CN117355331A - 抗Siglec组合物及其用途 - Google Patents
抗Siglec组合物及其用途 Download PDFInfo
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- CN117355331A CN117355331A CN202280031124.9A CN202280031124A CN117355331A CN 117355331 A CN117355331 A CN 117355331A CN 202280031124 A CN202280031124 A CN 202280031124A CN 117355331 A CN117355331 A CN 117355331A
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- Prior art keywords
- ser
- siglec
- thr
- val
- antibody
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Abstract
本公开涉及抗Siglec‑10抗体和此类抗体在癌症疗法中的用途。
Description
发明领域
本发明涉及选择性结合人Siglec-10的抗Siglec-10抗体,以及此类抗体在癌症疗法中的用途。
发明背景
CD24是小的高度糖基化粘蛋白样糖基磷脂酰肌醇(GPI)连接的细胞表面蛋白。CD24以较高水平在造血细胞(包括B细胞、T细胞、中性粒细胞、嗜酸性粒细胞、树突状细胞和巨噬细胞)以及非造血细胞(包括神经细胞、神经节细胞、上皮细胞、角质形成细胞、肌细胞、胰腺细胞和上皮干细胞)上表达。一般而言,CD24往往在祖细胞和代谢活跃细胞中以较高水平表达,而在终末分化细胞中以较低程度表达。CD24的功能在大多数细胞类型中尚不清楚,但已报道了CD24的各种不同免疫功能。
CD24与先天免疫细胞上的Siglec-10相互作用,以负向调节宿主对炎症相关联的细胞损伤的应答,并且至少两种重叠的机制可以解释这种活性。第一,CD24与包括HSP70、90、HMGB1和核仁素在内的数种损伤相关分子模式(Damage Associated MolecularPatterns,DAMP)结合,并且阻抑宿主对这些DAMP的应答。据推测CD24可能捕获炎症刺激物,以防止它们与TLR或RAGE相互作用。第二,通过与其受体Siglec G(Siglec-10的小鼠同源物)相互作用,CD24为宿主对组织损伤的应答提供强有力的负调节。为了实现该活性,CD24可结合Siglec G并刺激Siglec G的信号传导,其中Siglec G相关联的SHP1触发负调节。这两种机制可以协同作用,因为具有任一基因靶向突变的小鼠产生了更强的炎症应答。
Siglec是I型跨膜蛋白,其中NH3 +末端处于细胞外空间,而COO-末端在胞质中。Siglec-10的细胞外域含有N端V型免疫球蛋白域(Ig域),其充当唾液酸的结合受体;以及五个C2型Ig域,其不具有结合活性,但是从细胞表面向外延伸V型Ig结合域。大多数Siglec(包括Siglec-10)的胞质域具有基于免疫受体酪氨酸的抑制基序(ITIM),并且经由募集酪氨酸磷酸酶(如含SH2域的蛋白酪氨酸磷酸酶SHP1和SHP2)发出负信号。Siglec的主要功能是结合含唾液酸的聚糖。这些受体-聚糖相互作用可以用于细胞粘附、细胞信号传导和其他功能,这通常受限于它们的细胞分布。人Siglec-10是小鼠Siglec G的功能直系同源物,并且其结合小鼠和人CD24两者。
许多癌症通过过表达抗吞噬表面蛋白(称为“别吃我”信号)来避免被免疫系统清除。此类蛋白质的实例包括PD-L1和CD47,它们分别与免疫细胞上的PD-1和信号调节蛋白α(SIRPα)结合,从而抑制巨噬细胞的活性。因此,阻断或拮抗这些“别吃我”途径的抗体已开发为免疫肿瘤学药物。已经展示,CD24通过其与Siglec-10相互作用而代表又一种此类“别吃我”信号,尽管CD24存在于许多正常组织和细胞类型中,但CD24在近70%的人类癌症中过表达,并且是癌细胞中过表达最多的蛋白质之一。CD24表达在肿瘤发生期间上调,表明其在肿瘤进展和转移中的作用。CD24在癌症中的过表达也被鉴定为指示癌症患者的预后不良和更具侵袭性病程的标志物。
因此,本领域中需要靶向CD24:Siglec-10别吃我轴的新免疫疗法用于治疗癌症。
发明内容
本文提供了抗Siglec-10抗体,该抗Siglec-10抗体可以包含:(a)重链可变区,该重链可变区包含含有SEQ ID NO:3中所示的序列的互补决定区(CDR)1、含有SEQ ID NO:4中所示的序列的CDR2,以及含有SEQ ID NO:5中所示的序列的CDR3中的一者或多者;以及(b)轻链可变区,该轻链可变区包含含有SEQ ID NO:6中所示的序列的CDR1、含有SEQ ID NO:7中所示的序列的CDR2,以及含有SEQ ID NO:8中所示的序列的CDR3中的一者或多者。重链可变区可以包含SEQ ID NO:1中所示的序列,并且轻链可变区可以包含SEQ ID NO:2中所示的序列。抗体可以为嵌合抗体。
抗Siglec-10抗体的重链可变区可以包含SEQ ID NO:9-13中的一者所示的序列,并且轻链可变区可以包含SEQ ID NO:14-18中的一者所示的序列。重链可变区可以包含SEQID NO:9、10或11中所示的序列;并且轻链可变区可以包含SEQ ID NO:15中所示的序列。Siglec-10抗体的重链可变区可以包含SEQ ID NO:10或12中所示的序列;并且轻链可变区可以包含SEQ ID NO:17中所示的序列。抗Siglec-10抗体的重链可变区可以包含SEQ IDNO:10或12中所示的序列;并且轻链可变区可以包含SEQ ID NO:16中所示的序列。该抗体可以包含含有SEQ ID NO:9中所示的序列的重链可变区,以及含有SEQ ID NO:15中所示的序列的轻链可变区。该抗体可以包含含有SEQ ID NO:25中所示的序列的重链,并且可以进一步包含含有SEQ ID NO:27中所示的序列的轻链。该抗体可以包含含有SEQ ID NO:10中所示的序列的重链可变区,以及含有SEQ ID NO:15或16中所示的序列的轻链可变区。该抗体可以包含含有SEQ ID NO:32中所示的序列的重链,以及含有SEQ ID NO:27中所示的序列的轻链。该抗体可以包含含有SEQ ID NO:32中所示的序列的重链,以及含有SEQ ID NO:34中所示的序列的轻链。
本文还提供了在有此需要的患者中治疗癌症的方法,该方法可以包括向该患者施用抗Siglec-10抗体。进一步提供了抗Siglec-10抗体用于治疗癌症,以及抗Siglec-10抗体在制备用于治疗癌症的药物中的用途。还提供了包含抗Siglec-10抗体的组合物用于治疗癌症。该组合物可以为药物组合物。
抗Siglec-10抗体可以与第二癌症疗法联合施用,或者可以旨在与第二癌症疗法联合使用。第二癌症疗法可以为癌症靶向性免疫疗法或免疫细胞靶向性免疫疗法。第二癌症疗法可以为抗CTLA-4抗体。
癌症可以为晚期实体瘤、血液癌症或包含与抗Siglec-10抗体结合的浸润细胞的癌症。癌症可以为晚期实体瘤,该晚期实体瘤可以为肺腺癌(LUAD)、皮肤黑素瘤-转移性(SKCM-TM)、肺鳞状细胞癌(LUSC)、乳腺浸润性癌-基底型、乳腺浸润性癌-Her2、胰腺腺癌、头颈部鳞状细胞癌、肾脏肾透明细胞癌、胃腺癌、多形性胶质母细胞瘤、乳腺浸润性癌-LumB或乳腺浸润性癌-LumA、非小细胞肺癌、胶质母细胞瘤、黑素瘤、低级别胶质瘤、肾癌、基底型乳腺癌、Her2+乳腺癌、胰腺癌或卵巢癌。肺腺癌可以为非小细胞肺腺癌。血液癌症可以为白血病、骨髓增生异常综合征、B细胞淋巴瘤或多发性骨髓瘤。
附图简述
图1显示了抗Siglec-10抗体在抗体依赖性细胞介导的细胞毒性(ADCC)的报告物测定中的拮抗活性。比较了4种不同的抗Siglec-10抗体的分级剂量挽救受到Jurkat ADCC效应细胞中异位表达的Siglec-10抑制的ADCC的能力。靶标:CHO-CTLA4-OFP克隆9(2×10e4)。效应物:Jurkat-PWPI-Siglec10(2×104)。ADCC-触发抗体:抗CTLA4 mAb(0.1μg/ml)。
图2显示了如由ELISA所测定的抗Siglec-10mAb 31F11的结合特异性。将Siglec融合蛋白包被在板上,并添加生物素化31F11。结合的抗体通过辣根过氧化物酶缀合的链霉亲和素进行检测。
图3显示了如由流式细胞术所测定的抗Siglec-10mAb 31F11的结合特异性。将293T细胞用GFP缀合的Siglec cDNA转染。将细胞用31F11染色并通过Canto II细胞计数器进行分析。
图4A-B显示了抗Siglec-10mAb 31F11表现出对Siglec-10Fc与小鼠脾细胞结合的有力抑制。图4A.实验方案流程图。图4B.Siglec-10Fc(S10)与脾细胞结合的抑制的%。
图5显示了抗Siglec-10mAb 31F11促进巨噬细胞对癌细胞的吞噬作用。将从外周血分离的人单核细胞用补充有40ng/ml M-CSF的RPMI-1640培养基刺激5-7天。然后通过50ng/ml TGFβ1和IL10诱导M2巨噬细胞24小时。将MCF-7细胞用CELLTRACETMViolet BMQC染料标记,并且在存在指定浓度的抗siglec-10mAb(5G6、10H3和31F11(mFc=鼠Fc;hFc=人Fc))的情况下与供体衍生的M2巨噬细胞共培养2小时。将细胞用APC缀合的抗CD11b Ab染色,并且基于总CD11b+细胞中Violet染料阳性CD11b+细胞的%,通过流式细胞术来确定吞噬作用(%)。显示的数据是如由流式细胞术所测定的已吞噬癌细胞的%巨噬细胞的平均值和标准误差。
图6A-B显示了抗CD24和抗Siglec-10抗体的协同抗肿瘤活性。将1×106个MC38-hCD24细胞经皮下接种到BM嵌合体小鼠中,该小鼠包括来自表达人Siglec-10的转基因小鼠(n-4-5)的骨髓细胞。在肿瘤移植后第7、10、13和16天,用100μg hIgFc、α-hCD24、31F11(α-S10)或α-hCD24+31F11 Ab处理小鼠。图6A.肿瘤生长动力学。图6B.随时间推移的荷瘤小鼠%。
图7显示了人源化31F11克隆与在Jurkat细胞上异位表达的细胞表面Siglec-10的结合的表征。显示的数据是相对于抗体分级剂量的最大结合的%。
图8显示了人源化31F11克隆的热稳定性。各项数据显示于表1中。
表1人源化31F11克隆的Tm
图9显示了人源化31F11克隆基于其在挽救抗体依赖性细胞介导的细胞毒性(ADCC)报告物测定中的活性的拮抗活性。使5×104个Jurkat-PWPI-S10细胞和5×104个CHO-hCTLA4细胞与0.1μg/ml抗hCTLA4和指定浓度的抗siglec 10抗体共培养。在温育16-24小时后,将BIO-GLOTM萤光素酶测定试剂添加到所有测试孔中,并使用具有辉光型(glow-type)发光读取能力的读板器来测量发光。显示的数据是相对于抗体分级剂量的最大ADCC活性的%。
图10A-B显示了Siglec-10信号传导抑制ADCC报告物活性。图10A.报告物测定的示意图。在存在CTLA-4表达性靶细胞和不同浓度的抗CTLA-4mAb伊匹单抗(Ipilimumab)的情况下,Jurkat报告细胞在FcγRIIIA活化后活化NFAT表达。图10B.表达载体对照(ADCC3-p)、WT Siglec-10蛋白(ADCC3-10)或部分阻碍Siglec-10的负信号传导的在ITIM域位置667中具有Y>A突变的突变体Siglec-10(ADCC3-10-667)的Jurkat报告细胞的报告物活性。
图11显示了31F11在增强ADCC活性中的优异活性。Siglec-10表达性Jurkat报告细胞ADCC3-10用作报告细胞。CTLA-4表达性CHO细胞用作靶细胞。将细胞在存在0.1μg/mL的抗CTLA-4mAb ONC-392以及连续稀释的抗Siglec-10mAb 10H3、5G6和31F11的情况下共培养。测定设计绘制于图10A中。比较了给定剂量的3种抗Siglec-10mAb。
图12显示了认为ONC-841如何阻断CD24-Siglec-10的“别吃我”信号(DNEMS)以促进对肿瘤细胞的吞噬作用的示意图。
图13显示了ONC-841与ONC-392联合疗法的机制。ONC-392通过选择性消减肿瘤微环境中的Treg来引起肿瘤排斥,由此增强瘤内T细胞应答;而ONC-841通过拮抗Siglec-10介导的抑制来增强ADCC/ACDP介导的Treg消减。
图14A-B显示了ONC-841与重组Siglec家族蛋白的结合。图14A.ONC-841对His标签化或Fc标签化Siglec的特异性。图14B.ONC-841显示以与Siglec-5Fc、Siglec-6Fc、Siglec-11Fc和Siglec-14Fc类似的模式在高浓度下与人IgG1Fc结合,表明ONC-841与Siglec-5Fc、Siglec-6Fc、Siglec-11Fc和Siglec-14Fc的结合是由于与Fc标签的非特异性结合,而不是与重组Siglec蛋白的特异性结合。
图15显示了ONC-841阻断Siglec-10Fc与Jurkat-CTLA4细胞的结合。使Siglec-10Fc-生物素与链霉亲和素-PE预复合,并与浓度递增的ONC-841一起温育5分钟,然后与Jurkat-CTLA4细胞一起温育1小时。
图16A-B显示了ONC-841对Siglec-10Fc与Treg结合的效应。图16A.显示出在采用(浅灰色)或不采用(深灰色)100μg/mL的ONC-841的情况下Siglec-10-生物素+链霉亲和素-PE与Treg的结合的代表性数据。链霉亲和素-PE以灰色显示为阴性对照。图16B.ONC-841阻断Siglec-10Fc-生物素+链霉亲和素-PE与Treg的结合的非线性回归分析。
图17A-C显示了ONC-841在抗体依赖性ADCC报告物测定中的效应。图17A.ONC-841促进针对Raji细胞的抗CD20依赖性ADCC。图17B.ONC-841促进针对EGFR表达性B16细胞的西妥昔单抗(cetuximab)依赖性ADCC。图17C.ONC-841促进针对CTLA-4表达性CHO细胞的ONC-392依赖性ADCC。显示的数据归一化为显示ADCC活性相对于基线的倍数增加。
图18A-C显示了ONC-841在人NK细胞对白血病细胞的ADCC以及抗体非依赖性杀伤中的效应。图18A.不采用ONC-392。图18B.采用ONC-392。图18C.ONC-841对ONC-392介导的ADCC的%增强。
图19显示ONC-841在人PBMC对白血病细胞的抗体非依赖性杀伤中的效应。在不存在癌细胞靶向性抗体的情况下,ONC-841促进PBMC对Jurkat-CTLA-4细胞的杀伤。
图20展示了ONC-841在实体瘤中的治疗活性。使用表达人EGFR的B16F10细胞系。在肿瘤细胞攻击后6天,用对照IgG、ONC-841或ONC-841+西妥昔单抗处理荷瘤小鼠,并以盲法方式测量肿瘤生长。B16-EGFR荷瘤(s.c.)Siglec10TG+/+;Siglecg-/-小鼠(n=4-5)从肿瘤接种后第6天开始每三天用200μg对照hIgGFc或ONC-841经腹膜内(i.p.)以及用10μg对照hIgGFc或西妥昔单抗经瘤内(i.t.)进行处理,注射四次。
图21A-B显示ONC-841在联合疗法中的剂量应答。图21A.肿瘤生长动力学。图21B.使用来自图21A中最后时间点的数据进行线性回归分析以确定EC50。
图22显示了ONC-841和抗CTLA-4抗体9D9的组合引起B16F10黑素瘤细胞的排斥。将B16-F10荷瘤C57BL/6SIGLEC10TG+/+;Siglecg-/-小鼠(n=5-6)在第8、11、14和17天用200μg的9D9或/和400μg的ONC-841经i.p.进行处理。每3天测量肿瘤体积。显示的数据为平均值和SEM。
图23显示了检测ONC-841与来自不同物种的His标签化Siglec-10/Siglec-G的结合的比色ELISA测定。
图24显示了ONC-841与expi293上表达的Siglec-10直系同源物的结合的流式细胞术评价。使用Zombie染料对活细胞进行门控,并且评价ONC-841(深灰色线)的结合,并与多克隆抗Siglec-10抗体(浅灰色线)进行比较。荧光减一(FMO,灰色)用作阴性对照。每个柱状图的图例中的数字显示每个样品的中值荧光强度。
图25显示了ONC-841与人和食蟹猴单核细胞和B细胞的结合的流式细胞术评价。使用Zombie染料对活细胞进行门控,并且评价ONC-841(深灰色线)的结合,并与作为阴性对照的荧光减一(FMO,灰色)进行比较。为了测试结合是否具有特异性,在染色前将过量的人IgG添加到一些管中(浅灰色线)。每个柱状图的图例中的数字显示每个样品的中值荧光强度。
图26A-C显示了ONC-841与Siglec10转基因小鼠和人PBMC的结合。图26A.左侧,来自人Siglec10转基因小鼠与SiglecG敲除小鼠杂交的F1小鼠的血液分析。小鼠表达人Siglec-10和Siglec G两者。右侧,杂交F1小鼠的血液分析以及被选择用于生成转基因群体的小鼠的表型。仅具有人Siglec-10染色的F2小鼠被选择用于进一步繁殖。小鼠血液用市售抗体染色。图26B.小鼠血液亚集:NK细胞、B细胞、树突状细胞(DC)、中性粒细胞、单核细胞和T细胞的额外染色。Siglec-10染色显示于X轴上,并且对于每种细胞亚型,非转基因小鼠的染色显示于左图上,并且人Siglec-10转基因小鼠的染色显示于右图上。图26C.人PBMC的代表性染色。ONC-841处于Y轴(浅灰色)上,市售5G6抗Siglec-10mAb抗体处于X轴(深灰色)上。每个图具有相邻的柱状图,其显示单独的每种抗体的染色。针对Siglec-10呈阳性的B细胞和单核细胞,显示了阳性细胞的百分比。
图27显示了来自Siglec10TG+/+;Siglecg-/-小鼠的不同器官的冷冻切片的免疫组织化学染色。顶行显示Siglec-10表达性(左侧)和Siglec-10阴性(右侧)细胞沉淀物的阳性和阴性染色。棕色显示ONC-841的结合,蓝色是核染色(苏木精)。所有切片均以20X放大显示。
图28显示了针对其对抗CTLA-4抗体治疗的应答性而对人类癌症进行排名的策略的示意图。将新鉴定的抗CTLA-4抗体的作用机制以及另一组对FCGR3A多态性和对伊匹单抗的应答性执行的分析纳入考虑,我们首先基于CTLA-4应答数据库来鉴定影响抗CTLA-4抗体的治疗应答的分量。人类癌症类型基于各分量的中值进行排名。这些分量的权重相等并且分为5个类别,并对每个类别排名。然后对五个类别的排名进行加权,以产生最终排名。
图29显示了ONC-841不诱导细胞因子释放综合征(CRS)。显示了4名供体中一名的代表性数据。测定以一式两份进行。
详细描述
免疫系统可以识别并消除实验模型系统和患者中的癌症。因此,癌症免疫疗法正在成为癌症疗法的最具前景性的领域之一。主动癌症免疫疗法涉及通过阻断免疫检查点或“别吃我”信号来加强天然免疫应答的药剂(包括针对PD-1、PD-L1、CTLA-4和CD47的抗体)。
本文提供了抗Siglec-10抗体物质组合物及其抗原结合片段。抗体分子可以为单克隆抗体、人抗体、嵌合抗体或人源化抗体。抗体可以为单特异性、双特异性、三特异性或多特异性的。Siglec-10结合分子可以包含免疫特异性结合Siglec-10,并特别地人Siglec-10的抗体的抗原结合片段,该Siglec-10可以特别地在活细胞表面上以内源性或转染浓度表达。还提供了其抗原结合片段与Siglec-10结合的抗体分子。抗体可以被可检测地标记,或者包含缀合的毒素、药物、受体、酶或受体配体。
不同的肿瘤类型和患者的应答性有所不同,这意味着不同的抑制途径可能与不同的肿瘤类型或不同的群体有关。因此,额外的别吃我信号的鉴定可以导致开发出更有效用于特定肿瘤类型或患者的新疗法(无论单独地还是可能联合地)。通过单独地或与其他疗法联合施用如本文所述的抗Siglec-10抗体,本文所述的抗体分子可以用来治疗癌症。
发明人已发现了表现出与Siglec-10(特别是细胞表面上的)令人惊奇地有力结合的抗Siglec-10抗体。该抗体还通过抑制有力的别吃我信号来增强强烈的ADCC活性。
1.定义
本文使用的术语仅用于描述具体实施方案的目的,并非旨在进行限制。如在说明书和所附权利要求中所用,单数形式“一个”、“一种”和“所述”包括复数指代,除非上下文另有明确规定。与数值相关联的词语“约”表示该值的合理近似值。在某些情况下,“约”可以解释为在与其相关联的特定值的多达10%之内。例如,短语“约100”涵盖介于90与110之间的任何值。
对于本文中数值范围的叙述,明确地考虑其间具有相同精确度的每个中间数字。例如,对于6-9的范围,除6和9之外还考虑数字7和8,并且对于范围6.0-7.0,明确考虑数字6.0、6.1、6.2、6.3、6.4、6.5、6.6、6.7、6.8、6.9和7.0。
当涉及到保护动物免于疾病时,“处理(treatment)”或“治疗(treating)”意指预防、抑制、阻抑或完全消除疾病。预防疾病涉及在疾病发作之前向动物施用本公开的组合物。抑制疾病涉及在疾病诱导之后但在其临床外观之前向动物施用本公开的组合物。阻抑疾病涉及在疾病的临床外观后向动物施用本公开的组合物。
如本文所用,术语“抗体”旨在表示具有“可变区”抗原识别位点的免疫球蛋白分子。术语“可变区”旨在将免疫球蛋白的此类域与抗体广泛共享的域(如抗体Fc域)区分开。可变区包含残基负责抗原结合的“高变区”。高变区包含来自“互补决定区”或“CDR”的氨基酸残基(即,典型地在轻链可变域中大约残基24-34(L1)、50-56(L2)和89-97(L3)处,以及重链可变域中大约残基27-35(H1)、50-65(H2)和95-102(H3)处),和/或来自“高变环”的那些残基(即,在轻链可变域中的残基26-32(L1)、50-52(L2)和91-96(L3)以及重链可变域中的26-32(H1)、53-55(H2)和96-101(H3))。“框架区”或“FR”残基是除了如本文所定义的高变区残基之外的那些可变域残基。术语抗体包括单克隆抗体、多特异性抗体、人抗体、人源化抗体、合成抗体、嵌合抗体、骆驼抗体、单链抗体、二硫键连接的Fv(sdFv)、胞内抗体,以及抗独特型(抗Id)抗体(包括例如针对本文所公开的抗体的抗Id抗体和抗-抗Id抗体)。特别地,此类抗体包括任何类型的免疫球蛋白分子(例如,IgG、IgE、IgM、IgD、IgA和IgY)、种类(例如,IgG1、IgG2、IgG3、IgG4、IgA1和IgA2)或亚类。
如本文所用,术语抗体的“抗原结合片段”是指含有抗体的CDR和任选地框架残基的抗体的一个或多个部分,这些部分包含抗体的“可变区”抗原识别位点并且表现出免疫特异性结合抗原的能力。此类片段包括Fab'、F(ab')2、Fv、单链(ScFv)及其突变体、天然存在的变体,以及包含抗体的“可变区”抗原识别位点和异源蛋白(例如,毒素、用于不同抗原的抗原识别位点、酶、受体或受体配体等)的融合蛋白。如本文所用,术语“片段”是指包含至少5个连续氨基酸残基、至少10个连续氨基酸残基、至少15个连续氨基酸残基、至少20个连续氨基酸残基、至少25个连续氨基酸残基、至少40个连续氨基酸残基、至少50个连续氨基酸残基、至少60个连续氨基残基、至少70个连续氨基酸残基、至少80个连续氨基酸残基、至少90个连续氨基酸残基、至少100个连续氨基酸残基、至少125个连续氨基酸残基、至少150个连续氨基酸残基、至少175个连续氨基酸残基、至少200个连续氨基酸残基或至少250个连续氨基酸残基的氨基酸序列的肽或多肽。
人、嵌合或人源化抗体对于人类体内使用是特别优选的,然而,鼠抗体或其他物种的抗体可以有利地用于多种用途(例如,体外或原位检测测定、急性体内使用等)。
“嵌合抗体”是其中抗体的不同部分衍生自不同的免疫球蛋白分子的分子,如具有衍生自非人抗体的可变区以及人免疫球蛋白恒定区的抗体。包含来自非人物种的一个或多个CDR以及来自人免疫球蛋白分子的框架区的嵌合抗体可以使用本领域已知的多种技术来产生,包括例如CDR移植(EP 239,400;国际公开号WO 91/09967;和美国专利号5,225,539、5,530,101和5,585,089,它们各自的内容全文并入本文)、贴面化或表面再塑(EP 592,106;EP 519,596,它们各自的内容以引用方式并入本文),以及链改组(美国专利号5,565,332,其内容以引用方式并入本文)。
本文还设想了“人源化抗体”。如本文所用,术语“人源化抗体”是指包含人框架区以及来自非人(通常为小鼠或大鼠)免疫球蛋白的一个或多个CDR的免疫球蛋白。提供CDR的非人免疫球蛋白称为“供体”,并且提供框架的人免疫球蛋白称为“接受体”。恒定区不需要存在,但如果它们存在,则它们必须与人免疫球蛋白恒定区基本上相同,即,至少约85-90%,优选地约95%或更高相同。因此,除了可能地CDR之外,人源化免疫球蛋白的所有部分与天然人免疫球蛋白序列的相应部分基本上相同。人源化抗体是包含人源化轻链和人源化重链免疫球蛋白的抗体。例如,人源化抗体不涵盖典型的嵌合抗体,因为例如嵌合抗体的整个可变区是非人的。通过“人源化”过程,供体抗体可称为已被“人源化”,因为预期所得的人源化抗体与提供CDR的供体抗体结合相同的抗原。在大多数情况下,人源化抗体是人免疫球蛋白(受者抗体),其中受者的高变区残基被来自具有期望的特异性、亲和力和能力的非人物种(供体抗体)如小鼠、大鼠、兔或非人灵长类的高变区残基替换。在一些情况下,人免疫球蛋白的框架区(FR)残基被相应的非人残基替换。此外,人源化抗体可以包含不存在于受者抗体或供体抗体中的残基。进行这些修饰是为了进一步改善抗体性能。一般来讲,人源化抗体将包含基本上所有的至少一个,并且典型地两个可变域,其中所有或基本上所有的高变区对应于非人免疫球蛋白的那些,并且所有或基本上所有的FR是人免疫球蛋白序列的那些。人源化抗体还任选地包含通过引入氨基酸残基置换、缺失或添加(即突变)而改变的免疫球蛋白恒定区(Fc)的至少一部分,典型地免疫特异性结合FcγRIIB多肽的人免疫球蛋白的恒定区。
2.抗Siglec-10抗体组合物
本文提供了抗Siglec-10抗体或其抗原结合片段。应当理解,本文所述的抗体的一种或多种特征也可以包括在抗原结合片段中。抗Siglec-10抗体可以结合肿瘤相关巨噬细胞,并且可以抑制与癌细胞上表达的CD24的结合或信号传导,从而抑制来自癌细胞的抗吞噬信号。抗Siglec-10抗体可以为单克隆抗体、单链抗体、双特异性抗体、三特异性抗体、多特异性抗体或嵌合抗体。
抗Siglec-10抗体可以包含抗体31F11的一个或多个序列,其包含分别含有SEQ IDNO:1和2中所示的序列的重链和轻链可变区。该抗体可以包含含有SEQ ID NO:1中所示的序列的重链可变区,并且可以包含含有SEQ ID NO:2中所示的序列的轻链可变区。抗Siglec-10抗体的重链可变区可以包含以下项中的一者或多者:包含SEQ ID NO:3中所示的序列的CDR1、包含SEQ ID NO:4中所示的序列的CDR2,以及包含SEQ ID NO:5中所示的序列的CDR3。抗Siglec-10抗体的轻链可变区可以包含以下项中的一者或多者:包含SEQ ID NO:6中所示的序列的CDR1、包含SEQ ID NO:7中所示的序列的CDR2,以及包含SEQ ID NO:8中所示的序列的CDR3。在一个实例中,抗体是嵌合抗体,该嵌合抗体包含连接至人Fc域的31F11的可变域。
在一个实施方案中,重链可变区包含分别具有SEQ ID NO:3-5的CDR1-3。在另一个实施方案中,轻链可变区包含分别具有SEQ ID NO:6-8的CDR1-3。在另一个实例中,抗Siglec-10抗体包含含有SEQ ID NO:3-5的重链可变区,以及含有SEQ ID NO:6-8的轻链可变区。
抗Siglec-10抗体的重链和轻链中的一者或多者也可以相对于31F11人源化。抗Siglec-10抗体可以包含一个或多个重链可变区,每个重链可变区包含以下项的一者中所示的序列:SEQ ID NO:9、10、11、12和13(分别命名为Hu-VHv1、VHv2、VHv3、VHv4和VHv5)。抗Siglec-10抗体可以包含一个或多个轻链可变区,每个轻链可变区包含以下项的一者中所示的序列:SEQ ID NO:14-18(分别命名为Hu-VLv1、VLv2、VLv3、VLv4和VLv5)。
31F11的重链和轻链可变区的序列提供在以下中。
31F11重链可变区
31F11轻链可变区
人源化31F11重链可变区的序列提供在以下中(CDR加下划线)。
Hu-31F11-VHv1
Hu-31F11-VHv2
Hu-31F11-VHv3
Hu-31F11-VHv4
Hu-31F11-VHv5
人源化31F11轻链可变区的序列提供在以下中(CDR加下划线)。
Hu 31F11-VLv1
Hu 31F11-VLv2
Hu 31F11-VLv2—全轻链
Hu 31F11-VLv2—全轻链加上信号肽
Hu 31F11-VLv3
Hu 31F11-VLv3—全轻链
Hu 31F11-VLv3—全轻链加上信号肽
Hu 31F11-VLv4
Hu 31F11-VLv5
在一个实例中,抗Siglec-10抗体包含含有SEQ ID NO:9中所示的序列的重链可变区或含有SEQ ID NO:25中所示的序列的重链,以及含有SEQ ID NO:15中所示的序列的轻链可变区或含有SEQ ID NO:27中所示的序列的轻链。抗Siglec-10抗体可以包含hu-VHv1VLv2。
在另一个实例中,抗Siglec-10抗体包含含有SEQ ID NO:10中所示的序列的重链可变区或含有SEQ ID NO:32中所示的序列的重链,以及含有SEQ ID NO:15中所示的序列的轻链可变区或含有SEQ ID NO:27中所示的序列的轻链。抗Siglec-10抗体可以包含hu-VHv2VLv2。
在另一个实例中,抗Siglec-10抗体包含含有SEQ ID NO:10中所示的序列的重链可变区或含有SEQ ID NO:32中所示的序列的重链,以及含有SEQ ID NO:16中所示的序列的轻链可变区或含有SEQ ID NO:34中所示的序列的轻链。抗Siglec-10抗体可以包含hu-VHv2VLv3。
抗Siglec-10抗体可以包含含有SEQ ID NO:9、10或11中所示的序列的重链可变区;以及含有SEQ ID NO:15、27、16或34中所示的序列的轻链可变区。
在另一个实例中,抗Siglec-10抗体包含含有SEQ ID NO:10中所示的序列的重链可变区,以及含有SEQ ID NO:17中所示的序列的轻链可变区。抗Siglec-10抗体可以包含hu-VHv2VLv4。在另一个实例中,抗Siglec-10抗体包含含有SEQ ID NO:12中所示的序列的重链可变区,以及含有SEQ ID NO:17中所示的序列的轻链可变区。抗Siglec-10抗体可以包含hu-VHv4VLv4。抗Siglec-10抗体可以包含含有SEQ ID NO:10或12中所示的序列的重链可变区;以及含有SEQ ID NO:17中所示的序列的轻链可变区。
在另一个实例中,抗Siglec-10抗体包含含有SEQ ID NO:12中所示的序列的重链可变区,以及含有SEQ ID NO:16或34中所示的序列的轻链可变区。抗Siglec-10抗体可以包含hu-VHv4VLv3。
在另一个实例中,抗Siglec-10抗体包含含有SEQ ID NO:10中所示的序列的重链可变区;以及含有SEQ ID NO:15或17中所示的序列的轻链可变区。在另一个实例中,抗Siglec-10抗体包含含有SEQ ID NO:12中所示的序列的重链可变区;并且轻链可变区包含SEQ ID NO:16、34或17中所示的序列。
抗Siglec-10抗体可以包含人Igκ多肽。在一个实例中,Igκ具有SEQ ID NO:19中所示的序列。抗Siglec-10抗体可以包含人IgG多肽,其可以为IgG1、IgG2、IgG3、IgG4、IgA1或IgA2。在一个实例中,IgG为IgG4,其可以具有SEQ ID NO:20中所示的序列。在另一个实例中,IgG4可以包括S228P突变,其可以具有以下序列。
在另一个实例中,抗Siglec-10抗体包含含有SEQ ID NO:9中所示的序列的重链可变区,以及含有SEQ ID NO:24中所示的序列的S228P突变体IgG4。
重链(VHv1)可以包含以下所示的序列。
具有SEQ ID NO:25中所示的序列的重链(VHv1)还可以包含信号肽,并且可以具有以下所示的序列。
重链(VHv2)可以包含以下序列:
重链(VHv2)也可以包含以下序列:
抗Siglec-10抗体可以包含含有SEQ ID NO:9或25中所示的序列的重链,以及含有SEQ ID NO:15或27中所示的序列的轻链(VHv1VLv2)。在一个实例中,抗Siglec-10抗体可以包含含有SEQ ID NO:25中所示的序列的重链,以及含有SEQ ID NO:27中所示的序列的轻链。抗Siglec-10抗体可以包含含有SEQ ID NO:10或32中所示的序列的重链,以及含有SEQID NO:15或27中所示的序列的轻链(VHv2VLv2)。在一个实例中,抗体包含含有SEQ ID NO:32中所示的序列的重链,以及含有SEQ ID NO:27中所示的序列的轻链。抗Siglec-10抗体可以包含含有SEQ ID NO:10或32中所示的序列的重链,以及含有SEQ ID NO:16或34中所示的序列的轻链(VHv2VLv3)。在一个实例中,抗体包含含有SEQ ID NO:32中所示的序列的重链,以及含有SEQ ID NO:34中所示的序列的轻链。
3.双特异性抗体组合物
本文还提供了双特异性抗体,该双特异性抗体包含结合Siglec-10的抗体,该结合Siglec-10的抗体桥联到结合其他免疫刺激、免疫细胞靶向性或癌症靶向性分子的抗体。在具体的实施方案中,双特异性抗体包含抗Siglec-10抗体或其抗原结合片段,以及癌症靶向性抗体或其抗原结合片段。此类分子将在肿瘤微环境中富集。癌症靶向性抗体可以包括特异性T抗原、TN抗原、差异糖基化粘蛋白、CD24、her-2或PMSA。
在另一个实施方案中,抗Siglec-10双特异性抗体可以包含靶向互补抗肿瘤途径或机制的第二抗体或其抗原结合片段。在一个实施方案中,本文所述的抗Siglec-10抗体组合物可以与加强天然免疫应答的癌症免疫疗法抗体组合。此类癌症免疫疗法抗体的实例包括抗PD-1、抗CTLA-4、抗PD-L1、抗B7-H3、抗B7-H4、抗LIGHT、抗LAG3、抗TIM3、抗TIM4抗CD40、抗OX40、抗GITR、抗BTLA、抗CD27、抗CD47、抗ICOS或抗4-1BB。此类抗体可以用于治疗癌症。
本领域已知有许多不同的双特异性抗体技术。大多数这些要求双组分抗体呈单链形式,以使得两个部分可在单一构建体中表达。优选的方法是将抗体表达为单链可变片段(scFv)。双特异性抗体技术的非限制性实例包括BiTE(双特异性T细胞接合物)、DART(双亲和再靶向)、串联Fab免疫球蛋白(FIT-Ig)以及杵臼结构(knobs-into-holes)。
治疗方法
本文提供了本文所述的抗体组合物及其药物组合物用于治疗癌症的用途。如本文所用,术语“癌症”是指由异常不受控制的细胞生长所导致的赘生物或肿瘤。如本文所用,癌症明确地包括白血病和淋巴瘤。该术语是指涉及具有转移到远端部位潜能的细胞的疾病。
本文提供了在有此需要的受试者中治疗癌症或异常增殖性疾病的方法,该方法可以包括向受试者施用抗体组合物。受试者可以为哺乳动物,如狗、猫、猪、马、乳牛、猴、类人猿或人类。在一个实例中,受试者是人类受试者。还提供了用于治疗癌症或异常增殖性疾病的包含抗体组合物的药物组合物。还提供了抗体组合物在制备用于治疗癌症或异常增殖性疾病的药物中的用途。在一个实例中,抗体组合物用作单一疗法,其可以有利于巨噬细胞、ADCC以及抗体依赖性细胞吞噬作用(ADCP)中的一种或多种对癌细胞的吞噬作用。
癌症可以为以下中的一种或多种(但不限于):癌,包括膀胱癌、乳腺癌、结肠癌、肾癌、肝癌、肺癌、卵巢癌、胰腺癌、胃癌、子宫颈癌、甲状腺癌和皮肤癌;包括鳞状细胞癌;淋巴系血液系统肿瘤,包括白血病、急性淋巴性白血病、急性淋巴细胞白血病、B细胞淋巴瘤、T细胞淋巴瘤、伯基特淋巴瘤;髓系血液系统肿瘤,包括急性和慢性髓系白血病以及早幼粒细胞白血病;间叶来源的肿瘤,包括纤维肉瘤和横纹肌肉瘤;其他肿瘤,包括黑素瘤、精原细胞瘤、畸胎癌(tetratocarcinoma)、神经母细胞瘤和神经胶质瘤;中枢和周围神经系统肿瘤,包括星形细胞瘤、神经母细胞瘤、神经胶质瘤,以及神经鞘瘤;间叶来源的肿瘤,包括纤维肉瘤、横纹肌肉瘤,以及骨肉瘤;和其他肿瘤,包括黑素瘤、着色性干皮病(xenodermapegmentosum)、角化棘皮瘤、精原细胞瘤、甲状腺滤泡状癌,以及畸胎癌。特别地,癌症可以为本文所公开的乳腺癌、三阴性乳腺癌、卵巢癌或白血病。癌症可以包含与抗Siglec-10抗体结合的浸润细胞。
癌症可以为晚期实体瘤。晚期实体瘤可能在标准护理全身疗法后进展。癌症可以为肺腺癌(LUAD)、皮肤黑素瘤-转移性(SKCM-TM)、肺鳞状细胞癌(LUSC)、乳腺浸润性癌-基底型、乳腺浸润性癌-Her2、胰腺腺癌、头颈部鳞状细胞癌、肾脏肾透明细胞癌、胃腺癌、多形性胶质母细胞瘤、乳腺浸润性癌-LumB或乳腺浸润性癌-LumA、非小细胞肺癌、胶质母细胞瘤、黑素瘤、低级别胶质瘤、肾癌、基底型乳腺癌、Her2+乳腺癌、胰腺癌或卵巢癌。在一个实例中,癌症为LUAD、SKCM-TM或LUSC。特别地,癌症可以为非小细胞肺腺癌。癌症也可以为恶性血液病,其可以为白血病、骨髓增生异常综合征、B细胞淋巴瘤或多发性骨髓瘤。
癌症可能是由细胞凋亡畸变引起的,并且也可以通过本文所述的方法和组合物进行治疗。癌症可以为以下中的一种或多种(但不限于):滤泡性淋巴瘤、具有p53突变的癌、乳腺、前列腺或卵巢的激素依赖性肿瘤,以及癌前病变,如家族性腺瘤性息肉病或骨髓增生异常综合征。在具体实施方案中,通过本发明的方法和组合物治疗或预防卵巢、膀胱、乳腺、结肠、肺、皮肤、胰腺或子宫中的恶性肿瘤或增殖异常性(dysproliferative)变化(如组织变形和异型增生)或过度增殖性障碍。在其他具体实施方案中,通过本文所述的方法和组合物治疗或预防肉瘤、黑素瘤以及白血病中的一种或多种。
在另一个实施方案中,抗体组合物与一种或多种其他抗肿瘤疗法联合使用,包括但不限于当前的标准和实验化疗、激素疗法、生物疗法、免疫疗法、放射疗法或外科手术。在一些实施方案中,抗体组合物与治疗或预防有效量的一种或多种药剂、治疗性抗体或本领域的技术人员已知的其他药剂联合施用,以用于治疗和/或预防癌症、自身免疫疾病、感染性疾病或中毒。此类药剂包括例如任何以上所讨论的生物应答调节剂、细胞毒素、抗代谢剂、烷基化剂、抗生素或抗有丝分裂剂,以及免疫治疗剂。
在本发明的优选的实施方案中,抗体组合物与一种或多种抗肿瘤免疫疗法一起使用。抗肿瘤免疫疗法可以为如下的分子:破坏或增强一种或多种替代的免疫调节途径(如TIM3、TIM4、OX40、CD40、GITR、4-1-BB、PD-L1、PD-1、B7-H3、B7-H4、CTLA-4、LIGHT、BTLA、ICOS、CD27、CD47、TIGIT或LAG3),或者调节效应分子如细胞因子(例如,IL-4、IL-7、IL-10、IL-12、IL-15、IL-17、GF-β、IFNg、Flt3、BLys)和趋化因子(例如CCL21)的活性,以便增强免疫调节效应。在又一个实施方案中,抗体组合物与活化免疫应答的不同阶段或方面的一种或多种分子联合施用,以便实现更广泛的免疫应答。在更优选的实施方案中,抗体组合物与抗PD-1或抗4-1BB抗体组合,而不加剧自身免疫副作用。
抗体组合物可以与肿瘤靶向性抗体一起使用。肿瘤靶向性抗体可以为引起ADCC或ADCP中的一种或多种的任何抗体。肿瘤靶向性抗体可以为西妥昔单抗(爱必妥(Erbitux))、利妥昔单抗(rituximab)(美罗华(Rituxan))、曲妥珠单抗(trastuzumab)(赫赛汀(Herceptin))或达雷木单抗(daratumumab)(达拉他滨(Darzalex))。抗体组合物也可以与宿主细胞靶向性免疫治疗剂一起使用,该宿主细胞靶向性免疫治疗剂可以为抗CTLA-4抗体。抗CTLA-4抗体在本领域中是已知的。抗CTLA-4抗体可公开于美国专利号10,618,960中,其内容以引用方式并入本文。在一个实例中,抗CTLA-4抗体具有包含SEQ ID NO:21的重链可变区以及包含SEQ ID NO:22的轻链可变区。抗CTLA-4抗体轻链还可以包含含有SEQ IDNO:29的恒定区,并且重链还可以包含含有SEQ ID NO:30或31的恒定区。在另一个实例中,抗CTLA-4抗体具有包含含有SEQ ID NO:21的可变区和含有SEQ ID NO:31的恒定区的重链;以及包含含有SEQ ID NO:22的可变区和含有SEQ ID NO:29的恒定区的轻链。
生产
本文所述的抗Siglec-10抗体可以使用真核表达系统来制备。表达系统可能需要在哺乳动物细胞如中国仓鼠卵巢(Chinese Hamster Ovary,CHO)细胞中由载体表达。该系统也可以为病毒载体,如可以用于感染真核细胞的复制缺陷型逆转录病毒载体。抗体也可以由稳定细胞系产生,该细胞系由已经整合到细胞基因组中的载体或载体的一部分表达抗体。稳定细胞系可以由整合的复制缺陷型逆转录病毒载体表达抗体。
本文所述的抗Siglec-10抗体或其抗原结合片段可以使用例如层析法如亲和层析、离子交换层析、疏水相互作用层析、DEAE离子交换、凝胶过滤,以及羟基磷灰石层析进行纯化。在一些实施方案中,融合蛋白可以被工程化成包含含有允许多肽被捕获到亲和基质上的氨基酸序列的额外域。例如,可以使用蛋白A柱从细胞培养上清液或细胞质提取物中分离本文所述的包含免疫球蛋白域的Fc区的抗体。此外,标签如c-myc、血凝素、多组氨酸或FlagTM(Kodak)可以用来辅助多肽纯化。此类标签可以插入多肽内的任何之处,包括羧基或氨基末端。其他可能有用的融合物包括有助于检测多肽的酶,如碱性磷酸酶。免疫亲和层析也可以用于纯化多肽。
药物组合物
本文提供了一种药物组合物,该药物组合物包含治疗有效量的一种或多种本文所述的抗Siglec-10抗体和组合物,以及生理学上可接受的载剂或赋形剂。药物组合物可以包含预防或治疗有效量的抗Siglec-10抗体以及药学上可接受的载剂。
在一个具体的实施方案中,术语“药学上可接受的”意指经联邦或州政府的管理机构批准或者美国药典(U.S.Pharmacopeia)或其他公认药典中所列以用于动物,并且更特别地用于人类。术语“载剂”是指随治疗剂一起施用的稀释剂、佐剂(例如弗氏佐剂(完全和不完全)、赋形剂或媒介物。此类药物载剂可以为无菌液体,如水和油,包括石油、动物、植物或合成来源的那些,如花生油、大豆油、矿物油、芝麻油等等。当静脉内施用药物组合物时,水是优选的载剂。盐水溶液和右旋糖水溶液和甘油溶液也可以用作特别是可注射溶液剂的液体载剂。合适的药物赋形剂包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽、稻、面粉、白垩、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石、氯化钠、脱脂乳粉、甘油、丙烯、二醇、水、乙醇等等。组合物也可根据需要含有微量的润湿或乳化剂或pH缓冲剂。这些组合物可以采取溶液剂、混悬剂、乳剂、片剂、丸剂、胶囊剂、散剂、缓释制剂等形式。
一般而言,药物组合物的成分可以单独地供应,或者以单位剂型混合在一起,例如,作为指示活性剂的量的密封容器(如安瓿或小袋)中的冻干散剂或无水浓缩物。在组合物通过输注施用的情况下,其可以用含有无菌药物级水或盐水的输注瓶来分配。在组合物通过注射施用的情况下,可以提供注射用无菌水或盐水的安瓿,以便可以在施用之前混合成分。
可以将药物组合物配制为中性或盐形式。药学上可接受的盐包括但不限于与阴离子形成的那些,如衍生自盐酸、磷酸、乙酸、草酸、酒石酸等的那些,以及与阳离子形成的那些,如衍生自钠、钾、铵、钙、三价氢氧化铁、异丙胺、三乙胺、2-乙氨基乙醇、组氨酸、普鲁卡因等的那些。
药物组合物可以包含组氨酸缓冲液、蔗糖,以及聚山梨醇酯80(PS80)中的一种或多种或全部。在一个实例中,药物组合物包含约15、16、17、18、19、20、21、22、23、24或25mM组氨酸缓冲液。特别地,组氨酸缓冲液浓度可以为20mM。药物组合物可以包含约6、7、8、9或10%w/v蔗糖。在一个实例中,药物组合物包含8%蔗糖。药物组合物可以包含约0.01、0.02或0.03% PS80。在一个实例中,PS80浓度为0.02%。在一个实例中,药物组合物包含20mM组氨酸缓冲液、8%蔗糖,以及0.02%w/v PS80。药物组合物可以具有约5、5.5或6.0的pH。在一个实例中,pH为5.5。药物组合物在施用于受试者之前可以在0.9%氯化钠或5%右旋糖溶液中稀释。
抗Siglec-10抗体(其可以为ONC-841)可以以约10、15、20、25或30mg/mL存在于药物组合物中。抗Siglec-10抗体可以以约1、2、3、4 5、6、7、8或9mg/kg的剂量施用。剂量可以小于10mg/kg。在一个实例中,剂量为3-9mg/kg。在另一个实例中,剂量为3mg/kg。如果受试者遭受与抗体组合物的施用相关联的不良事件,则可以从先前剂量向下调节后续剂量。如果抗体组合物不具有足够强的抗癌效应,则可以从先前剂量向上调节后续剂量。
施用方法
施用本文所述的抗Siglec-10抗体组合物及其药物组合物的方法包括但不限于胃肠外施用(例如,皮内、肌内、腹膜内、静脉内和皮下)、硬膜外,以及粘膜(例如,鼻内和口服途径)。在一个具体的实施方案中,本发明的抗体经肌内、静脉内或皮下施用。组合物可以通过任何方便的途径施用,例如经由输注或推注、经由通过上皮或皮肤粘膜内层(例如,口腔粘膜、直肠和肠粘膜等)吸收,并且可以与其他生物活性剂一起施用。施用可以为全身或局部的。
实施例
本公开具有通过以下非限制性实施例说明的多个方面。
实施例1
单克隆抗Siglec-10抗体的生成
为了生成拮抗剂,将小鼠用Siglec-10转染的鼠细胞系免疫,在三次免疫后,收获得到脾细胞以用于生成杂交瘤。杂交瘤上清液针对其在逆转ADCC中Siglec-10抑制效应中的活性进行筛选,这使用表达人FcγRIIIa的效应细胞来测量。在超过20,000种克隆中,发现一种(31F11)在逆转Siglec-10的抑制中最有力(图1)。与另一种抗Siglec-10抗体(10H3和5G6)相比,31F11在拮抗Siglec-10功能中更有力。
为了确认31F11的特异性,我们用由Siglec 1、2、3、5、6、7、9、10和11的细胞外域组成的融合蛋白包被板,并测试3F11与这些Siglec的结合。如图2所显示,仅Siglec-10显示出与31F11的明显结合。作为替代方法,我们用GFP标签化Siglec 2、3、5、9、10、12和15转染293T细胞系。如图3所显示,31F11特异性结合表达Siglec-10的细胞,但不结合任何其他测试的Siglec。综上所述,图2和3中的数据展示出31F11结合Siglec-10,而非Siglec1、2、3、5、6、7、9、11、12和15。
实施例2
抗siglec10抗体阻断Siglec-10-Fc与脾细胞的结合
为了确认31F11是否阻断Siglec-10与其配体的结合,我们测试了31F11对Siglec-10-Fc与小鼠脾细胞的结合的效应。如图4所显示,31F11在阻断Siglec-10-Fc与脾细胞的结合方面比其他抗Siglec-10抗体(5G6和10H3)更有力。
实施例3
抗siglec-10抗体吞噬作用测定
为了测试抗Siglec-10是否促进巨噬细胞对癌细胞的吞噬作用,将从外周血分离的人单核细胞用补充有40ng/ml M-CSF的RPMI-1640培养基刺激5-7天。然后通过50ng/mlTGFβ1和IL10诱导M2巨噬细胞24小时。将MCF-7细胞用CellTrackerTMViolet BMQC染料标记,并且在存在指定浓度的抗Siglec-10 Ab的情况下与供体衍生的巨噬细胞共培养2小时。经历吞噬作用的巨噬细胞的%通过流式细胞术测定。如图5所显示,31F11的吞噬作用增加一倍以上,而其他抗Siglec-10抗体不具有明显效应。因此,31F11的独特之处在于促进吞噬作用。
实施例4
与抗hCD24抗体联合的抗肿瘤活性
由于31F11在体外促进ADCC,我们假设该抗体在与肿瘤细胞靶向性抗体联合使用时可促进肿瘤排斥。为了检验这一假设,将1×106个MC38-hCD24细胞接种到S10 BM嵌合体小鼠(n-4-5)上。在第7、10、13和16天,用100μghIgFc、α-hCD24、31F11(αS10)或α-hCD24+31F11处理小鼠。如图6所显示,抗CD24和31F11的组合(而非单独的任一种)在所有受者小鼠中诱导肿瘤排斥。这些数据支持了抗Siglec-10抗体在肿瘤排斥中的用途。
实施例5
用于癌症疗法的31F11的人源化
通过人Ig数据库blasting,将人种系V区序列IGHV2-70*04和J区序列JH6作为31F11 VH的CDR区的人框架接受体应用。将人种系V区IGKV3-15*01和J区序列JK4作为31F11VL的CDR区的人框架接受体应用。设计了5种huVH形式(VHv1、VHv2、VHv3、VHv4和VHv5,具有SEQ ID NO:9-13)和5种huVL形式(VLv1、VLv2、VLv3、VLv4和VLv5,具有SEQ ID NO:14-18)。/
为了选择用于Siglec-10结合的HuVH和HuVL的最佳工作组合,在表达构建体中合成了编码重链和轻链的DNA,并将不同的组合共转染到293细胞中,比较了7种人源化抗体和嵌合亲本抗体与表达人Siglec-10的Jurkat细胞的结合。克隆的特性汇总于表2中。
表2 31F11的人源化克隆的表征
抗体组合如下:#21(SEQ ID NO:9和15)、#22(SEQ ID NO:10和15)、#23(SEQ IDNO:11和15)、#32(SEQ ID NO:10和17)、#34(SEQ ID NO:12和17)、#52(SEQ ID NO:10和16),以及#54(SEQ ID NO:12和16)。在它们之中,亲本抗体的EC50为210ng/ml,而人源化抗体的EC50为228ng/ml至423ng/ml(图7)。这表明所有抗体均显示出与细胞表面Siglec-10的有力结合。热稳定性分析显示了所有人源化抗体均表现出良好的热稳定性(图8)。使用Biacore分析,我们测量了排名前5名的抗体的亲和力。如表2所显示,测试的所有5种抗体均显示出与Siglec-10的高亲和力结合。特别地,五种抗体中有三种(#22、#23和#52)比嵌合亲本克隆具有更高的亲和力。
为了测试生物学功能,我们将7种mAb与亲本嵌合抗体恢复ADCC活性的能力进行了比较。如图9所显示,在所有测试的克隆中均检测到强ADCC。
实施例6
抗Siglec-10抗体的临床前研究
临床前研究表明,抗CTLA-4mAb的治疗功效是由于瘤内Treg的消减,而其毒性则是由于CTLA-4的下调。将抗CTLA-4与可增加抗CTLA-4的ADCC的药物组合是很有意义的。Siglec-10已成为有前景的靶标,因为我们已经展示Siglec-10是ADCC(包括由抗CTLA-4触发的ADCC)的负调节因子(图10)。抗Siglec-10mAb即31F11是基于其增强ADCC(图11)和癌细胞的吞噬作用(图12)的能力而开发的。该抗体的人源化形式(命名为ONC-841)由此被开发用于治疗人类癌症。
综上所述,Siglec-10的拮抗剂可通过两种不同的机制促进抗肿瘤免疫。第一,它可使DNEMS失活,以促进肿瘤细胞的吞噬作用。第二,通过使ADCC的负调节因子失活,拮抗剂可以增强基于ADCC的治疗性抗体的治疗活性。
作用机制
累积数据确立,Siglec-10是用于吞噬作用、ADCC和ADCP的负调节因子。因此,ONC-841无论作为单一疗法还是联合疗法均可以促进肿瘤排斥。
单一疗法
作为单一疗法,ONC-841通过阻断Siglec-10-CD24 DNEMS相互作用来促进肿瘤排斥,如图13所示。对于过表达CD24或其他高亲和力Siglec-10配体的癌症,这种机制应最为活跃。现在很清楚的是,所有人类癌症中近70%过表达CD24,并且其表达与不良预后相对应。此外,Siglec-10也在肿瘤相关巨噬细胞(TAM)中以高水平表达。预期ONC-841可以对大多数癌症类型(包括非小细胞肺癌)的先天免疫具有广泛影响。
联合疗法
由于Siglec-10负调节ADCC和ADCP,ONC-841与通过ADCC和ADCP实现抗肿瘤活性的药物协同地作用。此类药物可以靶向癌细胞(例如爱必妥、利妥昔单抗),或者靶向宿主细胞(例如抗CTLA-4抗体)。Siglec-10负调节ADCC/ADCP,而CD24可以使Siglec-10负信号传导以抑制ADCC/ADCP,数据展示Siglec-10可识别非CD24配体。因此,对于不依赖于CD24表达的肿瘤类型,ONC-841可以用于增强对宿主或癌细胞的消减。图13示出了ONC-841可与抗CTLA-4(如ONC-392)联合使用以促进TME中Treg消减的机制,即通过阻断Siglec-10的负信号传导。
实施例7
抗Siglec-10抗体的药理学和毒理学
体外药理学
ONC-841的特异性
为了确认ONC-841的结合特异性,我们通过ELISA测试了其与其他人Siglec重组蛋白的结合。使带有His或Fc标签的不同Siglec细胞外域重组蛋白包被到ELISA板上。添加生物素化ONC-841以检测与包被的Siglec蛋白的结合。使用亲和素-HRP作为用于检测的二抗。如图14A和B所显示,ONC-841与Siglec 10强烈结合,Kd为约0.02247μg/mL,但不与所有其他测试的Siglec(包括Siglec 1-9、11、14和15)结合。ONC-841在高浓度下显示出与Siglec-5Fc、Siglec-6Fc、Siglec-11Fc和Siglec-14Fc的一些结合。为了阐明该结合是针对Siglec重组蛋白特异性的还是针对Fc非特异性结合,我们包括了人IgG1 Fc(hIgG1Fc)作为对照。结果表明ONC-841与Siglec-5Fc、Siglec-6Fc、Siglec-11Fc和Siglec-14Fc的结合是由于与Fc标签的非特异性结合,因为结合与hIgGFc相当(图14B)。
ONC-841阻断Siglec-10与其配体在人恶性Jurkat细胞和体外分化的调节性T细胞上的相互作用
Siglec蛋白识别细胞表面上的唾液酸化蛋白,其中α2,6唾液酸化相对于α2,3-唾液酸化是优选的。为了测试ONC-841是否阻断Siglec-10与恶性细胞上其天然配体的相互作用,我们测试了ONC-841阻断Siglec-10Fc与人白血病Jurkat细胞系结合的能力。使Siglec-10Fc-生物素与链霉亲和素-PE(SA-PE)以4:1的摩尔比预复合1小时,然后添加到不同浓度的ONC-841中5分钟。基于Siglec-10Fc-生物素浓度,将混合物以10μg/mL的浓度添加到Jurkat-CTLA4细胞中以在室温下温育一小时。将细胞彻底清洗以移除过量的未结合试剂,并通过流式细胞仪获取。在排除死细胞后进行分析。如图15中所显示,Siglec-10Fc与Jurkat细胞系强烈结合,并且这种结合被ONC-841以剂量依赖性方式阻断。IC50估计为2μg/mL(13.3nM)。
为了测试ONC-841对Siglec-10Fc-生物素与正常宿主细胞结合的效应,我们使用荧光Siglec-10Fc四聚体,并使用以上所提及的相同方法评价ONC-841的效应。我们专注于Treg以便支持我们提出的联合疗法。从新鲜PBMC中分离的初始CD4 T细胞中分化Treg。如图16所显示,Siglec-10Fc显示出与体外分化的人Treg明显结合。Siglec-10Fc与Treg的相互作用被ONC-841以剂量依赖性方式阻断。IC50估计为3.57μg/mL(23.8nM)。
ONC-841促进两种癌症靶向性抗体的ADCC报告物活性
测试了ONC-841促进癌症靶向性抗体(包括靶向CD20、CTLA-4和表皮生长因子受体(EGFR)的那些)的ADCC活性的能力。利用Promega的ADCC报告物测定,我们通过检测在存在癌症靶向性抗体的情况下FcγRIIIA活化后效应细胞中NFAT表达的发光测量了ADCC活性。简而言之,使靶细胞与ADCC效应细胞、模拟物转移的ADCC效应细胞(ADCC-Mock)或人Siglec-10表达性ADCC细胞(ADCC-hSiglec10)共温育。在滴定的ONC-841mAb中以固定浓度添加肿瘤靶向性抗体。测量相对发光单位(RLU)。如图17A所显示,ONC-841通过抗CD20促进针对Raji淋巴瘤细胞系的ADCC活性,EC50为0.5μg/ml。为了测试ONC-841对实体瘤的影响,我们使用了表达人EGFR的B16黑素瘤细胞系,并使用抗EGFR药物西妥昔单抗来触发ADCC。如图17B所显示,ONC-892的ADCC活性几乎是西妥昔单抗的两倍,EC50为0.3μg/ml。为了支持我们的联合疗法试验设计,我们测试了ONC-841通过ONC-392促进ADCC的功效。如图17C所显示,ONC-841增强了ONC-392的ADCC活性,IC50为0.08μg/ml。与ONC-392组合时EC50最低的这一事实支持了我们在早期临床试验中选择ONC-392作为联合伴侣,并且广泛的活性表明了使用ONC-841与癌症靶向性抗体在血液恶性肿瘤和实体瘤中的联合疗法的潜能。ONC-841促进人NK细胞对白血病细胞的ADCC以及抗体非依赖性杀伤
为了测试ONC-841对NK细胞杀伤肿瘤细胞的影响,我们使用了CTLA-4转染的Jurkat细胞作为靶细胞,以及新鲜分离的人NK细胞作为效应细胞。简而言之,在采用或不采用固定浓度的ONC-392的情况下,将钙黄绿素AM标记的Jurkat-CTLA-4靶细胞与来自新鲜全血的负选择人NK细胞与滴定的ONC-841mAb共温育6小时。在温育后,通过流式细胞术分析细胞。基于与对照相比剩余的钙黄绿素AM+活细胞的数量,计算细胞死亡百分比。如图18A-C所显示,在不存在肿瘤细胞靶向性抗体的情况下,ONC-841增强了NK介导的Jurkat细胞的细胞杀伤,其中估计的EC50为0.3744μg/ml。在存在饱和量的ONC-392(20μg/ml)的情况下,ONC-841进一步增强了NK细胞活性,其中估计的EC50为2.274μg/ml。因此,ONC-841促进NK细胞对恶性白血病细胞的ADCC以及抗体非依赖性细胞溶解两者。
ONC-841促进人PBMC杀伤人肿瘤细胞
Siglec-10主要表达于骨髓细胞上。因此,ONC-392的影响可能超出NK细胞的范围。为了更全面了解抗肿瘤效应,我们通过测试了ONC-841对从3名单独供体的新鲜全血中分离的PBMC裂解白血病细胞的效应。将钙黄绿素AM标记的Jurkat-CTLA-4靶细胞与从新鲜全血中分离的PBMC与滴定的ONC-841mAb共温育。在温育后,通过流式细胞术分析细胞。基于与对照相比剩余的钙黄绿素AM+活细胞的数量,计算细胞死亡百分比。如图19所显示,用低剂量的ONC-841实现了显著裂解,其中供体1、供体2和供体3的估计EC50分别为0.3645、0.01761和0.009572μg/ml。这些数据表明,ONC-841可以在不存在白血病靶向性抗体的情况下促进白血病杀伤。
体内药理学研究
为了测试ONC-841在动物模型中的治疗活性,我们生成了转基因小鼠模型,其中我们分别通过Siglecg基因的靶向突变以及插入含有人Siglec-10的Bacmid克隆移除了小鼠Siglec-G和插入了其人Siglec-10直系同源物(见下文)。由于Siglec-10在转基因小鼠中的组织分布与其在人白细胞中的分布一致,我们使用该模型在两个单独的模型中测试了ONC-841对肿瘤排斥的影响。单一疗法以及与癌症靶向性抗体的联合疗法
为了评价实体瘤的治疗效应,我们使用了表达人EGFR的B16F10细胞系。在肿瘤细胞攻击后6天,用对照IgG、ONC-841或ONC-841+西妥昔单抗处理荷瘤小鼠,并以盲法方式测量肿瘤生长。B16-EGFR荷瘤(s.c.)Siglec10TG+/+;Siglecg-/-小鼠(n=4-5)从肿瘤接种后第6天开始每三天用200μg对照hIgGFc或ONC-841经i.p.以及用10μg对照hIgGFc或西妥昔单抗经i.t.进行处理,共注射四次。如图20所显示,瘤内注射西妥昔单抗效应甚微,而ONC-841单一疗法实现了肿瘤生长的部分延缓。结合起来,实现了更显著的肿瘤生长延缓。这些数据表明ONC-841对小鼠模型中的实体瘤具有治疗活性。
为了测试肿瘤体积减少50%所需的ONC-841的量,我们在联合疗法模型中滴定了ONC-841的剂量。西妥昔单抗的瘤内治疗剂量固定为10μg/注射,而全身ONC-841剂量为5、10和20mg/kg。简而言之,将5×105个B16-EGFR肿瘤细胞注射(s.c.)到Siglec10TG+/+;Siglecg-/-小鼠(n=4-5)中,并且当肿瘤直径达到4-7mm时开始治疗。荷瘤小鼠每三天用2.5、10或20mg/kg ONC-841经i.p.处理,并且用10μg hIgFc或西妥昔单抗经i.t.注射,共注射四次。如图21所显示,实现了肿瘤体积的ONC-841剂量依赖性减小。使用线性回归分析,确定ONC-841的EC50为16.49mg/kg。
与抗CTLA-4抗体的联合疗法
作为显示ONC-841与宿主靶向性免疫治疗抗体的联合效应的模型,我们使用了未经修饰的B16F10模型以及抗小鼠CTLA-4mAb 9D9。如图22所显示,9D9和ONC-841均未引起肿瘤生长延缓。然而,结合起来,观察到肿瘤生长的显著减少。
药理学相关物种
ONC-841不与小鼠和非人灵长类Siglec G/10反应
已知Siglec蛋白进化迅速,且不同物种的直系同源物之间的同源性有限。人Siglec-10与一些其NHP直系同源物具有高相似性:与食蟹猴和恒河猴Siglec-10的相似性为90%,而与小鼠Siglec-G的相似性仅为60%(来自:Ensembl.org)。
为了确定何种动物物种是用于ONC-841的适当毒理学物种,我们在3项测定中评价了ONC-841抗体与NHP Siglec-10或小鼠直系同源物Siglec-G的结合:
A.与重组Siglec-10/Siglec-G的结合
B.与瞬时表达NHP Siglec-10/Siglec-G的expi293细胞的结合
C.与食蟹猴PBMC的结合
没有一项测定显示ONC-841与NHP Siglec-10或小鼠Siglec-G特异性结合,表明ONC-841结合的特异性表位不与这些物种共享。
与来自其他物种的重组Siglec-10/Siglec-G的结合
重组His标签化人和食蟹猴Siglec-10以及小鼠Siglec-G购自ACROBiosystems。Siglec蛋白被包被在ELISA板上作为捕获抗原。使用山羊抗人抗体检测捕获的ONC-841。如下在图23所显示,ONC-841显示与人Siglec-10特异性结合,而不与食蟹猴或小鼠蛋白结合。
与NHP Siglec-10基因转染的293T细胞的结合
分别用人、食蟹猴、恒河猴和狨猴Siglec-10表达质粒转染expi293细胞,以在细胞表面上产生这些蛋白质。使用流式细胞术对活expi293细胞评价了ONC-841的结合,并使用针对Siglec-10的多克隆抗体验证了不同Siglec-10蛋白的表达(图24,浅灰色线)。ONC-841显示仅与表达人Siglec-10的细胞结合,而不与任何NHP Siglec-10结合(图24,深灰色线)。
与食蟹猴PBMC的结合
为了测试ONC-841与天然表达的Siglec-10的结合,对人和食蟹猴PBMC染色并通过流式细胞术进行评价。Siglec-10由单核细胞(CD14+细胞)和B细胞(CD20+细胞)两者表达,并因此在这些群体上测试了ONC-841结合。为了验证特异性染色并消除ONC-841通过Fc受体的可能结合,将各物种的额外细胞样品在染色前用过量的人IgG封闭。ONC-841清楚地显示出与人单核细胞和B细胞的高度特异性结合,并且该结合不受过量人IgG存在的影响(图25)。相比之下,ONC-841揭示出与食蟹猴的两种细胞亚群的结合较弱。此外,过量的人IgG显著降低了这种结合,指示ONC-841与这些NHP Siglec-10的较低到非特异性结合特性(图27)。
不含内源性Siglecg基因的人SIGLEC10转基因小鼠的生成:Siglec10TG+/+;Siglecg-/-
由于ONC-841不结合可用的NHP和小鼠物种的白细胞,NHP和小鼠都不被视为毒性和药理学研究的相关物种。其他常用的毒性物种在遗传上比测试的NHP更远离人类,因此不太可能与毒性研究相关。因此,我们着手开发了用于毒性研究的转基因小鼠模型,其中人Siglec10基因替换了其小鼠直系同源物Siglecg。
Siglec10转基因品系(据此称为Siglec10TG+/+)是由Cyagen,Inc.(Santa Clara,CA)使用具有含有人Siglec10、Siglec8和Siglec12基因的基因组序列的Bacmid克隆由C57/BL6小鼠创建的。使用具有人类调节和编码序列的基因组克隆可以允许小鼠以与人白细胞基本上相似的方式表达Siglec10。我们在此呈现的数据支持了这一假设。此外,为了捕获体内阻断Siglec-10的效应,我们通过将转基因杂交到其中Siglecg的外显子2-11用GFP/Neo盒替换的Siglecg-/-小鼠中来移除内源性小鼠Siglecg基因。
C57BL/6Siglec10TG+/+;Siglecg-/-品系是通过将Siglec10TG+/+与Siglecg-/-小鼠杂交而创建的。通过血细胞流式细胞术,针对hSiglec-10和Siglec-G两者的表达对杂交小鼠的F1和F2代进行筛选(图26顶部和中间)以选择所期望的Siglec10TG+;Siglecg-/-基因型。该染色证实了人Siglec-10的表达以及小鼠Siglec-G的缺乏。数据显示出在小鼠PBMC中,Siglec-10在>30%的小鼠B细胞、NK细胞、单核细胞、树突状细胞(DC)和中性粒细胞中,以及在<10%的T细胞中表达。
为了比较Siglec10TG+/+;Siglecg-/-观察到的ONC-841与血液中细胞亚群的结合以及ONC-841与表达内源性Siglec-10的人细胞的结合,对人PBMC针对谱系标记以及荧光标记的ONC-841或市售抗Siglec-10抗体进行染色。图26下图显示了ONC-841对单核细胞和B细胞上的Siglec-10的清晰染色,而T细胞则没有如文献中报道的明显染色。令人惊奇地,尽管数据显示ONC-841增强了从PBMC中分离的NK细胞的ADCC活性,但血液中的NK细胞(无论是CD16-阳性还是16-阴性NK细胞)却没有清晰的染色(图26)。一种可能的解释是人NK细胞表达较低量的Siglec-10,并且当前的测定不敏感。另一种选项是购买冷冻的来自人PBMC的NK细胞,并且解冻以供Siglec-10染色。进一步探索Siglec10TG+/+;Siglecg-/-之间观察到的差异。
对来自Siglec10TG+/+;Siglecg-/-小鼠的冷冻切片执行免疫组织化学法,以检测小鼠组织中的ONC-841结合。简而言之,将快速冷冻的小鼠组织切片并固定在载玻片上。封闭切片,然后用1μg/mL的ONC-841探测,然后使用HRP标记的抗人二抗检测。使用DAB作为HRP的色原底物来可视化ONC-841的结合,其给出棕色,并且用苏木精对载玻片复染,以使细胞核可视化为蓝色。对载玻片的检查显示了造血器官和大多数其他组织中的免疫细胞的染色。这是重复进行的初步实验,并且切片由受过训练的病理学家进行检查。染色的实施例可见于图27中。
来自Siglec10TG+/+;Siglecg-/-小鼠的大多数组织/器官中的组织驻留白细胞上可见到Siglec-10的广泛表达,表明小鼠模型对于毒性和药理学研究很有价值。
体外细胞因子释放测定
某些单克隆抗体治疗剂已显示诱导了一系列的急性输注反应,包括细胞因子释放综合征(CRS),这可导致患者中的不良事件。在分子水平上,CRS的特征在于施用后1-2小时TNF-α和IFN-γ水平增大,随后是IL-6、IL-10并有时IL-2和IL-8增大。为了测试ONC-841单独或与ONC-392的组合对CRS的可能诱导,进行了初步细胞因子释放测定(CRA)。将采用或不采用ONC-392的情况下,将多至2mg/mL的不同浓度的ONC-841在96孔板中包被过夜。使用商业人IgG抗体(hIgG)作为阴性对照,并使用CD3_CD28珠作为阳性对照。次日,清洗板并将来自4名不同健康供体的PBMC添加到孔中。在添加PBMC后48小时,使用BioLegend的LegendPlex Human Inflammation Panel1(目录#740809)测试上清液中的细胞因子释放,并且包括IL-1β、IFN-α2、IFN-γ、TNF-α、MCP-1(CCL2)、IL-6、IL-8(CXCL8)、IL-10、IL-12p70、IL-17A、IL-18、IL-23和IL-33。该测定用来自4名不同供体的PBMC进行,并且结果是来自供体之一的代表性数据(图29)。在采用或不采用ONC-392的情况下,ONC-841诱导的细胞因子不超过未包被孔中检测到的水平。唯一诱导细胞因子的孔是阳性对照CD3/CD28珠。一些细胞因子也在含有商业来源的IgG4的孔中被诱导。总体而言,数据表明ONC-841不诱导wPBMC释放细胞因子,并且不诱导患者中的CRS。
执行额外的体外测定,以评估ONC-841(采用或不采用类似浓度的ONC-392)是否可以诱导正常静息人PBMC释放细胞因子。细胞因子释放测定遵循预测TGN1412的CRS高风险的方案执行。测试至少10名供体。用单独的ONC-392执行的实验显示,它不直接活化T细胞。
实施例8
抗Siglec-10抗体的临床试验
适应症
对于第1阶段,根据标准护理指南(如NCCN指南),入组了经组织学或细胞学确诊为实体瘤且在对既定标准医疗抗癌疗法失败或不耐受后患有进展性局部晚期或转移性疾病的患者。
对于第2阶段,免疫疗法失败的非小细胞肺癌患者将被选择用于开放标签研究,以使用Simon的两阶段设计测试临床功效。
基本原理汇总
如抗PD(L)1和抗CTLA-4抗体在临床上的成功所例示,在肿瘤微环境中释放抑制T细胞的抗体对癌症患者的护理具有变革性影响。该成功突出了靶向适应性T细胞免疫的免疫检查点的能力。最近的研究表明,靶向限制NK细胞和巨噬细胞功能的先天免疫检查点可能提供改善癌症免疫疗法的新方法。这些推定的先天检查点中有负调节巨噬细胞和NK细胞对肿瘤细胞的吞噬作用或杀伤的途径。阻抑巨噬细胞吞噬作用的分子统称为“别吃我”信号(DNEMS)。在已知的DNEMS中,CD47-SIRPα途径是癌症免疫疗法的主要先天免疫检查点,并且抗CD47 mAb正在临床研究中被积极测试。
临床前研究已经将CD24-Siglec-10相互作用揭示为有力的DNEMS,可与CD47-SIRPα途径相匹敌。CD24-Siglec-10途径首次被OncoC4联合创始人揭示为先天免疫检查点,以最小化对组织损伤的炎症应答[4]。CD24Fc作为Siglec-10激动剂,已显示发挥针对病毒性肺炎和病毒性结肠炎的保护作用。最近的3期临床试验展示,CD24Fc针对住院的COVID-19患者赋予显著的保护作用。相比之下,尽管有靶向该途径促进肿瘤细胞吞噬作用的较强临床前数据,但CD24-Siglec-10途径的拮抗剂尚未经过临床测试。所提出的临床试验可能通过测试抗Siglec-10mAb ONC-841在失败或不能耐受标准护理治疗剂的癌症患者中的安全性和功效来填补这一主要空白。
除了其在促进巨噬细胞对肿瘤细胞吞噬作用方面的作用之外,我们的临床前研究还揭示了ONC-841也促进抗体依赖性细胞介导的细胞毒性(ADCC)。这一新发现促使我们将ONC-841与主要功能是通过抗体依赖性细胞介导的细胞毒性(ADCC)和/或ADCP的药物(包括癌细胞靶向性和免疫细胞靶向性抗体)联合测试。细胞毒性T淋巴细胞相关蛋白4(CTLA-4)(也称为CD152(分化簇152))是与B7-1(CD80)和B7-2(CD86)相互作用的细胞表面蛋白受体,以确保调节性T细胞的适当功能并保护宿主免于自身炎症性疾病。抗CTLA-4单克隆抗体(mAb),如已获批准的抗体伊匹单抗(由Bristol Myers Squibb以销售),已在多种临床前模型中展示出较强而广泛的癌症免疫治疗效应(CITE),并在临床上用作单一疗法和与纳武单抗(抗PD-1,由Bristol Myers Squibb以/>销售)联合疗法的一部分。然而,CTLA-4单一疗法比抗PD-1/PD-L1疗法具有更多的免疫疗法相关不良效应(irAE)。此外,在接受伊匹单抗和纳武单抗的组合的黑素瘤患者中,严重irAE(3级和4级)比率达到55%。严重irAE进一步限制了癌症患者耐受的剂量。尽管如此,伊匹单抗与抗PD-1纳武单抗联合也导致多种类型癌症的应答率和总生存期得到显著改善。此外,抗CTLA-4抗体在癌症患者中诱导持久的免疫力。因此,CTLA-4仍然是重要的免疫疗法靶标,但在改善抗CTLA-4mAb的安全性和功效方面仍然具有重大挑战。
ONC-392是针对CTLA-4的高度选择性人源化单克隆IgG1-k同种型抗体。我们已经展示ONC-392在低pH下与CTLA-4解离,以允许其逃避溶酶体降解并循环到细胞表面。我们提供了对于如下观点的多方面证据:pH敏感抗体如ONC-392不仅比pH不敏感的伊匹单抗更安全,而且在Treg消减和肿瘤排斥方面更有效。
因为抗CTLA-4mAb的治疗功效是由于通过ADCC和/或ADCP消减瘤内Treg,而其毒性是由于CTLA-4的下调,将ONC-392与ONC-841联合是很有意义的,以观察这是否可以通过增强的ADCC消减Treg而导致更有力的抗肿瘤活性,且同时使ONC-392维持在更安全的剂量水平以避免irAE。
Siglec-10已成为免疫疗法的有前景的靶标。体外和体内研究的临床前研究展示,Siglec-10是ADCC(包括由ONC-392触发的ADCC)的负调节因子。我们基于ONC-841增强ONC-392的ADCC的能力开发了ONC-841。我们在动物模型中展示了ONC-841增强由抗CTLA-4mAb诱导的肿瘤排斥。
综上所述,作为Siglec-10的拮抗剂,ONC-841可通过两种不同的机制促进抗肿瘤免疫。第一,它可使DNEMS失活,以促进肿瘤细胞的吞噬作用。第二,经由阻断ADCC中通过Siglec-10的负信号传导,ONC-841可以增强基于ADCC的治疗性抗体的治疗活性。为了充分利用这些生物活性和治疗潜能,当前研究被设计成评价ONC-841作为单一疗法以及ONC-841与ONC-392联合在患有晚期或转移性实体瘤的患者中的安全性、药代动力学和功效。
研究设计的汇总
在患有晚期/转移性实体瘤的参与者中ONC-841作为单一药剂以及与ONC-392联合经静脉内(IV)施用的1/2期开放标签剂量递增研究。
1A期,剂量探索研究
1A期研究由两部分组成,以分别限定单一疗法(A部分)和联合疗法(B部分)的RP2D:
(1)A部分:单一疗法剂量递增,以限定单一疗法的推荐2期剂量(RP2D-M)。ONC-841的剂量递增将入组患有各种组织学类型的晚期癌症的未曾接受过ONC-392治疗的患者。测试ONC-841的六种水平,起始剂量依据GLP毒性数据确定。ONC-841通过IV输注施用,每21天一次(q3w)。该研究采用患者内剂量递增直至第二最高剂量,此时其过渡到3+3设计。六名患者以最终剂量水平入组,如果在2名或更多名患者中观察到DLT,则选择逐步降级。RP2D-M被确定为最高剂量水平,其中6名患者中少于2名出现DLT。
(2)B部分:联合疗法剂量探索研究,以确定ONC-841与3.0、6.0或10.0mg/kg的ONC-392联合的推荐2期剂量(RP2D-C)。与ONC-392联合的第一剂量比RP2D-M低一个剂量水平(q3w)。遵循3+3设计,三名患者入组第一队列。如果没有观察到DLT,剂量增加至RP2D-M。如果存在一名DLT,则另3名患者入组。如果六名患者中不超过一名具有DLT,则下一队列中的ONC-841处于比RP2D-M低一个水平与RP2D-M之间的中间水平,或处于RP2D-M,如由安全性数据所确定。六名患者以最终剂量水平入组。RP2D-C被确定为最高剂量水平,其中6名患者中少于2名出现DLT。
1B期,扩展队列
1B期由两个剂量扩展组组成,以测试RP2D-M的ONC-841单一疗法(A组)或RP2D-C的ONC-841与3.0、6.0或10.0mg/kg的ONC-392联合(B组)的安全性和临床活性。
我们计划每组入组30名患有晚期实体瘤或在标准护理(SOC)下疾病进展或对SOC不耐受的患者。合格标准与1A期的那些相同。
2期
2期试验将遵循Simon两阶段设计。在1期中,总共入组29名非小细胞肺癌患者来确定客观应答率。如果超过4名或更多名患者实现客观应答,试验进入2期以入组足够的患者(80至130名)以实现80%的功效来拒绝应答率低于20%的零假设。
我们对22种主要癌症类型对使用ONC-392+ONC-841的联合疗法的潜在应答性进行了排名。这继而是其基于采用RNAseq和TCGA数据库中的基因组数据重建的免疫学景观。如图28所显示,我们根据RNAseq和癌症基因组图谱(The Cancer Genomics Atla,TCGA)数据库中属于22种癌症类型的7279个独立癌症样本的基因组数据生成了免疫肿瘤微环境景观。主要从稍后被鉴定为抗CTLA-4抗体伊匹单抗的应答者和无应答者的黑素瘤患者的治疗前临床样本的基因组和RNAseq数据中,我们鉴定了抗CTLA-4的应答性的5个排名分量,包括CTLA-4基因表达、ADCC潜能、突变负荷,以及有利于CTLA-4应答性的基因富集和细胞组成。总排名数由5个独立分区值之和计算得出,每个分区值由1-3个分量组成。对ONC-841应答的排名基于SIGLEC10表达丰度和巨噬细胞丰度,由RNAseq数据确立。对联合疗法应答的排名基于它们对每种抗体的应答(表3)。我们的分析表明非小细胞肺腺癌是最具应答性的癌症类型。ONC-392的单一药剂活性得到我们正在进行的临床试验的支持。
表3 22种癌症类型对ONC-392、ONC-841以及它们的组合的应答的相对排名
基于我们的临床数据和计算机分析,我们选择非小细胞肺腺癌作为我们2期研究中的第一临床适应症,以测试ONC-841和ONC-392联合疗法的临床疗效。
剂量/剂型、途径,以及给药方案
对于单一疗法的剂量递增,ONC-841以最少60分钟IV输注来施用。评价ONC-841的六种剂量水平。给药间隔为21天。ONC-841以Q3W的计划表给予。在ONC-392和ONC-841的组合中,ONC-841首先以最少60分钟IV输注施用。然后,ONC-392以3.0、6.0或10.0mg/kg的剂量按最少60分钟IV输注来施用。ONC-392和ONC-841不应混合施用,并且两种药物施用之间应存在至少30分钟的间隔。单独的ONC-841或者ONC-392与ONC-841组合以Q3W的计划表给予。
序列表
<110> 昂科医药
马里兰大学巴尔的摩分校
<120> 抗Siglec组合物及其用途
<130> 111005.0900.01PC00
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Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Tyr Ser Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 16
<211> 107
<212> PRT
<213> 人工
<220>
<223> 人源化抗体
<400> 16
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Tyr Lys Ala Ser Gln Asn Val Gly Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Asn Arg Tyr Thr Gly Val Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 17
<211> 107
<212> PRT
<213> 人工
<220>
<223> 人源化抗体
<400> 17
Asp Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Tyr Lys Ala Ser Gln Asn Val Gly Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Asn Arg Tyr Thr Gly Val Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Tyr Ser Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 18
<211> 107
<212> PRT
<213> 人工
<220>
<223> 人源化抗体
<400> 18
Asp Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Thr Tyr Lys Ala Ser Gln Asn Val Gly Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Asn Arg Tyr Thr Gly Val Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Tyr Ser Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 19
<211> 106
<212> PRT
<213> 智人
<400> 19
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Asp Glu Gln
1 5 10 15
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
20 25 30
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
35 40 45
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
50 55 60
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
65 70 75 80
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
85 90 95
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
<210> 20
<211> 326
<212> PRT
<213> 智人
<400> 20
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly
325
<210> 21
<211> 125
<212> PRT
<213> 人工
<220>
<223> 人源化抗体
<400> 21
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Leu Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Trp Tyr Asp Gly Asn Thr Asn Phe His Ser Pro Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Lys Thr Glu Gly His Tyr Tyr Gly Ser Asn Tyr Gly Tyr Tyr Ala Leu
100 105 110
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 22
<211> 107
<212> PRT
<213> 人工
<220>
<223> 人源化抗体
<400> 22
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Tyr Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Gln Gly Lys Ala Pro Lys Leu Leu Leu
35 40 45
Tyr Ala Ala Thr Asn Leu Gln Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Phe Cys Gln His Leu Trp Gly Thr Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 23
<211> 120
<212> PRT
<213> 人工
<220>
<223> 人源化
<400> 23
Gln Val Thr Leu Lys Glu Ser Gly Pro Ala Leu Val Lys Pro Thr Gln
1 5 10 15
Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Ser
20 25 30
Gly Met Gly Leu Ser Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu
35 40 45
Trp Leu Ala His Ile Tyr Trp Asp Asp Asp Lys Arg Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val
65 70 75 80
Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr
85 90 95
Cys Val Arg Gly Leu Tyr Gly Asn Trp Phe Phe Asp Val Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 24
<211> 327
<212> PRT
<213> 人工
<220>
<223> 突变体人IgG4 Fc
<400> 24
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 25
<211> 447
<212> PRT
<213> 人工
<220>
<223> 人源化抗体
<400> 25
Gln Val Thr Leu Lys Glu Ser Gly Pro Ala Leu Val Lys Pro Thr Gln
1 5 10 15
Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Ser
20 25 30
Gly Met Gly Leu Ser Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu
35 40 45
Trp Leu Ala His Ile Tyr Trp Asp Asp Asp Lys Arg Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val
65 70 75 80
Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr
85 90 95
Cys Val Arg Gly Leu Tyr Gly Asn Trp Phe Phe Asp Val Trp Gly Gln
100 105 110
Gly Thr Thr 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> 26
<211> 466
<212> PRT
<213> 人工
<220>
<223> 人源化抗体
<400> 26
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gln Val Thr Leu Lys Glu Ser Gly Pro Ala Leu Val Lys
20 25 30
Pro Thr Gln Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu
35 40 45
Ser Thr Ser Gly Met Gly Leu Ser Trp Ile Arg Gln Pro Pro Gly Lys
50 55 60
Ala Leu Glu Trp Leu Ala His Ile Tyr Trp Asp Asp Asp Lys Arg Tyr
65 70 75 80
Asn Pro Ser Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys
85 90 95
Asn Gln Val Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala
100 105 110
Thr Tyr Tyr Cys Val Arg Gly Leu Tyr Gly Asn Trp Phe Phe Asp Val
115 120 125
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly
130 135 140
Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser
145 150 155 160
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
165 170 175
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
180 185 190
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
195 200 205
Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val
210 215 220
Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys
225 230 235 240
Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly
245 250 255
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
260 265 270
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu
275 280 285
Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
290 295 300
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg
305 310 315 320
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
325 330 335
Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu
340 345 350
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
355 360 365
Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu
370 375 380
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
385 390 395 400
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
405 410 415
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp
420 425 430
Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His
435 440 445
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu
450 455 460
Gly Lys
465
<210> 27
<211> 214
<212> PRT
<213> 人工
<220>
<223> 人源化抗体
<400> 27
Asp Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Lys Ala Ser Gln Asn Val Gly Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Asn Arg Tyr Thr Gly Val Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Tyr Ser Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val 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> 28
<211> 234
<212> PRT
<213> 人工
<220>
<223> 人源化抗体
<400> 28
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly Asp Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser
20 25 30
Val Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Lys Ala Ser Gln Asn
35 40 45
Val Gly Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro
50 55 60
Arg Leu Leu Ile Tyr Ser Ala Ser Asn Arg Tyr Thr Gly Val Pro Ala
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser
85 90 95
Ser Leu Gln Ser Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Tyr Ser
100 105 110
Ser Tyr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg
115 120 125
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
130 135 140
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
145 150 155 160
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
165 170 175
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
180 185 190
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
195 200 205
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
210 215 220
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230
<210> 29
<211> 107
<212> PRT
<213> 人工
<220>
<223> 合成
<400> 29
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
1 5 10 15
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
20 25 30
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
35 40 45
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
65 70 75 80
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
85 90 95
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
<210> 30
<211> 329
<212> PRT
<213> 智人
<400> 30
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly
325
<210> 31
<211> 329
<212> PRT
<213> 人工
<220>
<223> 突变体变体
<400> 31
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ala Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Ala Ala Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly
325
<210> 32
<211> 447
<212> PRT
<213> 人工
<220>
<223> 人源化抗体
<400> 32
Gln Val Thr Leu Lys Glu Ser Gly Pro Ala Leu Val Lys Pro Thr Gln
1 5 10 15
Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Ser
20 25 30
Gly Met Gly Leu Ser Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu
35 40 45
Trp Leu Ala His Ile Tyr Trp Asp Asp Asp Lys Arg Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val
65 70 75 80
Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr
85 90 95
Cys Val Arg Gly Leu Tyr Gly Asn Trp Phe Phe Asp Val Trp Gly Ala
100 105 110
Gly Thr Thr 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> 466
<212> PRT
<213> 人工
<220>
<223> 人源化抗体
<400> 33
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gln Val Thr Leu Lys Glu Ser Gly Pro Ala Leu Val Lys
20 25 30
Pro Thr Gln Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu
35 40 45
Ser Thr Ser Gly Met Gly Leu Ser Trp Ile Arg Gln Pro Pro Gly Lys
50 55 60
Ala Leu Glu Trp Leu Ala His Ile Tyr Trp Asp Asp Asp Lys Arg Tyr
65 70 75 80
Asn Pro Ser Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys
85 90 95
Asn Gln Val Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala
100 105 110
Thr Tyr Tyr Cys Val Arg Gly Leu Tyr Gly Asn Trp Phe Phe Asp Val
115 120 125
Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly
130 135 140
Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser
145 150 155 160
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
165 170 175
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
180 185 190
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
195 200 205
Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val
210 215 220
Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys
225 230 235 240
Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly
245 250 255
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
260 265 270
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu
275 280 285
Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
290 295 300
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg
305 310 315 320
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
325 330 335
Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu
340 345 350
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
355 360 365
Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu
370 375 380
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
385 390 395 400
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
405 410 415
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp
420 425 430
Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His
435 440 445
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu
450 455 460
Gly Lys
465
<210> 34
<211> 214
<212> PRT
<213> 人工
<220>
<223> 人源化抗体
<400> 34
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Tyr Lys Ala Ser Gln Asn Val Gly Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Asn Arg Tyr Thr Gly Val Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val 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> 234
<212> PRT
<213> 人工
<220>
<223> 人源化抗体
<400> 35
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser
20 25 30
Val Ser Pro Gly Glu Arg Ala Thr Leu Ser Tyr Lys Ala Ser Gln Asn
35 40 45
Val Gly Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro
50 55 60
Arg Leu Leu Ile Tyr Ser Ala Ser Asn Arg Tyr Thr Gly Val Pro Ala
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser
85 90 95
Ser Leu Gln Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser
100 105 110
Ser Tyr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg
115 120 125
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
130 135 140
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
145 150 155 160
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
165 170 175
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
180 185 190
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
195 200 205
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
210 215 220
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230
Claims (53)
1.抗Siglec-10抗体,其中所述抗体包含(a)重链可变区,所述重链可变区包含含有SEQID NO:3中所示的序列的互补决定区(CDR)1、含有SEQ ID NO:4中所示的序列的CDR2,以及含有SEQ ID NO:5中所示的序列的CDR3中的一者或多者;以及(b)轻链可变区,所述轻链可变区包含含有SEQ ID NO:6中所示的序列的CDR1、含有SEQ ID NO:7中所示的序列的CDR2,以及含有SEQ ID NO:8中所示的序列的CDR3中的一者或多者。
2.根据权利要求1所述的抗Siglec-10抗体,其中所述重链可变区包含SEQ ID NO:1中所示的序列,并且所述轻链可变区包含SEQ ID NO:2中所示的序列。
3.根据权利要求1或2所述的抗Siglec-10抗体,其中所述抗体是嵌合抗体。
4.根据权利要求1所述的抗Siglec-10抗体,其中所述重链可变区包含SEQ ID NO:9-13中的一者所示的序列,并且所述轻链可变区包含SEQ ID NO:14-18中的一者所示的序列。
5.根据权利要求4所述的抗Siglec-10抗体,其中所述重链可变区包含SEQ ID NO:9、10或11中所示的序列,并且所述轻链可变区包含SEQ ID NO:15中所示的序列。
6.根据权利要求5所述的抗Siglec-10抗体,其中所述重链可变区包含SEQ ID NO:9中所示的序列。
7.根据权利要求6所述的抗Siglec-10抗体,其中所述重链包含SEQ ID NO:25中所示的序列。
8.根据权利要求7所述的抗Siglec-10抗体,其中所述轻链包含SEQ ID NO:27中所示的序列。
9.根据权利要求5所述的抗Siglec-10抗体,其中所述重链可变区包含SEQ ID NO:10中所示的序列。
10.根据权利要求9所述的抗Siglec-10抗体,其中所述重链包含SEQ ID NO:32中所示的序列。
11.根据权利要求10所述的抗Siglec-10抗体,其中所述轻链包含SEQ ID NO:27中所示的序列。
12.根据权利要求5所述的抗Siglec-10抗体,其中所述重链可变区包含SEQ ID NO:11中所示的序列。
13.根据权利要求4所述的抗Siglec-10抗体,其中所述重链可变区包含SEQ ID NO:10或12中所示的序列,并且所述轻链可变区包含SEQ ID NO:17中所示的序列。
14.根据权利要求13所述的抗Siglec-10抗体,其中所述重链可变区包含SEQ NO:10中所示的序列。
15.根据权利要求13所述的抗Siglec-10抗体,其中所述重链可变区包含SEQ NO:12中所示的序列。
16.根据权利要求4所述的抗Siglec-10抗体,其中所述重链可变区包含SEQ ID NO:10或12中所示的序列,并且所述轻链可变区包含SEQ ID NO:16中所示的序列。
17.根据权利要求16所述的抗Siglec-10抗体,其中所述重链可变区包含SEQ ID NO:10中所示的序列。
18.根据权利要求17所述的抗Siglec-10抗体,其中所述重链包含SEQ ID NO:32中所示的序列。
19.根据权利要求18所述的抗Siglec-10抗体,其中所述轻链包含SEQ ID NO:34中所示的序列。
20.根据权利要求16所述的抗Siglec-10抗体,其中所述重链可变区包含SEQ ID NO:12中所示的序列。
21.在有此需要的患者中治疗癌症的方法,所述方法包括向所述患者施用根据权利要求1-20中任一项所述的抗Siglec-10抗体。
22.根据权利要求21所述的方法,其中所述抗Siglec-10抗体与第二癌症疗法联合施用。
23.根据权利要求22所述的方法,其中所述第二癌症疗法是癌症靶向性免疫疗法或免疫细胞靶向性免疫疗法。
24.根据权利要求23所述的方法,其中所述第二癌症疗法是抗CTLA-4抗体。
25.根据权利要求21-24中任一项所述的方法,其中所述癌症是晚期实体瘤、血液癌症或包含与所述抗Siglec-10抗体结合的浸润细胞的癌症。
26.根据权利要求25所述的方法,其中所述癌症是选自下组的晚期实体瘤:肺腺癌(LUAD)、皮肤黑素瘤-转移性(SKCM-TM)、肺鳞状细胞癌(LUSC)、乳腺浸润性癌-基底型、乳腺浸润性癌-Her2、胰腺腺癌、头颈部鳞状细胞癌、肾脏肾透明细胞癌、胃腺癌、多形性胶质母细胞瘤、乳腺浸润性癌-LumB或乳腺浸润性癌-LumA、非小细胞肺癌、胶质母细胞瘤、黑素瘤、低级别胶质瘤、肾癌、基底型乳腺癌、Her2+乳腺癌、胰腺癌以及卵巢癌。
27.根据权利要求26所述的方法,其中所述肺腺癌是非小细胞肺腺癌。
28.根据权利要求25所述的方法,其中所述癌症是选自由白血病、骨髓增生异常综合征、B细胞淋巴瘤和多发性骨髓瘤组成的组的血液癌症。
29.抗Siglec-10抗体,其中所述重链包含SEQ ID NO:32中所示的序列,并且所述轻链包含SEQ ID NO:27中所示的序列;所述重链包含SEQ ID NO:25中所示的序列,并且所述轻链包含SEQ ID NO:27中所示的序列;或者所述重链包含SEQ ID NO:32中所示的序列,并且所述轻链包含SEQ ID NO:34中所示的序列。
30.在有此需要的患者中治疗癌症的方法,所述方法包括向所述患者施用根据权利要求29所述的抗Siglec-10抗体。
31.根据权利要求30所述的方法,其中所述抗Siglec-10抗体与第二癌症疗法联合施用。
32.根据权利要求31所述的方法,其中所述第二癌症疗法是癌症靶向性免疫疗法或免疫细胞靶向性免疫疗法。
33.根据权利要求32所述的方法,其中所述第二癌症疗法是抗CTLA-4抗体。
34.根据权利要求30-33中任一项所述的方法,其中所述癌症是晚期实体瘤、血液癌症或包含与所述抗Siglec-10抗体结合的浸润细胞的癌症。
35.根据权利要求34所述的方法,其中所述癌症是选自下组的晚期实体瘤:肺腺癌(LUAD)、皮肤黑素瘤-转移性(SKCM-TM)、肺鳞状细胞癌(LUSC)、乳腺浸润性癌-基底型、乳腺浸润性癌-Her2、胰腺腺癌、头颈部鳞状细胞癌、肾脏肾透明细胞癌、胃腺癌、多形性胶质母细胞瘤、乳腺浸润性癌-LumB或乳腺浸润性癌-LumA、非小细胞肺癌、胶质母细胞瘤、黑素瘤、低级别胶质瘤、肾癌、基底型乳腺癌、Her2+乳腺癌、胰腺癌以及卵巢癌。
36.根据权利要求35所述的方法,其中所述肺腺癌是非小细胞肺腺癌。
37.根据权利要求34所述的方法,其中所述癌症是选自由白血病、骨髓增生异常综合征、B细胞淋巴瘤和多发性骨髓瘤组成的组的血液癌症。
38.根据权利要求1-20中任一项所述的抗Siglec-10抗体在制备用于治疗癌症的药物中的用途。
39.根据权利要求38所述的用途,其中所述药物旨在与第二癌症疗法联合使用。
40.根据权利要求39所述的用途,其中所述第二癌症疗法是癌症靶向性免疫疗法或免疫细胞靶向性免疫疗法。
41.根据权利要求40所述的用途,其中所述第二癌症疗法是抗CTLA-4抗体。
42.根据权利要求38-41中任一项所述的用途,其中所述癌症是晚期实体瘤、血液癌症或包含与所述抗Siglec-10抗体结合的浸润细胞的癌症。
43.根据权利要求42所述的用途,其中所述癌症是选自下组的晚期实体瘤:肺腺癌(LUAD)、皮肤黑素瘤-转移性(SKCM-TM)、肺鳞状细胞癌(LUSC)、乳腺浸润性癌-基底型、乳腺浸润性癌-Her2、胰腺腺癌、头颈部鳞状细胞癌、肾脏肾透明细胞癌、胃腺癌、多形性胶质母细胞瘤、乳腺浸润性癌-LumB或乳腺浸润性癌-LumA、非小细胞肺癌、胶质母细胞瘤、黑素瘤、低级别胶质瘤、肾癌、基底型乳腺癌、Her2+乳腺癌、胰腺癌以及卵巢癌。
44.根据权利要求43所述的用途,其中所述肺腺癌是非小细胞肺腺癌。
45.根据权利要求42所述的用途,其中所述癌症是选自由白血病、骨髓增生异常综合征、B细胞淋巴瘤和多发性骨髓瘤组成的组的血液癌症。
46.根据权利要求29所述的抗Siglec-10抗体在制备用于治疗癌症的药物中的用途。
47.根据权利要求46所述的用途,其中所述药物旨在与第二癌症疗法联合使用。
48.根据权利要求47所述的用途,其中所述第二癌症疗法是癌症靶向性免疫疗法或免疫细胞靶向性免疫疗法。
49.根据权利要求48所述的用途,其中所述第二癌症疗法是抗CTLA-4抗体。
50.根据权利要求46-49中任一项所述的用途,其中所述癌症是晚期实体瘤、血液癌症或包含与所述抗Siglec-10抗体结合的浸润细胞的癌症。
51.根据权利要求50所述的用途,其中所述癌症是选自下组的晚期实体瘤:肺腺癌(LUAD)、皮肤黑素瘤-转移性(SKCM-TM)、肺鳞状细胞癌(LUSC)、乳腺浸润性癌-基底型、乳腺浸润性癌-Her2、胰腺腺癌、头颈部鳞状细胞癌、肾脏肾透明细胞癌、胃腺癌、多形性胶质母细胞瘤、乳腺浸润性癌-LumB或乳腺浸润性癌-LumA、非小细胞肺癌、胶质母细胞瘤、黑素瘤、低级别胶质瘤、肾癌、基底型乳腺癌、Her2+乳腺癌、胰腺癌以及卵巢癌。
52.根据权利要求51所述的用途,其中所述肺腺癌是非小细胞肺腺癌。
53.根据权利要求50所述的用途,其中所述癌症是选自由白血病、骨髓增生异常综合征、B细胞淋巴瘤,以及多发性骨髓瘤组成的组的血液癌症。
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