CN116916956A - Fap结合分子及其用途 - Google Patents
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- CN116916956A CN116916956A CN202180093996.3A CN202180093996A CN116916956A CN 116916956 A CN116916956 A CN 116916956A CN 202180093996 A CN202180093996 A CN 202180093996A CN 116916956 A CN116916956 A CN 116916956A
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Abstract
本文公开了成纤维细胞活化蛋白(FAP)特异性结合多肽。这些结合多肽可掺入到嵌合抗原受体(CAR)中。本文还公开了使用这些结合多肽和/或CAR治疗例如癌症的方法。
Description
相关申请的交叉引用
本申请要求2020年12月18日提交的第63/127885号美国临时专利申请和2021年10月19日提交的第63/262706号美国临时专利申请的优先权的权益,所述美国临时专利申请中的每一个在此均通过引用整体明确地并入本文中。
序列表的引用
本申请与电子格式的序列表一起提交。序列表以标题为BWGB011_SeqListing.TXT的文件提供,其在2021年12月16日被创建和最后修改,大小为187,259字节。电子序列表中的信息在此通过引用整体并入本文中。
领域
本公开内容的方面总体上涉及成纤维细胞活化蛋白(FAP)特异性结合多肽。可以将这些结合多肽掺入到嵌合抗原受体(CAR)构建体中,以在免疫细胞中表达。这些结合多肽和CAR可用于治疗癌症。
背景
已经显示嵌合抗原受体(CAR)T细胞和其他过继细胞疗法在癌症的治疗中是有效的。由细胞外抗原结合结构域、跨膜结构域和细胞内信号传导结构域组成的CAR使得能够基于细胞表面抗原表达直接杀伤癌细胞,同时对不表达靶抗原的正常细胞影响最小。细胞外抗原结合结构域通常由抗体或其结合片段或衍生物,如单链可变片段(scFv)或单域抗体(sdAb)组成。目前需要在CAR中使用以用于治疗各种癌症或其他疾病的改进的细胞外抗原结合结构域。
公开内容的概述
本文公开了能够结合成纤维细胞活化蛋白(FAP)的结合多肽。这些结合多肽可以掺入到嵌合抗原受体(CAR)中,所述嵌合抗原受体可以由细胞表达。在一些实施方案中,结合多肽是单域抗体(sdAb)。
在一些实施方案中,本文公开了FAP结合多肽,其包含免疫球蛋白重链可变结构域,所述免疫球蛋白重链可变结构域包含CDR-H1、CDR-H2和CDR-H3。在一些实施方案中,CDR-H1包含与选自SEQ ID NO:1-108的序列具有至少90%、95%、99%或100%序列同一性的序列。在一些实施方案中,CDR-H2包含与选自SEQ ID NO:109-216的序列具有至少90%、95%、99%或100%序列同一性的序列。在一些实施方案中,CDR-H3包含与选自SEQ ID NO:217-324的序列具有至少90%、95%、99%或100%序列同一性的序列。在一些实施方案中,CDR-H1包含与选自SEQ ID NO:1-108的序列具有至少90%、95%、99%或100%序列同一性的序列,CDR-H2包含与选自SEQ ID NO:109-216的序列具有至少90%、95%、99%或100%序列同一性的序列,并且CDR-H3包含与选自SEQ ID NO:217-324的序列具有至少90%、95%、99%或100%序列同一性的序列。在一些实施方案中,免疫球蛋白重链可变结构域包含与选自SEQ ID NO:325-432的序列具有至少90%、95%、99%或100%序列同一性的序列。
本文还公开了编码本文公开的任何一种FAP结合多肽的核酸。
本文还公开了治疗有需要的对象中的癌症的方法。在一些实施方案中,方法包括向对象施用嵌合抗原受体细胞。在一些实施方案中,嵌合抗原受体细胞是本文公开的任何一种嵌合抗原受体细胞。在一些实施方案中,嵌合抗原受体细胞包含本文公开的任何一种或多种FAP结合多肽。
本文提供的本发明的实施方案通过以下编号的替代方案来描述:
1.成纤维细胞活化蛋白(FAP)结合多肽,其包含免疫球蛋白重链可变结构域,所述免疫球蛋白重链可变结构域包含CDR-H1、CDR-H2和CDR-H3,其中:
CDR-H1包含与选自SEQ ID NO:1-108的序列具有至少90%、95%、99%或100%序列同一性的序列;
CDR-H2包含与选自SEQ ID NO:109-216的序列具有至少90%、95%、99%或100%序列同一性的序列;并且
CDR-H3包含与选自SEQ ID NO:217-324的序列具有至少90%、95%、99%或100%序列同一性的序列。
2.如替代方案1所述的FAP结合多肽,其中:
1)CDR-H1包含SEQ ID NO:1的序列,CDR-H2包含SEQ ID NO:109的序列,并且CDR-H3包含SEQ ID NO:217的序列;
2)CDR-H1包含SEQ ID NO:2的序列,CDR-H2包含SEQ ID NO:110的序列,并且CDR-H3包含SEQ ID NO:218的序列;
3)CDR-H1包含SEQ ID NO:3的序列,CDR-H2包含SEQ ID NO:111的序列,并且CDR-H3包含SEQ ID NO:219的序列;
4)CDR-H1包含SEQ ID NO:4的序列,CDR-H2包含SEQ ID NO:112的序列,并且CDR-H3包含SEQ ID NO:220的序列;
5)CDR-H1包含SEQ ID NO:5的序列,CDR-H2包含SEQ ID NO:113的序列,并且CDR-H3包含SEQ ID NO:221的序列;
6)CDR-H1包含SEQ ID NO:6的序列,CDR-H2包含SEQ ID NO:114的序列,并且CDR-H3包含SEQ ID NO:222的序列;
7)CDR-H1包含SEQ ID NO:7的序列,CDR-H2包含SEQ ID NO:115的序列,并且CDR-H3包含SEQ ID NO:223的序列;
8)CDR-H1包含SEQ ID NO:8的序列,CDR-H2包含SEQ ID NO:116的序列,并且CDR-H3包含SEQ ID NO:224的序列;
9)CDR-H1包含SEQ ID NO:9的序列,CDR-H2包含SEQ ID NO:117的序列,并且CDR-H3包含SEQ ID NO:225的序列;
10)CDR-H1包含SEQ ID NO:10的序列,CDR-H2包含SEQ ID NO:118的序列,并且CDR-H3包含SEQ ID NO:226的序列;
11)CDR-H1包含SEQ ID NO:11的序列,CDR-H2包含SEQ ID NO:119的序列,并且CDR-H3包含SEQ ID NO:227的序列;
12)CDR-H1包含SEQ ID NO:12的序列,CDR-H2包含SEQ ID NO:120的序列,并且CDR-H3包含SEQ ID NO:228的序列;
13)CDR-H1包含SEQ ID NO:13的序列,CDR-H2包含SEQ ID NO:121的序列,并且CDR-H3包含SEQ ID NO:229的序列;
14)CDR-H1包含SEQ ID NO:14的序列,CDR-H2包含SEQ ID NO:122的序列,并且CDR-H3包含SEQ ID NO:230的序列;
15)CDR-H1包含SEQ ID NO:15的序列,CDR-H2包含SEQ ID NO:123的序列,并且CDR-H3包含SEQ ID NO:231的序列;
16)CDR-H1包含SEQ ID NO:16的序列,CDR-H2包含SEQ ID NO:124的序列,并且CDR-H3包含SEQ ID NO:232的序列;
17)CDR-H1包含SEQ ID NO:17的序列,CDR-H2包含SEQ ID NO:125的序列,并且CDR-H3包含SEQ ID NO:233的序列;
18)CDR-H1包含SEQ ID NO:18的序列,CDR-H2包含SEQ ID NO:126的序列,并且CDR-H3包含SEQ ID NO:234的序列;
19)CDR-H1包含SEQ ID NO:19的序列,CDR-H2包含SEQ ID NO:127的序列,并且CDR-H3包含SEQ ID NO:235的序列;
20)CDR-H1包含SEQ ID NO:20的序列,CDR-H2包含SEQ ID NO:128的序列,并且CDR-H3包含SEQ ID NO:236的序列;
21)CDR-H1包含SEQ ID NO:21的序列,CDR-H2包含SEQ ID NO:129的序列,并且CDR-H3包含SEQ ID NO:237的序列;
22)CDR-H1包含SEQ ID NO:22的序列,CDR-H2包含SEQ ID NO:130的序列,并且CDR-H3包含SEQ ID NO:238的序列;
23)CDR-H1包含SEQ ID NO:23的序列,CDR-H2包含SEQ ID NO:131的序列,并且CDR-H3包含SEQ ID NO:239的序列;
24)CDR-H1包含SEQ ID NO:24的序列,CDR-H2包含SEQ ID NO:132的序列,并且CDR-H3包含SEQ ID NO:240的序列;
25)CDR-H1包含SEQ ID NO:25的序列,CDR-H2包含SEQ ID NO:133的序列,并且CDR-H3包含SEQ ID NO:241的序列;
26)CDR-H1包含SEQ ID NO:26的序列,CDR-H2包含SEQ ID NO:134的序列,并且CDR-H3包含SEQ ID NO:242的序列;
27)CDR-H1包含SEQ ID NO:27的序列,CDR-H2包含SEQ ID NO:135的序列,并且CDR-H3包含SEQ ID NO:243的序列;
28)CDR-H1包含SEQ ID NO:28的序列,CDR-H2包含SEQ ID NO:136的序列,并且CDR-H3包含SEQ ID NO:244的序列;
29)CDR-H1包含SEQ ID NO:29的序列,CDR-H2包含SEQ ID NO:137的序列,并且CDR-H3包含SEQ ID NO:245的序列;
30)CDR-H1包含SEQ ID NO:30的序列,CDR-H2包含SEQ ID NO:138的序列,并且CDR-H3包含SEQ ID NO:246的序列;
31)CDR-H1包含SEQ ID NO:31的序列,CDR-H2包含SEQ ID NO:139的序列,并且CDR-H3包含SEQ ID NO:247的序列;
32)CDR-H1包含SEQ ID NO:32的序列,CDR-H2包含SEQ ID NO:140的序列,并且CDR-H3包含SEQ ID NO:248的序列;
33)CDR-H1包含SEQ ID NO:33的序列,CDR-H2包含SEQ ID NO:141的序列,并且CDR-H3包含SEQ ID NO:249的序列;
34)CDR-H1包含SEQ ID NO:34的序列,CDR-H2包含SEQ ID NO:142的序列,并且CDR-H3包含SEQ ID NO:250的序列;
35)CDR-H1包含SEQ ID NO:35的序列,CDR-H2包含SEQ ID NO:143的序列,并且CDR-H3包含SEQ ID NO:251的序列;
36)CDR-H1包含SEQ ID NO:36的序列,CDR-H2包含SEQ ID NO:144的序列,并且CDR-H3包含SEQ ID NO:252的序列;
37)CDR-H1包含SEQ ID NO:37的序列,CDR-H2包含SEQ ID NO:145的序列,并且CDR-H3包含SEQ ID NO:253的序列;
38)CDR-H1包含SEQ ID NO:38的序列,CDR-H2包含SEQ ID NO:146的序列,并且CDR-H3包含SEQ ID NO:254的序列;
39)CDR-H1包含SEQ ID NO:39的序列,CDR-H2包含SEQ ID NO:147的序列,并且CDR-H3包含SEQ ID NO:255的序列;
40)CDR-H1包含SEQ ID NO:40的序列,CDR-H2包含SEQ ID NO:148的序列,并且CDR-H3包含SEQ ID NO:256的序列;
41)CDR-H1包含SEQ ID NO:41的序列,CDR-H2包含SEQ ID NO:149的序列,并且CDR-H3包含SEQ ID NO:257的序列;
42)CDR-H1包含SEQ ID NO:42的序列,CDR-H2包含SEQ ID NO:150的序列,并且CDR-H3包含SEQ ID NO:258的序列;
43)CDR-H1包含SEQ ID NO:43的序列,CDR-H2包含SEQ ID NO:151的序列,并且CDR-H3包含SEQ ID NO:259的序列;
44)CDR-H1包含SEQ ID NO:44的序列,CDR-H2包含SEQ ID NO:152的序列,并且CDR-H3包含SEQ ID NO:260的序列;
45)CDR-H1包含SEQ ID NO:45的序列,CDR-H2包含SEQ ID NO:153的序列,并且CDR-H3包含SEQ ID NO:261的序列;
46)CDR-H1包含SEQ ID NO:46的序列,CDR-H2包含SEQ ID NO:154的序列,并且CDR-H3包含SEQ ID NO:262的序列;
47)CDR-H1包含SEQ ID NO:47的序列,CDR-H2包含SEQ ID NO:155的序列,并且CDR-H3包含SEQ ID NO:263的序列;
48)CDR-H1包含SEQ ID NO:48的序列,CDR-H2包含SEQ ID NO:156的序列,并且CDR-H3包含SEQ ID NO:264的序列;
49)CDR-H1包含SEQ ID NO:49的序列,CDR-H2包含SEQ ID NO:157的序列,并且CDR-H3包含SEQ ID NO:265的序列;
50)CDR-H1包含SEQ ID NO:50的序列,CDR-H2包含SEQ ID NO:158的序列,并且CDR-H3包含SEQ ID NO:266的序列;
51)CDR-H1包含SEQ ID NO:51的序列,CDR-H2包含SEQ ID NO:159的序列,并且CDR-H3包含SEQ ID NO:267的序列;
52)CDR-H1包含SEQ ID NO:52的序列,CDR-H2包含SEQ ID NO:160的序列,并且CDR-H3包含SEQ ID NO:268的序列;
53)CDR-H1包含SEQ ID NO:53的序列,CDR-H2包含SEQ ID NO:161的序列,并且CDR-H3包含SEQ ID NO:269的序列;
54)CDR-H1包含SEQ ID NO:54的序列,CDR-H2包含SEQ ID NO:162的序列,并且CDR-H3包含SEQ ID NO:270的序列;
55)CDR-H1包含SEQ ID NO:55的序列,CDR-H2包含SEQ ID NO:163的序列,并且CDR-H3包含SEQ ID NO:271的序列;
56)CDR-H1包含SEQ ID NO:56的序列,CDR-H2包含SEQ ID NO:164的序列,并且CDR-H3包含SEQ ID NO:272的序列;
57)CDR-H1包含SEQ ID NO:57的序列,CDR-H2包含SEQ ID NO:165的序列,并且CDR-H3包含SEQ ID NO:273的序列;
58)CDR-H1包含SEQ ID NO:58的序列,CDR-H2包含SEQ ID NO:166的序列,并且CDR-H3包含SEQ ID NO:274的序列;
59)CDR-H1包含SEQ ID NO:59的序列,CDR-H2包含SEQ ID NO:167的序列,并且CDR-H3包含SEQ ID NO:275的序列;
60)CDR-H1包含SEQ ID NO:60的序列,CDR-H2包含SEQ ID NO:168的序列,并且CDR-H3包含SEQ ID NO:276的序列;
61)CDR-H1包含SEQ ID NO:61的序列,CDR-H2包含SEQ ID NO:169的序列,并且CDR-H3包含SEQ ID NO:277的序列;
62)CDR-H1包含SEQ ID NO:62的序列,CDR-H2包含SEQ ID NO:170的序列,并且CDR-H3包含SEQ ID NO:278的序列;
63)CDR-H1包含SEQ ID NO:63的序列,CDR-H2包含SEQ ID NO:171的序列,并且CDR-H3包含SEQ ID NO:279的序列;
64)CDR-H1包含SEQ ID NO:64的序列,CDR-H2包含SEQ ID NO:172的序列,并且CDR-H3包含SEQ ID NO:280的序列;
65)CDR-H1包含SEQ ID NO:65的序列,CDR-H2包含SEQ ID NO:173的序列,并且CDR-H3包含SEQ ID NO:281的序列;
66)CDR-H1包含SEQ ID NO:66的序列,CDR-H2包含SEQ ID NO:174的序列,并且CDR-H3包含SEQ ID NO:282的序列;
67)CDR-H1包含SEQ ID NO:67的序列,CDR-H2包含SEQ ID NO:175的序列,并且CDR-H3包含SEQ ID NO:283的序列;
68)CDR-H1包含SEQ ID NO:68的序列,CDR-H2包含SEQ ID NO:176的序列,并且CDR-H3包含SEQ ID NO:284的序列;
69)CDR-H1包含SEQ ID NO:69的序列,CDR-H2包含SEQ ID NO:177的序列,并且CDR-H3包含SEQ ID NO:285的序列;
70)CDR-H1包含SEQ ID NO:70的序列,CDR-H2包含SEQ ID NO:178的序列,并且CDR-H3包含SEQ ID NO:286的序列;
71)CDR-H1包含SEQ ID NO:71的序列,CDR-H2包含SEQ ID NO:179的序列,并且CDR-H3包含SEQ ID NO:287的序列;
72)CDR-H1包含SEQ ID NO:72的序列,CDR-H2包含SEQ ID NO:180的序列,并且CDR-H3包含SEQ ID NO:288的序列;
73)CDR-H1包含SEQ ID NO:73的序列,CDR-H2包含SEQ ID NO:181的序列,并且CDR-H3包含SEQ ID NO:289的序列;
74)CDR-H1包含SEQ ID NO:74的序列,CDR-H2包含SEQ ID NO:182的序列,并且CDR-H3包含SEQ ID NO:290的序列;
75)CDR-H1包含SEQ ID NO:75的序列,CDR-H2包含SEQ ID NO:183的序列,并且CDR-H3包含SEQ ID NO:291的序列;
76)CDR-H1包含SEQ ID NO:76的序列,CDR-H2包含SEQ ID NO:184的序列,并且CDR-H3包含SEQ ID NO:292的序列;
77)CDR-H1包含SEQ ID NO:77的序列,CDR-H2包含SEQ ID NO:185的序列,并且CDR-H3包含SEQ ID NO:293的序列;
78)CDR-H1包含SEQ ID NO:78的序列,CDR-H2包含SEQ ID NO:186的序列,并且CDR-H3包含SEQ ID NO:294的序列;
79)CDR-H1包含SEQ ID NO:79的序列,CDR-H2包含SEQ ID NO:187的序列,并且CDR-H3包含SEQ ID NO:295的序列;
80)CDR-H1包含SEQ ID NO:80的序列,CDR-H2包含SEQ ID NO:188的序列,并且CDR-H3包含SEQ ID NO:296的序列;
81)CDR-H1包含SEQ ID NO:81的序列,CDR-H2包含SEQ ID NO:189的序列,并且CDR-H3包含SEQ ID NO:297的序列;
82)CDR-H1包含SEQ ID NO:82的序列,CDR-H2包含SEQ ID NO:190的序列,并且CDR-H3包含SEQ ID NO:298的序列;
83)CDR-H1包含SEQ ID NO:83的序列,CDR-H2包含SEQ ID NO:191的序列,并且CDR-H3包含SEQ ID NO:299的序列;
84)CDR-H1包含SEQ ID NO:84的序列,CDR-H2包含SEQ ID NO:192的序列,并且CDR-H3包含SEQ ID NO:300的序列;
85)CDR-H1包含SEQ ID NO:85的序列,CDR-H2包含SEQ ID NO:193的序列,并且CDR-H3包含SEQ ID NO:301的序列;
86)CDR-H1包含SEQ ID NO:86的序列,CDR-H2包含SEQ ID NO:194的序列,并且CDR-H3包含SEQ ID NO:302的序列;
87)CDR-H1包含SEQ ID NO:87的序列,CDR-H2包含SEQ ID NO:195的序列,并且CDR-H3包含SEQ ID NO:303的序列;
88)CDR-H1包含SEQ ID NO:88的序列,CDR-H2包含SEQ ID NO:196的序列,并且CDR-H3包含SEQ ID NO:304的序列;
89)CDR-H1包含SEQ ID NO:89的序列,CDR-H2包含SEQ ID NO:197的序列,并且CDR-H3包含SEQ ID NO:305的序列;
90)CDR-H1包含SEQ ID NO:90的序列,CDR-H2包含SEQ ID NO:198的序列,并且CDR-H3包含SEQ ID NO:306的序列;
91)CDR-H1包含SEQ ID NO:91的序列,CDR-H2包含SEQ ID NO:199的序列,并且CDR-H3包含SEQ ID NO:307的序列;
92)CDR-H1包含SEQ ID NO:92的序列,CDR-H2包含SEQ ID NO:200的序列,并且CDR-H3包含SEQ ID NO:308的序列;
93)CDR-H1包含SEQ ID NO:93的序列,CDR-H2包含SEQ ID NO:201的序列,并且CDR-H3包含SEQ ID NO:309的序列;
94)CDR-H1包含SEQ ID NO:94的序列,CDR-H2包含SEQ ID NO:202的序列,并且CDR-H3包含SEQ ID NO:310的序列;
95)CDR-H1包含SEQ ID NO:95的序列,CDR-H2包含SEQ ID NO:203的序列,并且CDR-H3包含SEQ ID NO:311的序列;
96)CDR-H1包含SEQ ID NO:96的序列,CDR-H2包含SEQ ID NO:204的序列,并且CDR-H3包含SEQ ID NO:312的序列;
97)CDR-H1包含SEQ ID NO:97的序列,CDR-H2包含SEQ ID NO:205的序列,并且CDR-H3包含SEQ ID NO:313的序列;
98)CDR-H1包含SEQ ID NO:98的序列,CDR-H2包含SEQ ID NO:206的序列,并且CDR-H3包含SEQ ID NO:314的序列;
99)CDR-H1包含SEQ ID NO:99的序列,CDR-H2包含SEQ ID NO:207的序列,并且CDR-H3包含SEQ ID NO:315的序列;
100)CDR-H1包含SEQ ID NO:100的序列,CDR-H2包含SEQ ID NO:208的序列,并且CDR-H3包含SEQ ID NO:316的序列;
101)CDR-H1包含SEQ ID NO:101的序列,CDR-H2包含SEQ ID NO:209的序列,并且CDR-H3包含SEQ ID NO:317的序列;
102)CDR-H1包含SEQ ID NO:102的序列,CDR-H2包含SEQ ID NO:210的序列,并且CDR-H3包含SEQ ID NO:318的序列;
103)CDR-H1包含SEQ ID NO:103的序列,CDR-H2包含SEQ ID NO:211的序列,并且CDR-H3包含SEQ ID NO:319的序列;
104)CDR-H1包含SEQ ID NO:104的序列,CDR-H2包含SEQ ID NO:212的序列,并且CDR-H3包含SEQ ID NO:320的序列;
105)CDR-H1包含SEQ ID NO:105的序列,CDR-H2包含SEQ ID NO:213的序列,并且CDR-H3包含SEQ ID NO:321的序列;
106)CDR-H1包含SEQ ID NO:106的序列,CDR-H2包含SEQ ID NO:214的序列,并且CDR-H3包含SEQ ID NO:322的序列;
107)CDR-H1包含SEQ ID NO:107的序列,CDR-H2包含SEQ ID NO:215的序列,并且CDR-H3包含SEQ ID NO:323的序列;或者
108)CDR-H1包含SEQ ID NO:108的序列,CDR-H2包含SEQ ID NO:216的序列,并且CDR-H3包含SEQ ID NO:324的序列。
3.如替代方案1或2所述的FAP结合多肽,其中重链可变结构域包含与选自SEQ IDNO:325-432的任何序列具有至少90%、95%、99%或100%序列同一性的氨基酸序列。
4.如替代方案1-3中任一项所述的FAP结合多肽,其中FAP结合多肽是人源化的。
5.如替代方案1-4中任一项所述的FAP结合多肽,其中FAP结合多肽是单域抗体(sdAb)。
6.FAP结合多肽,其包含含有CDR-H1的免疫球蛋白重链可变结构域,其中CDR-H1包含与选自SEQ ID NO:1-108的序列具有至少90%、95%、99%或100%序列同一性的序列。
7.如替代方案6所述的FAP结合多肽,其中CDR-H1包含与选自SEQ ID NO:4的序列具有至少90%、95%、99%或100%序列同一性的序列。
8.如替代方案6或7所述的FAP结合多肽,其中免疫球蛋白重链可变结构域还包含CDR-H2,其中CDR-H2包含与选自SEQ ID NO:109-216的序列具有至少90%、95%、99%或100%序列同一性的序列。
9.如替代方案6-8中任一项所述的FAP结合多肽,其中免疫球蛋白重链可变结构域还包含CDR-H3,其中CDR-H3包含与选自SEQ ID NO:217-324的序列具有至少90%、95%、99%或100%序列同一性的序列。
10.如替代方案6-9中任一项所述的FAP结合多肽,其中免疫球蛋白重链可变结构域包含与选自SEQ ID NO:325-432的任何序列具有至少90%、95%、99%或100%序列同一性的氨基酸序列。
11.FAP结合多肽,其包含含有CDR-H2的免疫球蛋白重链可变结构域,其中CDR-H2包含与选自SEQ ID NO:109-216的序列具有至少90%、95%、99%或100%序列同一性的序列。
12.如替代方案11所述的FAP结合多肽,其中CDR-H2包含与选自SEQ ID NO:110的序列具有至少90%、95%、99%或100%序列同一性的序列。
13.如替代方案11或12所述的FAP结合多肽,其中免疫球蛋白重链可变结构域还包含CDR-H1,其中CDR-H1包含与选自SEQ ID NO:1-108的序列具有至少90%、95%、99%或100%序列同一性的序列。
14.如替代方案11-13中任一项所述的FAP结合多肽,其中免疫球蛋白重链可变结构域还包含CDR-H3,其中CDR-H3包含与选自SEQ ID NO:217-324的序列具有至少90%、95%、99%或100%序列同一性的序列。
15.如替代方案11-14中任一项所述的FAP结合多肽,其中免疫球蛋白重链可变结构域包含与选自SEQ ID NO:325-432的任何序列具有至少90%、95%、99%或100%序列同一性的氨基酸序列。
16.嵌合抗原受体(CAR),其包含替代方案1-15中任一项所述的FAP结合多肽。
17.嵌合抗原受体(CAR)细胞,其包含替代方案16所述的CAR。
18.如替代方案17所述的CAR细胞,其中CAR细胞是CAR T细胞。
19.如替代方案17或18所述的CAR细胞,其中CAR细胞包含至少两种结合多肽,并且CAR细胞是多价CAR细胞。
20.如替代方案17-19中任一项所述的CAR细胞,其中CAR细胞来源于对象或细胞系。
21.如替代方案20所述的CAR细胞,其中对象患有癌症。
22.如替代方案21所述的CAR细胞,其中癌症是乳腺癌、结直肠癌、肾癌、肝癌、肺癌、脑癌、胰腺癌、膀胱癌、睾丸癌、前列腺癌、胃癌、卵巢癌、头颈癌、胆囊癌、血液恶性肿瘤或以上的任意组合。
23.编码多肽的核酸,所述多肽包含与替代方案1-15中任一项所述的FAP结合多肽或替代方案16所述的CAR具有至少90%、95%、99%或100%序列同一性的序列。
24.治疗有需要的对象中的癌症的方法,包括施用替代方案17-22中任一项所述的CAR细胞。
25.如替代方案24所述的方法,其中嵌合抗原受体细胞是对象自体的或同种异体的。
26.如替代方案24或25所述的方法,其中对象是哺乳动物。
27.如替代方案24-26中任一项所述的方法,其中对象是人。
28.如替代方案24-27中任一项所述的方法,其中癌症是乳腺癌、结直肠癌、肾癌、肝癌、肺癌、脑癌、胰腺癌、膀胱癌、睾丸癌、前列腺癌、胃癌、卵巢癌、头颈癌、胆囊癌、血液恶性肿瘤或以上的任意组合。
29.如替代方案24-28中任一项所述的方法,其中嵌合抗原受体细胞经肠胃外施用。
附图的简要说明
除了上述特征之外,根据下面对附图和示例性实施方案的描述,另外的特征和变化将易于显而易见。应当理解,这些附图描绘了典型的实施方案,且不旨在限制范围。
图1描绘了本文公开的重链可变结构域CDR的示例性比对。
公开内容的详述
本文公开了掺入到嵌合抗原受体细胞中的结合多肽。在一些实施方案中,嵌合抗原受体细胞是嵌合抗原受体T细胞(CAR-T细胞)。这些CAR-T可以通过本领域常规已知的方法构建。结合多肽提供针对它们各自的肿瘤相关抗原的特异性,使得能够通过CAR-T细胞靶向表达所述肿瘤相关抗原的癌症。
在一些实施方案中,结合多肽是设置于嵌合抗原受体细胞(例如CAR-T细胞)表面上的单域抗体(sdAb)。sdAb可以对肿瘤相关抗原具有特异性或具有结合亲和力。在一些实施方案中,肿瘤相关抗原是成纤维细胞活化蛋白(FAP)。
本文还公开了通过施用包含一种或多种本文公开的结合多肽的嵌合抗原受体细胞来治疗有需要的对象中的癌症的方法。在一些实施方案中,癌症可以是乳腺癌、结直肠癌、肾癌、肝癌、肺癌、脑癌、胰腺癌、膀胱癌、睾丸癌、前列腺癌、胃癌、卵巢癌、头颈癌、胆囊癌、血液恶性肿瘤或以上的任意组合。CAR-T细胞可以来源于对象以用于自体治疗。在一些实施方案中,血液恶性肿瘤可包括白血病、急性淋巴母细胞白血病、急性髓细胞白血病、慢性髓细胞白血病、慢性淋巴细胞白血病、毛细胞白血病、淋巴瘤、霍奇金病、非霍奇金淋巴瘤或多发性骨髓瘤。可选地,CAR-T细胞可以来源于与对象相同的物种,以用于同种异体治疗。
定义
除非另有定义,否则本文使用的所有技术和科学术语具有与所要求保护的主题所属领域的技术人员通常理解的相同含义。应当理解,前面的一般描述和下面的详细描述仅是示例性的和解释性的,并且不是对所要求保护的任何主题的限制。
本文所用的章节标题仅用于组织目的,且不应被解释为限制所描述的主题。
本文中使用的冠词“一个/一种(a)”和“一个/一种(an)”是指一个或多于一个(例如,至少一个)该冠词的语法对象。通过实例的方式,“一个元素(an element)”意指一个元素或多于一个元素。
“约”意指相对于参考量、水平、值、数字、频率、百分比、尺寸、大小、数量、重量或长度变化多达30%、25%、20%、15%、10%、9%、8%、7%、6%、5%、4%、3%、2%或1%的量、水平、值、数字、频率、百分比、尺寸、大小、数量、重量或长度。
在整个本说明书中,除非上下文另有要求,否则词语“包含(comprise)”、“包含(comprises)”和“包含(comprising)”将被理解为暗示包括所述步骤或元素或者步骤或元素的组,但不排除任何其他的步骤或元素或者步骤或元素的组。“由…组成(consistingof)”意指包括并且限于在短语“由…组成”之后的任何内容。因此,短语“由…组成”表示所列出的元素是必需的或强制性的,并且不可能存在其他元素。“基本上由…组成(consisting essentially of)”意指包括在该短语之后列出的任何元素,并且限于不干扰或有助于在本公开内容中针对所列出的元素指定的活动或动作的其他元素。因此,短语“基本上由…组成”表示所列元素是必需的或强制性的,但是其他元素是任选的,并且可以存在或不存在,这取决于它们是否实质上影响所列元素的活动或动作。
如本文所用,术语“个体”、“对象”和“患者”意指任何哺乳动物。在一些实施方案中,哺乳动物是人。在一些实施方案中,哺乳动物是非人类。这些术语都不要求或不限于以医疗保健工作人员(例如医生、注册护士、护士从业人员、医师助理、护理员或临终关怀工作人员)的监督(例如恒定的或间歇的)为特征的情况。
术语“施用(administering)”包括肠内、经口、鼻内、肠胃外、静脉内、腹膜内、肌内、小动脉内、心室内、皮内、病灶内、颅内、鞘内或皮下施用,或者向对象植入缓释装置,例如微渗透泵。
本文所用的术语“核酸”或“核酸分子”是指多核苷酸,如脱氧核糖核酸(DNA)或核糖核酸(RNA)、寡核苷酸、通过聚合酶链式反应(PCR)产生的片段,以及通过连接、断裂、核酸内切酶作用和核酸外切酶作用中的任一种产生的片段。核酸分子可以由作为天然存在的核苷酸(如DNA和RNA)或天然存在的核苷酸的类似物(例如,天然存在的核苷酸的对映体形式)或两者的组合的单体组成。可以通过磷酸二酯键或此类连键的类似物连接核酸单体。一种或多种核酸可包含在核酸载体或核酸构建体中(例如质粒、病毒、噬菌体、粘粒、fosmid、噬菌粒、细菌人工染色体(BAC)、酵母人工染色体(YAC)或人类人工染色体(HAC)),其可用于一种或多种核酸在各种生物系统中的扩增和/或表达。通常,载体或构建体还将含有元件,包括但不限于启动子、增强子、终止子、诱导物、核糖体结合位点、翻译起始位点、起始密码子、终止密码子、聚腺苷酸化信号、复制起点、克隆位点、多克隆位点、限制酶位点、表位、报道基因、选择标志物、抗生素选择标志物、靶向序列、肽纯化标签或附属基因(accessory gene),或者以上的任意组合。
核酸或核酸分子可以包含编码不同肽、多肽或蛋白质的一个或多个序列。这些一个或多个序列可以在相同的核酸或核酸分子中相邻地连接,或者与其间的额外核酸,例如接头、重复或限制酶位点,或者1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、150、200或300个碱基长度,或者在由前述长度中的任两个限定的范围内的任何长度的任何其他序列连接。本文所用的术语在核酸“下游”是指在先前序列的3’端之后的序列,如果核酸是双链,则在含有编码序列的链(有义链)上。本文所用的术语在核酸“上游”是指在后续序列的5’端之前的序列,如果核酸是双链,则在含有编码序列的链(有义链)上。本文所用的术语核酸上的“分组的”是指以下两个或更多个序列,其直接或与其间的额外核酸,例如接头、重复或限制酶位点,或者1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、150、200或300个碱基长度,或者在由前述长度中的任两个限定的范围内的任何长度的任何其他序列邻近出现,但通常不与其间的编码功能或催化多肽、蛋白或蛋白结构域的序列邻近出现。
本文所用的关于核酸的术语“密码子优化的”是指基于物种特异性密码子使用偏好和靶细胞细胞质中每个氨酰基-tRNA的相对可用性,取代核酸的密码子以增强或最大化在特定物种的宿主中的翻译,而不改变多肽序列。密码子优化和进行这种优化的技术是本领域已知的。本领域技术人员将理解基因表达水平取决于许多因素,如启动子序列和调控元件。在这一方面,可以设计许多合成基因以提高它们的蛋白表达水平。
本文所用的术语“肽”、“多肽”和“蛋白质”是指由通过肽键连接的氨基酸组成的大分子。肽、多肽和蛋白质的多种功能是本领域已知的,并且包括但不限于酶、结构、转运、防御、激素或信号传导。肽、多肽和蛋白质通常,但不总是通过使用核酸模板的核糖体复合物以生物方式产生,尽管化学合成也是可用的。通过操纵核酸模板,可以进行肽、多肽和蛋白质突变,如多于一种肽、多肽或蛋白质的取代、缺失、截短、添加、复制或融合。这些多于一种肽、多肽或蛋白质的融合物可以在相同的分子中相邻地连接,或者与其间的额外氨基酸,例如接头、重复、表位或标签,或者1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、150、200或300个碱基长度,或者在由上述长度中的任两个限定的范围内的任何长度的任何其他序列连接。本文所用的术语在多肽“下游”是指在先前序列的C端之后的序列。本文所用的术语在多肽“上游”是指在后续序列的N端之前的序列。
在一些实施方案中,本文呈现的并在实例中使用的核酸或肽序列在各种生物系统中是有功能的,所述生物系统包括但不限于人、小鼠、大鼠、猴、灵长类、猫、狗、兔、大肠杆菌、酵母和哺乳动物细胞。在其他实施方案中,与本文呈现的并在实例中使用的核酸或肽序列共有至少或低于0%、10%、20%、30%、40%、50%、60%、70%、80%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%同一性,或者在前述同一性百分比中的任两个定义的范围内的任何百分比的核酸或肽序列也可以在对生物系统中序列的功能影响很小或没有影响的情况下使用。如本文所用,术语“同一性”是指分别具有与模板核酸或肽序列相同的核苷酸或氨基酸总体顺序的核酸或肽序列,其在序列内具有特定的变化,如取代、缺失、重复或插入。在一些实施方案中,共有低至0%、10%、20%、30%、40%、50%、60%、70%、80%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的两种核酸序列可通过包含在翻译期间编码相同氨基酸的不同密码子来编码相同的多肽。
如本文所公开的,与本文所公开的任何序列具有%同源性的序列是可预见的,并且可被使用。术语“%同源性”是指当考虑两种序列的三维结构时,所述两种序列之间的保守性程度。例如,两种蛋白质序列之间的同源性可能取决于结构基序,如β链、α螺旋和其他折叠,以及它们在整个序列中的分布。可以根据经验或计算机,通过结构测定来确定同源性。在一些实施方案中,可以使用与本文公开的任何序列具有至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列同源性的任何序列。在一些实施方案中,可以使用相对于本文公开的任何序列具有至少0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49或50个取代、缺失或添加的任何序列,其可能影响或可能不影响总的%同源性。
如本文所应用的,与本文公开的任何序列具有一定%相似性的序列是可预见的,并且可被使用。在一些实施方案中,这些序列可以包括肽序列、核酸序列、CDR序列、可变区序列或者重链或轻链序列。如本领域关于肽序列所理解的,“相似性”是指氨基酸的基于其性质的比较,包括但不限于大小、极性、电荷、pK、芳香性、氢键合性质或官能团(例如羟基、硫醇、胺、羧基等)的存在。术语“相似性%”是指在两个或更多个序列之间相同的单位(即氨基酸)相对于序列长度的百分比。当被比较的两个或更多个序列是相同的长度时,%相似性将相应于该长度。当被比较的两个或更多个序列是不同的长度时,可以引入缺失和/或插入以获得最佳比对。两种氨基酸的相似性可以决定某种取代是保守的还是非保守的。确定氨基酸取代的保守性的方法在本领域中通常是已知的,并且可以涉及取代矩阵。通常使用的取代矩阵包括BLOSUM45、BLOSUM62、BLOSUM80、PAM100、PAM120、PAM160、PAM200、PAM250,但是本领域技术人员认为合适时也可以使用其他取代矩阵或方法。当考虑相关序列的诸如严格性、保守性和/或差异(例如在相同物种内或更广泛),以及所讨论的序列长度等方面时,某一取代矩阵可能优于其他取代矩阵。如本文所用,与另一序列具有某一%相似性的肽序列将具有高达该%的氨基酸,所述氨基酸是相同的或可接受的取代,其由所用的相似性测定方法决定。在一些实施方案中,可以使用与本文公开的任何序列具有至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列相似性的序列。在一些实施方案中,可以使用相对于本文公开的任何序列具有至少0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36,37、38、39、40、41、42、43、44、45、46、47、48、49或50个相似取代的任何序列。如适用于抗体序列的,这些相似的取代可适用于抗原结合区(即CDR)或不结合抗原或仅继发于抗原结合的区域(即框架区)。
本文所用的关于序列的术语“共有序列”是指在一组序列的每个位置处代表所有不同的可允许氨基酸组合的通用序列。共有序列可以提供对相关序列的保守区域的了解,其中单位(例如氨基酸或核苷酸)在大部分或全部序列,以及在序列之间显示出差异的区域中是相同的。在抗体的情况下,CDR的共有序列可以指示对于抗原结合重要或非必要的氨基酸。可以预见,可以用本文提供的任何序列制备共有序列,并且可以验证来源于共有序列的所得各种序列具有与模板序列相似的效果。
如本文所用,术语“抗体”表示本领域技术人员赋予其的含义,并且其进一步旨在包括具有适合并识别表位的特定形状的任何含多肽链的分子结构,其中一种或多种非共价结合相互作用稳定分子结构和表位之间的复合物。
术语“抗体文库”是指展示的用于筛选和/或组合成完整抗体的抗体和/或抗体片段的集合。抗体和/或抗体片段可以展示在核糖体上;展示在噬菌体上;或者展示在细胞表面上,特别是酵母细胞表面上。
本文所用的关于抗体或结合多肽的术语“竞争”意指第一抗体或结合多肽或其抗原结合部分以与第二抗体或结合多肽或其抗原结合部分的结合足够相似的方式与表位结合,使得与在没有第二抗体或结合多肽情况下第一抗体或结合多肽的结合相比,在存在第二抗体或结合多肽的情况下,第一抗体或结合多肽与其同源表位的结合结果可检测地降低。在存在第一抗体或结合多肽的情况下,第二抗体或结合多肽与其表位的结合也可检测地降低的替代方案可以,但不一定是这种情况。不管这种竞争发生的机制如何(例如,空间位阻、构象变化或与共同表位或其部分的结合),技术人员将基于本文提供的教导理解,这种竞争性抗体或结合多肽被涵盖并且可用于本文公开的方法。
与表位“优先结合”或“特异性结合”(本文可互换使用)的抗体或结合多肽是本领域充分理解的术语,并且测定这种特异性或优先结合的方法也是本领域熟知的。如果与分子与替代细胞或物质的反应或缔合相比,分子更频繁地和/或更快速地和/或以更长的持续时间和/或以更大的亲和力与特定细胞或物质反应或缔合,则认为该分子表现出“特异性结合”或“优先结合”。如果与抗体或结合多肽与其他物质的结合相比,抗体或结合多肽以更大的亲和力和/或亲合力和/或更易于和/或以更长的持续时间与靶标结合,则所述抗体或结合多肽与靶标“特异性结合”或“优先结合”。
适用于非人类(例如啮齿类或灵长类)抗体的术语“人源化的”是含有来源于非人类免疫球蛋白的最小序列的杂合免疫球蛋白、免疫球蛋白链或其片段。
本文所用的术语“单域结合多肽”或“单域抗体”(sdAb)是指包含完整的免疫球蛋白结构域或可识别抗原的其他蛋白折叠的单肽链(例如,不与具有二硫键的另一肽链结合)。单域结合多肽或sdAb可以来源于典型的重链或轻链免疫球蛋白链,如来自人或来自替代的来源,如单峰骆驼(例如VHH)和软骨鱼(例如VNAR)。在一些实施方案中,单域结合多肽或sdAb包含一个、两个或三个互补决定区(CDR)。在一些实施方案中,单域结合多肽或sdAb包含CDR1、CDR2和CDR3中的一种、两种或三种。
本文所用的术语“单链可变片段”(scFv)是包含免疫球蛋白重链(VH)和轻链(VL)的可变区的融合蛋白,其中VH和VL共价连接形成VH:VL异二聚体。VH和VL直接连接或通过肽编码接头连接,所述肽编码接头将VH的N端与VL的C端连接,或者将VH的C端与VL的N端连接。接头通常富含甘氨酸以获得柔性,以及丝氨酸或苏氨酸以获得溶解性。尽管除去了恒定区并引入了接头,scFv蛋白仍保留了原始免疫球蛋白的特异性。单链Fv多肽抗体可以由包括VH和VL编码序列的核酸表达。在一些实施方案中,scFv的VH和VL各自包含一个、两个或三个CDR。在一些实施方案中,scFv的VH和VL各自包含CDR1、CDR2和CDR3中的一种、两种或三种。
在某些实施方案中,通过揭示抗体或结合多肽的结构和/或揭示抗体-配体复合物的结构来完成CDR的明确描绘和包含抗体或结合多肽的结合位点的残基的鉴定。在某些实施方案中,其可以通过本领域技术人员已知的多种技术中的任一种来实现,如X-射线晶体学。在某些实施方案中,可以采用各种分析方法来鉴定或模拟CDR区。在某些实施方案中,可以采用各种分析方法来识别或模拟CDR区。这种方法的实例包括但不限于Kabat定义、Chothia定义、IMGT方法(Lefranc等人,2003)Dev Comp Immunol.27:55-77)、计算程序如Paratome(Kunik等人,2012,Nucl Acids Res.W521-4)、AbM定义和构象定义。
Kabat定义是用于对抗体中的残基进行编号的标准,并且通常用于鉴定CDR区。参见例如,Johnson&Wu,2000,Nucleic Acids Res.,28:214-8。Chothia定义类似于Kabat定义,但是Chothia定义考虑了某些结构环区域的位置。参见例如,Chothia等人,1986,J.Mol.Biol.,196:901-17;Chothia等人,1989,Nature,342:877-83。AbM定义使用OxfordMolecular Group生产的模拟抗体结构的计算机程序的集成套件。参见例如,Martin等人,1989,Proc Natl Acad Sci(USA),86:9268-9272;"AbM.TM.,AComputer Program forModeling Variable Regions of Antibodies,"Oxford,UK;Oxford Molecular,Ltd。AbM定义使用知识数据库和从头计算(ab initio)方法,如Samudrala等人,1999,"Ab InitioProtein Structure Prediction Using a Combined Hierarchical Approach,"PROTEINS,Structure,Function and Genetics Suppl.,3:194-198描述的那些,的组合模拟来自一级序列的抗体的三级结构。接触定义基于对可用的复杂晶体结构的分析。参见例如,MacCallum等人,1996,J.Mol.Biol.,5:732-45。在另一种方法中,本文称为CDR的“构象定义”,CDR的位置可以被鉴定为对抗原结合作出焓贡献的残基。参见例如,Makabe等人,2008,Journal of Biological Chemistry,283:1156-1166。还有其他CDR边界定义可能不严格遵循上述方法之一,但仍然与至少一部分Kabat CDR重叠,尽管它们可以根据特定残基或残基组不显著影响抗原结合的预测或实验发现而缩短或延长。如本文所用,CDR可指通过本领域已知的任何方法(包括方法的组合)定义的CDR。本文所用的方法可利用根据这些方法中的任一种定义的CDR。对于含有多于一种CDR的任何给定的实施方案,CDR可以根据Kabat、Chothia、extended、IMGT、Paratome、AbM和/或构象定义中的任一种或前述中的任一种的组合来定义。
本文所用的术语“嵌合抗原受体(CAR)”是指在免疫细胞中赋予针对某种抗原如肿瘤相关抗原的人工特异性的工程化的生物受体。其中可使用CAR的示例性免疫细胞是T细胞,但设想CAR可被工程化成任何可适应的细胞毒性免疫细胞,包括但不限于T细胞、自然杀伤(NK)细胞、自然杀伤T(NKT)细胞、树突细胞或巨噬细胞。在这一方面,与CAR T细胞有关的任何公开内容也可适用于包含CAR的其他免疫细胞。在其核心处,CAR包含细胞外抗原识别结构域(例如肿瘤受体配体或抗体)、铰链、跨膜和细胞内信号传导结构域(内结构域)。这些CAR组分的不同组合可导致针对某些癌症抗原的不同特异性和功效。
如本文所用,术语“治疗(treating)”或“治疗(treatment)”(并且如本领域中充分理解的)意指用于获得对象病况的有益或期望结果,包括临床结果的方法。有益的或期望的临床结果可包括但不限于减轻或改善一种或多种症状或病况、减少疾病的程度、稳定(即不恶化)疾病状态、预防疾病的传播或扩散、延迟或减缓疾病进展、改善或缓和疾病状态、减少疾病的复发,以及缓解,不论是部分的还是全部的,以及不论是可检测的还是不可检测的。本文所用的“治疗(treating)”或“治疗(treatment)”还包括预防性治疗。治疗方法包括向对象施用治疗有效量的活性剂。施用步骤可以由单次施用组成或可以包括一系列施用。以足以治疗对象的量和持续时间向对象施用组合物。治疗期的长度取决于多种因素,如病况的严重程度、对象的年龄和遗传特征、活性剂的浓度、用于治疗的组合物的活性或以上的组合。还应理解,用于治疗或预防的试剂的有效剂量可在特定治疗或预防方案的过程中增加或减少。剂量的变化可通过本领域已知的标准诊断测定导致并变得明显。在一些情况下,可能需要长期施用。
本文所用的术语“有效量”或“有效剂量”是指导致可观察到的指定效果的所述组合物或化合物的量。可以改变本公开主题的活性组合物中活性成分的实际剂量水平,以便施用有效实现针对特定对象和/或应用的指定响应的活性组合物或化合物的量。所选择的剂量水平可基于多种因素而变化,包括但不限于组合物的活性、制剂、施用途径、与其他药物或治疗的组合、所治疗的病况的严重程度,以及所治疗的对象的身体状况和先前医疗史。在一些实施方案中,施用最小剂量,并且在没有剂量限制毒性的情况下将剂量增加至最小有效量。本文中考虑了有效剂量的确定和调整,以及何时和如何进行这种调整的评估。
术语“施用”包括经口施用、局部接触、作为栓剂施用、肠胃外、静脉内、腹膜内、肌内、病灶内、鞘内、鼻内、真皮下或皮下施用,或者向对象植入缓释装置,例如微渗透泵。施用是通过任何途径,包括肠胃外和经粘膜(例如,口腔、舌下、腭、齿龈、鼻、阴道、直肠或透皮)。肠胃外施用包括例如静脉内、肌内、小动脉内、皮内、皮下、腹膜内、心室内和颅内。其他递送模式包括但不限于使用脂质体制剂、静脉内输注、透皮贴剂等。“共施用”意指在施用本文所述的第二化合物的同时、之前不久或之后不久施用本文所述的第一化合物。
如本文所用,术语“治疗靶标”是指在调节其活性(例如,通过调节表达、生物活性等)后,可提供调节疾病表型的基因或基因产物。如全文所用的,“调节”意在指所示现象的增加或降低(例如,生物活性的调节是指生物活性的增加或生物活性的降低)。
如本文所用,术语“护理标准”、“最佳实践”和“标准疗法”是指这样的治疗,其是医疗从业人员接受的治疗某种疾病的合适、适当、有效和/或广泛使用的治疗。某种疾病的护理标准取决于许多不同的因素,包括治疗的生物效应、体内的区域或位置、患者状态(例如年龄、体重、性别、遗传风险、其他残疾、继发性病况)、毒性、代谢、生物累积、治疗指数、剂量和本领域已知的其他因素。确定疾病的护理标准还取决于在由管理机构如美国食品和药品管理局(US Food and Drug Administration)、国际协调理事会(International Councilfor Harmonisation)、加拿大卫生部(Health Canada)、欧洲药品管理局(EuropeanMedicines Agency)、医疗用品管理局(Therapeutics Goods Administration)、中央药品标准监管局(Central Drugs Standard Control Organization)、国家药品监督管理局(National Medical Products Administration)、药品和医疗器械局(Pharmaceuticalsand Medical Devices Agency)、食品和药品安全部(Ministry of Food and DrugSafety)和世界卫生组织(World Health Organization)标准化的临床试验中建立安全性和功效。疾病的护理标准可以包括但不限于手术、放射、化疗、靶向治疗或免疫治疗。
术语“%w/w”或“%wt/wt”意指以成分或试剂的重量相比组合物的总重量乘以100表示的百分比。
抗原结合多肽
除非另有说明,否则本文公开的互补决定区(CDR)遵循IMGT定义。然而,也可以通过Kabat、Chothia或本领域技术人员所理解的其他定义来单独或在可变结构域的上下文中解释CDR。
本文公开了成纤维细胞活化蛋白(FAP)结合多肽。在一些实施方案中,FAP结合多肽包含免疫球蛋白重链可变结构域,其包含CDR-H1、CDR-H2和CDR-H3。在一些实施方案中,CDR-H1包含与选自SEQ ID NO:1-108的序列具有至少90%、95%、99%或100%序列同一性的序列。在一些实施方案中,CDR-H2包含与选自SEQ ID NO:109-216的序列具有至少90%、95%、99%或100%序列同一性的序列。在一些实施方案中,CDR-H3包含与选自SEQ ID NO:217-324的序列具有至少90%、95%、99%或100%序列同一性的序列。在一些实施方案中,CDR-H1包含与选自SEQ ID NO:1-108的序列具有至少90%、95%、99%或100%序列同一性的序列;CDR-H2包含与选自SEQ ID NO:109-216的序列具有至少90%、95%、99%或100%序列同一性的序列;并且CDR-H3包含与选自SEQ ID NO:217-324的序列具有至少90%、95%、99%或100%序列同一性的序列。
在FAP结合多肽的一些实施方案中:
1)CDR-H1包含SEQ ID NO:1的序列,CDR-H2包含SEQ ID NO:109的序列,并且CDR-H3包含SEQ ID NO:217的序列;
2)CDR-H1包含SEQ ID NO:2的序列,CDR-H2包含SEQ ID NO:110的序列,并且CDR-H3包含SEQ ID NO:218的序列;
3)CDR-H1包含SEQ ID NO:3的序列,CDR-H2包含SEQ ID NO:111的序列,并且CDR-H3包含SEQ ID NO:219的序列;
4)CDR-H1包含SEQ ID NO:4的序列,CDR-H2包含SEQ ID NO:112的序列,并且CDR-H3包含SEQ ID NO:220的序列;
5)CDR-H1包含SEQ ID NO:5的序列,CDR-H2包含SEQ ID NO:113的序列,并且CDR-H3包含SEQ ID NO:221的序列;
6)CDR-H1包含SEQ ID NO:6的序列,CDR-H2包含SEQ ID NO:114的序列,并且CDR-H3包含SEQ ID NO:222的序列;
7)CDR-H1包含SEQ ID NO:7的序列,CDR-H2包含SEQ ID NO:115的序列,并且CDR-H3包含SEQ ID NO:223的序列;
8)CDR-H1包含SEQ ID NO:8的序列,CDR-H2包含SEQ ID NO:116的序列,并且CDR-H3包含SEQ ID NO:224的序列;
9)CDR-H1包含SEQ ID NO:9的序列,CDR-H2包含SEQ ID NO:117的序列,并且CDR-H3包含SEQ ID NO:225的序列;
10)CDR-H1包含SEQ ID NO:10的序列,CDR-H2包含SEQ ID NO:118的序列,并且CDR-H3包含SEQ ID NO:226的序列;
11)CDR-H1包含SEQ ID NO:11的序列,CDR-H2包含SEQ ID NO:119的序列,并且CDR-H3包含SEQ ID NO:227的序列;
12)CDR-H1包含SEQ ID NO:12的序列,CDR-H2包含SEQ ID NO:120的序列,并且CDR-H3包含SEQ ID NO:228的序列;
13)CDR-H1包含SEQ ID NO:13的序列,CDR-H2包含SEQ ID NO:121的序列,并且CDR-H3包含SEQ ID NO:229的序列;
14)CDR-H1包含SEQ ID NO:14的序列,CDR-H2包含SEQ ID NO:122的序列,并且CDR-H3包含SEQ ID NO:230的序列;
15)CDR-H1包含SEQ ID NO:15的序列,CDR-H2包含SEQ ID NO:123的序列,并且CDR-H3包含SEQ ID NO:231的序列;
16)CDR-H1包含SEQ ID NO:16的序列,CDR-H2包含SEQ ID NO:124的序列,并且CDR-H3包含SEQ ID NO:232的序列;
17)CDR-H1包含SEQ ID NO:17的序列,CDR-H2包含SEQ ID NO:125的序列,并且CDR-H3包含SEQ ID NO:233的序列;
18)CDR-H1包含SEQ ID NO:18的序列,CDR-H2包含SEQ ID NO:126的序列,并且CDR-H3包含SEQ ID NO:234的序列;
19)CDR-H1包含SEQ ID NO:19的序列,CDR-H2包含SEQ ID NO:127的序列,并且CDR-H3包含SEQ ID NO:235的序列;
20)CDR-H1包含SEQ ID NO:20的序列,CDR-H2包含SEQ ID NO:128的序列,并且CDR-H3包含SEQ ID NO:236的序列;
21)CDR-H1包含SEQ ID NO:21的序列,CDR-H2包含SEQ ID NO:129的序列,并且CDR-H3包含SEQ ID NO:237的序列;
22)CDR-H1包含SEQ ID NO:22的序列,CDR-H2包含SEQ ID NO:130的序列,并且CDR-H3包含SEQ ID NO:238的序列;
23)CDR-H1包含SEQ ID NO:23的序列,CDR-H2包含SEQ ID NO:131的序列,并且CDR-H3包含SEQ ID NO:239的序列;
24)CDR-H1包含SEQ ID NO:24的序列,CDR-H2包含SEQ ID NO:132的序列,并且CDR-H3包含SEQ ID NO:240的序列;
25)CDR-H1包含SEQ ID NO:25的序列,CDR-H2包含SEQ ID NO:133的序列,并且CDR-H3包含SEQ ID NO:241的序列;
26)CDR-H1包含SEQ ID NO:26的序列,CDR-H2包含SEQ ID NO:134的序列,并且CDR-H3包含SEQ ID NO:242的序列;
27)CDR-H1包含SEQ ID NO:27的序列,CDR-H2包含SEQ ID NO:135的序列,并且CDR-H3包含SEQ ID NO:243的序列;
28)CDR-H1包含SEQ ID NO:28的序列,CDR-H2包含SEQ ID NO:136的序列,并且CDR-H3包含SEQ ID NO:244的序列;
29)CDR-H1包含SEQ ID NO:29的序列,CDR-H2包含SEQ ID NO:137的序列,并且CDR-H3包含SEQ ID NO:245的序列;
30)CDR-H1包含SEQ ID NO:30的序列,CDR-H2包含SEQ ID NO:138的序列,并且CDR-H3包含SEQ ID NO:246的序列;
31)CDR-H1包含SEQ ID NO:31的序列,CDR-H2包含SEQ ID NO:139的序列,并且CDR-H3包含SEQ ID NO:247的序列;
32)CDR-H1包含SEQ ID NO:32的序列,CDR-H2包含SEQ ID NO:140的序列,并且CDR-H3包含SEQ ID NO:248的序列;
33)CDR-H1包含SEQ ID NO:33的序列,CDR-H2包含SEQ ID NO:141的序列,并且CDR-H3包含SEQ ID NO:249的序列;
34)CDR-H1包含SEQ ID NO:34的序列,CDR-H2包含SEQ ID NO:142的序列,并且CDR-H3包含SEQ ID NO:250的序列;
35)CDR-H1包含SEQ ID NO:35的序列,CDR-H2包含SEQ ID NO:143的序列,并且CDR-H3包含SEQ ID NO:251的序列;
36)CDR-H1包含SEQ ID NO:36的序列,CDR-H2包含SEQ ID NO:144的序列,并且CDR-H3包含SEQ ID NO:252的序列;
37)CDR-H1包含SEQ ID NO:37的序列,CDR-H2包含SEQ ID NO:145的序列,并且CDR-H3包含SEQ ID NO:253的序列;
38)CDR-H1包含SEQ ID NO:38的序列,CDR-H2包含SEQ ID NO:146的序列,并且CDR-H3包含SEQ ID NO:254的序列;
39)CDR-H1包含SEQ ID NO:39的序列,CDR-H2包含SEQ ID NO:147的序列,并且CDR-H3包含SEQ ID NO:255的序列;
40)CDR-H1包含SEQ ID NO:40的序列,CDR-H2包含SEQ ID NO:148的序列,并且CDR-H3包含SEQ ID NO:256的序列;
41)CDR-H1包含SEQ ID NO:41的序列,CDR-H2包含SEQ ID NO:149的序列,并且CDR-H3包含SEQ ID NO:257的序列;
42)CDR-H1包含SEQ ID NO:42的序列,CDR-H2包含SEQ ID NO:150的序列,并且CDR-H3包含SEQ ID NO:258的序列;
43)CDR-H1包含SEQ ID NO:43的序列,CDR-H2包含SEQ ID NO:151的序列,并且CDR-H3包含SEQ ID NO:259的序列;
44)CDR-H1包含SEQ ID NO:44的序列,CDR-H2包含SEQ ID NO:152的序列,并且CDR-H3包含SEQ ID NO:260的序列;
45)CDR-H1包含SEQ ID NO:45的序列,CDR-H2包含SEQ ID NO:153的序列,并且CDR-H3包含SEQ ID NO:261的序列;
46)CDR-H1包含SEQ ID NO:46的序列,CDR-H2包含SEQ ID NO:154的序列,并且CDR-H3包含SEQ ID NO:262的序列;
47)CDR-H1包含SEQ ID NO:47的序列,CDR-H2包含SEQ ID NO:155的序列,并且CDR-H3包含SEQ ID NO:263的序列;
48)CDR-H1包含SEQ ID NO:48的序列,CDR-H2包含SEQ ID NO:156的序列,并且CDR-H3包含SEQ ID NO:264的序列;
49)CDR-H1包含SEQ ID NO:49的序列,CDR-H2包含SEQ ID NO:157的序列,并且CDR-H3包含SEQ ID NO:265的序列;
50)CDR-H1包含SEQ ID NO:50的序列,CDR-H2包含SEQ ID NO:158的序列,并且CDR-H3包含SEQ ID NO:266的序列;
51)CDR-H1包含SEQ ID NO:51的序列,CDR-H2包含SEQ ID NO:159的序列,并且CDR-H3包含SEQ ID NO:267的序列;
52)CDR-H1包含SEQ ID NO:52的序列,CDR-H2包含SEQ ID NO:160的序列,并且CDR-H3包含SEQ ID NO:268的序列;
53)CDR-H1包含SEQ ID NO:53的序列,CDR-H2包含SEQ ID NO:161的序列,并且CDR-H3包含SEQ ID NO:269的序列;
54)CDR-H1包含SEQ ID NO:54的序列,CDR-H2包含SEQ ID NO:162的序列,并且CDR-H3包含SEQ ID NO:270的序列;
55)CDR-H1包含SEQ ID NO:55的序列,CDR-H2包含SEQ ID NO:163的序列,并且CDR-H3包含SEQ ID NO:271的序列;
56)CDR-H1包含SEQ ID NO:56的序列,CDR-H2包含SEQ ID NO:164的序列,并且CDR-H3包含SEQ ID NO:272的序列;
57)CDR-H1包含SEQ ID NO:57的序列,CDR-H2包含SEQ ID NO:165的序列,并且CDR-H3包含SEQ ID NO:273的序列;
58)CDR-H1包含SEQ ID NO:58的序列,CDR-H2包含SEQ ID NO:166的序列,并且CDR-H3包含SEQ ID NO:274的序列;
59)CDR-H1包含SEQ ID NO:59的序列,CDR-H2包含SEQ ID NO:167的序列,并且CDR-H3包含SEQ ID NO:275的序列;
60)CDR-H1包含SEQ ID NO:60的序列,CDR-H2包含SEQ ID NO:168的序列,并且CDR-H3包含SEQ ID NO:276的序列;
61)CDR-H1包含SEQ ID NO:61的序列,CDR-H2包含SEQ ID NO:169的序列,并且CDR-H3包含SEQ ID NO:277的序列;
62)CDR-H1包含SEQ ID NO:62的序列,CDR-H2包含SEQ ID NO:170的序列,并且CDR-H3包含SEQ ID NO:278的序列;
63)CDR-H1包含SEQ ID NO:63的序列,CDR-H2包含SEQ ID NO:171的序列,并且CDR-H3包含SEQ ID NO:279的序列;
64)CDR-H1包含SEQ ID NO:64的序列,CDR-H2包含SEQ ID NO:172的序列,并且CDR-H3包含SEQ ID NO:280的序列;
65)CDR-H1包含SEQ ID NO:65的序列,CDR-H2包含SEQ ID NO:173的序列,并且CDR-H3包含SEQ ID NO:281的序列;
66)CDR-H1包含SEQ ID NO:66的序列,CDR-H2包含SEQ ID NO:174的序列,并且CDR-H3包含SEQ ID NO:282的序列;
67)CDR-H1包含SEQ ID NO:67的序列,CDR-H2包含SEQ ID NO:175的序列,并且CDR-H3包含SEQ ID NO:283的序列;
68)CDR-H1包含SEQ ID NO:68的序列,CDR-H2包含SEQ ID NO:176的序列,并且CDR-H3包含SEQ ID NO:284的序列;
69)CDR-H1包含SEQ ID NO:69的序列,CDR-H2包含SEQ ID NO:177的序列,并且CDR-H3包含SEQ ID NO:285的序列;
70)CDR-H1包含SEQ ID NO:70的序列,CDR-H2包含SEQ ID NO:178的序列,并且CDR-H3包含SEQ ID NO:286的序列;
71)CDR-H1包含SEQ ID NO:71的序列,CDR-H2包含SEQ ID NO:179的序列,并且CDR-H3包含SEQ ID NO:287的序列;
72)CDR-H1包含SEQ ID NO:72的序列,CDR-H2包含SEQ ID NO:180的序列,并且CDR-H3包含SEQ ID NO:288的序列;
73)CDR-H1包含SEQ ID NO:73的序列,CDR-H2包含SEQ ID NO:181的序列,并且CDR-H3包含SEQ ID NO:289的序列;
74)CDR-H1包含SEQ ID NO:74的序列,CDR-H2包含SEQ ID NO:182的序列,并且CDR-H3包含SEQ ID NO:290的序列;
75)CDR-H1包含SEQ ID NO:75的序列,CDR-H2包含SEQ ID NO:183的序列,并且CDR-H3包含SEQ ID NO:291的序列;
76)CDR-H1包含SEQ ID NO:76的序列,CDR-H2包含SEQ ID NO:184的序列,并且CDR-H3包含SEQ ID NO:292的序列;
77)CDR-H1包含SEQ ID NO:77的序列,CDR-H2包含SEQ ID NO:185的序列,并且CDR-H3包含SEQ ID NO:293的序列;
78)CDR-H1包含SEQ ID NO:78的序列,CDR-H2包含SEQ ID NO:186的序列,并且CDR-H3包含SEQ ID NO:294的序列;
79)CDR-H1包含SEQ ID NO:79的序列,CDR-H2包含SEQ ID NO:187的序列,并且CDR-H3包含SEQ ID NO:295的序列;
80)CDR-H1包含SEQ ID NO:80的序列,CDR-H2包含SEQ ID NO:188的序列,并且CDR-H3包含SEQ ID NO:296的序列;
81)CDR-H1包含SEQ ID NO:81的序列,CDR-H2包含SEQ ID NO:189的序列,并且CDR-H3包含SEQ ID NO:297的序列;
82)CDR-H1包含SEQ ID NO:82的序列,CDR-H2包含SEQ ID NO:190的序列,并且CDR-H3包含SEQ ID NO:298的序列;
83)CDR-H1包含SEQ ID NO:83的序列,CDR-H2包含SEQ ID NO:191的序列,并且CDR-H3包含SEQ ID NO:299的序列;
84)CDR-H1包含SEQ ID NO:84的序列,CDR-H2包含SEQ ID NO:192的序列,并且CDR-H3包含SEQ ID NO:300的序列;
85)CDR-H1包含SEQ ID NO:85的序列,CDR-H2包含SEQ ID NO:193的序列,并且CDR-H3包含SEQ ID NO:301的序列;
86)CDR-H1包含SEQ ID NO:86的序列,CDR-H2包含SEQ ID NO:194的序列,并且CDR-H3包含SEQ ID NO:302的序列;
87)CDR-H1包含SEQ ID NO:87的序列,CDR-H2包含SEQ ID NO:195的序列,并且CDR-H3包含SEQ ID NO:303的序列;
88)CDR-H1包含SEQ ID NO:88的序列,CDR-H2包含SEQ ID NO:196的序列,并且CDR-H3包含SEQ ID NO:304的序列;
89)CDR-H1包含SEQ ID NO:89的序列,CDR-H2包含SEQ ID NO:197的序列,并且CDR-H3包含SEQ ID NO:305的序列;
90)CDR-H1包含SEQ ID NO:90的序列,CDR-H2包含SEQ ID NO:198的序列,并且CDR-H3包含SEQ ID NO:306的序列;
91)CDR-H1包含SEQ ID NO:91的序列,CDR-H2包含SEQ ID NO:199的序列,并且CDR-H3包含SEQ ID NO:307的序列;
92)CDR-H1包含SEQ ID NO:92的序列,CDR-H2包含SEQ ID NO:200的序列,并且CDR-H3包含SEQ ID NO:308的序列;
93)CDR-H1包含SEQ ID NO:93的序列,CDR-H2包含SEQ ID NO:201的序列,并且CDR-H3包含SEQ ID NO:309的序列;
94)CDR-H1包含SEQ ID NO:94的序列,CDR-H2包含SEQ ID NO:202的序列,并且CDR-H3包含SEQ ID NO:310的序列;
95)CDR-H1包含SEQ ID NO:95的序列,CDR-H2包含SEQ ID NO:203的序列,并且CDR-H3包含SEQ ID NO:311的序列;
96)CDR-H1包含SEQ ID NO:96的序列,CDR-H2包含SEQ ID NO:204的序列,并且CDR-H3包含SEQ ID NO:312的序列;
97)CDR-H1包含SEQ ID NO:97的序列,CDR-H2包含SEQ ID NO:205的序列,并且CDR-H3包含SEQ ID NO:313的序列;
98)CDR-H1包含SEQ ID NO:98的序列,CDR-H2包含SEQ ID NO:206的序列,并且CDR-H3包含SEQ ID NO:314的序列;
99)CDR-H1包含SEQ ID NO:99的序列,CDR-H2包含SEQ ID NO:207的序列,并且CDR-H3包含SEQ ID NO:315的序列;
100)CDR-H1包含SEQ ID NO:100的序列,CDR-H2包含SEQ ID NO:208的序列,并且CDR-H3包含SEQ ID NO:316的序列;
101)CDR-H1包含SEQ ID NO:101的序列,CDR-H2包含SEQ ID NO:209的序列,并且CDR-H3包含SEQ ID NO:317的序列;
102)CDR-H1包含SEQ ID NO:102的序列,CDR-H2包含SEQ ID NO:210的序列,并且CDR-H3包含SEQ ID NO:318的序列;
103)CDR-H1包含SEQ ID NO:103的序列,CDR-H2包含SEQ ID NO:211的序列,并且CDR-H3包含SEQ ID NO:319的序列;
104)CDR-H1包含SEQ ID NO:104的序列,CDR-H2包含SEQ ID NO:212的序列,并且CDR-H3包含SEQ ID NO:320的序列;
105)CDR-H1包含SEQ ID NO:105的序列,CDR-H2包含SEQ ID NO:213的序列,并且CDR-H3包含SEQ ID NO:321的序列;
106)CDR-H1包含SEQ ID NO:106的序列,CDR-H2包含SEQ ID NO:214的序列,并且CDR-H3包含SEQ ID NO:322的序列;
107)CDR-H1包含SEQ ID NO:107的序列,CDR-H2包含SEQ ID NO:215的序列,并且CDR-H3包含SEQ ID NO:323的序列;或者
108)CDR-H1包含SEQ ID NO:108的序列,CDR-H2包含SEQ ID NO:216的序列,并且CDR-H3包含SEQ ID NO:324的序列。
在一些实施方案中,FAP结合多肽包含免疫球蛋白重链可变结构域,其包含CDR-H1、CDR-H2和CDR-H3,其中这些CDR中的一个或多个由共有序列定义。本文提供的共有序列来源于图1所示的CDR的比对。然而,可以设想,可以进行替代的比对(例如,使用全局或局部比对,或者利用不同的算法,如隐马尔可夫模型、种子引导树、Needleman-Wunsch算法或Smith-Waterman算法,或者其他已知的方法),并且因此,可以得到替代的共有序列(包括用本文提供的序列子集进行的那些)。
在一些实施方案中,CDR-H1由式X1X2X3X4X5X6X7X8X9定义,其中X1是G;X2是F、G、R、S或Y;X3是I或T;X4是F、L、S或Y;X5是D、G、N、R或S;X6是A、D、F、H、I、L、N、P、S、V或Y;X7是D、N或Y;X8是A、D、F、H、I、N、P、S、T、V或Y;X9是M。在一些实施方案中,CDR-H1包含与该共有序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%同一性的序列。在一些实施方案中,CDR-H1包含具有来自该共有序列的0、1、2、3、4、5或6个取代的序列。
在一些实施方案中,CDR-H2由式X1X2X3X4X5X6X7X8X9X10定义,其中X1是无氨基酸、是A、S或T;X2是I或T;X3是I、N、S或T;X4是A、G、P、R、S、T或W;X5是A、D、F、I、L、N、S、T、V或Y;X6是D、G或S;X7是A、D、G或S;X8是I、N、S或T;X9是T;X10是Y或N。在一些实施方案中,CDR-H2包含与该共有序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%同一性的序列。在一些实施方案中,CDR-H2包含具有来自该共有序列的0、1、2、3、4、5或6个取代的序列。
在一些实施方案中,CDR-H3由式X1X2X3X4X5X6X7X8X9X10X11X12X13X14X15X16X17X18X19X2 0X21X22X23定义,其中X1是无氨基酸或是A;X2是无氨基酸或是H;X3是无氨基酸或是Y;X4是无氨基酸或是N;X5是无氨基酸或是R;X6是无氨基酸或是Y;X7是无氨基酸、是A或V;X8是无氨基酸、是A、P、S或V;X9是无氨基酸、是D、P或T;X10是无氨基酸、是A、F或V;X11是无氨基酸、是A、G、K、L、R、S、T或W;X12是无氨基酸、是A、D、E、I、N、P、S、T或Y;X13是A、G、H、K、L、P、R、S、T、V、W或Y;X14是A、D、F、G、I、M、N、P、Q、R、S、T或W;X15是无氨基酸、是A、D、E、F、G、H、I、L、M、N、P、Q、R、S、T、V、W或Y;X16是无氨基酸、是A、D、E、F、H、I、K、L、M、N、P、Q、R、S、T、V、W或Y;X17是A、D、E、F、G、H、I、K、L、M、N、P、Q、S、T、V、W或Y;X18是A、D、F、G、H、K、L、M、N、P、Q、R、S、W或Y;X19是A、F、G、H、K、M、S、T或V;X20是F、H、L、M或Y;X21是D、G、N、S或Y;X22是无氨基酸或是Y;X23是无氨基酸或是W。
在一些实施方案中,CDR-H3包含与该共有序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%同一性的序列。在一些实施方案中,CDR-H3包含具有来自该共有序列的0、1、2、3、4、5或6个取代的序列。
在FAP结合多肽的一些实施方案中,重链可变结构域包含与选自SEQ ID NO:325-432的任何序列具有至少90%、95%、99%或100%序列同一性的氨基酸序列。
本文还公开了FAP结合多肽。在一些实施方案中,FAP结合多肽包含免疫球蛋白重链可变结构域,其包含CDR-H1。在一些实施方案中,CDR-H1包含与选自SEQ ID NO:1-108的序列具有至少90%、95%、99%或100%序列同一性的序列。在一些实施方案中,CDR-H1包含与选自SEQ ID NO:4,或者在替代方案中,SEQ ID NO:5、9、14、23、25、28、33、34、36、40、47、50、51、54、57、64、66、83、88、90、96、97、98或99的序列具有至少90%、95%、99%或100%序列同一性的序列。在一些实施方案中,免疫球蛋白重链可变结构域还包含CDR-H2,其中CDR-H2包含与选自SEQ ID NO:109-216的序列具有至少90%、95%、99%或100%序列同一性的序列。在一些实施方案中,免疫球蛋白重链可变结构域还包含CDR-H3,其中CDR-H3包含与选自SEQ ID NO:217-324的序列具有至少90%、95%、99%或100%序列同一性的序列。在一些实施方案中,免疫球蛋白重链可变结构域包含与选自SEQ ID NO:325-432的任何序列具有至少90%、95%、99%或100%序列同一性的氨基酸序列。
本文还公开了FAP结合多肽。在一些实施方案中,FAP结合多肽包含免疫球蛋白重链可变结构域,其包含CDR-H2。在一些实施方案中,CDR-H2包含与选自SEQ ID NO:109-216的序列具有至少90%、95%、99%或100%序列同一性的序列。在一些实施方案中,CDR-H2包含与选自SEQ ID NO:110,或者在替代方案中,SEQ ID NO:112-118、121-124、126、127、129-133、135、136、141、142、148-152、155、158-162、165、170、172、174、175、180、181、190、191、194-198、201、204-207、211或216的序列具有至少90%、95%、99%或100%序列同一性的序列。在一些实施方案中,免疫球蛋白重链可变结构域还包含CDR-H1,其中CDR-H1包含与选自SEQ ID NO:1-108的序列具有至少90%、95%、99%或100%序列同一性的序列。在一些实施方案中,免疫球蛋白重链可变结构域还包含CDR-H3,其中CDR-H3包含与选自SEQ ID NO:217-324的序列具有至少90%、95%、99%或100%序列同一性的序列。在一些实施方案中,免疫球蛋白重链可变结构域包含与选自SEQ ID NO:325-432的任何序列具有至少90%、95%、99%或100%序列同一性的氨基酸序列。
在一些实施方案中,FAP结合多肽是人源化的。在一些实施方案中,FAP结合多肽是单域抗体(sdAb)。
在一些实施方案中,FAP结合多肽以小于1nM、2nM、5nM、10nM、15nM、20nM、30nM、40nM、50nM、60nM、70nM、80nM、90nM、100nM、200nM、300nM、400nM、500nM、600nM、700nM、800nM、900nM或1000nM的解离常数(KD),或者在由前述KD中的任两个限定的范围内的任何KD与FAP结合。
本文公开的结合多肽可以从抗体文库获得。在一些实施方案中,抗体文库是免疫抗体文库、天然抗体文库、合成抗体文库或半合成抗体文库。在一些实施方案中,抗体文库包含来源于人的抗体或在人中无免疫原性的抗体,或者两者。在一些实施方案中,抗体文库包含人源化的抗体,例如来自小鼠、大鼠、豚鼠、兔、猫、狗、牛、马、绵羊、山羊、马、驴。在一些实施方案中,抗体文库包含单域抗体(sdAb)、纳米抗体、VHH片段、VNAR片段、单链可变片段(scFv)、骆驼科动物抗体或软骨鱼抗体,或者以上的任意组合。可以使用的一种示例性文库是完全人源化的、合成的sdAb文库,但是可以制备的或可获得的任何其他抗体文库可以用于本文公开的方法。在一些实施方案中,抗体文库包含sdAb。在一些实施方案中,抗体文库包含至少100、500、1000、2000、3000、4000、5000、6000、7000、8000、9000、10000、20000、30000、40000、50000、60000、70000、80000、90000、100000、500000或1000000种独特的抗体,或者在由前述数目的抗体中的任两种限定的范围内的任何数目的抗体。
可以通过计算或使用机器学习过程产生抗体文库。计算产生抗体文库的示例性方法包括修饰一个或多个互补决定区(CDR),如CDR1、CDR2或CDR3,或者以上的任意组合中具有合成多样性的通用VHH框架。通过随机化编码具有简并密码子的抗体的序列文库,引入CDR的多样性。例如,可以采用NNK密码子文库,其中NNK密码子包含N(A/T/C/G的25%混合物)和K(T/G的50%混合物)。在一些实施方案中,NNK密码子文库用所有可能的氨基酸构建,或者排除了一些氨基酸(例如半胱氨酸)和终止密码子组合。可以利用最少的实验,用其他简并密码子混合物取代所述NNK密码子文库。在其他实施方案中,可以使用三聚体密码子混合物产生抗体文库,这改善了有义密码子的平衡表示,同时减少了终止密码子的机会,提高了抗体产生和测试的效率。在一些实施方案中,基于人工智能的预测可用于使用可用的结合模型或结构数据随机化抗体的特异性结合口袋。
在一些实施方案中,淘选抗体文库包括通过噬菌体展示、酵母展示、细菌展示、核糖体展示或mRNA展示或以上的任意组合来筛选候选结合多肽。在一些实施方案中,淘选抗体文库包括一轮或多轮选择,其中针对对癌症相关抗原(例如FAP)或展示癌症相关抗原的细胞或组织的特异性选择候选结合多肽。在一些实施方案中,在包括但不限于肿瘤微环境样条件、免疫抑制条件、低或高pH、低或高氧气浓度、低温或高温、低或高粘度,或者以上的任意组合的条件下选择候选结合多肽,或针对对一种或多种癌症相关抗原的经修饰或衍生形式的特异性选择候选结合多肽。在一些实施方案中,免疫抑制性病况可包括存在肿瘤相关巨噬细胞(TAM)、骨髓来源的抑制细胞(MDSC)、肿瘤相关嗜中性粒细胞(TAN)、癌症相关成纤维细胞(CAF)或其他免疫抑制细胞,或者存在腺苷,或者二者。
在一些实施方案中,嵌合抗原受体细胞来自细胞系(例如Jurkat)。在一些实施方案中,嵌合抗原受体细胞来源于对象。在一些实施方案中,对象患有癌症。在一些实施方案中,对象患有癌症,并且该癌症表达本文公开的任何一种或多种癌症相关抗原(例如FAP)。在一些实施方案中,癌症是乳腺癌、结直肠癌、肾癌、肝癌、肺癌、脑癌、胰腺癌、膀胱癌、睾丸癌、前列腺癌、胃癌、卵巢癌、头颈癌、胆囊癌、血液恶性肿瘤或以上的任意组合。在一些实施方案中,血液恶性肿瘤可包括白血病、急性淋巴母细胞白血病、急性髓细胞白血病、慢性髓细胞白血病、慢性淋巴细胞白血病、毛细胞白血病、淋巴瘤、霍奇金病、非霍奇金淋巴瘤或多发性骨髓瘤。在一些实施方案中,对象是哺乳动物,如人、猫、狗、小鼠、大鼠、仓鼠、啮齿动物、牛、猪、马、山羊、绵羊、驴或猴。在一些实施方案中,对象是人。
嵌合抗原受体(CAR)和细胞
本文还公开了包含本文公开的任何一种或多种FAP结合多肽的嵌合抗原受体(CAR)。
在一些实施方案中,CAR包含至少两种结合多肽,并且CAR是多价CAR。在一些实施方案中,CAR包含两种结合多肽,并且CAR是二价CAR。在一些实施方案中,CAR包含三种结合多肽,并且CAR是三价CAR。
在一些实施方案中,CAR还包含一种或多种信号肽、具有不同长度和组成的接头、铰链、跨膜结构域、共刺激结构域、信号传导结构域、细胞质结构域、功能性信号、增殖信号、抗衰竭信号、抗抑制受体、肿瘤/癌症归巢蛋白或调节分子,或者以上的任意组合。在一些实施方案中,铰链包括CD3ζ、CD4、CD8或CD28铰链,或者计算设计的具有不同长度的合成铰链。在一些实施方案中,跨膜结构域包括CD3ζ、CD4、CD8或CD28跨膜结构域,或者计算设计的合成跨膜结构域。在一些实施方案中,共刺激结构域包括CD8、CD28、ICOS、4-1BB、OX40(CD134)、CD27、CD40、CD40L、TLR或其他TNFR超家族成员或Ig超家族成员共刺激结构域,或者经由IL-2Rβ、IL-15R-α、MyD88或CD40或任何其他Toll样受体或IL-1受体信号传导途径成员的细胞质结构域的其他信号传导。
在一些实施方案中,通过从编码本文公开的任一种结合多肽的核酸和编码不同CAR模块的相容性核酸的混合物组装CAR表达构建体来构建本文公开的CAR。在一些实施方案中,产生CAR的不同组合以用于CAR文库中,以用于筛选CAR功效(体外或体内)。在一些实施方案中,单独产生独特的CAR。在一些实施方案中,CAR对一种靶标是特异性的。在一些实施方案中,CAR对至少1、2、3、4、5、6、7、8、9或10种靶标是特异性的。在一些实施方案中,CAR是双特异性的或三特异性的。
为了构建本文公开的任何一种CAR,将编码通过淘选抗体文库鉴定的结合多肽的核酸与其他CAR模块一起组装成CAR表达构建体。在一些实施方案中,使用本领域已知的多片段组装反应组装CAR表达构建体。组装CAR表达构建体的一种示例性方法涉及使用IIS型限制酶以产生具有相容的突出序列的核酸片段,并用连接酶连接该核酸片段。当IIS型限制酶在其识别位点外切割时,可以同时制备多个相容的核酸片段。在其他实施方案中,可以通过重叠延伸PCR组装CAR表达构建体。可以设想,可以采用从多于一个核酸片段组装核酸构建体的任何其他方法。在一些实施方案中,不同的CAR模块包含信号肽、接头、铰链、跨膜结构域、共刺激结构域、活化结构域、信号传导结构域、细胞质结构域、功能性信号、增殖信号、抗衰竭信号、抗抑制剂受体、癌症归巢蛋白或调节分子或以上的任意组合。一些示例性铰链包括CD8铰链、CD28铰链、IgG1铰链或IgG4铰链。一些示例性跨膜结构域包括CD3ζ跨膜结构域、CD8α跨膜结构域、CD4跨膜结构域、CD28跨膜结构域或ICOS跨膜结构域。一些示例性共刺激结构域包括CD8共刺激结构域、CD28共刺激结构域、4-1BB共刺激结构域、OX40(CD134)共刺激结构域、ICOS共刺激结构域、CD27共刺激结构域、CD40共刺激结构域、CD40L共刺激结构域、TLR共刺激结构域、MYD88-CD40共刺激结构域或KIR2DS2共刺激结构域。在一些实施方案中,不同的CAR模块来源于CD8、CD28、4-1BB、CD3ζ或以上的任意组合。CAR也可以用各种添加物修饰,包括但不限于细胞因子、趋化因子、细胞因子受体、趋化因子受体、抗原受体或配体、抗体或酶。
本文还公开了包含本文公开的任何一种CAR的嵌合抗原受体(CAR)细胞。在一些实施方案中,CAR细胞是CAR-T细胞。在一些实施方案中,CAR细胞来源于对象或细胞系。在一些实施方案中,对象患有癌症。在一些实施方案中,对象患有癌症,并且该癌症表达本文公开的任何一种或多种癌症相关抗原(例如FAP)。在一些实施方案中,癌症是乳腺癌、结直肠癌、肾癌、肝癌、肺癌、脑癌、胰腺癌、膀胱癌、睾丸癌、前列腺癌、胃癌、卵巢癌、头颈癌、胆囊癌、血液恶性肿瘤或以上的任意组合。在一些实施方案中,血液恶性肿瘤可包括白血病、急性淋巴母细胞白血病、急性髓细胞白血病、慢性髓细胞白血病、慢性淋巴细胞白血病、毛细胞白血病、淋巴瘤、霍奇金病、非霍奇金淋巴瘤或多发性骨髓瘤。
核酸
本文还公开了编码多肽的核酸。在一些实施方案中,多肽是结合多肽。在一些实施方案中,多肽是单域结合多肽。在一些实施方案中,多肽是本文公开的结合多肽中的任一种。在一些实施方案中,多肽包含与本文公开的任何一种或多种FAP结合多肽具有至少90%、95%、99%或100%序列同一性的序列。在一些实施方案中,多肽是本文公开的任何一种CAR。
可以通过重组DNA技术、合成化学技术或以上的组合制备编码结合多肽的任何一种核酸。例如,可使用本领域已知的标准分子技术将编码结合多肽的核酸序列克隆到表达载体中。序列可以从编码所需蛋白序列的其他载体获得,从使用各自模板核酸的PCR产生的片段获得,或者通过编码所需序列的合成寡核苷酸的组装获得。在一些实施方案中,表达载体可以是CAR表达载体,其中它被提供给免疫细胞以使其表达CAR。在一些实施方案中,表达载体可以是适于大规模抗体或结合多肽产生的表达载体,从中可以分离肽产物以供进一步使用。
可以通过本领域已知的核酸或蛋白质测定确认结合多肽或CAR的表达。例如,可以通过常规杂交测定(例如Northern印迹分析)、扩增程序(例如RT-PCR)、SAGE(第5,695,937号美国专利)和基于阵列的技术(参见例如,第5,405,783号、第5,412,087号和第5,445,934号美国专利),使用与编码结合多肽或CAR的多核苷酸的任何区域互补的探针,来检测和/或定量结合多肽或CAR的转录的mRNA的存在。也可以通过检测表达的肽来确定结合多肽或CAR的表达。本领域有多种技术可用于蛋白质分析。它们包括但不限于放射免疫测定、ELISA(酶联免疫放射测定)、“夹心”免疫测定、免疫放射测定、原位免疫测定(使用例如胶体金、酶或放射性同位素标记)、蛋白质印迹分析、免疫沉淀测定、免疫荧光测定和SDS-PAGE。
使用或治疗方法
本文还公开了治疗有需要的对象中的癌症的方法。在一些实施方案中,方法包括向对象施用嵌合抗原受体细胞。在一些实施方案中,方法包括施用本文公开的任何一种嵌合抗原受体细胞。在一些实施方案中,嵌合抗原受体细胞表达和/或包含本文公开的任何一种或多种FAP结合多肽。在一些实施方案中,嵌合抗原受体细胞是CAR-T细胞。在一些实施方案中,嵌合抗原受体细胞来源于对象并且是对象自体的。在一些实施方案中,嵌合抗原受体细胞是对象同种异体的。在一些实施方案中,嵌合抗原受体细胞来自细胞系(例如Jurkat)。在一些实施方案中,对象是哺乳动物,如人、猫、狗、小鼠、大鼠、仓鼠、啮齿动物、牛、猪、马、山羊、绵羊、驴或猴。在一些实施方案中,对象是人。在一些实施方案中,对象患有表达本文公开的任何一种或多种癌症相关抗原(例如FAP)的癌症。在一些实施方案中,癌症是乳腺癌、结直肠癌、肾癌、肝癌、肺癌、脑癌、胰腺癌、膀胱癌、睾丸癌、前列腺癌、胃癌、卵巢癌、头颈癌、胆囊癌、血液恶性肿瘤或以上的任意组合。在一些实施方案中,血液恶性肿瘤可包括白血病、急性淋巴母细胞白血病、急性髓细胞白血病、慢性髓细胞白血病、慢性淋巴细胞白血病、毛细胞白血病、淋巴瘤、霍奇金病、非霍奇金淋巴瘤或多发性骨髓瘤。在一些实施方案中,嵌合抗原受体细胞经肠胃外施用。
在一些实施方案中,嵌合抗原受体细胞每天施用一次、每天施用两次、每天施用三次或更多次。在一些实施方案中,嵌合抗原受体细胞每天、每一天、每隔一天、每周五天、每周一次、每隔一周、每月两周、每月三周、每月一次、每月两次、每月三次或更多次施用。在一些实施方案中,施用免疫细胞至少1个月、2个月、3个月、4个月、5个月、6个月、7个月、8个月、9个月、10个月、11个月、12个月、18个月、2年、3年或更长时间。
在一些实施方案中,对应于这样的量的给定试剂的量根据诸如以下的因素而变化:特定的化合物、疾病的严重程度、需要治疗的对象或宿主的特征(例如,体重),但是仍然根据病例周围的特定情况,以本领域已知的方式常规地确定,包括例如所施用的具体试剂、施用途径以及所治疗的对象或宿主。在一些情况下,所需剂量方便地以单剂量或作为同时(或在短时间段内)或以适当间隔,例如作为每天两剂、三剂、四剂或更多剂亚剂量施用的分剂量呈现。
施用的范围仅仅是提示性的,因为关于个体治疗方案的变量的数目是较大的,并且与这些推荐值的相当大的偏移并不罕见。这种剂量根据多个变量而改变,这些变量不限于所使用的化合物的活性、待治疗的疾病或病况、施用方式、个体对象的需求、待治疗的疾病或病况的严重程度以及从业人员的判断。
在一些实施方案中,这种治疗方案的毒性和治疗功效通过细胞培养物或实验动物中的标准药学程序来确定,包括但不限于LD50(对50%群体致死的剂量)和ED50(在50%群体中治疗有效的剂量)的确定。毒性和治疗效果之间的剂量比是治疗指数,并且其表示为LD50和ED50之间的比例。表现高治疗指数的化合物是优选的。从细胞培养测定和动物研究获得的数据被用于配制用于人类中的剂量范围。这种化合物的剂量优选位于包括具有最小毒性的ED50的循环浓度范围内。剂量在此范围内根据所采用的剂型和所利用的施用途径而变化。
实施例
以上讨论的实施方案的一些方面在以下实施例中更详细地公开,这些实施例不以任何方式意图限制本公开内容的范围。本领域技术人员将理解,许多其他的实施方案也落入本发明的范围内,如上文和权利要求书中所描述的。
实施例1.方法
质粒制备和质量检查(QC)
Maxi质粒纯化试剂盒(Zymo,D4203)用于CAR质粒制备。通过Nanodrop(260/280比率和260/230比率)和ToxinSensor Chromogenic LAL内毒素测定(Genescript,L00350)分析质粒浓度和质量。优质质粒DNA将具有1.8-2.0的A260/A280比率、大于2.0的A260/A230比率和小于0.1EU/μg的内毒素。
质粒组装和QC
所有CAR均由Genewiz合成。将编码与FAP结合的抗体的合成单域抗体基因克隆到pLenti载体中,并使用Sanger测序确认构建体。CAR构建体含有信号肽(例如CD8信号肽)、铰链(例如CD8α柄(stalk))、跨膜结构域(例如CD8跨膜结构域或CD28跨膜结构域)和信号传导结构域(例如4-1BB共刺激结构域或CD3ζ信号传导结构域)和抗FAP sdAb。
为了监测CAR表达水平,CAR质粒的表达盒也可以被工程化以表达荧光eGFP+T2A自切割肽序列。可选地,可以使用截短的CD19或截短的EGFR盒通过抗体检测进行监测。人类序列(例如CD8、4-1BB、CD3ζ)可在GenBank上获得。
病毒产生和滴定
为了产生具有抗FAP CAR构建体的慢病毒,用编码CAR转基因的pLenti转移质粒和一种或多种必需的包装质粒(即编码Gag、Pol、Rev、VSVG和任选的Tat)一起共转染人胚肾293T(HEK293T)细胞。在转染后48或72小时收集HEK293T培养物的上清液,离心,并用0.45μm过滤器过滤。
在用稀释的慢病毒收集物转导的Jurkat细胞中进行病毒滴定。48小时后,用生物素化的重组蛋白L和藻红蛋白(PE)缀合的链霉亲和素对转导的Jurkat细胞进行染色,并通过流式细胞术测量抗FAP CAR丰度。
T细胞转导和扩增
通过用Lymphoprep试剂(StemCell Technologies)进行密度梯度离心从健康人类供体的外周血中分离人PBMC。将PBMC以1×106个细胞/mL重悬于具有10ng/mL IL-2(Novoprotein,GMP-CD66)和10ng/mL IL-7(Novoprotein,GMP-CD47)的X-VIVO 15无血清造血培养基(Lonza,04-418QCN)中。用50ng/mL抗CD3抗体(Novoprotein,GMP-A018)刺激PBMC24小时。然后,用抗FAP CAR慢病毒(以1-10的MOI)转导PBMC,并在适当的烧瓶中,在补充有10%胎牛血清的RPMI 1640基础培养基中扩增9-10天。在任何测定之前,将T细胞在37℃下静置24小时。在用抗CD3抗体初始刺激PBMC后12或14天,测量CAR表面水平、CD3和CD4/CD8比率(使用来自Biolegend的抗体317344、301012和317412)。
T细胞冷冻保存和解冻
在CAR-T扩增14天后,离心抗FAP CAR-T细胞,并弃去上清液。将细胞沉淀以5×107个细胞/mL的活细胞密度重悬于冷藏的CryoStor CS10(StemCell Technologies,07930)中。将细胞悬液的等分试样分配到冷冻小瓶中。以1℃/分钟的降低冷却冷冻小瓶。将冷冻的细胞转移到液氮中。
为了解冻,在温和搅拌下将细胞在37℃水浴中快速解冻。将解冻的细胞转移到50mL锥形管中,并通过逐滴添加20mL新鲜生长培养基进行洗涤。将细胞离心并以1×106个细胞/mL的细胞密度重悬于X-VIVO 15培养基中。
细胞毒性测定
通过标准的基于荧光素酶的测定来确定抗FAP CAR T细胞的细胞毒性。简言之,在X-VIVO 15培养基中,使用具有每孔总体积为100μL的2×104个靶细胞的白壁96孔板,以指定的效应物:靶标比,以一式三份将表达萤火虫荧光素酶的靶细胞与CAR-T细胞一起共培养。将作为对照的单独靶细胞以相同的细胞密度接种。共培养48小时后,将100μL荧光素酶底物(ONE-Glo,Promega)直接加入每个孔中。用发光板读数仪检测发射的光。
在类似的基于荧光素酶的细胞毒性测定中,在细胞培养基(如RPMI)中制备经工程化以过表达荧光素酶的靶癌细胞,并将其以5×104个至5×106个细胞接种到96孔板上,体积为100μL/孔,并在37℃下孵育24小时。然后,以不同的效应物:靶标(E:T)比(例如,5:1、1:1和1:5),将CAR T细胞以100μL/孔接种在具有CAR T细胞的相应孔中。然后将共培养物在37℃下孵育24或48小时。随后,根据制造商的说明,使用板读数仪,利用荧光素酶测定系统(Promega,E1501)处理细胞。使用BioTek Synergy H4杂交微孔板读数仪,以终点模式读取发光10秒。使用毛地黄皂苷处理的细胞的荧光素酶活性作为最大细胞死亡,并且使用未处理的细胞作为自发细胞死亡,使用公式%特异性裂解=100%x[(实验发光-自发细胞死亡发光)/(最大细胞死亡发光-自发细胞死亡发光)]来计算特异性裂解的百分比。
关于示例性荧光素酶细胞毒性测定的另外信息可以在Matta H等人,“Development and characterization of a novel luciferase based cytotoxicityassay”Scientific Reports(2018)8,199中找到,其在此通过引用整体明确地并入本文中。
干扰素-γ评估
在6孔组织培养板中,以指定的效应物:靶细胞比率,用靶细胞刺激每孔1×106个抗FAP CAR T细胞24小时。使用人IL-2ELISA试剂盒II(BD,550611)和人IFN-γELISA试剂盒II(BD,550612),通过酶联免疫吸附测定(ELISA)定量干扰素γ(IFN-γ)和IL-2分泌。
CD25/CD69测定
在6孔组织培养板中,以指定的效应物:靶细胞比,用靶细胞刺激每孔1×106个抗FAP CAR T细胞24小时。将细胞用活/死可固定的近IR死细胞染色试剂盒(ThermoFisher)染色以标记死细胞,并用抗CD3染色,并且通过流式细胞术将CAR-T细胞鉴定为CD3+GFP+细胞。用Alexa Fluor 700抗人CD69抗体(Biolegend)和PE抗CD25抗体(Biolegend)染色CAR-T细胞上的CD69和CD25。
CAR T细胞文库的测序
从抗FAP CAR-T文库筛选中收集细胞。使用血液/细胞基因组DNA微型试剂盒(Tiangen,DP304-03)提取基因组DNA (gDNA)。将75ng gDNA用于PCR以扩增文库的CAR区。扩增的区域用TA/Blunt-Zero克隆试剂盒(Vazyme,C601)进行TA克隆并测序。
实施例2.用于治疗癌症的抗FAP CAR-T细胞
患者患有癌症,例如,表达或过表达FAP(例如,使得FAP可用作生物标志物以检测和靶向癌症)的癌症。在一些情况下,癌症是乳腺癌、结直肠癌、肾癌、肝癌、肺癌、脑癌、胰腺癌、膀胱癌、睾丸癌、前列腺癌、胃癌、卵巢癌、头颈癌、胆囊癌、血液恶性肿瘤或以上的任意组合。在一些情况下,血液恶性肿瘤可包括白血病、急性淋巴母细胞白血病、急性髓细胞白血病、慢性髓细胞白血病、慢性淋巴细胞白血病、毛细胞白血病、淋巴瘤、霍奇金病、非霍奇金淋巴瘤或多发性骨髓瘤。
本文公开的可包括任何一种或多种抗FAP CAR和/或抗FAP结合物的一种或多种CAR T细胞经肠内、经口、鼻内、肠胃外、静脉内、腹膜内、肌内、动脉内、心室内、皮内、病灶内、颅内、鞘内或皮下施用至患者。
可以作为每剂量104、105、106、107、108或109个细胞,或者在由前述每剂量细胞中的任两个限定的范围内的任何数量的细胞,或者由受过训练的医学从业人员确定的有效和/或安全的任何数量的细胞的量的剂量施用CAR T细胞。每1、2、3、4、5、6、7、8、9、10、11、12、24、36或48天或数周,或者在由前述时间中的任两个限定的范围内的任何时间,或者由受过训练的医学从业人员确定的有效和/或安全的任何给药时间施用剂量。
在施用一种或多种CAR T细胞后,在患者中观察到癌症或其症状的改善。CAR T细胞的施用可以与癌症的另一种疗法联合进行,包括但不限于免疫疗法、化学疗法、放射疗法、手术、光动力疗法或靶向疗法。
在至少一些先前描述的实施方案中,在一个实施方案中使用的一个或多个元素可以互换地用于另一实施方案中,除非这样的替换在技术上不可行。本领域技术人员将了解,在不脱离要求保护的主题的范围的情况下,可对上述的方法和结构进行各种其他的省略、添加和修改。所有这些修改和变化都旨在落入由所附权利要求限定的主题的范围内。
关于本文中基本上任何复数和/或单数术语的使用,本领域技术人员可以视上下文和/或应用的适用性,从复数转换成单数和/或从单数转换成复数。为了清楚起见,本文可以明确地阐述各种单数/复数排列。
本领域技术人员将理解,通常,本文使用的术语,特别是在所附权利要求(例如,所附权利要求的主体)中,通常旨在作为“开放性”术语(例如,术语“包括(including)”应被解释为“包括但不限于”,术语“具有”应被解释为“至少具有”,术语“包括(includes)”应被解释为“包括但不限于”等)。本领域技术人员还将理解,如果旨在特定数量的所引入的权利要求叙述,则在权利要求中明确地叙述这种意图,并且在没有这种叙述的情况下,不存在这种意图。例如,为了帮助理解,以下所附权利要求可以包含使用引入性短语“至少一个/至少一种”和“一个或多个/一种或多种”来引入权利要求叙述。然而,这种短语的使用不应被解释为暗示通过不定冠词“一个/一种(a)”或“一个/一种(an)”引入的权利要求叙述将包含这种引入的权利要求叙述的任何特定权利要求限制为仅包含一种这种叙述的实施方案,即使当同一权利要求包括引入性短语“一个或多个/一种或多种”或“至少一个/至少一种”和不定冠词如“一个/一种(a)”或“一个/一种(an)”时也是如此(例如,“一个/一种(a)”和/或“一个/一种(an)”应被解释为意指“至少一个/至少一种”或“一个或多个/一种或多种”);对于用于引入权利要求叙述的定冠词的使用也是如此。另外,即使明确地叙述了所引入的权利要求叙述的具体数目,本领域技术人员将认识到,这种叙述应被解释为意指至少所叙述的数目(例如,没有其他修饰语的“两个叙述物”的简单叙述(bare recitation)意指至少两个叙述物,或者两个或更多个叙述物)。此外,在其中使用类似于“A、B和C中的至少一个等”的惯例的那些情况下,通常这种构造旨在使本领域技术人员将理解该惯例的含义(例如,“具有A、B和C中的至少一种的系统”将包括但不限于具有单独的A、单独的B、单独的C、A和B一起、A和C一起、B和C一起和/或A、B和C一起等的系统)。在其中使用类似于“A、B或C中的至少一个等”的惯例的那些情况下,通常这种构造旨在使本领域技术人员将理解该惯例的含义(例如,“具有A、B或C中的至少一种的系统”将包括但不限于具有单独的A、单独的B、单独的C、A和B一起、A和C一起、B和C一起和/或A、B和C一起等的系统)。本领域技术人员将进一步理解,无论在说明书、权利要求书或附图中,实际上呈现两个或更多个替代术语的任何分离性(disjunctive)词语和/或短语都应该被理解为考虑包括术语中的一个、术语中的任一个或两个术语的可能性。例如,短语“A或B”将被理解为包括“A”或“B”或“A和B”的可能性。
另外,在根据马库什组描述本公开内容的特征或方面的情况下,本领域技术人员将认识到,本公开内容也由此根据马库什组的任何单个成员或成员的亚组来描述。
如本领域技术人员将理解的,出于任何和所有目的,如就提供书面描述而言,本文公开的所有范围还涵盖任何和所有可能的子范围及其子范围的组合。任何列出的范围可以容易地被认为充分地描述并且使得相同的范围能够被分解为至少相等的一半、三分之一、四分之一、五分之一、十分之一等。作为非限制性实例,本文讨论的每个范围可以容易地分成下三分之一、中三分之一和上三分之一等。如本领域技术人员还将理解的,所有语言如“至多”、“至少”、“大于”、“小于”等包括所述的数字,并且是指可随后被分成如上文讨论的子范围的范围。最后,如本领域技术人员将理解的,范围包括每个单独的成员。因此,例如,具有1-3个物品的组是指具有1、2或3个物品的组。类似地,具有1-5个物品的组是指具有1、2、3、4或5个物品的组,等等。
虽然本文已经公开了不同的方面和实施方案,但是其他方面和实施方案对于本领域技术人员来说是显而易见的。本文公开的不同方面和实施方案是为了说明的目的,且并非旨在为限制性的,真正的范围和精神由以下权利要求来指示。
本文引用的所有参考文献,包括但不限于公开的和未公开的申请、专利和参考文献,均通过引用整体并入本文中,并由此构成本说明书的一部分。在通过引用并入的出版物和专利或专利申请与本说明书包含的公开内容矛盾的程度时,本说明书旨在取代和/或优先于任何这种矛盾的材料。
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<110> 博奥阿迪斯生物科技公司(BioArdis, LLC)
<120> FAP结合分子及其用途
<130> BWGB.011WO
<150> US 63/127885
<151> 2020-12-18
<150> US 63/262706
<151> 2021-10-19
<160> 432
<170> PatentIn version 3.5
<210> 1
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-A01 HCDR1
<400> 1
Gly Ser Thr Ser Asn Asn Tyr Phe Met
1 5
<210> 2
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-B01 HCDR1
<400> 2
Gly Phe Thr Ser Gly Val Tyr Phe Met
1 5
<210> 3
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-C01 HCDR1
<400> 3
Gly Phe Thr Phe Gly Phe Asn Tyr Met
1 5
<210> 4
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-E01 HCDR1
<400> 4
Gly Arg Thr Phe Ser Tyr Asn Pro Met
1 5
<210> 5
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-F01 HCDR1
<400> 5
Gly Arg Thr Phe Ser Tyr Asn Pro Met
1 5
<210> 6
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-G01 HCDR1
<400> 6
Gly Ser Ile Phe Ser His Tyr Ser Met
1 5
<210> 7
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-H01 HCDR1
<400> 7
Gly Tyr Ile Leu Arg Asp Asp Pro Met
1 5
<210> 8
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-B02 HCDR1
<400> 8
Gly Ser Thr Phe Ser Tyr Tyr Phe Met
1 5
<210> 9
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-C02 HCDR1
<400> 9
Gly Arg Thr Phe Ser Tyr Asn Pro Met
1 5
<210> 10
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-D02 HCDR1
<400> 10
Gly Phe Ile Tyr Ser Asn Tyr Tyr Met
1 5
<210> 11
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-E02 HCDR1
<400> 11
Gly Phe Ile Phe Ser Ala Tyr Tyr Met
1 5
<210> 12
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-H02 HCDR1
<400> 12
Gly Ser Thr Tyr Asp Val Asp Tyr Met
1 5
<210> 13
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-B03 HCDR1
<400> 13
Gly Ser Ile Tyr Ser Phe Tyr Phe Met
1 5
<210> 14
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-C03 HCDR1
<400> 14
Gly Arg Thr Phe Ser Tyr Asn Pro Met
1 5
<210> 15
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-D03 HCDR1
<400> 15
Gly Arg Ile Tyr Arg Asn Tyr Ser Met
1 5
<210> 16
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-F03 HCDR1
<400> 16
Gly Phe Ile Phe Ser Phe Tyr Phe Met
1 5
<210> 17
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-H03 HCDR1
<400> 17
Gly Tyr Ile Phe Ser Val Asn Phe Met
1 5
<210> 18
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-B04 HCDR1
<400> 18
Gly Ser Ile Phe Asp Tyr Tyr Tyr Met
1 5
<210> 19
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-D04 HCDR1
<400> 19
Gly Ser Ile Tyr Ser Asn Tyr Tyr Met
1 5
<210> 20
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-E04 HCDR1
<400> 20
Gly Phe Ile Phe Asn Ile Tyr Ser Met
1 5
<210> 21
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-G04 HCDR1
<400> 21
Gly Ser Ile Tyr Asp Leu Tyr Thr Met
1 5
<210> 22
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-A05 HCDR1
<400> 22
Gly Arg Ile Tyr Asp Leu Tyr Asn Met
1 5
<210> 23
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-C05 HCDR1
<400> 23
Gly Arg Thr Phe Ser Tyr Asn Pro Met
1 5
<210> 24
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-D05 HCDR1
<400> 24
Gly Phe Thr Tyr Gly Phe Asn Tyr Met
1 5
<210> 25
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-E05 HCDR1
<400> 25
Gly Arg Thr Phe Ser Tyr Asn Pro Met
1 5
<210> 26
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-F05 HCDR1
<400> 26
Gly Ser Ile Tyr Arg Phe Asp Ser Met
1 5
<210> 27
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-G05 HCDR1
<400> 27
Gly Phe Ile Ser Ser Ala Tyr Ser Met
1 5
<210> 28
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-H05 HCDR1
<400> 28
Gly Arg Thr Phe Ser Tyr Asn Pro Met
1 5
<210> 29
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-A06 HCDR1
<400> 29
Gly Ser Ile Phe Ser Ser Tyr Ile Met
1 5
<210> 30
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-B06 HCDR1
<400> 30
Gly Phe Thr Leu Asn Ile Tyr His Met
1 5
<210> 31
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-C06 HCDR1
<400> 31
Gly Gly Thr Phe Ser Phe Tyr Phe Met
1 5
<210> 32
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-D06 HCDR1
<400> 32
Gly Arg Ile Tyr Asp Ala Asn Phe Met
1 5
<210> 33
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-E06 HCDR1
<400> 33
Gly Arg Thr Phe Ser Tyr Asn Pro Met
1 5
<210> 34
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-F06 HCDR1
<400> 34
Gly Arg Thr Phe Ser Tyr Asn Pro Met
1 5
<210> 35
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-A07 HCDR1
<400> 35
Gly Phe Ile Phe Asp Tyr Tyr Phe Met
1 5
<210> 36
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-B07 HCDR1
<400> 36
Gly Arg Thr Phe Ser Tyr Asn Pro Met
1 5
<210> 37
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-C07 HCDR1
<400> 37
Gly Phe Thr Phe Ser Phe Tyr Phe Met
1 5
<210> 38
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-D07 HCDR1
<400> 38
Gly Arg Ile Phe Ser Ser Tyr Ser Met
1 5
<210> 39
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-E07 HCDR1
<400> 39
Gly Ser Thr Phe Gly Tyr Asp Asn Met
1 5
<210> 40
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-F07 HCDR1
<400> 40
Gly Arg Thr Phe Ser Tyr Asn Pro Met
1 5
<210> 41
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-G07 HCDR1
<400> 41
Gly Gly Ile Ser Asp Tyr Tyr Ser Met
1 5
<210> 42
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-H07 HCDR1
<400> 42
Gly Tyr Ile Phe Ser Phe Tyr Phe Met
1 5
<210> 43
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-A08 HCDR1
<400> 43
Gly Phe Ile Phe Gly Ile Tyr Phe Met
1 5
<210> 44
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-C08 HCDR1
<400> 44
Gly Ser Ile Tyr Gly Tyr Asp Tyr Met
1 5
<210> 45
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-D08 HCDR1
<400> 45
Gly Ser Ile Leu Gly Ser Tyr Ile Met
1 5
<210> 46
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-E08 HCDR1
<400> 46
Gly Phe Ile Tyr Ser Phe Tyr Val Met
1 5
<210> 47
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-G08 HCDR1
<400> 47
Gly Arg Thr Phe Ser Tyr Asn Pro Met
1 5
<210> 48
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-A09 HCDR1
<400> 48
Gly Phe Thr Phe Ser Phe Tyr Ser Met
1 5
<210> 49
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-B09 HCDR1
<400> 49
Gly Gly Thr Phe Gly Val Asn Pro Met
1 5
<210> 50
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-C09 HCDR1
<400> 50
Gly Arg Thr Phe Ser Tyr Asn Pro Met
1 5
<210> 51
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-D09 HCDR1
<400> 51
Gly Arg Thr Phe Ser Tyr Asn Pro Met
1 5
<210> 52
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-E09 HCDR1
<400> 52
Gly Phe Ile Ser Gly His Tyr Tyr Met
1 5
<210> 53
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-F09 HCDR1
<400> 53
Gly Gly Ile Leu Arg Ile Tyr Phe Met
1 5
<210> 54
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-G09 HCDR1
<400> 54
Gly Arg Thr Phe Ser Tyr Asn Pro Met
1 5
<210> 55
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-H09 HCDR1
<400> 55
Gly Phe Ile Phe Asn Val Tyr Tyr Met
1 5
<210> 56
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-B10 HCDR1
<400> 56
Gly Ser Ile Tyr Ser Phe Tyr Phe Met
1 5
<210> 57
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-C10 HCDR1
<400> 57
Gly Arg Thr Phe Ser Tyr Asn Pro Met
1 5
<210> 58
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-D10 HCDR1
<400> 58
Gly Ser Ile Phe Gly Ala Tyr Tyr Met
1 5
<210> 59
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-E10 HCDR1
<400> 59
Gly Ser Thr Phe Arg Phe Tyr Ser Met
1 5
<210> 60
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-F10 HCDR1
<400> 60
Gly Phe Ile Leu Gly Ser Asp Thr Met
1 5
<210> 61
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-G10 HCDR1
<400> 61
Gly Phe Ile Phe Ser Val Tyr Ser Met
1 5
<210> 62
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-H10 HCDR1
<400> 62
Gly Arg Thr Phe Asn Phe Tyr Ala Met
1 5
<210> 63
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-A11 HCDR1
<400> 63
Gly Arg Thr Leu Ser Ser Tyr Thr Met
1 5
<210> 64
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-C11 HCDR1
<400> 64
Gly Arg Thr Phe Ser Tyr Asn Pro Met
1 5
<210> 65
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-D11 HCDR1
<400> 65
Gly Tyr Ile Ser Ser Ser Tyr Ser Met
1 5
<210> 66
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-F11 HCDR1
<400> 66
Gly Arg Thr Phe Ser Tyr Asn Pro Met
1 5
<210> 67
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-G11 HCDR1
<400> 67
Gly Ser Ile Tyr Ser His Asn Phe Met
1 5
<210> 68
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-H11 HCDR1
<400> 68
Gly Phe Ile Phe Ser Phe Tyr Ser Met
1 5
<210> 69
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-B12 HCDR1
<400> 69
Gly Phe Ile Phe Asp Phe Tyr Phe Met
1 5
<210> 70
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-C12 HCDR1
<400> 70
Gly Phe Ile Tyr Ser Ser Asn Asn Met
1 5
<210> 71
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-D12 HCDR1
<400> 71
Gly Arg Ile Leu Arg His Tyr His Met
1 5
<210> 72
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-F12 HCDR1
<400> 72
Gly Phe Ile Phe Gly Ser Tyr Phe Met
1 5
<210> 73
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-G12 HCDR1
<400> 73
Gly Tyr Ile Phe Ser Ser Tyr Ala Met
1 5
<210> 74
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-H12 HCDR1
<400> 74
Gly Phe Thr Phe Gly Ala Tyr His Met
1 5
<210> 75
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-A01 HCDR1
<400> 75
Gly Arg Thr Phe Gly Leu Asp Phe Met
1 5
<210> 76
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-B01 HCDR1
<400> 76
Gly Tyr Ile Leu Ser Phe Tyr Tyr Met
1 5
<210> 77
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-E01 HCDR1
<400> 77
Gly Phe Ile Ser Ser Leu Tyr Ser Met
1 5
<210> 78
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-F01 HCDR1
<400> 78
Gly Phe Ile Phe Asn Tyr Tyr Tyr Met
1 5
<210> 79
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-H01 HCDR1
<400> 79
Gly Ser Thr Ser Gly Ala Tyr Asn Met
1 5
<210> 80
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-A02 HCDR1
<400> 80
Gly Phe Ile Tyr Asn Phe Asn Ser Met
1 5
<210> 81
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-C02 HCDR1
<400> 81
Gly Ser Thr Ser Arg Asp Tyr Ser Met
1 5
<210> 82
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-D02 HCDR1
<400> 82
Gly Ser Thr Tyr Asn Val Tyr Pro Met
1 5
<210> 83
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-F02 HCDR1
<400> 83
Gly Arg Thr Phe Ser Tyr Asn Pro Met
1 5
<210> 84
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-G02 HCDR1
<400> 84
Gly Ser Thr Phe Asn Tyr Tyr Asp Met
1 5
<210> 85
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-A03 HCDR1
<400> 85
Gly Phe Ile Ser Gly Val Tyr Phe Met
1 5
<210> 86
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-B03 HCDR1
<400> 86
Gly Phe Ile Leu Gly Ala Asn Pro Met
1 5
<210> 87
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-C03 HCDR1
<400> 87
Gly Phe Ile Tyr Gly Tyr Asn His Met
1 5
<210> 88
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-D03 HCDR1
<400> 88
Gly Arg Thr Phe Ser Tyr Asn Pro Met
1 5
<210> 89
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-A04 HCDR1
<400> 89
Gly Phe Ile Tyr Asn Tyr Asn His Met
1 5
<210> 90
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-B04 HCDR1
<400> 90
Gly Arg Thr Phe Ser Tyr Asn Pro Met
1 5
<210> 91
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-E04 HCDR1
<400> 91
Gly Ser Thr Tyr Ser Phe Asn Thr Met
1 5
<210> 92
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-G04 HCDR1
<400> 92
Gly Ser Thr Phe Ser Ala Tyr Ser Met
1 5
<210> 93
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-H04 HCDR1
<400> 93
Gly Ser Thr Phe Asn Pro Tyr Phe Met
1 5
<210> 94
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-D05 HCDR1
<400> 94
Gly Phe Ile Phe Ser Leu Tyr Ser Met
1 5
<210> 95
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-E05 HCDR1
<400> 95
Gly Phe Ile Phe Gly Tyr Tyr Ser Met
1 5
<210> 96
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-G05 HCDR1
<400> 96
Gly Arg Thr Phe Ser Tyr Asn Pro Met
1 5
<210> 97
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-H05 HCDR1
<400> 97
Gly Arg Thr Phe Ser Tyr Asn Pro Met
1 5
<210> 98
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-C06 HCDR1
<400> 98
Gly Arg Thr Phe Ser Tyr Asn Pro Met
1 5
<210> 99
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-E06 HCDR1
<400> 99
Gly Arg Thr Phe Ser Tyr Asn Pro Met
1 5
<210> 100
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-F06 HCDR1
<400> 100
Gly Arg Ile Phe Ser Ser Tyr Ser Met
1 5
<210> 101
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-G06 HCDR1
<400> 101
Gly Gly Ile Ser Ser Val Tyr Ala Met
1 5
<210> 102
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-H06 HCDR1
<400> 102
Gly Arg Thr Leu Asn Val Asp His Met
1 5
<210> 103
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-A07 HCDR1
<400> 103
Gly Phe Ile Ser Ser Tyr Tyr Tyr Met
1 5
<210> 104
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-B07 HCDR1
<400> 104
Gly Tyr Ile Tyr Ser Tyr Asn Phe Met
1 5
<210> 105
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-D07 HCDR1
<400> 105
Gly Tyr Thr Phe Arg Ile Tyr Phe Met
1 5
<210> 106
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-E07 HCDR1
<400> 106
Gly Phe Ile Tyr Arg Tyr Tyr Ser Met
1 5
<210> 107
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-F07 HCDR1
<400> 107
Gly Ser Ile Phe Asp Phe Asn His Met
1 5
<210> 108
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-G07 HCDR1
<400> 108
Gly Arg Thr Phe Ser Tyr Asn Pro Met
1 5
<210> 109
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-A01 HCDR2
<400> 109
Ala Ile Asn Pro Leu Asp Ser Asn Thr Tyr
1 5 10
<210> 110
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-B01 HCDR2
<400> 110
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 111
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-C01 HCDR2
<400> 111
Ala Ile Ser Arg Ile Ser Asp Ser Thr Tyr
1 5 10
<210> 112
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-E01 HCDR2
<400> 112
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 113
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-F01 HCDR2
<400> 113
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 114
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-G01 HCDR2
<400> 114
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 115
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-H01 HCDR2
<400> 115
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 116
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-B02 HCDR2
<400> 116
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 117
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-C02 HCDR2
<400> 117
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 118
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-D02 HCDR2
<400> 118
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 119
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-E02 HCDR2
<400> 119
Thr Ile Asn Ser Val Asp Asp Ile Thr Tyr
1 5 10
<210> 120
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-H02 HCDR2
<400> 120
Thr Ile Asn Ser Tyr Gly Gly Ile Thr Tyr
1 5 10
<210> 121
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-B03 HCDR2
<400> 121
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 122
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-C03 HCDR2
<400> 122
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 123
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-D03 HCDR2
<400> 123
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 124
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-F03 HCDR2
<400> 124
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 125
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-H03 HCDR2
<400> 125
Thr Ile Asn Trp Phe Asp Asp Ile Thr Tyr
1 5 10
<210> 126
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-B04 HCDR2
<400> 126
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 127
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-D04 HCDR2
<400> 127
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 128
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-E04 HCDR2
<400> 128
Ser Ile Asn Trp Ser Asp Ser Ser Thr Tyr
1 5 10
<210> 129
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-G04 HCDR2
<400> 129
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 130
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-A05 HCDR2
<400> 130
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 131
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-C05 HCDR2
<400> 131
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 132
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-D05 HCDR2
<400> 132
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 133
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-E05 HCDR2
<400> 133
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 134
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-F05 HCDR2
<400> 134
Thr Ile Thr Ser Leu Asp Ser Ile Thr Tyr
1 5 10
<210> 135
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-G05 HCDR2
<400> 135
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 136
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-H05 HCDR2
<400> 136
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 137
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-A06 HCDR2
<400> 137
Ser Ile Asn Ser Tyr Asp Ser Thr Thr Tyr
1 5 10
<210> 138
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-B06 HCDR2
<400> 138
Ala Ile Asn Ser Phe Ser Asp Ile Thr Tyr
1 5 10
<210> 139
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-C06 HCDR2
<400> 139
Thr Ile Asn Ser Phe Asp Asp Ile Thr Tyr
1 5 10
<210> 140
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-D06 HCDR2
<400> 140
Thr Ile Asn Thr Tyr Ser Asp Ile Thr Tyr
1 5 10
<210> 141
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-E06 HCDR2
<400> 141
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 142
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-F06 HCDR2
<400> 142
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 143
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-A07 HCDR2
<400> 143
Thr Ile Asn Ser Phe Ser Ser Ser Thr Tyr
1 5 10
<210> 144
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-B07 HCDR2
<400> 144
Thr Ile Ser Phe Ser Gly Ile Thr Tyr
1 5
<210> 145
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-C07 HCDR2
<400> 145
Ser Ile Asn Ala Tyr Ser Asp Ser Thr Tyr
1 5 10
<210> 146
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-D07 HCDR2
<400> 146
Thr Ile Ser Ser Phe Ser Asp Ile Thr Tyr
1 5 10
<210> 147
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-E07 HCDR2
<400> 147
Thr Ile Asn Ser Phe Gly Asp Ile Thr Asn
1 5 10
<210> 148
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-F07 HCDR2
<400> 148
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 149
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-G07 HCDR2
<400> 149
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 150
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-H07 HCDR2
<400> 150
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 151
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-A08 HCDR2
<400> 151
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 152
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-C08 HCDR2
<400> 152
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 153
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-D08 HCDR2
<400> 153
Thr Ile Asn Ser Asn Asp Ser Ile Thr Tyr
1 5 10
<210> 154
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-E08 HCDR2
<400> 154
Thr Ile Asn Ser Phe Asp Asp Thr Thr Tyr
1 5 10
<210> 155
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-G08 HCDR2
<400> 155
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 156
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-A09 HCDR2
<400> 156
Ser Ile Asn Ala Ile Asp Ser Ile Thr Tyr
1 5 10
<210> 157
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-B09 HCDR2
<400> 157
Thr Ile Thr Ser Thr Asp Asp Ile Thr Tyr
1 5 10
<210> 158
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-C09 HCDR2
<400> 158
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 159
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-D09 HCDR2
<400> 159
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 160
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-E09 HCDR2
<400> 160
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 161
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-F09 HCDR2
<400> 161
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 162
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-G09 HCDR2
<400> 162
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 163
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-H09 HCDR2
<400> 163
Thr Ile Ser Trp Tyr Ser Asp Ile Thr Tyr
1 5 10
<210> 164
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-B10 HCDR2
<400> 164
Thr Ile Asn Ser Phe Asp Ser Ile Thr Tyr
1 5 10
<210> 165
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-C10 HCDR2
<400> 165
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 166
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-D10 HCDR2
<400> 166
Ala Ile Asn Pro Asp Ser Asp Ile Thr Tyr
1 5 10
<210> 167
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-E10 HCDR2
<400> 167
Thr Ile Ser Ser Phe Asp Asp Ile Thr Tyr
1 5 10
<210> 168
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-F10 HCDR2
<400> 168
Ser Ile Asn Ser Phe Asp Ser Ile Thr Tyr
1 5 10
<210> 169
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-G10 HCDR2
<400> 169
Ala Ile Asn Thr Val Asp Ser Ile Thr Tyr
1 5 10
<210> 170
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-H10 HCDR2
<400> 170
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 171
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-A11 HCDR2
<400> 171
Ser Ile Ser Trp Val Asp Ser Ile Thr Tyr
1 5 10
<210> 172
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-C11 HCDR2
<400> 172
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 173
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-D11 HCDR2
<400> 173
Ala Ile Ser Ser Phe Ser Asp Ile Thr Tyr
1 5 10
<210> 174
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-F11 HCDR2
<400> 174
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 175
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-G11 HCDR2
<400> 175
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 176
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-H11 HCDR2
<400> 176
Thr Ile Asn Thr Phe Ser Asp Ile Thr Tyr
1 5 10
<210> 177
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-B12 HCDR2
<400> 177
Thr Ile Asn Ser Ile Ser Asp Ile Thr Tyr
1 5 10
<210> 178
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-C12 HCDR2
<400> 178
Ser Ile Asn Ser Phe Asp Asp Ser Thr Tyr
1 5 10
<210> 179
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-D12 HCDR2
<400> 179
Thr Ile Asn Thr Leu Asp Ser Ile Thr Tyr
1 5 10
<210> 180
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-F12 HCDR2
<400> 180
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 181
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-G12 HCDR2
<400> 181
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 182
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-H12 HCDR2
<400> 182
Thr Ile Asn Trp Phe Gly Gly Ile Thr Tyr
1 5 10
<210> 183
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-A01 HCDR2
<400> 183
Ser Ile Asn Ser Phe Asp Asp Ile Thr Asn
1 5 10
<210> 184
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-B01 HCDR2
<400> 184
Thr Ile Asn Ser Phe Ser Asp Ile Thr Tyr
1 5 10
<210> 185
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-E01 HCDR2
<400> 185
Thr Ile Thr Gly Ser Ser Ser Ile Thr Tyr
1 5 10
<210> 186
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-F01 HCDR2
<400> 186
Thr Ile Ser Ala Phe Asp Asp Ser Thr Tyr
1 5 10
<210> 187
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-H01 HCDR2
<400> 187
Thr Ile Asn Trp Phe Asp Asp Ile Thr Tyr
1 5 10
<210> 188
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-A02 HCDR2
<400> 188
Ala Ile Asn Arg Phe Asp Asp Ile Thr Tyr
1 5 10
<210> 189
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-C02 HCDR2
<400> 189
Thr Ile Asn Ser Asn Ser Asp Ile Thr Tyr
1 5 10
<210> 190
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-D02 HCDR2
<400> 190
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 191
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-F02 HCDR2
<400> 191
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 192
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-G02 HCDR2
<400> 192
Thr Ile Asn Arg Phe Ser Ser Ile Thr Tyr
1 5 10
<210> 193
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-A03 HCDR2
<400> 193
Thr Ile Ser Ser Ala Ser Asp Ile Thr Tyr
1 5 10
<210> 194
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-B03 HCDR2
<400> 194
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 195
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-C03 HCDR2
<400> 195
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 196
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-D03 HCDR2
<400> 196
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 197
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-A04 HCDR2
<400> 197
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 198
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-B04 HCDR2
<400> 198
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 199
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-E04 HCDR2
<400> 199
Ser Ile Asn Ser Ser Asp Ser Ser Thr Tyr
1 5 10
<210> 200
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-G04 HCDR2
<400> 200
Ala Ile Asn Ser Phe Asp Asp Ile Thr Tyr
1 5 10
<210> 201
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-H04 HCDR2
<400> 201
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 202
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-D05 HCDR2
<400> 202
Thr Ile Asn Ala Leu Asp Asp Ile Thr Tyr
1 5 10
<210> 203
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-E05 HCDR2
<400> 203
Ala Ile Ser Ser Phe Asp Asp Ile Thr Tyr
1 5 10
<210> 204
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-G05 HCDR2
<400> 204
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 205
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-H05 HCDR2
<400> 205
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 206
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-C06 HCDR2
<400> 206
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 207
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-E06 HCDR2
<400> 207
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 208
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-F06 HCDR2
<400> 208
Thr Ile Asn Ser Phe Ser Asp Ile Thr Tyr
1 5 10
<210> 209
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-G06 HCDR2
<400> 209
Ser Ile Asn Ser Ile Asp Ala Ile Thr Tyr
1 5 10
<210> 210
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-H06 HCDR2
<400> 210
Ala Ile Asn Ser Ile Asp Ser Ile Thr Tyr
1 5 10
<210> 211
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-A07 HCDR2
<400> 211
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 212
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-B07 HCDR2
<400> 212
Ser Ile Asn Ser Phe Asp Asp Ile Thr Tyr
1 5 10
<210> 213
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-D07 HCDR2
<400> 213
Ala Ile Asn Pro Tyr Gly Asp Ile Thr Asn
1 5 10
<210> 214
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-E07 HCDR2
<400> 214
Ser Ile Asn Ala Phe Asp Asp Ile Thr Tyr
1 5 10
<210> 215
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-F07 HCDR2
<400> 215
Ser Ile Ser Ser Phe Asp Asp Ile Thr Tyr
1 5 10
<210> 216
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-G07 HCDR2
<400> 216
Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr
1 5 10
<210> 217
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-A01 HCDR3
<400> 217
Ala Gly His Trp Asp Ser His Phe Asn Tyr Trp
1 5 10
<210> 218
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-B01 HCDR3
<400> 218
Val Gly Asp Trp Asp Ile Phe His Tyr Ser Tyr Trp
1 5 10
<210> 219
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-C01 HCDR3
<400> 219
Ala Gly Ile Val Gln Tyr His Tyr Asn Tyr Trp
1 5 10
<210> 220
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-E01 HCDR3
<400> 220
Ala Gly Glu Trp Met Met His Phe Asn Tyr Trp
1 5 10
<210> 221
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-F01 HCDR3
<400> 221
Ala Gly Thr Asp Thr Trp His Tyr Asn Tyr Trp
1 5 10
<210> 222
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-G01 HCDR3
<400> 222
Ala Gly Pro Trp His Ala His Phe Ser Tyr Trp
1 5 10
<210> 223
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-H01 HCDR3
<400> 223
Val Ser Thr Tyr Arg Ala Asp Ala Arg Ser Leu Gly Tyr Trp
1 5 10
<210> 224
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-B02 HCDR3
<400> 224
Ala Ala Thr Thr Gln Phe His Phe Gly Tyr Trp
1 5 10
<210> 225
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-C02 HCDR3
<400> 225
Ala Gly Thr Phe Asp Gln His Phe Asn Tyr Trp
1 5 10
<210> 226
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-D02 HCDR3
<400> 226
Ala Ser Arg Thr Trp Met His Phe Asn Tyr Trp
1 5 10
<210> 227
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-E02 HCDR3
<400> 227
Ala Gly Gln Tyr Gln Tyr His Tyr Ser Tyr Trp
1 5 10
<210> 228
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-H02 HCDR3
<400> 228
Ala Ser Ala Thr Lys Asp His Tyr Asn Tyr Trp
1 5 10
<210> 229
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-B03 HCDR3
<400> 229
Ala Gly Asn Ile His Tyr His Tyr Asn Tyr Trp
1 5 10
<210> 230
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-C03 HCDR3
<400> 230
Ala Gly Glu Ser Asp Arg His Tyr Asn Tyr Trp
1 5 10
<210> 231
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-D03 HCDR3
<400> 231
Val Gly Tyr Val Phe Gln His Phe Asn Tyr Trp
1 5 10
<210> 232
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-F03 HCDR3
<400> 232
Ala Ala Phe Trp Asp Tyr His Tyr Asp Tyr Trp
1 5 10
<210> 233
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-H03 HCDR3
<400> 233
Ala Gly Gly Thr Glu Trp His Phe Asn Tyr Trp
1 5 10
<210> 234
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-B04 HCDR3
<400> 234
Ala Ser Val Ile Ser Phe His Tyr Asn Tyr Trp
1 5 10
<210> 235
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-D04 HCDR3
<400> 235
Ala Gly Pro Met Asn Trp His Tyr Gly Tyr Trp
1 5 10
<210> 236
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-E04 HCDR3
<400> 236
Ala Gly Pro Tyr Tyr Trp Gly Leu Ser Tyr Trp
1 5 10
<210> 237
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-G04 HCDR3
<400> 237
Val Gly Gln Tyr Asp Trp His Phe Asp Tyr Trp
1 5 10
<210> 238
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-A05 HCDR3
<400> 238
Ala Gly Gln Pro Met Tyr His Phe Asn Tyr Trp
1 5 10
<210> 239
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-C05 HCDR3
<400> 239
Val Val Thr Val Trp Tyr Ser Pro Phe Lys Val Lys Met Tyr Asn Tyr
1 5 10 15
Trp
<210> 240
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-D05 HCDR3
<400> 240
Ala Gly Ile Trp His Met His Tyr Asn Tyr Trp
1 5 10
<210> 241
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-E05 HCDR3
<400> 241
Ala Thr Ser Trp Arg Ser Pro Pro Pro Ala Tyr Gly Tyr Trp
1 5 10
<210> 242
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-F05 HCDR3
<400> 242
Ala Gly Ala Trp Lys Asn His Phe Asn Tyr Trp
1 5 10
<210> 243
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-G05 HCDR3
<400> 243
Ala Gly Asp Ser Asp Leu His Tyr Ser Tyr Trp
1 5 10
<210> 244
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-H05 HCDR3
<400> 244
Ala Thr Ser Pro Arg Gly Leu Ser Ala Gly His Gly Tyr Trp
1 5 10
<210> 245
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-A06 HCDR3
<400> 245
Ala Thr Glu Val Pro Met His Tyr Asn Tyr Trp
1 5 10
<210> 246
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-B06 HCDR3
<400> 246
Ala Gly Glu Trp Pro Leu His Tyr Ser Tyr Trp
1 5 10
<210> 247
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-C06 HCDR3
<400> 247
Ala Gly Leu Trp His Gln His Tyr Asn Tyr Trp
1 5 10
<210> 248
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-D06 HCDR3
<400> 248
Ala Gly Asn Trp Thr Phe His Phe Asn Tyr Trp
1 5 10
<210> 249
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-E06 HCDR3
<400> 249
Ala Gly Arg Tyr Leu Trp His Tyr Asn Tyr Trp
1 5 10
<210> 250
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-F06 HCDR3
<400> 250
Ala Gly Leu Gln Glu Tyr His Tyr Asn Tyr Trp
1 5 10
<210> 251
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-A07 HCDR3
<400> 251
Ala Gly Asp Tyr Asp Arg His Tyr Ser Tyr Trp
1 5 10
<210> 252
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-B07 HCDR3
<400> 252
Ala Gly Val Glu Gln Phe His Phe Asn Tyr Trp
1 5 10
<210> 253
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-C07 HCDR3
<400> 253
Ala Gly His Trp Asn His His Tyr Asn Tyr Trp
1 5 10
<210> 254
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-D07 HCDR3
<400> 254
Val Gly Asp Trp Asp Trp His Phe Asn Tyr Trp
1 5 10
<210> 255
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-E07 HCDR3
<400> 255
Ala Gly Tyr Tyr Pro Met His Tyr Ser Tyr Trp
1 5 10
<210> 256
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-F07 HCDR3
<400> 256
Ala Gly Asp Asn Trp Met His His Asn Tyr Trp
1 5 10
<210> 257
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-G07 HCDR3
<400> 257
Ala Gly Tyr Trp Phe Ala His Phe Asn Tyr Trp
1 5 10
<210> 258
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-H07 HCDR3
<400> 258
Ala Gly Asp His Asp Leu His Tyr Asn Tyr Trp
1 5 10
<210> 259
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-A08 HCDR3
<400> 259
Val Gly Leu Tyr Asp Arg His Tyr Asn Tyr Trp
1 5 10
<210> 260
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-C08 HCDR3
<400> 260
Val Gly Ile Trp Asp Phe Tyr His Phe Asn Tyr Trp
1 5 10
<210> 261
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-D08 HCDR3
<400> 261
Ala Gly Asp Ile Met Tyr His Tyr Asn Tyr Trp
1 5 10
<210> 262
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-E08 HCDR3
<400> 262
Val Lys Glu Arg Phe Thr Thr Pro Tyr Ala His Ser Tyr Trp
1 5 10
<210> 263
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-G08 HCDR3
<400> 263
Ala Gly Pro Leu Trp Gln Leu Tyr Arg Ser His Gly Tyr Trp
1 5 10
<210> 264
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-A09 HCDR3
<400> 264
Val Gly Pro Val Tyr Leu His Tyr Asn Tyr Trp
1 5 10
<210> 265
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-B09 HCDR3
<400> 265
Ala Gly Arg Phe Pro Phe His Tyr Asp Tyr Trp
1 5 10
<210> 266
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-C09 HCDR3
<400> 266
Val Ser Ser Lys Gly Ser Ser Ala Ala Ser Leu Asn Tyr Trp
1 5 10
<210> 267
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-D09 HCDR3
<400> 267
Ala Gly Asp Tyr Tyr Gly His His Asn Tyr Trp
1 5 10
<210> 268
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-E09 HCDR3
<400> 268
Ala Gly Tyr Val Gln Trp His Tyr Gly Tyr Trp
1 5 10
<210> 269
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-F09 HCDR3
<400> 269
Ala Gly Thr Ala His Gln His Tyr Asp Tyr Trp
1 5 10
<210> 270
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-G09 HCDR3
<400> 270
Val Thr Asn His Met Glu Arg His Ala Ser Tyr Gly Tyr Trp
1 5 10
<210> 271
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-H09 HCDR3
<400> 271
Ala Thr Arg Thr Asp Trp His Phe Asn Tyr Trp
1 5 10
<210> 272
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-B10 HCDR3
<400> 272
Ala Gly Gln Tyr Asn Phe His Tyr Ser Tyr Trp
1 5 10
<210> 273
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-C10 HCDR3
<400> 273
Ala Gly Thr Thr Gly Leu His Tyr Asn Tyr Trp
1 5 10
<210> 274
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-D10 HCDR3
<400> 274
Ala Gly Thr Ile Leu His His Phe Asn Tyr Trp
1 5 10
<210> 275
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-E10 HCDR3
<400> 275
Ala Gly Pro Trp His Phe His Phe Gly Tyr Trp
1 5 10
<210> 276
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-F10 HCDR3
<400> 276
Ala Gly Asp Tyr Pro Trp His Tyr Asn Tyr Trp
1 5 10
<210> 277
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-G10 HCDR3
<400> 277
Ala Gly Pro Ala Met Leu His Phe Ser Tyr Trp
1 5 10
<210> 278
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-H10 HCDR3
<400> 278
Ala Gly Met Phe Lys Tyr His Phe Asn Tyr Trp
1 5 10
<210> 279
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-A11 HCDR3
<400> 279
Val Ile Phe Pro Glu Gln Val Tyr Asp Tyr Trp
1 5 10
<210> 280
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-C11 HCDR3
<400> 280
Val Ala Thr Phe Arg Thr Thr Asn Asp Tyr Tyr Ser Ser His Gly Tyr
1 5 10 15
Trp
<210> 281
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-D11 HCDR3
<400> 281
Ala Gly Gly Ser Met Phe His Tyr Asn Tyr Trp
1 5 10
<210> 282
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-F11 HCDR3
<400> 282
Ala Gly Arg Ile Met Met His Phe Asn Tyr Trp
1 5 10
<210> 283
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-G11 HCDR3
<400> 283
Ala Ser Tyr Thr Ala Phe His Tyr Asn Tyr Trp
1 5 10
<210> 284
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-H11 HCDR3
<400> 284
Ala Gly Pro Trp Ala Phe His Tyr Asn Tyr Trp
1 5 10
<210> 285
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-B12 HCDR3
<400> 285
Ala Thr Asp Thr Ala Asp His Tyr Asn Tyr Trp
1 5 10
<210> 286
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-C12 HCDR3
<400> 286
Ala Gly Met Ile Gln Phe His His Asn Tyr Trp
1 5 10
<210> 287
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-D12 HCDR3
<400> 287
Ala Gly Ile Trp Phe Arg His Tyr Asn Tyr Trp
1 5 10
<210> 288
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-F12 HCDR3
<400> 288
Ala Ser Pro Thr Trp Met His Phe Asn Tyr Trp
1 5 10
<210> 289
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-G12 HCDR3
<400> 289
Val Gly Ala Thr His Leu His Tyr Ser Tyr Trp
1 5 10
<210> 290
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-H12 HCDR3
<400> 290
Ala Gly Asp Phe Pro His His Phe Asn Tyr Trp
1 5 10
<210> 291
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-A01 HCDR3
<400> 291
Ala Gly Arg Trp Asp Arg His Tyr Asn Tyr
1 5 10
<210> 292
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-B01 HCDR3
<400> 292
Ala Gly Leu Val Ala Phe His Tyr Asn Tyr Trp
1 5 10
<210> 293
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-E01 HCDR3
<400> 293
Ala Gly Asp Phe His Arg His Tyr Asn Tyr Trp
1 5 10
<210> 294
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-F01 HCDR3
<400> 294
Ala Asp Ile Phe Pro Leu His Phe Ser Tyr Trp
1 5 10
<210> 295
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-H01 HCDR3
<400> 295
Ala Gly Gln Tyr Glu Trp His Tyr Ser Tyr Trp
1 5 10
<210> 296
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-A02 HCDR3
<400> 296
Ala Gly His Ala Trp Leu His His Asn Tyr Trp
1 5 10
<210> 297
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-C02 HCDR3
<400> 297
Ala Gly Pro Trp Asn His His Tyr Asn Tyr Trp
1 5 10
<210> 298
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-D02 HCDR3
<400> 298
Ala Gly Asp Asn Phe Met His His Asn Tyr Trp
1 5 10
<210> 299
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-F02 HCDR3
<400> 299
Ala Ala Asp Phe Pro Met His Phe Asn Tyr Trp
1 5 10
<210> 300
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-G02 HCDR3
<400> 300
Ala Thr Val Thr Pro Phe His Phe Ser Tyr Trp
1 5 10
<210> 301
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-A03 HCDR3
<400> 301
Ala Gly Ile Tyr Met Trp His Tyr Asn Tyr Trp
1 5 10
<210> 302
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-B03 HCDR3
<400> 302
Ala Gly Asp Glu Asp Tyr His Tyr Asn Tyr Trp
1 5 10
<210> 303
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-C03 HCDR3
<400> 303
Ala Ala Glu Phe Gln Trp His Phe Gly Tyr Trp
1 5 10
<210> 304
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-D03 HCDR3
<400> 304
Ala Gly His Ser Trp Leu His Phe Asn Tyr Trp
1 5 10
<210> 305
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-A04 HCDR3
<400> 305
Val Gly Gln Glu His Leu His Tyr Asn Tyr Trp
1 5 10
<210> 306
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-B04 HCDR3
<400> 306
Ala Thr Thr Tyr Gln Gly Arg Asp Asp Gly Phe Asn Tyr Trp
1 5 10
<210> 307
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-E04 HCDR3
<400> 307
Ala Gly Asp Tyr Asp Arg His Phe Asn Tyr Trp
1 5 10
<210> 308
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-G04 HCDR3
<400> 308
Ala Gly Pro Leu Tyr Leu His His Asp Tyr Trp
1 5 10
<210> 309
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-H04 HCDR3
<400> 309
Ala Gly Trp Trp Gln Met His Tyr Asn Tyr Trp
1 5 10
<210> 310
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-D05 HCDR3
<400> 310
Ala Gly Thr Ala Pro Phe His Tyr Asn Tyr Trp
1 5 10
<210> 311
<211> 23
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-E05 HCDR3
<400> 311
Ala His Tyr Asn Arg Tyr Ala Pro Pro Ala Ala Asp Gly Asn Thr Ala
1 5 10 15
Leu Gly Thr Leu Gly Tyr Trp
20
<210> 312
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-G05 HCDR3
<400> 312
Ala Gly His His Tyr His His Tyr Asn Tyr Trp
1 5 10
<210> 313
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-H05 HCDR3
<400> 313
Ala Ser Asp Ala Leu Ala Ala Asp Gly Val Asp Trp His Tyr Asn Tyr
1 5 10 15
Trp
<210> 314
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-C06 HCDR3
<400> 314
Ala Gly Asp Met His His His Tyr Asn Tyr Trp
1 5 10
<210> 315
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-E06 HCDR3
<400> 315
Ala Gly Met His Gly Leu His Tyr Asn Tyr Trp
1 5 10
<210> 316
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-F06 HCDR3
<400> 316
Val Gly Asp Trp Asp Trp Leu Phe Met Tyr
1 5 10
<210> 317
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-G06 HCDR3
<400> 317
Ala Gly Tyr Ala Pro Leu His Phe Asn Tyr Trp
1 5 10
<210> 318
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-H06 HCDR3
<400> 318
Ala Gly Tyr Ser Thr Phe His Tyr Asn Tyr Trp
1 5 10
<210> 319
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-A07 HCDR3
<400> 319
Ala Gly Asp Ile Asn Tyr His Tyr Asn Tyr Trp
1 5 10
<210> 320
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-B07 HCDR3
<400> 320
Ala Gly Pro Trp Asn Leu His Phe Asn Tyr Trp
1 5 10
<210> 321
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-D07 HCDR3
<400> 321
Ala Thr Phe Thr Pro Gly His Tyr Asn Tyr Trp
1 5 10
<210> 322
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-E07 HCDR3
<400> 322
Ala Gly Asp Tyr Ile Phe His Phe Asn Tyr Trp
1 5 10
<210> 323
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-F07 HCDR3
<400> 323
Ala Ile Ala His Gln Gln Lys Leu Ser Tyr Trp
1 5 10
<210> 324
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-G07 HCDR3
<400> 324
Ala Gly Glu Thr Ala Tyr His Phe Asn Tyr Trp
1 5 10
<210> 325
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-A01 VH
<400> 325
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Ser Asn Asn Tyr
20 25 30
Phe Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Asn Pro Leu Asp Ser Asn Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly His Trp Asp Ser His Phe Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 326
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-B01 VH
<400> 326
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ser Gly Val Tyr
20 25 30
Phe Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Val Gly Asp Trp Asp Ile Phe His Tyr Ser Tyr Trp Gly Gln Gly
100 105 110
Thr Gln Val Thr Val Ser Ser
115
<210> 327
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-C01 VH
<400> 327
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Phe Asn
20 25 30
Tyr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Ile Ser Asp Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Ile Val Gln Tyr His Tyr Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 328
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-E01 VH
<400> 328
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Tyr Asn
20 25 30
Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Glu Trp Met Met His Phe Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 329
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-F01 VH
<400> 329
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Tyr Asn
20 25 30
Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Thr Asp Thr Trp His Tyr Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 330
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-G01 VH
<400> 330
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Phe Ser His Tyr
20 25 30
Ser Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Pro Trp His Ala His Phe Ser Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 331
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-H01 VH
<400> 331
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Ile Leu Arg Asp Asp
20 25 30
Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Val Ser Thr Tyr Arg Ala Asp Ala Arg Ser Leu Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 332
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-B02 VH
<400> 332
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Ser Tyr Tyr
20 25 30
Phe Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Ala Thr Thr Gln Phe His Phe Gly Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 333
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-C02 VH
<400> 333
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Tyr Asn
20 25 30
Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Thr Phe Asp Gln His Phe Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 334
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-D02 VH
<400> 334
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Tyr Ser Asn Tyr
20 25 30
Tyr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Ser Arg Thr Trp Met His Phe Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 335
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-E02 VH
<400> 335
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Phe Ser Ala Tyr
20 25 30
Tyr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Thr Ile Asn Ser Val Asp Asp Ile Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Gln Tyr Gln Tyr His Tyr Ser Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 336
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-H02 VH
<400> 336
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Tyr Asp Val Asp
20 25 30
Tyr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Thr Ile Asn Ser Tyr Gly Gly Ile Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Ser Ala Thr Lys Asp His Tyr Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 337
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-B03 VH
<400> 337
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Tyr Ser Phe Tyr
20 25 30
Phe Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Asn Ile His Tyr His Tyr Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 338
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-C03 VH
<400> 338
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Tyr Asn
20 25 30
Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Glu Ser Asp Arg His Tyr Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 339
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-D03 VH
<400> 339
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Tyr Arg Asn Tyr
20 25 30
Ser Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Val Gly Tyr Val Phe Gln His Phe Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 340
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-F03 VH
<400> 340
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Phe Ser Phe Tyr
20 25 30
Phe Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Ala Phe Trp Asp Tyr His Tyr Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 341
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-H03 VH
<400> 341
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Ile Phe Ser Val Asn
20 25 30
Phe Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Thr Ile Asn Trp Phe Asp Asp Ile Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Gly Thr Glu Trp His Phe Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 342
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-B04 VH
<400> 342
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Phe Asp Tyr Tyr
20 25 30
Tyr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Ser Val Ile Ser Phe His Tyr Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 343
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-D04 VH
<400> 343
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Tyr Ser Asn Tyr
20 25 30
Tyr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Pro Met Asn Trp His Tyr Gly Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 344
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-E04 VH
<400> 344
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Phe Asn Ile Tyr
20 25 30
Ser Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ser Ile Asn Trp Ser Asp Ser Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Pro Tyr Tyr Trp Gly Leu Ser Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 345
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-G04 VH
<400> 345
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Tyr Asp Leu Tyr
20 25 30
Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Val Gly Gln Tyr Asp Trp His Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 346
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-A05 VH
<400> 346
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Tyr Asp Leu Tyr
20 25 30
Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Gln Pro Met Tyr His Phe Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 347
<211> 124
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-C05 VH
<400> 347
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Tyr Asn
20 25 30
Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Val Val Thr Val Trp Tyr Ser Pro Phe Lys Val Lys Met Tyr Asn
100 105 110
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 348
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-D05 VH
<400> 348
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Tyr Gly Phe Asn
20 25 30
Tyr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Ile Trp His Met His Tyr Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 349
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-E05 VH
<400> 349
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Tyr Asn
20 25 30
Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Thr Ser Trp Arg Ser Pro Pro Pro Ala Tyr Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 350
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-F05 VH
<400> 350
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Tyr Arg Phe Asp
20 25 30
Ser Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Thr Ile Thr Ser Leu Asp Ser Ile Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Ala Trp Lys Asn His Phe Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 351
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-G05 VH
<400> 351
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Ser Ser Ala Tyr
20 25 30
Ser Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Asp Ser Asp Leu His Tyr Ser Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 352
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-H05 VH
<400> 352
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Tyr Asn
20 25 30
Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Thr Ser Pro Arg Gly Leu Ser Ala Gly His Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 353
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-A06 VH
<400> 353
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Phe Ser Ser Tyr
20 25 30
Ile Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ser Ile Asn Ser Tyr Asp Ser Thr Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Thr Glu Val Pro Met His Tyr Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 354
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-B06 VH
<400> 354
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asn Ile Tyr
20 25 30
His Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Asn Ser Phe Ser Asp Ile Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Glu Trp Pro Leu His Tyr Ser Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 355
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-C06 VH
<400> 355
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Ser Phe Tyr
20 25 30
Phe Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Thr Ile Asn Ser Phe Asp Asp Ile Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Leu Trp His Gln His Tyr Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 356
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-D06 VH
<400> 356
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Tyr Asp Ala Asn
20 25 30
Phe Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Thr Ile Asn Thr Tyr Ser Asp Ile Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Asn Trp Thr Phe His Phe Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 357
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-E06 VH
<400> 357
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Tyr Asn
20 25 30
Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Arg Tyr Leu Trp His Tyr Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 358
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-F06 VH
<400> 358
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Tyr Asn
20 25 30
Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Leu Gln Glu Tyr His Tyr Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 359
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-A07 VH
<400> 359
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Phe Asp Tyr Tyr
20 25 30
Phe Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Thr Ile Asn Ser Phe Ser Ser Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Asp Tyr Asp Arg His Tyr Ser Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 360
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-B07 VH
<400> 360
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Tyr Asn
20 25 30
Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Thr Ile Ser Phe Ser Gly Ile Thr Tyr Tyr Pro Asp Ser Val Glu
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Ala Gly Val Glu Gln Phe His Phe Asn Tyr Trp Gly Gln Gly Thr Gln
100 105 110
Val Thr Val Ser Ser
115
<210> 361
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-C07 VH
<400> 361
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Phe Tyr
20 25 30
Phe Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ser Ile Asn Ala Tyr Ser Asp Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly His Trp Asn His His Tyr Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 362
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-D07 VH
<400> 362
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Ser Tyr
20 25 30
Ser Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Thr Ile Ser Ser Phe Ser Asp Ile Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Val Gly Asp Trp Asp Trp His Phe Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 363
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-E07 VH
<400> 363
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Gly Tyr Asp
20 25 30
Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Thr Ile Asn Ser Phe Gly Asp Ile Thr Asn Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Tyr Tyr Pro Met His Tyr Ser Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 364
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-F07 VH
<400> 364
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Tyr Asn
20 25 30
Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Asp Asn Trp Met His His Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 365
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-G07 VH
<400> 365
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Ile Ser Asp Tyr Tyr
20 25 30
Ser Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Tyr Trp Phe Ala His Phe Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 366
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-H07 VH
<400> 366
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Ile Phe Ser Phe Tyr
20 25 30
Phe Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Asp His Asp Leu His Tyr Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 367
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-A08 VH
<400> 367
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Phe Gly Ile Tyr
20 25 30
Phe Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Val Gly Leu Tyr Asp Arg His Tyr Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 368
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-C08 VH
<400> 368
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Tyr Gly Tyr Asp
20 25 30
Tyr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Val Gly Ile Trp Asp Phe Tyr His Phe Asn Tyr Trp Gly Gln Gly
100 105 110
Thr Gln Val Thr Val Ser Ser
115
<210> 369
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-D08 VH
<400> 369
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Leu Gly Ser Tyr
20 25 30
Ile Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Thr Ile Asn Ser Asn Asp Ser Ile Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Asp Ile Met Tyr His Tyr Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 370
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-E08 VH
<400> 370
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Tyr Ser Phe Tyr
20 25 30
Val Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Thr Ile Asn Ser Phe Asp Asp Thr Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Val Lys Glu Arg Phe Thr Thr Pro Tyr Ala His Ser Tyr Trp Gly
100 105 110
Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 371
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-G08 VH
<400> 371
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Tyr Asn
20 25 30
Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Pro Leu Trp Gln Leu Tyr Arg Ser His Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 372
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-A09 VH
<400> 372
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Phe Tyr
20 25 30
Ser Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ser Ile Asn Ala Ile Asp Ser Ile Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Val Gly Pro Val Tyr Leu His Tyr Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 373
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-B09 VH
<400> 373
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe Gly Val Asn
20 25 30
Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Thr Ile Thr Ser Thr Asp Asp Ile Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Arg Phe Pro Phe His Tyr Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 374
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-C09 VH
<400> 374
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Tyr Asn
20 25 30
Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Val Ser Ser Lys Gly Ser Ser Ala Ala Ser Leu Asn Tyr Trp Gly
100 105 110
Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 375
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-D09 VH
<400> 375
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Tyr Asn
20 25 30
Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Asp Tyr Tyr Gly His His Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 376
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-E09 VH
<400> 376
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Ser Gly His Tyr
20 25 30
Tyr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Tyr Val Gln Trp His Tyr Gly Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 377
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-F09 VH
<400> 377
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Ile Leu Arg Ile Tyr
20 25 30
Phe Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Thr Ala His Gln His Tyr Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 378
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-G09 VH
<400> 378
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Tyr Asn
20 25 30
Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Val Thr Asn His Met Glu Arg His Ala Ser Tyr Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 379
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-H09 VH
<400> 379
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Phe Asn Val Tyr
20 25 30
Tyr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Thr Ile Ser Trp Tyr Ser Asp Ile Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Thr Arg Thr Asp Trp His Phe Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 380
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-B10 VH
<400> 380
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Tyr Ser Phe Tyr
20 25 30
Phe Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Thr Ile Asn Ser Phe Asp Ser Ile Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Gln Tyr Asn Phe His Tyr Ser Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 381
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-C10 VH
<400> 381
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Tyr Asn
20 25 30
Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Thr Thr Gly Leu His Tyr Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 382
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-D10 VH
<400> 382
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Phe Gly Ala Tyr
20 25 30
Tyr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Asn Pro Asp Ser Asp Ile Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Thr Ile Leu His His Phe Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 383
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-E10 VH
<400> 383
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Arg Phe Tyr
20 25 30
Ser Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Thr Ile Ser Ser Phe Asp Asp Ile Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Pro Trp His Phe His Phe Gly Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 384
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-F10 VH
<400> 384
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Leu Gly Ser Asp
20 25 30
Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ser Ile Asn Ser Phe Asp Ser Ile Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Asp Tyr Pro Trp His Tyr Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 385
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-G10 VH
<400> 385
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Phe Ser Val Tyr
20 25 30
Ser Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Asn Thr Val Asp Ser Ile Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Pro Ala Met Leu His Phe Ser Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 386
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-H10 VH
<400> 386
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Asn Phe Tyr
20 25 30
Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Met Phe Lys Tyr His Phe Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 387
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-A11 VH
<400> 387
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser Ser Tyr
20 25 30
Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ser Ile Ser Trp Val Asp Ser Ile Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Val Ile Phe Pro Glu Gln Val Tyr Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 388
<211> 124
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-C11 VH
<400> 388
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Tyr Asn
20 25 30
Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Val Ala Thr Phe Arg Thr Thr Asn Asp Tyr Tyr Ser Ser His Gly
100 105 110
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 389
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-D11 VH
<400> 389
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Ile Ser Ser Ser Tyr
20 25 30
Ser Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Ser Phe Ser Asp Ile Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Gly Ser Met Phe His Tyr Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 390
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-F11 VH
<400> 390
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Tyr Asn
20 25 30
Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Arg Ile Met Met His Phe Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 391
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-G11 VH
<400> 391
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Tyr Ser His Asn
20 25 30
Phe Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Ser Tyr Thr Ala Phe His Tyr Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 392
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-H11 VH
<400> 392
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Phe Ser Phe Tyr
20 25 30
Ser Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Thr Ile Asn Thr Phe Ser Asp Ile Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Pro Trp Ala Phe His Tyr Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 393
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-B12 VH
<400> 393
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Phe Asp Phe Tyr
20 25 30
Phe Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Thr Ile Asn Ser Ile Ser Asp Ile Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Thr Asp Thr Ala Asp His Tyr Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 394
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-C12 VH
<400> 394
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Tyr Ser Ser Asn
20 25 30
Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ser Ile Asn Ser Phe Asp Asp Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Met Ile Gln Phe His His Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 395
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-D12 VH
<400> 395
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Leu Arg His Tyr
20 25 30
His Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Thr Ile Asn Thr Leu Asp Ser Ile Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Ile Trp Phe Arg His Tyr Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 396
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-F12 VH
<400> 396
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Phe Gly Ser Tyr
20 25 30
Phe Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Ser Pro Thr Trp Met His Phe Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 397
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-G12 VH
<400> 397
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Ile Phe Ser Ser Tyr
20 25 30
Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Val Gly Ala Thr His Leu His Tyr Ser Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 398
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR2-H12 VH
<400> 398
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ala Tyr
20 25 30
His Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Thr Ile Asn Trp Phe Gly Gly Ile Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Asp Phe Pro His His Phe Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 399
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-A01 VH
<400> 399
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Gly Leu Asp
20 25 30
Phe Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ser Ile Asn Ser Phe Asp Asp Ile Thr Asn Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Arg Trp Asp Arg His Tyr Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 400
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-B01 VH
<400> 400
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Ile Leu Ser Phe Tyr
20 25 30
Tyr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Thr Ile Asn Ser Phe Ser Asp Ile Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Leu Val Ala Phe His Tyr Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 401
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-E01 VH
<400> 401
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Ser Ser Leu Tyr
20 25 30
Ser Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Thr Ile Thr Gly Ser Ser Ser Ile Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Asp Phe His Arg His Tyr Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 402
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-F01 VH
<400> 402
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Phe Asn Tyr Tyr
20 25 30
Tyr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Thr Ile Ser Ala Phe Asp Asp Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Asp Ile Phe Pro Leu His Phe Ser Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 403
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-H01 VH
<400> 403
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Ser Gly Ala Tyr
20 25 30
Asn Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Thr Ile Asn Trp Phe Asp Asp Ile Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Gln Tyr Glu Trp His Tyr Ser Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 404
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-A02 VH
<400> 404
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Tyr Asn Phe Asn
20 25 30
Ser Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Asn Arg Phe Asp Asp Ile Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly His Ala Trp Leu His His Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 405
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-C02 VH
<400> 405
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Ser Arg Asp Tyr
20 25 30
Ser Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Thr Ile Asn Ser Asn Ser Asp Ile Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Pro Trp Asn His His Tyr Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 406
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-D02 VH
<400> 406
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Tyr Asn Val Tyr
20 25 30
Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Asp Asn Phe Met His His Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 407
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-F02 VH
<400> 407
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Tyr Asn
20 25 30
Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Ala Asp Phe Pro Met His Phe Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 408
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-G02 VH
<400> 408
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Asn Tyr Tyr
20 25 30
Asp Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Thr Ile Asn Arg Phe Ser Ser Ile Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Thr Val Thr Pro Phe His Phe Ser Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 409
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-A03 VH
<400> 409
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Ser Gly Val Tyr
20 25 30
Phe Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Thr Ile Ser Ser Ala Ser Asp Ile Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Ile Tyr Met Trp His Tyr Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 410
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-B03 VH
<400> 410
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Leu Gly Ala Asn
20 25 30
Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Asp Glu Asp Tyr His Tyr Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 411
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-C03 VH
<400> 411
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Tyr Gly Tyr Asn
20 25 30
His Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Ala Glu Phe Gln Trp His Phe Gly Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 412
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-D03 VH
<400> 412
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Tyr Asn
20 25 30
Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly His Ser Trp Leu His Phe Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 413
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-A04 VH
<400> 413
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Tyr Asn Tyr Asn
20 25 30
His Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Val Gly Gln Glu His Leu His Tyr Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 414
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-B04 VH
<400> 414
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Tyr Asn
20 25 30
Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Thr Thr Tyr Gln Gly Arg Asp Asp Gly Phe Asn Tyr Trp Gly
100 105 110
Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 415
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-E04 VH
<400> 415
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Tyr Ser Phe Asn
20 25 30
Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ser Ile Asn Ser Ser Asp Ser Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Asp Tyr Asp Arg His Phe Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 416
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-G04 VH
<400> 416
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Ser Ala Tyr
20 25 30
Ser Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Asn Ser Phe Asp Asp Ile Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Pro Leu Tyr Leu His His Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 417
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-H04 VH
<400> 417
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Asn Pro Tyr
20 25 30
Phe Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Trp Trp Gln Met His Tyr Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 418
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-D05 VH
<400> 418
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Phe Ser Leu Tyr
20 25 30
Ser Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Thr Ile Asn Ala Leu Asp Asp Ile Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Thr Ala Pro Phe His Tyr Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 419
<211> 130
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-E05 VH
<400> 419
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Phe Gly Tyr Tyr
20 25 30
Ser Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Ser Phe Asp Asp Ile Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala His Tyr Asn Arg Tyr Ala Pro Pro Ala Ala Asp Gly Asn Thr
100 105 110
Ala Leu Gly Thr Leu Gly Tyr Trp Gly Gln Gly Thr Gln Val Thr Val
115 120 125
Ser Ser
130
<210> 420
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-G05 VH
<400> 420
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Tyr Asn
20 25 30
Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly His His Tyr His His Tyr Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 421
<211> 124
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-H05 VH
<400> 421
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Tyr Asn
20 25 30
Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Ser Asp Ala Leu Ala Ala Asp Gly Val Asp Trp His Tyr Asn
100 105 110
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 422
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-C06 VH
<400> 422
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Tyr Asn
20 25 30
Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Asp Met His His His Tyr Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 423
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-E06 VH
<400> 423
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Tyr Asn
20 25 30
Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Met His Gly Leu His Tyr Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 424
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-F06 VH
<400> 424
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Ser Tyr
20 25 30
Ser Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Thr Ile Asn Ser Phe Ser Asp Ile Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Val Gly Asp Trp Asp Trp Leu Phe Met Tyr Trp Gly Gln Gly Thr
100 105 110
Lys Val Thr Val Ser Ser
115
<210> 425
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-G06 VH
<400> 425
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Ile Ser Ser Val Tyr
20 25 30
Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ser Ile Asn Ser Ile Asp Ala Ile Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Tyr Ala Pro Leu His Phe Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 426
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-H06 VH
<400> 426
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Asn Val Asp
20 25 30
His Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Asn Ser Ile Asp Ser Ile Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Tyr Ser Thr Phe His Tyr Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 427
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-A07 VH
<400> 427
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Ser Ser Tyr Tyr
20 25 30
Tyr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Asp Ile Asn Tyr His Tyr Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 428
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-B07 VH
<400> 428
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Ile Tyr Ser Tyr Asn
20 25 30
Phe Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ser Ile Asn Ser Phe Asp Asp Ile Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Pro Trp Asn Leu His Phe Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 429
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-D07 VH
<400> 429
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Arg Ile Tyr
20 25 30
Phe Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Asn Pro Tyr Gly Asp Ile Thr Asn Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Thr Phe Thr Pro Gly His Tyr Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 430
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-E07 VH
<400> 430
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Tyr Arg Tyr Tyr
20 25 30
Ser Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ser Ile Asn Ala Phe Asp Asp Ile Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Asp Tyr Ile Phe His Phe Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 431
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-F07 VH
<400> 431
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Phe Asp Phe Asn
20 25 30
His Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ser Ile Ser Ser Phe Asp Asp Ile Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Ile Ala His Gln Gln Lys Leu Ser Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 432
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FAP-FR3-G07 VH
<400> 432
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Tyr Asn
20 25 30
Pro Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Ala Ile Ser Arg Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Arg Met Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Glu Thr Ala Tyr His Phe Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
Claims (29)
1.成纤维细胞活化蛋白(FAP)结合多肽,其包含免疫球蛋白重链可变结构域,所述免疫球蛋白重链可变结构域包含CDR-H1、CDR-H2和CDR-H3,其中:
所述CDR-H1包含与选自SEQ ID NO:1-108的序列具有至少90%、95%、99%或100%序列同一性的序列;
所述CDR-H2包含与选自SEQ ID NO:109-216的序列具有至少90%、95%、99%或100%序列同一性的序列;并且
所述CDR-H3包含与选自SEQ ID NO:217-324的序列具有至少90%、95%、99%或100%序列同一性的序列。
2.如权利要求1所述的FAP结合多肽,其中:
1)所述CDR-H1包含SEQ ID NO:1的序列,所述CDR-H2包含SEQ ID NO:109的序列,并且所述CDR-H3包含SEQ ID NO:217的序列;
2)所述CDR-H1包含SEQ ID NO:2的序列,所述CDR-H2包含SEQ ID NO:110的序列,并且所述CDR-H3包含SEQ ID NO:218的序列;
3)所述CDR-H1包含SEQ ID NO:3的序列,所述CDR-H2包含SEQ ID NO:111的序列,并且所述CDR-H3包含SEQ ID NO:219的序列;
4)所述CDR-H1包含SEQ ID NO:4的序列,所述CDR-H2包含SEQ ID NO:112的序列,并且所述CDR-H3包含SEQ ID NO:220的序列;
5)所述CDR-H1包含SEQ ID NO:5的序列,所述CDR-H2包含SEQ ID NO:113的序列,并且所述CDR-H3包含SEQ ID NO:221的序列;
6)所述CDR-H1包含SEQ ID NO:6的序列,所述CDR-H2包含SEQ ID NO:114的序列,并且所述CDR-H3包含SEQ ID NO:222的序列;
7)所述CDR-H1包含SEQ ID NO:7的序列,所述CDR-H2包含SEQ ID NO:115的序列,并且所述CDR-H3包含SEQ ID NO:223的序列;
8)所述CDR-H1包含SEQ ID NO:8的序列,所述CDR-H2包含SEQ ID NO:116的序列,并且所述CDR-H3包含SEQ ID NO:224的序列;
9)所述CDR-H1包含SEQ ID NO:9的序列,所述CDR-H2包含SEQ ID NO:117的序列,并且所述CDR-H3包含SEQ ID NO:225的序列;
10)所述CDR-H1包含SEQ ID NO:10的序列,所述CDR-H2包含SEQ ID NO:118的序列,并且所述CDR-H3包含SEQ ID NO:226的序列;
11)所述CDR-H1包含SEQ ID NO:11的序列,所述CDR-H2包含SEQ ID NO:119的序列,并且所述CDR-H3包含SEQ ID NO:227的序列;
12)所述CDR-H1包含SEQ ID NO:12的序列,所述CDR-H2包含SEQ ID NO:120的序列,并且所述CDR-H3包含SEQ ID NO:228的序列;
13)所述CDR-H1包含SEQ ID NO:13的序列,所述CDR-H2包含SEQ ID NO:121的序列,并且所述CDR-H3包含SEQ ID NO:229的序列;
14)所述CDR-H1包含SEQ ID NO:14的序列,所述CDR-H2包含SEQ ID NO:122的序列,并且所述CDR-H3包含SEQ ID NO:230的序列;
15)所述CDR-H1包含SEQ ID NO:15的序列,所述CDR-H2包含SEQ ID NO:123的序列,并且所述CDR-H3包含SEQ ID NO:231的序列;
16)所述CDR-H1包含SEQ ID NO:16的序列,所述CDR-H2包含SEQ ID NO:124的序列,并且所述CDR-H3包含SEQ ID NO:232的序列;
17)所述CDR-H1包含SEQ ID NO:17的序列,所述CDR-H2包含SEQ ID NO:125的序列,并且所述CDR-H3包含SEQ ID NO:233的序列;
18)所述CDR-H1包含SEQ ID NO:18的序列,所述CDR-H2包含SEQ ID NO:126的序列,并且所述CDR-H3包含SEQ ID NO:234的序列;
19)所述CDR-H1包含SEQ ID NO:19的序列,所述CDR-H2包含SEQ ID NO:127的序列,并且所述CDR-H3包含SEQ ID NO:235的序列;
20)所述CDR-H1包含SEQ ID NO:20的序列,所述CDR-H2包含SEQ ID NO:128的序列,并且所述CDR-H3包含SEQ ID NO:236的序列;
21)所述CDR-H1包含SEQ ID NO:21的序列,所述CDR-H2包含SEQ ID NO:129的序列,并且所述CDR-H3包含SEQ ID NO:237的序列;
22)所述CDR-H1包含SEQ ID NO:22的序列,所述CDR-H2包含SEQ ID NO:130的序列,并且所述CDR-H3包含SEQ ID NO:238的序列;
23)所述CDR-H1包含SEQ ID NO:23的序列,所述CDR-H2包含SEQ ID NO:131的序列,并且所述CDR-H3包含SEQ ID NO:239的序列;
24)所述CDR-H1包含SEQ ID NO:24的序列,所述CDR-H2包含SEQ ID NO:132的序列,并且所述CDR-H3包含SEQ ID NO:240的序列;
25)所述CDR-H1包含SEQ ID NO:25的序列,所述CDR-H2包含SEQ ID NO:133的序列,并且所述CDR-H3包含SEQ ID NO:241的序列;
26)所述CDR-H1包含SEQ ID NO:26的序列,所述CDR-H2包含SEQ ID NO:134的序列,并且所述CDR-H3包含SEQ ID NO:242的序列;
27)所述CDR-H1包含SEQ ID NO:27的序列,所述CDR-H2包含SEQ ID NO:135的序列,并且所述CDR-H3包含SEQ ID NO:243的序列;
28)所述CDR-H1包含SEQ ID NO:28的序列,所述CDR-H2包含SEQ ID NO:136的序列,并且所述CDR-H3包含SEQ ID NO:244的序列;
29)所述CDR-H1包含SEQ ID NO:29的序列,所述CDR-H2包含SEQ ID NO:137的序列,并且所述CDR-H3包含SEQ ID NO:245的序列;
30)所述CDR-H1包含SEQ ID NO:30的序列,所述CDR-H2包含SEQ ID NO:138的序列,并且所述CDR-H3包含SEQ ID NO:246的序列;
31)所述CDR-H1包含SEQ ID NO:31的序列,所述CDR-H2包含SEQ ID NO:139的序列,并且所述CDR-H3包含SEQ ID NO:247的序列;
32)所述CDR-H1包含SEQ ID NO:32的序列,所述CDR-H2包含SEQ ID NO:140的序列,并且所述CDR-H3包含SEQ ID NO:248的序列;
33)所述CDR-H1包含SEQ ID NO:33的序列,所述CDR-H2包含SEQ ID NO:141的序列,并且所述CDR-H3包含SEQ ID NO:249的序列;
34)所述CDR-H1包含SEQ ID NO:34的序列,所述CDR-H2包含SEQ ID NO:142的序列,并且所述CDR-H3包含SEQ ID NO:250的序列;
35)所述CDR-H1包含SEQ ID NO:35的序列,所述CDR-H2包含SEQ ID NO:143的序列,并且所述CDR-H3包含SEQ ID NO:251的序列;
36)所述CDR-H1包含SEQ ID NO:36的序列,所述CDR-H2包含SEQ ID NO:144的序列,并且所述CDR-H3包含SEQ ID NO:252的序列;
37)所述CDR-H1包含SEQ ID NO:37的序列,所述CDR-H2包含SEQ ID NO:145的序列,并且所述CDR-H3包含SEQ ID NO:253的序列;
38)所述CDR-H1包含SEQ ID NO:38的序列,所述CDR-H2包含SEQ ID NO:146的序列,并且所述CDR-H3包含SEQ ID NO:254的序列;
39)所述CDR-H1包含SEQ ID NO:39的序列,所述CDR-H2包含SEQ ID NO:147的序列,并且所述CDR-H3包含SEQ ID NO:255的序列;
40)所述CDR-H1包含SEQ ID NO:40的序列,所述CDR-H2包含SEQ ID NO:148的序列,并且所述CDR-H3包含SEQ ID NO:256的序列;
41)所述CDR-H1包含SEQ ID NO:41的序列,所述CDR-H2包含SEQ ID NO:149的序列,并且所述CDR-H3包含SEQ ID NO:257的序列;
42)所述CDR-H1包含SEQ ID NO:42的序列,所述CDR-H2包含SEQ ID NO:150的序列,并且所述CDR-H3包含SEQ ID NO:258的序列;
43)所述CDR-H1包含SEQ ID NO:43的序列,所述CDR-H2包含SEQ ID NO:151的序列,并且所述CDR-H3包含SEQ ID NO:259的序列;
44)所述CDR-H1包含SEQ ID NO:44的序列,所述CDR-H2包含SEQ ID NO:152的序列,并且所述CDR-H3包含SEQ ID NO:260的序列;
45)所述CDR-H1包含SEQ ID NO:45的序列,所述CDR-H2包含SEQ ID NO:153的序列,并且所述CDR-H3包含SEQ ID NO:261的序列;
46)所述CDR-H1包含SEQ ID NO:46的序列,所述CDR-H2包含SEQ ID NO:154的序列,并且所述CDR-H3包含SEQ ID NO:262的序列;
47)所述CDR-H1包含SEQ ID NO:47的序列,所述CDR-H2包含SEQ ID NO:155的序列,并且所述CDR-H3包含SEQ ID NO:263的序列;
48)所述CDR-H1包含SEQ ID NO:48的序列,所述CDR-H2包含SEQ ID NO:156的序列,并且所述CDR-H3包含SEQ ID NO:264的序列;
49)所述CDR-H1包含SEQ ID NO:49的序列,所述CDR-H2包含SEQ ID NO:157的序列,并且所述CDR-H3包含SEQ ID NO:265的序列;
50)所述CDR-H1包含SEQ ID NO:50的序列,所述CDR-H2包含SEQ ID NO:158的序列,并且所述CDR-H3包含SEQ ID NO:266的序列;
51)所述CDR-H1包含SEQ ID NO:51的序列,所述CDR-H2包含SEQ ID NO:159的序列,并且所述CDR-H3包含SEQ ID NO:267的序列;
52)所述CDR-H1包含SEQ ID NO:52的序列,所述CDR-H2包含SEQ ID NO:160的序列,并且所述CDR-H3包含SEQ ID NO:268的序列;
53)所述CDR-H1包含SEQ ID NO:53的序列,所述CDR-H2包含SEQ ID NO:161的序列,并且所述CDR-H3包含SEQ ID NO:269的序列;
54)所述CDR-H1包含SEQ ID NO:54的序列,所述CDR-H2包含SEQ ID NO:162的序列,并且所述CDR-H3包含SEQ ID NO:270的序列;
55)所述CDR-H1包含SEQ ID NO:55的序列,所述CDR-H2包含SEQ ID NO:163的序列,并且所述CDR-H3包含SEQ ID NO:271的序列;
56)所述CDR-H1包含SEQ ID NO:56的序列,所述CDR-H2包含SEQ ID NO:164的序列,并且所述CDR-H3包含SEQ ID NO:272的序列;
57)所述CDR-H1包含SEQ ID NO:57的序列,所述CDR-H2包含SEQ ID NO:165的序列,并且所述CDR-H3包含SEQ ID NO:273的序列;
58)所述CDR-H1包含SEQ ID NO:58的序列,所述CDR-H2包含SEQ ID NO:166的序列,并且所述CDR-H3包含SEQ ID NO:274的序列;
59)所述CDR-H1包含SEQ ID NO:59的序列,所述CDR-H2包含SEQ ID NO:167的序列,并且所述CDR-H3包含SEQ ID NO:275的序列;
60)所述CDR-H1包含SEQ ID NO:60的序列,所述CDR-H2包含SEQ ID NO:168的序列,并且所述CDR-H3包含SEQ ID NO:276的序列;
61)所述CDR-H1包含SEQ ID NO:61的序列,所述CDR-H2包含SEQ ID NO:169的序列,并且所述CDR-H3包含SEQ ID NO:277的序列;
62)所述CDR-H1包含SEQ ID NO:62的序列,所述CDR-H2包含SEQ ID NO:170的序列,并且所述CDR-H3包含SEQ ID NO:278的序列;
63)所述CDR-H1包含SEQ ID NO:63的序列,所述CDR-H2包含SEQ ID NO:171的序列,并且所述CDR-H3包含SEQ ID NO:279的序列;
64)所述CDR-H1包含SEQ ID NO:64的序列,所述CDR-H2包含SEQ ID NO:172的序列,并且所述CDR-H3包含SEQ ID NO:280的序列;
65)所述CDR-H1包含SEQ ID NO:65的序列,所述CDR-H2包含SEQ ID NO:173的序列,并且所述CDR-H3包含SEQ ID NO:281的序列;
66)所述CDR-H1包含SEQ ID NO:66的序列,所述CDR-H2包含SEQ ID NO:174的序列,并且所述CDR-H3包含SEQ ID NO:282的序列;
67)所述CDR-H1包含SEQ ID NO:67的序列,所述CDR-H2包含SEQ ID NO:175的序列,并且所述CDR-H3包含SEQ ID NO:283的序列;
68)所述CDR-H1包含SEQ ID NO:68的序列,所述CDR-H2包含SEQ ID NO:176的序列,并且所述CDR-H3包含SEQ ID NO:284的序列;
69)所述CDR-H1包含SEQ ID NO:69的序列,所述CDR-H2包含SEQ ID NO:177的序列,并且所述CDR-H3包含SEQ ID NO:285的序列;
70)所述CDR-H1包含SEQ ID NO:70的序列,所述CDR-H2包含SEQ ID NO:178的序列,并且所述CDR-H3包含SEQ ID NO:286的序列;
71)所述CDR-H1包含SEQ ID NO:71的序列,所述CDR-H2包含SEQ ID NO:179的序列,并且所述CDR-H3包含SEQ ID NO:287的序列;
72)所述CDR-H1包含SEQ ID NO:72的序列,所述CDR-H2包含SEQ ID NO:180的序列,并且所述CDR-H3包含SEQ ID NO:288的序列;
73)所述CDR-H1包含SEQ ID NO:73的序列,所述CDR-H2包含SEQ ID NO:181的序列,并且所述CDR-H3包含SEQ ID NO:289的序列;
74)所述CDR-H1包含SEQ ID NO:74的序列,所述CDR-H2包含SEQ ID NO:182的序列,并且所述CDR-H3包含SEQ ID NO:290的序列;
75)所述CDR-H1包含SEQ ID NO:75的序列,所述CDR-H2包含SEQ ID NO:183的序列,并且所述CDR-H3包含SEQ ID NO:291的序列;
76)所述CDR-H1包含SEQ ID NO:76的序列,所述CDR-H2包含SEQ ID NO:184的序列,并且所述CDR-H3包含SEQ ID NO:292的序列;
77)所述CDR-H1包含SEQ ID NO:77的序列,所述CDR-H2包含SEQ ID NO:185的序列,并且所述CDR-H3包含SEQ ID NO:293的序列;
78)所述CDR-H1包含SEQ ID NO:78的序列,所述CDR-H2包含SEQ ID NO:186的序列,并且所述CDR-H3包含SEQ ID NO:294的序列;
79)所述CDR-H1包含SEQ ID NO:79的序列,所述CDR-H2包含SEQ ID NO:187的序列,并且所述CDR-H3包含SEQ ID NO:295的序列;
80)所述CDR-H1包含SEQ ID NO:80的序列,所述CDR-H2包含SEQ ID NO:188的序列,并且所述CDR-H3包含SEQ ID NO:296的序列;
81)所述CDR-H1包含SEQ ID NO:81的序列,所述CDR-H2包含SEQ ID NO:189的序列,并且所述CDR-H3包含SEQ ID NO:297的序列;
82)所述CDR-H1包含SEQ ID NO:82的序列,所述CDR-H2包含SEQ ID NO:190的序列,并且所述CDR-H3包含SEQ ID NO:298的序列;
83)所述CDR-H1包含SEQ ID NO:83的序列,所述CDR-H2包含SEQ ID NO:191的序列,并且所述CDR-H3包含SEQ ID NO:299的序列;
84)所述CDR-H1包含SEQ ID NO:84的序列,所述CDR-H2包含SEQ ID NO:192的序列,并且所述CDR-H3包含SEQ ID NO:300的序列;
85)所述CDR-H1包含SEQ ID NO:85的序列,所述CDR-H2包含SEQ ID NO:193的序列,并且所述CDR-H3包含SEQ ID NO:301的序列;
86)所述CDR-H1包含SEQ ID NO:86的序列,所述CDR-H2包含SEQ ID NO:194的序列,并且所述CDR-H3包含SEQ ID NO:302的序列;
87)所述CDR-H1包含SEQ ID NO:87的序列,所述CDR-H2包含SEQ ID NO:195的序列,并且所述CDR-H3包含SEQ ID NO:303的序列;
88)所述CDR-H1包含SEQ ID NO:88的序列,所述CDR-H2包含SEQ ID NO:196的序列,并且所述CDR-H3包含SEQ ID NO:304的序列;
89)所述CDR-H1包含SEQ ID NO:89的序列,所述CDR-H2包含SEQ ID NO:197的序列,并且所述CDR-H3包含SEQ ID NO:305的序列;
90)所述CDR-H1包含SEQ ID NO:90的序列,所述CDR-H2包含SEQ ID NO:198的序列,并且所述CDR-H3包含SEQ ID NO:306的序列;
91)所述CDR-H1包含SEQ ID NO:91的序列,所述CDR-H2包含SEQ ID NO:199的序列,并且所述CDR-H3包含SEQ ID NO:307的序列;
92)所述CDR-H1包含SEQ ID NO:92的序列,所述CDR-H2包含SEQ ID NO:200的序列,并且所述CDR-H3包含SEQ ID NO:308的序列;
93)所述CDR-H1包含SEQ ID NO:93的序列,所述CDR-H2包含SEQ ID NO:201的序列,并且所述CDR-H3包含SEQ ID NO:309的序列;
94)所述CDR-H1包含SEQ ID NO:94的序列,所述CDR-H2包含SEQ ID NO:202的序列,并且所述CDR-H3包含SEQ ID NO:310的序列;
95)所述CDR-H1包含SEQ ID NO:95的序列,所述CDR-H2包含SEQ ID NO:203的序列,并且所述CDR-H3包含SEQ ID NO:311的序列;
96)所述CDR-H1包含SEQ ID NO:96的序列,所述CDR-H2包含SEQ ID NO:204的序列,并且所述CDR-H3包含SEQ ID NO:312的序列;
97)所述CDR-H1包含SEQ ID NO:97的序列,所述CDR-H2包含SEQ ID NO:205的序列,并且所述CDR-H3包含SEQ ID NO:313的序列;
98)所述CDR-H1包含SEQ ID NO:98的序列,所述CDR-H2包含SEQ ID NO:206的序列,并且所述CDR-H3包含SEQ ID NO:314的序列;
99)所述CDR-H1包含SEQ ID NO:99的序列,所述CDR-H2包含SEQ ID NO:207的序列,并且所述CDR-H3包含SEQ ID NO:315的序列;
100)所述CDR-H1包含SEQ ID NO:100的序列,所述CDR-H2包含SEQ ID NO:208的序列,并且所述CDR-H3包含SEQ ID NO:316的序列;
101)所述CDR-H1包含SEQ ID NO:101的序列,所述CDR-H2包含SEQ ID NO:209的序列,并且所述CDR-H3包含SEQ ID NO:317的序列;
102)所述CDR-H1包含SEQ ID NO:102的序列,所述CDR-H2包含SEQ ID NO:210的序列,并且所述CDR-H3包含SEQ ID NO:318的序列;
103)所述CDR-H1包含SEQ ID NO:103的序列,所述CDR-H2包含SEQ ID NO:211的序列,并且所述CDR-H3包含SEQ ID NO:319的序列;
104)所述CDR-H1包含SEQ ID NO:104的序列,所述CDR-H2包含SEQ ID NO:212的序列,并且所述CDR-H3包含SEQ ID NO:320的序列;
105)所述CDR-H1包含SEQ ID NO:105的序列,所述CDR-H2包含SEQ ID NO:213的序列,并且所述CDR-H3包含SEQ ID NO:321的序列;
106)所述CDR-H1包含SEQ ID NO:106的序列,所述CDR-H2包含SEQ ID NO:214的序列,并且所述CDR-H3包含SEQ ID NO:322的序列;
107)所述CDR-H1包含SEQ ID NO:107的序列,所述CDR-H2包含SEQ ID NO:215的序列,并且所述CDR-H3包含SEQ ID NO:323的序列;或者
108)所述CDR-H1包含SEQ ID NO:108的序列,所述CDR-H2包含SEQ ID NO:216的序列,并且所述CDR-H3包含SEQ ID NO:324的序列。
3.如权利要求1或2所述的FAP结合多肽,其中所述重链可变结构域包含与选自SEQ IDNO:325-432的任何序列具有至少90%、95%、99%或100%序列同一性的氨基酸序列。
4.如权利要求1-3中任一项所述的FAP结合多肽,其中所述FAP结合多肽是人源化的。
5.如权利要求1-4中任一项所述的FAP结合多肽,其中所述FAP结合多肽是单域抗体(sdAb)。
6.FAP结合多肽,其包含含有CDR-H1的免疫球蛋白重链可变结构域,其中所述CDR-H1包含与选自SEQ ID NO:1-108的序列具有至少90%、95%、99%或100%序列同一性的序列。
7.如权利要求6所述的FAP结合多肽,其中所述CDR-H1包含与选自SEQ ID NO:4的序列具有至少90%、95%、99%或100%序列同一性的序列。
8.如权利要求6或7所述的FAP结合多肽,其中所述免疫球蛋白重链可变结构域还包含CDR-H2,其中所述CDR-H2包含与选自SEQ ID NO:109-216的序列具有至少90%、95%、99%或100%序列同一性的序列。
9.如权利要求6-8中任一项所述的FAP结合多肽,其中所述免疫球蛋白重链可变结构域还包含CDR-H3,其中所述CDR-H3包含与选自SEQ ID NO:217-324的序列具有至少90%、95%、99%或100%序列同一性的序列。
10.如权利要求6-9中任一项所述的FAP结合多肽,其中所述免疫球蛋白重链可变结构域包含与选自SEQ ID NO:325-432的任何序列具有至少90%、95%、99%或100%序列同一性的氨基酸序列。
11.FAP结合多肽,其包含含有CDR-H2的免疫球蛋白重链可变结构域,其中所述CDR-H2包含与选自SEQ ID NO:109-216的序列具有至少90%、95%、99%或100%序列同一性的序列。
12.如权利要求11所述的FAP结合多肽,其中所述CDR-H2包含与选自SEQ ID NO:110的序列具有至少90%、95%、99%或100%序列同一性的序列。
13.如权利要求11或12所述的FAP结合多肽,其中所述免疫球蛋白重链可变结构域还包含CDR-H1,其中所述CDR-H1包含与选自SEQ ID NO:1-108的序列具有至少90%、95%、99%或100%序列同一性的序列。
14.如权利要求11-13中任一项所述的FAP结合多肽,其中所述免疫球蛋白重链可变结构域还包含CDR-H3,其中所述CDR-H3包含与选自SEQ ID NO:217-324的序列具有至少90%、95%、99%或100%序列同一性的序列。
15.如权利要求11-14中任一项所述的FAP结合多肽,其中所述免疫球蛋白重链可变结构域包含与选自SEQ ID NO:325-432的任何序列具有至少90%、95%、99%或100%序列同一性的氨基酸序列。
16.嵌合抗原受体(CAR),其包含权利要求1-15中任一项所述的FAP结合多肽。
17.嵌合抗原受体(CAR)细胞,其包含权利要求16所述的CAR。
18.如权利要求17所述的CAR细胞,其中所述CAR细胞是CAR T细胞。
19.如权利要求17或18所述的CAR细胞,其中所述CAR细胞包含至少两种结合多肽,并且所述CAR细胞是多价CAR细胞。
20.如权利要求17-19中任一项所述的CAR细胞,其中所述CAR细胞来源于对象或细胞系。
21.如权利要求20所述的CAR细胞,其中所述对象患有癌症。
22.如权利要求21所述的CAR细胞,其中所述癌症是乳腺癌、结直肠癌、肾癌、肝癌、肺癌、脑癌、胰腺癌、膀胱癌、睾丸癌、前列腺癌、胃癌、卵巢癌、头颈癌、胆囊癌、血液恶性肿瘤或以上的任意组合。
23.编码多肽的核酸,所述多肽包含与权利要求1-15中任一项所述的FAP结合多肽或权利要求16所述的CAR具有至少90%、95%、99%或100%序列同一性的序列。
24.治疗有需要的对象中的癌症的方法,其包括施用权利要求17-22中任一项所述的CAR细胞。
25.如权利要求24所述的方法,其中所述嵌合抗原受体细胞是所述对象自体的或同种异体的。
26.如权利要求24或25所述的方法,其中所述对象是哺乳动物。
27.如权利要求24-26中任一项所述的方法,其中所述对象是人。
28.如权利要求24-27中任一项所述的方法,其中所述癌症是乳腺癌、结直肠癌、肾癌、肝癌、肺癌、脑癌、胰腺癌、膀胱癌、睾丸癌、前列腺癌、胃癌、卵巢癌、头颈癌、胆囊癌、血液恶性肿瘤或以上的任意组合。
29.如权利要求24-28中任一项所述的方法,其中所述嵌合抗原受体细胞经肠胃外施用。
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