CN110461877A - 抗il-36r抗体联合治疗 - Google Patents
抗il-36r抗体联合治疗 Download PDFInfo
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- CN110461877A CN110461877A CN201880022517.7A CN201880022517A CN110461877A CN 110461877 A CN110461877 A CN 110461877A CN 201880022517 A CN201880022517 A CN 201880022517A CN 110461877 A CN110461877 A CN 110461877A
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Abstract
本发明涉及抗IL‑36R结合化合物，特别是新的抗IL‑36R抗体和治疗和诊断方法以及使用它们的组合物。
Description
发明技术领域
本发明总体上涉及用于诊断和治疗用途的抗IL-36R抗体。所述抗体可用于包含这样的化合物的药物组合物和试剂盒中。所述抗体用于治疗各种疾病或疾患例如人类的免疫、炎症、自身免疫、纤维化和呼吸系统疾病的方法中。
发明背景
IL-1细胞因子家族由11种不同的配体组成，即IL-1α(也称为IL-1F1)、IL-1β(IL-1F2)、IL-1受体拮抗剂(IL-1Ra或IL-1F3)、IL-18(IL-1F4)、IL-1F5至IL-1F10和IL-1F11(或IL-33)。已知IL-1α和IL-1β诱导与I型IL-1受体(IL-1RI)结合时的促炎活性和共受体IL-1受体辅助蛋白(IL-1RAcP)的募集，而IL-1Ra充当IL-1与IL-1RI结合的竞争性抑制剂，因此发挥抗炎活性。许多研究报道IL-18是促炎性细胞因子，其为IFN-γ的诱导物，而IL-33被描述为特别涉及Th2应答控制的免疫调节细胞因子。通过在DNA数据库中搜索IL-1的同源物，鉴定了IL-1家族的新成员，包括IL-1F5、IL-1F6、IL-1F8和IL-1F9。在人类和小鼠中，编码这些细胞因子的所有基因都映射到小于300kb的染色体2q，其中它们的侧翼是IL1A、IL1B和IL1RN基因。IL-1F6、IL-1F8和IL-1F9与IL-1和IL-1Ra共享21％至37％的氨基酸序列同源性，而IL-1F5与IL-1Ra显示52％的氨基酸序列同源性，表明IL-1F5可能代表内源性受体拮抗剂。IL-1F6、IL-1F8和IL-1F9与IL-1Rrp2(IL-1R家族的受体)结合，并且利用IL-1RAcP作为共受体来刺激与IL-1所诱导的信号相似的细胞内信号，而IL-1F5显示在过度表达IL-1Rrp2的Jurkat T细胞中抑制IL-1F9诱导的NF-κB活化。与IL-1β一样，所有这些IL-1同源物都缺乏前导肽并且不能通过常规分泌途径释放，尽管研究表明IL-1Rrp2激动剂的释放可受控于与调节IL-1β分泌的机制不同的机制。为了肯定这些细胞因子的具体生物效应并认识到它们都与相同的受体结合，最近提出修改IL-1同源物的命名法。因此，IL-1Rrp2现在称为IL-36R，其配体命名为IL-36α(IL-1F6)、IL-36β(IL-1F8)和IL-36γ(IL-1F9)。另外，显示发挥受体拮抗剂活性的IL-1F5已被重新命名为IL-36Ra。
IL-36α、IL-36β和IL-36γ的信使RNA在几种组织中，特别是在暴露于病原体的内部上皮组织和皮肤中高度表达。有趣的是，IL-36Ra和IL-36α的表达在IL-1β/TNF-α刺激的人角质形成细胞中显著上调，并且IL-36Ra和IL-36γmRNA在损伤性银屑病皮肤中高度增加。而且，在TNF-α和IFN-γ刺激后，在人角质形成细胞中IL-36γ蛋白的产生增强。也报道了在慢性肾脏病中升高的IL-36αmRNA和蛋白质表达。
在角质形成细胞中过表达IL-36α的转基因小鼠表现出与银屑病共有一些特征的炎性皮肤损害。当转基因小鼠与IL-36Rα缺陷小鼠杂交时，这个表型更为严重，这支持IL-36Ra的体内调节功能。如果用12-O-十四烷酰佛波醇-13-乙酸酯处理角质形成细胞特异性IL-36α转基因小鼠，则在所述小鼠中的炎性皮肤病症甚至与人类银屑病更相似，其在组织学、分子和对治疗的反应方面类似于人类疾病。而且，当用抗IL-36R抗体处理免疫缺陷小鼠时，移植到所述小鼠上的人银屑病损伤皮肤被归一化，证明IL-36轴对于维持人银屑病皮肤中的损伤表型是必需的。总之，这些数据表明，IL-36R配体(包括IL-36α、IL-36β和IL-36γ)发挥了体外和体内促炎作用，并且IL-36Ra充当天然拮抗剂，由此模拟IL-1/IL-1Ra系统。
因此，有证据表明IL-36R配体涉及许多疾病状况，并且对于靶向这个途径特别是用于治疗炎性疾病的新治疗剂存在着需要。
发明概述
通过提供与IL-36R结合的生物治疗剂，特别是抗体，本发明着手解决上述需要。在一个方面，本发明抗体阻断IL36配体介导的信号传导(α、β和/或γ)。在一个方面，本发明抗体可用于例如治疗诸如银屑病、炎性肠病、硬皮病、COPD和慢性肾脏病等疾病中的上皮介导的炎症/纤维化。
在一个方面，本发明涉及治疗患有硬皮病、掌跖脓疱病、泛发性脓疱型银屑病、糖尿病肾病、狼疮性肾炎、硬皮病、强直性脊柱炎或IBD的患者的方法，所述方法包括：对患者联合施用抗IL-36R抗体与TNF抑制剂、循环受体融合蛋白、整合素抑制剂或IL-23抑制剂。
在涉及上述方面的实施方案中，TNF抑制剂包括英夫利昔单抗、阿达木单抗、聚乙二醇结合赛妥珠单抗(赛妥珠单抗)，循环受体融合蛋白包括依那西普，整合素抑制剂包括维多珠单抗。在涉及上述方面的另一个实施方案中，抗IL-36R抗体包括：a)轻链可变区，其包含氨基酸序列SEQ ID NO:26(L-CDR1)；氨基酸序列SEQ ID NO:35、102、103、104、105、106或140(L-CDR2)；氨基酸序列SEQ ID NO:44(L-CDR3)；和b)重链可变区，其包含氨基酸序列SEQ ID NO:53(H-CDR1)；氨基酸序列SEQ ID NO:62、108、109、110或111(H-CDR2)；氨基酸序列SEQ ID NO:72(H-CDR3)。在涉及上述方面的另一个实施方案中，抗IL-36R抗体包括：
I.a)轻链可变区，其包含氨基酸序列SEQ ID NO:26(L-CDR1)；氨基酸序列SEQ IDNO:102(L-CDR2)；氨基酸序列SEQ ID NO:44(L-CDR3)；和b)重链可变区，其包含氨基酸序列SEQ ID NO:53(H-CDR1)；氨基酸序列SEQ ID NO:62、108、109、110或111(H-CDR2)；氨基酸序列SEQ ID NO:72(H-CDR3)。
II.a)轻链可变区，其包含氨基酸序列SEQ ID NO:26(L-CDR1)；氨基酸序列SEQ IDNO:103(L-CDR2)；氨基酸序列SEQ ID NO:44(L-CDR3)；和b)重链可变区，其包含氨基酸序列SEQ ID NO:53(H-CDR1)；氨基酸序列SEQ ID NO:62、108、109、110或111(H-CDR2)；氨基酸序列SEQ ID NO:72(H-CDR3)。
III.a)轻链可变区，其包含氨基酸序列SEQ ID NO:26(L-CDR1)；氨基酸序列SEQID NO:104(L-CDR2)；氨基酸序列SEQ ID NO:44(L-CDR3)；和b)重链可变区，其包含氨基酸序列SEQ ID NO:53(H-CDR1)；氨基酸序列SEQ ID NO:62、108、109、110或111(H-CDR2)；氨基酸序列SEQ ID NO:72(H-CDR3)。
IV.a)轻链可变区，其包含氨基酸序列SEQ ID NO:26(L-CDR1)；氨基酸序列SEQ IDNO:105(L-CDR2)；氨基酸序列SEQ ID NO:44(L-CDR3)；和b)重链可变区，其包含氨基酸序列SEQ ID NO:53(H-CDR1)；氨基酸序列SEQ ID NO:62、108、109、110或111(H-CDR2)；氨基酸序列SEQ ID NO:72(H-CDR3)。
V.a)轻链可变区，其包含氨基酸序列SEQ ID NO:26(L-CDR1)；氨基酸序列SEQ IDNO:106(L-CDR2)；氨基酸序列SEQ ID NO:44(L-CDR3)；和b)重链可变区，其包含氨基酸序列SEQ ID NO:53(H-CDR1)；氨基酸序列SEQ ID NO:62、108、109、110或111(H-CDR2)；氨基酸序列SEQ ID NO:72(H-CDR3)。
VI.a)轻链可变区，其包含氨基酸序列SEQ ID NO:26(L-CDR1)；氨基酸序列SEQ IDNO:140(L-CDR2)；氨基酸序列SEQ ID NO:44(L-CDR3)；和b)重链可变区，其包含氨基酸序列SEQ ID NO:53(H-CDR1)；氨基酸序列SEQ ID NO:62、108、109、110或111(H-CDR2)；氨基酸序列SEQ ID NO:72(H-CDR3)。
在涉及上述方面的另一个实施方案中，抗IL-36R抗体包括：
(i)包含氨基酸序列SEQ ID NO:77的轻链可变区；和包含氨基酸序列SEQ ID NO:87的重链可变区；或
(ii)包含氨基酸序列SEQ ID NO:77的轻链可变区；和包含氨基酸序列SEQ ID NO:88的重链可变区；或
(iii)包含氨基酸序列SEQ ID NO:77的轻链可变区；和包含氨基酸序列SEQ IDNO:89的重链可变区；或
(iv)包含氨基酸序列SEQ ID NO:80的轻链可变区；和包含氨基酸序列SEQ ID NO:87的重链可变区；或
(v)包含氨基酸序列SEQ ID NO:80的轻链可变区；和包含氨基酸序列SEQ ID NO:88的重链可变区；或
(vi)包含氨基酸序列SEQ ID NO:80的轻链可变区；和包含氨基酸序列SEQ ID NO:89的重链可变区；或
(vii)包含氨基酸序列SEQ ID NO:85的轻链可变区；和包含氨基酸序列SEQ IDNO:100的重链可变区；或
(viii)包含氨基酸序列SEQ ID NO:85的轻链可变区；和包含氨基酸序列SEQ IDNO:101的重链可变区；或
(ix)包含氨基酸序列SEQ ID NO:86的轻链可变区；和包含氨基酸序列SEQ ID NO:100的重链可变区；或
(x)包含氨基酸序列SEQ ID NO:86的轻链可变区；和包含氨基酸序列SEQ ID NO:101的重链可变区。
在涉及上述方面的另一个实施方案中，抗IL-36R抗体包括：
i.包含氨基酸序列SEQ ID NO:115的轻链；和包含氨基酸序列SEQ ID NO:125的重链；或
ii.包含氨基酸序列SEQ ID NO:115的轻链；和包含氨基酸序列SEQ ID NO:126的重链；或
iii.包含氨基酸序列SEQ ID NO:115的轻链；和包含氨基酸序列SEQ ID NO:127的重链；或
iv.包含氨基酸序列SEQ ID NO:118的轻链；和包含氨基酸序列SEQ ID NO:125的重链；或
v.包含氨基酸序列SEQ ID NO:118的轻链；和包含氨基酸序列SEQ ID NO:126的重链；或
vi.包含氨基酸序列SEQ ID NO:118的轻链；和包含氨基酸序列SEQ ID NO:127的重链；或
vii.包含氨基酸序列SEQ ID NO:123的轻链；和包含氨基酸序列SEQ ID NO:138的重链；或
viii.包含氨基酸序列SEQ ID NO:123的轻链；和包含氨基酸序列SEQ ID NO:139的重链；或
ix.包含氨基酸序列SEQ ID NO:124的轻链；和包含氨基酸序列SEQ ID NO:138的重链。
在涉及上述方面的另一个实施方案中，通过静脉内负荷剂量施用抗IL-36R抗体，然后进行一次或多次皮下注射。
在一个方面，本发明提供了具有以下一种或多种特性的抗IL-36R抗体。
在一个方面，本发明的抗IL-36R抗体具有高的分子/细胞结合效力。在一个方面，本发明的抗IL-36R抗体以KD<0.1nM与人IL-36R结合。在一个另外的方面，本发明的抗IL-36R抗体特别是人源化抗IL-36R抗体以KD<50pM与人IL-36R结合。在一个方面，本发明的抗IL-36R抗体以EC90<5nM与表达IL-36R的细胞结合。
在另一方面，本发明的抗IL-36R抗体具有高的基于细胞的功能阻断效力。在一个方面，本发明的抗IL-36R抗体以IC90≤5nM在疾病相关细胞系和原代细胞中阻断所有三种IL-36R激动配体(α、β、γ)。
在一个方面，本发明的抗IL-36R抗体具有上文所述的分子/细胞结合效力和基于细胞的功能阻断效力。
在一个另外的方面，本发明的抗IL-36R抗体具有高选择性，例如针对人IL-1R1或IL-36R阴性细胞系大于1000倍的选择性。在一个另外的方面，本发明的抗IL-36R抗体不与人IL-1R1或IL-36R阴性细胞系结合。
在实施方案1中，本发明提供了以等于或<0.1nM的KD与人IL-36R结合的抗IL-36R抗体或其抗原结合片段。
在实施方案2中，本发明提供了根据实施方案1的抗IL-36R抗体或其抗原结合片段，其中所述抗体或抗原结合片段是单克隆抗体或其抗原结合片段。
在实施方案3中，本发明提供了根据实施方案1或2的抗IL-36R抗体或其抗原结合片段，其中所述抗体或抗原结合片段是人源化抗体或其抗原结合片段。
在实施方案4中，本发明提供了根据实施方案3的以等于或<50pM的KD与人IL-36R结合的抗IL-36R抗体或其抗原结合片段。
在实施方案5中，本发明提供了根据实施方案1至4中任一项的不与人IL-1R1结合的抗IL-36R抗体或其抗原结合片段。
在实施方案6中，本发明提供了根据实施方案1的抗IL-36R抗体或其抗原结合片段，其中所述抗体或其抗原结合片段包含：
a)轻链可变区，其包含氨基酸序列SEQ ID NO:26(L-CDR1)；氨基酸序列SEQ IDNO:35、102、103、104、105、106或140(L-CDR2)；氨基酸序列SEQ ID NO:44(L-CDR3)；和
b)重链可变区，其包含氨基酸序列SEQ ID NO:53(H-CDR1)；氨基酸序列SEQ IDNO:62、108、109、110或111(H-CDR2)；氨基酸序列SEQ ID NO:72(H-CDR3)。
在实施方案7中，本发明提供了根据实施方案6的抗IL-36R抗体或其抗原结合片段，其中所述抗体或其抗原结合片段包含：
a)轻链可变区，其包含氨基酸序列SEQ ID NO:26(L-CDR1)；氨基酸序列SEQ IDNO:102(L-CDR2)；氨基酸序列SEQ ID NO:44(L-CDR3)；和
b)重链可变区，其包含氨基酸序列SEQ ID NO:53(H-CDR1)；氨基酸序列SEQ IDNO:62、108、109、110或111(H-CDR2)；氨基酸序列SEQ ID NO:72(H-CDR3)。
在实施方案8中，本发明提供了根据实施方案6的抗IL-36R抗体或其抗原结合片段，其中所述抗体或其抗原结合片段包含：
a)轻链可变区，其包含氨基酸序列SEQ ID NO:26(L-CDR1)；氨基酸序列SEQ IDNO:103(L-CDR2)；氨基酸序列SEQ ID NO:44(L-CDR3)；和
b)重链可变区，其包含氨基酸序列SEQ ID NO:53(H-CDR1)；氨基酸序列SEQ IDNO:62、108、109、110或111(H-CDR2)；氨基酸序列SEQ ID NO:72(H-CDR3)。
在实施方案9中，本发明提供了根据实施方案6的抗IL-36R抗体或其抗原结合片段，其中所述抗体或其抗原结合片段包含：
a)轻链可变区，其包含氨基酸序列SEQ ID NO:26(L-CDR1)；氨基酸序列SEQ IDNO:104(L-CDR2)；氨基酸序列SEQ ID NO:44(L-CDR3)；和
b)重链可变区，其包含氨基酸序列SEQ ID NO:53(H-CDR1)；氨基酸序列SEQ IDNO:62、108、109、110或111(H-CDR2)；氨基酸序列SEQ ID NO:72(H-CDR3)。
在实施方案10中，本发明提供了根据实施方案6的抗IL-36R抗体或其抗原结合片段，其中所述抗体或其抗原结合片段包含：
a)轻链可变区，其包含氨基酸序列SEQ ID NO:26(L-CDR1)；氨基酸序列SEQ IDNO:105(L-CDR2)；氨基酸序列SEQ ID NO:44(L-CDR3)；和
b)重链可变区，其包含氨基酸序列SEQ ID NO:53(H-CDR1)；氨基酸序列SEQ IDNO:62、108、109、110或111(H-CDR2)；氨基酸序列SEQ ID NO:72(H-CDR3)。
在实施方案11中，本发明提供了根据实施方案6的抗IL-36R抗体或其抗原结合片段，其中所述抗体或其抗原结合片段包含：
a)轻链可变区，其包含氨基酸序列SEQ ID NO:26(L-CDR1)；氨基酸序列SEQ IDNO:106(L-CDR2)；氨基酸序列SEQ ID NO:44(L-CDR3)；和
b)重链可变区，其包含氨基酸序列SEQ ID NO:53(H-CDR1)；氨基酸序列SEQ IDNO:62、108、109、110或111(H-CDR2)；氨基酸序列SEQ ID NO:72(H-CDR3)。
在实施方案12中，本发明提供了根据实施方案6的抗IL-36R抗体或其抗原结合片段，其中所述抗体或其抗原结合片段包含：
a)轻链可变区，其包含氨基酸序列SEQ ID NO:26(L-CDR1)；氨基酸序列SEQ IDNO:140(L-CDR2)；氨基酸序列SEQ ID NO:44(L-CDR3)；和
b)重链可变区，其包含氨基酸序列SEQ ID NO:53(H-CDR1)；氨基酸序列SEQ IDNO:62、108、109、110或111(H-CDR2)；氨基酸序列SEQ ID NO:72(H-CDR3)。
在实施方案13中，本发明提供了根据实施方案1的抗IL-36R抗体或其抗原结合片段，其中所述抗体或其抗原结合片段包括包含SEQ ID NO:76、77、78、79、80、81、82或83中任一者的氨基酸序列的轻链可变区；和包含SEQ ID NO:87、88、89、90、91、92、93、94或95中任一者的氨基酸序列的重链可变区。
在实施方案14中，本发明提供了根据实施方案13的抗IL-36R抗体或其抗原结合片段，其中所述抗体或其抗原结合片段包括包含氨基酸序列SEQ ID NO:77的轻链可变区；和包含氨基酸序列SEQ ID NO:87的重链可变区；或
包含氨基酸序列SEQ ID NO:77的轻链可变区；和包含氨基酸序列SEQ ID NO:88的重链可变区；或
包含氨基酸序列SEQ ID NO:77的轻链可变区；和包含氨基酸序列SEQ ID NO:89的重链可变区。
在实施方案15中，本发明提供了抗体或其抗原结合片段，其包括包含氨基酸序列SEQ ID NO:80的轻链可变区；和包含氨基酸序列SEQ ID NO:87的重链可变区；或
包含氨基酸序列SEQ ID NO:80的轻链可变区；和包含氨基酸序列SEQ ID NO:88的重链可变区；或
包含氨基酸序列SEQ ID NO:80的轻链可变区；和包含氨基酸序列SEQ ID NO:89的重链可变区。
在实施方案16中，本发明提供了根据实施方案1的抗IL-36R抗体或其抗原结合片段，其中所述抗体或其抗原结合片段包含：
轻链可变区，其包含氨基酸序列SEQ ID NO:27(L-CDR1)；氨基酸序列SEQ ID NO:36(L-CDR2)；氨基酸序列SEQ ID NO:45(L-CDR3)；和重链可变区，其包含氨基酸序列SEQ IDNO:107(H-CDR1)；氨基酸序列SEQ ID NO:63(H-CDR2)；氨基酸序列SEQ ID NO:73(H-CDR3)；或
轻链可变区，其包含氨基酸序列SEQ ID NO:27(L-CDR1)；氨基酸序列SEQ ID NO:36(L-CDR2)；氨基酸序列SEQ ID NO:45(L-CDR3)；和重链可变区，其包含氨基酸序列SEQ IDNO:107(H-CDR1)；氨基酸序列SEQ ID NO:64(H-CDR2)；氨基酸序列SEQ ID NO:73(H-CDR3)；或
轻链可变区，其包含氨基酸序列SEQ ID NO:27(L-CDR1)；氨基酸序列SEQ ID NO:36(L-CDR2)；氨基酸序列SEQ ID NO:45(L-CDR3)；和重链可变区，其包含氨基酸序列SEQ IDNO:54(H-CDR1)；氨基酸序列SEQ ID NO:63或64(H-CDR2)；氨基酸序列SEQ ID NO:73(H-CDR3)。
在实施方案17中，本发明提供了根据实施方案1的抗IL-36R抗体或其抗原结合片段，其中所述抗体或其抗原结合片段包括包含SEQ ID NO:84、85或86中任一者的氨基酸序列的轻链可变区；和包含SEQ ID NO:96、97、98、99、100或101中任一者的氨基酸序列的重链可变区。
在实施方案18中，本发明提供了根据实施方案17的抗IL-36R抗体或其抗原结合片段，其中所述抗体或其抗原结合片段包括包含氨基酸序列SEQ ID NO:85的轻链可变区；和包含氨基酸序列SEQ ID NO:100的重链可变区；或
包含氨基酸序列SEQ ID NO:85的轻链可变区；和包含氨基酸序列SEQ ID NO:101的重链可变区。
在实施方案19中，本发明提供了根据实施方案17的抗IL-36R抗体或其抗原结合片段，其中所述抗体或其抗原结合片段包括包含氨基酸序列SEQ ID NO:86的轻链可变区；和包含氨基酸序列SEQ ID NO:100的重链可变区；或
包含氨基酸序列SEQ ID NO:86的轻链可变区；和包含氨基酸序列SEQ ID NO:101的重链可变区。
在实施方案20中，本发明提供了抗IL-36R抗体，其中所述抗体包括包含SEQ IDNO:114、115、116、117、118、119、120或121中任一者的氨基酸序列的轻链；和包含SEQ IDNO:125、126、127、128、129、130、131、132或133中任一者的氨基酸序列的重链。
在实施方案21中，本发明提供了根据实施方案20的抗IL-36R抗体，其中所述抗体包括包含氨基酸序列SEQ ID NO:115的轻链；和包含氨基酸序列SEQ ID NO:125的重链。
在实施方案22中，本发明提供了根据实施方案20的抗IL-36R抗体，其中所述抗体包括包含氨基酸序列SEQ ID NO:115的轻链；和包含氨基酸序列SEQ ID NO:126的重链。
在实施方案23中，本发明提供了根据实施方案20的抗IL-36R抗体，其中所述抗体包括包含氨基酸序列SEQ ID NO:115的轻链；和包含氨基酸序列SEQ ID NO:127的重链。
在实施方案24中，本发明提供了根据实施方案20的抗IL-36R抗体，其中所述抗体包括包含氨基酸序列SEQ ID NO:118的轻链；和包含氨基酸序列SEQ ID NO:125的重链。
在实施方案25中，本发明提供了根据实施方案20的抗IL-36R抗体，其中所述抗体包括包含氨基酸序列SEQ ID NO:118的轻链；和包含氨基酸序列SEQ ID NO:126的重链。
在实施方案26中，本发明提供了根据实施方案20的抗IL-36R抗体，其中所述抗体包括包含氨基酸序列SEQ ID NO:118的轻链；和包含氨基酸序列SEQ ID NO:127的重链。
在实施方案27中，本发明提供了抗IL-36R抗体，其中所述抗体包括包含SEQ IDNO:122、123或124中任一者的氨基酸序列的轻链；和包含SEQ ID NO:134、135、136、137、138或139中任一者的氨基酸序列的重链。
在实施方案28中，本发明提供了根据实施方案27的抗IL-36R抗体，其中所述抗体包括包含氨基酸序列SEQ ID NO:123的轻链；和包含氨基酸序列SEQ ID NO:138的重链。
在实施方案29中，本发明提供了根据实施方案27的抗IL-36R抗体，其中所述抗体包括包含氨基酸序列SEQ ID NO:123的轻链；和包含氨基酸序列SEQ ID NO:139的重链。
在实施方案30中，本发明提供了根据实施方案27的抗IL-36R抗体，其中所述抗体包括包含氨基酸序列SEQ ID NO:124的轻链；和包含氨基酸序列SEQ ID NO:138的重链。
在实施方案31中，本发明提供了根据实施方案1的抗IL-36R抗体或其抗原结合片段，其中所述抗体或其抗原结合片段包含：
a)轻链可变区，其包含氨基酸序列SEQ ID NO:26(L-CDR1)；氨基酸序列SEQ IDNO:103(L-CDR2)；氨基酸序列SEQ ID NO:44(L-CDR3)；和
b)重链可变区，其包含氨基酸序列SEQ ID NO:53(H-CDR1)；氨基酸序列SEQ IDNO:62(H-CDR2)；氨基酸序列SEQ ID NO:72(H-CDR3)。
在实施方案32中，本发明提供了根据实施方案1的抗IL-36R抗体或其抗原结合片段，其中所述抗体或其抗原结合片段包含：
a)轻链可变区，其包含氨基酸序列SEQ ID NO:26(L-CDR1)；氨基酸序列SEQ IDNO:104(L-CDR2)；氨基酸序列SEQ ID NO:44(L-CDR3)；和
b)重链可变区，其包含氨基酸序列SEQ ID NO:53(H-CDR1)；氨基酸序列SEQ IDNO:62(H-CDR2)；氨基酸序列SEQ ID NO:72(H-CDR3)。
在实施方案33中，本发明提供了根据实施方案1的抗IL-36R抗体或其抗原结合片段，其中所述抗体或其抗原结合片段包含：
a)轻链可变区，其包含氨基酸序列SEQ ID NO:27(L-CDR1)；氨基酸序列SEQ IDNO:36(L-CDR2)；氨基酸序列SEQ ID NO:45(L-CDR3)；和
b)重链可变区，其包含氨基酸序列SEQ ID NO:107(H-CDR1)；氨基酸序列SEQ IDNO:63(H-CDR2)；氨基酸序列SEQ ID NO:73(H-CDR3)。
在实施方案34中，本发明提供了根据实施方案1的抗IL-36R抗体或其抗原结合片段，其中所述抗体或其抗原结合片段包含：
a)轻链可变区，其包含氨基酸序列SEQ ID NO:27(L-CDR1)；氨基酸序列SEQ IDNO:36(L-CDR2)；氨基酸序列SEQ ID NO:45(L-CDR3)；和
b)重链可变区，其包含氨基酸序列SEQ ID NO:107(H-CDR1)；氨基酸序列SEQ IDNO:64(H-CDR2)；氨基酸序列SEQ ID NO:73(H-CDR3)。
在一个实施方案中，根据实施方案1至34中任一项的抗体或其抗原结合片段是单克隆抗体。在一个实施方案中，根据实施方案1至34中任一项的抗体或其抗原结合片段是人源化抗体。在一个实施方案中，根据实施方案1至34中任一项的抗体或其抗原结合片段是单克隆人源化抗体。
在实施方案35中，本发明提供了抗IL-36R抗体或其抗原结合片段，其中所述抗体或其抗原结合片段包含：
轻链可变区，其包含氨基酸序列SEQ ID NO:21(L-CDR1)；氨基酸序列SEQ ID NO:30(L-CDR2)；氨基酸序列SEQ ID NO:39(L-CDR3)；和重链可变区，其包含氨基酸序列SEQ IDNO:48(H-CDR1)；氨基酸序列SEQ ID NO:57(H-CDR2)；氨基酸序列SEQ ID NO:67(H-CDR3)；或
轻链可变区，其包含氨基酸序列SEQ ID NO:22(L-CDR1)；氨基酸序列SEQ ID NO:31(L-CDR2)；氨基酸序列SEQ ID NO:40(L-CDR3)；和重链可变区，其包含氨基酸序列SEQ IDNO:49(H-CDR1)；氨基酸序列SEQ ID NO:58(H-CDR2)；氨基酸序列SEQ ID NO:68(H-CDR3)；或
轻链可变区，其包含氨基酸序列SEQ ID NO:23(L-CDR1)；氨基酸序列SEQ ID NO:32(L-CDR2)；氨基酸序列SEQ ID NO:41(L-CDR3)；和重链可变区，其包含氨基酸序列SEQ IDNO:50(H-CDR1)；氨基酸序列SEQ ID NO:59(H-CDR2)；氨基酸序列SEQ ID NO:69(H-CDR3)；或
轻链可变区，其包含氨基酸序列SEQ ID NO:24(L-CDR1)；氨基酸序列SEQ ID NO:33(L-CDR2)；氨基酸序列SEQ ID NO:42(L-CDR3)；和重链可变区，其包含氨基酸序列SEQ IDNO:51(H-CDR1)；氨基酸序列SEQ ID NO:60(H-CDR2)；氨基酸序列SEQ ID NO:70(H-CDR3)；或
轻链可变区，其包含氨基酸序列SEQ ID NO:25(L-CDR1)；氨基酸序列SEQ ID NO:34(L-CDR2)；氨基酸序列SEQ ID NO:43(L-CDR3)；和重链可变区，其包含氨基酸序列SEQ IDNO:52(H-CDR1)；氨基酸序列SEQ ID NO:61(H-CDR2)；氨基酸序列SEQ ID NO:71(H-CDR3)；或
轻链可变区，其包含氨基酸序列SEQ ID NO:26(L-CDR1)；氨基酸序列SEQ ID NO:35(L-CDR2)；氨基酸序列SEQ ID NO:44(L-CDR3)；和重链可变区，其包含氨基酸序列SEQ IDNO:53(H-CDR1)；氨基酸序列SEQ ID NO:62(H-CDR2)；氨基酸序列SEQ ID NO:72(H-CDR3)；或
轻链可变区，其包含氨基酸序列SEQ ID NO:27(L-CDR1)；氨基酸序列SEQ ID NO:36(L-CDR2)；氨基酸序列SEQ ID NO:45(L-CDR3)；和重链可变区，其包含氨基酸序列SEQ IDNO:54(H-CDR1)；氨基酸序列SEQ ID NO:63(H-CDR2)；氨基酸序列SEQ ID NO:73(H-CDR3)；或
轻链可变区，其包含氨基酸序列SEQ ID NO:27(L-CDR1)；氨基酸序列SEQ ID NO:36(L-CDR2)；氨基酸序列SEQ ID NO:45(L-CDR3)；和重链可变区，其包含氨基酸序列SEQ IDNO:54(H-CDR1)；氨基酸序列SEQ ID NO:64(H-CDR2)；氨基酸序列SEQ ID NO:73(H-CDR3)；或
轻链可变区，其包含氨基酸序列SEQ ID NO:28(L-CDR1)；氨基酸序列SEQ ID NO:37(L-CDR2)；氨基酸序列SEQ ID NO:46(L-CDR3)；和重链可变区，其包含氨基酸序列SEQ IDNO:55(H-CDR1)；氨基酸序列SEQ ID NO:65(H-CDR2)；氨基酸序列SEQ ID NO:74(H-CDR3)；或
轻链可变区，其包含氨基酸序列SEQ ID NO:29(L-CDR1)；氨基酸序列SEQ ID NO:38(L-CDR2)；氨基酸序列SEQ ID NO:47(L-CDR3)；和重链可变区，其包含氨基酸序列SEQ IDNO:56(H-CDR1)；氨基酸序列SEQ ID NO:66(H-CDR2)；氨基酸序列SEQ ID NO:75(H-CDR3)。
在实施方案36中，本发明提供了抗IL-36R抗体或其抗原结合片段，其中所述抗体或其抗原结合片段包括包含氨基酸序列SEQ ID NO:1的轻链可变区；和包含氨基酸序列SEQID NO:11的重链可变区；或
包含氨基酸序列SEQ ID NO:2的轻链可变区；和包含氨基酸序列SEQ ID NO:12的重链可变区；或
包含氨基酸序列SEQ ID NO:3的轻链可变区；和包含氨基酸序列SEQ ID NO:13的重链可变区；或
包含氨基酸序列SEQ ID NO:4的轻链可变区；和包含氨基酸序列SEQ ID NO:14的重链可变区；或
包含氨基酸序列SEQ ID NO:5的轻链可变区；和包含氨基酸序列SEQ ID NO:15的重链可变区；或
包含氨基酸序列SEQ ID NO:6的轻链可变区；和包含氨基酸序列SEQ ID NO:16的重链可变区；或
包含氨基酸序列SEQ ID NO:7的轻链可变区；和包含氨基酸序列SEQ ID NO:17的重链可变区；或
包含氨基酸序列SEQ ID NO:8的轻链可变区；和包含氨基酸序列SEQ ID NO:18的重链可变区；或
包含氨基酸序列SEQ ID NO:9的轻链可变区；和包含氨基酸序列SEQ ID NO:19的重链可变区；或
包含氨基酸序列SEQ ID NO:10的轻链可变区；和包含氨基酸序列SEQ ID NO:20的重链可变区。
在一个另外的实施方案37中，本发明提供了一种包含根据前述实施方案中任一项的抗体或抗原结合片段和药学上可接受的载体的药物组合物。
在一个另外的实施方案38中，本发明提供了用于医学的根据前述实施方案中任一项的抗体或抗原结合片段或药物组合物。
在一个另外的实施方案39中，本发明提供了根据实施方案1-37中任一项的抗体或抗原结合片段或药物组合物，其中所述用途是炎性疾病、自身免疫性疾病、呼吸系统疾病、代谢病症、上皮介导的炎性疾患、纤维化或癌症的治疗。
在一个另外的实施方案40中，本发明提供了根据实施方案1-37中任一项的抗体或抗原结合片段或药物组合物，其中所述用途是用于治疗银屑病、炎性肠病、银屑病关节炎、多发性硬化、类风湿性关节炎、COPD、慢性哮喘或强直性脊柱炎。
在一个另外的实施方案41中，本发明提供了根据实施方案1-37中任一项的抗体或抗原结合片段或药物组合物，其中所述用途是用于治疗炎性肠病。
在又一个另外的实施方案42中，本发明提供了根据实施方案41的抗体或抗原结合片段或药物组合物，其中所述疾病是克罗恩病。
在另一个实施方案43中，本发明提供了一种治疗疾病的方法，所述方法包括将实施方案1-37中任一项的抗体或抗原结合片段或药物组合物施用于有此需要的患者，其中所述疾病选自炎性疾病、自身免疫性疾病、呼吸系统疾病、代谢病症、上皮介导的炎性疾患、纤维化和癌症。
在另一个实施方案44中，本发明提供了根据实施方案43的方法，其中所述疾病选自银屑病、炎性肠病、银屑病关节炎、多发性硬化、类风湿性关节炎、COPD、慢性哮喘和强直性脊柱炎。
在又一个另外的实施方案45中，本发明提供了一种治疗克罗恩病的方法。
本发明的进一步实施方案涵盖：
分离的多核苷酸，其包含编码根据本发明的抗IL-36R抗体或抗原结合片段的序列，优选DNA或RNA序列；
-根据本发明的分离的多核苷酸，其编码如由SEQ ID NO.1至140中的一者或多者定义的序列；
载体，其包含根据本发明的多核苷酸，优选表达载体，更优选包含与表达控制序列处于功能关联的根据本发明的多核苷酸的载体；
宿主细胞，其包含根据本发明的多核苷酸和/或根据本发明的载体；
产生根据本发明的抗IL-36R抗体或抗原结合片段的方法，优选包括使用根据本发明的多核苷酸和/或根据本发明的载体和/或根据本发明的宿主细胞的重组产生方法；
这样的方法优选包括步骤(a)在允许表达抗IL-36R抗体或抗原结合片段的条件下培养宿主细胞和(b)回收抗IL-36R抗体或抗原结合片段；
诊断试剂盒或诊断方法或其用途，其包括根据本发明的抗IL-36R抗体或抗原结合片段；
根据本发明的诊断试剂盒或诊断方法，其用于诊断炎性疾病、自身免疫性疾病、呼吸系统疾病、代谢病症、上皮介导的炎性疾患、纤维化、癌症、银屑病、炎性肠病、银屑病关节炎、多发性硬化、类风湿性关节炎、COPD、慢性哮喘、强直性脊柱炎或克罗恩病。
附图简述
图1：IL-36拮抗剂配体(IL-36RA/IL1F5、IL-38/ILF10)抑制信号级联。
图2：基因芯片分析证明IL-36R配体在银屑病皮肤中上调(IL-36RA、IL-36α和IL-36γ)。
图3：使用人皮肤切片的表达谱。
使用抗体33D10的抗体滴定的福尔马林固定石蜡包埋切片
图4：评估人皮肤切片的表皮厚度的方法
发明描述
本发明涉及抗IL-36R抗体。在一个方面，本发明的抗体用于诊断和治疗用途，例如用于人。
本发明提供了与IL-36R特别是人IL-36R结合的抗体。本发明还涉及结合IL-36R的人源化抗体。在具体的实施方案中，已经基于某些先导小鼠抗体的序列鉴定了这些人源化抗体的序列。
不希望受该理论的束缚，人们相信抗IL-36R抗体或其抗原结合片段与人IL-36R结合并因此干扰IL-36激动剂的结合，如此至少部分阻断从IL-36R到炎症介质的信号级联放大。这通过图1来说明。
在一个方面，本发明抗体用于人类疾病模型。IL-36R也称为IL-1RL2和IL-1Rrp2。据报道，激动性IL-36配体(α、β或γ)通过接合IL-36受体而启动信号级联放大，IL-36受体然后与IL-1受体辅助蛋白(IL-1RAcP)形成异二聚体。IL-36拮抗剂配体(IL-36RA/IL1F5、IL-38/ILF10)抑制信号级联放大(参见图1)。
在一个方面，本发明提供了具有以下一种或多种特性的抗IL-36R抗体。
在一个方面，本发明的抗IL-36R抗体具有高的
分子/细胞结合效力。在一个方面，本发明的抗IL-36R抗体以KD<0.1nM与人IL-36R结合。在一个另外的方面，本发明的抗IL-36R抗体特别是人源化抗IL-36R抗体以KD<50pM与人IL-36R结合。在一个方面，本发明的抗IL-36R抗体以EC90<5nM与表达IL-36R的细胞结合。
在另一方面，本发明的抗IL-36R抗体具有高的基于细胞的功能阻断效力。在一个方面，本发明的抗IL-36R抗体以IC90≤5nM在疾病相关细胞系和原代细胞中阻断所有三种IL-36R激动配体(α、β、γ)。
在一个方面，本发明的抗IL-36R抗体具有上文所述的分子/细胞结合效力和基于细胞的功能阻断效力。
在一个方面，本发明的抗IL-36R抗体是人源化抗体。在一个方面，本发明的抗IL-36R抗体是单克隆抗体。在一个方面，本发明的抗IL-36R抗体是全长抗体。在一个方面，本发明的抗IL-36R抗体是人源化单克隆抗体，例如全长人源化单克隆抗体。
本发明的抗体或其抗原结合片段识别特异性“IL-36R抗原表位”或“IL-36R表位”。如本文中使用的，这些术语是指能够与抗IL-36R抗体具有免疫反应性的分子(例如肽)或分子片段。
表位最常见的是蛋白质、短寡肽、寡肽模拟物(即模拟IL-36R抗原的抗体结合特性的有机化合物)或其组合。抗体的肽或多肽表位的最小大小被认为是约4至5个氨基酸。肽或多肽表位含有例如至少7个氨基酸或例如至少9个氨基酸或例如约15至约20个氨基酸。由于抗体可以识别三级形式的抗原肽或多肽，因此构成表位的氨基酸不必是连续的，并且在一些情况下，甚至可能不在同一条肽链上。可以通过本领域已知的各种技术确定表位，比如X射线晶体学、氢/氘交换质谱(HXMS)、定点诱变、丙氨酸扫描诱变和肽筛选方法。
抗体或免疫球蛋白的广义结构是本领域技术人员熟知的。这些分子是通常约150,000道尔顿的异四聚体糖蛋白，由两条完全相同的轻(L)链和两条完全相同的重(H)链组成，并且通常被称为全长抗体。每条轻链通过一个二硫键与重链共价连接以形成异二聚体，并且通过异二聚体的两条完全相同重链之间的共价二硫键而形成异四聚体(heterotrameric)分子。虽然轻链和重链通过一个二硫键连接在一起，但两条重链之间的二硫键的数目因免疫球蛋白同种型而异。每条轻链和重链还具有规则间隔的链内二硫桥。每条重链在氨基末端具有可变结构域(VH)，接着是三个或四个恒定结构域(CH1、CH2、CH3和CH4)，以及在CH1和CH2之间的铰链区。每条轻链具有两个结构域，氨基末端可变结构域(VL)和羧基末端恒定结构域(CL)。VL结构域与VH结构域非共价结合，而CL结构域通常经由二硫键与CH1结构域共价连接。人们认为特定的氨基酸残基在轻链和重链可变结构域之间形成界面(Chothia等人，1985,J.Mol.Biol.186:651-663)。可变结构域在本文中也称为可变区。
可变结构域内的某些结构域在不同抗体之间差异很大，即，是“高变的”。这些高变结构域含有直接参与每种特定抗体针对其特异性抗原决定簇的结合和特异性的残基。轻链和重链可变结构域中的高变性集中在三个区段中，其被称为互补决定区(CDR)或高变环(HVL)。通过在Kabat等人，1991,In:Sequences of Proteins of ImmunologicalInterest，第5版，Public Health Service,National Institutes of Health,Bethesda,Md.中的序列比较定义了CDR，而根据可变结构域的三维结构在结构上定义了HVL(本文中也称为CDR)，如Chothia和Lesk在1987,J.Mol.Biol.196:901-917中所述。这两种方法导致CDR的鉴定略有不同。如由Kabat定义，CDR-L1位于轻链可变结构域中的约残基24-34，CDR-L2在约残基50-56，并且CDR-L3在约残基89-97；CDR-H1位于重链可变结构域中的约残基31-35，CDR-H2在约残基50-65，并且CDR-H3在约残基95-102。涵盖特定CDR的确切残基数将取决于CDR的序列和大小而变化。考虑到抗体的可变区氨基酸序列，本领域技术人员可以常规地确定哪些残基构成特定的CDR。因此，重链和轻链的CDR1、CDR2、CDR3限定了对给定抗体特异的独特特性和功能特性。
每条重链和轻链内的三个CDR被框架区(FR)分开，框架区含有倾向于变化较小的序列。从重链和轻链可变结构域的氨基末端到羧基末端，FR和CDR的排列顺序为：FR1、CDR1、FR2、CDR2、FR3、CDR3和FR4。FR的β片层构型在很大程度上使每条链内的CDR彼此之间并且与来自另一条链的CDR非常接近。作为结果的构象有助于抗原结合位点(参见Kabat等人，1991,NIH Publ.No.91-3242，第I卷，第647-669页)，尽管并非所有CDR残基都必定直接参与抗原结合。
FR残基和Ig恒定结构域不直接参与抗原结合，但有助于抗原结合和/或介导抗体效应子功能。一些FR残基被认为以至少三种方式对抗原结合具有显著影响：通过与表位直接地非共价结合，通过与一个或多个CDR残基相互作用，以及通过影响重链和轻链之间的界面。恒定结构域不直接参与抗原结合，但介导各种Ig效应子功能，比如抗体参与抗体依赖性细胞介导的细胞毒性(ADCC)、补体依赖性细胞毒性(CDC)和抗体依赖性细胞吞噬作用(ADCP)。
基于恒定结构域的氨基酸序列，脊椎动物免疫球蛋白的轻链被指定为两个明显不同的类别之一，卡帕(κ)和兰布达(λ)。相比之下，根据恒定结构域的序列，哺乳动物免疫球蛋白的重链被指定为五大类别之一：IgA、IgD、IgE、IgG和IgM。IgG和IgA进一步分为亚类(同种型)，例如IgG1、IgG2、IgG3、IgG4、IgA1和IgA2。对应于不同类别免疫球蛋白的重链恒定结构域分别称作αδ、ε、γ和μ。天然免疫球蛋白类别的亚单位结构和三维构型是熟知的。
术语“抗体”、“抗IL-36R抗体”、“人源化抗IL-36R抗体”、“人源化抗IL-36R表位抗体”和“变体人源化抗IL-36R表位抗体”具体涵盖单克隆抗体(包括全长单克隆抗体)、多克隆抗体、多特异性抗体(例如，双特异性抗体)和抗体片段，比如抗体的可变结构域和表现出期望的生物活性(例如IL-36R结合)的其他部分。术语“单克隆抗体”(mAb)是指针对单个抗原决定簇(“表位”)高度特异的抗体。因此，修饰语“单克隆的”表示针对完全相同的表位的抗体，并且不被解释为需要通过任何特定的方法产生抗体。应该理解的是，单克隆抗体可以通过本领域已知的任何技术或方法制备；包括例如杂交瘤方法(Kohler等人，1975,Nature256:495)、或本领域已知的重组DNA方法(参见，例如，美国专利No.4,816,5677)、或使用噬菌体抗体文库重组产生的单克隆抗体的分离方法，其中使用在Clackson等人，1991,Nature352:624-628和Marks等人，1991,J.Mol.Biol.222:581-597中描述的技术。
术语“单体”是指抗体的同质形式。例如，对于全长抗体，单体表示具有两条完全相同的重链和两条完全相同的轻链的单体抗体。
嵌合抗体由来自一个物种(例如，非人哺乳动物，比如小鼠)的抗体的重链和轻链可变区以及另一物种(例如人)抗体的重链和轻链恒定区组成，并且可以通过如下方式获得：将编码来自第一物种(例如小鼠)的抗体可变区的DNA序列与来自第二(例如人)物种的抗体恒定区的DNA序列连接，并且用含有所述连接的序列的表达载体转化宿主以使所述宿主产生嵌合抗体。或者，嵌合抗体也可以是这样的嵌合抗体，其中重链和/或轻链的一个或多个区域或结构域与来自另一个免疫球蛋白类别或同种型的单克隆抗体中的相应序列相同、同源或为所述相应序列的变体，或来自共有序列或种系序列。嵌合抗体可包括这样的抗体的片段，条件是抗体片段表现出期望的其亲本抗体的生物活性，例如与相同的表位结合(参见，例如，美国专利No.4,816,567；和Morrison等人，1984,Proc.Natl.Acad.Sci.USA81:6851-6855)。
术语“抗体片段”、“抗IL-36R抗体片段”、“抗IL-36R表位抗体片段”、“人源化抗IL-36R抗体片段”、“人源化抗IL-36R表位抗体片段”、”变体人源化抗IL-36R表位抗体片段“是指其中保留了可变区或功能能力(例如特异性IL-36R表位结合)的全长抗IL-36R抗体的一部分。抗体片段的实例包括但不限于Fab、Fab'、F(ab')2、Fd、Fv、scFv和scFv-Fc片段、双抗体、线性抗体、单链抗体、微型抗体、由抗体片段形成的双抗体和由抗体片段形成的多特异性抗体。
可以用诸如木瓜蛋白酶或胃蛋白酶的酶类处理全长抗体来产生有用的抗体片段。利用木瓜蛋白酶消化来产生被称为“Fab”的两个完全相同的抗原结合抗体片段(每个片段具有单个抗原结合位点)和残余的“Fc”片段。Fab片段还含有轻链的恒定结构域和重链的CH1结构域。胃蛋白酶处理产生F(ab')2片段，其具有两个抗原结合位点并且仍然能够交联抗原。
Fab'片段与Fab片段的不同之处在于存在另外的残基，包括来自位于CH1结构域C末端的抗体铰链区的一个或多个半胱氨酸。F(ab')2抗体片段是通过铰链区中的半胱氨酸残基连接的Fab'片段对。抗体片段的其他化学偶联也是已知的。
“Fv”片段含有完整的抗原识别和结合位点，其由紧密、非共价结合的一个重链可变结构域和一个轻链可变结构域的二聚体组成。在这种构型中，每个可变结构域的三个CDR相互作用，以限定VH-VL二聚体表面上的抗原结合位点。六个CDR共同赋予抗体的抗原结合特异性。
单链Fv或“scFv”抗体片段是包含抗体的VH和VL结构域的单链Fv变体，其中这些结构域存在于单个多肽链中。单链Fv能够识别和结合抗原。scFv多肽还可任选地含有位于VH和VL结构域之间的多肽接头，以促进通过scFv结合抗原的期望的三维结构的形成(参见，例如，Pluckthun，1994,In The Pharmacology of monoclonal Antibodies,Vol.113，Rosenburg和Moore编辑，Springer-Verlag，New York，第269-315页)。
“双抗体”是指具有两个抗原结合位点的小抗体片段，所述片段包含与同一条多肽链中的轻链可变结构域(V.sub.L)连接的重链可变结构域(V.sub.H)(V.sub.H-V.sub.L或V.sub.L-V.sub.H)。双抗体在例如Holliger等人(1993)Proc.Natl.Acad.Sci.USA 90:6444-6448中有更全面的描述。
其他公认的抗体片段包括包含一对串联Fd区段(VH-CH1-VH-CH1)以形成一对抗原结合区的那些抗体片段。这些“线性抗体”可以是双特异性或单特异性的，如例如在Zapata等人，1995,Protein Eng.8(10):1057-1062中所述。
“人源化抗体”或“人源化抗体片段”是特定类型的嵌合抗体，其包括免疫球蛋白氨基酸序列变体或其片段，其能够与预定抗原结合并且包含一个或多个具有基本上是人免疫球蛋白的氨基酸序列的FR和一个或多个具有基本上是非人免疫球蛋白的氨基酸序列的CDR。这种非人氨基酸序列通常被称为“输入”序列，其一般取自“输入”抗体结构域，特别是可变结构域。一般而言，人源化抗体至少包括在人重链或轻链可变结构域的FR之间插入的非人抗体的CDR或HVL。本发明描述了特异性人源化抗IL-36R抗体，其含有衍生自小鼠单克隆抗体的CDR或在人种系序列重链和轻链可变结构域的FR之间插入的人源化CDR。应当理解的是，某些小鼠FR残基可能对人源化抗体的功能很重要，因此将某些人种系序列重链和轻链可变结构域残基修饰为与相应小鼠序列的残基相同。
在另一个方面，人源化抗IL-36R抗体包含至少一个(通常两个)的基本上所有可变结构域(比如包含在例如Fab、Fab'、F(ab')2、Fabc和Fv片段中)，其中所有或基本上所有CDR对应于非人免疫球蛋白的那些CDR，并且在本文中具体地说，所有CDR是如下文详述的小鼠或人源化序列，并且所有或基本上所有FR是人免疫球蛋白共有序列或种系序列的FR。在另一个方面，人源化抗IL-36R抗体还包括免疫球蛋白Fc区(一般是人免疫球蛋白的Fc区)的至少一部分。通常，所述抗体将包含轻链并且至少包含重链的可变结构域。在适当时，抗体还可以包括重链的CH1、铰链、CH2、CH3和/或CH4区中的一个或多个。
人源化抗IL-36r抗体可选自任何类别(包括IgM、IgG、IgD、IgA和IgE)以及任何同种型(包括IgG1、IgG2、IgG3、IgG4、IgA1和IgA2)的免疫球蛋白。例如，恒定结构域可以是补体固定恒定结构域，此时希望人源化抗体表现出细胞毒活性，并且同种型通常是IgG1。当不希望这样的细胞毒活性时，恒定结构域可以是另一种同种型，例如IgG2。替代的人源化抗IL-36R抗体可包含来自多于一种免疫球蛋白类或同种型的序列，并且选择特定的恒定结构域以优化期望的效应子功能在本领域普通技术范围内。在具体的实施方案中，本发明提供了抗体，其为IgG1抗体，更具体地，是其中存在效应子功能敲除的IgG1抗体。
人源化抗IL-36R抗体的FR和CDR或HVL不必与亲本序列精确对应。例如，可以通过取代、插入或缺失来改变(例如，诱变)在输入CDR或HVL或共有或种系FR序列中的一个或多个残基，使得作为结果的氨基酸残基不再与任一亲本序列中相应位置的原始残基相同，但是所述抗体仍然保留与IL-36R结合的功能。这样的改变通常不广泛并且将是保守的改变。通常，至少75％(更常见的是至少90％，最常见的是大于95％，或大于98％或大于99％)的人源化抗体残基将对应于亲本共有或种系FR和输入CDR序列的那些残基。
影响重链和轻链可变区之间的界面(“VL-VH界面”)的免疫球蛋白残基是影响两条链相对于彼此的接近或定向的那些残基。可能参与链间相互作用的某些残基包括VL残基34、36、38、44、46、87、89、91、96和98以及VH残基35、37、39、45、47、91、93、95、100和103(利用Kabat等人，Sequences of Proteins of Immunological Interest(National Institutesof Health,Bethesda,Md.,1987)中所述的编号系统)。美国专利美国专利No.6,407,213还论述了诸如VL残基43和85以及VH残基43和60的残基也可以参与这种相互作用。虽然这些残基仅指示人IgG，但它们适用于各种物种。选择合理预期参与链间相互作用的重要抗体残基，用于取代共有序列。
术语“共有序列”和“共有抗体”是指包含在所有免疫球蛋白的任何特定类别、同种型或亚单位结构(例如人免疫球蛋白可变结构域)中的每个位置处最常出现的氨基酸残基的氨基酸序列。共有序列可以基于特定物种或许多物种的免疫球蛋白。“共有”序列、结构或抗体应理解为涵盖如某些实施方案中描述的共有人序列，并且是指包含在所有人免疫球蛋白的任何特定类别、同种型或亚单位结构中的每个位置处最常出现的氨基酸残基的氨基酸序列。因此，共有序列含有这样的氨基酸序列，所述氨基酸序列在每个位置具有存在于一种或多种已知免疫球蛋白中的氨基酸，但其可能未精确复制任何单个免疫球蛋白的整个氨基酸序列。可变区共有序列不是从任何天然产生的抗体或免疫球蛋白及其变体获得的。Kabat等人，1991,Sequences of Proteins of Immunological Interest，第5版，Public HealthService,National Institutes of Health,Bethesda,Md.。
人种系序列天然存在于人类群体中。这些种系基因的组合产生了抗体多样性。抗体轻链的种系抗体序列来自保守的人种系κ或λv基因和j基因。类似地，重链序列来自种系v-、d-和j-基因(LeFranc,M-P和LeFranc,G,“The Immunoglobulin Facts Book”AcademicPress,2001)。
如本文中使用的，“变体”、“抗IL-36R变体”、“人源化抗IL-36R变体”或“变体人源化抗IL-36R变体”各自指的是至少具有轻链可变鼠CDR的人源化抗IL-36R抗体。变体包括在一个或两个轻链或重链可变结构域中具有一个或多个氨基酸变化的变体，条件是氨基酸变化基本上不损害抗体与IL-36R的结合。
“分离的”抗体是已经从其天然环境的组分中鉴定和分离和/或回收的抗体。抗体的天然环境的污染组分是可能干扰所述抗体的诊断或治疗用途的物质，并且可以是酶、激素、或其他蛋白质性或非蛋白质性溶质。在一个方面，将抗体纯化至按抗体重量计至少大于95％分离。
分离的抗体包括在产生它的重组细胞内的原位抗体，因为抗体的天然环境的至少一种组分将不存在。然而，通常通过至少一个纯化步骤制备分离的抗体，在所述纯化步骤中除去重组细胞物质。
术语“抗体性能”是指有助于抗体识别抗原或体内抗体有效性的因素。抗体氨基酸序列的变化可以影响抗体性质(比如折叠)，并且可以影响物理因子，比如抗体与抗原结合的初始速率(ka)、抗体与抗原的解离常数(kd)、抗体对抗原的亲和常数(Kd)、抗体构象、抗体的蛋白质稳定性和半衰期。
当在本文中使用时，术语“带有表位标签的”是指与“表位标签”融合的抗IL-36R抗体。“表位标签”是指具有足够数目的氨基酸的多肽，其提供用于抗体产生的表位，但被设计成使其不干扰人源化抗IL-36R抗体的期望活性。表位标签通常是足够独特的，使得针对表位标签产生的抗体基本上不与其他表位交叉反应。适合的标签多肽通常含有至少6个氨基酸残基，并且通常含有约8至50个氨基酸残基，或约9至30个残基。表位标签和结合表位的抗体的实例包括flu HA标签多肽及其抗体12CA5(Field等人，1988Mol.Cell.Biol.8:2159-2165)；c-myc标签及其8F9、3C7、6E10、G4、B7和9E10抗体(Evan等人，1985,Mol.Cell.Biol.5(12):3610-3616)；和单纯疱疹病毒糖蛋白D(gD)标签及其抗体(Paborsky等人，1990,Protein Engineering 3(6):547-553)。在某些实施方案中，表位标签是“补救受体结合表位”。如本文中使用的，术语“补救受体结合表位”是指负责增加IgG分子的体内血清半衰期的IgG分子(比如IgG1、IgG2、IgG3或IgG4)的Fc区的表位。
在一些实施方案中，本发明抗体可以与细胞毒性剂缀合。这(细胞毒性剂)是抑制或阻止细胞功能和/或引起细胞破坏的任何物质。该术语预期包括放射性同位素(比如I131、I125、Y90和Re1866)、化学治疗剂和毒素，比如细菌、真菌、植物或动物来源的酶活性毒素及其片段。可以使用标准程序将这样的细胞毒性剂与本发明的人源化抗体偶联，并且用于例如治疗具有抗体疗法指征的患者。
“化学治疗剂”是用于治疗癌症的化合物。有许多可以与本发明的治疗性抗体缀合的化学治疗剂的实例。这样的化学治疗剂的实例包括烷化剂，如噻替派和环磷酰胺；烷基磺酸盐，如白消安、英丙舒凡和哌泊舒凡；氮丙啶类，如苯并多巴、卡波醌、美妥多巴和乌瑞多巴；乙烯亚胺类和甲基蜜胺类，包括六甲蜜胺、三亚乙基蜜胺、三亚乙基磷酰胺、三亚乙基硫代磷酰胺和三羟甲基蜜胺；番荔枝内酯类化合物(特别是布拉它辛和布拉它辛酮)；喜树碱(包括合成类似物托泊替康)；苔藓抑素；卡利他汀；CC-1065(包括它的阿多来新、卡折来新和比折来新合成类似物)；隐藻素类(cryptophycines)(特别是隐藻素1和隐藻素8)；多拉司他汀；澳瑞他汀(包括类似物单甲基澳瑞他汀E和单甲基澳瑞他汀F)；倍癌霉素(包括合成类似物、KW-2189和CBI-TMI)；艾植塞洛素；水鬼蕉碱；匍枝珊瑚醇；海绵抑素；氮芥类，如苯丁酸氮芥、萘氮芥、胆磷酰胺、雌莫司汀、异环磷酰胺、氮芥、盐酸氧氮芥、美法仑、新氮芥、苯芥胆甾醇、泼尼莫司汀；曲磷胺、尿嘧啶氮芥；亚硝基脲类，如卡莫司汀、氯脲菌素、福莫司汀、洛莫司汀、尼莫司汀、雷莫司汀；抗生素，如烯二炔类抗生素(例如，卡奇霉素，特别是卡奇霉素γ1I和卡奇霉素phiI1(参见，例如Agnew,Chem.Intl.Ed.Engl.,33:183-186；达内霉素，包括达内霉素A；双膦酸盐类，如氯屈膦酸盐；埃斯波霉素；以及新制癌菌素发色团和相关色蛋白烯二炔抗生素发色团)、阿克拉霉素类、放线菌素、氨茴霉素、偶氮丝氨酸、博来霉素、放线菌素C、卡柔比星、洋红霉素、嗜癌霉素、色霉素、放线菌素D、柔红霉素、多柔比星、6-重氮-5-氧代-L-正亮氨酸、多柔比星(AdriamycinTM)(包括吗啉代多柔比星、多柔比星(包括吗啉代-多柔比星、氰基吗啉代-多柔比星、2-吡咯啉-多柔比星和脱氧多柔比星)、表柔比星、依索比星、伊达比星、麻西罗霉素、丝裂霉素类如丝裂霉素C、霉酚酸、诺拉霉素、橄榄霉素类、培洛霉素、泊非霉素、嘌呤霉素、三铁阿霉素、罗多比星、链黑霉素、链脲佐菌素、杀结核菌素、乌苯美司、净司他丁、佐柔比星；抗代谢物如甲氨蝶呤和5-氟尿嘧啶(5-FU)；叶酸类似物，如二甲叶酸、甲氨蝶呤、蝶罗呤、三甲曲沙；嘌呤类似物如氟达拉滨、6-巯基嘌呤、硫咪嘌呤、硫鸟嘌呤；嘧啶类似物如安西他滨、阿扎胞苷、6-氮杂尿苷、卡莫氟、阿糖胞苷、二脱氧尿苷、去氧氟尿苷、依诺他滨、氟尿苷；雄性激素，如卡普睾酮、屈他雄酮丙酸酯、环硫雄醇、美雄烷、睾内酯酮；抗肾上腺素，如氨鲁米特、米托坦、曲洛司坦；叶酸补充剂，如亚叶酸；醋葡醛内酯；醛磷酰胺糖苷；氨基乙酰丙酸；恩尿嘧啶；安吖啶；阿莫司汀；比生群；依达曲沙；地磷酰胺；地美可辛；地吖醌；依氟鸟氨酸；依利醋鞍；埃坡霉素；依托格鲁；硝酸镓；羟基脲；香菇多糖；氯尼达明；美登素生物碱类如美登素和安丝菌素；米托胍腙；米托蒽醌；莫哌达醇；尼曲吖啶；喷司他丁；苯来美特；吡柔比星；洛索蒽醌；鬼臼酸；2-乙基酰肼；丙卡巴肼；雷佐生；根霉素；西佐喃；锗螺胺；细交链孢菌酮酸；三亚胺醌；2,2',2'’-三氯三乙胺；单端孢霉烯类(特别是T-2毒素、疣孢菌素A、杆孢菌素A和蛇行菌素)；乌拉坦；长春地辛；达卡巴嗪；甘露莫司汀；二溴甘露醇；二溴卫矛醇；哌泊溴烷；加西托新；阿拉伯糖苷(“Ara-C”)；环磷酰胺；噻替派；紫杉烷类，例如紫杉醇(Bristol-Myers SquibbOncology,Princeton,N.J.)和多西他赛(Rhone-Poulenc Rorer,Antony,France)；苯丁酸氮芥；吉西他滨(GemzarTM)；6-硫鸟嘌呤；巯嘌呤；甲氨蝶呤；铂类似物，如顺铂和卡铂；长春碱；铂；依托泊苷(VP-16)；异环磷酰胺；米托蒽醌；长春新碱；长春瑞滨NavelbineTM；诺消灵；替尼泊苷；依达曲沙；道诺霉素；氨基喋呤；希罗达；伊班膦酸盐；CPT-11；拓扑异构酶抑制剂RFS 2000；二氟甲基鸟氨酸(DMFO)；类视黄醇，如视黄酸；卡培他滨；以及上述任一项的药学上可接受的盐、酸或衍生物。该定义还包括作用于调节或抑制对肿瘤的激素作用的抗激素剂，比如抗雌激素和选择性雌激素受体调节剂(SERM)，包括例如他莫昔芬(包括NolvadexTM)、雷洛昔芬(raloxifene)、屈洛昔芬、4-羟基他莫昔芬、曲沃昔芬、雷洛昔芬(keoxifene)、LY117018、奥那司酮和托瑞米芬(FarestonTM)；抑制酶芳香酶(调节肾上腺中的雌激素产生)的芳香酶抑制剂，例如4(5)-咪唑、氨鲁米特、醋酸甲地孕酮(MegaceTM)、依西美坦、福美司坦、法倔唑、伏氯唑(RivisorTM)、来曲唑(FemaraTM)和阿那曲唑(ArimidexTM)；以及抗雄激素，如氟他胺、尼鲁米特、比卡鲁胺、亮丙瑞林和戈舍瑞林；以及任何上述药学上可接受的盐、酸或衍生物。这些药剂中的任何一种或多种可以与本发明的人源化抗体缀合，以提供用于治疗各种疾患的有用治疗剂。
抗体也可以与前药缀合。“前药”是药物活性物质的前体或衍生物形式，其与母体药物相比对肿瘤细胞的细胞毒性较小，并且能够被酶促活化或转化为更有活性的形式。参见，例如，Wilman,1986,"Prodrugs in Cancer Chemotherapy",In Biochemical SocietyTransactions,14，第375-382页，615th Meeting Belfast以及Stella等人，1985,"Prodrugs:A Chemical Approach to Targeted Drug Delivery,In:"Directed DrugDelivery,Borchardt等人(编辑)，第247-267页，Humana Press。有用的前药包括但不限于含磷酸酯的前药、含硫代磷酸酯的前药、含硫酸盐的前药、含肽前药、D-氨基酸修饰的前药、糖基化前药、含β-内酰胺的前药、含任选取代的苯氧基乙酰胺的前药和含任选取代的苯基乙酰胺的前药、5-氟胞嘧啶和其它5-氟尿苷前药，它们可以转化成更有活性的细胞毒性游离药物。可衍生成前药形式的细胞毒性药物的实例包括但不限于上述那些化学治疗剂。
为了诊断和治疗监测目的，本发明抗体还可以与标记物缀合，可以是单独的标记物或标记物连同另外的第二药剂(前药、化学治疗剂等)。区别于其他第二试药剂，标记物是指作为可检测化合物或组合物的药剂，并且它可与本发明的人源化抗体直接或间接缀合。标记物本身可以是可检测的(例如，放射性同位素标记物或荧光标记物)，或者在酶标记物的情况下，可以催化可检测的底物化合物或组合物的化学改变。可以制备标记的人源化抗IL-36R抗体，并将其用于包括体外和体内诊断在内的各种应用中。
可以将本发明的抗体配制成脂质体制剂的一部分，以便影响其体内递送。“脂质体”是指是由各种类型的脂质、磷脂和/或表面活性剂组成的小囊泡。脂质体可用于给哺乳动物递送化合物或制剂，比如任选地与一种或多种药物活性剂和/或标记物偶联或联合的本文中公开的人源化抗IL-36R抗体。脂质体的组分通常以双层形式排列，类似于生物膜的脂质排列。
本发明的某些方面涉及编码本发明的人源化抗体的一个或多个结构域的分离的核酸。“分离的”核酸分子是从通常与抗体核酸的天然来源关联的至少一种污染性核酸分子中鉴定和分离的核酸分子。分离的核酸分子区别于在它存在的天然细胞中的核酸分子。
在本发明的各个方面，将重组表达人源化抗体的一个或多个结构域。这样的重组表达可以利用一个或多个控制序列，即，在特定宿主生物中表达可操作连接的编码序列必需的多核苷酸序列。适用于原核细胞的控制序列包括例如启动子、操纵子和核糖体结合位点序列。真核生物控制序列包括但不限于启动子、多腺苷酸化信号和增强子。这些控制序列可用于在原核和真核宿主细胞中表达和产生人源化抗IL-36R抗体。
当核酸序列被置于与另一个核酸序列的功能关系中时，所述核酸序列是“可操作连接的”。例如，如果核酸前序列或分泌前导序列被表达为参与多肽分泌的前蛋白，则其与所述多肽的核酸可操作连接；如果启动子或增强子影响编码序列的转录，则其与所述编码序列可操作连接；或者如果核糖体结合位点被定位为便于翻译，则其与编码序列可操作连接。通常，“可操作连接”意指被连接的DNA序列是连续的，并且在分泌前导序列的情况下是连续的并处于阅读框中。然而，增强子任选地是连续的。可通过连接在合适的限制性位点处完成连接。如果这样的位点不存在，则可以使用合成的寡核苷酸衔接子或接头。
如本文中使用的，用语“细胞”、“细胞系”和“细胞培养物”可互换使用，并且所有这些名称包括其后代。因此，“转化体”和“转化的细胞”包括原代受试者细胞和从其衍生的培养物，而无需考虑转移次数。
为了治疗目的，术语“哺乳动物”是指被分类为哺乳动物的任何动物，包括人类、驯养动物和农场动物、动物园动物、运动动物或宠物动物，比如狗、马、猫、牛等。优选地，哺乳动物是人。
如本文中使用的，“疾患”是将受益于用本文所述的人源化抗IL-36R抗体治疗的任何病症。这包括慢性和急性疾患或疾病，包括使哺乳动物易患所述疾患的那些病理状况。本文中待治疗的非限制性实例或疾患包括炎性、血管生成性、自身免疫性和免疫性疾患、呼吸系统疾患、癌症、血液恶性肿瘤、良性和恶性肿瘤、白血病和淋巴系统恶性肿瘤。
术语“癌症”和“癌性的”是指或描述在哺乳动物中典型地以不受调节的细细胞生长为特征的生理状况。癌症的实例包括但不限于，癌、淋巴瘤、母细胞瘤、肉瘤、和白血病。
IL-36R相关疾患包括免疫系统的疾病和疾患，比如自身免疫性疾患和炎性疾患。这样的病症包括但不限于类风湿性关节炎(RA)、系统性红斑狼疮(SLE)、硬皮病、干燥综合征、多发性硬化、银屑病、银屑病关节炎、炎性肠病(例如，溃疡性结肠炎和克罗恩病)、肺部炎症、哮喘、特发性血小板减少性紫癜(ITP)、上皮炎性疾患、纤维化和强直性脊柱炎。
术语“静脉内输注”是指在大于约15分钟、通常在大约30至90分钟之间的时间段内将药剂引入到动物或人类患者的静脉中。
术语“静脉推注”或“静脉内推注”是指将药物施用到动物或人的静脉中，使得身体在约15分钟或更短、通常在5分钟或更短的时间内接收药物。
术语“皮下施用”是指通过从药物容器中的相对缓慢、持续的递送将药剂引入到动物或人类患者的皮肤之下，优选在皮肤和下层组织之间的袋囊内。将皮肤向上捏或拉并且使其离开下层织可以产生袋囊。
术语“皮下输注”是指通过从药物容器中相对缓慢、持续地递送一段时间，包括但不限于30分钟或更短，或90分钟或更短，将药物引入到动物或人类患者的皮肤之下，优选在皮肤和下层组织之间的袋囊内。任选地，可以通过将药物递送泵皮下植入到动物或人类患者的皮肤之下来进行输注，其中所述泵递送预定量的药物持续一段预定的时间，比如30分钟、90分钟，或跨越治疗方案长度的时间段。
术语“皮下推注”是指在动物或人类患者的皮肤之下施用药物，其中推注药物递送短于约15分钟；在另一方面，短于5分钟，并且在又另一方面，短于60秒。在又另一个方面，在皮肤和下层组织之间的袋囊内施用，其中可以通过向上捏或拉皮肤并且使其离开下层组织来产生袋囊。
术语“治疗有效量”用于指减轻或改善被治疗的疾患的一种或多种症状的活性剂的量。在另一个方面，治疗有效量是指已显示在例如减缓疾病进展中有效的目标血清浓度。可以以常规方式测量功效，这取决于待治疗的病症。
术语“治疗”和“疗法”等意指包括针对疾病或疾患的治疗以及预防或抑制性措施，其产生任何临床上期望的或有益的效果，包括但不限于一种或多种症状的减轻或缓解、疾病或疾患的消退、进展的减缓或停止。因此，例如，术语治疗包括在疾病或疾患的症状发作之前或之后的药剂施用，由此预防或去除疾病或疾患的一种或多种体征。作为另一个实例，该术语包括在疾病的临床表现之后施用药剂以对抗疾病的症状。此外，在施用影响疾病或疾患的临床参数，比如组织损伤的程度或转移的数量或范围的情况下，无论治疗是否导致疾病改善，在发作之后和临床症状发生之后的药剂施用都构成如本文中使用的“治疗”或“疗法”。而且，与不使用人源化抗IL-36R抗体组合物时的症状相比，只要单独的或与另一种治疗剂联合的本发明组合物减轻或改善被治疗疾患的至少一种症状，无论是否减轻疾患的所有症状，结果都应被视为对基础疾患的有效治疗。
术语“包装说明书”用于指通常包括在治疗产品的商业包装中的说明书，其包含关于使用这种治疗产品的适应症、用法、施用、禁忌症和/或警告的信息。
抗体
在一个方面，本文中描述和公开了抗IL-36R抗体，特别是人源化抗IL-36R抗体，以及包含一种或多种抗IL-36R抗体特别是本发明的一种或多种人源化抗IL-36R抗体的组合物和制品。还描述了结合剂，其包括抗IL-36R抗体特别是人源化抗IL-36R抗体的抗原结合片段。
下面公开了本发明的代表性抗体的可变区和CDR：
抗IL-36R小鼠抗体序列
本发明的代表性小鼠先导抗体的可变区和CDR(小鼠先导序列)如下所示：
轻链可变区(VK)氨基酸序列
>33D10B12vK蛋白(抗体33D10)
QIVLTQSPAIMSASLGERVTMTCTASSSVSSSYLHWYQKKPGSSPKLWVYSTSNLASGVPVRFSGSGSGTSYSLTISSMEAEDAATYYCHQHHRSPVTFGSGTKLEMK(SEQ ID NO:1)
>172C8B12 vK蛋白(抗体172C8)
DIQMTQSPASQSASLGESVTFTCLASQTIGTWLAWYQQRPGKSPQLLIYAATSLADGVPSRFSGSGSGTQFSFNIRSLQAEDFASYYCQQVYTTPLTFGGGTKLEIK(SEQ ID NO:2)
>67E7E8 vK蛋白(抗体67E7)
DIQMTQSPASQSASLGESVTFTCLASQTIGTWLGWYQQKPGKSPQLLIYRSTTLADGVPSRFSGSGSGTKFSFKISSLQAADFASYYCQQLYSAPYTFGGGTKLEIR(SEQ ID NO:3)
>78C8D1 vK蛋白(抗体78C8)
DVLLTQTPLSLPVSLGDQASISCRSSQNIVHSNGNTYLQWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHVPFTFGAGTKLELK(SEQ ID NO:4)
>81A1D1 vK蛋白(抗体81A1)
DIQMTQTTSSLSASLGDRVTISCRASQDIYKYLNWYQQKPDGTLKLLIYYTSGLHSGVPSRFSGSGSGTDFSLTISNLEPEDIATYFCQQDSKFPWTFGGDTKLEIK(SEQ ID NO:5)
>81B4E11 vK蛋白(抗体81B4)
QIVLTQSPAIMSASLGERVTMTCTASSSVSSSYFHWYQQKPGSSPKLWIYRTSNLASGVPGRFSGSGSGTSYSLTISSMEAEDAATYYCHQFHRSPLTFGAGTKLELK(SEQ ID NO:6)
>73C5C10 vK蛋白(抗体73C5)
DIVMTQSQKFLSTSVGVRVSVTCKASQDVGTNVLWYQQKIGQSPKPLIYSASYRHSGVPDRFTGSGSGTDFTLIISNVQSEDLAEYFCQQYSRYPLTFGPGTKLELK(SEQ ID NO:7)
>73F6F8 vK蛋白(抗体73F6)
DIVMTQSQKFLSTSVGVRVSVTCKASQDVGTNVLWYQQKIGQSPKALIYSASYRHSGVPDRFTGSGSGTDFTLIITNVQSEDLAEYFCQQYSRYPLTFGPGTKLELK(SEQ ID NO:8)
>76E10E8 vK蛋白(抗体76E10)
DIVMTQSQKFMSATVGGRVNITCKASQNVGRAVAWYQQKPGQSPKLLTHSASNRYTGVPDRFTGSGSGTDFTLTITNMQSEDLADYFCQQYSSYPLTFGAGTKLDLK(SEQ ID NO:9)
>89A12B8 vK蛋白(抗体89A12)
DIQMTQSPASQSASLGESVTFSCLASQTIGTWLGWYQQKPGKSPQLLIYRATSLADGVPSRFSGSGSGTNFSFKISSLQAEDLASYYCQQLYSGPYTFGGGTKLEIR(SEQ ID NO:10)
重链可变区(VH)氨基酸序列
>33D10B12vH蛋白(抗体33D10)
QVQLQQSGTELLKPGASVKLSCKASGNTVTSYWMHWVKQRPGQGLEWIGEILPSTGRTNYNENFKGKAMLTVDKSSSTAYMQLSSLASEDSAVYYCTIVYFGNPWFAYWGQGTLVTVSA(SEQ ID NO:11)
>172C8B12 vH蛋白(抗体172C8)
EVQLQQSGPELVKPGASVKLSCKASGYTFTDNYMNWVRQSHGKSLEWIGRVNPSNGDTKYNQNFKGKATLTVDKSLSTAYMQLNGLTSEDSAVYYCGRTKNFYSSYSYDDAMDYWGQGTSVTVSS(SEQ ID NO:12)
>67E7E8 vH蛋白(抗体67E7)
EVQLQQSGAEFVRPGASVKFSCTASGFNIKDDYIHWVRQRPEQGLEWVGRIDPANGNTKYAPKFQDKATITADTSSNTAYLQLSSLTSEDTAVYYCAKSFPNNYYSYDDAFAYWGQGTLVTVSA(SEQ ID NO:13)
>78C8D1 vH蛋白(抗体78C8)
QVQLKESGPVLVAPSQSLSITCTVSGFSLTKFGVHWIRQTPGKGLEWLGVIWAGGPTNYNSALMSRLTISKDISQSQVFLRIDSLQTDDTAMYYCAKQIYYSTLVDYWGQGTSVTVSS(SEQ ID NO:14)
>81A1D1 vH蛋白(抗体81A1)
QVQLKESGPGLVAPSQSLFITCTVSGFSLSSYEINWVRQVPGKGLEWLGVIWTGITTNYNSALISRLSISKDNSKSLVFLKMNSLQTDDTAIYYCARGTGTGFYYAMDYWGQGTSVTVSS(SEQ ID NO:15)
>81B4E11 vH蛋白(抗体81B4)
QVQLQQPGADFVRPGASMRLSCKASGYSFTSSWIHWVKQRPGQGLEWIGEINPGNVRTNYNENFRNKATLTVDKSSTTAYMQLRSLTSADSAVYYCTVVFYGEPYFPYWGQGTLVTVSA(SEQ ID NO:16)
>73C5C10 vH蛋白(抗体73C5)
QVQLKESGPGLVAPSQSLSITCTVSGFSLTNYAVHWVRQFPGKGLEWLGVIWSDGSTDFNAPFKSRLSINKDNSKSQVFFKMNSLQIDDTAIYYCARKGGYSGSWFAYWGQGTLVTVSA(SEQ ID NO:17)
>73F6F8 vH蛋白(抗体73F6)
QVQLKESGPGLVAPSQSLSITCTVSGFSLTNYAVHWVRQFPGKGLEWLGVIWSDGSTDYNAPFKSRLSINKDNSKSQVFFKMNSLQTDDTAIYYCARKGGYSGSWFAYWGQGTLVTVSA(SEQ ID NO:18)
>76E10E8 vH蛋白(抗体76E10)
QVQLKESGPVLVAPSQSLSITCTVSGFSLTNYGVHWVRQPPGKGLEWLGVIWPVGSTNYNSALMSRLSIHKDNSKSQVFLRMNSLQTDDTAIYYCAKMDWDDFFDYWGQGTTLTVSS(SEQ ID NO:19)
>89A12B8 vH蛋白(抗体89A12)
EVQLQQSGAELVRPGASVRLSCTASGFNIKDDYIHWVRQRPKQGLEWLGRIDPANGNTKYDPRFQDKATITADTSSNTAYLHLSSLTSEDTAVYYCAKSFPDNYYSYDDAFAYWGQGTLVTVSA(SEQ ID NO:20)
轻链CDR-1(L-CDR1)氨基酸序列
>33D10G1 L-CDR1
TASSSVSSSYLH (SEQ ID NO:21)
>172C8B12 L-CDR1
LASQTIGTWLA (SEQ ID NO:22)
>67E7E8 L-CDR1
LASQTIGTWLG (SEQ ID NO:23)
>78C8D1 L-CDR1
RSSQNIVHSNGNTYLQ (SEQ ID NO:24)
>81A1D1 L-CDR1
RASQDIYKYLN (SEQ ID NO:25)
>81B4E11 L-CDR1
TASSSVSSSYFH (SEQ ID NO:26)
>73C5C10 L-CDR1
KASQDVGTNVL (SEQ ID NO:27)
>73F6F8 L-CDR1
KASQDVGTNVL (SEQ ID NO:27)
>76E10E8 L-CDR1
KASQNVGRAVA (SEQ ID NO:28)
>89A12B8 L-CDR1
LASQTIGTWLG (SEQ ID NO:29)
轻链CDR-2(L-CDR2)氨基酸序列
>33D10B12 L-CDR2
STSNLAS (SEQ ID NO:30)
>172C8B12 L-CDR2
AATSLAD (SEQ ID NO:31)
>67E7E8 L-CDR2
RSTTLAD (SEQ ID NO:32)
>78C8D1 L-CDR2
KVSNRFS (SEQ ID NO:33)
>81A1D1 L-CDR2
YTSGLHS (SEQ ID NO:34)
>81B4E11 L-CDR2
RTSNLAS (SEQ ID NO:35)
>73C5C10 L-CDR2
SASYRHS (SEQ ID NO:36)
>73F6F8 L-CDR2
SASYRHS (SEQ ID NO:36)
>76E10E8 L-CDR2
SASNRYT (SEQ ID NO:37)
>89A12B8 L-CDR2
RATSLAD (SEQ ID NO:38)
轻链CDR-3(L-CDR3)氨基酸序列
>33D10B12 L-CDR3
HQHHRSPVT (SEQ ID NO:39)
>172C8B12 L-CDR3
QQVYTTPLT (SEQ ID NO:40)
>67E7E8 L-CDR3
QQLYSAPYT (SEQ ID NO:41)
>78C8D1 L-CDR3
FQGSHVPFT (SEQ ID NO:42)
>81A1D1 L-CDR3
QQDSKFPWT (SEQ ID NO:43)
>81B4E11 L-CDR3
HQFHRSPLT (SEQ ID NO:44)
>73C5C10 L-CDR3
QQYSRYPLT (SEQ ID NO:45)
>73F6F8 L-CDR3
QQYSRYPLT (SEQ ID NO:45)
>76E10E8 L-CDR3
QQYSSYPLT (SEQ ID NO:46)
>89A12B8 L-CDR3
QQLYSGPYT (SEQ ID NO:47)
重链CDR-1(H-CDR1)氨基酸序列
>33D10B12 H-CDR1
GNTVTSYWMH (SEQ ID NO:48)
>172C8B12 H-CDR1
GYTFTDNYMN (SEQ ID NO:49)
>67E7E8 H-CDR1
GFNIKDDYIH (SEQ ID NO:50)
>78C8D1 H-CDR1
GFSLTKFGVH (SEQ ID NO:51)
>81A1D1 H-CDR1
GFSLSSYEIN (SEQ ID NO:52)
>81B4E11 H-CDR1
GYSFTSSWIH (SEQ ID NO:53)
>73C5C10 H-CDR1
GFSLTNYAVH (SEQ ID NO:54)
>73F6F8 H-CDR1
GFSLTNYAVH (SEQ ID NO:54)
>76E10E8 H-CDR1
GFSLTNYGVH (SEQ ID NO:55)
>89A12B8 H-CDR1
GFNIKDDYIH (SEQ ID NO:56)
重链CDR-2(H-CDR2)氨基酸序列
>33D10B12 H-CDR2
EILPSTGRTNYNENFKG (SEQ ID NO:57)
>172C8B12 H-CDR2
RVNPSNGDTKYNQNFKG (SEQ ID NO:58)
>67E7E8 H-CDR2
RIDPANGNTKYAPKFQD (SEQ ID NO:59)
>78C8D1 H-CDR2
VIWAGGPTNYNSALMS (SEQ ID NO:60)
>81A1D1 H-CDR2
VIWTGITTNYNSALIS (SEQ ID NO:61)
>81B4E11 H-CDR2
EINPGNVRTNYNENF (SEQ ID NO:62)
>73C5C10 H-CDR2
VIWSDGSTDFNAPFKS (SEQ ID NO:63)
>73F6F8 H-CDR2
VIWSDGSTDYNAPFKS (SEQ ID NO:64)
>76E10E8 H-CDR2
VIWPVGSTNYNSALMS (SEQ ID NO:65)
>89A12B8 H-CDR2
RIDPANGNTKYDPRFQD (SEQ ID NO:66)
重链CDR-3(H-CDR3)氨基酸序列
>33D10B12 H-CDR3
VYFGNPWFAY (SEQ ID NO:67)
>172C8B12 H-CDR3
TKNFYSSYSYDDAMDY (SEQ ID NO:68)
>67E7E8 H-CDR3
SFPNNYYSYDDAFAY (SEQ ID NO:69)
>78C8D1 H-CDR3
QIYYSTLVDY (SEQ ID NO:70)
>81A1D1 H-CDR3
GTGTGFYYAMDY (SEQ ID NO:71)
>81B4E11 H-CDR3
VFYGEPYFPY (SEQ ID NO:72)
>73C5C10 H-CDR3
KGGYSGSWFAY (SEQ ID NO:73)
>73F6F8 H-CDR3
KGGYSGSWFAY (SEQ ID NO:73)
>76E10E8 H-CDR3
MDWDDFFDY (SEQ ID NO:74)
>89A12B8 H-CDR3
SFPDNYYSYDDAFAY (SEQ ID NO:75)
抗IL-36R小鼠CDR序列
先导小鼠抗体CDR序列的总结如下所示：
抗IL-36R人源化抗体序列
基于框架同源性、CDR结构、保守的规范残基、保守的界面填充残基和其他参数来选择针对小鼠先导序列的人框架序列，以产生人源化可变区(参见实施例5)。
衍生自抗体81B4和73C5的代表性人源化可变区如下所示。
轻链可变区(VK)氨基酸序列
>81B4vK32_3vK蛋白
EIVLTQSPGTLSLSPGERATMSCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSTLASGIPDRFSGSGSGTDFTLTISRLEPEDAATYYCHQFHRSPLTFGQGTKLEIK(SEQ ID NO:76)
>81B4vK32_105vK蛋白
EIVLTQSPGTLSLSPGERATMSCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSILASGVPDRFSGSGSGTDFTLTISRLEPEDFATYYCHQFHRSPLTFGQGTKLEIK(SEQ ID NO:77)
>81B4vK32_116vK蛋白
EIVLTQSPGTLSLSPGERATMSCTASSSVSSSYFHWYQQKPGQAPRLWIYRTSRLASGVPDRFSGSGSGTDFTLTISRLEPEDAATYYCHQFHRSPLTFGQGTKLEIK(SEQ ID NO:78)
>81B4vK32_127vK蛋白
EIVLTQSPGTLSLSPGERATMTCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSRLASGVPDRFSGSGSGTDFTLTISRLEPEDFAVYYCHQFHRSPLTFGQGTKLEIK(SEQ ID NO:79)
>81B4vK32_138vK蛋白
QIVLTQSPGTLSLSPGERATMTCTASSSVSSSYFHWYQQKPGQAPRLWIYRTSRLASGVPDRFSGSGSGTDFTLTISRLEPEDAATYYCHQFHRSPLTFGAGTKLEIK(SEQ ID NO:80)
>81B4vK32_140vK蛋白
QIVLTQSPGTLSLSPGERVTMSCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSQLASGIPDRFSGSGSGTDFTLTISRLEPEDAATYYCHQFHRSPLTFGQGTKLEIK(SEQ ID NO:81)
>81B4vK32_141vK蛋白
QIVLTQSPGTLSLSPGERATMTCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSKLASGVPDRFSGSGSGTDFTLTISRLEPEDFATYYCHQFHRSPLTFGQGTKLEIK(SEQ ID NO:82)
>81B4vK32_147vK蛋白
EIVLTQSPGTLSLSPGERATMSCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSHLASGIPGRFSGSGSGTDFTLTISRLEPEDAAVYYCHQFHRSPLTFGQGTKLEIK(SEQ ID NO:83)
>73C5vK39_2vK蛋白
EIVMTQSPATLSVSPGVRATLSCKASQDVGTNVLWYQQKPGQAPRPLIYSASYRHSGIPDRFSGSGSGTEFTLTISSLQSEDFAEYFCQQYSRYPLTFGQGTKLEIK(SEQ ID NO:84)
>73C5vK39_7vK蛋白
EIVMTQSPATLSVSPGVRATLSCKASQDVGTNVLWYQQKPGQAPRPLIYSASYRHSGIPDRFSGSGSGTEFTLTISSLQSEDFAVYYCQQYSRYPLTFGQGTKLEIK(SEQ ID NO:85)
>73C5vK39_15vK蛋白
EIVMTQSPATLSVSPGVRATLSCKASQDVGTNVLWYQQKPGQAPRPLIYSASYRHSGIPARFSGSGSGTEFTLTISSLQSEDFAEYYCQQYSRYPLTFGQGTKLEIK(SEQ ID NO:86)
重链可变区(VH)氨基酸序列
>81B4vH33_49vH蛋白
QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQAPGQGLEWIGEINPGNVRTNYNENFRNKATMTVDTSISTAYMELSRLRSDDTAVYYCAVVFYGEPYFPYWGQGTLVTVSS(SEQ ID NO:87)
>81B4vH33_85T vH蛋白
QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQRPGQGLEWIGEINPGNVRTNYNENFRNRVTMTVDTSISTAYMELSRLRSDDTAVYYCTVVFYGEPYFPYWGQGTLVTVSS(SEQ ID NO:88)
>81B4vH33_90vH蛋白
QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVKQAPGQGLEWMGEINPGNVRTNYNENFRNKVTMTVDTSISTAYMELSRLRSDDTAVYYCTVVFYGEPYFPYWGQGTLVTVSS(SEQ ID NO:89)
>81B4vH33_93vH蛋白
QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQRPGQGLEWMGEINPGNVRTNYNENFRNRATLTRDTSISTAYMELSRLRSDDTAVYYCAVVFYGEPYFPYWGQGTLVTVSS(SEQ ID NO:90)
>81B4vH50_22vH蛋白
QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQRPGQGLEWMGEILPGVVRTNYNENFRNKVTMTVDTSISTAYMELSRLRSDDTAVYYCTVVFYGEPYFPYWGQGTLVTVSS(SEQ ID NO:91)
>81B4vH50_30vH蛋白
QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQRPGQGLEWIGEINPGAVRTNYNENFRNRVTMTVDTSISTAYMELSRLRSDDTAVYYCTVVFYGEPYFPYWGQGTLVTVSS(SEQ ID NO:92)
>81B4vH51_13vH蛋白
QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQAPGQGLEWIGEINPGLVRTNYNENFRNKVTMTVDTSISTAYMELSRLRSDDTAVYYCAVVFYGEPYFPYWGQGTLVTVSS(SEQ ID NO:93)
>81B4vH51_15vH蛋白
QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQAPGQGLEWIGEINPGAVRTNYNENFRNKVTMTVDTSISTAYMELSRLRSDDTAVYYCAVVFYGEPYFPYWGQGTLVTVSS(SEQ ID NO:94)
>81B4vH52_83vH蛋白
QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQAPGQGLEWIGEINPGSVRTNYNENFRNKATMTVDTSISTAYMELSRLRSDDTAVYYCAVVFYGEPYFPYWGQGTLVTVSS(SEQ ID NO:95)
>73C5vH46_4vH蛋白
QVQLQESGPGLVKPSETLSITCTVSGFSLTDYAVHWIRQPPGKGLEWIGVIWSDGSTDYNAPFKSRVTINKDTSKSQVSFKMSSVQAADTAVYYCARKGGYSGSWFAYWGQGTLVTVSS(SEQ ID NO:96)
>73C5vH46_19vH蛋白
QVQLQESGPGLVKPSETLSITCTVSGFSLTDYAVHWIRQPPGKGLEWIGVIWSDGSTDYNAPFKSRVTISKDTSKNQVSLKMNSLTTDDTAVYYCARKGGYSGSWFAYWGQGTLVTVSS(SEQ ID NO:97)
>73C5vH46_40vH蛋白
QVQLQESGPGLVKPSETLSITCTVSGFSLTDYAVHWIRQPPGKGLEWIGVIWSDGSTDYNAPFKSRVTISKDNSKSQVSLKMNSVTVADTAVYYCARKGGYSGSWFAYWGQGTLVTVSS(SEQ ID NO:98)
>73C5vH47_65vH蛋白
QVQLQESGPGLVKPSETLSITCTVSGFSLTDYAVHWVRQPPGKGLEWIGVIWSDGSTDYNAPFKSRVTISKDTSKNQVSFKLSSVTVDDTAVYYCARKGGYSGSWFAYWGQGTLVTVSS(SEQ ID NO:99)
>73C5vH47_77vH蛋白
QVQLQESGPGLVAPSETLSLTCTVSGFSLTDYAVHWIRQFPGKGLEWIGVIWSDGSTDFNAPFKSRVTISKDTSKNQVSFKLSSVTTDDTAVYYCARKGGYSGSWFAYWGQGTLVTVSS(SEQ ID NO:100)
>73C5vH58_91vH蛋白
QVQLQESGPGLVKPSETLSITCTVSGFSLTDYAVHWIRQPPGKGLEWIGVIWSDGSTDYNAPFKSRVTISKDNSKSQVSFKMSSVTADDTAVYYCARKGGYSGSWFAYWGQGTLVTVSS(SEQ ID NO:101)
衍生自上文所示的抗体81B4和73C5的人源化可变区的CDR序列描绘如下。
L-CDR1氨基酸序列
>81B4vK32_3L-CDR1
TASSSVSSSYFH(SEQ ID NO:26)
>81B4vK32_105L-CDR1
TASSSVSSSYFH(SEQ ID NO:26)
>81B4vK32_116L-CDR1
TASSSVSSSYFH(SEQ ID NO:26)
>81B4vK32_127L-CDR1
TASSSVSSSYFH(SEQ ID NO:26)
>81B4vK32_138L-CDR1
TASSSVSSSYFH(SEQ ID NO:26)
>81B4vK32_140L-CDR1
TASSSVSSSYFH(SEQ ID NO:26)
>81B4vK32_141L-CDR1
TASSSVSSSYFH(SEQ ID NO:26)
>81B4vK32_147L-CDR1
TASSSVSSSYFH(SEQ ID NO:26)
>73C5vK39_2L-CDR1
KASQDVGTNVL(SEQ ID NO:27)
>73C5vK39_7L-CDR1
KASQDVGTNVL(SEQ ID NO:27)
>73C5vK39_15L-CDR1
KASQDVGTNVL(SEQ ID NO:27)
L-CDR2氨基酸序列
>81B4vK32_3L-CDR2 (SEQ ID 102)
RTSTLAS
>81B4vK32_105 L-CDR2 (SEQ ID 103)
RTSILAS
>81B4vK32_116 L-CDR2 (SEQ ID 104)
RTSRLAS
>81B4vK32_127 L-CDR2 (SEQ ID 104)
RTSRLAS
>81B4vK32_138 L-CDR2 (SEQ ID 104)
RTSRLAS
>81B4vK32_140 L-CDR2 (SEQ ID 105)
RTSQLAS
>81B4vK32_141 L-CDR2 (SEQ ID 106)
RTSKLAS
>81B4vK32_147 L-CDR2 (SEQ ID 140)
RTSHLAS
>73C5vK39_2 L-CDR2
SASYRHS(SEQ ID NO:36)
>73C5vK39_7 L-CDR2
SASYRHS(SEQ ID NO:36)
>73C5vK39_15 L-CDR2
SASYRHS(SEQ ID NO:36)
L-CDR3氨基酸序列
>81B4vK32_3L-CDR3
HQFHRSPLT(SEQ ID NO:44)
>81B4vK32_105L-CDR3
HQFHRSPLT(SEQ ID NO:44)
>81B4vK32_116L-CDR3
HQFHRSPLT(SEQ ID NO:44)
>81B4vK32_127L-CDR3
HQFHRSPLT(SEQ ID NO:44)
>81B4vK32_138L-CDR3
HQFHRSPLT(SEQ ID NO:44)
>81B4vK32_140L-CDR3
HQFHRSPLT(SEQ ID NO:44)
>81B4vK32_141L-CDR3
HQFHRSPLT(SEQ ID NO:44)
>81B4vK32_147L-CDR3
HQFHRSPLT(SEQ ID NO:44)
>73C5vK39_2L-CDR3
QQYSRYPLT(SEQ ID NO:45)
>73C5vK39_7L-CDR3
QQYSRYPLT(SEQ ID NO:45)
>73C5vK39_15L-CDR3
QQYSRYPLT(SEQ ID NO:45)
H-CDR1氨基酸序列
>81B4vH33_49H-CDR1
GYSFTSSWIH (SEQ ID NO:53)
>81B4vH33_85T H-CDR1
GYSFTSSWIH (SEQ ID NO:53)
>81B4vH33_90H-CDR1
GYSFTSSWIH (SEQ ID NO:53)
>81B4vH33_93H-CDR1
GYSFTSSWIH (SEQ ID NO:53)
>81B4vH50_22H-CDR1
GYSFTSSWIH (SEQ ID NO:53)
>81B4vH50_30H-CDR1
GYSFTSSWIH (SEQ ID NO:53)
>81B4vH51_13H-CDR1
GYSFTSSWIH (SEQ ID NO:53)
>81B4vH51_15H-CDR1
GYSFTSSWIH (SEQ ID NO:53)
>81B4vH52_83H-CDR1
GYSFTSSWIH (SEQ ID NO:53)
>73C5vH46_4H-CDR1
GFSLTDYAVH(SEQ ID NO:107)
>73C5vH46_19H-CDR1
GFSLTDYAVH(SEQ ID NO:107)
>73C5vH46_40H-CDR1
GFSLTDYAVH(SEQ ID NO:107)
>73C5vH47_65H-CDR1
GFSLTDYAVH(SEQ ID NO:107)
>73C5vH47_77H-CDR1
GFSLTDYAVH(SEQ ID NO:107)
>73C5vH58_91H-CDR1
GFSLTDYAVH(SEQ ID NO:107)
H-CDR2氨基酸序列
>81B4vH33_49H-CDR2
EINPGNVRTNYNENF(SEQ ID NO:62)
>81B4vH33_85T H-CDR2
EINPGNVRTNYNENF(SEQ ID NO:62)
>81B4vH33_90 H-CDR2
EINPGNVRTNYNENF(SEQ ID NO:62)
>81B4vH33_93 H-CDR2
EINPGNVRTNYNENF(SEQ ID NO:62)
>81B4vH50_22 H-CDR2
EILPGVVRTNYNENF(SEQ ID NO:108)
>81B4vH50_30 H-CDR2
EINPGAVRTNYNENF(SEQ ID NO:109)
>81B4vH51_13 H-CDR2
EINPGLVRTNYNENF(SEQ ID NO:110)
>81B4vH51_15 H-CDR2
EINPGAVRTNYNENF(SEQ ID NO:109)
>81B4vH52_83 H-CDR2
EINPGSVRTNYNENF(SEQ ID NO:111)
>73C5vH46_4 H-CDR2
VIWSDGSTDYNAPFKS(SEQ ID NO:64)
>73C5vH46_19 H-CDR2
VIWSDGSTDYNAPFKS(SEQ ID NO:64)
>73C5vH46_40H-CDR2
VIWSDGSTDYNAPFKS(SEQ ID NO:64)
>73C5vH47_65H-CDR2
VIWSDGSTDYNAPFKS(SEQ ID NO:64)
>73C5vH47_77H-CDR2
VIWSDGSTDFNAPFKS(SEQ ID NO:63)
>73C5vH58_91H-CDR2
VIWSDGSTDYNAPFKS(SEQ ID NO:64)
H-CDR3氨基酸序列
>81B4vH33_49H-CDR3
VFYGEPYFPY(SEQ ID NO:72)
>81B4vH33_85T H-CDR3
VFYGEPYFPY(SEQ ID NO:72)
>81B4vH33_90H-CDR3
VFYGEPYFPY(SEQ ID NO:72)
>81B4vH33_93H-CDR3
VFYGEPYFPY(SEQ ID NO:72)
>81B4vH50_22H-CDR3
VFYGEPYFPY(SEQ ID NO:72)
>81B4vH50_30H-CDR3
VFYGEPYFPY(SEQ ID NO:72)
>81B4vH51_13 H-CDR3
VFYGEPYFPY(SEQ ID NO:72)
>81B4vH51_15 H-CDR3
VFYGEPYFPY(SEQ ID NO:72)
>81B4vH52_83 H-CDR3
VFYGEPYFPY(SEQ ID NO:72)
>73C5vH46_4 H-CDR3
KGGYSGSWFAY(SEQ ID NO:73)
>73C5vH46_19 H-CDR3
KGGYSGSWFAY(SEQ ID NO:73)
>73C5vH46_40 H-CDR3
KGGYSGSWFAY(SEQ ID NO:73)
>73C5vH47_65 H-CDR3
KGGYSGSWFAY(SEQ ID NO:73)
>73C5vH47_77 H-CDR3
KGGYSGSWFAY(SEQ ID NO:73)
>73C5vH58_91 H-CDR3
KGGYSGSWFAY(SEQ ID NO:73)
在一个方面，本发明的可变区与恒定区连接。例如，本发明的可变区与下面所示的恒定区连接，以形成抗体的重链或轻链。
连接在人源化重链可变区的下游的重链恒定区：
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:112)
连接在人源化轻链可变区的下游的轻链恒定区：
RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:113)
下面显示了本发明的代表性轻链和重链序列(与恒定区连接的衍生自抗体81B4和73C5的人源化可变区)。
轻链氨基酸序列
>81B4vK32_3轻链
EIVLTQSPGTLSLSPGERATMSCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSTLASGIPDRFSGSGSGTDFTLTISRLEPEDAATYYCHQFHRSPLTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQID NO:114)
>81B4vK32_105轻链
EIVLTQSPGTLSLSPGERATMSCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSILASGVPDRFSGSGSGTDFTLTISRLEPEDFATYYCHQFHRSPLTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQID NO:115)
>81B4vK32_116轻链
EIVLTQSPGTLSLSPGERATMSCTASSSVSSSYFHWYQQKPGQAPRLWIYRTSRLASGVPDRFSGSGSGTDFTLTISRLEPEDAATYYCHQFHRSPLTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQID NO:116)
>81B4vK32_127轻链
EIVLTQSPGTLSLSPGERATMTCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSRLASGVPDRFSGSGSGTDFTLTISRLEPEDFAVYYCHQFHRSPLTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQID NO:117)
>81B4vK32_138轻链
QIVLTQSPGTLSLSPGERATMTCTASSSVSSSYFHWYQQKPGQAPRLWIYRTSRLASGVPDRFSGSGSGTDFTLTISRLEPEDAATYYCHQFHRSPLTFGAGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQID NO:118)
>81B4vK32_140轻链
QIVLTQSPGTLSLSPGERVTMSCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSQLASGIPDRFSGSGSGTDFTLTISRLEPEDAATYYCHQFHRSPLTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQID NO:119)
>81B4vK32_141轻链
QIVLTQSPGTLSLSPGERATMTCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSKLASGVPDRFSGSGSGTDFTLTISRLEPEDFATYYCHQFHRSPLTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQID NO:120)
>81B4vK32_147轻链
EIVLTQSPGTLSLSPGERATMSCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSHLASGIPGRFSGSGSGTDFTLTISRLEPEDAAVYYCHQFHRSPLTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQID NO:121)
>73C5vK39_2轻链
EIVMTQSPATLSVSPGVRATLSCKASQDVGTNVLWYQQKPGQAPRPLIYSASYRHSGIPDRFSGSGSGTEFTLTISSLQSEDFAEYFCQQYSRYPLTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ IDNO:122)
>73C5vK39_7轻链
EIVMTQSPATLSVSPGVRATLSCKASQDVGTNVLWYQQKPGQAPRPLIYSASYRHSGIPDRFSGSGSGTEFTLTISSLQSEDFAVYYCQQYSRYPLTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ IDNO:123)
>73C5vK39_15轻链
EIVMTQSPATLSVSPGVRATLSCKASQDVGTNVLWYQQKPGQAPRPLIYSASYRHSGIPARFSGSGSGTEFTLTISSLQSEDFAEYYCQQYSRYPLTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ IDNO:124)
重链氨基酸序列
>81B4vH33_49重链
QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQAPGQGLEWIGEINPGNVRTNYNENFRNKATMTVDTSISTAYMELSRLRSDDTAVYYCAVVFYGEPYFPYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:125)
>81B4vH33_85T重链
QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQRPGQGLEWIGEINPGNVRTNYNENFRNRVTMTVDTSISTAYMELSRLRSDDTAVYYCTVVFYGEPYFPYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:126)
>81B4vH33_90重链
QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVKQAPGQGLEWMGEINPGNVRTNYNENFRNKVTMTVDTSISTAYMELSRLRSDDTAVYYCTVVFYGEPYFPYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:127)
>81B4vH33_93重链
QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQRPGQGLEWMGEINPGNVRTNYNENFRNRATLTRDTSISTAYMELSRLRSDDTAVYYCAVVFYGEPYFPYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:128)
>81B4vH50_22重链
QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQRPGQGLEWMGEILPGVVRTNYNENFRNKVTMTVDTSISTAYMELSRLRSDDTAVYYCTVVFYGEPYFPYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:129)
>81B4vH50_30重链
QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQRPGQGLEWIGEINPGAVRTNYNENFRNRVTMTVDTSISTAYMELSRLRSDDTAVYYCTVVFYGEPYFPYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:130)
>81B4vH51_13重链
QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQAPGQGLEWIGEINPGLVRTNYNENFRNKVTMTVDTSISTAYMELSRLRSDDTAVYYCAVVFYGEPYFPYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:131)
>81B4vH51_15重链
QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQAPGQGLEWIGEINPGAVRTNYNENFRNKVTMTVDTSISTAYMELSRLRSDDTAVYYCAVVFYGEPYFPYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:132)
>81B4vH52_83重链
QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQAPGQGLEWIGEINPGSVRTNYNENFRNKATMTVDTSISTAYMELSRLRSDDTAVYYCAVVFYGEPYFPYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:133)
>73C5vH46_4重链
QVQLQESGPGLVKPSETLSITCTVSGFSLTDYAVHWIRQPPGKGLEWIGVIWSDGSTDYNAPFKSRVTINKDTSKSQVSFKMSSVQAADTAVYYCARKGGYSGSWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:134)
>73C5vH46_19重链
QVQLQESGPGLVKPSETLSITCTVSGFSLTDYAVHWIRQPPGKGLEWIGVIWSDGSTDYNAPFKSRVTISKDTSKNQVSLKMNSLTTDDTAVYYCARKGGYSGSWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:135)
>73C5vH46_40重链
QVQLQESGPGLVKPSETLSITCTVSGFSLTDYAVHWIRQPPGKGLEWIGVIWSDGSTDYNAPFKSRVTISKDNSKSQVSLKMNSVTVADTAVYYCARKGGYSGSWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:136)
>73C5vH47_65重链
QVQLQESGPGLVKPSETLSITCTVSGFSLTDYAVHWVRQPPGKGLEWIGVIWSDGSTDYNAPFKSRVTISKDTSKNQVSFKLSSVTVDDTAVYYCARKGGYSGSWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:137)
>73C5vH47_77重链
QVQLQESGPGLVAPSETLSLTCTVSGFSLTDYAVHWIRQFPGKGLEWIGVIWSDGSTDFNAPFKSRVTISKDTSKNQVSFKLSSVTTDDTAVYYCARKGGYSGSWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:138)
>73C5vH58_91重链
QVQLQESGPGLVKPSETLSITCTVSGFSLTDYAVHWIRQPPGKGLEWIGVIWSDGSTDYNAPFKSRVTISKDNSKSQVSFKMSSVTADDTAVYYCARKGGYSGSWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:139)
使用Chothia编号系统(Al-Lazikani等人，(1997)JMB 273,927-948)定义上面列出的CDR。
在一个方面，本发明抗体包含例如如上所述的3个轻链CDR和3个重链CDR。
在一个方面，本发明抗体包含如上所述的轻链和重链可变区。在一个方面，本发明的轻链可变区与轻链恒定区例如κ或λ恒定区融合。在一个方面，本发明的重链可变区与重链恒定区融合，例如IgA、IgD、IgE、IgG或IgM，特别是IgG1、IgG2、IgG3或IgG4。
本发明提供了包括包含氨基酸序列SEQ ID NO:115的轻链和包含氨基酸序列SEQID NO:125的重链的抗IL-36R抗体(抗体B1)。
本发明提供了包括包含氨基酸序列SEQ ID NO:115的轻链和包含氨基酸序列SEQID NO:126的重链的抗IL-36R抗体(抗体B2)。
本发明提供了包括包含氨基酸序列SEQ ID NO:115的轻链和包含氨基酸序列SEQID NO:127的重链的抗IL-36R抗体(抗体B3)。
本发明提供了包括包含氨基酸序列SEQ ID NO:118的轻链和包含氨基酸序列SEQID NO:125的重链的抗IL-36R抗体(抗体B4)。
本发明提供了包括包含氨基酸序列SEQ ID NO:118的轻链和包含氨基酸序列SEQID NO:126的重链的抗IL-36R抗体(抗体B5)。
本发明提供了包括包含氨基酸序列SEQ ID NO:118的轻链和包含氨基酸序列SEQID NO:127的重链的抗IL-36R抗体(抗体B6)。
本发明提供了包括包含氨基酸序列SEQ ID NO:123的轻链和包含氨基酸序列SEQID NO:138的重链的抗IL-36R抗体(抗体C3)。
本发明提供了包括包含氨基酸序列SEQ ID NO:123的轻链和包含氨基酸序列SEQID NO:139的重链的抗IL-36R抗体(抗体C2)。
本发明提供了包括包含氨基酸序列SEQ ID NO:124的轻链和包含氨基酸序列SEQID NO:138的重链的抗IL-36R抗体(抗体C1)。
本发明的代表性抗体如下所示。
表A
表B
本发明抗体用于治疗各种疾病或疾患例如人类的免疫、炎症、自身免疫性疾病和呼吸系统疾病的方法中。例如，本发明抗体用于治疗银屑病、类风湿性关节炎、炎性肠病或银屑病关节炎的方法中。例如，本发明抗体用于治疗慢性阻塞性肺病(COPD)或哮喘的方法中。例如，本发明抗体用于治疗硬皮病、掌跖脓疱病、泛发性脓疱型银屑病、糖尿病肾病、狼疮性肾炎、硬皮病、强直性脊柱炎、IL-36受体拮抗剂缺乏性自身免疫性疾病(DITRA)、IL-1受体拮抗剂缺乏性自身免疫性疾病(DIRA)或冷吡啉(cryopyrin)相关周期性综合征(CAPS)的方法中。
在一些方面，人源化抗体显示出阻断活性，由此其将IL-36配体与IL-36受体的结合降低至少45％、至少50％、至少55％、至少60％、至少65％、至少70％、至少75％、至少80％、至少85％、至少90％或至少95％。可以使用本领域已知的竞争性结合测定来测量抗体阻断IL-36配体与IL-36受体结合的能力。或者，通过评估IL-36的生物效应(例如IL-8、IL-6和GM-CSF的产生)以确定IL-36受体介导的信号传导是否被抑制，可以测量抗体的阻断活性。
在一个另外的方面，本发明提供了具有有利的生物物理特性的人源化抗IL-36R抗体。在一个方面，本发明的人源化抗IL-36R抗体以至少90％单体形式、或以至少92％单体形式、或以至少95％单体形式存在于缓冲液中。在一个另外的方面，本发明的人源化抗IL-36R抗体以至少90％单体形式、或以至少92％单体形式、或以至少95％单体形式在缓冲液中保持一个月或四个月。
在一个方面，本发明的人源化抗体是抗体B1、抗体B2、抗体B3、抗体B4、抗体B5、抗体B6、抗体C1、抗体C2或抗体C3。因此，在一个实施方案中，本发明的人源化抗体包含轻链序列SEQ ID NO:115和重链序列SEQ ID NO:125(抗体B1)。在另一个实施方案中，本发明的人源化抗体包含轻链序列SEQ ID NO:115和重链序列SEQ ID NO:126(抗体B2)。在另一个实施方案中，本发明的人源化抗体包含轻链序列SEQ ID NO:115和重链序列SEQ ID NO:127(抗体B3)。在另一个实施方案中，本发明的人源化抗体包含轻链序列SEQ ID NO:118和重链序列SEQ ID NO:125(抗体B4)。在另一个实施方案中，本发明的人源化抗体包含轻链序列SEQID NO:118和重链序列SEQ ID NO:126(抗体B5)。在另一个实施方案中，本发明的人源化抗体包含轻链序列SEQ ID NO:118和重链序列SEQ ID NO:127(抗体B6)。在另一个实施方案中，本发明的人源化抗体包含轻链序列SEQ ID NO:124和重链序列SEQ ID NO:138(抗体C1)。在另一个实施方案中，本发明的人源化抗体包含轻链序列SEQ ID NO:123和重链序列SEQ ID NO:139(抗体C2)。在另一个实施方案中，本发明的人源化抗体包含轻链序列SEQ IDNO:123和重链序列SEQ ID NO:138(抗体C3)。
在一个另外的实施方案中，本发明的人源化抗体由轻链序列SEQ ID NO:115和重链序列SEQ ID NO:125组成(抗体B1)。在另一个实施方案中，本发明的人源化抗体由轻链序列SEQ ID NO:115和重链序列SEQ ID NO:126组成(抗体B2)。在另一个实施方案中，本发明的人源化抗体由轻链序列SEQ ID NO:115和重链序列SEQ ID NO:127组成(抗体B3)。在另一个实施方案中，本发明的人源化抗体由轻链序列SEQ ID NO:118和重链序列SEQ ID NO:125组成(抗体B4)。在另一个实施方案中，本发明的人源化抗体由轻链序列SEQ ID NO:118和重链序列SEQ ID NO:126组成(抗体B5)。在另一个实施方案中，本发明的人源化抗体由轻链序列SEQ ID NO:118和重链序列SEQ ID NO:127组成(抗体B6)。在另一个实施方案中，本发明的人源化抗体由轻链序列SEQ ID NO:124和重链序列SEQ ID NO:138组成(抗体C1)。在另一个实施方案中，本发明的人源化抗体由轻链序列SEQ ID NO:123和重链序列SEQ ID NO:139组成(抗体C2)。在另一个实施方案中，本发明的人源化抗体由轻链序列SEQ ID NO:123和重链序列SEQ ID NO:138组成(抗体C3)。
在一些实施方案中，人源化抗IL-36R抗体(包括其抗原结合片段，比如重链和轻链可变区)包含衍生自抗体B1、抗体B2、抗体B3、抗体B4、抗体B5、抗体B6、抗体C1、抗体C2或抗体C3的残基的氨基酸序列。
在一个另外的实施方案中，本发明提供了与本发明抗体例如本文所述的抗体B1、抗体B2、抗体B3、抗体B4、抗体B5、抗体B6、抗体C1、抗体C2或抗体C3竞争性结合人IL-36R的抗IL-36R抗体或其抗原结合片段。可以使用本领域已知的竞争性结合测定来测量抗体或抗原结合片段竞争性结合IL-36R的能力。
人源化抗IL-36R抗体任选地包含在共有或种系框架区中的特定氨基酸取代。相比于通过将CDR或HVL“直接交换”到人种系框架区中形成的人源化抗体所显示的抗体性能，在这些框架位置中的氨基酸残基的特定取代可以改善抗体性能的各个方面，包括结合亲和力和/或稳定性。
在一些实施方案中，本发明描述了具有轻链可变区的其他单克隆抗体，所述轻链可变区具有在SEQ ID NO:1-10的任一者中列出的氨基酸序列。在一些实施方案中，本发明描述了具有重链可变区的其他单克隆抗体，所述重链可变区具有在SEQ ID NO:11-20的任一者中列出的氨基酸序列。将这样的CDR置于人共有重链和轻链可变结构域的FR中将产生有用的本发明的人源化抗体。
具体而言，本发明提供了具有SEQ ID NO:1/11、2/12、3/13、4/14、5/15、6/16、7/17、8/18、9/19、10/20的轻链可变区和重链可变区的组合的单克隆抗体。这样的可变区可以与人恒定区组合。
在一些实施方案中，本发明描述了具有轻链可变区序列的其他人源化抗体，所述轻链可变区序列具有在SEQ ID NO:76-86的任一者中列出的氨基酸序列。在一些实施方案中，本发明描述了具有重链可变区序列的其他人源化抗体，所述重链可变区序列具有在SEQID NO:87-101的任一者中列出的氨基酸序列。具体而言，本发明提供了具有SEQ ID NO:77/89、80/88、80/89、77/87、77/88、80/87、86/100、85/101、85/101、85/100的轻链可变区和重链可变区的组合的单克隆抗体。这样的可变区可以与人恒定区组合。
在一个另外的实施方案中，本发明涉及包含人源化轻链可变结构域和人源化重链可变结构域的抗IL-36R抗体或其抗原结合片段，所述人源化轻链可变结构域包含具有SEQID NO:77的CDR和框架区，所述框架区具有与可变结构域轻链氨基酸序列SEQ ID NO:77的框架区氨基酸序列至少90％相同、至少93％相同或至少95％相同的氨基酸序列，所述人源化重链可变结构域包含具有SEQ ID NO:89的CDR和框架区，所述框架区具有与可变结构域重链氨基酸序列SEQ ID NO:89的框架区氨基酸序列至少90％相同、至少93％相同或至少95％相同的氨基酸序列。在一个实施方案中，抗IL-36R抗体是人源化单克隆抗体。
在一个另外的实施方案中，本发明涉及包含人源化轻链可变结构域和人源化重链可变结构域的抗IL-36R抗体或其抗原结合片段，所述人源化轻链可变结构域包含具有SEQID NO:80的CDR和框架区，所述框架区具有与可变结构域轻链氨基酸序列SEQ ID NO:80的框架区氨基酸序列至少90％相同、至少93％相同或至少95％相同的氨基酸序列，所述人源化重链可变结构域包含具有SEQ ID NO:88的CDR和框架区，所述框架区具有与可变结构域重链氨基酸序列SEQ ID NO:88的框架区氨基酸序列至少90％相同、至少93％相同或至少95％相同的氨基酸序列。在一个实施方案中，抗IL-36R抗体是人源化单克隆抗体。
在一个另外的实施方案中，本发明涉及包含人源化轻链可变结构域和人源化重链可变结构域的抗IL-36R抗体或其抗原结合片段，所述人源化轻链可变结构域包含具有SEQID NO:80的CDR和框架区，所述框架区具有与可变结构域轻链氨基酸序列SEQ ID NO:80的框架区氨基酸序列至少90％相同、至少93％相同或至少95％相同的氨基酸序列，所述人源化重链可变结构域包含具有SEQ ID NO:89的CDR和框架区，所述框架区具有与可变结构域重链氨基酸序列SEQ ID NO:89的框架区氨基酸序列至少90％相同、至少93％相同或至少95％相同的氨基酸序列。在一个实施方案中，抗IL-36R抗体是人源化单克隆抗体。
在一个另外的实施方案中，本发明涉及包含人源化轻链可变结构域和人源化重链可变结构域的抗IL-36R抗体或其抗原结合片段，所述人源化轻链可变结构域包含具有SEQID NO:77的CDR和框架区，所述框架区具有与可变结构域轻链氨基酸序列SEQ ID NO:77的框架区氨基酸序列至少90％相同、至少93％相同或至少95％相同的氨基酸序列，所述人源化重链可变结构域包含具有SEQ ID NO:87的CDR和框架区，所述框架区具有与可变结构域重链氨基酸序列SEQ ID NO:87的框架区氨基酸序列至少90％相同、至少93％相同或至少95％相同的氨基酸序列。在一个实施方案中，抗IL-36R抗体是人源化单克隆抗体。
在一个另外的实施方案中，本发明涉及包含人源化轻链可变结构域和人源化重链可变结构域的抗IL-36R抗体或其抗原结合片段，所述人源化轻链可变结构域包含具有SEQID NO:77的CDR和框架区，所述框架区具有与可变结构域轻链氨基酸序列SEQ ID NO:77的框架区氨基酸序列至少90％相同、至少93％相同或至少95％相同的氨基酸序列，所述人源化重链可变结构域包含具有SEQ ID NO:88的CDR和框架区，所述框架区具有与可变结构域重链氨基酸序列SEQ ID NO:88的框架区氨基酸序列至少90％相同、至少93％相同或至少95％相同的氨基酸序列。在一个实施方案中，抗IL-36R抗体是人源化单克隆抗体。
在一个另外的实施方案中，本发明涉及包含人源化轻链可变结构域和人源化重链可变结构域的抗IL-36R抗体或其抗原结合片段，所述人源化轻链可变结构域包含具有SEQID NO:80的CDR和框架区，所述框架区具有与可变结构域轻链氨基酸序列SEQ ID NO:80的框架区氨基酸序列至少90％相同、至少93％相同或至少95％相同的氨基酸序列，所述人源化重链可变结构域包含具有SEQ ID NO:87的CDR和框架区，所述框架区具有与可变结构域重链氨基酸序列SEQ ID NO:87的框架区氨基酸序列至少90％相同、至少93％相同或至少95％相同的氨基酸序列。在一个实施方案中，抗IL-36R抗体是人源化单克隆抗体。
在一个另外的实施方案中，本发明涉及包含人源化轻链可变结构域和人源化重链可变结构域的抗IL-36R抗体或其抗原结合片段，所述人源化轻链可变结构域包含具有SEQID NO:86的CDR和框架区，所述框架区具有与可变结构域轻链氨基酸序列SEQ ID NO:86的框架区氨基酸序列至少90％相同、至少93％相同或至少95％相同的氨基酸序列，所述人源化重链可变结构域包含具有SEQ ID NO:100的CDR和框架区，所述框架区具有与可变结构域重链氨基酸序列SEQ ID NO:100的框架区氨基酸序列至少90％相同、至少93％相同或至少95％相同的氨基酸序列。在一个实施方案中，抗IL-36R抗体是人源化单克隆抗体。
在一个另外的实施方案中，本发明涉及包含人源化轻链可变结构域和人源化重链可变结构域的抗IL-36R抗体或其抗原结合片段，所述人源化轻链可变结构域包含具有SEQID NO:85的CDR和框架区，所述框架区具有与可变结构域轻链氨基酸序列SEQ ID NO:85的框架区氨基酸序列至少90％相同、至少93％相同或至少95％相同的氨基酸序列，所述人源化重链可变结构域包含具有SEQ ID NO:101的CDR和框架区，所述框架区具有与可变结构域重链氨基酸序列SEQ ID NO:101的框架区氨基酸序列至少90％相同、至少93％相同或至少95％相同的氨基酸序列。在一个实施方案中，抗IL-36R抗体是人源化单克隆抗体。
在一个另外的实施方案中，本发明涉及包含人源化轻链可变结构域和人源化重链可变结构域的抗IL-36R抗体或其抗原结合片段，所述人源化轻链可变结构域包含具有SEQID NO:85的CDR和框架区，所述框架区具有与可变结构域轻链氨基酸序列SEQ ID NO:85的框架区氨基酸序列至少90％相同、至少93％相同或至少95％相同的氨基酸序列，所述人源化重链可变结构域包含具有SEQ ID NO:100的CDR和框架区，所述框架区具有与可变结构域重链氨基酸序列SEQ ID NO:100的框架区氨基酸序列至少90％相同、至少93％相同或至少95％相同的氨基酸序列。在一个实施方案中，抗IL-36R抗体是人源化单克隆抗体。
在一些具体的实施方案中，本文中公开的人源化抗IL-36R抗体包含至少一个重链或轻链可变结构域，所述重链或轻链可变结构域包含本文中公开的鼠单克隆抗体或人源化抗体的CDR或HVL以及人种系重链和轻链可变结构域的FR。
在一个另外的方面，本发明提供了抗IL-36R抗体或其抗原结合片段，其包含SEQID NO:21-29中任一者的轻链CDR1(L-CDR1)序列；SEQ ID NO:30-38中任一者的轻链CDR2(L-CDR2)序列；SEQ ID NO:39-47中任一者的轻链CDR3(L-CDR3)序列；SEQ ID NO:48-56中任一者的重链CDR1(H-CDR1)序列；SEQ ID NO:57-66中任一者的重链CDR2(H-CDR2)序列；和SEQ ID NO:67-75中任一者的重链CDR3(H-CDR3)序列。在一个方面，抗IL-36R抗体或其抗原结合片段包含轻链可变区和重链可变区，所述轻链可变区包含上文列出的L-CDR1、上文列出的L-CDR2和上文列出的L-CDR3，所述重链可变区包含上文列出的H-CDR1、上文列出的H-CDR2和上文列出的H-CDR3。
在一个另外的方面，本发明提供了抗IL-36R抗体或其抗原结合片段，其包含：
a)分别为SEQ ID NO:21、30、39、48、57和67的L-CDR1、L-CDR2、L-CDR3、H-CDR1、H-CDR2和H-CDR3序列；或
b)分别为SEQ ID NO:22、31、40、49、58和68的L-CDR1、L-CDR2、L-CDR3、H-CDR1、H-CDR2和H-CDR3序列；或
c)分别为SEQ ID NO:23、32、41、50、59和69的L-CDR1、L-CDR2、L-CDR3、H-CDR1、H-CDR2和H-CDR3序列；或
d)分别为SEQ ID NO:24、33、42、51、60和70的L-CDR1、L-CDR2、L-CDR3、H-CDR1、H-CDR2和H-CDR3序列；或
e)分别为SEQ ID NO:25、34、43、52、61和71的L-CDR1、L-CDR2、L-CDR3、H-CDR1、H-CDR2和H-CDR3序列；或
f)分别为SEQ ID NO:26、35、44、53、62和72的L-CDR1、L-CDR2、L-CDR3、H-CDR1、H-CDR2和H-CDR3序列；或
g)分别为SEQ ID NO:27、36、45、54、63和73的L-CDR1、L-CDR2、L-CDR3、H-CDR1、H-CDR2和H-CDR3序列；或
h)分别为SEQ ID NO:27、36、45、54、64和74的L-CDR1、L-CDR2、L-CDR3、H-CDR1、H-CDR2和H-CDR3序列；或
i)分别为SEQ ID NO:27、36、45、54、64和73的L-CDR1、L-CDR2、L-CDR3、H-CDR1、H-CDR2和H-CDR3序列；或
j)分别为SEQ ID NO:28、37、46、55、65和74的L-CDR1、L-CDR2、L-CDR3、H-CDR1、H-CDR2和H-CDR3序列；或
k)分别为SEQ ID NO:29、38、47、56、66和75的L-CDR1、L-CDR2、L-CDR3、H-CDR1、H-CDR2和H-CDR3序列。
在一个另外的方面，本发明提供了抗IL-36R抗体或其抗原结合片段，其包含：
a)分别为SEQ ID NO:26、103、44、53、62和72的L-CDR1、L-CDR2、L-CDR3、H-CDR1、H-CDR2和H-CDR3序列；或
b)分别为SEQ ID NO:26、104、44、53、62和72的L-CDR1、L-CDR2、L-CDR3、H-CDR1、H-CDR2和H-CDR3序列；或
c)分别为SEQ ID NO:27、36、45、107、63和73的L-CDR1、L-CDR2、L-CDR3、H-CDR1、H-CDR2和H-CDR3序列；或
d)分别为SEQ ID NO:27、36、45、107、64和73的L-CDR1、L-CDR2、L-CDR3、H-CDR1、H-CDR2和H-CDR3序列。
在一个方面，抗IL-36R抗体或其抗原结合片段包含轻链可变区和重链可变区，所述轻链可变区包含上文列出的L-CDR1、L-CDR2和L-CDR3组合，所述重链可变区包含上文列出的H-CDR1、H-CDR2和H-CDR3组合。
在具体的实施方案中，预期在这些示例性免疫球蛋白之间具有转换的CDR区(即，例如小鼠抗体或由其衍生的人源化抗体之一的一个或两个CDR与来自另一种小鼠抗体或由其衍生的人源化抗体的类似CDR转换)的嵌合抗体可以产生有用的抗体。
在某些实施方案中，人源化抗IL-36R抗体是抗体片段。上文一般性地讨论了各种抗体片段，并且存在已经开发用于产生抗体片段的技术。可以通过完整抗体的蛋白水解消化来衍生片段(参见，例如，Morimoto等人，1992,Journal of Biochemical andBiophysical Methods 24:107-117；和Brennan等人，1985,Science 229:81)。或者，可以在重组宿主细胞中直接产生片段。例如，可以直接从大肠杆菌中回收Fab'-SH片段并进行化学偶联以形成F(ab')2片段(参见，例如，Carter等人，1992,Bio/Technology 10:163-167)。通过另一种方法，可以直接从重组宿主细胞培养物中分离F(ab')2片段。用于产生抗体片段的其他技术对于技术人员来说将是显而易见的。因此，在一个方面，本发明提供了包含本文所述的CDR，特别是本文所述的L-CDR1、L-CDR2、L-CDR3、H-CDR1、H-CDR2和H-CDR3的组合之一的抗体片段。在一个另外的方面，本发明提供了包含本文所述的可变区，例如本文所述的轻链可变区和重链可变区的组合之一的抗体片段。
某些实施方案包括人源化抗IL-36R抗体的F(ab')2片段，其包含轻链序列SEQ IDNO:115或118中的任一者与重链序列SEQ ID NO:125、126或127的组合。这样的实施方案可包括包含这样的F(ab')2的完整抗体。
某些实施方案包括人源化抗IL-36R抗体的F(ab')2片段，其包含轻链序列SEQ IDNO:123或124中的任一者与重链序列SEQ ID NO:138或139的组合。这样的实施方案可包括包含这样的F(ab')2的完整抗体。
在一些实施方案中，抗体或抗体片段包括介导效应子功能的恒定区。恒定区可以提供针对表达IL-36R的靶细胞的抗体依赖性细胞介导的细胞毒性(ADCC)、抗体依赖性细胞吞噬作用(ADCP)和/或补体依赖性细胞毒性(CDC)应答。效应子结构域可以是例如Ig分子的Fc区。
抗体的效应子结构域可以来自任何适合的脊椎动物物种和同种型。来自不同动物物种的同种型介导效应子功能的能力不同。例如，人免疫球蛋白介导CDC和ADCC/ADCP的能力通常分别排序为IgM≈IgG1≈IgG3>IgG2>IgG4和IgG1≈IgG3>IgG2/IgM/IgG4。鼠免疫球蛋白通常分别以鼠IgM≈IgG3>>IgG2b>IgG2a>>IgG1和IgG2b>IgG2a>IgG1>>IgG3的顺序介导CDC和ADCC/ADCP。在另一个实例中，鼠IgG2a介导ADCC，而鼠IgG2a和IgM两者都介导CDC。
抗体修饰
人源化抗IL-36R抗体和药剂可包括人源化抗IL-36R抗体或其抗原结合片段的修饰。例如，可能希望在效应子功能方面修饰抗体，以增强抗体治疗癌症的有效性。一种这样的修饰是将半胱氨酸残基引入到Fc区中，从而允许在该区域中形成链间二硫键。由此生成的同二聚体抗体可具有改善的内化能力和/或增加的补体介导的细胞杀伤和/或抗体依赖性细胞介导的细胞毒性(ADCC)。参见，例如，Caron等人，J.Exp Med.176:1191-1195；和Shopes,1992,J.Immunol.148:2918-2922。也可以使用异双功能交联剂制备具有增强的抗肿瘤活性的同二聚体抗体，如Wolff等人，1993,Cancer Research 53:2560-2565中所述。或者，可以将抗体工程化为含有双Fc区，从而增强抗体的补体裂解和ADCC能力。参见Stevenson等人，1989,Anti-Cancer Drug Design 3:219-230。
已经通过修饰其Fc区的糖基化模式生成了具有提高的支持ADCC的能力的抗体。这是可能的，因为在CH2结构域中天冬酰胺残基N297处的抗体糖基化参与IgG和Fcγ受体之间的相互作用，所述相互作用是ADCC的先决条件。已经工程改造宿主细胞系以表达具有改变的糖基化(比如增加的二等分N-乙酰葡糖胺或减少的岩藻糖)的抗体。与增加二等分N-乙酰葡糖胺的存在相比，岩藻糖减少提供了更大的ADCC活性增强。而且，低岩藻糖抗体对ADCC的增强与FcγRIIIa V/F多态性无关。
修饰抗体Fc区的氨基酸序列是用于增强ADCC的糖基化工程的替代方案。已经通过广泛突变分析确定了人IgG1上的Fcγ受体结合位点。这导致具有Fc突变的人源化IgG1抗体的生成，所述Fc突变增加对FcγRIIIa的结合亲和力并在体外增强ADCC。另外，已经获得具有结合特性的许多不同排列的Fc变体，例如，与特异性FcγR受体的结合改善，与其他FcγR受体的结合不变或减少。
另一方面包括免疫缀合物，其包含与细胞毒性剂比如化学治疗剂、毒素(例如细菌、真菌、植物或动物来源的酶活性毒素或其片段)或放射性同位素(即放射性共轭物)缀合的人源化抗体或其片段。
上文已经描述了用于生成这样的免疫缀合物的化学治疗剂。可用于形成有用的免疫缀合物的酶活性毒素及其片段包括白喉A链、白喉毒素的非结合活性片段、外毒素A链(来自铜绿假单胞菌)、蓖麻毒蛋白A链、相思豆毒蛋白A链、蒴莲根毒蛋白A链、α-帚曲菌素、油桐蛋白、石竹素蛋白、美洲商陆蛋白(PAPI、PAPII和PAP-S)、苦瓜抑制剂、麻疯树毒蛋白、巴豆毒素、肥皂草抑制剂、白树毒素、米托菌素、局限曲菌素、酚霉素、伊诺霉素、单端孢霉烯类毒素，等。多种放射性核素可用于产生放射性缀合的人源化抗IL-36R抗体。实例包括212Bi、131I、131In、90Y和186Re。
可以通过已知的方法使用多种双功能蛋白质偶联剂制造人源化抗IL-36R抗体和细胞毒性剂或化学治疗剂的缀合物，所述双功能蛋白质偶联剂比如N-琥珀酰亚胺-3-(2-吡啶二硫代)丙酸酯(SPDP)、亚胺酯的双功能衍生物(比如二亚胺代己二酸二甲酯盐酸盐)、活性酯(比如辛二酸二琥珀酰亚胺酯)、醛(如戊二醛)、双叠氮基化合物(比如双(对叠氮基苯甲酰基)己二胺)、双重氮衍生物(比如双(对重氮苯甲酰基)-乙二胺)、二异氰酸酯(比如甲苯2,6-二异氰酸酯)和双活性氟化合物(比如1,5-二氟-2,4-二硝基苯)。例如，可以如Vitetta等人，1987,Science 238:1098中所述制备蓖麻毒蛋白免疫毒素。碳-14标记的1-异硫氰基苄基-3-甲基二亚乙基三胺五乙酸(MX-DTPA)是用于将放射性核素与抗体缀合的示例性螯合剂。也可以用可切割接头形成缀合物。
也可以将本文中公开的人源化抗IL-36R抗体配制成免疫脂质体。通过本领域已知的方法制备含有抗体的脂质体，例如描述于Epstein等人，1985,Proc.Natl.Acad.Sci.USA82:3688；Hwang等人，1980,Proc.Natl.Acad.Sci.USA77:4030；和美国专利No.4,485,045和4,544,545。具有延长的循环时间的脂质体公开于例如美国专利No.5,013,556。
可以利用包含磷脂酰胆碱、胆固醇和PEG衍生的磷脂酰乙醇胺(PEG-PE)的脂质组合物通过反相蒸发法生成特别有用的脂质体。通过具有确定孔径的过滤器挤出脂质体，以产生具有期望直径的脂质体。如Martin等人，1982,J.Biol.Chem.257:286-288中所述，本文中公开的抗体的Fab'片段可经由二硫化物互换反应与脂质体缀合。脂质体内任选地包含化学治疗剂(例如多柔比星)。参见，例如，Gabizon等人，1989,J.National Cancer Inst.81(19):1484。
通过将抗体与将前药(例如肽基化学治疗剂)转化为活性抗癌药物的前药活化酶缀合，本文中描述和公开的抗体还可以用于ADEPT(抗体导向酶前药疗法)程序。参见，例如WO 81/01145、WO 88/07378和美国专利No.4,975,278。可用于ADEPT的免疫缀合物的酶组分是能够以这样的方式作用于前药的酶，所述方式以便将所述前药转化为其更有活性的细胞毒性形式。在ADEPT中有用的特异性酶包括但不限于：用于将含磷酸盐的前药转化成游离药物的碱性磷酸酶；用于将含硫酸盐的前药转化成游离药物的芳基硫酸酯酶；用于将无毒的5-氟胞嘧啶转化成抗癌药物5-氟尿嘧啶的胞嘧啶脱氨酶；用于将含肽的前药转化成游离药物的蛋白酶，比如沙雷菌蛋白酶、嗜热菌蛋白酶、枯草杆菌蛋白酶、羧肽酶和组织蛋白酶(例如组织蛋白酶B和L)；用于转化含有D-氨基酸取代基的前药的D-丙氨酰羧肽酶；用于将糖基化前药转化成游离药物的碳水化合物切割酶，比如β-半乳糖苷酶和神经氨酸酶；用于将经β-内酰胺衍生化的药物转化成游离药物的β-内酰胺酶；和青霉素酰胺酶，比如青霉素V酰胺酶或青霉素G酰胺酶，用于将在其胺氮处分别经苯氧基乙酰基或苯基乙酰基衍生化的药物转化成游离药物。或者，可以使用具有酶活性的抗体(“抗体酶”)将前药转化成游离活性药物(参见，例如，Massey,1987,Nature 328:457-458)。可以通过已知的方法制备抗体-抗体酶缀合物，以便将抗体酶递送至肿瘤细胞群，例如，通过将酶与上文论述的人源化抗IL-36R抗体/异双功能交联试剂共价结合。或者，可以使用重组DNA技术构建至少包含本文中公开的抗体的抗原结合区的融合蛋白，所述抗原结合区至少与如上所述的酶的功能活性部分连接(参见，例如，Neuberger等人，1984,Nature 312:604-608)。
在某些实施方案中，例如，可能希望使用人源化抗IL-36R抗体片段而不是完整抗体来增加组织穿透。可能希望修饰抗体片段以增加其血清半衰期。这可以例如通过将补救受体结合表位掺入到抗体片段中来实现。在一种方法中，例如通过DNA或肽合成，可以改变(例如，突变)抗体片段的适当区域，或者可以将表位掺入到肽标签中，然后所述肽标签在抗体片段的任一端或中间与其融合。参见，例如WO 96/32478。
在其他实施方案中，还包括人源化抗IL-36R抗体的共价修饰。共价修饰包括半胱氨酰残基、组氨酰残基、赖氨酰和氨基末端残基、精氨酰残基、酪氨酰残基、羧基侧基(天冬氨酰基或谷氨酰基)、谷氨酰胺酰基和天冬酰胺酰基残基、或丝氨酰基或苏氨酰残基的修饰。另一种类型的共价修饰涉及将糖苷与抗体化学偶联或酶促偶联。如果适用，可以通过抗体的化学合成或通过酶促或化学切割来进行这样的修饰。通过使抗体的靶向氨基酸残基与能够与选择的侧链或氨基或羧基末端残基反应的有机衍生剂反应，可以将抗体的其他类型的共价修饰引入到该抗体分子中。
可以通过化学或酶促方式完成存在于抗体上的任何碳水化合物模块的去除。Hakimuddin等人，1987,Arch.Biochem.Biophys.259:52和Edge等人1981,Anal.Biochem.,118:131描述了化学去糖基化。可以通过使用多种内切和外切糖苷酶来实现抗体上的碳水化合物模块的酶促切割，如Thotakura等人，1987,Meth.Enzymol 138:350所述。
另一种类型的有用的共价修饰包括以美国专利No.4,640,835、美国专利No.4,496,689、美国专利No.4,301,144、美国专利No.4,670,417、美国专利No.4,791,192和美国专利No.4,179,337的一者或多者中阐述的方式将抗体与多种非蛋白质聚合物(例如聚乙二醇、聚丙二醇或聚氧化烯)之一连接。
人源化和氨基酸序列变体
可通过将适当的核苷酸变化引入到抗IL-36R抗体DNA中或通过肽合成来制备抗IL-36R抗体的氨基酸序列变体。这样的变体包括，例如，本文实施例的抗IL-36R抗体的氨基酸序列内的残基的缺失和/或插入和/或取代。进行缺失、插入和取代的任何组合以得到最终构建体，条件是最终构建体具有期望的特征。氨基酸变化还可以改变人源化或变体抗IL-36R抗体的翻译后过程，比如改变糖基化位点的数目或位置。
用于鉴定作为优选的诱变位置的抗IL-36R抗体的某些残基或区域的有用方法被称为“丙氨酸扫描诱变”，如Cunningham和Wells(Science,244:1081-1085(1989))所述。在此，鉴定了残基或一组靶残基(例如，带电荷的残基，比如arg、asp、his、lys和glu)，并用中性或带负电荷的氨基酸(通常为丙氨酸)替换，以影响氨基酸与IL-36R抗原的相互作用。然后通过在取代位点或针对取代位点引入另外的或其他的变体，将那些证明对取代具有功能敏感性的氨基酸位置精细化。因此，虽然预先确定了引入氨基酸序列变异的位点，但不需要预先确定突变本身的性质。例如，为了分析给定位点突变的性能，在靶密码子或区域进行丙氨酸扫描或随机诱变，并针对期望活性筛选表达的抗IL-36R抗体变体。
氨基酸序列插入包括长度范围从一个残基到含有一百个或更多个残基的多肽的氨基和/或羧基末端融合物，以及单个或多个氨基酸残基的序列内插入。末端插入的实例包括与表位标签融合的抗IL-36R抗体。抗IL-36R抗体分子的其他插入变体包括所述抗IL-36R抗体的N或C末端与酶或增加所述抗体的血清半衰期的多肽的融合物。
另一种类型的变体是氨基酸取代变体。这些变体为在抗IL-36R抗体分子中至少一个氨基酸残基被除去并且具有在其位置插入的不同残基。用于取代诱变的最感兴趣的位点包括高变区，但也考虑了FR改变。表5中以表头“优选取代”表示保守取代。如果这样的取代导致生物活性的变化，则可引入命名为“示例性取代”或如下文参考氨基酸类别进一步描述的更实质的变化，并筛选产物。
表C：
在蛋白质化学中，人们普遍接受的是，通过选择取代可以实现抗体的生物特性，所述取代在其维持下述项的作用方面显著不同：(a)在取代区中的多肽主链结构，例如作为片层或螺旋构象，(b)在靶位点的分子的电荷或疏水性，或(c)侧链的体积。根据常见的侧链性质，将天然存在的残基分为几组：
(1)疏水的：正亮氨酸、met、ala、val、leu、ile；
(2)中性亲水的：cys、ser、thr；
(3)酸性的：asp、glu；
(4)碱性的：asn、gin、his、lys、arg；
(5)影响链取向的残基：gly、pro；和
(6)芳香族的：trp、tyr、phe。
非保守取代需要将这些类之一的成员替换为另一类。
任何不参与维持人源化或变体抗IL-36R抗体的正确构象的半胱氨酸残基也可以被取代，通常用丝氨酸取代，以改善分子的氧化稳定性，防止异常交联，或提供确定的与细胞毒性或细胞生长抑制性化合物缀合的点。相反，可以将半胱氨酸键添加到抗体中以改善其稳定性(特别是当抗体是抗体片段比如Fv片段时)。
一种类型的取代变体涉及取代亲本抗体(例如，人源化或人抗体)的一个或多个高变区残基。通常，经选择用于进一步开发的所得变体相对于生成它们的亲本抗体具有改善的生物特性。用于生成这样的取代变体的便利方式是使用噬菌体展示的亲和力成熟。简言之，使几个高变区位点(例如，6-7个位点)突变，以在每个位点产生所有可能的氨基酸取代。由此产生的抗体变体以单价方式从丝状噬菌体颗粒展示为与每个颗粒内包装的M13的基因III产物的融合物。然后筛选噬菌体展示变体的生物活性(例如结合亲和力)。为了鉴定用于修饰的候选高变区位点，可以进行丙氨酸扫描诱变以鉴定对抗原结合有显著贡献的高变区残基。替代地，或另外地，分析抗原-抗体复合物的晶体结构可能是有益的，以便鉴定抗体和人IL-36R之间的接触点。根据本文中详细说明的技术，这样的接触残基和相邻残基是取代候选者。一旦生成这样的变体，就如本文所述对变体组进行筛选，并且可以选择在一种或多种相关测定法中具有优越特性的抗体用于进一步开发。
抗体的另一种类型的氨基酸变体改变了抗体的原始糖基化模式。“改变”表示使抗体中发现的一个或多个碳水化合物模块缺失，和/或添加抗体中不存在的一个或多个糖基化位点。
在一些实施方案中，可能希望修饰本发明抗体，以便添加糖基化位点。抗体的糖基化通常是N-连接的或O-连接的。N-连接是指碳水化合物模块与天冬酰胺残基侧链的附接。三肽序列天冬酰胺-X-丝氨酸和天冬酰胺-X-苏氨酸(其中X是除脯氨酸外的任何氨基酸)是用于碳水化合物模块与天冬酰胺侧链的酶附接的识别序列。因此，多肽中的这些三肽序列中任一个的存在产生了潜在的糖基化位点。O-连接的糖基化是指糖类N-乙酰半乳糖胺、半乳糖或木糖之一与羟基氨基酸的附接，所述羟基氨基酸最常见的是丝氨酸或苏氨酸，不过也可以使用5-羟脯氨酸或5-羟赖氨酸。因此，为了使给定蛋白质(例如抗体)糖基化，将蛋白质的氨基酸序列工程化为含有一种或多种上述三肽序列(对于N-连接的糖基化位点)。也可以通过针对原始抗体的序列的一个或多个丝氨酸或苏氨酸残基的添加、缺失或取代来进行改变(对于O-连接的糖基化位点)。
通过本领域已知的多种方法制备编码抗体的氨基酸序列变体的核酸分子。这些方法包括但不限于，从天然来源分离(在天然存在的氨基酸序列变体的情况下)或通过对早前制备的抗IL-36R抗体的变体或非变体版本进行寡核苷酸介导的(或定点)诱变、PCR诱变和盒式诱变来加以制备。
B.载体、宿主细胞和重组方法
其他实施方案包括：分离的多核苷酸，其包含编码人源化抗IL-36R抗体的序列；包含所述多核苷酸的载体和宿主细胞；和用于产生人源化抗体的重组技术。分离的多核苷酸可编码抗IL-36R抗体的任何所需形式，包括例如全长单克隆抗体，Fab，Fab'，F(ab')2和Fv片段，双抗体，线性抗体，单链抗体分子和由抗体片段形成的多特异性抗体。
一些实施方案包括分离的多核苷酸，其包含编码具有SEQ ID NO:1-10中任一氨基酸序列的抗体或抗体片段的轻链可变区的序列。一些实施方案包括分离的多核苷酸，其包含编码具有SEQ ID NO:11-20的氨基酸序列的抗体或抗体片段的重链可变区的序列。
一些实施方案包括分离的多核苷酸，其包含编码具有SEQ ID NO:76-86中任一氨基酸序列的抗体或抗体片段的轻链可变区的序列。一些实施方案包括分离的多核苷酸，其包含编码具有SEQ ID NO:87-101的氨基酸序列的抗体或抗体片段的重链可变区的序列。
一些实施方案包括分离的多核苷酸，其包含编码具有SEQ ID NO:114-124的氨基酸序列的抗体的轻链的序列。一些实施方案包括分离的多核苷酸，其包含编码具有SEQ IDNO:125-139的氨基酸序列的抗体的重链的序列。
在一个方面，分离的多核苷酸序列编码具有轻链和重链可变区的抗体或抗体片段，所述轻链和重链可变区包含下述氨基酸序列：分别为SEQ ID NO:115和SEQ ID NO:127；分别为SEQ ID NO:118和SEQ ID NO:126；分别为SEQ ID NO:118和SEQ ID NO:127；分别为SEQ ID NO:115和SEQ ID NO:125；分别为SEQ ID NO:115和SEQ ID NO:126；分别为SEQ IDNO:118和SEQ ID NO:125；分别为SEQ ID NO:124和SEQ ID NO:138；分别为SEQ ID NO:123和SEQ ID NO:139；分别为SEQ ID NO:123和SEQ ID NO:138。
包含编码人源化抗IL-36R抗体或其片段或链的序列的多核苷酸可以与本领域已知的一种或多种调节或控制序列融合，并且可以包含在本领域已知的合适的表达载体或宿主细胞中。编码重链或轻链可变结构域的每个多核苷酸分子可独立地融合至编码恒定结构域(例如人恒定结构域)的多核苷酸序列，从而能够产生完整抗体。或者，多核苷酸或其部分可以融合在一起，提供用于产生单链抗体的模板。
对于重组生产，将编码抗体的多核苷酸导入可复制的载体用于克隆(DNA扩增)或用于表达。可获得许多用于表达重组抗体的合适载体。对于真核表达，载体组分通常包括但不限于以下一者或多者：信号序列、复制起点、一个或多个标志物基因、增强子元件、启动子和转录终止序列。
人源化抗IL-36R抗体也可以作为融合多肽产生，其中抗体与异源多肽融合，例如信号序列或在成熟蛋白质或多肽的氨基末端具有特异性切割位点的其他多肽。选择的异源信号序列典型地是被宿主细胞识别和加工(即，由信号肽酶切割)的信号序列。对于不识别和处理人源化抗IL-36R抗体信号序列的原核宿主细胞，信号序列可以被原核信号序列取代。信号序列可以是例如碱性磷酸酶，青霉素酶，脂蛋白，热稳定肠毒素II前导序列等。对于酵母分泌，天然信号序列可以用，例如，从酵母转化酶α-因子(包括酵母属和克鲁维酵母α-因子前导序列)、酸性磷酸酶、白色假丝酵母葡糖淀粉酶或者WO90/13646中描述的信号中获得的前导序列取代。在哺乳动物细胞中，可使用哺乳动物信号序列以及病毒分泌前导序列，例如单纯疱疹gD信号。这样的前体区域的DNA以合框方式连接于编码人源化抗IL-36R抗体的DNA。
表达载体和克隆载体两者都包含使所述载体能够在一个或多个选定的宿主细胞中复制的核酸序列。通常，在克隆载体中，这个序列是使所述载体能够独立于宿主染色体DNA而复制的序列，并且包括复制起点或自主复制序列。多种细菌、酵母和病毒的此类序列是熟知的。来自质粒pBR322的复制起点适合于大多数革兰氏阴性细菌，2微米质粒起点适合于酵母，而各种病毒起点(SV40、多瘤病毒、腺病毒、VSV和BPV)可用于哺乳动物细胞中的克隆载体。通常，复制起点组分对于哺乳动物表达载体是不需要的(一般可以使用SV40起点，仅仅是因为它含有早期启动子)。
表达和克隆载体可含有编码选择标记的基因，以便于鉴定表达。典型的选择基因编码这样的蛋白质，所述蛋白质赋予对抗生素或其他毒素例如氨苄青霉素、新霉素、甲氨蝶呤、或四环素的抗性，或者补足营养缺陷型缺陷，或提供从复合培养基中不存在的特定养分，例如，编码用于杆菌的D-丙氨酸消旋酶的基因。
选择方案的一个实例利用药物来阻止宿主细胞的生长。用异源基因成功转化的那些细胞产生赋予抗药性的蛋白质，因此可以在选择方案中存活。这种显性选择的实例使用药物新霉素、霉酚酸和潮霉素。适合的用于哺乳动物细胞的选择标志物的另一个实例是可以鉴定能够摄取编码人源化抗IL-36R抗体的核酸的细胞的标志物，比如DHFR(二氢叶酸还原酶)、胸苷激酶、金属硫蛋白I和II(优选灵长类金属硫蛋白基因)、腺苷脱氨酶、鸟氨酸脱羧酶等。例如，首先通过在含有DHFR的竞争性拮抗剂甲氨蝶呤(Mtx)的培养基中培养所有转化体来鉴定用DHFR选择基因转化的细胞。当采用野生型DHFR时，适当的宿主细胞是DHFR活性缺陷型中国仓鼠卵巢(CHO)细胞系(例如DG44)。
或者，用编码抗IL-36R抗体、野生型DHFR蛋白和另一种可选择标志物如氨基糖苷3'-磷酸转移酶(APH)的DNA序列转化或共转化的宿主细胞(特别是含有内源DHFR的野生型宿主)，可以通过在含有针对可选择标志物的选择剂(比如氨基糖苷类抗生素，例如卡那霉素、新霉素或G418)的培养基中的细胞生长来加以选择。参见，例如，美国专利号4,965,199。
当在酵母细胞中作为宿主细胞进行重组生产时，存在于酵母质粒YRp7中的TRP1基因(Stinchcomb等，1979，Nature 282：39)可用作选择标记。trp1基因针对缺乏在色氨酸中生长的能力的酵母突变株例如No.44076或PEP4-1提供选择标志物。Jones,Genetics,85:12(12)。此外，通过在缺乏色氨酸的情况下的生长，在酵母宿主细胞基因组中trp1损害的存在提供了检测转化的有效环境。类似地，Leu2缺陷型酵母株(20,622或38,626)通过已知的荷Leu2基因的质粒而得到补全。
另外，衍生自1.6μm环形质粒pKD1的载体可用于转化克鲁维酵母。或者，报道了用于乳酸克鲁维酵母的大规模生产重组小牛凝乳酶的表达系统(Van den Berg，1990，Bio/Technology 8：135)。还公开了用于通过克鲁维酵母的工业菌株分泌成熟重组人血清白蛋白的稳定的多拷贝表达载体(Fleer等，1991，Bio/Technology 9：968-975)。
表达载体和克隆载体常常含有被宿主生物识别并且与编码期望的多肽序列的核酸可操作连接的启动子。适合于与原核宿主一起使用的启动子包括phoA启动子、β-内酰胺酶和乳糖启动子系统、碱性磷酸酶、色氨酸(trp)启动子系统、和杂合启动子例如tac启动子。然而，其他已知的细菌启动子也是适合的。用于细菌系统中的启动子还将包含Shine-Dalgarno(S.D.)序列，其与编码抗体的DNA可操作连接。
许多真核启动子序列是已知的。几乎所有的真核基因都具有富AT区，它位于转录起始的位点上游大约25至30个碱基处。在许多基因的转录起点上游70至80个碱基处发现的另一个序列为CNCAAT区，其中N可以是任何核苷酸。大多数真核基因的3′端为AATAAA序列，其可以是将多聚A尾添加到编码序列的3′端的信号。所有这些序列都适宜地插入真核表达载体中。
适合于与酵母宿主一起使用的启动序列的实例包括3-磷酸甘油酸激酶或其他糖酵解酶，如烯醇化酶、3-磷酸甘油醛脱氢酶、己糖激酶、丙酮酸脱羧酶、磷酸果糖激酶、6-磷酸葡萄糖异构酶、3-磷酸甘油酸变位酶、丙酮酸激酶、磷酸丙糖异构酶、磷酸葡糖异构酶和葡糖激酶的启动子。
诱导型启动子具有受生长条件控制的转录的额外优势。这些包括用于醇脱氢酶2的酵母启动子区域，异细胞色素C，酸性磷酸酶，与氮代谢相关的衍生酶，金属硫蛋白，甘油醛-3-磷酸脱氢酶，以及负责麦芽糖和半乳糖利用的酶。用于酵母表达的合适载体和启动子进一步描述于EP 73,657中。将酵母增强子与酵母启动子一起使用也是有利的。
人源化抗IL-36R抗体在哺乳动物宿主细胞中从载体的转录例如受到从病毒(如多瘤病毒、禽痘病毒、腺病毒(如腺病毒2)、牛乳头瘤病毒、禽肉瘤病毒、巨细胞病毒、逆转录病毒、乙型肝炎病毒和猴病毒40(SV40))的基因组中获得的启动子、来自异源哺乳动物的启动子例如肌动蛋白启动子或免疫球蛋白启动子、热休克启动子的控制，只要这样的启动子与宿主细胞系统相容即可。
以SV40限制性片段的形式合宜地获得SV40病毒的早期启动子和晚期启动子，所述片段还包含SV40病毒复制起点。以HindIII E限制性片段的形式合宜地获得人巨细胞病毒的立即早期启动子。美国专利No.4,419,446中公开了利用牛乳头瘤病毒作为载体在哺乳动物宿主中表达DNA的系统。在美国专利No.4,601,978中描述了对这个系统的改良。还参见Reyes等人，Nature,297:598-601(1982)，其公开了人β-干扰素cDNA在来自单纯疱疹病毒的胸苷激酶启动子控制下在小鼠细胞中的表达。或者，可使用劳斯肉瘤病毒长末端重复序列作为启动子。
可用于重组表达载体的另一有用元件是增强子序列，其用于增加高等真核生物编码人源化抗IL-36R抗体的DNA的转录。目前已知许多来自哺乳动物基因(珠蛋白、弹性蛋白酶、白蛋白、α甲胎蛋白、和胰岛素)的增强子序列。然而，通常使用来自真核细胞病毒的增强子。实例包括位于复制起点晚期侧(late side)的SV40增强子(bp 100-270)、巨细胞病毒早期启动子增强子、位于复制起点晚期侧的多瘤病毒增强子、以及腺病毒增强子。关于真核生物启动子活化的增强元件的描述还可参见Yaniv,1982,Nature 297:17-18。可在人源化抗IL-36R抗体编码序列5′或3′位置、但优选在启动子的5′的位置，将增强子剪接到载体中。
在真核宿主细胞(酵母、真菌、昆虫、植物、动物、人类、或来自其他多细胞生物的有核细胞)中使用的表达载体还将含有对于终止转录和稳定化mRNA必需的序列。这样的序列通常可从真核生物或病毒DNA的5'、且有时从3'非翻译区或cDNA得到。这些区域含有转录为编码抗体的mRNA的非翻译部分中的多腺苷酸化片段的核苷酸区段。一种有用的转录终止组分为牛生长激素多腺苷酸化区。参见WO94/11026及其中所公开的表达载体。在一些实施方案中，可以使用CHEF系统表达人源化抗IL-36R抗体。(参见例如美国专利No.6,423,685，将其通过提述并入本文。)
用于在本文载体中克隆或表达DNA的合适宿主细胞是上述原核生物，酵母或高等真核细胞。用于此目的的合适的原核生物包括真细菌，例如革兰氏阴性或革兰氏阳性生物，例如肠杆菌科，例如埃希氏菌属，例如大肠杆菌，肠杆菌属，欧文氏菌属，克雷伯氏菌属，变形杆菌属，沙门氏菌属例如鼠伤寒沙门氏菌，沙雷氏菌属例如粘质沙雷氏菌和志贺氏菌，以及芽孢杆菌属例如枯草芽孢杆菌和地衣芽孢杆菌等(例如，1989年4月12日公开的DD 266,710中公开的地衣芽孢杆菌41P)，假单胞菌如铜绿假单胞菌，和链霉菌属。一种优选的大肠杆菌克隆宿主是大肠杆菌294(ATCC 31,446)，但其他菌株如大肠杆菌B、大肠杆菌X1776(ATCC 31,537)和大肠杆菌W3110(ATCC 27,325)也是合适的。这些实例是说明性而非限制性的。
除原核生物外，真核微生物如丝状真菌或酵母是人源化抗IL-36R抗体编码载体的合适克隆或表达宿主。酿酒酵母(Saccharomyces cerevisiae)，又称普通面包酵母，是低等真核宿主微生物中最常用的。然而，许多其他属、种和菌株通常可用于本文，例如粟酒裂殖酵母(Schizosaccharomyces pombe)；克鲁维酵母属宿主，例如乳酸克鲁维酵母，脆弱克鲁维酵母(K.fragilis)(ATCC12,424)，保加利亚克鲁维酵母(K.bulgaricus)(ATCC 16,045)，K.wickeramii(ATCC 24,178)，K。waltii(ATCC 56,500)，果蝇克鲁维酵母(K.drosophilarum)(ATCC 36,906)，耐热克鲁维酵母(K.thermotolerans)和马克斯克鲁维酵母(K.marxianus)；耶氏酵母属(yarrowia)(EP 402,226)；巴斯德毕赤酵母(EP 183,070)；假丝酵母属(Candida)；里氏木霉(Trichoderma reesia)(EP 244,234)；粗糙脉孢菌(Neurospora crassa)；许旺酵母属(Schwanniomyces)，如西方许旺酵母(Schwanniomyces)occidentalis；和丝状真菌，例如，脉孢菌属、青霉属、Tolypocladium和曲霉属宿主，例如构巢曲霉(A.nidulans)和黑曲霉(A.niger)。
用于表达糖基化的人源化抗IL-36R抗体的合适宿主细胞衍生自多细胞生物。无脊椎动物细胞的实例包括植物和昆虫细胞，包括例如许多杆状病毒株和变体以及来自宿主的相应的受纳性昆虫宿主细胞，例如草地夜蛾(Spodoptera frugiperda)(毛虫)，埃及伊蚊(蚊子)，白纹伊蚊(蚊子)，黑腹果蝇(Drosophila melanogaster)(果蝇)和Bombyx mori(家蚕)。用于转染的多种病毒株是公众可获得的，例如，苜蓿银纹夜蛾NPV的L-1变体和家蚕NPV的Bm-5株，可以使用这些病毒，特别是用于转染草地贪夜蛾(Spodoptera frugiperda)细胞。
棉花，玉米，马铃薯，大豆，矮牵牛，番茄和烟草的植物细胞培养物也可用作宿主。
另一方面，人源化抗IL-36R的表达在脊椎动物细胞中进行。脊椎动物细胞在培养物(组织培养物)中的繁殖已成为常规程序，并且技术广泛可用。有用的哺乳动物宿主细胞系的实例为：经SV40转化的猴肾CV1系(COS-7,ATCC CRL 1651)；人胚胎肾系(经亚克隆在悬浮培养物中生长的293或293细胞，Graham等人，J.Gen Virol.36:59(59))；幼仓鼠肾细胞(BHK,ATCC CCL 10)；中国仓鼠卵巢细胞/-DHFR(CHO,Urlaub等人，Proc.Natl.Acad.Sci.USA77:4216(1980))；小鼠塞托利(Sertoli)细胞(TM4,Mather,Biol.Reprod.23:243-251(1980))；猴肾细胞(CV1 ATCC CCL 70)；非洲绿猴肾细胞(VERO-76,ATCC CRL-1587)；人宫颈癌细胞(HELA,ATCC CCL2)；犬肾细胞(MDCK,ATCC CCL 34)；牛鼠(buffalo rat)肝细胞(BRL 3A,ATCC CRL 1442)；人肺细胞(W138,ATCC CCL 75)；人肝细胞(Hep G2,HB 8065)；小鼠乳腺肿瘤(MMT060562,ATCC CCL51)；TRI细胞(Mather等人，Annals N.Y.Acad.Sci.383:44-68(1982))；MRC 5细胞；FS4细胞；和人肝细胞瘤系(HepG2)。
用上述用于产生抗体的表达载体或克隆载体转化宿主细胞，并在常规营养培养基中培养宿主细胞，所述营养培养基改良为适于诱导启动子、选择转化体、或扩增编码期望序列的基因。
可在各种培养基中培养用于产生本发明抗体的宿主细胞。可商购的培养基，如Ham's F10(Sigma)、最低必需培养基((MEM)，(Sigma-Aldrich Co.)、RPMI-1640(Sigma)、和达尔伯克改良伊格尔培养(Dulbecco's Modified Eagle's Medium)((DMEM),Sigma-Aldrich Co.)适合于培养宿主细胞。另外，在Ham et al.,1979,Meth.Enz.58:44,Barneset al.,1980,Anal.Biochem.102:255,U.S.Pat.No.4,767,704,U.S.Pat.No.4,657,866,U.S.Pat.No.4,927,762,U.S.Pat.No.4,560,655,U.S.Pat.No.5,122,469,WO 90/103430,和WO 87/00195的一篇或多篇中描述的任何培养基都可用作宿主细胞的培养基。在需要时，可对任何这些培养基补充激素和/或其他生长因子(如胰岛素、转铁蛋白或表皮生长因子)、盐(如氯化钠、钙、镁、和磷酸盐)、缓冲液(如HEPES)、核苷酸(如腺苷和胸苷)、抗生素(如庆大霉素)、微量元素(定义为通常以微摩尔范围内的终浓度存在的无机化合物)、以及葡萄糖或等效能源。还可包括适当浓度的本领域技术人员已知的任何其他补充剂。培养条件，诸如温度、PH值等，为先前用于经选择用于表达的宿主细胞的那些条件，且对于普通技术人员而言是显而易见的。
当使用重组技术时，抗体可以在细胞内、在周质空间中产生，或者直接分泌到培养基中。如果抗体在细胞内产生，则作为第一步可以破坏细胞以释放蛋白质。颗粒碎片，或是宿主细胞或是裂解片段，可以例如通过离心或超滤除去。Carter等人，Bio/Technology 10:163-167(1992)描述了分泌到大肠杆菌周质空间的抗体的分离程序。简言之，经过约30分钟，在乙酸钠(pH 3.5)、EDTA和苯甲基磺酰氟(PMSF)的存在下融化细胞糊。细胞碎片可以通过离心去除。在抗体分泌到培养基中的场合，通常首先使用可商购的蛋白质浓缩滤器例如Amicon或Millipore Pellicon超滤单元浓缩来自这样的表达系统的上清液。蛋白酶抑制剂如PMSF可包括在任何前述步骤中，以抑制蛋白水解，并可包括抗生素以防止偶然污染物的生长。可以使用多种方法从宿主细胞中分离抗体。
可以使用例如羟基磷灰石色谱法、凝胶电泳、透析和亲和色谱法来纯化由细胞制备的抗体组合物，其中亲和色谱法是典型的纯化技术。蛋白A作为亲和配体的适合性取决于存在于抗体中的任何免疫球蛋白Fc结构域的种类和同种型。蛋白A可用于纯化基于人γ1、γ2或γ4重链的抗体(Lindmark等人，J.Immunol.Methods 62:1-13(1983))。蛋白G被推荐用于所有小鼠同种型和人γ3(Guss等人，EMBO J.5:1567-1575(1986))。亲和配体所连接的基质最常见的是琼脂糖，但可以用其他基质。机械稳定的基质，比如可控孔径的玻璃或聚(苯乙烯二乙烯基)苯，可以提供比琼脂糖所能达到的更快的流速和更短的处理时间。在抗体包含CH3结构域的情况下，使用Bakerbond ABXTM树脂(J.T.Baker,Phillipsburg,N.J.)进行纯化。取决于待回收的抗体，还可以利用蛋白质纯化的其他技术，比如在离子交换柱上分级、乙醇沉淀、反相HPLC、硅胶色谱法、在肝素SEPHAROSETM上的色谱法、在阴离子或阳离子交换树脂(如聚天冬氨酸柱)上的色谱法、色谱聚焦、SDS-PAGE和硫酸铵沉淀。
在任何初步纯化步骤之后，可以使用pH介于约2.5-4.5之间的洗脱缓冲液对包含感兴趣的抗体和污染物的混合物进行低pH疏水相互作用色谱，优选在低盐浓度(例如0-0.25M的盐)下进行。
还包括在如本文所定义的低、中和高严格条件下与编码本发明的抗体或抗体片段的分离的多核苷酸序列所代表的核苷酸序列的全部或部分(例如，编码可变区的部分)杂交的核酸。杂交核酸的杂交部分的长度通常为至少15个(例如，20、25、30或50)个核苷酸。杂交核酸的杂交部分与编码抗IL-36R多肽(例如重链或轻链可变区)的核酸或其互补物的部分或全部的序列至少80％，例如，至少90％，至少95％，或至少98％相同。本文所述类型的杂交核酸可用作例如克隆探针、引物，例如PCR引物或诊断探针。
非治疗用途
本文描述的抗体可用作亲和纯化剂。在这种方法中，使用本领域中熟知的方法将抗体固定在固定相(如Protein A树脂)上。使固定化抗体与含有待纯化的IL-36R蛋白(或其片段)的样品接触，然后用合适的溶剂洗涤载体，该溶剂会除去样品中除了IL-36R蛋白之外基本上所有的物质，而IL-36R蛋白与固定化抗体结合。最后，用另一种合适的溶剂洗涤载体，该溶剂将从抗体中释放IL-36R蛋白。
抗IL-36R抗体，例如人源化抗IL-36R抗体，也可用于检测和/或定量IL-36R蛋白的诊断测定，例如，检测特定细胞、组织或血清中的IL-36R表达。。可以在诊断性使用抗IL-36R抗体，用于例如监测疾病的发生和进展，作为一项临床测试步骤的一部分，例如用于确定给定治疗和/或预防方案的效力。可以通过将抗IL-36R抗体与可检测的物质偶联来促进检测。可检测的物质的实例包括各种酶、辅基、荧光材料、发光材料、生物发光材料、放射性材料、利用正电子发射计算机断层显像的各种正电子发射金属、和非放射性顺磁金属离子。参见，例如，美国专利No.4,741,900关于可以与用作根据本发明的诊断剂的抗体结合的金属离子。
抗IL-36R抗体可用于诊断IL-36R相关病症(例如，以IL-36R异常表达为特征的病症)的方法或确定受试者是否具有增加的发生IL-36R相关病症的风险。这些方法包括使来自受试者的生物样品与IL-36R抗体接触并检测抗体与IL-36R的结合。“生物样品”意图指从个体、细胞系、组织培养物或可能表达IL-36R的其他细胞来源获得的任何生物样品。从哺乳动物获得组织活检和体液的方法是本领域熟知的。
在一些实施方案中，该方法可以进一步包括将患者样品中的IL-36R水平与对照样品(例如，不具有IL-36R相关病症的受试者)进行比较，以确定患者是否患有IL-36R相关疾病或有发展IL-36R相关疾病的风险。
在一些实施方案中，例如，为了诊断目的，用可检测的部分标记抗体将是有利的。有许多可检测的标记物，包括放射性同位素，荧光标记物，酶底物标记物等。可以使用各种已知技术将标记物与抗体间接缀合。例如，抗体可以与生物素缀合，并且可以将上述三大类标记物中的任何一种与抗生物素蛋白缀合，或反之。生物素选择性地结合抗生物素蛋白，由此，标记物可以以这种间接方式与抗体缀合。或者，为了实现标记物与抗体的间接缀合，可以将抗体与小的半抗原(例如地高辛)缀合，并且上述不同类型的标记之一与抗半抗原抗体缀合(例如，抗-地高辛抗体)。由此，可以实现标记物与抗体的间接缀合。
示例性放射性同位素标记物包括35S，14C，125I，3H和131I。可以用放射性同位素标记抗体，使用例如Current Protocols in Immunology,Volumes 1and2,1991,Coligen etal.,Ed.Wiley-Interscience,New York,N.Y.,Pubs.。放射性可以例如通过闪烁计数来测量。
可用的示例性荧光标记物包括衍生自稀土螯合物(铕螯合物)或荧光素及其衍生物的标记，罗丹明及其衍生物，丹酰，丽丝胺，藻红蛋白和德克萨斯红。荧光标记物可以通过已知技术与抗体缀合，例如Current Protocols in Immunology中公开的那些技术。可以使用荧光计定量荧光。
本领域已知有多种充分表征的酶-底物标记物(参见例如美国专利No.4,275,149的综述)。该酶通常催化发色底物的化学改变，该化学改变可使用各种技术测量。例如，改变可以是基质中的颜色变化，其可以通过分光光度法测量。或者，酶可以改变底物的荧光或化学发光。用于定量荧光变化的技术于上文描述。化学发光底物通过化学反应被电子激发，然后可以发射能够用例如化学发光计测量的光，或者将能量提供给荧光受体。
酶标记物的实例包括荧光素酶(例如，萤火虫荧光素酶和细菌荧光素酶(US 4,737,456))、荧光素、2,3-二氢酞嗪二酮、苹果酸脱氢酶、脲酶、过氧化物酶如辣根过氧化物酶(HRPO)、碱性磷酸酶、β-半乳糖苷酶、葡糖淀粉酶、溶菌酶、糖氧化酶(例如，葡萄糖氧化酶、半乳糖氧化酶和葡萄糖-6-磷酸脱氢酶)、杂环氧化酶(例如尿酸酶和黄嘌呤氧化酶)、乳过氧化物酶、微过氧化物酶等。用于将酶与抗体结合的技术描述于例如O'Sullivan etal.,1981,Methods for the Preparation of Enzyme-Antibody Conjugates for use inEnzyme Immunoassay,in Methods in Enzym.(J.Langone&H.Van Vunakis,eds.),Academic press,N.Y.,73:147-166。
酶-底物组合的实例包括，例如：以氢过氧化物酶作为底物的辣根过氧化物酶(HRPO)，其中氢过氧化物酶氧化染料前体如邻苯二胺(OPD)或3,3',5,5'-四甲基盐酸联苯胺(TMB)；对硝基苯磷酸盐作为显色底物的碱性磷酸酶(AP)；以及具有生色底物的β-D-半乳糖苷酶(β-D-Gal)，如对硝基苯基-β-D-半乳糖苷酶或具有荧光底物的4-甲基伞形基-β-D-半乳糖苷酶。
有许多其他酶-底物组合可供本领域技术人员使用。关于这些的一般性综述，参见美国专利4,275,149和美国专利4,318,980。
在另一个实施方案中，人源化抗IL-36R抗体未标记地使用，并用结合人源化抗IL-36R抗体的标记抗体检测。
本文中提供的抗体可用于任何已知的测定方法，比如竞争性结合测定法、直接和间接夹心测定法和免疫沉淀测定法。参见例如Zola,Monoclonal Antibodies:A Manual ofTechniques,pp.147-158(CRC Press,Inc.1987)。
抗IL-36R抗体或其抗原结合片段可用于抑制配体与IL-36受体的结合。这些方法包括将抗IL-36R抗体或其抗原结合片段给予细胞(例如哺乳动物细胞)或细胞环境，由此抑制IL-36受体介导的信号传导。这些方法可以在体外或体内实施。“细胞环境”是指细胞周围的组织、介质或细胞外基质。将抗IL-36R抗体或其抗原结合片段以这样的方式施用于细胞的细胞环境，使得抗体或片段能够结合细胞外部和周围的IL-36R分子，由此阻止IL-36配体与其受体的结合。
诊断试剂盒
抗IL-36R抗体可用于诊断试剂盒，即预定量的试剂的包装组合与实施诊断测定的说明书。当抗体用酶标记时，试剂盒可包括酶所需的底物和辅因子，例如提供可检测的发色团或荧光团的底物前体。另外，可以包括其他添加剂，例如稳定剂，缓冲剂(例如封闭缓冲剂或裂解缓冲剂)等。各种试剂的相对量可以广泛变化，以提供试剂在溶液中的浓度，实质上优化了测定法的灵敏度。试剂可以干粉形式提供，通常是冻干的，包括赋形剂，其在溶解时将提供具有适当浓度的试剂溶液。
治疗用途
在另一个实施方案中，本文公开的人源化抗IL-36R抗体可用于治疗与本文所述的IL-36R表达相关的各种病症。治疗IL-36R相关病症的方法包括随有需要的受试者施用治疗有效量的人源化抗IL-36R抗体。
人源化抗IL-36R抗体或药剂通过任何合适的方式施用，包括肠胃外、皮下、腹膜内、肺内和鼻内，并且如果需要，用于局部免疫抑制治疗、病灶内施用(包括灌注或以其他方式在移植前使移植物与抗体接触)。人源化抗IL-36R抗体或药剂可以例如作为输注或推注施用。肠胃外输注包括肌内、静脉内、动脉内、腹膜内或皮下施用。另外，人源化抗IL-36R抗体适合通过脉冲输注施用，特别是以递减剂量的抗体。在一个方面，通过注射给药，最优选静脉内或皮下注射，这部分取决于施用是短暂的还是慢性的。在一个方面，人源化抗IL-36R抗体或药剂通过静脉内负荷剂量，然后进行一次或多次皮下注射来施用。在一个方面，皮下注射以本文公开的任何一种给药间隔施用。
对于疾病的预防或治疗，适当的抗体剂量将取决于多种因素，例如有待治疗的疾病的类型(如上定义的)、疾病的严重性和病程、所述抗体是为预防目的还是治疗目的而施用、先前治疗、患者的临床病史和对抗体的反应、以及主治医师的判定。适当地以一次或经过一系列治疗向患者施用抗体。
根据疾病的类型和严重程度，约1μg/kg至15mg/kg(例如20mg/kg-10mg/kg)的抗体是向患者施用的初始候选剂量，无论是例如通过一次或多次分开施用，还是通过连续输注。取决于上面提到的因素，一个典型的日剂量可能在约1μg/kg至100mg/kg或更高的范围内。对于数天或更长时间的重复施用，根据情况，治疗将持续到出现期望的疾病症状的抑制时为止。然而，其他剂量方案可能是有用的。通过常规技术和测定法易于监测这种疗法的进展。示例性施用方案是WO 94/04188中公开的方案。
术语“抑制”在本文中与“改善”和“缓解”相同的上下文中使用，意指减轻疾病的一种或多种特征。
抗体组合物将以符合良好医学实践的方式配制、确定剂量和施用。在该语境中考虑的因素包括正在治疗的具体病症、被治疗的具体哺乳动物、个体患者的临床状况、病症的原因、药剂的递送部位、施用方法、施用时间表、以及执业医师知晓的其他因素。待施用的抗体的“治疗有效量”将受到这些考虑因素的控制，并且是预防、改善或治疗与IL-36R表达相关的病症所必需的最小量。
抗体不必是，但任选地是，与一种或多种目前用于预防或治疗相关病症的药剂一起配制的。此类其他药剂的有效量取决于制剂中人源化抗IL-36R抗体的量、病症或治疗的类型、以及以上讨论的其他因素。它们通常以与以往相同的剂量和施用途径使用，或者是迄今使用的剂量的约1至99％。
药物组合物及其施用
包含IL-36R结合剂(例如，抗IL-36R抗体)的组合物可以施用于患有免疫性病症，呼吸病症或癌症，或具有患有免疫性病症、呼吸病症或癌症的风险的受试者。本发明还提供IL-36R结合剂(例如抗IL-36R抗体)在制备用于预防或治疗癌症、呼吸病症或免疫性病症的药物中的用途。术语“受试者”如本文所用的，意指任何可以施用IL-36R结合剂的哺乳动物患者，包括例如人和非人哺乳动物，例如灵长类动物、啮齿动物和犬类。特别预期使用本文所述方法治疗的受试者包括人。抗体或药剂可以单独给药或与其他组合物一起给药，用于预防或治疗免疫性病症，呼吸病症或癌症。可与抗体或药剂联合给药的此类组合物包括甲氨蝶呤(MTX)和免疫调节剂，例如抗体或小分子。
在一个实施方案中，抗体或药剂可以单独施用或与其他组合物一起施用，以预防或治疗免疫性病症，呼吸病症或癌症。可以与抗体或药剂组合施用的此类组合物包括免疫调节剂，例如硫唑嘌呤和6-MP。
在本发明的另一个实施方案中，所述抗体或药剂可以单独施用或与其他组合物一起施用，用于预防或治疗免疫性病症、呼吸病症或癌症。可与抗体或药剂组合施用的此类组合物包括多种类型的生物制剂，例如TNF抑制剂例如英夫利昔单抗、阿达木单抗、赛妥珠单抗，或循环受体融合蛋白如依那西普，整联蛋白抑制剂例如维多珠单抗，或IL-23抑制剂。
本发明的其他实施方案包括在预防或治疗免疫性病症、呼吸病症或癌症中施用包含IL-36R结合剂(例如，抗IL-36R抗体)的组合物，所述组合物单独施用或与其它组合物一起施用。可与抗体或药剂组合施用的此类组合物包括多种类型的生物制剂，例如TNF抑制剂例如英夫利昔单抗、阿达木单抗、赛妥珠单抗，或循环受体融合蛋白如依那西普，整联蛋白抑制剂例如维多珠单抗，或IL-23抑制剂。
例如，本发明的抗体与TNF抑制剂例如英夫利昔单抗、阿达木单抗，赛妥珠单抗，或循环受体融合蛋白如依那西普，整联蛋白抑制剂例如维多珠单抗，或IL-23抑制剂组合，可用于治疗硬皮病，掌跖脓疱病，全身性脓疱性银屑病，糖尿病肾病，狼疮性肾炎，硬皮病，强直性脊柱炎，IBD(溃疡性结肠炎-轻度、中度活跃和重度；克罗恩病-轻度、中度和重度)。
在另一个实施方案中，将本发明的抗体与TNF抑制剂例如英夫利昔单抗，阿达木单抗，赛妥珠单抗标记或循环受体融合蛋白如依那西普，整联蛋白抑制剂例如维多珠单抗或IL-23抑制剂组合施用于患者以治疗硬皮病，掌跖脓疱病，全身性脓疱性银屑病，糖尿病肾病，狼疮性肾炎，硬皮病，强直性脊柱炎，IBD(溃疡性结肠炎-轻度、中度活跃和重度，克罗恩病-轻度、中度和重度)。
本发明的另一个实施方案提供了治疗轻度、中度活跃、重度溃疡性结肠炎的方法。
本发明的另一个实施方案提供了治疗轻度、中度活跃、重度克罗恩病的方法。
在另一个实施方案中，本发明的抗体可以在TNF抑制剂之前，之后或同时施用，所述TNF抑制剂例如英夫利昔单抗、阿达木单抗、赛妥珠单抗，或者循环受体融合蛋白如依那西普，整联蛋白抑制剂如维多珠单抗，或IL-23抑制剂。。
在另一个实施方案中，本发明的抗体可以作为用TNF抑制剂治疗的附加疗法(add-on therapy)施用，所述TNF抑制剂例如英夫利昔单抗、阿达木单抗、赛妥珠单抗，或者循环受体融合蛋白如依那西普，整联蛋白抑制剂如维多珠单抗，或IL-23抑制剂。
用于此类药物组合物的抗体的实例是包含具有SEQ ID NO:1-10中任一个的轻链可变区氨基酸序列的抗体或抗体片段的抗体。用于此类药物组合物的抗体的实例也是包含具有SEQ ID NO:11-20中任一项的重链可变区氨基酸序列的人源化抗体或抗体片段的抗体。
用于此类药物组合物的抗体的其他实例也是包含具有SEQ ID NO:76-86中任一项的轻链可变区氨基酸序列的人源化抗体或抗体片段的那些。用于此类药物组合物的优选抗体也是包含具有SEQ ID NO:87-101中任一项的重链可变区氨基酸序列的人源化抗体或抗体片段的抗体。
用于此类药物组合物的抗体的其他实例还包括具有以下任一项的轻链可变区和重链可变区的人源化抗体或抗体片段的那些：SEQ ID NO:77和89，SEQ ID NO:80和88。SEQID NO:80和89，SEQ ID NO:77和87，SEQ ID NO:77和88，SEQ ID NO:80和87，SEQ ID NO:86和100，SEQ ID NO:85和101，或SEQ ID NO:85和10。
用于此类药物组合物的抗体的其他实例也是包含具有SEQ ID NO:115、118、123或124中任一个的轻链区氨基酸序列的人源化抗体的那些。用于此类药物组合物的优选抗体也是包含具有SEQ ID NO:125、126、127、138或139中任一个的重链可变区氨基酸序列的人源化抗体的抗体。
用于此类药物组合物的抗体的其他实例也是包含抗体B1，抗体B2，抗体B3，抗体B4，抗体B5，抗体B6，抗体C1，抗体C2或抗体C3的抗体。
各种递送系统是已知的并且可用于施用IL-36R结合剂。导入方法包括但不限于皮内、肌内、腹膜内、静脉内、皮下、鼻内、气管内、硬膜外以及口服途径。IL-36R结合剂可以例如通过输注，推注或注射给药，并且可以与其他生物活性剂如化学治疗剂一起给药。施用可以是全身性的或局部的。在优选的实施方案中，通过皮下注射施用。用于这种注射的制剂可以在例如每隔一周施用一次的预填充注射器中制备。
在具体的实施方案中，IL-36R结合剂组合物通过注射、通过导管、通过栓剂或通过植入物施用，所述植入物是多孔的、无孔的或凝胶状的材料，包括膜，例如弹性(sialastic)膜或纤维。通常，当施用组合物时，使用不吸收抗IL-36R抗体或抗IL-36R剂的材料。
在其他实施方案中，抗IL-36R抗体或药剂在控释系统中递送。在一个实施方案中，可以使用泵(参见，例如，Langer,1990,Science 249:1527-1533；Sefton,1989,CRCCrit.Ref.Biomed.Eng.14:201；Buchwald et al.,1980,Surgery 88:507；Saudek et al.,1989,N.Engl.J.Med.321:574)。在一个实施例中，可以使用超吸收剂。(参见，例如，MedicalApplications of Controlled Release(Langer and Wise eds.,CRC Press,Boca Raton,Fla.,1974)；Controlled Drug Bioavailability,Drug Product Design andPerformance(Smolen and Ball eds.,Wiley,New York,1984)；Ranger and Peppas,1983,Macromol.Sci.Rev.Macromol.Chem.23:61。另外参见Levy et al.,1985,Science 228:190；During et al.,1989,Ann.Neurol.25:351；Howard et al.,1989,J.Neurosurg.71:105)。其他控制释放系统在例如Langer(同上)中讨论过。
IL-36R结合剂(例如，抗IL-36R抗体)可以作为药物组合物施用，所述药物组合物包含治疗有效量的结合剂和一种或多种药学上相容的成分。
在典型的实施方案中，药物组合物根据常规程序配制成适合于对人类静脉内或皮下施用的药物组合物。通常，用于注射给药的组合物是无菌等渗水性缓冲液中的溶液。必要时，药物还可以包括增溶剂和局部麻醉剂如利多卡因，以缓解注射部位的疼痛。通常，成分单独供应或以单位剂量形式混合在一起，例如，作为干燥的冻干粉末或无水浓缩物置于标示有活性剂的量的密封容器如安瓿或小药囊中。当药物通过输注施用时，可以用含有无菌药用级水或盐水的输液瓶分配。当药物通过注射施用时，可以提供一安瓿的无菌注射用水或盐水，以便在施用前混合各成分。
此外，药物组合物可以作为药物试剂盒提供，其包含(a)含有冻干形式的IL-36R结合剂(例如，抗IL-36R抗体)的容器和(b)含有用于注射的药学上可接受的稀释剂(例如，无菌水)的第二容器。药学上可接受的稀释剂可用于重构或稀释冻干的抗IL-36R抗体或试剂。这样的容器可以任选地伴随由管理药品或生物制品的制造、使用或销售的政府机构规定的形式的通知，该通知反映了该机构对人类施用的制造、使用或销售的批准。
可以通过标准临床技术确定有效治疗或预防免疫疾病或癌症的IL-36R结合剂(例如，抗IL-36R抗体)的量。此外，可任选地使用体外测定来帮助确定最佳剂量范围。制剂中使用的精确剂量还取决于施用途径和免疫性病症或癌症的阶段，并且应根据从业者的判断和每个患者的情况来决定。可从源自体外或动物模型测试系统的剂量-反应曲线外推有效剂量。
通常，施用给患有免疫性病症或表达IL-36R的癌症的患者的抗IL-36R抗体或IL-36R结合剂的剂量通常为约0.1mg/kg至约100mg/kg受试者体重。施用于受试者的剂量为约0.1mg/kg至约50mg/kg，约1mg/kg至约30mg/kg，约1mg/kg至约20mg/kg，约1mg/kg至约15mg/kg，或约1mg/kg至约10mg/kg受试者体重。
示例性剂量包括但不限于1ng/kg至100mg/kg。在一些实施方案中，剂量为约0.5mg/kg，约1mg/kg，约2mg/kg，约3mg/kg，约4mg/kg，约5mg/kg，约6mg/kg，约7mg/kg，约8mg/kg，约9mg/kg，约10mg/kg，约11mg/kg，约12mg/kg，约13mg/kg，约14mg/kg，约15mg/kg或约16mg/kg。剂量可以例如每天一次施用，每周一次(每周一次)，每周两次，每周三次，每周四次，每周五次，每周六次，每两周或每月一次，每八周一次或每两个月，或每三个月一次施用。在具体的实施方案中，剂量为约0.5mg/kg/周，约1mg/kg/周，约2mg/kg/周，约3mg/kg/周，约4mg/kg/周，约5mg。/kg/周，约6mg/kg/周，约7mg/kg/周，约8mg/kg/周，约9mg/kg/周，约10mg/kg/周，约11mg/kg/周，约12mg/kg/周，约13mg/kg/周，约14mg/kg/周，约15mg/kg/周或约16mg/kg/周。在一些实施方案中，剂量范围为约1mg/kg/周至约15mg/kg/周。
在一些实施方案中，包含IL-36R结合剂的药物组合物可以进一步包含治疗剂，该治疗剂可以与也可以不与所述结合剂缀合。抗IL-36R抗体或IL-36R结合剂可与一种或多种治疗剂联合施用，用于治疗或预防免疫性病症或癌症。
这种联合治疗施用可以对疾病参数(例如，症状的严重程度，症状的数量或复发的频率)具有加和或协同效应。
关于组合施用的治疗方案，在一个具体实施方案中，抗IL-36R抗体或IL-36R结合剂与治疗剂同时施用。在另一个具体实施方案中，治疗剂在施用抗IL-36R抗体或IL-36R结合剂之前或之后至少1小时至数月施用，例如在施用抗IL-36R抗体或IL-36R结合剂之前或之后至少1小时，5小时，12小时，一天，一周，一个月或三个月施用。
制品
在本发明的另一个方面，提供了含有用于治疗、预防和/或诊断上述病症的物质的制品。所述制品包括容器和标签。适合的容器包括例如瓶子、小瓶、注射器和试管。容器可以由各种材料如玻璃或塑料形成。容器容纳有效治疗病症的组合物，并且可具有无菌进入口。例如，容器可以是静脉内溶液袋或具有可由皮下注射针刺穿的塞子的小瓶。组合物中的活性剂是人源化抗IL-36R抗体。标签或包装说明书指示该组合物用于治疗选择的病症。所述制品可以进一步包括第二容器，所述第二容器包含药学上可接受的缓冲剂，比如磷酸盐缓冲盐水、林格氏溶液和右旋糖溶液。它可以进一步包括从商业和用户立场看可取的其他材料，包括其他缓冲剂、稀释剂、过滤器、针头、注射器和具有使用说明的包装说明书。
本发明进一步通过参考以下实例进行限定，这些实例并不旨在限制本发明的范围。
本发明的实施方案在下面的实施例中进一步限定。
实施例
实施例1：抗人IL-36R抗体的鉴定
用重组产生的人IL-36R(ECD-细胞外结构域：Genbank登录号#NP_003845的氨基酸20-332)蛋白质免疫多个小鼠品系，并且选取产生强滴度响应的小鼠进行传统杂交瘤生产。对于可引发与人IL-36R(ECD)的强结合但不与人IL-1R1(最近缘的IL-1R家族成员)结合的融合产物，将其亚克隆并重新筛选。鉴定出多个杂交瘤可产生能结合并中和来自IL-36R的信号传导的单克隆抗体(参见实施例2、3和4)。使用标准PCR引物组从这些杂交瘤克隆可变结构域。代表性单克隆抗体的可变结构域和特定CDR如上文所述。将所有小鼠抗体转化为嵌合抗体，其由人恒定结构域上的小鼠可变结构域组成(hu IgG1KO/kappa)。hu IgG1KO(K.O：Knock Out，敲除)具有两个置换突变(Leu234Ala和Leu235Ala)，其降低效应子功能例如FcRγ和补体结合从而消除ADCC和CDC活性。小鼠的可变结构域和嵌合抗体是相同的。产生嵌合抗体以确认抗体的功能并确保获得了正确的可变结构域序列。
实施例2：鉴定的小鼠抗人IL-36R抗体的分子结合亲和力
A)使用从杂交瘤产生经单柱纯化后材料，利用Proteon(Bio-Rad，Hercules，CA)测量抗IL-36R抗体结合重组人IL-36R的的动力学和结合亲和力。所有小鼠先导物对单个IL-36R表面包被浓度下测试的人IL-36R的结合亲和力均估计为<100pM。表1中显示了小鼠抗体与在7种不同表面密度(全局拟合)下测试的人IL-36R的结合亲和力。嵌合抗IL36R IgG的结合与各自的小鼠先导物相当。
表1：小鼠抗人IL-36R抗体的结合亲和力。
| 先导物 | 结合K<sub>D</sub>(pM) |
| 小鼠73C5 | 57 |
| 小鼠73F6 | 25 |
| 小鼠78C8 | 63 |
| 小鼠81A1 | 16 |
| 小鼠81B4 | 24 |
| 小鼠33D10 | 9 |
B)对小鼠IL-36R和人IL-1R1的分子选择性
还将小鼠抗IL-36R抗体和嵌合抗IL-36R抗体以100nM的浓度注射到小鼠IL-36R或人IL-1R1表面上。使用Fortebio Octet(Fortebio，Menlo Park，CA)测得这些抗体对小鼠IL-36R和人IL-1R1的结合信号为零，表明这些抗体选择性地结合人IL-36R。还在50％人血清存在下分析了抗IL-36R抗体与人IL-36R的结合，并且未观察到血清对结合率有显著影响，证明了高特异性。
实施例3：小鼠和嵌合抗人IL-36R抗体在人和食蟹猴功能性测定中的效力
操作程序：人NCI/ADR-RES细胞pNFκB/细胞因子释放测定
试剂：
R&D Systems：截短的rhIL36β
R&D Systems:截短的rh IL36γ
R&D Systems:截短的rh IL36α:
MA6000磷酸-NFκB(Ser536)全细胞裂解液试剂盒
Meso Scale Diagnostics，LLC
MSD ELISA定制人96孔4点测定法
Meso Scale Diagnostics，LLC
含有0.25％血清的RPMI培养基中将NCI/ADR-RES细胞以45000个细胞/孔接种在96孔板中。将一块平板用于分析pNFκB，另一块用于分析细胞因子释放。然后将板在37℃，5％CO2下温育过夜。在血清饥饿(SS)培养基中以4x所需浓度稀释配体(IL36α、β或γ)和抗体。在配体之前将拮抗剂(抗体)加入细胞中。对于pNFκB:将NCI细胞+/-配体和拮抗剂在37℃，5％CO2温育1小时。然后吸出培养基，将细胞在100μl/孔的完全裂解缓冲液(Completelysis buffer)中于冰上裂解30分钟。然后将裂解物在2500RPM，20分钟，4℃下离心，并转移至MSD ELISA板，并按照制造商的方案测定pNFκB。对于细胞因子释放：刺激后18-24小时，将上清液转移至MSD ELISA板并按照制造商的操作规程测定细胞因子。
操作规程：pNFκB(S536)BaF/3食蟹猴IL-36R细胞的MSD ELISA
将BaF/3食蟹猴IL-36R细胞在SS培养基中以90,000个细胞/孔接种在96孔板中。对照孔中加入100μl培养基。将拮抗剂(抗体)以4x所需浓度稀释，并向每个孔中加入50μl。将配体(IL36α，β或γ)在SS培养基中以4x所需浓度稀释，并向每个孔中加入50μl(最终体积为200μl)。将板在37℃，5％CO2温育15分钟。将板短暂离心，吸出培养基，在100μl/孔完全裂解缓冲液中裂解细胞(参见MSDpNFκB操作规程)，在冰上温育30分钟。然后将裂解物在2500RPM，20分钟，4℃下离心并转移至MSD ELISA板。然后使用MSD试剂盒如上所述地评估裂解物的pNFκB活性。
结果：小鼠抗人IL-36R抗体在人功能测定法(pNFκB和细胞因子释放)和食蟹猴功能测定法(pNFκB)中与人IL-36配体的IC90结果显示在表2中。嵌合抗人IL-36R抗体在人功能测定法(pNFκB和细胞因子释放)和食蟹猴功能测定法(pNFκB)中与人IL-36配体的IC90结果显示在表3中。
表2：小鼠抗体在功能细胞测定法中的效力
(同种型对照显示在样品测试的最高浓度下未显示活性的抑制)
表3：嵌合抗体在功能细胞测定法中的效力
(同种型对照显示在样品测试的最高浓度下未显示活性的抑制)
| NCI/ADR-RES | C33D10 | C73C5 | C81B4 | |
| pNFκB | trun-IL-36a IC90(nM) | 1.9 | 2.1 | 1.3 |
| trun-IL-36b IC90(nM) | 2 | 0.9 | 0.9 | |
| trun-IL-36g IC90(nM) | 1.3 | 1.8 | 0.4 | |
| GM-CSF | trun-IL-36a IC90(nM) | 0.3 | 0.9 | ND |
| trun-IL-36b IC90(nM) | 0.3 | 1.1 | ND | |
| trun-IL-36g IC90(nM) | 0.3 | 0.7 | ND | |
| IL-6 | trun-IL-36a IC90(nM) | 0.4 | 2.1 | ND |
| trun-IL-36b IC90(nM) | 0.6 | 6.7 | ND | |
| trun-IL-36g IC90(nM) | 0.7 | 6 | ND | |
| IL-8 | trun-IL-36a IC90(nM) | 0.4 | 0.7 | 0.4 |
| trun-IL-36b IC90(nM) | 0.3 | 0.4 | 0.1 | |
| trun-IL-36g IC90(nM) | 0.2 | 0.4 | 0.1 | |
| TNFα | trun-IL-36a IC90(nM) | 2.4 | 2.5 | ND |
| trun-IL-36b IC90(nM) | 0.9 | 7.9 | ND | |
| trun-IL-36g IC90(nM) | 0.6 | 1.3 | ND | |
| BaF cyno | - | |||
| pNFκB | trun-IL-36a IC90(nM) | ND | 1.2 | 42 |
| trun-IL-36b IC90(nM) | ND | 4.1 | 48 | |
| trun-IL-36g IC90(nM) | ND | 4.3 | 28 |
实施例4：小鼠抗人IL-36R抗体与人IL-36R表达细胞的结合
通过流式细胞术结合抗体的方案
将用全长人IL-36R或NCI/ADR-RES细胞转染的HEK293细胞传代24小时，然后染色。通过用10ml含5mM EDTA的PBS冲洗从烧瓶中取出细胞，然后将细胞在37℃下与另外10ml的5mM EDTA和2.5ml的Accumax温育10分钟以使细胞解离/分散。然后将抗体在PBS+2％BSA中稀释至指定浓度，并将细胞在室温下温育20分钟。然后通过加入200μl PBS洗去过量的抗体，然后离心。然后以每孔50μl加入第二试剂，将细胞在室温下温育15分钟，然后如上洗涤。将细胞重悬于200μl PBS中并通过流式细胞术分析。小鼠抗人IL-36R抗体结合人IL-36RHEK转染子的结合EC50示于表4中。
表4
实施例5：人源化IL-36R抗体的产生
为了降低人体施用后的潜在免疫原性，通过设计和筛选过程使小鼠抗人IL-36R单克隆抗体81B4和73C5“人源化”。基于框架同源性、CDR结构、保守的规范残基、保守的界面包装残基及其他参数，为小鼠先导物选择人框架序列。相比于通过将CDR或HVL“直接交换”为人种系框架区域而形成的人源化抗体所显示的抗体性能，在这些框架位置中的氨基酸残基的特定取代可以改善抗体性能的各个方面，包括结合亲和力和/或稳定性。选择与嵌合亲本Fab相比显示出更好或相等的结合、且表达改善的Fab，用于进一步表征。抗体81B4和73C5的代表性人源化可变区显示在说明书部分中。以这种方式，抗体B1至抗体B6是衍生自小鼠抗体81B4的人源化抗体(克隆到人IgG1KO(KO＝敲除)/κ骨架中)。抗体B1至B6显示于表A中。抗体C1至抗体C3是源自小鼠抗体73C5的人源化抗体(克隆到人IgG1-KO(KO＝敲除)/κ骨架中)。抗体C1至C3显示在表C中。
实施例6：人源化IL-36R抗体的结合
使用Proteon(Bio-Rad，Hercules，CA)测量人源化抗IL-36R抗体与重组人IL-36R结合的动力学和结合亲和力。在5种不同的表面密度下固定化人IL-36R，并使用全局拟合分析结果(参见表5，显示了三次实验的结果)。通过流式细胞术使用实施例4中描述的规程测量人源化抗体与NCI/ADR-RES细胞的结合(EC90值参见表5)。
表5-人源化抗人IL-36R抗体的分子和细胞结合亲和力。
实施例7：人源化抗人IL-36R抗体在人功能性测定中的效力
如实施例3中所述测试了用来自人NCI/ADR-RES细胞的人源化IL-36R变体的信号传导的功能性阻断。人源化抗人IL-36R抗体与人IL-36配体在人功能测定(pNFκB和细胞因子释放)中的IC90结果显示在表6中。
表6：人功能性NCI/ADR-RES细胞测定法中人源化抗体的效力[IC90(nM)](结果等于至少2次实验的平均值。同种型对照在样品的最高浓度下没有显示活性抑制)
实施例8：抗IL-36R抗体在功能性人原代角质形成细胞测定法中的效力
操作规程：人原代表皮角质形成细胞pNFκB/细胞因子释放测定法
将细胞以30,000个细胞/孔接种在96孔板中的培养基中，并在37℃，5％CO2下温育过夜。基本上如实施例3中所述生成文库。结果：用人IL-36配体刺激的人原代角质形成细胞测定法(pNFκB和IL-8释放)中的小鼠、嵌合和人源化抗IL-36R抗体的IC90结果分别显示于表7、表8和表9中。
表7(同种型对照在样品的最高浓度下没有显示活性的抑制)
表8：嵌合抗IL-36R抗体在原代人角质形成细胞测定法中的效力
(同种型对照在样品测试的最高浓度下未显示活性的抑制)
表9：人源化抗IL-36R抗体在原代人角质形成细胞测定法中的效力
(同种型对照在样品测试的最高浓度下未显示活性的抑制)
实施例9：抗-IL-36R抗体在功能性人原代肠上皮细胞测定法中的效力
操作规程：人原代肠上皮细胞pNFκB/细胞因子释放测定法：
将细胞以30,000个细胞/孔接种在96孔板中的培养基中，并在37℃，5％CO2下温育过夜。然后如实施例3中所述进行测定。
结果：表10中显示了用人IL-36配体刺激的人原代肠上皮细胞测定法(pNFκB和IL-8释放)中小鼠抗IL-36R抗体的IC90结果。
表10：小鼠抗IL-36R抗体在原代人肠上皮细胞测定法中的效力
(同种型对照在样品测试的最高浓度下未显示活性的抑制)
| HIE | 73C5 | 81B4 | |
| pNFκB | trun-IL-36a IC90(nM) | 21 | 1.3 |
| trun-IL-36b IC90(nM) | 20 | 7.4 | |
| trun-IL-36g IC90(nM) | 32 | 9.5 | |
| IL-8 | trun-IL-36a IC90(nM) | 123 | 5.8 |
| trun-IL-36b IC90(nM) | 154 | 9.8 | |
| trun-IL-36g IC90(nM) | ND | 16 |
实施例10：抗IL-36R抗体在功能性人原代肠肌成纤维细胞测定法中的效力
操作规程：人原代肠道肌成纤维细胞pNFκB/细κ胞因子释放测定法
将细胞以30,000个细胞/孔接种在96孔板中的培养基中，并在37℃，5％CO2下温育。然后如实施例3中所述进行测定。
结果：用人IL-36配体刺激的人原代肠肌成纤维细胞测定法(pNFκB和IL-8释放)中抗IL-36R抗体的IC90结果显示在表11和表12中。
表11：小鼠和嵌合抗IL-36R抗体在原代人肠肌成纤维细胞测定法中的效力
(同种型对照在样品测试的最高浓度下未显示活性的抑制)
表12：人源化抗IL-36R抗体在原代人肠肌成纤维细胞测定法中的效力
(同种型对照在样品测试的最高浓度下未显示活性的抑制)
实施例11：抗IL-36R抗体在功能性人原代真皮成纤维细胞测定法中的效力
操作规程：人原代真皮成纤维细胞pNFκB/细胞因子释放测定法
将细胞以30,000个细胞/孔接种在96孔板中的培养基中，并在37℃，5％CO 2下温育过夜。然后如实施例3中所述进行测定。
结果：用人IL-36配体刺激的人原代真皮成纤维细胞测定(pNFkB和IL-8释放)中抗IL-36R抗体的IC90结果显示在表13和表14中。
表13：小鼠和嵌合抗IL-36R抗体在原代人真皮成纤维细胞测定法中的效力
(同种型对照在样品测试的最高浓度下未显示活性的抑制)
表14：人源化抗IL-36R抗体在原代人真皮成纤维细胞测定法中的效力
(同种型对照在样品测试的最高浓度下未显示活性的抑制)
实施例12：小鼠抗IL-36R抗体在功能性人原代近端肾小管细胞测定法中的效力
操作规程：人原代近端肾小管细胞pNFκB/细胞因子释放测定法。
将细胞以5,000个细胞/孔接种在96孔板中的培养基中，并在37℃，5％CO2下温育过夜。如实施例3中所述进行试验。
结果：表15中显示了用人IL-36配体刺激的人原代近端肾小管细胞测定(IL-8释放)中小鼠抗IL-36R抗体、嵌合抗IL-36R抗体和人源化抗IL-36R抗体的IC90结果。
表15：小鼠和人类抗IL-36R抗体在原代人近端肾小管细胞测定法中的效力
(同种型对照在样品测试的最高浓度下未显示活性的抑制)
实施例13：IL-36抑制IL-8的产生刺激γ了重建的人表皮
重建表皮操作规程
将抗IL-36R抗体(1.5μg/ml)与重建的人表皮预温育，并用人重组IL-36γ(20ng/ml)刺激。使用重组人IL-1β(20ng/ml；R&D Systems)作为阳性对照。培养24小时后，收集细胞上清液并测定IL-8(IL-8的测定法描述于实施例3中)。样品一式三份进行测试，平均pg/ml±标准误差显示在下表中(表16)。
表16
实施例14：IL-36配体的抑制诱导了重建人表皮中的S100A7和S100A12基因表达
用竞争性(agonistic)IL-36配体刺激重建的人表皮，诱导了S100A7和S100A12基因表达。S100A7和S100A12是位于表皮分化复合体内的基因。
操作规程：将重建的人表皮与抗IL-36R抗体(1.5μg/ml)一起温育，并用人重组IL-36γ(20ng/ml)刺激。使用重组人IL-1β(20ng/mL；R&D Systems)作为阳性对照。在5％CO2和37℃培养24小时后，从重建的人表皮中分离RNA，并通过实时逆转录酶-聚合酶链反应测定基因表达。使用2-ΔΔCt方法计算相对表达。样品一式三份进行测试，平均表达±标准误差显示在下表中(表17)。
表17
实施例15：抗IL-36R抗体在银屑病异种移植模型中的疗效
操作规程：从皮肤科医生临床诊断的24名银屑病患者获得血液和非病变皮肤活检。将皮肤活检移植到免疫缺陷的NIH-III小鼠上，并容许其植活4到5周。
在活组织检查时从每个供体收集的血液中分离外周血单个核细胞(PBMC)，用于皮内注射到植活的皮肤中。在注射之前，用1μg/ml葡萄球菌肠毒素B(Toxin Technologies，Florida，USA)和80U/ml人重组IL-2(Peprotech Inc.，Oosterhout，The Netherlands)刺激PBMC。用PBS中的7.5×105个细胞皮内注射自体PBMC以同步诱导皮肤炎症和银屑病表型。注射细胞三周后，从小鼠中取出活检并通过组织学分析。
对所有组的冷冻保存的皮肤组织进行组织学染色。如图4所述制备覆盖所有表层的对角线切片(8μm)。为了评估表皮厚度，从活检查中心随机选择两片非连续切片并用苏木精-伊红染色。随后，以100倍放大率评估切片。在两片切片中，在整块活检的长度上，使用Olympus DP71相机和Cell^D成像软件(V2.7，Munster，Germany)测量皮嵴长度(ridgelengths)。皮嵴长度定义为：颗粒层上边缘到皮嵴底部之间的距离。对活检进行随机和盲法评分。
表18中显示了每个处理组的平均表皮厚度和最大表皮厚度的结果。表19中显示了每个处理组中表皮厚度的净变化的结果。
表18
表19
实施例16：在野生型和白细胞介素-1受体样2纯合基因敲除小鼠中暴露于香烟烟雾3周后的亚慢性肺部炎症
操作规程：将野生型或白细胞介素-1受体样2小鼠暴露于香烟烟雾中3周以诱导肺窘迫。第1周和第2周由连续5个暴露日组成，而小鼠在第3周期间连续暴露4天。小鼠每天以24分钟的周期(香烟16分钟，新鲜空气8分钟)暴露于5支香烟。在最后一次暴露后18小时，用2×0.8ml Hank氏盐溶液(0.6mM EDTA)灌洗小鼠。离心10分钟后，从支气管肺泡灌洗液中收集上清液和细胞沉淀。表20显示了每个暴露组在支气管肺泡灌洗中巨噬细胞和嗜中性白细胞的总数。
表20
序列表
<110> BOECHER, Wulf Otto
<120> 抗IL-36R抗体联合治疗
<130> 09-0671-WO-1
<150> 62/476,940
<151> 2017-03-27
<160> 140
<170> PatentIn version 3.5
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Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Phe Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105 110
<210> 5
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 5
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Tyr Lys Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Leu Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Gly Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Ser Leu Thr Ile Ser Asn Leu Glu Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Asp Ser Lys Phe Pro Trp
85 90 95
Thr Phe Gly Gly Asp Thr Lys Leu Glu Ile Lys
100 105
<210> 6
<211> 108
<212> PRT
<213> Mus sp.
<400> 6
Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Leu Gly
1 5 10 15
Glu Arg Val Thr Met Thr Cys Thr Ala Ser Ser Ser Val Ser Ser Ser
20 25 30
Tyr Phe His Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pro Lys Leu Trp
35 40 45
Ile Tyr Arg Thr Ser Asn Leu Ala Ser Gly Val Pro Gly Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu
65 70 75 80
Ala Glu Asp Ala Ala Thr Tyr Tyr Cys His Gln Phe His Arg Ser Pro
85 90 95
Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 7
<211> 107
<212> PRT
<213> Mus sp.
<400> 7
Asp Ile Val Met Thr Gln Ser Gln Lys Phe Leu Ser Thr Ser Val Gly
1 5 10 15
Val Arg Val Ser Val Thr Cys Lys Ala Ser Gln Asp Val Gly Thr Asn
20 25 30
Val Leu Trp Tyr Gln Gln Lys Ile Gly Gln Ser Pro Lys Pro Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg His Ser Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ile Ile Ser Asn Val Gln Ser
65 70 75 80
Glu Asp Leu Ala Glu Tyr Phe Cys Gln Gln Tyr Ser Arg Tyr Pro Leu
85 90 95
Thr Phe Gly Pro Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 8
<211> 107
<212> PRT
<213> Mus sp.
<400> 8
Asp Ile Val Met Thr Gln Ser Gln Lys Phe Leu Ser Thr Ser Val Gly
1 5 10 15
Val Arg Val Ser Val Thr Cys Lys Ala Ser Gln Asp Val Gly Thr Asn
20 25 30
Val Leu Trp Tyr Gln Gln Lys Ile Gly Gln Ser Pro Lys Ala Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg His Ser Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ile Ile Thr Asn Val Gln Ser
65 70 75 80
Glu Asp Leu Ala Glu Tyr Phe Cys Gln Gln Tyr Ser Arg Tyr Pro Leu
85 90 95
Thr Phe Gly Pro Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 9
<211> 107
<212> PRT
<213> Mus sp.
<400> 9
Asp Ile Val Met Thr Gln Ser Gln Lys Phe Met Ser Ala Thr Val Gly
1 5 10 15
Gly Arg Val Asn Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Arg Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Thr
35 40 45
His Ser Ala Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Thr Asn Met Gln Ser
65 70 75 80
Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln Tyr Ser Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Asp Leu Lys
100 105
<210> 10
<211> 107
<212> PRT
<213> Mus sp.
<400> 10
Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Gln Ser Ala Ser Leu Gly
1 5 10 15
Glu Ser Val Thr Phe Ser Cys Leu Ala Ser Gln Thr Ile Gly Thr Trp
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Gln Leu Leu Ile
35 40 45
Tyr Arg Ala Thr Ser Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asn Phe Ser Phe Lys Ile Ser Ser Leu Gln Ala
65 70 75 80
Glu Asp Leu Ala Ser Tyr Tyr Cys Gln Gln Leu Tyr Ser Gly Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Arg
100 105
<210> 11
<211> 119
<212> PRT
<213> Mus sp.
<400> 11
Gln Val Gln Leu Gln Gln Ser Gly Thr Glu Leu Leu Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Asn Thr Val Thr Ser Tyr
20 25 30
Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Leu Pro Ser Thr Gly Arg Thr Asn Tyr Asn Glu Asn Phe
50 55 60
Lys Gly Lys Ala Met Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Thr Ile Val Tyr Phe Gly Asn Pro Trp Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ala
115
<210> 12
<211> 125
<212> PRT
<213> Mus sp.
<400> 12
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Asn
20 25 30
Tyr Met Asn Trp Val Arg Gln Ser His Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Arg Val Asn Pro Ser Asn Gly Asp Thr Lys Tyr Asn Gln Asn Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Leu Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Gly Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Gly Arg Thr Lys Asn Phe Tyr Ser Ser Tyr Ser Tyr Asp Asp Ala Met
100 105 110
Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser
115 120 125
<210> 13
<211> 124
<212> PRT
<213> Mus sp.
<400> 13
Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Phe Val Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Phe Ser Cys Thr Ala Ser Gly Phe Asn Ile Lys Asp Asp
20 25 30
Tyr Ile His Trp Val Arg Gln Arg Pro Glu Gln Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Asp Pro Ala Asn Gly Asn Thr Lys Tyr Ala Pro Lys Phe
50 55 60
Gln Asp Lys Ala Thr Ile Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr
65 70 75 80
Leu Gln Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Ser Phe Pro Asn Asn Tyr Tyr Ser Tyr Asp Asp Ala Phe Ala
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
115 120
<210> 14
<211> 118
<212> PRT
<213> Mus sp.
<400> 14
Gln Val Gln Leu Lys Glu Ser Gly Pro Val Leu Val Ala Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Lys Phe
20 25 30
Gly Val His Trp Ile Arg Gln Thr Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ala Gly Gly Pro Thr Asn Tyr Asn Ser Ala Leu Met
50 55 60
Ser Arg Leu Thr Ile Ser Lys Asp Ile Ser Gln Ser Gln Val Phe Leu
65 70 75 80
Arg Ile Asp Ser Leu Gln Thr Asp Asp Thr Ala Met Tyr Tyr Cys Ala
85 90 95
Lys Gln Ile Tyr Tyr Ser Thr Leu Val Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Ser Val Thr Val Ser Ser
115
<210> 15
<211> 120
<212> PRT
<213> Mus sp.
<400> 15
Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln
1 5 10 15
Ser Leu Phe Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Ser Tyr
20 25 30
Glu Ile Asn Trp Val Arg Gln Val Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Thr Gly Ile Thr Thr Asn Tyr Asn Ser Ala Leu Ile
50 55 60
Ser Arg Leu Ser Ile Ser Lys Asp Asn Ser Lys Ser Leu Val Phe Leu
65 70 75 80
Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Arg Gly Thr Gly Thr Gly Phe Tyr Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 16
<211> 119
<212> PRT
<213> Mus sp.
<400> 16
Gln Val Gln Leu Gln Gln Pro Gly Ala Asp Phe Val Arg Pro Gly Ala
1 5 10 15
Ser Met Arg Leu Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Ser
20 25 30
Trp Ile His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn Pro Gly Asn Val Arg Thr Asn Tyr Asn Glu Asn Phe
50 55 60
Arg Asn Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Thr Thr Ala Tyr
65 70 75 80
Met Gln Leu Arg Ser Leu Thr Ser Ala Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Thr Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ala
115
<210> 17
<211> 119
<212> PRT
<213> Mus sp.
<400> 17
Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr
20 25 30
Ala Val His Trp Val Arg Gln Phe Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ser Asp Gly Ser Thr Asp Phe Asn Ala Pro Phe Lys
50 55 60
Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe
65 70 75 80
Lys Met Asn Ser Leu Gln Ile Asp Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Arg Lys Gly Gly Tyr Ser Gly Ser Trp Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ala
115
<210> 18
<211> 119
<212> PRT
<213> Mus sp.
<400> 18
Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr
20 25 30
Ala Val His Trp Val Arg Gln Phe Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ser Asp Gly Ser Thr Asp Tyr Asn Ala Pro Phe Lys
50 55 60
Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe
65 70 75 80
Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Arg Lys Gly Gly Tyr Ser Gly Ser Trp Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ala
115
<210> 19
<211> 117
<212> PRT
<213> Mus sp.
<400> 19
Gln Val Gln Leu Lys Glu Ser Gly Pro Val Leu Val Ala Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr
20 25 30
Gly Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Pro Val Gly Ser Thr Asn Tyr Asn Ser Ala Leu Met
50 55 60
Ser Arg Leu Ser Ile His Lys Asp Asn Ser Lys Ser Gln Val Phe Leu
65 70 75 80
Arg Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Lys Met Asp Trp Asp Asp Phe Phe Asp Tyr Trp Gly Gln Gly Thr Thr
100 105 110
Leu Thr Val Ser Ser
115
<210> 20
<211> 124
<212> PRT
<213> Mus sp.
<400> 20
Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ala
1 5 10 15
Ser Val Arg Leu Ser Cys Thr Ala Ser Gly Phe Asn Ile Lys Asp Asp
20 25 30
Tyr Ile His Trp Val Arg Gln Arg Pro Lys Gln Gly Leu Glu Trp Leu
35 40 45
Gly Arg Ile Asp Pro Ala Asn Gly Asn Thr Lys Tyr Asp Pro Arg Phe
50 55 60
Gln Asp Lys Ala Thr Ile Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr
65 70 75 80
Leu His Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Ser Phe Pro Asp Asn Tyr Tyr Ser Tyr Asp Asp Ala Phe Ala
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
115 120
<210> 21
<211> 12
<212> PRT
<213> Mus sp.
<400> 21
Thr Ala Ser Ser Ser Val Ser Ser Ser Tyr Leu His
1 5 10
<210> 22
<211> 11
<212> PRT
<213> Mus sp.
<400> 22
Leu Ala Ser Gln Thr Ile Gly Thr Trp Leu Ala
1 5 10
<210> 23
<211> 11
<212> PRT
<213> Mus sp.
<400> 23
Leu Ala Ser Gln Thr Ile Gly Thr Trp Leu Gly
1 5 10
<210> 24
<211> 16
<212> PRT
<213> Mus sp.
<400> 24
Arg Ser Ser Gln Asn Ile Val His Ser Asn Gly Asn Thr Tyr Leu Gln
1 5 10 15
<210> 25
<211> 11
<212> PRT
<213> Mus sp.
<400> 25
Arg Ala Ser Gln Asp Ile Tyr Lys Tyr Leu Asn
1 5 10
<210> 26
<211> 12
<212> PRT
<213> Mus sp.
<400> 26
Thr Ala Ser Ser Ser Val Ser Ser Ser Tyr Phe His
1 5 10
<210> 27
<211> 11
<212> PRT
<213> Mus sp.
<400> 27
Lys Ala Ser Gln Asp Val Gly Thr Asn Val Leu
1 5 10
<210> 28
<211> 11
<212> PRT
<213> Mus sp.
<400> 28
Lys Ala Ser Gln Asn Val Gly Arg Ala Val Ala
1 5 10
<210> 29
<211> 11
<212> PRT
<213> Mus sp.
<400> 29
Leu Ala Ser Gln Thr Ile Gly Thr Trp Leu Gly
1 5 10
<210> 30
<211> 7
<212> PRT
<213> Mus sp.
<400> 30
Ser Thr Ser Asn Leu Ala Ser
1 5
<210> 31
<211> 7
<212> PRT
<213> Mus sp.
<400> 31
Ala Ala Thr Ser Leu Ala Asp
1 5
<210> 32
<211> 7
<212> PRT
<213> Mus sp.
<400> 32
Arg Ser Thr Thr Leu Ala Asp
1 5
<210> 33
<211> 7
<212> PRT
<213> Mus sp.
<400> 33
Lys Val Ser Asn Arg Phe Ser
1 5
<210> 34
<211> 7
<212> PRT
<213> Mus sp.
<400> 34
Tyr Thr Ser Gly Leu His Ser
1 5
<210> 35
<211> 7
<212> PRT
<213> Mus sp.
<400> 35
Arg Thr Ser Asn Leu Ala Ser
1 5
<210> 36
<211> 7
<212> PRT
<213> Mus sp.
<400> 36
Ser Ala Ser Tyr Arg His Ser
1 5
<210> 37
<211> 7
<212> PRT
<213> Mus sp.
<400> 37
Ser Ala Ser Asn Arg Tyr Thr
1 5
<210> 38
<211> 7
<212> PRT
<213> Mus sp.
<400> 38
Arg Ala Thr Ser Leu Ala Asp
1 5
<210> 39
<211> 9
<212> PRT
<213> Mus sp.
<400> 39
His Gln His His Arg Ser Pro Val Thr
1 5
<210> 40
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
peptide
<400> 40
Gln Gln Val Tyr Thr Thr Pro Leu Thr
1 5
<210> 41
<211> 9
<212> PRT
<213> Mus sp.
<400> 41
Gln Gln Leu Tyr Ser Ala Pro Tyr Thr
1 5
<210> 42
<211> 9
<212> PRT
<213> Mus sp.
<400> 42
Phe Gln Gly Ser His Val Pro Phe Thr
1 5
<210> 43
<211> 9
<212> PRT
<213> Mus sp.
<400> 43
Gln Gln Asp Ser Lys Phe Pro Trp Thr
1 5
<210> 44
<211> 9
<212> PRT
<213> Mus sp.
<400> 44
His Gln Phe His Arg Ser Pro Leu Thr
1 5
<210> 45
<211> 9
<212> PRT
<213> Mus sp.
<400> 45
Gln Gln Tyr Ser Arg Tyr Pro Leu Thr
1 5
<210> 46
<211> 9
<212> PRT
<213> Mus sp.
<400> 46
Gln Gln Tyr Ser Ser Tyr Pro Leu Thr
1 5
<210> 47
<211> 9
<212> PRT
<213> Mus sp.
<400> 47
Gln Gln Leu Tyr Ser Gly Pro Tyr Thr
1 5
<210> 48
<211> 10
<212> PRT
<213> Mus sp.
<400> 48
Gly Asn Thr Val Thr Ser Tyr Trp Met His
1 5 10
<210> 49
<211> 10
<212> PRT
<213> Mus sp.
<400> 49
Gly Tyr Thr Phe Thr Asp Asn Tyr Met Asn
1 5 10
<210> 50
<211> 10
<212> PRT
<213> Mus sp.
<400> 50
Gly Phe Asn Ile Lys Asp Asp Tyr Ile His
1 5 10
<210> 51
<211> 10
<212> PRT
<213> Mus sp.
<400> 51
Gly Phe Ser Leu Thr Lys Phe Gly Val His
1 5 10
<210> 52
<211> 10
<212> PRT
<213> Mus sp.
<400> 52
Gly Phe Ser Leu Ser Ser Tyr Glu Ile Asn
1 5 10
<210> 53
<211> 10
<212> PRT
<213> Mus sp.
<400> 53
Gly Tyr Ser Phe Thr Ser Ser Trp Ile His
1 5 10
<210> 54
<211> 10
<212> PRT
<213> Mus sp.
<400> 54
Gly Phe Ser Leu Thr Asn Tyr Ala Val His
1 5 10
<210> 55
<211> 10
<212> PRT
<213> Mus sp.
<400> 55
Gly Phe Ser Leu Thr Asn Tyr Gly Val His
1 5 10
<210> 56
<211> 10
<212> PRT
<213> Mus sp.
<400> 56
Gly Phe Asn Ile Lys Asp Asp Tyr Ile His
1 5 10
<210> 57
<211> 17
<212> PRT
<213> Mus sp.
<400> 57
Glu Ile Leu Pro Ser Thr Gly Arg Thr Asn Tyr Asn Glu Asn Phe Lys
1 5 10 15
Gly
<210> 58
<211> 17
<212> PRT
<213> Mus sp.
<400> 58
Arg Val Asn Pro Ser Asn Gly Asp Thr Lys Tyr Asn Gln Asn Phe Lys
1 5 10 15
Gly
<210> 59
<211> 17
<212> PRT
<213> Mus sp.
<400> 59
Arg Ile Asp Pro Ala Asn Gly Asn Thr Lys Tyr Ala Pro Lys Phe Gln
1 5 10 15
Asp
<210> 60
<211> 16
<212> PRT
<213> Mus sp.
<400> 60
Val Ile Trp Ala Gly Gly Pro Thr Asn Tyr Asn Ser Ala Leu Met Ser
1 5 10 15
<210> 61
<211> 16
<212> PRT
<213> Mus sp.
<400> 61
Val Ile Trp Thr Gly Ile Thr Thr Asn Tyr Asn Ser Ala Leu Ile Ser
1 5 10 15
<210> 62
<211> 15
<212> PRT
<213> Mus sp.
<400> 62
Glu Ile Asn Pro Gly Asn Val Arg Thr Asn Tyr Asn Glu Asn Phe
1 5 10 15
<210> 63
<211> 16
<212> PRT
<213> Mus sp.
<400> 63
Val Ile Trp Ser Asp Gly Ser Thr Asp Phe Asn Ala Pro Phe Lys Ser
1 5 10 15
<210> 64
<211> 16
<212> PRT
<213> Mus sp.
<400> 64
Val Ile Trp Ser Asp Gly Ser Thr Asp Tyr Asn Ala Pro Phe Lys Ser
1 5 10 15
<210> 65
<211> 16
<212> PRT
<213> Mus sp.
<400> 65
Val Ile Trp Pro Val Gly Ser Thr Asn Tyr Asn Ser Ala Leu Met Ser
1 5 10 15
<210> 66
<211> 17
<212> PRT
<213> Mus sp.
<400> 66
Arg Ile Asp Pro Ala Asn Gly Asn Thr Lys Tyr Asp Pro Arg Phe Gln
1 5 10 15
Asp
<210> 67
<211> 10
<212> PRT
<213> Mus sp.
<400> 67
Val Tyr Phe Gly Asn Pro Trp Phe Ala Tyr
1 5 10
<210> 68
<211> 16
<212> PRT
<213> Mus sp.
<400> 68
Thr Lys Asn Phe Tyr Ser Ser Tyr Ser Tyr Asp Asp Ala Met Asp Tyr
1 5 10 15
<210> 69
<211> 15
<212> PRT
<213> Mus sp.
<400> 69
Ser Phe Pro Asn Asn Tyr Tyr Ser Tyr Asp Asp Ala Phe Ala Tyr
1 5 10 15
<210> 70
<211> 10
<212> PRT
<213> Mus sp.
<400> 70
Gln Ile Tyr Tyr Ser Thr Leu Val Asp Tyr
1 5 10
<210> 71
<211> 12
<212> PRT
<213> Mus sp.
<400> 71
Gly Thr Gly Thr Gly Phe Tyr Tyr Ala Met Asp Tyr
1 5 10
<210> 72
<211> 10
<212> PRT
<213> Mus sp.
<400> 72
Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr
1 5 10
<210> 73
<211> 11
<212> PRT
<213> Mus sp.
<400> 73
Lys Gly Gly Tyr Ser Gly Ser Trp Phe Ala Tyr
1 5 10
<210> 74
<211> 9
<212> PRT
<213> Mus sp.
<400> 74
Met Asp Trp Asp Asp Phe Phe Asp Tyr
1 5
<210> 75
<211> 15
<212> PRT
<213> Mus sp.
<400> 75
Ser Phe Pro Asp Asn Tyr Tyr Ser Tyr Asp Asp Ala Phe Ala Tyr
1 5 10 15
<210> 76
<211> 108
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 76
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Met Ser Cys Thr Ala Ser Ser Ser Val Ser Ser Ser
20 25 30
Tyr Phe His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Arg Thr Ser Thr Leu Ala Ser Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Ala Ala Thr Tyr Tyr Cys His Gln Phe His Arg Ser Pro
85 90 95
Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 77
<211> 108
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 77
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Met Ser Cys Thr Ala Ser Ser Ser Val Ser Ser Ser
20 25 30
Tyr Phe His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Arg Thr Ser Ile Leu Ala Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys His Gln Phe His Arg Ser Pro
85 90 95
Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 78
<211> 108
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 78
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Met Ser Cys Thr Ala Ser Ser Ser Val Ser Ser Ser
20 25 30
Tyr Phe His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Trp
35 40 45
Ile Tyr Arg Thr Ser Arg Leu Ala Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Ala Ala Thr Tyr Tyr Cys His Gln Phe His Arg Ser Pro
85 90 95
Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 79
<211> 108
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 79
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Met Thr Cys Thr Ala Ser Ser Ser Val Ser Ser Ser
20 25 30
Tyr Phe His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Arg Thr Ser Arg Leu Ala Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys His Gln Phe His Arg Ser Pro
85 90 95
Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 80
<211> 108
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 80
Gln Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Met Thr Cys Thr Ala Ser Ser Ser Val Ser Ser Ser
20 25 30
Tyr Phe His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Trp
35 40 45
Ile Tyr Arg Thr Ser Arg Leu Ala Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Ala Ala Thr Tyr Tyr Cys His Gln Phe His Arg Ser Pro
85 90 95
Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 81
<211> 108
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 81
Gln Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Val Thr Met Ser Cys Thr Ala Ser Ser Ser Val Ser Ser Ser
20 25 30
Tyr Phe His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Arg Thr Ser Gln Leu Ala Ser Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Ala Ala Thr Tyr Tyr Cys His Gln Phe His Arg Ser Pro
85 90 95
Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 82
<211> 108
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 82
Gln Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Met Thr Cys Thr Ala Ser Ser Ser Val Ser Ser Ser
20 25 30
Tyr Phe His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Arg Thr Ser Lys Leu Ala Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys His Gln Phe His Arg Ser Pro
85 90 95
Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 83
<211> 108
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 83
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Met Ser Cys Thr Ala Ser Ser Ser Val Ser Ser Ser
20 25 30
Tyr Phe His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Arg Thr Ser His Leu Ala Ser Gly Ile Pro Gly Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Ala Ala Val Tyr Tyr Cys His Gln Phe His Arg Ser Pro
85 90 95
Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 84
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 84
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Val Arg Ala Thr Leu Ser Cys Lys Ala Ser Gln Asp Val Gly Thr Asn
20 25 30
Val Leu Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Pro Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg His Ser Gly Ile Pro Asp 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 Glu Tyr Phe Cys Gln Gln Tyr Ser Arg Tyr Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 85
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 85
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Val Arg Ala Thr Leu Ser Cys Lys Ala Ser Gln Asp Val Gly Thr Asn
20 25 30
Val Leu Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Pro Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg His Ser Gly Ile Pro Asp 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 Arg Tyr Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 86
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 86
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Val Arg Ala Thr Leu Ser Cys Lys Ala Ser Gln Asp Val Gly Thr Asn
20 25 30
Val Leu Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Pro Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg His Ser Gly Ile 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 Glu Tyr Tyr Cys Gln Gln Tyr Ser Arg Tyr Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 87
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 87
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Ser
20 25 30
Trp Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn Pro Gly Asn Val Arg Thr Asn Tyr Asn Glu Asn Phe
50 55 60
Arg Asn Lys Ala Thr Met Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 88
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 88
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Ser
20 25 30
Trp Ile His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn Pro Gly Asn Val Arg Thr Asn Tyr Asn Glu Asn Phe
50 55 60
Arg Asn Arg Val Thr Met Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 89
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 89
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Ser
20 25 30
Trp Ile His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Ile Asn Pro Gly Asn Val Arg Thr Asn Tyr Asn Glu Asn Phe
50 55 60
Arg Asn Lys Val Thr Met Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 90
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 90
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Ser
20 25 30
Trp Ile His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Ile Asn Pro Gly Asn Val Arg Thr Asn Tyr Asn Glu Asn Phe
50 55 60
Arg Asn Arg Ala Thr Leu Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 91
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 91
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Ser
20 25 30
Trp Ile His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Ile Leu Pro Gly Val Val Arg Thr Asn Tyr Asn Glu Asn Phe
50 55 60
Arg Asn Lys Val Thr Met Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 92
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 92
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Ser
20 25 30
Trp Ile His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn Pro Gly Ala Val Arg Thr Asn Tyr Asn Glu Asn Phe
50 55 60
Arg Asn Arg Val Thr Met Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 93
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 93
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Ser
20 25 30
Trp Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn Pro Gly Leu Val Arg Thr Asn Tyr Asn Glu Asn Phe
50 55 60
Arg Asn Lys Val Thr Met Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 94
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 94
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Ser
20 25 30
Trp Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn Pro Gly Ala Val Arg Thr Asn Tyr Asn Glu Asn Phe
50 55 60
Arg Asn Lys Val Thr Met Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 95
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 95
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Ser
20 25 30
Trp Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn Pro Gly Ser Val Arg Thr Asn Tyr Asn Glu Asn Phe
50 55 60
Arg Asn Lys Ala Thr Met Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 96
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 96
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asp Tyr
20 25 30
Ala Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Trp Ser Asp Gly Ser Thr Asp Tyr Asn Ala Pro Phe Lys
50 55 60
Ser Arg Val Thr Ile Asn Lys Asp Thr Ser Lys Ser Gln Val Ser Phe
65 70 75 80
Lys Met Ser Ser Val Gln Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Lys Gly Gly Tyr Ser Gly Ser Trp Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 97
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 97
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asp Tyr
20 25 30
Ala Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Trp Ser Asp Gly Ser Thr Asp Tyr Asn Ala Pro Phe Lys
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Ser Leu
65 70 75 80
Lys Met Asn Ser Leu Thr Thr Asp Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Lys Gly Gly Tyr Ser Gly Ser Trp Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 98
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 98
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asp Tyr
20 25 30
Ala Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Trp Ser Asp Gly Ser Thr Asp Tyr Asn Ala Pro Phe Lys
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Ser Leu
65 70 75 80
Lys Met Asn Ser Val Thr Val Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Lys Gly Gly Tyr Ser Gly Ser Trp Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 99
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 99
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asp Tyr
20 25 30
Ala Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Trp Ser Asp Gly Ser Thr Asp Tyr Asn Ala Pro Phe Lys
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Ser Phe
65 70 75 80
Lys Leu Ser Ser Val Thr Val Asp Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Lys Gly Gly Tyr Ser Gly Ser Trp Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 100
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 100
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asp Tyr
20 25 30
Ala Val His Trp Ile Arg Gln Phe Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Trp Ser Asp Gly Ser Thr Asp Phe Asn Ala Pro Phe Lys
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Ser Phe
65 70 75 80
Lys Leu Ser Ser Val Thr Thr Asp Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Lys Gly Gly Tyr Ser Gly Ser Trp Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 101
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 101
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asp Tyr
20 25 30
Ala Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Trp Ser Asp Gly Ser Thr Asp Tyr Asn Ala Pro Phe Lys
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Ser Phe
65 70 75 80
Lys Met Ser Ser Val Thr Ala Asp Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Lys Gly Gly Tyr Ser Gly Ser Trp Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 102
<211> 7
<212> PRT
<213> Mus sp.
<400> 102
Arg Thr Ser Thr Leu Ala Ser
1 5
<210> 103
<211> 7
<212> PRT
<213> Mus sp.
<400> 103
Arg Thr Ser Ile Leu Ala Ser
1 5
<210> 104
<211> 7
<212> PRT
<213> Mus sp.
<400> 104
Arg Thr Ser Arg Leu Ala Ser
1 5
<210> 105
<211> 7
<212> PRT
<213> Mus sp.
<400> 105
Arg Thr Ser Gln Leu Ala Ser
1 5
<210> 106
<211> 7
<212> PRT
<213> Mus sp.
<400> 106
Arg Thr Ser Lys Leu Ala Ser
1 5
<210> 107
<211> 10
<212> PRT
<213> Mus sp.
<400> 107
Gly Phe Ser Leu Thr Asp Tyr Ala Val His
1 5 10
<210> 108
<211> 15
<212> PRT
<213> Mus sp.
<400> 108
Glu Ile Leu Pro Gly Val Val Arg Thr Asn Tyr Asn Glu Asn Phe
1 5 10 15
<210> 109
<211> 15
<212> PRT
<213> Mus sp.
<400> 109
Glu Ile Asn Pro Gly Ala Val Arg Thr Asn Tyr Asn Glu Asn Phe
1 5 10 15
<210> 110
<211> 15
<212> PRT
<213> Mus sp.
<400> 110
Glu Ile Asn Pro Gly Leu Val Arg Thr Asn Tyr Asn Glu Asn Phe
1 5 10 15
<210> 111
<211> 15
<212> PRT
<213> Mus sp.
<400> 111
Glu Ile Asn Pro Gly Ser Val Arg Thr Asn Tyr Asn Glu Asn Phe
1 5 10 15
<210> 112
<211> 330
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 112
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
Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Ala Ala 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 Glu Glu
225 230 235 240
Met 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 Lys
325 330
<210> 113
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 113
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> 114
<211> 215
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 114
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Met Ser Cys Thr Ala Ser Ser Ser Val Ser Ser Ser
20 25 30
Tyr Phe His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Arg Thr Ser Thr Leu Ala Ser Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Ala Ala Thr Tyr Tyr Cys His Gln Phe His Arg Ser Pro
85 90 95
Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 115
<211> 215
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 115
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Met Ser Cys Thr Ala Ser Ser Ser Val Ser Ser Ser
20 25 30
Tyr Phe His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Arg Thr Ser Ile Leu Ala Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys His Gln Phe His Arg Ser Pro
85 90 95
Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 116
<211> 215
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 116
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Met Ser Cys Thr Ala Ser Ser Ser Val Ser Ser Ser
20 25 30
Tyr Phe His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Trp
35 40 45
Ile Tyr Arg Thr Ser Arg Leu Ala Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Ala Ala Thr Tyr Tyr Cys His Gln Phe His Arg Ser Pro
85 90 95
Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 117
<211> 215
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 117
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Met Thr Cys Thr Ala Ser Ser Ser Val Ser Ser Ser
20 25 30
Tyr Phe His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Arg Thr Ser Arg Leu Ala Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys His Gln Phe His Arg Ser Pro
85 90 95
Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 118
<211> 215
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 118
Gln Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Met Thr Cys Thr Ala Ser Ser Ser Val Ser Ser Ser
20 25 30
Tyr Phe His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Trp
35 40 45
Ile Tyr Arg Thr Ser Arg Leu Ala Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Ala Ala Thr Tyr Tyr Cys His Gln Phe His Arg Ser Pro
85 90 95
Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 119
<211> 215
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 119
Gln Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Val Thr Met Ser Cys Thr Ala Ser Ser Ser Val Ser Ser Ser
20 25 30
Tyr Phe His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Arg Thr Ser Gln Leu Ala Ser Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Ala Ala Thr Tyr Tyr Cys His Gln Phe His Arg Ser Pro
85 90 95
Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 120
<211> 215
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 120
Gln Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Met Thr Cys Thr Ala Ser Ser Ser Val Ser Ser Ser
20 25 30
Tyr Phe His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Arg Thr Ser Lys Leu Ala Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys His Gln Phe His Arg Ser Pro
85 90 95
Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 121
<211> 215
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 121
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Met Ser Cys Thr Ala Ser Ser Ser Val Ser Ser Ser
20 25 30
Tyr Phe His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Arg Thr Ser His Leu Ala Ser Gly Ile Pro Gly Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Ala Ala Val Tyr Tyr Cys His Gln Phe His Arg Ser Pro
85 90 95
Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 122
<211> 214
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 122
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Val Arg Ala Thr Leu Ser Cys Lys Ala Ser Gln Asp Val Gly Thr Asn
20 25 30
Val Leu Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Pro Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg His Ser Gly Ile Pro Asp 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 Glu Tyr Phe Cys Gln Gln Tyr Ser Arg Tyr Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Lys 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> 123
<211> 214
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 123
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Val Arg Ala Thr Leu Ser Cys Lys Ala Ser Gln Asp Val Gly Thr Asn
20 25 30
Val Leu Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Pro Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg His Ser Gly Ile Pro Asp 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 Arg Tyr Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Lys 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> 124
<211> 214
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 124
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Val Arg Ala Thr Leu Ser Cys Lys Ala Ser Gln Asp Val Gly Thr Asn
20 25 30
Val Leu Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Pro Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg His Ser Gly Ile 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 Glu Tyr Tyr Cys Gln Gln Tyr Ser Arg Tyr Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Lys 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> 125
<211> 449
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 125
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Ser
20 25 30
Trp Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn Pro Gly Asn Val Arg Thr Asn Tyr Asn Glu Asn Phe
50 55 60
Arg Asn Lys Ala Thr Met Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 126
<211> 449
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 126
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Ser
20 25 30
Trp Ile His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn Pro Gly Asn Val Arg Thr Asn Tyr Asn Glu Asn Phe
50 55 60
Arg Asn Arg Val Thr Met Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 127
<211> 449
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 127
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Ser
20 25 30
Trp Ile His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Ile Asn Pro Gly Asn Val Arg Thr Asn Tyr Asn Glu Asn Phe
50 55 60
Arg Asn Lys Val Thr Met Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 128
<211> 449
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 128
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Ser
20 25 30
Trp Ile His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Ile Asn Pro Gly Asn Val Arg Thr Asn Tyr Asn Glu Asn Phe
50 55 60
Arg Asn Arg Ala Thr Leu Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 129
<211> 449
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 129
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Ser
20 25 30
Trp Ile His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Ile Leu Pro Gly Val Val Arg Thr Asn Tyr Asn Glu Asn Phe
50 55 60
Arg Asn Lys Val Thr Met Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 130
<211> 449
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 130
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Ser
20 25 30
Trp Ile His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn Pro Gly Ala Val Arg Thr Asn Tyr Asn Glu Asn Phe
50 55 60
Arg Asn Arg Val Thr Met Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 131
<211> 449
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 131
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Ser
20 25 30
Trp Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn Pro Gly Leu Val Arg Thr Asn Tyr Asn Glu Asn Phe
50 55 60
Arg Asn Lys Val Thr Met Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 132
<211> 449
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 132
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Ser
20 25 30
Trp Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn Pro Gly Ala Val Arg Thr Asn Tyr Asn Glu Asn Phe
50 55 60
Arg Asn Lys Val Thr Met Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 133
<211> 449
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 133
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Ser
20 25 30
Trp Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn Pro Gly Ser Val Arg Thr Asn Tyr Asn Glu Asn Phe
50 55 60
Arg Asn Lys Ala Thr Met Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 134
<211> 449
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 134
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asp Tyr
20 25 30
Ala Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Trp Ser Asp Gly Ser Thr Asp Tyr Asn Ala Pro Phe Lys
50 55 60
Ser Arg Val Thr Ile Asn Lys Asp Thr Ser Lys Ser Gln Val Ser Phe
65 70 75 80
Lys Met Ser Ser Val Gln Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Lys Gly Gly Tyr Ser Gly Ser Trp Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 135
<211> 449
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 135
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asp Tyr
20 25 30
Ala Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Trp Ser Asp Gly Ser Thr Asp Tyr Asn Ala Pro Phe Lys
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Ser Leu
65 70 75 80
Lys Met Asn Ser Leu Thr Thr Asp Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Lys Gly Gly Tyr Ser Gly Ser Trp Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 136
<211> 449
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 136
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asp Tyr
20 25 30
Ala Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Trp Ser Asp Gly Ser Thr Asp Tyr Asn Ala Pro Phe Lys
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Ser Leu
65 70 75 80
Lys Met Asn Ser Val Thr Val Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Lys Gly Gly Tyr Ser Gly Ser Trp Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 137
<211> 449
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 137
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asp Tyr
20 25 30
Ala Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Trp Ser Asp Gly Ser Thr Asp Tyr Asn Ala Pro Phe Lys
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Ser Phe
65 70 75 80
Lys Leu Ser Ser Val Thr Val Asp Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Lys Gly Gly Tyr Ser Gly Ser Trp Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 138
<211> 449
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 138
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asp Tyr
20 25 30
Ala Val His Trp Ile Arg Gln Phe Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Trp Ser Asp Gly Ser Thr Asp Phe Asn Ala Pro Phe Lys
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Ser Phe
65 70 75 80
Lys Leu Ser Ser Val Thr Thr Asp Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Lys Gly Gly Tyr Ser Gly Ser Trp Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 139
<211> 449
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 139
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asp Tyr
20 25 30
Ala Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Trp Ser Asp Gly Ser Thr Asp Tyr Asn Ala Pro Phe Lys
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Ser Phe
65 70 75 80
Lys Met Ser Ser Val Thr Ala Asp Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Lys Gly Gly Tyr Ser Gly Ser Trp Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 140
<211> 7
<212> PRT
<213> Mus sp.
<400> 140
Arg Thr Ser His Leu Ala Ser
1 5
Claims (7)
1.一种治疗患有硬皮病、掌跖脓疱病、泛发性脓疱型银屑病、糖尿病肾病、狼疮性肾炎、硬皮病、强直性脊柱炎或IBD的患者的方法，所述方法包括：对患者联合施用抗IL-36R抗体与TNF抑制剂、循环受体融合蛋白、整合素抑制剂或IL-23抑制剂。
2.权利要求1的方法，其中TNF抑制剂包括英夫利昔单抗、阿达木单抗、赛妥珠单抗、循环受体融合蛋白包括依那西普，整合素抑制剂包括维多珠单抗。
3.根据前述权利要求中任一项的方法，其中抗IL-36R抗体包括：a)轻链可变区，其包含氨基酸序列SEQ ID NO:26(L-CDR1)；氨基酸序列SEQ ID NO:35、102、103、104、105、106或140(L-CDR2)；氨基酸序列SEQ ID NO:44(L-CDR3)；和b)重链可变区，其包含氨基酸序列SEQID NO:53(H-CDR1)；氨基酸序列SEQ ID NO:62、108、109、110或111(H-CDR2)；氨基酸序列SEQ ID NO:72(H-CDR3)。
4.根据前述权利要求中任一项所述的方法，其中抗IL-36R抗体包括：
I.a)轻链可变区，其包含氨基酸序列SEQ ID NO:26(L-CDR1)；氨基酸序列SEQ ID NO:102(L-CDR2)；氨基酸序列SEQ ID NO:44(L-CDR3)；和b)重链可变区，其包含氨基酸序列SEQID NO:53(H-CDR1)；氨基酸序列SEQ ID NO:62、108、109、110或111(H-CDR2)；氨基酸序列SEQ ID NO:72(H-CDR3)，
II.a)轻链可变区，其包含氨基酸序列SEQ ID NO:26(L-CDR1)；氨基酸序列SEQ ID NO:103(L-CDR2)；氨基酸序列SEQ ID NO:44(L-CDR3)；和b)重链可变区，其包含氨基酸序列SEQID NO:53(H-CDR1)；氨基酸序列SEQ ID NO:62、108、109、110或111(H-CDR2)；氨基酸序列SEQ ID NO:72(H-CDR3)，
III.a)轻链可变区，其包含氨基酸序列SEQ ID NO:26(L-CDR1)；氨基酸序列SEQ IDNO:104(L-CDR2)；氨基酸序列SEQ ID NO:44(L-CDR3)；和b)重链可变区，其包含氨基酸序列SEQ ID NO:53(H-CDR1)；氨基酸序列SEQ ID NO:62、108、109、110或111(H-CDR2)；氨基酸序列SEQ ID NO:72(H-CDR3)。
IV.a)轻链可变区，其包含氨基酸序列SEQ ID NO:26(L-CDR1)；氨基酸序列SEQ ID NO:105(L-CDR2)；氨基酸序列SEQ ID NO:44(L-CDR3)；和b)重链可变区，其包含氨基酸序列SEQID NO:53(H-CDR1)；氨基酸序列SEQ ID NO:62、108、109、110或111(H-CDR2)；氨基酸序列SEQ ID NO:72(H-CDR3)，
V.a)轻链可变区，其包含氨基酸序列SEQ ID NO:26(L-CDR1)；氨基酸序列SEQ ID NO:106(L-CDR2)；氨基酸序列SEQ ID NO:44(L-CDR3)；和b)重链可变区，其包含氨基酸序列SEQID NO:53(H-CDR1)；氨基酸序列SEQ ID NO:62、108、109、110或111(H-CDR2)；氨基酸序列SEQ ID NO:72(H-CDR3)。
VI.a)轻链可变区，其包含氨基酸序列SEQ ID NO:26(L-CDR1)；氨基酸序列SEQ ID NO:140(L-CDR2)；氨基酸序列SEQ ID NO:44(L-CDR3)；和b)重链可变区，其包含氨基酸序列SEQID NO:53(H-CDR1)；氨基酸序列SEQ ID NO:62、108、109、110或111(H-CDR2)；氨基酸序列SEQ ID NO:72(H-CDR3)。
5.根据前述权利要求中任一项所述的方法，其中抗IL-36R抗体包括：
(i)包含氨基酸序列SEQ ID NO:77的轻链可变区；和包含氨基酸序列SEQ ID NO:87的重链可变区；或
(ii)包含氨基酸序列SEQ ID NO:77的轻链可变区；和包含氨基酸序列SEQ ID NO:88的重链可变区；或
(iii)包含氨基酸序列SEQ ID NO:77的轻链可变区；和包含氨基酸序列SEQ ID NO:89的重链可变区；或
(iv)包含氨基酸序列SEQ ID NO:80的轻链可变区；和包含氨基酸序列SEQ ID NO:87的重链可变区；或
(v)包含氨基酸序列SEQ ID NO:80的轻链可变区；和包含氨基酸序列SEQ ID NO:88的重链可变区；或
(vi)包含氨基酸序列SEQ ID NO:80的轻链可变区；和包含氨基酸序列SEQ ID NO:89的重链可变区；或
(vii)包含氨基酸序列SEQ ID NO:85的轻链可变区；和包含氨基酸序列SEQ ID NO:100的重链可变区；或
(viii)包含氨基酸序列SEQ ID NO:85的轻链可变区；和包含氨基酸序列SEQ ID NO:101的重链可变区；或
(ix)包含氨基酸序列SEQ ID NO:86的轻链可变区；和包含氨基酸序列SEQ ID NO:100的重链可变区；或
(x)包含氨基酸序列SEQ ID NO:86的轻链可变区；和包含氨基酸序列SEQ ID NO:101的重链可变区。
6.根据前述权利要求中任一项所述的方法，其中抗IL-36R抗体包括：
i.包含氨基酸序列SEQ ID NO:115的轻链；和包含氨基酸序列SEQ ID NO:125的重链；或
ii.包含氨基酸序列SEQ ID NO:115的轻链；和包含氨基酸序列SEQ ID NO:126的重链；或
iii.包含氨基酸序列SEQ ID NO:115的轻链；和包含氨基酸序列SEQ ID NO:127的重链；或
iv.包含氨基酸序列SEQ ID NO:118的轻链；和包含氨基酸序列SEQ ID NO:125的重链；或
v.包含氨基酸序列SEQ ID NO:118的轻链；和包含氨基酸序列SEQ ID NO:126的重链；或
vi.包含氨基酸序列SEQ ID NO:118的轻链；和包含氨基酸序列SEQ ID NO:127的重链；或
vii.包含氨基酸序列SEQ ID NO:123的轻链；和包含氨基酸序列SEQ ID NO:138的重链；或
viii.包含氨基酸序列SEQ ID NO:123的轻链；和包含氨基酸序列SEQ ID NO:139的重链；或
ix.包含氨基酸序列SEQ ID NO:124的轻链；和包含氨基酸序列SEQ ID NO:138的重链。
7.根据前述权利要求中任一项的方法，其中通过静脉内负荷剂量，然后进行一次或多次皮下注射来施用所述抗IL-36R抗体。
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| US201762476940P | 2017-03-27 | 2017-03-27 | |
| US62/476,940 | 2017-03-27 | ||
| PCT/US2018/024296 WO2018183173A1 (en) | 2017-03-27 | 2018-03-26 | Anti il-36r antibodies combination therapy |
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| EP (1) | EP3601350A1 (zh) |
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| WO2022095926A1 (zh) * | 2020-11-04 | 2022-05-12 | 上海华奥泰生物药业股份有限公司 | 靶向于白介素36r的抗体及其制备方法和应用 |
| WO2022262828A1 (zh) * | 2021-06-18 | 2022-12-22 | 正大天晴药业集团股份有限公司 | 抗il-36r抗体及其用途 |
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