式保护这些体细胞组织免受免疫攻击)。肿瘤抗原亦可为因体细胞突变(其改变蛋白质序列或在两个非相关序列之间创建融合蛋白(即费城染色体(Philadelphia chromosome)中的bcr-abl))表达于癌细胞中的“新抗原”,或来自B细胞肿瘤的独特型。
其他肿瘤疫苗可包含来自与人癌症有关的病毒(例如人乳头瘤病毒(HPV)、肝炎病毒(HBV及HCV)及卡波西氏疱疹肉瘤病毒(KHSV))的蛋白质。可与LAG-3阻断结合使用的肿瘤特异性抗原的另一形式是自肿瘤组织本身分离的经纯化热激蛋白(HSP)。这些热激蛋白含有来自肿瘤细胞的蛋白质片段且这些HSP可高度有效地递送至抗原呈现细胞以用于引发肿瘤免疫性(Suot及Srivastava(1995)Science 269:1585-1588;Tamura等人(1997)Science278:117-120)。
树突细胞(DC)是可用于引发抗原特异性反应的强力抗原呈现细胞。DC可离体产生且载有各种蛋白质及肽抗原以及肿瘤细胞提取物(Nestle等人(1998)Nature Medicine 4:328-332)。亦可通过遗传手段转导DC以亦表达这类肿瘤抗原。亦将DC直接融合至肿瘤细胞以用于免疫目的(Kugler等人(2000)Nature Medicine 6:332-336)。作为一种疫苗接种方法,DC免疫可与LAG-3阻断有效组合以活化更强力的抗肿瘤反应。
LAG-3阻断亦可与标准癌症治疗进行组合。LAG-3阻断可与化学治疗方案有效组合。在这类情况下,可减小所施用化学治疗试剂的剂量(Mokyr等人(1998)Cancer Research58:5301-5304)。此一组合的一实例是抗LAG-3抗体与达卡巴嗪(decarbazine)的用于治疗黑素瘤的组合。此一组合的另一实例是抗LAG-3抗体与白介素-2(IL-2)的用于治疗黑素瘤的组合。组合使用LAG-3阻断及化疗的科学原理在于,细胞死亡(其是大部分化疗化合物的细胞毒性作用的结果)应使得抗原呈现路径中的肿瘤抗原的水平有所增加。可与LAG-3阻断经由细胞死亡产生协同作用的其他组合疗法是放射、手术及激素剥夺。这类方案中的每一者皆产生宿主中的肿瘤抗原的来源。亦可组合血管生成抑制剂与LAG-3阻断。对血管生成的抑制会引起肿瘤细胞死亡,此可将肿瘤抗原供给至宿主抗原呈现途径中。
LAG-3阻断抗体亦可与使Fcα或Fcγ受体表达效应器细胞靶向肿瘤细胞的双特异性抗体组合使用(例如参见美国专利第5,922,845号及第5,837,243号)。可使用双特异性抗体靶向两种分别的抗原。举例而言,使用抗Fc受体/抗肿瘤抗原(例如Her-2/neu)双特异性抗体将巨噬细胞靶向至肿瘤位点。此靶向可更有效地活化肿瘤特异性反应。通过使用LAG-3阻断来增大这类反应的T细胞分支。或者,可通过使用结合肿瘤抗原及树突细胞特异性细胞表面标记物的双特异性抗体来将抗原直接递送至DC。
肿瘤通过诸多机制逃避宿主免疫监控。可通过钝化由肿瘤表达且是免疫阻抑性的蛋白质来克服许多这类机制。这些包括TGF-β(Kehrl等人(1986)J.Exp.Med.163:1037-1050)、IL-10(Howard及O'Garra(1992)Immunology Today13:198-200)及Fas配体(Hahne等人(1996)Science 274:1363-1365)等。针对这些实体中每一种的抗体可与抗LAG-3组合使用以抵抗免疫阻抑剂的作用且有益于宿主的肿瘤免疫反应。
其他活化宿主免疫反应性的抗体可与抗LAG-3组合使用。这些抗体包括位于树突细胞表面上的活化DC功能及抗原呈现的分子。抗CD40抗体能够有效替代T辅助细胞活性(Ridge等人(1998)Nature 393:474-478)且可与LAG-3抗体结合使用(Ito等人(2000)Immunobiology 201(5)527-40)。活化针对T细胞共刺激性分子(例如CTLA-4(例如美国专利第5,811,097号)、OX-40(Weinberg等人(2000)Immunol 164:2160-2169)、4-1BB(Melero等人(1997)Nature Medicine 3:682-685(1997)及ICOS(Hutloff等人(1999)Nature 397:262-266))亦可提供增加的T细胞活化水平。
当前使用骨髓移植来治疗各种造血源的肿瘤。尽管移植物对宿主病是此治疗的结果,但可自移植物对肿瘤反应获得治疗益处。可使用LAG-3阻断来增加供体植入的肿瘤特异性T细胞的有效性。
亦存在若干实验治疗方案,其涉及离体活化及扩展抗原特异性T细胞且将这类细胞过继性转移至接受者中以刺激针对肿瘤的抗原特异性T细胞(Greenberg及Riddell(1999)Science 285:546-51)。这类方法亦可用于活化对感染剂(例如CMV)的T细胞反应。在抗LAG-3抗体存在下的离体活化可增加过继性转移的T细胞的频率及活性。
传染病
使用本发明的其他方法来治疗已暴露于特定毒素或病原体的患者。因此,本发明的另一方面提供治疗受试者中的传染病的方法,其包括向受试者施用抗LAG-3抗体或其抗原结合部分,从而治疗受试者的传染病。优选地,所述抗体是人的抗人LAG-3抗体(例如本文所阐述人抗LAG-3抗体中的任一者)。另外或备选地,所述抗体可为嵌合或人源化抗体。
类似于如上文所论述在肿瘤中的应用,可单独使用抗体介导的LAG-3阻断或作为辅助方式与疫苗组合使用以刺激对病原体、毒素及自体抗原的免疫反应。此治疗方式可尤其有用的病原体的实例包含当前并无有效疫苗的病原体或常规疫苗不能完全有效的病原体。这些病原体包含但不限于HIV、肝炎(A、B及C)、流感、疱疹、梨形鞭毛虫属(Giardia)、疟疾、利什曼虫(Leishmania)、金黄色葡萄球菌(Staphylococcus aureus)、绿脓假单胞菌(Pseudomonas aeruginosa)。LAG-3阻断尤其可用于在感染过程中呈现改变的抗原的因子(例如HIV)的确立感染。这类新的表位在施用抗人LAG-3时可识别为外来物,由此引起较强的T细胞反应,其不通过经由LAG-3的负信号减弱。
引起可通过本发明方法治疗的感染的病原性病毒的一些实例包含HIV、肝炎(A、B或C)、疱疹病毒(例如VZV、HSV-1、HAV-6、HSV-II及CMV、爱泼斯坦巴尔病毒(Epstein Barrvirus))、腺病毒、流感病毒、黄病毒、埃可病毒(echovirus)、鼻病毒、柯萨奇病毒(coxsackie virus)、冠状病毒、呼吸道合胞病毒、腮腺炎病毒、轮状病毒、麻疹病毒、风疹病毒、细小病毒、牛痘病毒、HTLV病毒、登革病毒(dengue virus)、乳头状瘤病毒、软疣病毒、脊髓灰质炎病毒、狂犬病病毒、JC病毒及虫媒病毒性脑炎病毒。
引起可通过本发明方法治疗的感染的病原性细菌的一些实例包含衣原体(chlamydia)、立克次氏体细菌(rickettsial bacteria)、分枝杆菌(mycobacteria)、葡萄球菌(staphylococci)、链球菌(streptococci)、肺炎球菌(pneumonococci)、脑膜炎球菌及淋球菌(meningococci and gonococci)、克雷伯菌(klebsiella)、变形杆菌(proteus)、沙雷氏菌(serratia)、假单胞菌(pseudomonas)、军团杆菌(legionella)、白喉(diphtheria)、沙门氏菌(salmonella)、杆菌(bacilli)、霍乱、破伤风(tetanus)、肉毒杆菌(botulism)、炭疽热、瘟疫、钩端螺旋体(leptospirosis)及莱姆病细菌(Lymes disease bacteria)。
引起可通过本发明方法治疗的感染的病原性真菌的一些实例包含假丝酵母(Candida)(白色(albicans)、克鲁斯氏(krusei)、光滑(glabrata)、热带(tropicalis)假丝酵母等)、新型隐球菌(Cryptococcus neoformans)、曲霉菌(Aspergillus)(烟曲菌(fumigatus)、黑曲霉(niger)等)、毛霉菌属(Genus Mucorales)(毛霉菌(mucor)、犁头霉菌(absidia)、根霉菌(rhizopus))、申克氏孢丝菌(Sporothrix schenkii)、皮炎芽生菌(Blastomyces dermatitidis)、巴西副球孢子菌(Paracoccidioides brasiliensis)、粗球孢子菌(Coccidioides immitis)及夹膜组织胞浆菌(Histoplasma capsulatum)。
引起可通过本发明方法治疗的感染的病原性寄生虫的一些实例包含溶组织内阿米巴(Entamoeba histolytica)、大肠纤毛虫(Balantidium coli)、福氏耐格里变形虫(Naegleriafowleri)、棘阿米巴属的种(Acanthamoeba sp.)、梨形鞭毛虫(Giardialambia)、隐孢子虫属的种(Cryptosporidium sp.)、卡氏肺囊虫(Pneumocystis carinii)、间日疟原虫(Plasmodium vivax)、巴贝亚原虫(Babesia microti)、布鲁斯锥虫(Trypanosoma brucei)、克氏锥虫(Trypanosoma cruzi)、多氏利什曼虫(Leishmaniadonovani)、刚地弓形虫(Toxoplasma gondii)、巴西日圆线虫(Nippostrongylusbrasiliensis)。
在所有上述方法中,LAG-3阻断可与其他形式的免疫疗法(例如细胞因子治疗(例如干扰素、GM-CSF、G-CSF、IL-2)或双特异性抗体疗法)组合,这会提供增强的肿瘤抗原呈现(例如参见Holliger(1993)Proc.Natl.Acad.Sci.USA 90:6444-6448;Poljak(1994)Structure 2:1121-1123)。
自体免疫反应
抗LAG-3抗体可引起且扩大自体免疫反应。实际上,使用肿瘤细胞及肽疫苗诱导抗肿瘤反应揭示,许多抗肿瘤反应涉及抗自身反应性(van Elsas等人(2001)J.Exp.Med.194:481-489;Overwijk等人(1999)Proc.Natl.Acad.Sci.U.S.A.96:2982-2987;Hurwitz,(2000),参见上文;Rosenberg及White(1996)J.Immunother Emphasis Tumor Immunol 19(1):81-4)。因此,可考虑将各种自体蛋白质与使用抗LAG-3阻断结合以设计疫苗接种方案,从而有效生成针对这类自体蛋白质的免疫反应以用于疾病治疗。举例而言,阿兹海默氏病(Alzheimer’s disease)涉及淀粉样蛋白沉积物中的Aβ肽在脑中的不恰当积累;针对淀粉样蛋白的抗体反应能够清除这些淀粉样蛋白沉积物(Schenk等人,(1999)Nature 400:173-177)。
亦可使用其他自体蛋白质作为靶物,例如IgE(用于治疗过敏及哮喘)及TNFα(用于类风湿性关节炎)。最后,可通过使用抗LAG-3抗体来诱导对各种激素的抗体反应。可使用针对生殖激素的中和抗体反应来进行避孕。针对激素及特定肿瘤的生长所需的其他可溶性因子的中和抗体反应亦可视为可能的疫苗接种靶物。
可使用如上文所阐述使用抗LAG-3抗体的类似方法来诱导治疗性自体免疫反应以治疗具有其他自体抗原(例如淀粉样蛋白沉积物(包括阿兹海默氏病中的Aβ)、细胞因子(例如TNFα)及IgE)的不恰当积累的患者。
疫苗
可使用抗LAG-3抗体来刺激抗原特异性免疫反应,其通过将抗LAG-3抗体与感兴趣的抗原(例如疫苗)共施用。因此,在另一个方面,本发明提供增强受试者中对抗原的免疫反应的方法,其包括向受试者施用:(i)该抗原;及(ii)抗LAG-3抗体或其抗原结合部分,从而增强受试者中对该抗原的免疫反应。优选地,所述抗体是人的抗人LAG-3抗体(例如本文所阐述人抗LAG-3抗体中的任一者)。另外或备选地,所述抗体可为嵌合或人源化抗体。所述抗原可为例如肿瘤抗原、病毒抗原、细菌抗原或来自病原体的抗原。这类抗原的非限制性实例包含上文部分中论述的那些,例如上述肿瘤抗原(或肿瘤疫苗)、或来自病毒、细菌或上述其他病原体的抗原。
在体内及体外施用本发明的抗体组合物(例如人单克隆抗体、多特异性及双特异性分子及免疫缀合物)的适宜路径在本领域中已众所周知且可由本领域普通技术人员进行选择。举例而言,可通过注射(例如静脉内或皮下)施用抗体组合物。所用分子的适宜剂量取决于受试者的年龄及体重及抗体组合物的浓度和/或剂型。
如先前所阐述,本发明的人抗LAG-3抗体可与一或多种其他治疗剂(例如细胞毒性剂、放射性毒性剂或免疫阻抑剂)共施用。抗体可连接至药剂(呈免疫复合物形式)或可与药剂分开施用。在后一情形(分开施用)下,抗体可在药剂之前、之后或与该药剂同时施用,或可与其他已知疗法(例如抗癌疗法,例如放射)共施用。这类治疗剂包括本身仅在对患者具有毒性或亚毒性的水平有效的抗肿瘤剂,例如多柔比星(doxorubicin)(阿霉素(adriamycin))、顺铂(cisplatin)、硫酸博来霉素(bleomycin sulfate)、卡莫司汀(carmustine)、苯丁酸氮芥(chlorambucil)、达卡巴嗪(dacarbazine)及环磷酰胺(cyclophosphamide)、羟基脲(hydroxyurea)。以100mg/ml剂量每四周一次经静脉内施用顺铂,且以60-75mg/ml剂量每21天一次静脉内施用阿霉素。将本发明的人抗LAG-3抗体或其抗原结合片段与化学治疗剂共施用会提供两种抗癌剂,该两种抗癌剂经由不同机制发挥作用以得到对人肿瘤细胞的细胞毒性效应。这类共施用可解决由对药物产生抗性或肿瘤细胞的抗原性发生变化(这会使得其与抗体无反应性)所致的问题。
试剂盒亦在本发明范围内,其包括本发明的抗体组合物(例如人抗体、双特异性或多特异性分子、或免疫缀合物)及使用说明书。试剂盒可进一步含有至少一种另外的试剂、或本发明的一或多种其他人抗体(例如具有互补活性的人抗体,其结合LAG-3抗原中与第一人抗体不同的表位)。试剂盒通常包含指示试剂盒内容物的预期用途的标签。术语标签包括提供于试剂盒上或与试剂盒一起提供或以其他方式伴随试剂盒的任意书写或记录材料。
组合疗法
在另一方面,本发明提供组合疗法的方法,其中将本发明的抗LAG-3抗体(或其抗原结合部分)与一或多种其他抗体(其有效刺激免疫反应以由此进一步增强、刺激或上调受试者中的免疫反应)共施用。在一个实施方案中,本发明提供刺激受试者中的免疫反应的方法,其包括向受试者施用抗LAG-3抗体及一或多种其他免疫刺激性抗体(例如抗PD-1抗体、抗PD-L1抗体和/或抗CTLA-4抗体),从而刺激受试者中的免疫反应(例如抑制肿瘤生长或刺激抗病毒反应)。在另一个实施方案中,向受试者施用抗LAG-3抗体及抗PD-1抗体。在再一实施方案中,向受试者施用抗LAG-3抗体及抗PD-L1抗体。在又一实施方案中,向受试者施用抗LAG-3抗体及抗CTLA-4抗体。在一个实施方案中,抗LAG-3抗体是人抗体(例如本公开的抗体)。或者,所述抗LAG-3抗体可为例如嵌合或人源化抗体(例如自小鼠抗LAG-3mAb制得)。在另一个实施方案中,至少一种另外的免疫刺激性抗体(例如抗PD-1、抗PD-L1和/或抗CTLA-4抗体)是人抗体。或者,至少一种另外的免疫刺激性抗体可为例如嵌合或人源化抗体(例如自小鼠抗PD-1、抗PD-L1和/或抗CTLA-4抗体制得)。
在另一个实施方案中,本发明提供治疗过度增殖性疾病(例如癌症)的方法,其包括向受试者施用LAG-3抗体及CTLA-4抗体。在进一步的实施方案中,以亚治疗性(subtherapeutic)剂量施用抗LAG-3抗体,以亚治疗性剂量施用抗CTLA-4抗体,或以亚治疗性剂量施用二者。在另一个实施方案中,本发明提供改变与使用免疫刺激剂治疗过度增殖性疾病有关的不良事件的方法,其包括向受试者施用抗LAG-3抗体及亚治疗性剂量的抗CTLA-4抗体。在某些实施方案中,受试者是人。在其他实施方案中,抗CTLA-4抗体是人序列单克隆抗体10D1(阐述于PCT公开文本WO 01/14424中)且抗LAG-3抗体是人序列单克隆抗体(例如本文中所阐述的LAG3.5)。本发明方法所涵盖的其他抗CTLA-4抗体包含例如披露在以下中的那些抗体:WO 98/42752;WO 00/37504;美国专利第6,207,156号;Hurwitz等人(1998)Proc.Natl.Acad.Sci.USA 95(17):10067-10071;Camacho等人(2004)J.Clin.Oncology 22(145):摘要编号:2505(抗体CP-675206);及Mokyr等人(1998)CancerRes.58:5301-5304。在某些实施方案中,抗CTLA-4抗体以5×10-8M或更小的KD结合人CTLA-4,以1×10-8M或更小的KD结合人CTLA-4,以5×10-9M或更小的KD结合人CTLA-4,或以介于1×10-8M至1×10-10M之间或更小的KD结合人CTLA-4。
在另一个实施方案中,本发明提供治疗过度增殖性疾病(例如癌症)的方法,其包括向受试者施用LAG-3抗体及PD-1抗体。在进一步的实施方案中,以亚治疗性剂量施用抗LAG-3抗体,以亚治疗性剂量施用抗PD-1抗体,或以亚治疗性剂量施用二者。在另一个实施方案中,本发明提供改变与使用免疫刺激剂治疗过度增殖性疾病有关的不良事件的方法,其包括向受试者施用抗LAG-3抗体及亚治疗性剂量的抗PD-1抗体。在某些实施方案中,受试者是人。在某些实施方案中,抗PD-1抗体是人序列单克隆抗体且抗LAG-3抗体是人序列单克隆抗体(例如本文中所阐述的LAG3.5)。人序列抗PD-1抗体的实例包括PCT公开文本WO 06/121168中所阐述的17D8、2D3、4H1、5C4及4A11。其他抗PD-1抗体包括(例如)拉姆珠单抗(lambrolizumab)(WO2008/156712)及AMP514(WO2010/027423、WO2010/027827、WO2010/027828、WO2010/098788)。在某些实施方案中,抗PD-1抗体以5×10-8M或更小的KD结合人PD-1,以1×10-8M或更小的KD结合人PD-1,以5×10-9M或更小的KD结合人PD-1,或以介于1×10-8M与1×10-10M之间或更小的KD结合人PD-1。
在另一个实施方案中,本发明提供治疗过度增殖性疾病(例如癌症)的方法,其包括向受试者施用LAG-3抗体及PD-L1抗体。在进一步的实施方案中,以亚治疗性剂量施用抗LAG-3抗体,以亚治疗性剂量施用抗PD-L1抗体,或以亚治疗性剂量施用二者。在另一个实施方案中,本发明提供改变与使用免疫刺激剂治疗过度增殖性疾病有关的不良事件的方法,其包括向受试者施用抗LAG-3抗体及亚治疗性剂量的抗PD-L1抗体。在某些实施方案中,受试者是人。在其他实施方案中,抗PD-L1抗体是人序列单克隆抗体且抗LAG-3抗体是人序列单克隆抗体(例如本文中所阐述的LAG3.5)。人序列抗PD-L1抗体的实例包括PCT公开文本WO07/005874中所阐述的3G10、12A4、10A5、5F8、10H10、1B12、7H1、11E6、12B7及13G4。其他抗PD-L1抗体包括例如MPDL3280A(RG7446)(WO2010/077634)、MEDI4736(WO2011/066389)及MDX1105(WO2007/005874)。在某些实施方案中,抗PD-L1抗体以5×10-8M或更小的KD结合人PD-L1,以1×10-8M或更小的KD结合人PD-L1,以5×10-9M或更小的KD结合人PD-L1,或以介于1×10-8M与1×10-10M之间或更小的KD结合人PD-L1。
通过抗体阻断LAG-3及一或多种第二靶抗原(例如CTLA-4和/或PD-1和/或PD-L1)可增强患者中对于癌细胞的免疫反应。可使用本公开的抗体抑制生长的癌症包括通常对免疫疗法具有响应性的癌症。使用本公开的组合疗法治疗的癌症的代表性实例包括在论述抗LAG-3抗体单一疗法时于上文中具体列示的那些癌症。
在某些实施方案中,本文所论述治疗性抗体的组合可作为在药学可接受的载体中的单一组合物同时施用,或作为分开的组合物(其中每一抗体皆在药学可接受的载体中)同时施用。在另一个实施方案中,可序贯施用治疗性抗体的组合。举例而言,可序贯施用抗CTLA-4抗体及抗LAG-3抗体,例如首先施用抗CTLA-4抗体然后施用抗LAG-3抗体,或首先施用抗LAG-3抗体然后施用抗CTLA-4抗体。另外或备选地,可序贯施用抗PD-1抗体及抗LAG-3抗体,例如首先施用抗PD-1抗体然后施用抗LAG-3抗体,或首先施用抗LAG-3抗体然后施用抗PD-1抗体。另外或备选地,可序贯施用抗PD-L1抗体及抗LAG-3抗体,例如首先施用抗PD-L1抗体然后施用抗LAG-3抗体,或首先施用抗LAG-3抗体然后施用抗PD-L1抗体。
另外,若序贯施用超过一剂的组合疗法,则在每一施用时间点可逆转序贯施用的次序或保持同一次序,序贯施用可与同时施用组合,或使用其任一组合。举例而言,抗CTLA-4抗体及抗LAG-3抗体的组合的第一施用可同时进行,第二施用可为序贯的,即首先施用抗CTLA-4且然后施用抗LAG-3,而第三施用可为序贯的,即首先施用抗LAG-3且然后施用抗CTLA-4,等等。另外或备选地,抗PD-1抗体及抗LAG-3抗体的组合的第一施用可同时进行,第二施用可为首先施用抗PD-1然后施用抗LAG-3的序贯施用,而第三施用可为首先施用抗LAG-3然后施用抗PD-1的序贯施用,等等。另外或备选地,抗PD-L1抗体及抗LAG-3抗体的组合的第一施用可同时进行,第二施用可为首先施用抗PD-L1然后施用抗LAG-3的序贯施用,而第三施用可为首先施用抗LAG-3然后施用抗PD-L1的序贯施用,等等。另一代表性投药方案可涉及为首先施用抗LAG-3然后施用抗CTLA-4(和/或抗PD-1和/或抗PD-L1)的序贯施用的第一施用,及随后可同时施用。
任选地,抗LAG-3及一或多种其他抗体(例如抗CTLA-4和/或抗PD-1和/或抗PD-L1抗体)的组合可进一步与免疫原性剂(例如癌细胞、经纯化肿瘤抗原(包括重组蛋白、肽及碳水化合物分子)、细胞及经编码免疫刺激细胞因子的基因转染的细胞)组合(He等人(2004)J.Immunol.173:4919-28)。可使用的肿瘤疫苗的非限制性实例包括黑素瘤抗原的肽(例如gp100、MAGE抗原、Trp-2、MART1和/或酪氨酸酶的肽),或经转染以表达细胞因子GM-CSF的肿瘤细胞(进一步论述于下文中)。组合的LAG-3及CTLA-4和/或PD-1和/或PD-L1阻断可进一步与疫苗接种方案(例如上文针对使用抗LAG-3抗体的单一疗法详细论述的疫苗接种方案中的任一者)组合。
组合的LAG-3及CTLA-4和/或PD-1和/或PD-L1阻断亦可进一步与标准癌症治疗组合。举例而言,组合的LAG-3及CTLA-4和/或PD-1和/或PD-L1阻断可与化学治疗方案有效组合。在这类情况下,可减小与本公开的组合一起施用的另一化学治疗试剂的剂量(Mokyr等人(1998)Cancer Research 58:5301-5304)。这类组合的一个例子是抗LAG-3及抗CTLA-4抗体和/或抗PD-1抗体和/或抗PD-L1抗体的组合进一步与达卡巴嗪组合以用于治疗黑素瘤。另一个例子是抗LAG-3及抗CTLA-4抗体和/或抗PD-1抗体和/或抗PD-L1抗体的组合进一步与白介素-2(IL-2)组合用于治疗黑素瘤。组合使用LAG-3及CTLA-4和/或PD-1和/或PD-L1阻断及化学疗法的科学原理在于,细胞死亡(其是大部分化疗化合物的细胞毒性作用的结果)应使得抗原呈现途径中的肿瘤抗原水平增加。可与组合的LAG-3及CTLA-4和/或PD-1和/或PD-L1阻断经由细胞死亡产生协同作用的其他组合疗法包含放射、手术或激素剥夺。这类方案中的每一者皆产生宿主中的肿瘤抗原的来源。血管生成抑制剂亦可与组合的LAG-3及CTLA-4和/或PD-1和/或PD-L1阻断组合。对血管生成的抑制会引起肿瘤细胞死亡,此可为供给至宿主抗原呈现途径中的肿瘤抗原的来源。
LAG-3及CTLA-4和/或PD-1和/或PD-L1阻断抗体的组合亦可与使Fcα或Fcγ受体表达效应器细胞靶向肿瘤细胞的双特异性抗体组合使用(例如参见美国专利第5,922,845号及第5,837,243号)。可使用双特异性抗体靶向两种分别的抗原。通过使用组合的LAG-3及CTLA-4和/或PD-1和/或PD-L1阻断来增大这类反应的T细胞分支。
在另一例子中,抗LAG-3及抗CTLA-4和/或抗PD-1抗体和/或抗PD-L1抗体的组合可与抗肿瘤性抗体(例如(利妥昔单抗(rituximab))、(曲妥珠单抗(trastuzumab))、(托西莫单抗(tositumomab))、(替伊莫单抗(ibritumomab))、(阿来组单抗(alemtuzumab))、(依帕珠单抗(eprtuzumab))、(贝伐珠单抗(bevacizumab))及(厄洛替尼(erlotinib))及诸如此类)结合使用。举例且不希望受理论束缚地,使用抗癌性抗体或缀合于毒素的抗癌性抗体进行治疗可引起癌细胞死亡(例如肿瘤细胞),此将强化由CTLA-4、PD-1、PD-L1或LAG-3介导的免疫反应。在一例示性实施方案中,对过度增殖性疾病(例如癌症肿瘤)的治疗可包括抗癌症抗体与抗LAG-3及抗CTLA-4和/或抗PD-1和/或抗PD-L1抗体的组合(同时或序贯或其任一组合),此可强化宿主的抗肿瘤免疫反应。
肿瘤通过诸多机制逃避宿主免疫监控。可通过钝化由肿瘤表达且是免疫阻抑性的蛋白质来克服许多这类机制。这些机制包括TGF-β(Kehrl等人(1986)J.Exp.Med.163:1037-1050)、IL-10(Howard及O'Garra(1992)Immunology Today 13:198-200)及Fas配体(Hahne等人(1996)Science 274:1363-1365)等。在另一例子中,针对这些实体中每一种的抗体可进一步与抗LAG-3及抗CTLA-4和/或抗PD-1和/或抗PD-L1抗体组合进行组合以抵抗免疫阻抑剂的作用且有益于宿主的抗肿瘤免疫反应。
可将可用于活化宿主免疫反应性的其他抗体进一步用于与抗LAG-3及抗CTLA-4和/或抗PD-1和/或抗PD-L1抗体组合。这些抗体包含树突细胞表面上的活化DC功能及抗原呈现的分子。抗CD40抗体(Ridge等人,参见上文)可与抗LAG-3及抗CTLA-4和/或抗PD-1和/或抗PD-L1的组合结合使用(Ito等人,参见上文)。对T细胞共刺激性分子的其他活化抗体(Weinberg等人,参见上文;Melero等人,参见上文;Hutloff等人,参见上文)亦可提供增加的T细胞活化水平。
如上文所论述,当前使用骨髓移植来治疗各种造血源肿瘤。可使用组合的LAG-3及CTLA-4和/或PD-1和/或PD-L1阻断来增加供体植入的肿瘤特异性T细胞的有效性。
几种实验治疗方案涉及离体活化及扩展抗原特异性T细胞且将这类细胞过继性转移至接受者以获得针对肿瘤的抗原特异性T细胞(Greenberg及Riddell的参考文献,参见上文)。这类方法亦可用于活化对感染剂(例如CMV)的T细胞反应。在抗LAG-3及抗CTLA-4和/或抗PD-1和/或抗PD-L1抗体存在下的离体活化预期可增加过继性转移的T细胞的频率及活性。
在某些实施方案中,本发明提供改变与使用免疫刺激剂治疗过度增殖性疾病(例如癌症)有关的不良事件的方法,其包括向受试者施用抗LAG-3抗体及亚治疗性剂量的抗CTLA-4和/或抗PD-1和/或抗PD-L1抗体。举例而言,本发明方法提供通过向患者施用不可吸收性类固醇来减小免疫刺激性治疗性抗体诱导的结肠炎或腹泻的发病率的方法。由于任一接受免疫刺激性治疗性抗体的患者皆有形成由这类抗体诱导的结肠炎或腹泻的风险,因此这整个患者群体适用于根据本发明方法的疗法。尽管已施用类固醇来治疗炎性肠病(IBD)且预防IBD的加重,但尚未使用其来预防(降低发病率)并未诊断有IBD患者的IBD。与类固醇(即使是不可吸收性类固醇)有关的显著副作用已阻碍了预防性应用。
在进一步的实施方案中,LAG-3及CTLA-4和/或PD-1和/或PD-L1阻断的组合(即免疫刺激性治疗性抗体抗LAG-3及抗CTLA-4和/或抗PD-1抗体和/或抗PD-L1抗体)可进一步与任意不可吸收性类固醇的使用组合。如本文中所使用,“不可吸收性类固醇”是一种糖皮质激素,其展现出广泛首过代谢从而使得在肝中代谢后,类固醇的生物可用度较低(即小于约20%)。在本发明的一个实施方案中,所述不可吸收性类固醇是布地奈德(budesonide)。布地奈德是局部作用性糖皮质激素,其在口服施用后主要由肝充分代谢。ENTOCORT(Astra-Zeneca)是布地奈德的pH及时间依赖性口服制剂,其被开发以用于优化至回肠及在整个结肠内的药物递送。ENTOCORT在美国经批准用于治疗涉及回肠和/或升结肠的轻度至中等克罗恩氏病(Crohn’s disease)。用于治疗克罗恩氏病的ENTOCORT的常用口服剂量为6至9mg/天。ENTOCORT释放于肠中,然后被吸收且保留于肠黏膜中。在通过肠黏膜靶组织后,ENTOCORT由肝中的细胞色素P450系统充分代谢成具有可忽略的糖皮质激素活性的代谢物。因此,生物可用度较低(约10%)。布地奈德的较低的生物可用度使得与其他具有较小广泛首过代谢的糖皮质激素相比具有改进的治疗比率。布地奈德产生较少不良效应,包含下丘脑-垂体阻抑小于全身作用的皮质类固醇。然而,长期施用ENTOCORT可导致全身性糖皮质激素效应,例如肾上腺功能亢进及肾上腺阻抑。参见PDR第58版,2004;608-610。
在仍进一步的实施方案中,结合不可吸收性类固醇的组合LAG-3及CTLA-4和/或PD-1和/或PD-L1阻断(即免疫刺激性治疗性抗体抗LAG-3及抗CTLA-4和/或抗PD-1和/或抗PD-L1抗体)可进一步与水杨酸盐组合。水杨酸盐包含5-ASA药剂,例如:柳氮磺吡啶(sulfasalazine)(Pharmacia&UpJohn);奥色拉嗪(olsalazine)(Pharmacia&UpJohn);巴柳氮(balsalazide)(SalixPharmaceuticals公司);和美色拉嗪(mesalamine)(Procter&GamblePharmaceuticals;Shire US;Axcan Scandipharm公司;Solvay)。
根据本发明方法,出于降低由免疫刺激性抗体诱导的结肠炎的发病率的目的,与抗LAG-3及抗CTLA-4和/或抗PD-1和/或抗PD-L1抗体及不可吸收性类固醇组合施用的水杨酸盐可包含水杨酸盐及不可吸收性类固醇的任一重叠或序贯施用。因此,举例而言,根据本发明减小由免疫刺激性抗体诱导的结肠炎的发病率的方法涵盖同时或序贯施用水杨酸盐及不可吸收性类固醇(例如在不可吸收性类固醇之后6小时施用水杨酸盐),或其任一组合。另外,根据本发明,可通过相同途径(例如二者皆经口施用)或通过不同途径(例如经口施用水杨酸盐且经直肠施用不可吸收性类固醇)施用水杨酸盐及不可吸收性类固醇,其可不同于用于施用抗LAG-3及抗CTLA-4和/或抗PD-1和/或抗PD-L1抗体的途径。
通过下列实例进一步阐释本公开,不能将其视为进一步限制。贯穿本申请中所引用的所有图及所有参考文献、Genbank序列、专利及公开专利申请案的内容均通过提述明确并入本文中。具体地,PCT公开文本WO 09/045957、WO 09/073533、WO 09/073546及WO 09/054863的公开内容均通过提述明确并入本文中。
实施例
实施例1:LAG3.1(抗体25F7)的变体的设计
创建先前描述的抗LAG-3抗体25F7(在本文中称为LAG3.1)的抗体变体,其通过首先分析抗体的氨基酸序列的潜在降解位点。使用QuikChange II 定点诱变试剂盒(Agilent Technologies)来实施LAG3.1VH区的定点诱变的表达。然后将改变的VH区亚克隆至含有人IgG4-S228P恒定区的(EMD Millipore)载体中。将各重链载体各自与表达LAG3.1κ链的载体一起共转染至CHO-S细胞中,且选择稳定的集合物(pool)用于表达。
在可变区重链CDR2内鉴别5个潜在的去酰胺化基序。这些位点位于LAG3.1的重链可变区(SEQ ID NO:2)的52、54、56、58及60位处(参见图1A)。具体地,在所有条件下皆观察到VH CDR2(SEQ ID NO:6)内的“NG”序列发生去酰胺化且序列进一步发生异构化。起始材料的去酰胺化约为10%。另外,发现此“NG”序列不对应于种系序列(参见图3)。然而,共有种系序列是潜在的糖基化位点且由此不包含于抗体变体间。
设计4个变体(在本文中称为LAG3.5、LAG3.6、LAG3.7及LAG3.8),其寻址于两个潜在的去酰胺化基序(54及56位),如图3中所展示。使这类变体经受如下表1中所概述的各种条件且分析下列特征:(a)化学及热稳定性(物理稳定性);(b)大小排阻层析(聚集);(c)等电聚焦凝胶(IEF)(电荷异质性);(d)通过Biacore分析得到的活性(结合及功能活性);及(e)通过质谱分析得到的肽图谱(mapping)(化学修饰/分子稳定性)。
表1
实施例2:LAG-3变体的表征
1.活化的人CD4+ T细胞结合
为测试抗体变体结合经活化的人T细胞表面上的天然人LAG-3的能力,在2x 10e6个细胞/mL密度的15cm组织培养板中使用分别以5μg/mL及3μg/mL存于溶液中的抗CD3(eBioscience,目录编号:16-0037-85)及抗CD28(BD Bioscience,目录编号:555725)抗体的组合刺激正常健康供体外周血单核细胞。在刺激三天后,收获细胞,使用1x PFAE缓冲液(1×PBS+2%FBS、0.02%叠氮化钠、2mM Na EDTA)洗涤1次,且重悬于1×PFAE缓冲液中用于染色。
为进行结合反应,使用冷1×PFAE缓冲液连续稀释LAG3.1变体,然后将50μl经稀释的抗体溶液与以1:16稀释于1×PFAE缓冲液中的50μl Fitc标记的抗人CD4(BDBioscience,目录编号:555346)混合。为进行结合反应,将100μl此经稀释抗体混合物添加至2×105个细胞中且将混合物在4℃培育30分钟。然后使用1×PFAE缓冲液将细胞洗涤两次。添加经PE标记的山羊抗人Fcγ特异性抗体(Jackson ImmunoResearch,目录编号:109-116-170)的1:200稀释液且将混合物在4℃温育30分钟,随后使用冷1×PFAE缓冲液洗涤两次。在最后洗涤之后,向每一溶液中添加150μl冷1×PFAE且通过流式细胞术使用FACSCanto流式细胞仪(BD Bioscience)分析抗体结合。
流式细胞术分析的结果汇总于图4A中,该图显示抗体结合经活化的人CD4+T细胞的EC50。图4B显示抗体结合可溶性人LAG-3/Fc抗原(通过BIACORE)。如所展示,LAG3.5及LAG3.8的结合亲和力略低于LAG3.1,而其解离速率常数略高于LAG3.1。
2.物理稳定性
使用Microcal VP-DSC测试变体的热稳定性及热变性。具体而言,将每一变体稀释至PBS(Mediatech目录编号:21-040-CV,批号:21040139)中。在稀释至PBS中后,样品的最终浓度为250μg/mL。在74℃扫描样品,冷却至25℃,且再加热至74℃。使用PBS缓冲液作为空白对照。将数据拟合至非2态模型(Non-2-state model)且通过Origin软件实施曲线拟合。
如表2中所汇总及图5中所展示的,LAG3.5的熔解温度TM2高于LAG3.1,从而指示较大的总体稳定性。
表2
抗体在变性后的再折叠是长期聚集可能性的反量度(inverse measure)。因此,亦测试LAG-3变体且针对热可逆性进行比较。具体而言,将抗体加热至74℃且冷却至室温,然后加热回74℃。第二热分析图对第一热分析图的曲线下面积的比率提供热可逆性的估计,这是对构象可逆性的直接量度。
如表3中所汇总及图6中所展示的,LAG3.5的热可逆性实质性高于所有其他变体。显而易见,LAG3.5的可逆性百分比(47%)是LAG3.1的可逆性百分比(20%)的超过两倍。热可逆性与长期聚集可能性密切相关。较低可逆性对应于较高的潜在聚集。基于此观察,LAG3.1将潜在地随时间展现出实质性高于LAG3.5的聚集。类似地,所有其他变体皆可潜在地随时间展现出实质性高于LAG3.5的聚集。
表3
MAb | 热可逆性(%) |
LAG3.1 | 20 |
LAG3.5 | 47 |
LAG3.6 | 0 |
LAG3.7 | 11 |
LAG3.8 | 26 |
3.聚集
亦使用标准大小排阻HPLC(SEC-HPLC)根据下列方案测试变体的稳定性作为蛋白质聚集的量度:使用磷酸盐缓冲盐水(PBS)将抗体测试样品稀释至1.0mg/ml且将10uL施加至HPLC(Waters,2795型)。在凝胶过滤柱(TOSOH Bioscience,TSKgel G3000SWxl,7.8mm×300mm,产品编号:08541)上使用0.1M磷酸钠、0.15M氯化钠、0.1M硫酸钠的流动相(pH 7.2)来达成分离。通过监测280nm处的UV吸光度来检测分析物,且使用Empower软件测定抗体峰面积百分比组成。如表4中所展示,LAG3.5展现实质性小于LAG3.1的聚集。
表4
实施例3:变体选择
基于上述研究,选择抗体变体LAG3.5用于进一步分析,此是基于其与其未修饰形式(LAG3.1)相比显著改进的物理及化学稳定性,尤其是其具有高构象重折叠能力(热可逆性)。此分析包含以下两步骤方式:(a)加速的应激,(b)随后12周实时稳定性评估。具体而言,将LAG3.5以1.0mg/ml在40℃于pH8.0的50mM碳酸氢铵中培育5天。分析在5天后的修饰程度以及对于活性及稳定性的影响。然后使LAG3.5变体在PBS中经受实时稳定性条件达12周的持续时间且随后进行分析。这些研究的结果阐述于下文中。
1.抗原结合
如图7(及表5)中所展示,观察到在5天后抗原结合并无变化。亦如图10A及B中所展示,LAG3.5展现在12周后抗原结合或物理稳定性并未变化。具体地,LAG3.5在整个12周时段中于4℃及40℃皆维持高于LAG3.8的亲和力。
表5
2.化学修饰/分子稳定性
使用通过质谱术实施的肽图谱法来分析LAG3.5与LAG3.1相比的化学/分子稳定性。具体而言,将纯化的抗体还原,实施烷基化,实施透析,且使用胰蛋白酶(Promega编号:V5111)及GluC(Roche编号:11047817001)进行消化。通过纳(nano)-LC MSMS质谱术(ThermoFisher LTQ Orbitrap)分析消化物。
如图8中所展示,在经受较高pH的加速稳定性(其使天冬酰胺残基去酰胺化(步骤1))时,LAG3.1与LAG3.5相比展示增加的VH异质性。在当前实验条件下不能检测出由异构化所致的质量变化。将变化百分比表示为组合的所有变化对原峰(parental peak)的比率。
此外,如图11中所展示,在于4℃及40℃经受12周的延长实时稳定性条件(步骤2)时,LAG3.1与LAG3.5相比展示增加的VH异质性。
3.物理稳定性
在PBS中且于pH 8.0量测热可逆性。在两种条件下,LAG3.5同样与LAG3.1相比展现大约2倍的重折叠水平。具体而言,如表6-8中所展示,LAG3.5在PBS中展现43%重折叠(与之相比LAG3.1为18%)。LAG3.5亦在pH 8.0展现48%重折叠(与之相比LAG3.1展现29%重折叠)。
表6–DSC:熔化
MAb | 条件 | Tm1 | Tm2 |
Lag3.1 | PBS | 70.7 | 75.7 |
Lag3.1 | pH8 | 70.4 | 75.6 |
Lag3.5 | PBS | 70.8 | 76.4 |
Lag3.5 | pH8 | 70.5 | 76.3 |
表7–Fluorolog-2:解折叠
表8:DSC:重折叠
MAb | 可逆性%,PBS | 可逆性%,pH8 |
Lag3.1 | 18 | 29 |
Lag3.5 | 43 | 48 |
4.电荷异质性
为评价电荷异质性,使用等电聚焦(IEF)利用pI 5.5及pI 10.0的标准标记物与LAG3.1相比来分析变体。简言之,将抗体溶液与pI 3-10标记物(SERVA目录编号:39212)一起施加于1mm厚IEF pI 3-7预制凝胶(Invitrogen目录编号:EC6648BOX)上。使用IEF 3-7阴极缓冲液(Invitrogen目录编号:LC5370)及IEF阳极缓冲液(Invitrogen目录编号:LC5300)实施电泳且按以下顺序施加电流:100V恒定1hr、200V恒定1hr及500V恒定30min。使用考马斯蓝(Coomassie blue)对IEF凝胶实施染色以检测蛋白质带且使用甲醇-乙酸溶液脱色。然后通过ImageQuant TL软件分析IEF凝胶。基于此分析(数据未展示),LAG3.5展现显著小于LAG3.1的异质性。
5.HIC-HPLC
为评价溶解性,使用标准疏水性相互作用层析(HIC-HPLC)根据下列方案来分析变体:将50uL 2M硫酸铵添加至50uL的1mg/ml抗体测试样品中。然后将80uL测试样品施加至在线连接至HIC柱(TOSOH Bioscience,Ether-5PW TSK-gel,7.5mm×75mm,产品编号:07573)的HPLC(Waters,2795型)中。以1.0ml/min的流速使用100%缓冲液A(2M硫酸铵、0.1M磷酸钠,pH 7.0)至100%缓冲液B(0.1M磷酸钠,pH 7.0)的梯度经50分钟来洗脱样品。通过监测280nm处的UV吸光度来检测抗体且使用Empower软件分析数据。如图9中所展示的,LAG3.5的亲水性展现在高硫酸铵浓度下的溶解性。
实施例4:T细胞介导的免疫反应抑制的逆转
藉助利用抗原特异性小鼠T细胞杂交瘤(3A9)的功能测定法来测定LAG3.5的活性。杂交瘤3A9表达特异于来自鸡蛋溶菌酶(HEL48-62)的肽的T细胞受体,且在与肽脉冲的、MHC匹配的抗原呈现细胞(LK35.2)共培养时分泌IL-2。由于huLAG-3-Fc能够结合MHC II类阳性小鼠B细胞系,因此3A9细胞系中的huLAG-3表达可经由与鼠类呈现细胞系上的II类分子衔接来施加抑制效应。3A9亲本细胞与同MHC匹配的抗原呈现细胞共培养的、经人LAG-3转导的3A9细胞的肽反应概况的比较显示,与对照3A9细胞相比,人LAG-3的表达会抑制肽反应性。通过使用LAG3.5进行LAG-3阻断来逆转此抑制。因此,对于LAG3.5显示阻断LAG-3介导的抑制。
实施例5:通过LAG3.5的T细胞活化
使用通过超抗原SEB刺激的人PBMC培养物来评价LAG3.5对原代T细胞的功能活性。自18名人供体的血液分离总PBMC且以以下两种测定形式中的任一者刺激72小时:(i)固定量的抗体(20μg/mL)及SEB的连续稀释液,或(ii)固定量的SEB(85ng/mL)及抗体的连续稀释液。通过ELISA监测分泌性IL-2(作为T细胞活性的量度)。使用抗体抗PD-1抗体及易普利姆玛(Ipilimumab)作为阳性对照且亦评估供体子组中LAG3.5与抗PD-1或抗CTLA-4的组合的活性。
与同种型对照抗体治疗相比,在18名仅使用LAG3.5治疗的供体中有15名于一定范围SEB浓度内观察到增强的IL-2分泌。在大部分情况下,刺激小于针对使用抗PD-1或易普利姆玛进行治疗所观察到的。对于LAG3.5而言,两种测定形式(阐述于上文中)的结果彼此一致。另外,在所测试6名供体中的5名中,组合LAG3.5与抗PD-1或易普利姆玛使得刺激水平高于针对与抗PD-1或易普利姆玛组合的同种型对照抗体所观察到的。这些数据揭示,LAG3.5可在正常人T细胞测定中发挥作用且可进一步活化通过抑制PD-1及CTLA-4功能介导的反应。
序列表汇总
>1408_LAG-3_403_25F7.1_VH1_NT
CAGGTGCAGCTACAGCAGTGGGGCGCAGGACTGTTGAAGCCTTCGGAGACCCTGTCCCTCACCTGCGCTGTCTATGGTGGGTCCTTCAGTGATTACTACTGGAACTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGGAAATCAATCATAATGGAAACACCAACTCCAACCCGTCCCTCAAGAGTCGAGTCACCCTATCACTAGACACGTCCAAGAACCAGTTCTCCCTGAAGCTGAGGTCTGTGACCGCCGCGGACACGGCTGTGTATTACTGTGCGTTTGGATATAGTGACTACGAGTACAACTGGTTCGACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
2 | VH a.a.25F7 |
>1408_LAG-3_403_25F7.1_VH1_AA
QVQLQQWGAGLLKPSETLSLTCAVYGGSFSDYYWNWIRQPPGKGLEWIGEINHNGNTNSNPSLKSRVTLSLDTSKNQFSLKLRSVTAADTAVYYCAFGYSDYEYNWFDPWGQGTLVTVSS
3 | VK n.a.25F7 |
>1408_LAG-3_403_25F7.1_VK1_NT
GAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTATTAGCAGCTACTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGATGCATCCAACAGGGCCACTGGCATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTAGAGCCTGAAGATTTTGCAGTTTATTACTGTCAGCAGCGTAGCAACTGGCCTCTCACTTTTGGCCAGGGGACCAACCTGGAGATCAAA
4 | VK a.a.25F7 |
>1408_LAG-3_403_25F7.1_VK1_AA
EIVLTQSPATLSLSPGERATLSCRASQSISSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPLTFGQGTNLEIK
VH n.a.LAG3.5
caggtgcagctacagcagtggggcgcaggactgttgaagccttcggagaccctgtccctcacctgcgctgtctatggtgggtccttcagtgattactactggaactggatccgccagcccccagggaaggggctggagtggattggggaaatcaatcatcgtggaagcaccaactccaacccgtccctcaagagtcgagtcaccctatcactagacacgtccaagaaccagttctccctgaagctgaggtctgtgaccgccgcggacacggctgtgtattactgtgcgtttggatatagtgactacgagtacaactggttcgacccctggggccagggaaccctggtcaccgtctcctca
12 | VH a.a.LAG3.5 |
VH a.a.LAG3.5
QVQLQQWGAGLLKPSETLSLTCAVYGGSFSDYYWNWIRQPPGKGLEWIGEINHRGSTNSNPSLKSRVTLSLDTSKNQFSLKLRSVTAADTAVYYCAFGYSDYEYNWFDPWGQGTLVTVSS
13 | VK n.a.LAG3.5 |
VK n.a.LAG3.5
gaaattgtgttgacacagtctccagccaccctgtctttgtctccaggggaaagagccaccctctcctgcagggccagtcagagtattagcagctacttagcctggtaccaacagaaacctggccaggctcccaggctcctcatctatgatgcatccaacagggccactggcatcccagccaggttcagtggcagtgggtctgggacagacttcactctcaccatcagcagcctagagcctgaagattttgcagtttattactgtcagcagcgtagcaactggcctctcacttttggccaggggaccaacctggagatcaaa
14 | VK a.a.LAG3.5 |
VK a.a.LAG3.5
EIVLTQSPATLSLSPGERATLSCRASQSISSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPLTFGQGTNLEIK
15 | VH CDR1a.a.LAG3.5 | DYYWN |
16 | VH CDR2a.a.LAG3.5 | EINHRGSTNSNPSLKS |
17 | VH CDR3a.a.LAG3.5 | GYSDYEYNWFDP |
18 | VK CDR1a.a.LAG3.5 | RASQSISSYLA |
19 | VK CDR2a.a.LAG3.5 | DASNRAT |
20 | VK CDR3a.a.LAG3.5 | QQRSNWPLT |
21 | LAG-3表位 | PGHPLAPG |
22 | LAG-3表位 | HPAAPSSW |
23 | LAG-3表位 | PAAPSSWG |
24 | VH CDR2a.a.LAG3.6 | EIIHSGSTNSNPSLKS |
25 | VH CDR2a.a.LAG3.7 | EINHGGGTNSNPSLKS |
26 | VH CDR2a.a.LAG3.8 | EINHIGNTNSNPSLKS |
27 | VH CDR2a.a.人种系 | GEINHSGSTNY |
28 | (Gly4-Ser)3 | |
29 | 人LAG-3a.a. |
人LAG-3氨基酸序列
MWEAQFLGLLFLQPLWVAPVKPLQPGAEVPVVWAQEGAPAQLPCSPTIPLQDLSLLRRAGVTWQHQPDSGPPAAAPGHPLAPGPHPAAPSSWGPRPRRYTVLSVGPGGLRSGRLPLQPRVQLDERGRQRGDFSLWLRPARRADAGEYRAAVHLRDRALSCRLRLRLGQASMTASPPGSLRASDWVILNCSFSRPDRPASVHWFRNRGQGRVPVRESPHHHLAESFLFLPQVSPMDSGPWGCILTYRDGFNVSIMYNLTVLGLEPPTPLTVYAGAGSRVGLPCRLPAGVGTRSFLTAKWTPPGGGPDLLVTGDNGDFTLRLEDVSQAQAGTYTCHIHLQEQQLNATVTLAIITVTPKSFGSPGSLGKLLCEVTPVSGQERFVWSSLDTPSQRSFSGPWLEAQEAQLLSQPWQCQLYQGERLLGAAVYFTELSSPGAQRSGRAPGALPAGHLLLFLTLGVLSLLLLVTGAFGFHLWRRQWRPRRFSALEQGIHPPQAQSKIEELEQEPEPEPEPEPEPEPEPEPEQL*
LAG3.1HC
CAGGTGCAGCTACAGCAGTGGGGCGCAGGACTGTTGAAGCCTTCGGAGACCCTGTCCCTCACCTGCGCTGTCTATGGTGGGTCCTTCAGTGATTACTACTGGAACTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGGAAATCAATCATAATGGAAACACCAACTCCAACCCGTCCCTCAAGAGTCGAGTCACCCTATCACTAGACACGTCCAAGAACCAGTTCTCCCTGAAGCTGAGGTCTGTGACCGCCGCGGACACGGCTGTGTATTACTGTGCGTTTGGATATAGTGACTACGAGTACAACTGGTTCGACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCATGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAATGA
32 | VH LAG3.1 a.a. |
TRANSLATION\OF\LAG3.1HC
QVQLQQWGAGLLKPSETLSLTCAVYGGSFSDYYWNWIRQPPGKGLEWIGEINHNGNTNSNPSLKSRVTLSLDTSKNQFSLKLRSVTAADTAVYYCAFGYSDYEYNWFDPWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK*
33 | VL LAG3.1 n.a. |
LAG3.1LC
GAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTATTAGCAGCTACTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGATGCATCCAACAGGGCCACTGGCATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTAGAGCCTGAAGATTTTGCAGTTTATTACTGTCAGCAGCGTAGCAACTGGCCTCTCACTTTTGGCCAGGGGACCAACCTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG
34 | VL LAG3.1a.a. |
TRANSLATION\OF\LAG3.1LC
EIVLTQSPATLSLSPGERATLSCRASQSISSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPLTFGQGTNLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC*
35 | VH LAG3.5a.a. |
LAG3.5重链序列-全部
QVQLQQWGAGLLKPSETLSLTCAVYGGSFSDYYWNWIRQPPGKGLEWIGEINHRGSTNSNPSLKSRVTLSLDTSKNQFSLKLRSVTAADTAVYYCAFGYSDYEYNWFDPWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYT
LPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK*
36 | VH LAG3.5n.a. |
LAG3.5重链序列-全部
caggtgcagctacagcagtggggcgcaggactgttgaagccttcggagaccctgtccctcacctgcgctgtctatggtgggtccttcagtgattactactggaactggatccgccagcccccagggaaggggctggagtggattggggaaatcaatcatcgtggaagcaccaactccaacccgtccctcaagagtcgagtcaccctatcactagacacgtccaagaaccagttctccctgaagctgaggtctgtgaccgccgcggacacggctgtgtattactgtgcgtttggatatagtgactacgagtacaactggttcgacccctggggccagggaaccctggtcaccgtctcctcagctagcaccaagggcccatccgtcttccccctggcgccctgctccaggagcacctccgagagcacagccgccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacgaagacctacacctgcaacgtagatcacaagcccagcaacaccaaggtggacaagagagttgagtccaaatatggtcccccatgcccaccatgcccagcacctgagttcctggggggaccatcagtcttcctgttccccccaaaacccaaggacactctcatgatctcccggacccctgaggtcacgtgcgtggtggtggacgtgagccaggaagaccccgaggtccagttcaactggtacgtggatggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagttcaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaacggcaaggagtacaagtgcaaggtctccaacaaaggcctcccgtcctccatcgagaaaaccatctccaaagccaaagggcagccccgagagccacaggtgtacaccctgcccccatcccaggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctaccccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaggctaaccgtggacaagagcaggtggcaggaggggaatgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacacagaagagcctctccctgtctctgggtaaatga
37 | VL LAG3.5a.a. |
LAG3.5kappa链序列-全部
EIVLTQSPATLSLSPGERATLSCRASQSISSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPLTFGQGTNLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQG
LSSPVTKSFNRGEC*
38 | VL LAG3.5n.a. |
LAG3.5-kappa链序列-全部
gaaattgtgttgacacagtctccagccaccctgtctttgtctccaggggaaagagccaccctctcctgcagggccagtcagagtattagcagctacttagcctggtaccaacagaaacctggccaggctcccaggctcctcatctatgatgcatccaacagggccactggcatcccagccaggttcagtggcagtgggtctgggacagacttcactctcaccatcagcagcctagagcctgaagattttgcagtttattactgtcagcagcgtagcaactggcctctcacttttggccaggggaccaacctggagatcaaacgtacggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgttag
序列表
<110> 百时美施贵宝公司
<120> 结合淋巴细胞活化基因-3 (LAG-3)的抗体的优化及该抗体的用途
<130> 11911-WO-PCT
<140> PCT/US2013/048999
<141> 2013-07-02
<150> 61/667,058
<151> 2012-07-02
<160> 52
<170> PatentIn version 3.5
<210> 1
<211> 360
<212> DNA
<213> 人工序列
<220>
<221> 来源
<223> /记录="人工序列的描述: 合成的
多核苷酸"
<220>
<221> CDS
<222> (1)..(360)
<400> 1
cag gtg cag cta cag cag tgg ggc gca gga ctg ttg aag cct tcg gag 48
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
acc ctg tcc ctc acc tgc gct gtc tat ggt ggg tcc ttc agt gat tac 96
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Asp Tyr
20 25 30
tac tgg aac tgg atc cgc cag ccc cca ggg aag ggg ctg gag tgg att 144
Tyr Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
ggg gaa atc aat cat aat gga aac acc aac tcc aac ccg tcc ctc aag 192
Gly Glu Ile Asn His Asn Gly Asn Thr Asn Ser Asn Pro Ser Leu Lys
50 55 60
agt cga gtc acc cta tca cta gac acg tcc aag aac cag ttc tcc ctg 240
Ser Arg Val Thr Leu Ser Leu Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
aag ctg agg tct gtg acc gcc gcg gac acg gct gtg tat tac tgt gcg 288
Lys Leu Arg Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
ttt gga tat agt gac tac gag tac aac tgg ttc gac ccc tgg ggc cag 336
Phe Gly Tyr Ser Asp Tyr Glu Tyr Asn Trp Phe Asp Pro Trp Gly Gln
100 105 110
gga acc ctg gtc acc gtc tcc tca 360
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 2
<211> 120
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /记录="人工序列的描述: 合成的
多肽"
<400> 2
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Asp Tyr
20 25 30
Tyr Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn His Asn Gly Asn Thr Asn Ser Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Leu Ser Leu Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Arg Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Phe Gly Tyr Ser Asp Tyr Glu Tyr Asn Trp Phe Asp Pro Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 3
<211> 321
<212> DNA
<213> 人工序列
<220>
<221> 来源
<223> /记录="人工序列的描述: 合成的
多核苷酸"
<220>
<221> CDS
<222> (1)..(321)
<400> 3
gaa att gtg ttg aca cag tct cca gcc acc ctg tct ttg tct cca ggg 48
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
gaa aga gcc acc ctc tcc tgc agg gcc agt cag agt att agc agc tac 96
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
tta gcc tgg tac caa cag aaa cct ggc cag gct ccc agg ctc ctc atc 144
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
tat gat gca tcc aac agg gcc act ggc atc cca gcc agg ttc agt ggc 192
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
agt ggg tct ggg aca gac ttc act ctc acc atc agc agc cta gag cct 240
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
gaa gat ttt gca gtt tat tac tgt cag cag cgt agc aac tgg cct ctc 288
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Leu
85 90 95
act ttt ggc cag ggg acc aac ctg gag atc aaa 321
Thr Phe Gly Gln Gly Thr Asn Leu Glu Ile Lys
100 105
<210> 4
<211> 107
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /记录="人工序列的描述: 合成的
多肽"
<400> 4
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Asn Leu Glu Ile Lys
100 105
<210> 5
<211> 5
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /记录="人工序列的描述: 合成的
肽"
<400> 5
Asp Tyr Tyr Trp Asn
1 5
<210> 6
<211> 16
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /记录="人工序列的描述: 合成的
肽"
<400> 6
Glu Ile Asn His Asn Gly Asn Thr Asn Ser Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 7
<211> 12
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /记录="人工序列的描述: 合成的
肽"
<400> 7
Gly Tyr Ser Asp Tyr Glu Tyr Asn Trp Phe Asp Pro
1 5 10
<210> 8
<211> 11
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /记录="人工序列的描述: 合成的
肽"
<400> 8
Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Ala
1 5 10
<210> 9
<211> 7
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /记录="人工序列的描述: 合成的
肽"
<400> 9
Asp Ala Ser Asn Arg Ala Thr
1 5
<210> 10
<211> 9
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /记录="人工序列的描述: 合成的
肽"
<400> 10
Gln Gln Arg Ser Asn Trp Pro Leu Thr
1 5
<210> 11
<211> 360
<212> DNA
<213> 人工序列
<220>
<221> 来源
<223> /记录="人工序列的描述: 合成的
多核苷酸"
<400> 11
caggtgcagc tacagcagtg gggcgcagga ctgttgaagc cttcggagac cctgtccctc 60
acctgcgctg tctatggtgg gtccttcagt gattactact ggaactggat ccgccagccc 120
ccagggaagg ggctggagtg gattggggaa atcaatcatc gtggaagcac caactccaac 180
ccgtccctca agagtcgagt caccctatca ctagacacgt ccaagaacca gttctccctg 240
aagctgaggt ctgtgaccgc cgcggacacg gctgtgtatt actgtgcgtt tggatatagt 300
gactacgagt acaactggtt cgacccctgg ggccagggaa ccctggtcac cgtctcctca 360
<210> 12
<211> 120
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /记录="人工序列的描述: 合成的
多肽"
<400> 12
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Asp Tyr
20 25 30
Tyr Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn His Arg Gly Ser Thr Asn Ser Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Leu Ser Leu Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Arg Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Phe Gly Tyr Ser Asp Tyr Glu Tyr Asn Trp Phe Asp Pro Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 13
<211> 321
<212> DNA
<213> 人工序列
<220>
<221> 来源
<223> /记录="人工序列的描述: 合成的
多核苷酸"
<220>
<221> CDS
<222> (1)..(321)
<400> 13
gaa att gtg ttg aca cag tct cca gcc acc ctg tct ttg tct cca ggg 48
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
gaa aga gcc acc ctc tcc tgc agg gcc agt cag agt att agc agc tac 96
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
tta gcc tgg tac caa cag aaa cct ggc cag gct ccc agg ctc ctc atc 144
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
tat gat gca tcc aac agg gcc act ggc atc cca gcc agg ttc agt ggc 192
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
agt ggg tct ggg aca gac ttc act ctc acc atc agc agc cta gag cct 240
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
gaa gat ttt gca gtt tat tac tgt cag cag cgt agc aac tgg cct ctc 288
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Leu
85 90 95
act ttt ggc cag ggg acc aac ctg gag atc aaa 321
Thr Phe Gly Gln Gly Thr Asn Leu Glu Ile Lys
100 105
<210> 14
<211> 107
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /记录="人工序列的描述: 合成的
多肽"
<400> 14
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Asn Leu Glu Ile Lys
100 105
<210> 15
<211> 5
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /记录="人工序列的描述: 合成的
肽"
<400> 15
Asp Tyr Tyr Trp Asn
1 5
<210> 16
<211> 16
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /记录="人工序列的描述: 合成的
肽"
<400> 16
Glu Ile Asn His Arg Gly Ser Thr Asn Ser Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 17
<211> 12
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /记录="人工序列的描述: 合成的
肽"
<400> 17
Gly Tyr Ser Asp Tyr Glu Tyr Asn Trp Phe Asp Pro
1 5 10
<210> 18
<211> 11
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /记录="人工序列的描述: 合成的
肽"
<400> 18
Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Ala
1 5 10
<210> 19
<211> 7
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /记录="人工序列的描述: 合成的
肽"
<400> 19
Asp Ala Ser Asn Arg Ala Thr
1 5
<210> 20
<211> 9
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /记录="人工序列的描述: 合成的
肽"
<400> 20
Gln Gln Arg Ser Asn Trp Pro Leu Thr
1 5
<210> 21
<211> 8
<212> PRT
<213> 人
<400> 21
Pro Gly His Pro Leu Ala Pro Gly
1 5
<210> 22
<211> 8
<212> PRT
<213> 人
<400> 22
His Pro Ala Ala Pro Ser Ser Trp
1 5
<210> 23
<211> 8
<212> PRT
<213> 人
<400> 23
Pro Ala Ala Pro Ser Ser Trp Gly
1 5
<210> 24
<211> 16
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /记录="人工序列的描述: 合成的
肽"
<400> 24
Glu Ile Ile His Ser Gly Ser Thr Asn Ser Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 25
<211> 16
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /记录="人工序列的描述: 合成的
肽"
<400> 25
Glu Ile Asn His Gly Gly Gly Thr Asn Ser Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 26
<211> 16
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /记录="人工序列的描述: 合成的
肽"
<400> 26
Glu Ile Asn His Ile Gly Asn Thr Asn Ser Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 27
<211> 11
<212> PRT
<213> 人
<400> 27
Gly Glu Ile Asn His Ser Gly Ser Thr Asn Tyr
1 5 10
<210> 28
<211> 15
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /记录="人工序列的描述: 合成的
肽"
<400> 28
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 29
<211> 525
<212> PRT
<213> 人
<400> 29
Met Trp Glu Ala Gln Phe Leu Gly Leu Leu Phe Leu Gln Pro Leu Trp
1 5 10 15
Val Ala Pro Val Lys Pro Leu Gln Pro Gly Ala Glu Val Pro Val Val
20 25 30
Trp Ala Gln Glu Gly Ala Pro Ala Gln Leu Pro Cys Ser Pro Thr Ile
35 40 45
Pro Leu Gln Asp Leu Ser Leu Leu Arg Arg Ala Gly Val Thr Trp Gln
50 55 60
His Gln Pro Asp Ser Gly Pro Pro Ala Ala Ala Pro Gly His Pro Leu
65 70 75 80
Ala Pro Gly Pro His Pro Ala Ala Pro Ser Ser Trp Gly Pro Arg Pro
85 90 95
Arg Arg Tyr Thr Val Leu Ser Val Gly Pro Gly Gly Leu Arg Ser Gly
100 105 110
Arg Leu Pro Leu Gln Pro Arg Val Gln Leu Asp Glu Arg Gly Arg Gln
115 120 125
Arg Gly Asp Phe Ser Leu Trp Leu Arg Pro Ala Arg Arg Ala Asp Ala
130 135 140
Gly Glu Tyr Arg Ala Ala Val His Leu Arg Asp Arg Ala Leu Ser Cys
145 150 155 160
Arg Leu Arg Leu Arg Leu Gly Gln Ala Ser Met Thr Ala Ser Pro Pro
165 170 175
Gly Ser Leu Arg Ala Ser Asp Trp Val Ile Leu Asn Cys Ser Phe Ser
180 185 190
Arg Pro Asp Arg Pro Ala Ser Val His Trp Phe Arg Asn Arg Gly Gln
195 200 205
Gly Arg Val Pro Val Arg Glu Ser Pro His His His Leu Ala Glu Ser
210 215 220
Phe Leu Phe Leu Pro Gln Val Ser Pro Met Asp Ser Gly Pro Trp Gly
225 230 235 240
Cys Ile Leu Thr Tyr Arg Asp Gly Phe Asn Val Ser Ile Met Tyr Asn
245 250 255
Leu Thr Val Leu Gly Leu Glu Pro Pro Thr Pro Leu Thr Val Tyr Ala
260 265 270
Gly Ala Gly Ser Arg Val Gly Leu Pro Cys Arg Leu Pro Ala Gly Val
275 280 285
Gly Thr Arg Ser Phe Leu Thr Ala Lys Trp Thr Pro Pro Gly Gly Gly
290 295 300
Pro Asp Leu Leu Val Thr Gly Asp Asn Gly Asp Phe Thr Leu Arg Leu
305 310 315 320
Glu Asp Val Ser Gln Ala Gln Ala Gly Thr Tyr Thr Cys His Ile His
325 330 335
Leu Gln Glu Gln Gln Leu Asn Ala Thr Val Thr Leu Ala Ile Ile Thr
340 345 350
Val Thr Pro Lys Ser Phe Gly Ser Pro Gly Ser Leu Gly Lys Leu Leu
355 360 365
Cys Glu Val Thr Pro Val Ser Gly Gln Glu Arg Phe Val Trp Ser Ser
370 375 380
Leu Asp Thr Pro Ser Gln Arg Ser Phe Ser Gly Pro Trp Leu Glu Ala
385 390 395 400
Gln Glu Ala Gln Leu Leu Ser Gln Pro Trp Gln Cys Gln Leu Tyr Gln
405 410 415
Gly Glu Arg Leu Leu Gly Ala Ala Val Tyr Phe Thr Glu Leu Ser Ser
420 425 430
Pro Gly Ala Gln Arg Ser Gly Arg Ala Pro Gly Ala Leu Pro Ala Gly
435 440 445
His Leu Leu Leu Phe Leu Thr Leu Gly Val Leu Ser Leu Leu Leu Leu
450 455 460
Val Thr Gly Ala Phe Gly Phe His Leu Trp Arg Arg Gln Trp Arg Pro
465 470 475 480
Arg Arg Phe Ser Ala Leu Glu Gln Gly Ile His Pro Pro Gln Ala Gln
485 490 495
Ser Lys Ile Glu Glu Leu Glu Gln Glu Pro Glu Pro Glu Pro Glu Pro
500 505 510
Glu Pro Glu Pro Glu Pro Glu Pro Glu Pro Glu Gln Leu
515 520 525
<210> 30
<211> 17
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /记录="人工序列的描述: 合成的
肽"
<400> 30
Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 31
<211> 1344
<212> DNA
<213> 人工序列
<220>
<221> 来源
<223> /记录="人工序列的描述: 合成的
多核苷酸"
<400> 31
caggtgcagc tacagcagtg gggcgcagga ctgttgaagc cttcggagac cctgtccctc 60
acctgcgctg tctatggtgg gtccttcagt gattactact ggaactggat ccgccagccc 120
ccagggaagg ggctggagtg gattggggaa atcaatcata atggaaacac caactccaac 180
ccgtccctca agagtcgagt caccctatca ctagacacgt ccaagaacca gttctccctg 240
aagctgaggt ctgtgaccgc cgcggacacg gctgtgtatt actgtgcgtt tggatatagt 300
gactacgagt acaactggtt cgacccctgg ggccagggaa ccctggtcac cgtctcctca 360
gctagcacca agggcccatc cgtcttcccc ctggcgccct gctccaggag cacctccgag 420
agcacagccg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 480
tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 540
ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacgaagacc 600
tacacctgca acgtagatca caagcccagc aacaccaagg tggacaagag agttgagtcc 660
aaatatggtc ccccatgccc accatgccca gcacctgagt tcctgggggg accatcagtc 720
ttcctgttcc ccccaaaacc caaggacact ctcatgatct cccggacccc tgaggtcacg 780
tgcgtggtgg tggacgtgag ccaggaagac cccgaggtcc agttcaactg gtacgtggat 840
ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagttcaa cagcacgtac 900
cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaacggcaa ggagtacaag 960
tgcaaggtct ccaacaaagg cctcccgtcc tccatcgaga aaaccatctc caaagccaaa 1020
gggcagcccc gagagccaca ggtgtacacc ctgcccccat cccaggagga gatgaccaag 1080
aaccaggtca gcctgacctg cctggtcaaa ggcttctacc ccagcgacat cgccgtggag 1140
tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 1200
gacggctcct tcttcctcta cagcaggcta accgtggaca agagcaggtg gcaggagggg 1260
aatgtcttct catgctccgt gatgcatgag gctctgcaca accactacac acagaagagc 1320
ctctccctgt ctctgggtaa atga 1344
<210> 32
<211> 447
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /记录="人工序列的描述: 合成的
多肽"
<400> 32
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Asp Tyr
20 25 30
Tyr Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn His Asn Gly Asn Thr Asn Ser Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Leu Ser Leu Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Arg Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Phe Gly Tyr Ser Asp Tyr Glu Tyr Asn Trp Phe Asp Pro 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 Cys Ser Arg Ser Thr Ser Glu Ser 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 Lys Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro
210 215 220
Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
260 265 270
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440 445
<210> 33
<211> 645
<212> DNA
<213> 人工序列
<220>
<221> 来源
<223> /记录="人工序列的描述: 合成的
多核苷酸"
<400> 33
gaaattgtgt tgacacagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60
ctctcctgca gggccagtca gagtattagc agctacttag cctggtacca acagaaacct 120
ggccaggctc ccaggctcct catctatgat gcatccaaca gggccactgg catcccagcc 180
aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctagagcct 240
gaagattttg cagtttatta ctgtcagcag cgtagcaact ggcctctcac ttttggccag 300
gggaccaacc tggagatcaa acgtacggtg gctgcaccat ctgtcttcat cttcccgcca 360
tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420
cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480
gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540
ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600
ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gttag 645
<210> 34
<211> 214
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /记录="人工序列的描述: 合成的
多肽"
<400> 34
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Asn Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 35
<211> 447
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /记录="人工序列的描述: 合成的
多肽"
<400> 35
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Asp Tyr
20 25 30
Tyr Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn His Arg Gly Ser Thr Asn Ser Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Leu Ser Leu Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Arg Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Phe Gly Tyr Ser Asp Tyr Glu Tyr Asn Trp Phe Asp Pro 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 Cys Ser Arg Ser Thr Ser Glu Ser 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 Lys Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro
210 215 220
Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
260 265 270
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440 445
<210> 36
<211> 1344
<212> DNA
<213> 人工序列
<220>
<221> 来源
<223> /记录="人工序列的描述: 合成的
多核苷酸"
<400> 36
caggtgcagc tacagcagtg gggcgcagga ctgttgaagc cttcggagac cctgtccctc 60
acctgcgctg tctatggtgg gtccttcagt gattactact ggaactggat ccgccagccc 120
ccagggaagg ggctggagtg gattggggaa atcaatcatc gtggaagcac caactccaac 180
ccgtccctca agagtcgagt caccctatca ctagacacgt ccaagaacca gttctccctg 240
aagctgaggt ctgtgaccgc cgcggacacg gctgtgtatt actgtgcgtt tggatatagt 300
gactacgagt acaactggtt cgacccctgg ggccagggaa ccctggtcac cgtctcctca 360
gctagcacca agggcccatc cgtcttcccc ctggcgccct gctccaggag cacctccgag 420
agcacagccg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 480
tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 540
ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacgaagacc 600
tacacctgca acgtagatca caagcccagc aacaccaagg tggacaagag agttgagtcc 660
aaatatggtc ccccatgccc accatgccca gcacctgagt tcctgggggg accatcagtc 720
ttcctgttcc ccccaaaacc caaggacact ctcatgatct cccggacccc tgaggtcacg 780
tgcgtggtgg tggacgtgag ccaggaagac cccgaggtcc agttcaactg gtacgtggat 840
ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagttcaa cagcacgtac 900
cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaacggcaa ggagtacaag 960
tgcaaggtct ccaacaaagg cctcccgtcc tccatcgaga aaaccatctc caaagccaaa 1020
gggcagcccc gagagccaca ggtgtacacc ctgcccccat cccaggagga gatgaccaag 1080
aaccaggtca gcctgacctg cctggtcaaa ggcttctacc ccagcgacat cgccgtggag 1140
tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 1200
gacggctcct tcttcctcta cagcaggcta accgtggaca agagcaggtg gcaggagggg 1260
aatgtcttct catgctccgt gatgcatgag gctctgcaca accactacac acagaagagc 1320
ctctccctgt ctctgggtaa atga 1344
<210> 37
<211> 214
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /记录="人工序列的描述: 合成的
多肽"
<400> 37
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Asn Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 38
<211> 645
<212> DNA
<213> 人工序列
<220>
<221> 来源
<223> /记录="人工序列的描述: 合成的
多核苷酸"
<400> 38
gaaattgtgt tgacacagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60
ctctcctgca gggccagtca gagtattagc agctacttag cctggtacca acagaaacct 120
ggccaggctc ccaggctcct catctatgat gcatccaaca gggccactgg catcccagcc 180
aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctagagcct 240
gaagattttg cagtttatta ctgtcagcag cgtagcaact ggcctctcac ttttggccag 300
gggaccaacc tggagatcaa acgtacggtg gctgcaccat ctgtcttcat cttcccgcca 360
tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420
cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480
gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540
ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600
ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gttag 645
<210> 39
<211> 5
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /记录="人工序列的描述: 合成的
肽"
<400> 39
Pro Val Gly Val Val
1 5
<210> 40
<211> 13
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /记录="人工序列的描述: 合成的
肽"
<400> 40
Gly Glu Ile Asn His Arg Gly Ser Thr Asn Ser Asn Pro
1 5 10
<210> 41
<211> 11
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /记录="人工序列的描述: 合成的
肽"
<400> 41
Gly Glu Ile Asn His Asn Gly Asn Thr Asn Ser
1 5 10
<210> 42
<211> 11
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /记录="人工序列的描述: 合成的
肽"
<400> 42
Gly Glu Ile Asn His Arg Gly Ser Thr Asn Ser
1 5 10
<210> 43
<211> 11
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /记录="人工序列的描述: 合成的
肽"
<400> 43
Gly Glu Ile Ile His Ser Gly Ser Thr Asn Ser
1 5 10
<210> 44
<211> 11
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /记录="人工序列的描述: 合成的
肽"
<400> 44
Gly Glu Ile Asn His Gly Gly Gly Thr Asn Ser
1 5 10
<210> 45
<211> 11
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /记录="人工序列的描述: 合成的
肽"
<400> 45
Gly Glu Ile Asn His Ile Gly Asn Thr Asn Ser
1 5 10
<210> 46
<211> 14
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /记录="人工序列的描述: 合成的
肽"
<220>
<221> MOD_RES
<222> (4)..(4)
<223> 异构化的残基
<400> 46
Ile Asn His Asp Gly Asn Thr Asn Ser Asn Pro Ser Leu Lys
1 5 10
<210> 47
<211> 14
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /记录="人工序列的描述: 合成的
肽"
<400> 47
Ile Asn His Asp Gly Asn Thr Asn Ser Asn Pro Ser Leu Lys
1 5 10
<210> 48
<211> 14
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /记录="人工序列的描述: 合成的
肽"
<400> 48
Ile Asn His Asn Gly Asn Thr Asp Ser Asn Pro Ser Leu Lys
1 5 10
<210> 49
<211> 14
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /记录="人工序列的描述: 合成的
肽"
<400> 49
Ile Asp His Asn Gly Asn Thr Asn Ser Asn Pro Ser Leu Lys
1 5 10
<210> 50
<211> 14
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /记录="人工序列的描述: 合成的
肽"
<220>
<221> MOD_RES
<222> (8)..(8)
<223> 异构化的残基
<400> 50
Ile Asn His Arg Gly Ser Thr Asp Ser Asn Pro Ser Leu Lys
1 5 10
<210> 51
<211> 14
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /记录="人工序列的描述: 合成的
肽"
<400> 51
Ile Asn His Arg Gly Ser Thr Asn Ser Asn Pro Ser Leu Lys
1 5 10
<210> 52
<211> 14
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /记录="人工序列的描述: 合成的
肽"
<220>
<221> MOD_RES
<222> (2)..(2)
<223> 异构化的残基
<400> 52
Ile Asp His Arg Gly Ser Thr Asp Ser Asn Pro Ser Leu Lys
1 5 10
Claims (10)
1.一种分离的单克隆抗体或其抗原结合部分,其结合人LAG-3且包含重链和轻链可变区,其中所述重链可变区包含来自SEQ ID NO:12的重链可变区的CDR1、CDR2和CDR3区。
2.权利要求1的抗体或其抗原结合部分,其中所述重链CDR1、CDR2和CDR3区分别包括SEQ ID NO:15、16和17的氨基酸序列。
3.权利要求1的抗体或其抗原结合部分,其中所述轻链可变区包含来自SEQ ID NO:14的轻链可变区的CDR1、CDR2和CDR3区。
4.权利要求3的抗体或其抗原结合部分,其中所述轻链CDR1、CDR2和CDR3区分别包含SEQ ID NO:18、19和20的氨基酸序列。
5.权利要求1或3的抗体或其抗原结合部分,其中所述重链可变区包含SEQ ID NO:12的氨基酸序列。
6.前述权利要求中任一项的抗体或其抗原结合部分,其中所述轻链可变区包含SEQ IDNO:14的氨基酸序列。
7.一种分离的单克隆抗体或其抗原结合部分,其结合人LAG-3且包含重链和轻链CDR1、CDR2和CDR3区,所述重链CDR1、CDR2和CDR3区分别包含SEQ ID NO:15、16、17的氨基酸序列,所述轻链CDR1、CDR2和CDR3区分别包含SEQ ID NO:18、19和20的氨基酸序列。
8.一种分离的单克隆抗体或其抗原结合部分,其结合人LAG-3且包含重链和轻链可变区,所述重链和轻链可变区分别包含SEQ ID NO:12和14的氨基酸序列。
9.前述权利要求中任一项的抗体或其抗原结合部分,其展现下列特性的一种或组合:
(a)结合猴LAG-3;
(b)缺少对小鼠LAG-3的结合;
(c)结合LAG-3主要组织相容性(MHC)II类分子;
(d)抑制LAG-3对主要组织相容性(MHC)II类分子的结合;或
(e)刺激免疫反应。
10.前述权利要求中任一项的抗体或其抗原结合部分,其刺激抗原特异性T细胞反应中的白介素-2(IL-2)产生。
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US61/667,058 | 2012-07-02 | ||
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CN201711460279.1A Active CN108101991B (zh) | 2012-07-02 | 2013-07-02 | 结合淋巴细胞活化基因-3(lag-3)的抗体的优化及该抗体的用途 |
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CN110172099A (zh) * | 2018-08-16 | 2019-08-27 | 上海健信生物医药科技有限公司 | 抗lag-3人源化单克隆抗体分子,抗原结合片段及其医药用途 |
WO2019238074A1 (zh) * | 2018-06-14 | 2019-12-19 | 华博生物医药技术(上海)有限公司 | 一种高亲和力高生物活性的lag-3抗体及其应用 |
CN111205371A (zh) * | 2020-01-22 | 2020-05-29 | 北京吉尔麦迪生物医药科技有限公司 | 一种抗淋巴细胞激活基因3的抗体及应用 |
CN115819595A (zh) * | 2023-01-03 | 2023-03-21 | 上海百英生物科技股份有限公司 | 一种抗lag3纳米抗体及其制备方法与应用 |
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PL2439273T3 (pl) * | 2005-05-09 | 2019-08-30 | Ono Pharmaceutical Co., Ltd. | Ludzkie przeciwciała monoklonalne przeciwko białku programowanej śmierci komórki 1(pd-1) oraz metody leczenia nowotworów z wykorzystaniem przeciwciał anty-pd-1 samodzielnie lub w połączeniu z innymi immunoterapeutykami |
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AR072999A1 (es) | 2008-08-11 | 2010-10-06 | Medarex Inc | Anticuerpos humanos que se unen al gen 3 de activacion linfocitaria (lag-3) y los usos de estos |
HUE061117T2 (hu) | 2009-03-25 | 2023-05-28 | Genentech Inc | Anti-FGFR3 antitestek és eljárások alkalmazásukra |
ES2671748T3 (es) | 2011-07-21 | 2018-06-08 | Tolero Pharmaceuticals, Inc. | Inhibidores heterocíclicos de proteína quinasas |
AR091649A1 (es) | 2012-07-02 | 2015-02-18 | Bristol Myers Squibb Co | Optimizacion de anticuerpos que se fijan al gen de activacion de linfocitos 3 (lag-3) y sus usos |
SI2970464T1 (sl) * | 2013-03-15 | 2020-08-31 | Glaxosmithkline Intellectual Propety Development Limited | Anti-LAG-3 vezavni proteini |
WO2014169078A2 (en) | 2013-04-09 | 2014-10-16 | Boston Biomedical, Inc. | Methods for treating cancer |
EP3508502B1 (en) * | 2013-09-20 | 2023-04-26 | Bristol-Myers Squibb Company | Combination of anti-lag-3 antibodies and anti-pd-1 antibodies to treat tumors |
EP3757130A1 (en) | 2013-09-26 | 2020-12-30 | Costim Pharmaceuticals Inc. | Methods for treating hematologic cancers |
WO2015066413A1 (en) | 2013-11-01 | 2015-05-07 | Novartis Ag | Oxazolidinone hydroxamic acid compounds for the treatment of bacterial infections |
DK3081576T3 (da) | 2013-12-12 | 2019-10-21 | Shanghai hengrui pharmaceutical co ltd | Pd-1-antistof, antigenbindende fragment deraf og medicinsk anvendelse deraf |
MX369491B (es) | 2013-12-24 | 2019-11-11 | Bristol Myers Squibb Co | Compuestos tricíclicos como agentes anticancerígenos. |
JO3517B1 (ar) | 2014-01-17 | 2020-07-05 | Novartis Ag | ان-ازاسبيرو الكان حلقي كبديل مركبات اريل-ان مغايرة وتركيبات لتثبيط نشاط shp2 |
TWI680138B (zh) * | 2014-01-23 | 2019-12-21 | 美商再生元醫藥公司 | 抗pd-l1之人類抗體 |
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WO2019238074A1 (zh) * | 2018-06-14 | 2019-12-19 | 华博生物医药技术(上海)有限公司 | 一种高亲和力高生物活性的lag-3抗体及其应用 |
CN110172099A (zh) * | 2018-08-16 | 2019-08-27 | 上海健信生物医药科技有限公司 | 抗lag-3人源化单克隆抗体分子,抗原结合片段及其医药用途 |
CN110172099B (zh) * | 2018-08-16 | 2020-03-03 | 上海健信生物医药科技有限公司 | 抗lag-3人源化单克隆抗体分子,抗原结合片段及其医药用途 |
CN111205371A (zh) * | 2020-01-22 | 2020-05-29 | 北京吉尔麦迪生物医药科技有限公司 | 一种抗淋巴细胞激活基因3的抗体及应用 |
CN111205371B (zh) * | 2020-01-22 | 2022-03-29 | 北京吉尔麦迪生物医药科技有限公司 | 一种抗淋巴细胞激活基因3的抗体及应用 |
CN115819595A (zh) * | 2023-01-03 | 2023-03-21 | 上海百英生物科技股份有限公司 | 一种抗lag3纳米抗体及其制备方法与应用 |
CN115819595B (zh) * | 2023-01-03 | 2023-05-16 | 上海百英生物科技股份有限公司 | 一种抗lag3纳米抗体及其制备方法与应用 |
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