TW202219068A - 包含il—12及抗fap抗體的融合蛋白及其用途 - Google Patents
包含il—12及抗fap抗體的融合蛋白及其用途 Download PDFInfo
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Abstract
本發明提供一種雙特異性抗體,其包含IL-12或其變體及特異性結合於FAP之抗原結合位點。該雙特異性抗體藉由IL-12展現抗癌效應。特定言之,當以一種抗體實施抗FAP抗體時,可藉由特異性靶向腫瘤中高度表現之FAP且將IL-12特異性定位至腫瘤部位來有效治療癌症。因此,該雙特異性抗體可用作用於抗癌治療之醫藥組成物,且因此具有較高的工業應用潛力。
Description
發明領域
本發明係關於一種新穎融合蛋白,其包含IL-12或其變體;及抗FAP抗體,以及一種包含該融合蛋白之抗癌醫藥組成物。
發明背景
介白素-12 (IL-12)為一種有代表性的發炎性細胞介素,且在有效地誘導細胞免疫反應中起重要作用。IL-12為一種異二聚蛋白質,包含藉由雙硫鍵連接的40 kDa (p40)及35 kDa (p35)次單元,且藉由活化巨噬細胞、單核球、樹突狀細胞及活化B淋巴球產生。IL-12可增強1型T輔助細胞免疫,增加細胞T淋巴球之細胞毒性且抑制血管生成。一般而言,IL-12活化T細胞及NK細胞中之IFN-γ的產生。
IL-12之局部表現使得腫瘤細胞對T細胞介導之細胞毒性敏感,從而引起腫瘤生長抑制及建立體液免疫。然而,IL-12之臨床應用中之缺點為在投予後,可能全身性地出現細胞介素相關毒性。此等臨床結果展示出IL-12作為單一治療劑用於治療癌症之侷限性。
另一方面,纖維母細胞活化蛋白α (FAP)為一種在活化纖維母細胞上表現之明膠酶。已知FAP在包括前列腺癌及胰臟癌之各種人類癌瘤的癌症相關纖維母細胞中表現超過90%。因此,近來,對研發靶向表現FAP之細胞之免疫療法的關注快速增加(Fang J.等人,
Mol. Ther. Oncolytics., 3:16007, 2016)。
發明概要
技術問題
因此,本發明人已研究研發一種具有抗癌效應之新穎融合蛋白。因而,本發明人已發現,包含IL-12及抗FAP抗體之融合蛋白具有增加之抗癌活性,同時降低全身性毒性,藉此完成本發明。
問題之解決方案
在本發明之一個態樣中,提供一種融合蛋白,其包含:包含IL-12或其變體之第一單體;及包含特異性結合於FAP之抗原結合位點之第二單體。
在本發明之另一態樣中,提供一種用於預防或治療癌症之醫藥組成物,其包含融合蛋白作為活性成分。
在本發明之另一態樣中,提供一種編碼該第一單體之多核苷酸。
在本發明之另一態樣中,提供一種編碼該第二單體之多核苷酸。
在本發明之另一態樣中,提供一種包含多核苷酸之載體。
在本發明之另一態樣中,提供一種已引入載體之轉型細胞。
在本發明之另一態樣中,提供一種產生融合蛋白之方法,其包含i)培養轉型細胞;及ii)回收包含第一單體及第二單體之融合蛋白。
在本發明之又一態樣中,提供一種用於治療或預防癌症之方法,其包含向個體投予融合蛋白,該融合蛋白包含第一單體及第二單體,該第一單體包含IL-12或其變體,且該第二單體包含特異性結合於FAP之抗原結合位點。
在本發明之又一態樣中,提供一種融合蛋白用於治療癌症之用途,該融合蛋白包含第一單體及第二單體,該第一單體包含IL-12或其變體,且該第二單體包含特異性結合於FAP之抗原結合位點。
在本發明之又一態樣中,提供一種融合蛋白用於製造供治療癌症用之藥劑之用途,該融合蛋白包含第一單體及第二單體,該第一單體包含IL-12或其變體,且該第二單體包含特異性結合於FAP之抗原結合位點。
本發明之效應
包含IL-12及特異性結合於FAP之抗原結合位點的融合蛋白可藉由IL-12展現抗癌效應。另外,發現當抗FAP抗體以一種抗體實施時,IL-12特異地積聚於具有高FAP表現之腫瘤中,由此降低全身性毒性且展現腫瘤特異性抗癌效應。亦即,可藉由特異性靶向腫瘤中高度表現之FAP且將IL-12特異性定位至腫瘤部位來有效治療癌症。
較佳實施例之詳細說明
包含IL-12 及抗FAP 抗體之融合蛋白
在本發明之一個態樣中,提供一種融合蛋白,其包含IL-12或其變體及特異性結合於FAP (纖維母細胞活化蛋白α)之抗原結合位點。特定言之,融合蛋白可包含免疫球蛋白Fc區。接著,IL-12或其變體可為具有低肝素結合能力之變體。
在一個實施例中,提供一種融合蛋白,其包含:包含IL-12或其變體之第一單體;及包含特異性結合於FAP之抗原結合位點之第二單體。
在另一實施例中,提供一種融合蛋白二聚體,其包含IL-12或其變體及特異性結合於FAP之抗原結合位點。
IL-12 或其變體
如本文所用,術語「IL-12」為由分別由二個獨立基因IL-12A及IL-12B編碼之p35及p40次單元構成之異二聚細胞介素。IL-12由諸如巨噬細胞之抗原呈現細胞產生且結合於活化T細胞及NK細胞之細胞表面上的受體。IL-12促進T細胞及NK細胞之增殖,且增強T細胞、NK細胞及巨噬細胞之細胞毒性效應。另外,IL-12誘導IFN-γ、TNF-α及GM-CSF之產生,且用以誘導Th1細胞之活化。另一方面,IL-12結合於IL-12受體,亦即由IL-12Rβ1及IL-12Rβ2形成之異二聚受體。
如本文所用,IL-12之術語「變體」包括具有與野生型IL-12蛋白質類似或與其一致之功能的胺基酸序列。特定言之,構成IL-12之p35及p40次單元之胺基酸序列與野生型相比可具有取代、插入或缺失。
IL-12或其變體可包括IL-12A (p35)或其變體,及IL-12B (p40)或其變體。
另外,IL-12或其變體可包括其中IL-12A或其變體以及IL-12B或其變體藉由肽連接子結合之結構。
在一個實施例中,IL-12或其變體可為包含以下結構式(I)或(II)的融合蛋白:
N'-Y-[連接子(1)]o-Z-C' (I)
N'-Z-[連接子(1)]o-Y-C' (II)
在該結構式(I)及該結構式(II)中,
N'可為融合蛋白之N端,
C'可為融合蛋白之C端,
Y可為IL-12A或其變體,
Z可為IL-12B或其變體,
連接子(1)可為肽連接子,及
o可為0或1。
IL-12或其變體之一個實施例可為其中IL-12B或其變體、肽連接子及IL-12A或其變體自N端依序結合的結構。另外,IL-12或其變體之一個實施例可為其中IL-12A或其變體、肽連接子及IL-12B或其變體自N端依序結合的結構。
如本文所用,術語「IL-12A」為IL-12之35 kDa次單元(p35),其經由雙硫鍵結合於IL-12之40 kDa次單元(p40)以產生活性細胞介素。
IL-12A之胺基酸序列可為以GenBank寄存編號AAK84425描述之胺基酸序列(關於小鼠p35之胺基酸序列,參見GenBank寄存編號AAA39292)。另外,IL-12A (p35)基因為編碼IL-12A次單元之序列,且可為對應於以GenBank寄存編號AF404773描述之序列當中之編碼序列(CDS)的核苷酸序列(關於小鼠序列,參見GenBank寄存編號M86672)。
如本文所用,術語IL-12A之「變體」包括具有與野生型IL-12A蛋白質類似或與其一致之功能的胺基酸序列。特定言之,其意謂IL-12A之胺基酸序列與野生型相比具有取代、插入或缺失。特定言之,IL-12A變體可為IL-12A之片段,且可具有其中缺失SEQ ID NO: 122之第1至第22個胺基酸之胺基酸序列。更特定言之,IL-12A之變體可具有SEQ ID NO: 75之胺基酸序列。
另外,本發明之一個實施例中所用的IL-12A可為SEQ ID NO: 75之胺基酸序列作為人類IL-12A。在一個實施例中,小鼠IL-12A可為SEQ ID NO: 87之胺基酸序列。
如本文所用,術語「IL-12B」係指IL-12之40 kDa次單元(p40),其經由雙硫鍵結合於IL-12之35 kDa次單元(p35)以形成IL-12,且亦結合於IL-23之次單元p19以形成IL-23。另一方面,IL-12B亦稱為自然殺手細胞刺激因子2。
「IL-12B」之胺基酸序列可為以GenBank寄存編號AAD56386描述之胺基酸序列(關於小鼠p40之胺基酸序列,參見GenBank寄存編號AAA39296)。另外,IL-12B (p40)基因為編碼IL-12B次單元之序列,且可為對應於以GenBank寄存編號AF180563描述之序列當中之編碼序列(CDS)的核苷酸序列(關於小鼠序列,參見GenBank寄存編號M86671)。
另外,本發明之一個實施例中所用的IL-12B可為人類IL-12B,且特定言之,IL-12B可為SEQ ID NO: 74之胺基酸序列。在一個實施例中,小鼠IL-12B可具有SEQ ID NO: 86之胺基酸序列。
如本文所用,術語IL-12B之「變體」包括具有與野生型IL-12B蛋白質類似或與其一致之功能的胺基酸序列。特定言之,其意謂IL-12B之胺基酸序列與野生型相比具有取代、插入或缺失。
特定言之,IL-12B變體可為其中缺失SEQ ID NO: 121之第1至第22個胺基酸的變體。更特定言之,IL-12B變體可為其中SEQ ID NO: 74之序列中1至8個胺基酸經取代之變體。另外,IL-12B變體可為其中缺失SEQ ID NO: 123之第1至第22個胺基酸的變體。更特定言之,IL-12B變體可為其中SEQ ID NO: 86之序列中至多1至8個胺基酸經取代之變體。
IL-12B (p40)之變體可為其中涉及IL-12之肝素結合的胺基酸經取代的變體。
在一個實施例中,IL-12B (p40)之變體可為其中IL-12B中結合於肝素之離胺酸(K)經另一胺基酸取代的形式。特定言之,其可為其中SEQ ID NO: 74之第258、第260、第263及第264離胺酸經其他胺基酸取代的形式。特定言之,IL-12B (p40)之變體可包括在SEQ ID NO: 74之胺基酸序列中藉由至少一個選自由K258A、K260A、K263A及K264A組成之群之取代獲得的胺基酸序列。特定言之,IL-12B (p40)之變體可包括在SEQ ID NO: 74之胺基酸序列中藉由K258A及K263A之取代獲得的胺基酸序列,或可進一步包括SEQ ID NO: 74之胺基酸序列中的K260A及/或K264A之突變。
在一個實施例中,IL-12B (p40)之變體可為其中IL-12B中結合於肝素之精胺酸(R)或離胺酸(K)經另一胺基酸取代的形式。特定言之,其可為其中SEQ ID NO: 86之第254精胺酸及/或第255、第256及第260離胺酸經其他胺基酸取代的形式。特定言之,IL-12B (p40)之變體可包括在SEQ ID NO: 86之胺基酸序列中藉由至少一個選自由R254A、K255A、K256A及K260A組成之群之取代獲得的胺基酸序列。特定言之,IL-12B (p40)之變體可包括在SEQ ID NO: 86之胺基酸序列中藉由R254A及K260A之取代獲得的胺基酸序列,或可進一步包括SEQ ID NO: 86之序列中的K255A及/或K256A之突變。
在一個實施例中,IL-12B (p40)之變體可包括SEQ ID NO: 77、SEQ ID NO: 79、SEQ ID NO: 89或SEQ ID NO: 91之胺基酸序列。
在一個實施例中,人類IL-12B變體可由以下結構式A組成:
[結構式A]
X
1-L-X
2其中,X
1為SEQ ID NO: 125之胺基酸序列,
X
2為SEQ ID NO: 126之胺基酸序列,且
L為由V-A
1-A
2-Q-A
3-K
*-A
4-A
5-A
6-A
7-K
*-A
8組成之胺基酸序列。
A
1為R或Q,A
2為V、A或I,A
3為G或R
*,A
4為S、N或K
*,A
5為K
*、N或E,A
6為R或K,A
7為E、M或T,且A
8為K
*或E。
至少一個標記為「*」之胺基酸殘基可經選自由以下組成之群的非極性胺基酸殘基取代:A、G、I、L、M、F、P及V,但不限於此。
在一個實施例中,IL-12B (p40)之變體可包括涉及肝素結合之胺基酸的取代以降低IL-12之細胞介素相關毒性,同時維持對癌細胞之殺死效應。
FAP 及特異性結合於 FAP 之抗原結合位點
如本文所用,術語「FAP(纖維母細胞活化蛋白)」係指纖維母細胞活化蛋白,其為表現於細胞表面上且呈現於各種腫瘤類型之腫瘤細胞的環境中或各種腫瘤類型之腫瘤細胞中的蛋白質。已知FAP在腫瘤微環境中選擇性過度表現於癌症相關纖維母細胞(CAF)之表面上。
另外,FAP為均二聚體,其含有二個具有C端胞外區域的N糖基化次單元,其中酶催化區域位於該C端胞外區域,且FAP之糖基化形式具有後脯胺醯基二肽基肽酶及明膠酶活性。
另一方面,FAP為脯胺醯基內肽酶,其為約170 kDa膜結合明膠酶。脯胺醯基內肽酶FAP可識別及裂解特定胺基酸序列。因此,FAP亦稱為FAPα、分離酶或循環抗血織維蛋白溶酶-裂解酶(circulating antiplasmin-cleaving enzyme)。
FAP之胺基酸序列可為以GenBank寄存編號AAC51668描述之胺基酸序列,且首先經由使用單株抗體(mAb) F19在經培養之纖維母細胞中鑑別人類FAP(參見國際專利申請公開案第WO 93/05804號)。FAP表現於許多癌症中且由於其在正常組織中之有限表現而用作有前景的抗原目標以用於成像、診斷及治療各種癌瘤。
FAP包括人類FAP之任何變體、同功異型物及物種同系物,其藉由細胞天然表現或天然表現於經FAP基因轉染之細胞上。本發明之抗體可結合於存在於癌細胞(腫瘤細胞或腫瘤基質之細胞)之膜或細胞表面上的FAP,且可引起ADCC或其他效應子介導之癌細胞殺滅。此外,其可用於阻斷FAP之酶活性(例如絲胺酸肽酶、明膠酶、膠原蛋白酶活性)、FAP介導之ECM降解及FAP介導之細胞侵襲或遷移。
如本文所用,術語「特異性結合」係指可量測地不同於非特異性相互作用之結合。特異性結合可藉由與類似於不具有結合活性之目標的對照分子競爭來確定。
如本文所用,術語「抗原結合位點(抗原決定基)」係指與抗體可變區中之特異性抗原結合位點相互作用的決定子。抗原結合位點為一組分子,諸如胺基酸或糖側鏈,其通常具有特定結構特徵以及荷質比特徵。特異性結合於FAP之抗原結合位點可為能夠使抗原-抗體特異性結合於FAP之分子的通用術語。
另外,抗體或其片段可以任何形式使用,只要其含有能夠特異性結合於FAP之抗原結合區域即可。
抗原結合位點可包括不直接涉及結合之其他胺基酸,或效應經抗原結合位點之胺基酸殘基阻斷的胺基酸。
特定言之,抗原結合位點可為特異性結合於FAP之抗體或其片段。
如本文所用,術語「抗體」係指含有抗原結合位點之分子,及含有抗原結合位點之免疫球蛋白分子之免疫活性片段。免疫球蛋白分子可為IgG、IgE、IgM、IgD、IgA、IgY之免疫球蛋白分子或其子類。抗體包括合成抗體、單株抗體、單區域抗體、單鏈抗體、以重組方式產生之抗體、多特異性抗體(包括雙特異性抗體)、人類抗體、人類化抗體、嵌合抗體、胞內抗體、scFv(包括例如單特異性及雙特異性scFv等)、Fab片段、F(ab')片段、雙硫鍵連接的Fv (sdFv)、抗個體基因型(抗Id)抗體及該抗體之抗原結合片段,但不限於此。
如本文所用,術語「抗體片段」可為抗體之一部分,諸如F(ab')
2、F(ab)
2、Fab'、Fab、Fv、scFv。不管結構如何,抗體片段結合於完整抗體所識別之相同抗原。
在一個實施例中,特異性結合於FAP之抗原結合位點可包含:重鏈可變區,其包含SEQ ID NO: 96之HCDR1、SEQ ID NO: 97之HCDR2及SEQ ID NO: 98之HCDR3;及輕鏈可變區,其包含SEQ ID NO: 99之LCDR1、SEQ ID NO: 100之LCDR2及SEQ ID NO: 101之LCDR3。接著,在一個實施例中,特異性結合於FAP之抗原結合位點可具有SEQ ID NO: 102之重鏈可變區及SEQ ID NO: 103之輕鏈可變區。
另外,在一個實施例中,特異性結合於FAP之抗原結合位點可包含:重鏈可變區,其包含SEQ ID NO: 104之HCDR1、SEQ ID NO: 105之HCDR2及SEQ ID NO: 106之HCDR3;及輕鏈可變區,其包含SEQ ID NO: 107之LCDR1、SEQ ID NO: 108之LCDR2及SEQ ID NO: 109之LCDR3。接著,在一個實施例中,特異性結合於FAP之抗原結合位點可具有SEQ ID NO: 110之重鏈可變區及SEQ ID NO: 111之輕鏈可變區。
在一個實施例中,特異性結合於FAP之抗原結合位點可為scFv。接著,scFv可包含上述重鏈及輕鏈CDR。在一個實施例中,特異性結合於FAP之scFv可具有SEQ ID NO: 72或SEQ ID NO: 84之胺基酸序列。
另外,特異性結合於FAP之抗原結合位點可包括已知抗FAP抗體或其片段。抗FAP抗體或其片段可非限制性地指熟習此項技術者已知之抗體。
抗FAP抗體或其片段可包括至少一個選自由以下組成之群的可變區:NG-641、AMG-506/MP-0310、RG-7827之28H1、RG-7827之4B9、OMTX-705、3F2、4G8、3D9、4B3、19G1、20G8、5B8、5F1、14B3、16F1、16F8、O3C9、29B11、O2D7及23C10。
在另一實例中,作為抗體,可使用韓國專利申請公開案第KR 20200037826 A號、美國專利申請公開案第US 2020-0385488 A1號、美國專利案第US 3,924,445 B2號、美國專利案第US 9,011,847 B2號或美國專利申請公開案第US 2017-007716 A1號中所揭露之抗FAP抗體或其片段。
在一個實施例中,抗FAP抗體可包含NG-641之可變區。特定言之,該抗體可包含:重鏈可變區,其包含SEQ ID NO: 127之HCDR1、SEQ ID NO: 128之HCDR2及SEQ ID NO: 129之HCDR3;及輕鏈可變區,其包含SEQ ID NO: 130之LCDR1、SEQ ID NO: 131之LCDR2及SEQ ID NO: 132之LCDR3。另外,抗FAP抗體可包含SEQ ID NO: 248之重鏈可變區及SEQ ID NO: 249之輕鏈可變區。
在一個實施例中,抗FAP抗體可包含28H1之可變區。特定言之,該抗體可包含:重鏈可變區,其包含SEQ ID NO: 133之HCDR1、SEQ ID NO: 134之HCDR2及SEQ ID NO: 135之HCDR3;及輕鏈可變區,其包含SEQ ID NO: 136之LCDR1、SEQ ID NO: 137之LCDR2及SEQ ID NO: 138之LCDR3。另外,抗FAP抗體可包含SEQ ID NO: 250之重鏈可變區及SEQ ID NO: 251之輕鏈可變區。
在一個實施例中,抗FAP抗體可包含4B9之可變區。特定言之,該抗體可包含:重鏈可變區,其包含SEQ ID NO: 139之HCDR1、SEQ ID NO: 140之HCDR2及SEQ ID NO: 141之HCDR3;及輕鏈可變區,其包含SEQ ID NO: 142之LCDR1、SEQ ID NO: 143之LCDR2及SEQ ID NO: 144之LCDR3。另外,抗FAP抗體可包含SEQ ID NO: 252之重鏈可變區及SEQ ID NO: 253之輕鏈可變區。
在一個實施例中,抗FAP抗體可包含OMTX-705之可變區。特定言之,該抗體可包含:重鏈可變區,其包含SEQ ID NO: 145之HCDR1、SEQ ID NO: 146之HCDR2及SEQ ID NO: 147之HCDR3;及輕鏈可變區,其包含SEQ ID NO: 148之LCDR1、SEQ ID NO: 149之LCDR2及SEQ ID NO: 150之LCDR3。另外,抗FAP抗體可包含SEQ ID NO: 254之重鏈可變區及SEQ ID NO: 255之輕鏈可變區。
在一個實施例中,抗FAP抗體可包含3F2之可變區。特定言之,該抗體可包含:重鏈可變區,其包含SEQ ID NO: 151之HCDR1、SEQ ID NO: 152之HCDR2及SEQ ID NO: 153之HCDR3;及輕鏈可變區,其包含SEQ ID NO: 154之LCDR1、SEQ ID NO: 155之LCDR2及SEQ ID NO: 156之LCDR3。另外,抗FAP抗體可包含SEQ ID NO: 256之重鏈可變區及SEQ ID NO: 257之輕鏈可變區。
在一個實施例中,抗FAP抗體可包含4G8之可變區。特定言之,該抗體可包含:重鏈可變區,其包含SEQ ID NO: 157之HCDR1、SEQ ID NO: 158之HCDR2及SEQ ID NO: 159之HCDR3;及輕鏈可變區,其包含SEQ ID NO: 160之LCDR1、SEQ ID NO: 161之LCDR2及SEQ ID NO: 162之LCDR3。另外,抗FAP抗體可包含SEQ ID NO: 258之重鏈可變區及SEQ ID NO: 259之輕鏈可變區。
在一個實施例中,抗FAP抗體可包含3D9之可變區。特定言之,該抗體可包含:重鏈可變區,其包含SEQ ID NO: 163之HCDR1、SEQ ID NO: 164之HCDR2及SEQ ID NO: 165之HCDR3;及輕鏈可變區,其包含SEQ ID NO: 166之LCDR1、SEQ ID NO: 167之LCDR2及SEQ ID NO: 168之LCDR3。另外,抗FAP抗體可包含SEQ ID NO: 260之重鏈可變區及SEQ ID NO: 261之輕鏈可變區。
在一個實施例中,抗FAP抗體可包含4B3之可變區。特定言之,該抗體可包含:重鏈可變區,其包含SEQ ID NO: 169之HCDR1、SEQ ID NO: 170之HCDR2及SEQ ID NO: 171之HCDR3;及輕鏈可變區,其包含SEQ ID NO: 172之LCDR1、SEQ ID NO: 173之LCDR2及SEQ ID NO: 174之LCDR3。另外,抗FAP抗體可包含SEQ ID NO: 262之重鏈可變區及SEQ ID NO: 263之輕鏈可變區。
在一個實施例中,抗FAP抗體可包含19G1之可變區。特定言之,該抗體可包含:重鏈可變區,其包含SEQ ID NO: 175之HCDR1、SEQ ID NO: 176之HCDR2及SEQ ID NO: 177之HCDR3;及輕鏈可變區,其包含SEQ ID NO: 178之LCDR1、SEQ ID NO: 179之LCDR2及SEQ ID NO: 180之LCDR3。另外,抗FAP抗體可包含SEQ ID NO: 264之重鏈可變區及SEQ ID NO: 265之輕鏈可變區。
在一個實施例中,抗FAP抗體可包含20G8之可變區。特定言之,該抗體可包含:重鏈可變區,其包含SEQ ID NO: 181之HCDR1、SEQ ID NO: 182之HCDR2及SEQ ID NO: 183之HCDR3;及輕鏈可變區,其包含SEQ ID NO: 184之LCDR1、SEQ ID NO: 185之LCDR2及SEQ ID NO: 186之LCDR3。另外,抗FAP抗體可包含SEQ ID NO: 266之重鏈可變區及SEQ ID NO: 267之輕鏈可變區。
在一個實施例中,抗FAP抗體可包含5B8之可變區。特定言之,該抗體可包含:重鏈可變區,其包含SEQ ID NO: 187之HCDR1、SEQ ID NO: 188之HCDR2及SEQ ID NO: 189之HCDR3;及輕鏈可變區,其包含SEQ ID NO: 190之LCDR1、SEQ ID NO: 191之LCDR2及SEQ ID NO: 192之LCDR3。另外,抗FAP抗體可包含SEQ ID NO: 268之重鏈可變區及SEQ ID NO: 269之輕鏈可變區。
在一個實施例中,抗FAP抗體可包含5F1之可變區。特定言之,該抗體可包含:重鏈可變區,其包含SEQ ID NO: 193之HCDR1、SEQ ID NO: 194之HCDR2及SEQ ID NO: 195之HCDR3;及輕鏈可變區,其包含SEQ ID NO: 196之LCDR1、SEQ ID NO: 197之LCDR2及SEQ ID NO: 198之LCDR3。另外,抗FAP抗體可包含SEQ ID NO: 270之重鏈可變區及SEQ ID NO: 271之輕鏈可變區。
在一個實施例中,抗FAP抗體可包含14B3之可變區。特定言之,該抗體可包含:重鏈可變區,其包含SEQ ID NO: 199之HCDR1、SEQ ID NO: 200之HCDR2及SEQ ID NO: 201之HCDR3;及輕鏈可變區,其包含SEQ ID NO: 202之LCDR1、SEQ ID NO: 203之LCDR2及SEQ ID NO: 204之LCDR3。另外,抗FAP抗體可包含SEQ ID NO: 272之重鏈可變區及SEQ ID NO: 273之輕鏈可變區。
在一個實施例中,抗FAP抗體可包含16F1之可變區。特定言之,該抗體可包含:重鏈可變區,其包含SEQ ID NO: 205之HCDR1、SEQ ID NO: 206之HCDR2及SEQ ID NO: 207之HCDR3;及輕鏈可變區,其包含SEQ ID NO: 208之LCDR1、SEQ ID NO: 209之LCDR2及SEQ ID NO: 210之LCDR3。另外,抗FAP抗體可包含SEQ ID NO: 274之重鏈可變區及SEQ ID NO: 275之輕鏈可變區。
在一個實施例中,抗FAP抗體可包含16F8之可變區。特定言之,該抗體可包含:重鏈可變區,其包含SEQ ID NO: 211之HCDR1、SEQ ID NO: 212之HCDR2及SEQ ID NO: 213之HCDR3;及輕鏈可變區,其包含SEQ ID NO: 214之LCDR1、SEQ ID NO: 215之LCDR2及SEQ ID NO: 216之LCDR3。另外,抗FAP抗體可包含SEQ ID NO: 276之重鏈可變區及SEQ ID NO: 277之輕鏈可變區。
在一個實施例中,抗FAP抗體可包含O3C9之可變區。特定言之,該抗體可包含:重鏈可變區,其包含SEQ ID NO: 217之HCDR1、SEQ ID NO: 218之HCDR2及SEQ ID NO: 219之HCDR3;及輕鏈可變區,其包含SEQ ID NO: 220之LCDR1、SEQ ID NO: 221之LCDR2及SEQ ID NO: 222之LCDR3。另外,抗FAP抗體可包含SEQ ID NO: 278之重鏈可變區及SEQ ID NO: 279之輕鏈可變區。
在一個實施例中,抗FAP抗體可包含22A3之可變區。特定言之,該抗體可包含:重鏈可變區,其包含SEQ ID NO: 223之HCDR1、SEQ ID NO: 224之HCDR2及SEQ ID NO: 225之HCDR3;及輕鏈可變區,其包含SEQ ID NO: 226之LCDR1、SEQ ID NO: 227之LCDR2及SEQ ID NO: 228之LCDR3。另外,抗FAP抗體可包含SEQ ID NO: 280之重鏈可變區及SEQ ID NO: 281之輕鏈可變區。
在一個實施例中,抗FAP抗體可包含29B11之可變區。特定言之,該抗體可包含:重鏈可變區,其包含SEQ ID NO: 229之HCDR1、SEQ ID NO: 230之HCDR2及SEQ ID NO: 231之HCDR3;及輕鏈可變區,其包含SEQ ID NO: 232之LCDR1、SEQ ID NO: 233之LCDR2及SEQ ID NO: 234之LCDR3。另外,抗FAP抗體可包含SEQ ID NO: 282之重鏈可變區及SEQ ID NO: 283之輕鏈可變區。
在一個實施例中,抗FAP抗體可包含O2D7之可變區。特定言之,該抗體可包含:重鏈可變區,其包含SEQ ID NO: 235之HCDR1、SEQ ID NO: 236之HCDR2及SEQ ID NO: 237之HCDR3;及輕鏈可變區,其包含SEQ ID NO: 238之LCDR1、SEQ ID NO: 239之LCDR2及SEQ ID NO: 240之LCDR3。另外,抗FAP抗體可包含SEQ ID NO: 284之重鏈可變區及SEQ ID NO: 285之輕鏈可變區。
在一個實施例中,抗FAP抗體可包含23C10之可變區。特定言之,該抗體可包含:重鏈可變區,其包含SEQ ID NO: 241之HCDR1、SEQ ID NO: 242之HCDR2及SEQ ID NO: 243之HCDR3;及輕鏈可變區,其包含SEQ ID NO: 244之LCDR1、SEQ ID NO: 245之LCDR2及SEQ ID NO: 246之LCDR3。另外,抗FAP抗體可包含SEQ ID NO: 286之重鏈可變區及SEQ ID NO: 287之輕鏈可變區。
在一個實施例中,抗FAP抗體可為AMG-506/MP-0310。特定言之,該抗體可包括SEQ ID NO: 247之胺基酸序列。
抗FAP抗體特異性結合於癌細胞上所存在之FAP,且可使用任何抗體,只要其可誘導癌細胞死亡即可。
第一單體之結構
第一單體包含IL-12或其變體。
第一單體可進一步包含特異性結合於FAP之抗原結合位點。
在一個實施例中,第一單體可包含IL-12或其變體;以及Fc區片段或其變體。
在一個實施例中,第一單體可包含IL-12或其變體、Fc區片段或其變體,及特異性結合於FAP之抗原結合位點。
第一單體可包括以下結構式(III)或(IV):
N'-X-[連接子(2)]p-Fc區片段或其變體-[連接子(3)]q-(T)r-C' (III)
N'-(T)r-[連接子(2)]q-Fc區片段或其變體-[連接子(3)]p-X-C' (IV)
在該結構式(III)及該結構式(IV)中,
N'可為融合蛋白之N端,
C'可為融合蛋白之C端,
X可為結構式(I)或(II),
T可為特異性結合於FAP之抗原結合位點,
連接子(2)及(3)可為肽連接子,及
p、q及r可各自獨立地為0或1。
在一個實施例中,當r為0時,第一單體可呈融合蛋白形式,其中IL-12或其變體及Fc區片段或其變體藉由肽連接子連接。
接著,第一單體可包括SEQ ID NO: 3、SEQ ID NO: 4、SEQ ID NO: 5、SEQ ID NO: 15、SEQ ID NO: 20、SEQ ID NO: 21、SEQ ID NO: 22或SEQ ID NO: 32之胺基酸序列。
接著,在結構式(III)中,當r為1時,第一單體可呈其中抗FAP抗體之單體結合於IL-12或其變體的形式。
接著,在結構式(III)中,當r為1時,第一單體可包括SEQ ID NO: 292、SEQ ID NO: 293、SEQ ID NO: 296、SEQ ID NO: 297、SEQ ID NO: 298、SEQ ID NO: 299、SEQ ID NO: 302或SEQ ID NO: 303之胺基酸序列。
接著,在結構式(IV)中,當r為1時,第一單體可包括SEQ ID NO: 294、SEQ ID NO: 295、SEQ ID NO: 300或SEQ ID NO: 301之胺基酸序列。
在一個實施例中,當r為1時,結構式(III)可包括以下結構式(III')及(III''):
N'-X-[連接子(2)]p-Fc區片段或其變體-[連接子(3)]q-(T')-C' (III')
N'-(T'')-C' (III'')
在該結構式(III')及該結構式(III'')中,
T'為特異性結合於FAP之抗體之重鏈區,包含可變區及CH1區;或為該抗體之輕鏈區;
T''為特異性結合於FAP之抗體之輕鏈區;或為該抗體之重鏈區,包含可變區及CH1區;
其中,T'與T''彼此結合以形成該抗體之可變區,其中該可變區特異性結合於FAP;
連接子(2)至(3)為肽連接子,
p及q各自獨立地為0或1,及
N'、X及C'如上文所定義。
在一個實施例中,當r為1時,結構式(IV)可包括以下結構式(IV')及(IV''):
N'-(T')-[連接子(2)]q-Fc區片段或其變體-[連接子(3)]p-X-C' (IV');及
N'-(T'')-C' (IV'')
在該結構式(IV')及該結構式(IV'')中,
T'為特異性結合於FAP之抗體之重鏈區,包含可變區及CH1區;或為該抗體之輕鏈區;
T''為特異性結合於FAP之抗體之輕鏈區;或為該抗體之重鏈區,包含可變區及CH1區;
其中,T'與T''彼此結合以形成該抗體之可變區,其中該可變區特異性結合於FAP;
連接子(2)至(3)為肽連接子,
p及q各自獨立地為0或1,及
N'、X及C'如上文所定義。
接著,第一單體可包括以下之胺基酸序列:SEQ ID NO: 10及SEQ ID NO: 2;SEQ ID NO: 11及SEQ ID NO: 2;SEQ ID NO: 27及SEQ ID NO: 19;SEQ ID NO: 28及SEQ ID NO: 19;SEQ ID NO: 294及SEQ ID NO: 2;SEQ ID NO: 295及SEQ ID NO: 2;SEQ ID NO: 300及SEQ ID NO: 19;或SEQ ID NO: 301及SEQ ID NO: 19。
第二單體之結構
第二單體可進一步包含特異性結合於FAP之抗原結合位點。
在一個實施例中,第二單體可包含第一FAP結合位點;及第二FAP結合位點。
特異性結合於FAP之抗原結合位點可為Fab、scFv、Fv或其片段。接著,第一FAP結合位點可為Fab,且第二FAP結合位點可為Fv或scFv。
第二FAP結合位點可結合於第二單體之N端或C端。特定言之,第二FAP結合位點可另外結合於重鏈之C端、輕鏈之C端或可變區之N端。
第二單體可包括以下結構式(V):
N'-(R)s-[連接子(4)]t-Q-[連接子(5)]u-Fc區片段或其變體-[連接子(6)]v-(W)a-C' (V)
在該結構式(V)中,
N'可為融合蛋白之N端,
C'可為融合蛋白之C端,
R及Q可為特異性結合於FAP之抗原結合位點,
W可為特異性結合於FAP之scFv;或具有結構式(I)或(II)之IL-12或其變體,
連接子(4)、(5)及(6)可各自為肽連接子,及
s、t、u、v及a可各自獨立地為0或1。
在一個實施例中,結構式(V)可包括至少一個選自由以下組成之群的胺基酸序列:SEQ ID NO: 1、SEQ ID NO: 2、SEQ ID NO: 6、SEQ ID NO: 7、SEQ ID NO: 8、SEQ ID NO: 9、SEQ ID NO: 14、SEQ ID NO: 18、SEQ ID NO: 19、SEQ ID NO: 23、SEQ ID NO: 24、SEQ ID NO: 25、SEQ ID NO: 26、SEQ ID NO: 31、SEQ ID NO: 294、SEQ ID NO: 295、SEQ ID NO: 300及SEQ ID NO: 301。
在一個實施例中,結構式(V)可包括以下結構式(V')及(V''):
N'-(R')s-[連接子(4)]t-Q'-[連接子(5)]u-Fc區片段或其變體-[連接子(6)]p-(W)a-C' (V')
N'-(R'')s-[連接子(4)]t-Q''-[連接子(7)]x-(W)b-C' (V'')
在該結構式(V')及該結構式(V'')中,
R'可為特異性結合於FAP之抗體之重鏈區,包含可變區及CH1區;或為該抗體之輕鏈區;
R''可為特異性結合於FAP之抗體之輕鏈區;或為該抗體之重鏈區,包含可變區及CH1區;
其中R'與R''可彼此結合以形成該抗體之可變區,其中該可變區特異性結合於FAP;
Q'可為特異性結合於FAP之抗體之重鏈區,包含可變區及CH1區;或為該抗體之輕鏈區;
Q''可為特異性結合於FAP之抗體之輕鏈區;或為該抗體之重鏈區,包含可變區及CH1區;
其中Q'與Q''可彼此結合以形成該抗體之可變區,其中該可變區特異性結合於FAP,
W可為特異性結合於FAP之scFv;或具有結構式(I)或(II)之IL-12或其變體,
連接子(4)、(5)、(6)及(7)可各自為肽連接子,及
s、t、u、x、a及b可各自獨立地為0或1。
在一個實施例中,結構式(V')可為SEQ ID NO: 1、SEQ ID NO: 6、SEQ ID NO: 8、SEQ ID NO: 14、SEQ ID NO: 18、SEQ ID NO: 23、SEQ ID NO: 25、SEQ ID NO: 31、SEQ ID NO: 294、SEQ ID NO: 295、SEQ ID NO: 300或SEQ ID NO: 301。
在一個實施例中,結構式(V'')可為SEQ ID NO: 2、SEQ ID NO: 7、SEQ ID NO: 9、SEQ ID NO: 19、SEQ ID NO: 24或SEQ ID NO: 26。
在一個實施例中,第二單體可包括由SEQ ID NO: 102之胺基酸序列組成的重鏈及由SEQ ID NO: 103之胺基酸序列組成的輕鏈;或由SEQ ID NO: 110之胺基酸序列組成的重鏈及由SEQ ID NO: 111之胺基酸序列組成的輕鏈。
另外,當W為scFv時,W可具有SEQ ID NO: 72或SEQ ID NO: 84之胺基酸序列。
肽連接子
如本文所用,術語「肽連接子」係指用於提供物理化學距離或在融合蛋白中之區域之間進行連接的肽。連接子可包含免疫球蛋白之鉸鏈區。
肽連接子(1)至(7)係指由胺基酸構成之肽連接子。特定言之,肽連接子(2)或(5)可由5至80個連續胺基酸、7至70個連續胺基酸或10至60個連續胺基酸或12至50個胺基酸組成。肽連接子可包括(G
4S)n (其中n為1至10之整數)。接著,在(G
4S)n中,n可各自為1、2、3、4、5、6、7、8、9或10。
在一個實施例中,肽連接子(1)可為由SEQ ID NO: 93、SEQ ID NO: 94或SEQ ID NO: 95之胺基酸序列組成的肽連接子。
肽連接子(2)或(5)可由5至80個連續胺基酸、7至70個連續胺基酸或10至60個連續胺基酸或12至50個胺基酸組成。在一個實施例中,肽連接子(2)可由30個胺基酸組成。另外,肽連接子(2)可包含至少一個半胱胺酸。特定言之,其可包含一個、二個或三個半胱胺酸。另外,肽連接子(2)可來源於免疫球蛋白之鉸鏈,且可進一步包括(G
4S)n (其中n為1至10之整數)。特定言之,肽連接子(2)可包含由SEQ ID NO: 112、SEQ ID NO: 113、SEQ ID NO: 114、SEQ ID NO: 115、SEQ ID NO: 116、SEQ ID NO: 117、SEQ ID NO: 118、SEQ ID NO: 119及SEQ ID NO: 120中之任一者之胺基酸序列組成的鉸鏈區。
此外,肽連接子(3)、(4)、(6)及(7)可由1至30個連續胺基酸、5至20個連續胺基酸或10至15個連續胺基酸組成。肽連接子可包括(G
4S)n (其中n為1至10之整數)。接著,在(G
4S)n中,n可各自為1、2、3、4、5、6、7、8、9或10。
另外,特定言之,肽連接子(2)、(3)或(5)可包括SEQ ID NO: 93或SEQ ID NO: 94。
在本發明之一個實施例中,肽連接子(2)或(5)可為包含SEQ ID NO: 118或120之胺基酸序列的肽連接子。
Fc 區或其片段
接著,上述免疫球蛋白片段可為免疫球蛋白之Fc區。免疫球蛋白之Fc區可為野生型Fc區域以及Fc區域變體。接著,Fc區可為IgG、IgA、IgE、IgD或IgM之Fc區。特定言之,其可來源於IgG1或IgG2a。
如本文所用,術語「Fc區域變體」可指在糖基化模式方面不同於野生型Fc區域、糖基化高於野生型Fc區域或糖基化低於野生型Fc區域或具有去糖基化形式的形式。另外,其中包括去糖基化Fc區域。Fc區域或其變體可以經由培養條件或宿主基因操控加以調適以具有經調整之數目個唾液酸、岩藻糖基化或糖基化。
另外,可以藉由習知方法(諸如化學方法、酶方法,及使用微生物的基因工程方法)修改免疫球蛋白Fc區域的糖基化。另外,Fc區域變體可呈免疫球蛋白IgG、IgA、IgE、IgD或IgM之相應Fc區的混合形式。另外,Fc區域變體可呈其中Fc區域之一些胺基酸被其他胺基酸取代的形式。
藉由取代及/或添加引入之「胺基酸」可為選自由以下組成之群的任一者:離胺酸(K)、丙胺酸(A)、精胺酸(R)、天冬醯胺(N)、天冬胺酸(D)、半胱胺酸(C)、麩醯胺酸(Q)、麩胺酸(E)、甘胺酸(G)、組胺酸(H)、異白胺酸(I)、白胺酸(L)、甲硫胺酸(M)、苯丙胺酸(F)、脯胺酸(P)、絲胺酸(S)、蘇胺酸(T)、色胺酸(W)、酪胺酸(Y)及纈胺酸(V)。
另外,Fc區可包含杵結構或臼結構。
如本文所用,術語「杵-入-臼(knob-into-hole)」為用於製造特異性結合於不同區之抗體的設計策略,該等抗體諸如雙特異性抗體、多特異性抗體或異二聚抗體。一般而言,此技術涉及在第一多肽之界面(例如第一抗體重鏈之第一CH3區域)處引入杵及在第二多肽之界面(例如第二抗體重鏈之第二CH3區域)處引入相應臼,使得杵可定位於臼內以促進異二聚體形成且阻礙均二聚體形成。
藉由用較大側鏈(例如精胺酸、苯丙胺酸、酪胺酸或色胺酸)置換來自第一多肽之界面(例如第一抗體重鏈之第一CH3區域)的小胺基酸側鏈來構築『杵』。具有與杵中相同或類似大小的互補『臼』藉由用較小側鏈(例如丙胺酸、絲胺酸、纈胺酸或蘇胺酸)置換來自第二多肽之界面(例如第二抗體重鏈之第二CH3區域)的較大胺基酸側鏈而產生。杵及臼可藉由改變編碼多肽之核酸,例如藉由位點特異性突變誘發或藉由肽合成產生。
在一個實施例中,IgG1之杵結構可為SEQ ID NO: 13或288,且臼結構可為SEQ ID NO: 12或289。杵結構或臼結構可為其中SEQ ID NO: 304之胺基酸序列之第146、第148及第187胺基酸經其他胺基酸取代的形式。特定言之,在本發明之一個實施例中,杵結構或臼結構可為其中SEQ ID NO: 304之胺基酸序列經T146W、T146S、L148A及Y187A取代之形式。特定言之,杵結構可為其中該胺基酸序列經T146W取代的形式,且臼結構可為其中該胺基酸序列經T146S、L148A及Y148V取代的形式。
另一方面,在本發明之一個實施例中,IgG2a之杵結構可為SEQ ID NO: 30或290,且臼結構可為SEQ ID NO: 29或291。杵結構或臼結構可為其中SEQ ID NO: 305之胺基酸序列之第152、第154及第193胺基酸經其他胺基酸取代的形式。特定言之,在本發明之一個實施例中,杵結構或臼結構可為其中SEQ ID NO: 305之胺基酸序列經T152W或T152S、M154A及Y193V取代的形式。特定言之,杵結構可為其中該胺基酸序列經T152W取代的形式,且臼結構可為其中該胺基酸序列經T152S、M154A及Y193V取代的形式。
在一個實施例中,Fc區域變體可包括DANG突變或NG突變。接著,「DANG突變」係指用於移除人類IgG1或小鼠IgG2a中之效應功能的D265A/N297G突變。
IgG分子中由Fc區介導之效應功能包括C1q結合、補體依賴性細胞毒性、Fc受體結合、抗體依賴性細胞介導之細胞毒性(ADCC)、吞噬作用、細胞表面受體(例如B細胞受體,BCR)下調及其類似者。一般而言,此等效應功能需要Fc區與結合區域(例如抗體可變區域)之結合。
效應功能可藉由非突變Fc區之胺基酸序列之取代而改變,且效應功能改變之Fc區可例如藉由修飾C1q結合及/或FcR結合來設計,藉此改變CDC活性及/或ADCC活性。亦即,『DANG突變』意謂自IgG分子移除由Fc區介導之效應功能,使得在抗體產生期間不發生不合需要之效應功能。
在一個實施例中,DANG突變可為其中人類IgG1中SEQ ID NO: 289之胺基酸經D45A/N77G取代之形式。另外,該DANG突變可為其中小鼠IgG2a中SEQ ID NO: 291之胺基酸經D51A/N83G取代的形式。
融合蛋白之結構
融合蛋白可為抗體。特定言之,抗體可為異二聚抗體,包括杵-入-臼結構。
融合蛋白可包括結構式(III)及結構式(V);或結構式(IV)及結構式(V)。
更特定言之,融合蛋白之一個實施例可包含以下(i)或(ii)之第一單體;及以下(iii)、(iv)、(v)或(vi)之第二單體:
第一單體之實例 :(i)當r為0時,結構式(III)
(ii)當r為1時,結構式(IV)
第二單體之實例 :(iii)當s、a及b為0時,結構式(V')及結構式(V'')
(iv)當s為1且a及b為0時,結構式(V')及結構式(V'')
(v)當s及b為0且a為1時,結構式(V')及結構式(V'')
(vi)當b為1且s及a為0時,結構式(V')及結構式(V'')。
在一個實施例中,融合蛋白可包含:第一單體,其包含以上(i);及第二單體,其包含以上(iii) (圖33中的左側第一個)。接著,融合蛋白可包括至少一個選自由以下組成之群的胺基酸序列:SEQ ID NO: 1、SEQ ID NO: 2、SEQ ID NO: 3、SEQ ID NO: 4、SEQ ID NO: 5、SEQ ID NO: 18、SEQ ID NO: 19、SEQ ID NO: 20、SEQ ID NO: 21及SEQ ID NO: 22。特定言之,融合蛋白可包括SEQ ID NO: 1、SEQ ID NO: 2及SEQ ID NO: 3;SEQ ID NO: 1、SEQ ID NO: 2及SEQ ID NO: 4;SEQ ID NO: 1、SEQ ID NO: 2及SEQ ID NO: 5;SEQ ID NO: 18、SEQ ID NO: 19及SEQ ID NO: 20;SEQ ID NO: 18、SEQ ID NO: 19及SEQ ID NO: 21;或SEQ ID NO: 18、SEQ ID NO: 19及SEQ ID NO: 22。
在一個實施例中,融合蛋白可包含:第一單體,其包含以上(i);及第二單體,其包含以上(iv) (圖33中的左側第二個)。接著,融合蛋白可包括至少一個選自由以下組成之群的胺基酸序列:SEQ ID NO: 3、SEQ ID NO: 5、SEQ ID NO: 6、SEQ ID NO: 7、SEQ ID NO: 20、SEQ ID NO: 22、SEQ ID NO: 23及SEQ ID NO: 24。特定言之,融合蛋白可包括SEQ ID NO: 3、SEQ ID NO: 6及SEQ ID NO: 7;SEQ ID NO: 5、SEQ ID NO: 6及SEQ ID NO: 7;SEQ ID NO: 20、SEQ ID NO: 23及SEQ ID NO: 24;或SEQ ID NO: 22、SEQ ID NO: 23及SEQ ID NO: 24。
在一個實施例中,融合蛋白可包含:第一單體,其包含以上(i);及第二單體,其包含以上(v) (圖33中的左側第三個)。接著,融合蛋白可包括至少一個選自由以下組成之群的胺基酸序列:SEQ ID NO: 2、SEQ ID NO: 3、SEQ ID NO: 5、SEQ ID NO: 8、SEQ ID NO: 19、SEQ ID NO: 20、SEQ ID NO: 22及SEQ ID NO: 25。特定言之,融合蛋白可包括SEQ ID NO: 2、SEQ ID NO: 3及SEQ ID NO: 8;SEQ ID NO: 2、SEQ ID NO: 5及SEQ ID NO: 8;SEQ ID NO: 19、SEQ ID NO: 20及SEQ ID NO: 25;或SEQ ID NO: 19、SEQ ID NO: 22及SEQ ID NO: 25。
在一個實施例中,融合蛋白可包含:第一單體,其包含以上(i);及第二單體,其包含以上(vi) (圖33中的左側第四個)。接著,融合蛋白可包括至少一個選自由以下組成之群的胺基酸序列:SEQ ID NO: 1、SEQ ID NO: 3、SEQ ID NO: 5、SEQ ID NO: 9、SEQ ID NO: 18、SEQ ID NO: 20、SEQ ID NO: 22及SEQ ID NO: 26。特定言之,融合蛋白可包括SEQ ID NO: 1、SEQ ID NO: 3及SEQ ID NO: 9;SEQ ID NO: 1、SEQ ID NO: 5及SEQ ID NO: 9;SEQ ID NO: 18、SEQ ID NO: 20及SEQ ID NO: 26;或SEQ ID NO: 18、SEQ ID NO: 22及SEQ ID NO: 26。
在一個實施例中,融合蛋白可包含:第一單體,其包含以上(ii);及第二單體,其包含以上(iii) (圖33中的左側第五個)。接著,融合蛋白可包括至少一個選自由以下組成之群的胺基酸序列:SEQ ID NO: 1、SEQ ID NO: 2、SEQ ID NO: 10、SEQ ID NO: 11、SEQ ID NO: 18、SEQ ID NO: 19、SEQ ID NO: 27及SEQ ID NO: 28。特定言之,融合蛋白可包括SEQ ID NO: 1、SEQ ID NO: 2及SEQ ID NO: 10;SEQ ID NO: 1、SEQ ID NO: 2及SEQ ID NO: 11;SEQ ID NO: 18、SEQ ID NO: 19及SEQ ID NO: 27;或SEQ ID NO: 18、SEQ ID NO: 19及SEQ ID NO: 28。
另外,在一個實施例中,包含IL-12或其變體及特異性結合於FAP之抗原結合位點的融合蛋白二聚體可為包含結構式(III)之單體及結構式(V)之單體的融合蛋白二聚體(圖34中的左側)。接著,在結構式(III)中,r為1,且在結構式(V)中,s、a及t為0。接著,結構式(V)可包括(V')及(V'')。接著,在(V')及(V'')中,s、a、t及b為0。另外,二聚體之Fc區具有杵-入-臼結構,不同融合蛋白可經由該結構彼此結合。
特定言之,融合蛋白可包括至少一個選自由以下組成之群的胺基酸序列:SEQ ID NO: 1、SEQ ID NO: 2、SEQ ID NO: 18、SEQ ID NO: 19、SEQ ID NO: 292、SEQ ID NO: 293、SEQ ID NO: 298及SEQ ID NO: 299。特定言之,融合蛋白可包括SEQ ID NO: 1、SEQ ID NO: 2及SEQ ID NO: 292;SEQ ID NO: 1、SEQ ID NO: 2及SEQ ID NO: 293;SEQ ID NO: 18、SEQ ID NO: 19及SEQ ID NO: 298;或SEQ ID NO: 18、SEQ ID NO: 19及SEQ ID NO: 299。
另外,包含IL-12或其變體及特異性結合於FAP之抗原結合位點的融合蛋白二聚體可為包括結構(V)之結構的融合蛋白二聚體(圖34中之中間)。接著,融合蛋白二聚體可包括(V')及(V'')。接著,在結構式(V)中,s及t為0,且a為1。另外,在(V')及(V'')中,s、t及b為0,且a為1。另外,融合蛋白二聚體可為包括結構式(IV)之結構的融合蛋白二聚體。接著,在結構式(IV)中,r為1。
特定言之,融合蛋白可包括至少一個選自由以下組成之群的胺基酸序列:SEQ ID NO: 2、SEQ ID NO: 19、SEQ ID NO: 294、SEQ ID NO: 295、SEQ ID NO: 300及SEQ ID NO: 301。特定言之,融合蛋白可包括SEQ ID NO: 2及SEQ ID NO: 294;SEQ ID NO: 2及SEQ ID NO: 295;SEQ ID NO: 19及SEQ ID NO: 300;或SEQ ID NO: 19及SEQ ID NO: 301。
在一個實施例中,包含IL-12或其變體及特異性結合於FAP之抗原結合位點的融合蛋白二聚體可為包括結構式(III)之結構的融合蛋白二聚體(圖34中之右側)。接著,在結構式(III)中,r為1。
特定言之,融合蛋白可包括SEQ ID NO: 296、SEQ ID NO: 297、SEQ ID NO: 302或SEQ ID NO: 303。
本文中之多特異性融合蛋白可呈化學修飾形式。在一個實施例中,融合蛋白可藉由糖基化、乙醯化、PEG化、磷酸化、醯胺化、利用已知保護基/阻隔基之衍生化、蛋白水解裂解及/或與細胞配體或其他蛋白質進行結合而經化學修飾。許多此等化學修飾可藉由已知技術進行。
編碼融合蛋白之多核苷酸
在本發明之另一態樣中,提供一種編碼第一單體之多核苷酸或編碼第二單體之多核苷酸。
在一個實施例中,第一單體之多肽可包含與SEQ ID NO: 3、SEQ ID NO: 4、SEQ ID NO: 5、SEQ ID NO: 10、SEQ ID NO: 11、SEQ ID NO: 15、SEQ ID NO: 20、SEQ ID NO: 21、SEQ ID NO: 22、SEQ ID NO: 27、SEQ ID NO: 28、SEQ ID NO: 32、SEQ ID NO: 292、SEQ ID NO: 293、SEQ ID NO: 294、SEQ ID NO: 295、SEQ ID NO: 296、SEQ ID NO: 297、SEQ ID NO: 298、SEQ ID NO: 299、SEQ ID NO: 300、SEQ ID NO: 301、SEQ ID NO: 302或SEQ ID NO: 303至少約70%、至少約75%、至少約80%、至少約85%、至少約86%、至少約87%、至少約88%、至少約89%、至少約90%、至少約91%、至少約92%、至少約93%、至少約94%、至少約95%、至少約96%、至少約97%、至少約98%、至少約99%或至少約100%一致的胺基酸序列。
在一個實施例中,編碼第一單體之多核苷酸可具有與SEQ ID NO: 38、SEQ ID NO: 39、SEQ ID NO: 40、SEQ ID NO: 45、SEQ ID NO: 46、SEQ ID NO: 50、SEQ ID NO: 55、SEQ ID NO: 56、SEQ ID NO: 57、SEQ ID NO: 62、SEQ ID NO: 63或SEQ ID NO: 67至少約70%、至少約75%、至少約80%、至少約85%、至少約86%、至少約87%、至少約88%、至少約89%、至少約90%、至少約91%、至少約92%、至少約93%、至少約94%、至少約95%、至少約96%、至少約97%、至少約98%、至少約99%或至少約100%的一致性。
在一個實施例中,第二單體之多肽可包含與SEQ ID NO: 1、SEQ ID NO: 2、SEQ ID NO: 6、SEQ ID NO: 7、SEQ ID NO: 8、SEQ ID NO: 9、SEQ ID NO: 14、SEQ ID NO: 18、SEQ ID NO: 19、SEQ ID NO: 23、SEQ ID NO: 24、SEQ ID NO: 25、SEQ ID NO: 26、SEQ ID NO: 31、SEQ ID NO: 294、SEQ ID NO: 295、SEQ ID NO: 300或SEQ ID NO: 301約70%、至少約75%、至少約80%、至少約85%、至少約86%、至少約87%、至少約88%、至少約89%、至少約90%、至少約91%、至少約92%、至少約93%、至少約94%、至少約95%、至少約96%、至少約97%、至少約98%、至少約99%或至少約100%一致的胺基酸序列。
在一個實施例中,編碼第二單體之多核苷酸可具有與SEQ ID NO: 36、SEQ ID NO: 37、SEQ ID NO: 41、SEQ ID NO: 42、SEQ ID NO: 43、SEQ ID NO: 44、SEQ ID NO: 49、SEQ ID NO: 53、SEQ ID NO: 54、SEQ ID NO: 58、SEQ ID NO: 59、SEQ ID NO: 60、SEQ ID NO: 61或SEQ ID NO: 66至少約70%、至少約75%、至少約80%、至少約85%、至少約86%、至少約87%、至少約88%、至少約89%、至少約90%、至少約91%、至少約92%、至少約93%、至少約94%、至少約95%、至少約96%、至少約97%、至少約98%、至少約99%或至少約100%的一致性。
多核苷酸可進一步包含編碼信號序列或前導序列之核酸。如本文所用,術語「信號序列」係指引導目標蛋白之分泌的信號肽。信號肽在宿主細胞中轉譯且隨後裂解。具體而言,信號序列為起始蛋白質跨越內質網(ER)膜進行轉運之胺基酸序列。
信號序列因其特徵而為此項技術中所熟知。此類信號序列典型地含有16至30個胺基酸殘基,且可含有比此類胺基酸殘基更多或更少的胺基酸殘基。典型信號肽由三個區構成,亦即,鹼性N端區、中心疏水區及更極性之C端區。中心疏水區含有4至12個疏水性殘基,其在不成熟多肽之轉運期間經由膜脂質雙層固定信號序列。
在起始之後,信號序列在ER之內腔中藉由通常稱為信號肽酶之細胞酶裂解。接著,信號序列可為tPa(組織纖維蛋白溶酶原活化因子)、HSV gD(單純疱疹病毒糖蛋白D之信號序列)或生長激素之分泌信號序列。較佳地,可使用包括哺乳動物及其類似物之高級真核細胞中所用的分泌信號序列。另外,可使用野生型信號序列,或可使用已被在宿主細胞中具有高表現頻率之密碼子取代的信號序列。
具有多核苷酸之載體
在本發明之另一態樣中,提供一種包含多核苷酸之載體。
載體可引入至宿主細胞中以與宿主細胞之基因體重組且插入至宿主細胞之基因體中。或者,載體被理解為含有多核苷酸序列之核酸手段,該載體可作為游離基因體自主複製。載體包括線性核酸、質體、噬質體、黏質體、RNA載體、病毒載體及其類似物。病毒載體之實例包括但不限於反轉錄病毒、腺病毒及腺相關病毒。
特定言之,載體可包括質體DNA、噬菌體DNA及其類似物;及商業上研發之質體(pUC18、pBAD、pIDTSAMRT-AMP及其類似物)、大腸桿菌(
E. coli)衍生之質體(pYG601BR322、pBR325、pUC118、pUC119及其類似物)、枯草芽孢桿菌(
Bacillus subtilis)衍生之質體(pUB110、pTP5及其類似物)、酵母菌衍生之質體(YEp13、YEp24、YCp50及其類似物)、噬菌體DNA (Charon4A、Charon21A、EMBL3、EMBL4、λgt10、λgt11、λZAP及其類似物)、動物病毒載體(反轉錄病毒、腺病毒、痘瘡病毒及其類似物)、昆蟲病毒載體(桿狀病毒(baculoviruses)及其類似物)。因為載體展現不同表現位準及視宿主細胞而定之蛋白質修飾,所以較佳地選擇及使用最適於該目的之宿主細胞。
如本文所用,術語目標蛋白之「基因表現」或「表現」應理解為意謂DNA序列之轉錄、mRNA轉錄物之轉譯及融合蛋白產物或其片段之分泌。適用表現載體可為RcCMV (Invitrogen,Carlsbad)或其變體。表現載體可含有用於促進哺乳動物細胞中之目標基因之連續轉錄的人類巨細胞病毒(CMV)啟動子,及用於增加轉錄之後的RNA之穩定性程度的牛生長激素聚腺苷酸化信號序列。
表現融合蛋白之轉型細胞
在本發明之另一態樣中,提供一種已引入載體之轉型細胞。
用於轉型細胞之宿主細胞可包括但不限於原核細胞、真核細胞及哺乳動物、植物、昆蟲、真菌或細菌來源之細胞。作為原核細胞之實例,可使用大腸桿菌。另外,作為真核細胞之實例,可使用酵母。另外,對於哺乳動物細胞,可使用CHO細胞、F2N細胞、CSO細胞、BHK細胞、波韋氏黑色素瘤細胞(Bowes melanoma cells)、HeLa細胞、911細胞、AT1080細胞、A549細胞、HEK 293細胞、HEK293T細胞或其類似物。然而,哺乳動物細胞不限於此,且可使用熟習此項技術者已知可用作哺乳動物宿主細胞之任何細胞。
另外,對於將表現載體引入至宿主細胞中,可使用CaCl
2沈澱、Hanahan法(其功效已藉由在CaCl
2沈澱中使用諸如二甲亞碸(DMSO)之還原劑而提高)、電穿孔、磷酸鈣沈澱、原生質體融合、使用碳化矽纖維之攪動、土壤桿菌(agrobacteria)介導之轉型、使用PEG之轉型、硫酸聚葡萄糖、脂染胺或乾式/抑制(dry/inhibition)介導之轉型或類似者。
如上文所描述,為使融合蛋白作為治療劑之特性最佳化或出於任何其他目的,融合蛋白之糖基化模式(例如唾液酸、岩藻糖基化、糖基化)可經由熟習此項技術者已知之方法,藉由操控宿主細胞所具有之糖基化相關基因來調節。
生產融合蛋白之方法
在本發明之另一態樣中,提供一種產生融合蛋白之方法,其包含i)培養轉型細胞;及ii)回收包含第一單體及第二單體之融合蛋白。
培養轉型細胞之方法可使用此項技術中熟知之方法進行。特定言之,培養可在分批製程中進行或在饋料分批或反覆饋料分批製程中連續進行。
融合蛋白之用途
在本發明之另一態樣中,提供一種用於預防或治療癌症之醫藥組成物,其包含融合蛋白作為活性成分。
接著,癌症可為選自由以下組成之群中之一者:胃癌、肝癌、肺癌、大腸直腸癌、乳癌、前列腺癌、皮膚癌、骨癌、多發性骨髓瘤、神經膠質瘤、卵巢癌、胰臟癌、子宮頸癌、甲狀腺癌、喉癌、急性骨髓性白血病、慢性骨髓性白血病、急性淋巴母細胞性白血病、慢性淋巴母細胞性白血病、腦瘤、神經母細胞瘤、視網膜母細胞瘤、頭頸癌、唾液腺癌及淋巴瘤。
醫藥組成物之較佳劑量視以下而定:患者之狀況及體重、疾病嚴重度、藥物形式、投予路徑及持續時間,且可由熟習此項技術者適當地選擇。在本發明之用於治療或預防腫瘤之醫藥組成物中,視應用、劑型、摻合目的及其類似者而定,可以任何量(有效量)含有活性成分,只要活性成分可展現治療腫瘤或尤其對癌症之治療效應的活性即可。以組成物之總重量計,其習知有效量經確定在按重量計0.001%至20.0%範圍內。接著,術語「有效量」係指能夠誘發改良或治療疾病之病狀之效應,且尤其誘發改良或治療癌症之病狀之效應的活性成分之量。熟習此項技術者可在常識範圍內以實驗方式確定此類有效量。
如本文所用,術語「治療」可用於意謂治療性治療及預防性治療。接著,預防可用於意謂緩解或減輕個體之病理性病狀或疾病。在一個實施例中,術語「治療」包括用於治療哺乳動物(包括人類)之疾病的施藥(application)或任何投予形式。另外,術語包括抑制或減緩疾病進展;且包括如下含義:恢復或修復受損或消失之功能,使得疾病部分地或完全地緩解;刺激效率低的過程;或緩解嚴重的疾病。
藥物動力學參數(諸如生物可用性)及基礎參數(諸如清除率)亦可影響功效。因此,「增強功效」(例如功效之提高)可歸因於增強之藥物動力學參數及增強之功效,其可藉由比較諸如清除率之參數及測試動物或人類個體中之腫瘤治療或改善來量測。
如本文所用,術語「治療有效量」或「醫藥學上有效量」係指有效預防或治療所討論之疾病之化合物或組成物之量,其足以以適用於醫學治療之合理收益/風險比來治療該疾病且不引起副作用。有效量的位準可視包括以下的因素確定:患者之健康狀況、疾病的類型及嚴重度、藥物活性、患者對藥物的敏感性、投予模式、投予時間、投予途徑及排出速率、治療持續時間、配方或同時使用的藥物,以及醫學領域中熟知的其他因素。在一個實施例中,治療有效量係指可有效治療癌症之藥物之量。
接著,醫藥組成物可進一步包含醫藥學上可接受之載劑。醫藥學上可接受之載劑可為任何載劑,只要該載劑為適用於遞送至患者之無毒物質即可。可含有蒸餾水、醇、脂肪、蠟及惰性固體作為載劑。醫藥學上可接受之佐劑(緩衝劑、分散劑)亦可含於醫藥組成物中。
特定言之,除活性成分之外,亦藉由包括醫藥學上可接受之載劑,可使用此項技術中已知的習知方法將醫藥組成物製備成非經腸調配物,此可視投予途徑而定。接著,術語「醫藥學上可接受」意謂載劑不具有與待施用(開處)之個體可適應相比更多的毒性,同時不抑制活性成分之活性。
當醫藥組成物製備成非經腸調配物時,其可根據此項技術中已知之方法,使用適合載劑製備成呈注射劑、經皮貼片、經鼻吸入劑或栓劑形式的製劑。在製備成注射劑的情況下,可使用無菌水、乙醇、多元醇(諸如甘油或丙二醇)或其混合物作為適合載劑;且可較佳使用等張溶液,諸如林格氏溶液(Ringer's solution)、含有三乙醇胺的磷酸鹽緩衝鹽水(PBS),或無菌注射用水,及5%右旋糖,或其類似物。醫藥組成物之調配物為此項技術中已知的,且特定言之,可參考《雷明頓氏藥物科學(Remington's Pharmaceutical Sciences)》(第19版, 1995)及其類似物。將此文件視為本說明書之部分。
醫藥組成物的較佳劑量可在每天0.01 μg/kg至10 g/kg或0.01 mg/kg至1 g/kg範圍內,此視患者之狀況、體重、性別、年齡、患者之嚴重度及投予途徑而定。劑量可一天投予一次或可分成一天若干次。此類劑量不應視為在任何態樣中限制本發明之範圍。
可施用(開處)醫藥組成物的個體為哺乳動物及人類,尤其較佳地為人類。除活性成分以外,本申請案之醫藥組成物亦可進一步含有任何已知對腫瘤具有治療效應之化合物或天然提取物。
在本發明之另一態樣中,提供一種融合蛋白用於治療癌症之用途,該融合蛋白包含第一單體及第二單體,該第一單體包含IL-12或其變體,且該第二單體包含特異性結合於FAP之抗原結合位點。
在本發明之另一態樣中,提供一種融合蛋白用於製造供治療癌症用之藥劑之用途,該融合蛋白包含第一單體及第二單體,該第一單體包含IL-12或其變體,且該第二單體包含特異性結合於FAP之抗原結合位點。
在本發明之又一態樣中,提供一種用於治療或預防癌症之方法,其包含向個體投予融合蛋白,該融合蛋白包含第一單體及第二單體,該第一單體包含IL-12或其變體,且該第二單體包含特異性結合於FAP之抗原結合位點。
接著,個體可為罹患癌症之個體。另外,個體可為哺乳動物,較佳人類。
融合蛋白或融合蛋白二聚體的投予途徑、劑量及投予頻率可視患者之狀況及副作用是否存在而變,且因此,融合蛋白或融合蛋白二聚體可以各種方式及量向個體投予。熟習此項技術者可在適當範圍內選擇最佳投予方法、劑量及投予頻率。另外,融合蛋白或融合蛋白二聚體可與已知在待治療疾病方面具有治療效應之其他藥物或生理學活性物質組合投予,或可調配成與其他藥物一起之組合調配物形式。
在下文中,將藉助於以下實例更詳細地描述本發明。然而,以下實例僅用於說明本發明,且本發明之範圍不限於此。
製備實例 1. 抗 FAP/IL-12 IgG1 DANG 人類融合蛋白之概述[表1]
蛋白質 | 型式 | 描述 | 對應序列 |
T1.01 | K&H | 抗人類FAP/人類IL-12、人類IgG1 DANG | 序列1、序列2、序列3 |
T1.02 | K&H | 抗人類FAP/人類IL-12突變1、人類IgG1 DANG | 序列1、序列2、序列4 |
T1.03 | K&H | 抗人類FAP/人類IL-12突變2、人類IgG1 DANG | 序列1、序列2、序列5 |
T1.04 | K&H | 抗人類FAP/人類IL-12、人類IgG1 DANG (2+1) | 序列3、序列6、序列7 |
T1.05 | K&H | 抗人類FAP/人類IL-12突變2、人類IgG1 DANG (2+1) | 序列5、序列6、序列7 |
T1.06 | K&H | 抗人類FAP/人類IL-12、人類IgG1 DANG (2+1,HC scFv) | 序列2、序列3、序列8 |
T1.07 | K&H | 抗人類FAP/人類IL-12突變2、人類IgG1 DANG (2+1,HC scFv) | 序列2、序列5、序列8 |
T1.08 | K&H | 抗人類FAP/人類IL-12、人類IgG1 DANG (2+1,LC scFv) | 序列1、序列3、序列9 |
T1.09 | K&H | 抗人類FAP/人類IL-12突變2、人類IgG1 DANG (2+1,LC scFv) | 序列1、序列5、序列9 |
T1.10 | K&H | 抗人類FAP/抗人類FAP-人類IL-12、人類IgG1 DANG (2+1) | 序列1、序列2、序列10 |
T1.11 | K&H | 抗人類FAP/抗人類FAP-人類IL-12突變2、人類IgG1 DANG (2+1) | 序列1、序列2、序列11 |
T1.12 | K&H | 抗人類FAP/空、人類IgG1 DANG | 序列1、序列2、序列12 |
T1.13 | K&H | 空/人類IL-12、人類IgG1 DANG | 序列3、序列13 |
T1.14 | K&H | 空/人類IL-12突變1、人類IgG1 DANG | 序列4、序列13 |
T1.15 | K&H | 空/人類IL-12突變2、人類IgG1 DANG | 序列5、序列13 |
T1.16 | Mab | 抗人類FAP、人類IgG1 DANG | 序列2、序列14 |
T1.17 | Fc融合 | 人類IL-12突變2、人類IgG1 DANG | 序列15 |
T1.18 | K&H | 抗人類CD20/人類IL-12、人類IgG1 DANG | 序列3、序列16、序列17 |
T1.19 | K&H | 抗人類CD20/人類IL-12突變1、人類IgG1 DANG | 序列4、序列16、序列17 |
T1.20 | K&H | 抗人類CD20/人類IL-12突變2、人類IgG1 DANG | 序列5、序列16、序列17 |
T1.21 | K&H | 抗人類CD20/空、人類IgG1 DANG | 序列12、序列16、序列17 |
T1.23 | K&H | 抗人類FAP/人類IL-12-抗人類FAP scFv、人類IgG1 DANG (2+1) | 序列1、序列2、序列292 |
T1.24 | K&H | 抗人類FAP/人類IL-12突變2-抗人類FAP scFv、人類IgG1 DANG (2+1) | 序列1、序列2、序列293 |
T1.25 | Fc融合 | 抗人類FAP-人類IL-12、人類IgG1 DANG | 序列2、序列294 |
T1.26 | Fc融合 | 抗人類FAP-人類IL-12突變2、人類IgG1 DANG | 序列2、序列295 |
T1.27 | Fc融合 | 人類IL-12-抗人類FAP scFv、人類IgG1 DANG | 序列296 |
T1.28 | Fc融合 | 人類IL-12突變2-抗人類FAP scFv、人類IgG1 DANG | 序列297 |
[序列1]由人類抗FAP重鏈可變區序列及人類IgG1 Fc構成,其中經由DANG突變(D265A、N297G)移除效應功能,且藉由T366W突變形成杵結構。
[序列2]由人類抗FAP輕鏈序列構成。
[序列3]由人類IL-12 p40 (β)區序列及連接子GGGGSGGGGSGGGGS、人類介白素12 p35 (α)區序列、連接子GGGGSGGGGS及人類IgG1 Fc構成,其中經由DANG突變(D265A、N297G)移除效應功能,且藉由T366S、L368A及Y407V突變形成臼結構。
[序列4]由其中人類IL-12 p40 (β)區中涉及肝素結合之第280及第285胺基酸處之離胺酸(K)突變成丙胺酸(A)的序列、連接子GGGGSGGGGSGGGGS、人類IL-12 p35 (α)區序列、連接子GGGGSGGGGS及人類IgG1 Fc臼DANG構成。
[序列5]由其中人類IL-12 p40 (β)區中參與肝素結合之第280、第282、第285及第286胺基酸處之離胺酸(K)突變成丙胺酸(A)的序列、連接子GGGGSGGGGSGGGGS、人類IL-12 p35 (α)區序列、連接子GGGGSGGGGS及人類IgG1 Fc臼DANG構成。
[序列6]由人類抗FAP重鏈可變區序列、連接子GGGGSGGGGSGGGGS、人類抗FAP重鏈可變區序列及人類IgG1 Fc杵DANG構成。
[序列7]由人類抗FAP輕鏈可變區序列、連接子GGGGSGGGGSGGGGS及人類抗FAP輕鏈序列構成。
[序列8]由人類抗FAP重鏈可變區序列、人類IgG1 Fc杵DANG、連接子GGGGSGGGGSGGGGS、人類抗FAP重鏈可變區序列、連接子GGGGSGGGGSGGGGSGGGGS及人類抗FAP輕鏈可變區序列構成。
[序列9]由人類抗FAP輕鏈序列、連接子GGGGSGGGGSGGGGS、人類抗FAP重鏈可變區序列、連接子GGGGSGGGGSGGGGSGGGGS及人類抗FAP輕鏈可變區序列構成。
[序列10]由人類抗FAP重鏈序列、人類IgG1 Fc臼DANG、連接子GGGGSGGGGSGGGGSS、人類IL-12之p40 (β)區序列、連接子GGGGSGGGGSGGGGS及人類IL-12 p35 (α)區序列構成。
[序列11]由人類抗FAP重鏈序列、人類IgG1 Fc臼DANG、連接子GGGGSGGGGSGGGGS、含有涉及肝素結合之胺基酸的突變(四個)的人類IL-12的p40 (β)區序列、連接子GGGGSGGGGSGGGGS及人類IL-12 p35 (α)區序列構成。
[序列12]僅由人類IgG1 Fc臼DANG構成。
[序列13]僅由人類IgG1 Fc杵DANG構成。
[序列14]由人類抗FAP重鏈可變區序列及人類IgG1 Fc DANG構成。
[序列15]由含有涉及肝素結合之胺基酸之突變(四個)的人類IL-12之p40 (β)區序列、連接子GGGGSGGGGSGGGGS、人類IL-12 p35 (α)區序列、連接子GGGGSGGGGS及人類IgG1 Fc DANG構成。
[序列16]由人類抗CD20抗體之重鏈序列及人類IgG1 Fc杵DANG構成。
[序列17]為人類抗CD20抗體之輕鏈序列。
[序列292]由人類IL-12 p40 (β)區序列、連接子GGGGSGGGGSGGGGS、人類IL-12 p35 (α)區序列、連接子GGGGSGGGGS及人類IgG1 Fc臼DANG、連接子GGGGSGGGGSGGGGS、人類抗FAP重鏈可變區序列、連接子GGGGSGGGGSGGGGSGGGGS及人類抗FAP輕鏈可變區序列構成。
[序列293]由含有涉及肝素結合之胺基酸之突變(四個)的人類IL-12 p40 (β)區序列、連接子GGGGSGGGGSGGGGS、人類IL-12 p35 (α)區序列、連接子GGGGSGGGGS及人類IgG1 Fc臼DANG、連接子GGGGSGGGGSGGGGS、人類抗FAP重鏈可變區序列、連接子GGGGSGGGGSGGGGSGGGGS及人類抗FAP輕鏈可變區序列構成。
[序列294]由人類抗FAP重鏈序列、人類IgG1 Fc DANG、連接子GGGGSGGGGSGGGGS、人類IL-12之p40 (β)區序列、連接子GGGGSGGGGSGGGGS及人類IL-12 p35 (α)區序列構成。
[序列295]由人類抗FAP重鏈序列、人類IgG1 Fc DANG、連接子GGGGSGGGGSGGGGS、含有涉及肝素結合之胺基酸的突變(四個)的人類IL-12的p40 (β)區序列、連接子GGGGSGGGGSGGGGS及人類IL-12 p35 (α)區序列構成。
[序列296]由人類IL-12 p40 (β)區序列、連接子GGGGSGGGGSGGGGS、人類IL-12 p35 (α)區序列、連接子GGGGSGGGGS及人類IgG1 Fc DANG、連接子GGGGSGGGGSGGGGS、人類抗FAP重鏈可變區序列、連接子GGGGSGGGGSGGGGSGGGGS及人類抗FAP輕鏈可變區序列構成。
[序列297]由含有涉及肝素結合之胺基酸的突變(四個)的人類IL-12 p40 (β)區序列、連接子GGGGSGGGGSGGGGS、人類IL-12 p35 (α)區序列、連接子GGGGSGGGGS及人類IgG1 Fc DANG、連接子GGGGSGGGGSGGGGS、人類抗FAP重鏈可變區序列、連接子GGGGSGGGGSGGGGSGGGGS及人類抗FAP輕鏈可變區序列構成。
T1.01 (序列1、序列2、序列3)為雙特異性抗體,其中靶向人類FAP之人類抗FAP序列及人類IL-12序列形成杵-入-臼結構,且移除效應功能。
T1.02 (序列1、序列2、序列4)為雙特異性抗體,其中靶向人類FAP之人類抗FAP序列及含有涉及肝素結合之胺基酸之突變(二個)的人類IL-12序列形成杵-入-臼結構,且移除效應功能。
T1.03 (序列1、序列2、序列5)為雙特異性抗體,其中靶向人類FAP之人類抗FAP序列及含有涉及肝素結合之胺基酸之突變(四個)的人類IL-12序列形成杵-入-臼結構,且移除效應功能。
T1.04 (序列3、序列6、序列7)為雙特異性抗體,其中呈雙可變區域免疫球蛋白(DVD-Ig)形式之人類抗FAP序列及人類IL-12序列形成杵-入-臼結構,且移除效應功能。
T1.05 (序列5、序列6、序列7)為雙特異性抗體,其中呈DVD-Ig形式之人類抗FAP序列及含有涉及肝素結合之胺基酸之突變(四個)的人類IL-12序列形成杵-入-臼結構,且移除效應功能。
T1.06 (序列2、序列3、序列8)為雙特異性抗體,其中單鏈可變片段(靶向人類FAP之人類抗FAP序列之scFv)連接至重鏈之C端的人類抗FAP序列及人類IL-12序列形成杵-入-臼結構,且移除效應功能。
T1.07 (序列2、序列5、序列8)為雙特異性抗體,其中靶向人類FAP之人類抗FAP序列之scFv連接至重鏈之C端的人類抗FAP序列及含有涉及肝素結合之胺基酸之突變(四個)的人類IL-12序列形成杵-入-臼結構,且移除效應功能。
T1.08 (序列1、序列3、序列9)為雙特異性抗體,其中靶向人類FAP之人類抗FAP序列之scFv連接至輕鏈之C端的人類抗FAP序列及人類IL-12序列形成杵-入-臼結構,且移除效應功能。
T1.09 (序列1、序列5、序列9)為雙特異性抗體,其中靶向人類FAP之人類抗FAP序列之scFv連接至輕鏈之C端的人類抗FAP序列及含有涉及肝素結合之胺基酸之突變(四個)的人類IL-12序列形成杵-入-臼結構,且移除效應功能。
T1.10 (序列1、序列2、序列10)為靶向人類FAP之人類抗FAP序列及其中人類IL-12序列連接至重鏈之C端的人類抗FAP序列形成杵-入-臼結構的抗體。
T1.11 (序列1、序列2、序列11)為靶向人類FAP之人類抗FAP序列及其中含有涉及肝素結合之胺基酸之突變(四個)的人類IL-12序列連接至重鏈之C端的人類抗FAP序列形成杵-入-臼結構的抗體。
T1.12 (序列1、序列2、序列12)為一種抗體,其中移除僅具有靶向人類FAP之人類抗FAP序列之杵-入-臼結構的效應功能。
T1.13 (序列3、序列13)為一種抗體,其中移除僅具有人類IL-12序列之杵-入-臼結構之效應功能。
T1.14 (序列4、序列13)為一種抗體,其中移除僅具有含有涉及肝素結合之胺基酸之突變(二個)的人類IL-12序列之杵-入-臼結構的效應功能。
T1.15 (序列5、序列13)為一種抗體,其中移除僅具有含有涉及肝素結合之胺基酸之突變(四個)的人類IL-12序列之杵-入-臼結構的效應功能。
T1.16 (序列2、序列14)為靶向人類FAP之人類抗FAP抗體。
T1.17 (序列15)為僅具有含有涉及肝素結合之胺基酸之突變(四個)的人類IL-12序列之Fc融合蛋白。
T1.18 (序列3、序列16、序列17)為雙特異性抗體,其中靶向人類CD20之人類抗CD20序列及人類IL-12序列形成杵-入-臼結構,且移除效應功能。
T1.19 (序列4、序列16、序列17)為雙特異性抗體,其中靶向人類CD20之人類抗CD20序列及含有涉及肝素結合之胺基酸之突變(二個)的人類IL-12序列形成杵-入-臼結構,且移除效應功能。
T1.20 (序列5、序列16、序列17)為雙特異性抗體,其中靶向人類CD20之人類抗CD20序列及含有涉及肝素結合之胺基酸之突變(四個)的人類IL-12序列形成杵-入-臼結構,且移除效應功能。
T1.21 (序列12、序列16、序列17)為一種抗體,其中移除僅具有靶向人類CD20之人類抗CD20序列之杵-入-臼結構的效應功能。
T1.23 (序列1、序列2、序列292)為雙特異性抗體,其中人類抗FAP序列及其中人類抗FAP序列之scFv連接至C端的人類IL-12序列形成杵-入-臼結構,且移除效應功能。
T1.24 (序列1、序列2、序列293)為雙特異性抗體,其中人類抗FAP重鏈序列及其中人類抗FAP序列之scFv連接至C端的含有涉及肝素結合之胺基酸之突變(四個)的人類IL-12序列形成杵-入-臼結構,且移除效應功能。
T1.25 (序列2、序列294)為含有人類抗FAP序列之Fc融合蛋白二聚體,其中人類IL-12序列連接至重鏈之C端。
T1.26 (序列2、序列295)為含有人類抗FAP序列之Fc融合蛋白二聚體,其中含有涉及肝素結合之胺基酸之突變(四個)的人類IL-12序列連接至重鏈之C端。
T1.27 (序列296)為含有人類IL-12序列之Fc融合蛋白二聚體,其中人類抗FAP序列之scFv連接至C端。
T1.28 (序列297)為由含有涉及肝素結合之胺基酸之突變(四個)的人類IL-12序列構成之Fc融合蛋白二聚體,其中人類抗FAP序列之scFv連接至C端。
[序列1]抗人類FAP HC人類IgG1 Fc杵DANG
QVQLVQSGAEVKKPGASVKVSCKTSRYTFTEYTIHWVRQAPGQRLEWIGGINPNNGIPNYNQKFKGRVTITVDTSASTAYMELSSLRSEDTAVYYCARRRIAYGYDEGHAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
[序列2]抗人類FAP LC
DIVMTQSPDSLAVSLGERATINCKSSQSLLYSRNQKNYLAWYQQKPGQPPKLLIFWASTRESGVPDRFSGSGFGTDFTLTISSLQAEDVAVYYCQQYFSYPLTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
[序列3]人類scIL-12-人類IgG1 Fc臼DANG
IWELKKDVYVVELDWYPDAPGEMVVLTCDTPEEDGITWTLDQSSEVLGSGKTLTIQVKEFGDAGQYTCHKGGEVLSHSLLLLHKKEDGIWSTDILKDQKEPKNKTFLRCEAKNYSGRFTCWWLTTISTDLTFSVKSSRGSSDPQGVTCGAATLSAERVRGDNKEYEYSVECQEDSACPAAEESLPIEVMVDAVHKLKYENYTSSFFIRDIIKPDPPKNLQLKPLKNSRQVEVSWEYPDTWSTPHSYFSLTFCVQVQGKSKREKKDRVFTDKTSATVICRKNASISVRAQDRYYSSSWSEWASVPCSGGGGSGGGGSGGGGSRNLPVATPDPGMFPCLHHSQNLLRAVSNMLQKARQTLEFYPCTSEEIDHEDITKDKTSTVEACLPLELTKNESCLNSRETSFITNGSCLASRKTSFMMALCLSSIYEDLKMYQVEFKTMNAKLLMDPKRQIFLDQNMLAVIDELMQALNFNSETVPQKSSLEEPDFYKTKIKLCILLHAFRIRAVTIDRVMSYLNASGGGGSGGGGSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
[序列4]人類scIL-12突變1-人類IgG1 Fc臼DANG
IWELKKDVYVVELDWYPDAPGEMVVLTCDTPEEDGITWTLDQSSEVLGSGKTLTIQVKEFGDAGQYTCHKGGEVLSHSLLLLHKKEDGIWSTDILKDQKEPKNKTFLRCEAKNYSGRFTCWWLTTISTDLTFSVKSSRGSSDPQGVTCGAATLSAERVRGDNKEYEYSVECQEDSACPAAEESLPIEVMVDAVHKLKYENYTSSFFIRDIIKPDPPKNLQLKPLKNSRQVEVSWEYPDTWSTPHSYFSLTFCVQVQGASKREAKDRVFTDKTSATVICRKNASISVRAQDRYYSSSWSEWASVPCSGGGGSGGGGSGGGGSRNLPVATPDPGMFPCLHHSQNLLRAVSNMLQKARQTLEFYPCTSEEIDHEDITKDKTSTVEACLPLELTKNESCLNSRETSFITNGSCLASRKTSFMMALCLSSIYEDLKMYQVEFKTMNAKLLMDPKRQIFLDQNMLAVIDELMQALNFNSETVPQKSSLEEPDFYKTKIKLCILLHAFRIRAVTIDRVMSYLNASGGGGSGGGGSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
[序列5]人類scIL-12突變2-人類IgG1 Fc臼DANG
IWELKKDVYVVELDWYPDAPGEMVVLTCDTPEEDGITWTLDQSSEVLGSGKTLTIQVKEFGDAGQYTCHKGGEVLSHSLLLLHKKEDGIWSTDILKDQKEPKNKTFLRCEAKNYSGRFTCWWLTTISTDLTFSVKSSRGSSDPQGVTCGAATLSAERVRGDNKEYEYSVECQEDSACPAAEESLPIEVMVDAVHKLKYENYTSSFFIRDIIKPDPPKNLQLKPLKNSRQVEVSWEYPDTWSTPHSYFSLTFCVQVQGASAREAADRVFTDKTSATVICRKNASISVRAQDRYYSSSWSEWASVPCSGGGGSGGGGSGGGGSRNLPVATPDPGMFPCLHHSQNLLRAVSNMLQKARQTLEFYPCTSEEIDHEDITKDKTSTVEACLPLELTKNESCLNSRETSFITNGSCLASRKTSFMMALCLSSIYEDLKMYQVEFKTMNAKLLMDPKRQIFLDQNMLAVIDELMQALNFNSETVPQKSSLEEPDFYKTKIKLCILLHAFRIRAVTIDRVMSYLNASGGGGSGGGGSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
[序列6] (抗人類FAP VH)2-人類IgG1 Fc杵DANG
QVQLVQSGAEVKKPGASVKVSCKTSRYTFTEYTIHWVRQAPGQRLEWIGGINPNNGIPNYNQKFKGRVTITVDTSASTAYMELSSLRSEDTAVYYCARRRIAYGYDEGHAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKTSRYTFTEYTIHWVRQAPGQRLEWIGGINPNNGIPNYNQKFKGRVTITVDTSASTAYMELSSLRSEDTAVYYCARRRIAYGYDEGHAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
[序列7] (抗人類FAP VL)2
DIVMTQSPDSLAVSLGERATINCKSSQSLLYSRNQKNYLAWYQQKPGQPPKLLIFWASTRESGVPDRFSGSGFGTDFTLTISSLQAEDVAVYYCQQYFSYPLTFGQGTKVEIKGGGGSGGGGSGGGGSDIVMTQSPDSLAVSLGERATINCKSSQSLLYSRNQKNYLAWYQQKPGQPPKLLIFWASTRESGVPDRFSGSGFGTDFTLTISSLQAEDVAVYYCQQYFSYPLTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
[序列8]抗人類FAP HC人類IgG1 Fc杵DANG-抗人類FAP scFv
QVQLVQSGAEVKKPGASVKVSCKTSRYTFTEYTIHWVRQAPGQRLEWIGGINPNNGIPNYNQKFKGRVTITVDTSASTAYMELSSLRSEDTAVYYCARRRIAYGYDEGHAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKTSRYTFTEYTIHWVRQAPGQRLEWIGGINPNNGIPNYNQKFKGRVTITVDTSASTAYMELSSLRSEDTAVYYCARRRIAYGYDEGHAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIVMTQSPDSLAVSLGERATINCKSSQSLLYSRNQKNYLAWYQQKPGQPPKLLIFWASTRESGVPDRFSGSGFGTDFTLTISSLQAEDVAVYYCQQYFSYPLTFGQGTKVEIK
[序列9]抗人類FAP LC-抗人類FAP scFv
DIVMTQSPDSLAVSLGERATINCKSSQSLLYSRNQKNYLAWYQQKPGQPPKLLIFWASTRESGVPDRFSGSGFGTDFTLTISSLQAEDVAVYYCQQYFSYPLTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKTSRYTFTEYTIHWVRQAPGQRLEWIGGINPNNGIPNYNQKFKGRVTITVDTSASTAYMELSSLRSEDTAVYYCARRRIAYGYDEGHAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIVMTQSPDSLAVSLGERATINCKSSQSLLYSRNQKNYLAWYQQKPGQPPKLLIFWASTRESGVPDRFSGSGFGTDFTLTISSLQAEDVAVYYCQQYFSYPLTFGQGTKVEIK
[序列10]抗人類FAP HC人類IgG1 Fc臼DANG-人類scIL-12
QVQLVQSGAEVKKPGASVKVSCKTSRYTFTEYTIHWVRQAPGQRLEWIGGINPNNGIPNYNQKFKGRVTITVDTSASTAYMELSSLRSEDTAVYYCARRRIAYGYDEGHAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSIWELKKDVYVVELDWYPDAPGEMVVLTCDTPEEDGITWTLDQSSEVLGSGKTLTIQVKEFGDAGQYTCHKGGEVLSHSLLLLHKKEDGIWSTDILKDQKEPKNKTFLRCEAKNYSGRFTCWWLTTISTDLTFSVKSSRGSSDPQGVTCGAATLSAERVRGDNKEYEYSVECQEDSACPAAEESLPIEVMVDAVHKLKYENYTSSFFIRDIIKPDPPKNLQLKPLKNSRQVEVSWEYPDTWSTPHSYFSLTFCVQVQGKSKREKKDRVFTDKTSATVICRKNASISVRAQDRYYSSSWSEWASVPCSGGGGSGGGGSGGGGSRNLPVATPDPGMFPCLHHSQNLLRAVSNMLQKARQTLEFYPCTSEEIDHEDITKDKTSTVEACLPLELTKNESCLNSRETSFITNGSCLASRKTSFMMALCLSSIYEDLKMYQVEFKTMNAKLLMDPKRQIFLDQNMLAVIDELMQALNFNSETVPQKSSLEEPDFYKTKIKLCILLHAFRIRAVTIDRVMSYLNAS
[序列11]抗人類FAP HC人類IgG1 Fc臼DANG-人類scIL-12突變2
QVQLVQSGAEVKKPGASVKVSCKTSRYTFTEYTIHWVRQAPGQRLEWIGGINPNNGIPNYNQKFKGRVTITVDTSASTAYMELSSLRSEDTAVYYCARRRIAYGYDEGHAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSIWELKKDVYVVELDWYPDAPGEMVVLTCDTPEEDGITWTLDQSSEVLGSGKTLTIQVKEFGDAGQYTCHKGGEVLSHSLLLLHKKEDGIWSTDILKDQKEPKNKTFLRCEAKNYSGRFTCWWLTTISTDLTFSVKSSRGSSDPQGVTCGAATLSAERVRGDNKEYEYSVECQEDSACPAAEESLPIEVMVDAVHKLKYENYTSSFFIRDIIKPDPPKNLQLKPLKNSRQVEVSWEYPDTWSTPHSYFSLTFCVQVQGASAREAADRVFTDKTSATVICRKNASISVRAQDRYYSSSWSEWASVPCSGGGGSGGGGSGGGGSRNLPVATPDPGMFPCLHHSQNLLRAVSNMLQKARQTLEFYPCTSEEIDHEDITKDKTSTVEACLPLELTKNESCLNSRETSFITNGSCLASRKTSFMMALCLSSIYEDLKMYQVEFKTMNAKLLMDPKRQIFLDQNMLAVIDELMQALNFNSETVPQKSSLEEPDFYKTKIKLCILLHAFRIRAVTIDRVMSYLNAS
[序列12]人類IgG1 Fc臼DANG
DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
[序列13]人類IgG1 Fc杵DANG
DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
[序列14]抗人類FAP HC人類IgG1 Fc DANG
QVQLVQSGAEVKKPGASVKVSCKTSRYTFTEYTIHWVRQAPGQRLEWIGGINPNNGIPNYNQKFKGRVTITVDTSASTAYMELSSLRSEDTAVYYCARRRIAYGYDEGHAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
[序列15]人類scIL-12突變2-人類IgG1 Fc DANG
IWELKKDVYVVELDWYPDAPGEMVVLTCDTPEEDGITWTLDQSSEVLGSGKTLTIQVKEFGDAGQYTCHKGGEVLSHSLLLLHKKEDGIWSTDILKDQKEPKNKTFLRCEAKNYSGRFTCWWLTTISTDLTFSVKSSRGSSDPQGVTCGAATLSAERVRGDNKEYEYSVECQEDSACPAAEESLPIEVMVDAVHKLKYENYTSSFFIRDIIKPDPPKNLQLKPLKNSRQVEVSWEYPDTWSTPHSYFSLTFCVQVQGASAREAADRVFTDKTSATVICRKNASISVRAQDRYYSSSWSEWASVPCSGGGGSGGGGSGGGGSRNLPVATPDPGMFPCLHHSQNLLRAVSNMLQKARQTLEFYPCTSEEIDHEDITKDKTSTVEACLPLELTKNESCLNSRETSFITNGSCLASRKTSFMMALCLSSIYEDLKMYQVEFKTMNAKLLMDPKRQIFLDQNMLAVIDELMQALNFNSETVPQKSSLEEPDFYKTKIKLCILLHAFRIRAVTIDRVMSYLNASGGGGSGGGGSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
[序列16]抗人類CD20 HC人類IgG1 Fc杵DANG
QVQLQQPGAELVKPGASVKMSCKASGYTFTSYNMHWVKQTPGRGLEWIGAIYPGNGDTSYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYCARSTYYGGDWYFNVWGAGTTVTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
[序列17]抗人類CD20 LC
QIVLSQSPAILSASPGEKVTMTCRASSSVSYIHWFQQKPGSSPKPWIYATSNLASGVPVRFSGSGSGTSYSLTISRVEAEDAATYYCQQWTSNPPTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
[序列292]人類scIL-12-人類IgG1 Fc臼DANG-抗人類FAP scFv
IWELKKDVYVVELDWYPDAPGEMVVLTCDTPEEDGITWTLDQSSEVLGSGKTLTIQVKEFGDAGQYTCHKGGEVLSHSLLLLHKKEDGIWSTDILKDQKEPKNKTFLRCEAKNYSGRFTCWWLTTISTDLTFSVKSSRGSSDPQGVTCGAATLSAERVRGDNKEYEYSVECQEDSACPAAEESLPIEVMVDAVHKLKYENYTSSFFIRDIIKPDPPKNLQLKPLKNSRQVEVSWEYPDTWSTPHSYFSLTFCVQVQGKSKREKKDRVFTDKTSATVICRKNASISVRAQDRYYSSSWSEWASVPCSGGGGSGGGGSGGGGSRNLPVATPDPGMFPCLHHSQNLLRAVSNMLQKARQTLEFYPCTSEEIDHEDITKDKTSTVEACLPLELTKNESCLNSRETSFITNGSCLASRKTSFMMALCLSSIYEDLKMYQVEFKTMNAKLLMDPKRQIFLDQNMLAVIDELMQALNFNSETVPQKSSLEEPDFYKTKIKLCILLHAFRIRAVTIDRVMSYLNASGGGGSGGGGSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKTSRYTFTEYTIHWVRQAPGQRLEWIGGINPNNGIPNYNQKFKGRVTITVDTSASTAYMELSSLRSEDTAVYYCARRRIAYGYDEGHAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIVMTQSPDSLAVSLGERATINCKSSQSLLYSRNQKNYLAWYQQKPGQPPKLLIFWASTRESGVPDRFSGSGFGTDFTLTISSLQAEDVAVYYCQQYFSYPLTFGQGTKVEIK
[序列293]人類scIL-12突變2-人類IgG1 Fc臼DANG-抗人類FAP scFv
IWELKKDVYVVELDWYPDAPGEMVVLTCDTPEEDGITWTLDQSSEVLGSGKTLTIQVKEFGDAGQYTCHKGGEVLSHSLLLLHKKEDGIWSTDILKDQKEPKNKTFLRCEAKNYSGRFTCWWLTTISTDLTFSVKSSRGSSDPQGVTCGAATLSAERVRGDNKEYEYSVECQEDSACPAAEESLPIEVMVDAVHKLKYENYTSSFFIRDIIKPDPPKNLQLKPLKNSRQVEVSWEYPDTWSTPHSYFSLTFCVQVQGASAREAADRVFTDKTSATVICRKNASISVRAQDRYYSSSWSEWASVPCSGGGGSGGGGSGGGGSRNLPVATPDPGMFPCLHHSQNLLRAVSNMLQKARQTLEFYPCTSEEIDHEDITKDKTSTVEACLPLELTKNESCLNSRETSFITNGSCLASRKTSFMMALCLSSIYEDLKMYQVEFKTMNAKLLMDPKRQIFLDQNMLAVIDELMQALNFNSETVPQKSSLEEPDFYKTKIKLCILLHAFRIRAVTIDRVMSYLNASGGGGSGGGGSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKTSRYTFTEYTIHWVRQAPGQRLEWIGGINPNNGIPNYNQKFKGRVTITVDTSASTAYMELSSLRSEDTAVYYCARRRIAYGYDEGHAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIVMTQSPDSLAVSLGERATINCKSSQSLLYSRNQKNYLAWYQQKPGQPPKLLIFWASTRESGVPDRFSGSGFGTDFTLTISSLQAEDVAVYYCQQYFSYPLTFGQGTKVEIK
[序列294]抗人類FAP HC人類IgG1 Fc DANG-人類scIL-12
QVQLVQSGAEVKKPGASVKVSCKTSRYTFTEYTIHWVRQAPGQRLEWIGGINPNNGIPNYNQKFKGRVTITVDTSASTAYMELSSLRSEDTAVYYCARRRIAYGYDEGHAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSIWELKKDVYVVELDWYPDAPGEMVVLTCDTPEEDGITWTLDQSSEVLGSGKTLTIQVKEFGDAGQYTCHKGGEVLSHSLLLLHKKEDGIWSTDILKDQKEPKNKTFLRCEAKNYSGRFTCWWLTTISTDLTFSVKSSRGSSDPQGVTCGAATLSAERVRGDNKEYEYSVECQEDSACPAAEESLPIEVMVDAVHKLKYENYTSSFFIRDIIKPDPPKNLQLKPLKNSRQVEVSWEYPDTWSTPHSYFSLTFCVQVQGKSKREKKDRVFTDKTSATVICRKNASISVRAQDRYYSSSWSEWASVPCSGGGGSGGGGSGGGGSRNLPVATPDPGMFPCLHHSQNLLRAVSNMLQKARQTLEFYPCTSEEIDHEDITKDKTSTVEACLPLELTKNESCLNSRETSFITNGSCLASRKTSFMMALCLSSIYEDLKMYQVEFKTMNAKLLMDPKRQIFLDQNMLAVIDELMQALNFNSETVPQKSSLEEPDFYKTKIKLCILLHAFRIRAVTIDRVMSYLNAS
[序列295]抗人類FAP HC人類IgG1 Fc DANG-人類scIL-12突變2
QVQLVQSGAEVKKPGASVKVSCKTSRYTFTEYTIHWVRQAPGQRLEWIGGINPNNGIPNYNQKFKGRVTITVDTSASTAYMELSSLRSEDTAVYYCARRRIAYGYDEGHAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSIWELKKDVYVVELDWYPDAPGEMVVLTCDTPEEDGITWTLDQSSEVLGSGKTLTIQVKEFGDAGQYTCHKGGEVLSHSLLLLHKKEDGIWSTDILKDQKEPKNKTFLRCEAKNYSGRFTCWWLTTISTDLTFSVKSSRGSSDPQGVTCGAATLSAERVRGDNKEYEYSVECQEDSACPAAEESLPIEVMVDAVHKLKYENYTSSFFIRDIIKPDPPKNLQLKPLKNSRQVEVSWEYPDTWSTPHSYFSLTFCVQVQGASAREAADRVFTDKTSATVICRKNASISVRAQDRYYSSSWSEWASVPCSGGGGSGGGGSGGGGSRNLPVATPDPGMFPCLHHSQNLLRAVSNMLQKARQTLEFYPCTSEEIDHEDITKDKTSTVEACLPLELTKNESCLNSRETSFITNGSCLASRKTSFMMALCLSSIYEDLKMYQVEFKTMNAKLLMDPKRQIFLDQNMLAVIDELMQALNFNSETVPQKSSLEEPDFYKTKIKLCILLHAFRIRAVTIDRVMSYLNAS
[序列296]人類scIL-12-人類IgG1 Fc DANG-抗人類FAP scFv
IWELKKDVYVVELDWYPDAPGEMVVLTCDTPEEDGITWTLDQSSEVLGSGKTLTIQVKEFGDAGQYTCHKGGEVLSHSLLLLHKKEDGIWSTDILKDQKEPKNKTFLRCEAKNYSGRFTCWWLTTISTDLTFSVKSSRGSSDPQGVTCGAATLSAERVRGDNKEYEYSVECQEDSACPAAEESLPIEVMVDAVHKLKYENYTSSFFIRDIIKPDPPKNLQLKPLKNSRQVEVSWEYPDTWSTPHSYFSLTFCVQVQGKSKREKKDRVFTDKTSATVICRKNASISVRAQDRYYSSSWSEWASVPCSGGGGSGGGGSGGGGSRNLPVATPDPGMFPCLHHSQNLLRAVSNMLQKARQTLEFYPCTSEEIDHEDITKDKTSTVEACLPLELTKNESCLNSRETSFITNGSCLASRKTSFMMALCLSSIYEDLKMYQVEFKTMNAKLLMDPKRQIFLDQNMLAVIDELMQALNFNSETVPQKSSLEEPDFYKTKIKLCILLHAFRIRAVTIDRVMSYLNASGGGGSGGGGSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKTSRYTFTEYTIHWVRQAPGQRLEWIGGINPNNGIPNYNQKFKGRVTITVDTSASTAYMELSSLRSEDTAVYYCARRRIAYGYDEGHAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIVMTQSPDSLAVSLGERATINCKSSQSLLYSRNQKNYLAWYQQKPGQPPKLLIFWASTRESGVPDRFSGSGFGTDFTLTISSLQAEDVAVYYCQQYFSYPLTFGQGTKVEIK
[序列297]人類scIL-12突變2-人類IgG1 Fc DANG-抗人類FAP scFv
IWELKKDVYVVELDWYPDAPGEMVVLTCDTPEEDGITWTLDQSSEVLGSGKTLTIQVKEFGDAGQYTCHKGGEVLSHSLLLLHKKEDGIWSTDILKDQKEPKNKTFLRCEAKNYSGRFTCWWLTTISTDLTFSVKSSRGSSDPQGVTCGAATLSAERVRGDNKEYEYSVECQEDSACPAAEESLPIEVMVDAVHKLKYENYTSSFFIRDIIKPDPPKNLQLKPLKNSRQVEVSWEYPDTWSTPHSYFSLTFCVQVQGASAREAADRVFTDKTSATVICRKNASISVRAQDRYYSSSWSEWASVPCSGGGGSGGGGSGGGGSRNLPVATPDPGMFPCLHHSQNLLRAVSNMLQKARQTLEFYPCTSEEIDHEDITKDKTSTVEACLPLELTKNESCLNSRETSFITNGSCLASRKTSFMMALCLSSIYEDLKMYQVEFKTMNAKLLMDPKRQIFLDQNMLAVIDELMQALNFNSETVPQKSSLEEPDFYKTKIKLCILLHAFRIRAVTIDRVMSYLNASGGGGSGGGGSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKTSRYTFTEYTIHWVRQAPGQRLEWIGGINPNNGIPNYNQKFKGRVTITVDTSASTAYMELSSLRSEDTAVYYCARRRIAYGYDEGHAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIVMTQSPDSLAVSLGERATINCKSSQSLLYSRNQKNYLAWYQQKPGQPPKLLIFWASTRESGVPDRFSGSGFGTDFTLTISSLQAEDVAVYYCQQYFSYPLTFGQGTKVEIK
製備實例2. 抗FAP/IL-12 IgG2a DANG 小鼠融合蛋白之概述[表2]
編碼 | 型式 | 描述 | 對應序列 |
T1.01m | K&H | 抗小鼠FAP/小鼠IL-12、小鼠IgG2a DANG | 序列18、序列19、序列20 |
T1.02m | K&H | 抗小鼠FAP/小鼠IL-12突變1、小鼠IgG2a DANG | 序列18、序列19、序列21 |
T1.03m | K&H | 抗小鼠FAP/小鼠IL-12突變2、小鼠IgG2a DANG | 序列18、序列19、序列22 |
T1.04m | K&H | 抗小鼠FAP/小鼠IL-12、小鼠IgG2a DANG (2+1) | 序列20、序列23、序列24 |
T1.05m | K&H | 抗小鼠FAP/小鼠IL-12突變2、小鼠IgG2a DANG (2+1) | 序列22、序列23、序列24 |
T1.06m | K&H | 抗小鼠FAP/小鼠IL-12、小鼠IgG2a DANG (2+1,HC scFv) | 序列19、序列20、序列25 |
T1.07m | K&H | 抗小鼠FAP/小鼠IL-12突變2、小鼠IgG2a DANG (2+1,HC scFv) | 序列19、序列22、序列25 |
T1.08m | K&H | 抗小鼠FAP/小鼠IL-12、小鼠IgG2a DANG (2+1,LC scFv) | 序列18、序列20、序列26 |
T1.09m | K&H | 抗小鼠FAP/小鼠IL-12突變2、小鼠IgG2a DANG (2+1、LC scFv) | 序列18、序列22、序列26 |
T1.10m | K&H | 抗小鼠FAP/抗小鼠FAP-小鼠IL-12、小鼠IgG2a DANG (2+1) | 序列18、序列19、序列27 |
T1.11m | K&H | 抗小鼠FAP/抗小鼠FAP-小鼠IL-12突變2、小鼠IgG2a DANG (2+1) | 序列18、序列19、序列28 |
T1.12m | K&H | 抗小鼠FAP/空、小鼠IgG2a DANG | 序列18、序列19、序列29 |
T1.13m | K&H | 空/小鼠IL-12、小鼠IgG2a DANG | 序列20、序列30 |
T1.14m | K&H | 空/小鼠IL-12突變1、小鼠IgG2a DANG | 序列21、序列30 |
T1.15m | K&H | 空/小鼠IL-12突變2、小鼠IgG2a DANG | 序列22、序列30 |
T1.16m | Mab | 抗小鼠FAP、小鼠IgG2a DANG | 序列19、序列31 |
T1.17m | Fc融合 | 小鼠IL-12突變2、小鼠IgG2a DANG | 序列32 |
T1.18m | K&H | 抗小鼠CD20/小鼠IL-12、小鼠IgG2a DANG | 序列20、序列33、序列34 |
T1.19m | K&H | 抗小鼠CD20/小鼠IL-12突變1、小鼠IgG2a DANG | 序列21、序列33、序列34 |
T1.20m | K&H | 抗小鼠CD20/小鼠IL-12突變2、小鼠IgG2a DANG | 序列22、序列33、序列34 |
T1.21m | K&H | 抗小鼠CD20/空、小鼠IgG2a DANG | 序列29、序列33、序列34 |
T1.22m | Fc融合 | 小鼠IgG2a Fc DANG | 序列35 |
T1.23m | K&H | 抗小鼠FAP/小鼠IL-12-抗小鼠FAP scFv、小鼠IgG2a DANG (2+1) | 序列18、序列19、序列298 |
T1.24m | K&H | 抗小鼠FAP/小鼠IL-12突變2-抗小鼠FAP scFv、小鼠IgG2a DANG (2+1) | 序列18、序列19、序列299 |
T1.25m | Fc融合 | 抗小鼠FAP-小鼠IL-12、小鼠IgG2a DANG | 序列19、序列300 |
T1.26m | Fc融合 | 抗小鼠FAP-小鼠IL-12突變2、小鼠IgG2a DANG | 序列19、序列301 |
T1.27m | Fc融合 | 小鼠IL-12-抗小鼠FAP scFv、小鼠IgG2a DANG | 序列302 |
T1.28m | Fc融合 | 小鼠IL-12突變2-抗小鼠FAP scFv、小鼠IgG2a DANG | 序列303 |
[序列18]由小鼠抗FAP重鏈可變區序列及小鼠IgG2a Fc構成,其中經由DANG突變(D265A、N297G)移除效應功能,且藉由T321W突變形成杵結構。
[序列19]由小鼠抗FAP輕鏈序列構成。
[序列20]由小鼠IL-12 p40 (β)區序列、連接子GGGGSGGGGSGGGGS、小鼠IL-12 p35 (α)區序列、連接子GGGGSGGGGS及小鼠IgG2a Fc構成,其中經由DANG突變移除效應功能且藉由T321S、M323A、Y362V突變形成臼結構。
[序列21]由其中小鼠IL-12 p40 (β)區中涉及肝素結合之第277及第282胺基酸處之離胺酸(K)突變成丙胺酸(A)的序列、連接子GGGGSGGGGSGGGGS、小鼠IL-12 p35 (α)區序列、連接子GGGGSGGGGS及小鼠IgG2a Fc臼DANG構成。
[序列22]由其中小鼠IL-12 p40 (β)區中涉及肝素結合之第276胺基酸處之精胺酸(R)及第277、第278及第282胺基酸處之離胺酸(K)突變成丙胺酸(A)的序列、連接子GGGGSGGGGSGGGGS、小鼠IL-12 p35 (α)區序列、連接子GGGGSGGGGS及小鼠IgG2a Fc臼DANG構成。
[序列23]由小鼠抗FAP重鏈可變區序列、連接子GGGGSGGGGSGGGGS、小鼠抗FAP重鏈可變區序列及小鼠IgG2a Fc杵DANG構成。
[序列24]由小鼠抗FAP輕鏈可變區序列、連接子GGGGSGGGGSGGGGS及小鼠抗FAP輕鏈序列構成。
[序列25]由小鼠抗FAP重鏈可變區序列、小鼠IgG2a Fc杵DANG、連接子GGGGSGGGGSGGGGS、小鼠抗FAP重鏈可變區序列、連接子GGGGSGGGGSGGGGSGGGGS及小鼠抗FAP輕鏈可變區序列構成。
[序列26]由小鼠抗FAP輕鏈序列、連接子GGGGSGGGGSGGGGS、小鼠抗FAP重鏈可變區序列、連接子GGGGSGGGGSGGGGSGGGGS及小鼠抗FAP輕鏈可變區序列構成。
[序列27]由小鼠抗FAP重鏈序列、小鼠IgG2a Fc臼DANG、連接子GGGGSGGGGSGGGGS、小鼠IL-12之p40 (β)區序列、連接子GGGGSGGGGSGGGGS及小鼠IL-12 p35 (α)區序列構成。
[序列28]由小鼠抗FAP重鏈序列、小鼠IgG2a Fc臼DANG、連接子GGGGSGGGGSGGGGS、含有涉及肝素結合之胺基酸的突變(四個)的小鼠IL-12的p40 (β)區序列、連接子GGGGSGGGGSGGGGS及小鼠IL-12 p35 (α)區序列構成。
[序列29]僅由小鼠IgG2a Fc臼DANG構成。
[序列30]僅由小鼠IgG2a Fc杵DANG構成。
[序列31]由小鼠抗FAP重鏈可變區及小鼠IgG2a Fc DANG構成。
[序列32]由含有涉及肝素結合之胺基酸之突變(四個)的小鼠IL-12之p40 (β)區序列、連接子GGGGSGGGGSGGGGS、小鼠IL-12 p35 (α)區序列、連接子GGGGSGGGGS及小鼠IgG2a Fc DANG構成。
[序列33]由小鼠抗CD20抗體18B12之重鏈可變區序列及小鼠IgG2a杵DANG構成。
[序列34]由小鼠抗CD20抗體18B12之輕鏈序列構成。
[序列35]僅由小鼠IgG2a Fc DANG構成。
[序列298]由小鼠IL-12 p40 (β)區序列、連接子GGGGSGGGGSGGGGS、小鼠IL-12 p35 (α)區序列、連接子GGGGSGGGGS及小鼠IgG2a Fc臼DANG、連接子GGGGSGGGGSGGGGS、小鼠抗FAP重鏈可變區序列、連接子GGGGSGGGGSGGGGSGGGGS及小鼠抗FAP輕鏈可變區序列構成。
[序列299]由含有涉及肝素結合之胺基酸之突變(四個)的小鼠IL-12 p40 (β)區序列、連接子GGGGSGGGGSGGGGS、小鼠IL-12 p35 (α)區序列、連接子GGGGSGGGGS及小鼠IgG2a Fc臼DANG、連接子GGGGSGGGGSGGGGS、小鼠抗FAP重鏈可變區序列、連接子GGGGSGGGGSGGGGSGGGGS及小鼠抗FAP輕鏈可變區序列構成。
[序列300]由小鼠抗FAP重鏈序列、小鼠IgG2a Fc DANG、連接子GGGGSGGGGSGGGGS、小鼠IL-12之p40 (β)區序列、連接子GGGGSGGGGSGGGGS及小鼠IL-12 p35 (α)區序列構成。
[序列301]由小鼠抗FAP重鏈序列、小鼠IgG1 Fc DANG、連接子GGGGSGGGGSGGGGS、含有涉及肝素結合之胺基酸的突變(四個)的小鼠IL-12的p40 (β)區序列、連接子GGGGSGGGGSGGGGS及小鼠IL-12 p35 (α)區序列構成。
[序列302]由小鼠IL-12 p40 (β)區序列、連接子GGGGSGGGGSGGGGS、小鼠IL-12 p35 (α)區序列、連接子GGGGSGGGGS及小鼠IgG2a Fc DANG、連接子GGGGSGGGGSGGGGS、小鼠抗FAP重鏈可變區序列、連接子GGGGSGGGGSGGGGSGGGGS及小鼠抗FAP輕鏈可變區序列構成。
[序列303]由含有涉及肝素結合之胺基酸之突變(四個)的小鼠IL-12 p40 (β)區序列、連接子GGGGSGGGGSGGGGS、小鼠IL-12 p35 (α)區序列、連接子GGGGSGGGGS及小鼠IgG2a Fc DANG、連接子GGGGSGGGGSGGGGS、小鼠抗FAP重鏈可變區序列、連接子GGGGSGGGGSGGGGSGGGGS及小鼠抗FAP輕鏈可變區序列構成。
T1.01m (序列18、序列19、序列20)為雙特異性抗體,其中靶向小鼠FAP之小鼠抗FAP序列及小鼠IL-12序列形成杵-入-臼結構,且移除效應功能。
T1.02m (序列18、序列19、序列21)為雙特異性抗體,其中靶向小鼠FAP之小鼠抗FAP序列及含有涉及肝素結合之胺基酸之突變(二個)的小鼠IL-12序列形成杵-入-臼結構,且移除效應功能。
T1.03m (序列18、序列19、序列22)為雙特異性抗體,其中靶向小鼠FAP之小鼠抗FAP序列及含有涉及肝素結合之胺基酸之突變(四個)的小鼠IL-12序列形成杵-入-臼結構,且移除效應功能。
T1.04m (序列20、序列23、序列24)為雙特異性抗體,其中呈雙可變區域免疫球蛋白(DVD-Ig)形式之靶向小鼠FAP之小鼠抗FAP序列及小鼠IL-12序列形成杵-入-臼結構,且移除效應功能。
T1.05m (序列22、序列23、序列24)為雙特異性抗體,其中呈DVD-Ig形式之靶向小鼠FAP之小鼠抗FAP序列及含有涉及肝素結合之胺基酸之突變(四個)的小鼠IL-12序列形成杵-入-臼結構,且移除效應功能。
T1.06m (序列19、序列20、序列25)為雙特異性抗體,其中靶向小鼠FAP之小鼠抗FAP序列之單鏈可變片段(scFv)包括於重鏈之C端的小鼠抗FAP序列及小鼠IL-12序列形成杵-入-臼結構,且移除效應功能。
T1.07m (序列19、序列22、序列25)為雙特異性抗體,其中靶向小鼠FAP之小鼠抗FAP序列之scFv包括於重鏈之C端的小鼠抗FAP序列及含有涉及肝素結合之胺基酸之突變(四個)的小鼠IL-12序列形成杵-入-臼結構,且移除效應功能。
T1.08m (序列18、序列20、序列26)為雙特異性抗體,其中靶向小鼠FAP之小鼠抗FAP序列之scFv包括於輕鏈之C端的小鼠抗FAP序列及小鼠IL-12序列形成杵-入-臼結構,且移除效應功能。
T1.09m (序列18、序列22、序列26)為雙特異性抗體,其中靶向小鼠FAP之小鼠抗FAP序列之scFv包括於輕鏈之C端的小鼠抗FAP序列及含有涉及肝素結合之胺基酸之突變(四個)的小鼠IL-12序列形成杵-入-臼結構,且移除效應功能。
T1.10m (序列18、序列19、序列27)為靶向小鼠FAP之小鼠抗FAP序列及其中小鼠IL-12序列連接至重鏈之C端的小鼠抗FAP序列形成杵-入-臼結構的抗體。
T1.11m (序列18、序列19、序列28)為靶向小鼠FAP之小鼠抗FAP序列及其中含有涉及肝素結合之胺基酸之突變(四個)的小鼠IL-12序列連接於重鏈之C端的小鼠抗FAP序列形成杵-入-臼結構的抗體。
T1.12m (序列18、序列19、序列29)為一種抗體,其中移除僅具有靶向小鼠FAP之小鼠抗FAP序列之杵-入-臼結構的效應功能。
T1.13m (序列20、序列30)為其中移除僅具有小鼠IL-12序列之杵-入-臼結構之效應功能的抗體。
T1.14m (序列21、序列30)為一種抗體,其中移除僅具有含有涉及肝素結合之胺基酸之突變(二個)的小鼠IL-12序列之杵-入-臼結構的效應功能。
T1.15m (序列22、序列30)為一種抗體,其中移除僅具有含有涉及肝素結合之胺基酸之突變(四個)的小鼠IL-12序列之杵-入-臼結構的效應功能。
T1.16m (序列19、序列31)為靶向小鼠FAP之小鼠抗FAP抗體。
T1.17m (序列32)為僅具有含有涉及肝素結合之胺基酸之突變(四個)的小鼠IL-12序列之Fc融合蛋白二聚體。
T1.18m (序列20、序列33、序列34)為雙特異性抗體,其中靶向小鼠CD20之小鼠抗CD20 (18B12)序列及小鼠IL-12序列形成杵-入-臼結構,且移除效應功能。
T1.19m (序列21、序列33、序列34)為雙特異性抗體,其中靶向小鼠CD20之小鼠抗CD20 (18B12)序列及含有涉及肝素結合之胺基酸之突變(二個)的小鼠IL-12序列形成杵-入-臼結構,且移除效應功能。
T1.20m (序列22、序列33、序列34)為雙特異性抗體,其中靶向小鼠CD20之小鼠抗CD20序列及含有涉及肝素結合之胺基酸之突變(四個)的小鼠IL-12序列形成杵-入-臼結構,且移除效應功能。
T1.21m (序列29、序列33、序列34)為一種抗體,其中移除僅具有靶向小鼠CD20之小鼠抗CD20序列之杵-入-臼結構的效應功能。
T1.22m (序列35)為僅具有小鼠Fc序列的蛋白質,其中移除效應功能。
T1.23m (序列18、序列19、序列298)為雙特異性抗體,其中小鼠抗FAP序列及其中小鼠抗FAP序列之scFv連接至C端的小鼠IL-12序列形成杵-入-臼結構,且移除效應功能。
T1.24m (序列18、序列19、序列299)為雙特異性抗體,其中小鼠抗FAP重鏈序列及其中小鼠抗FAP序列之scFv連接至C端的含有涉及肝素結合之胺基酸之突變(四個)的小鼠IL-12序列形成杵-入-臼結構,且移除效應功能。
T1.25m (序列19、序列300)為含有小鼠抗FAP序列之Fc融合蛋白二聚體,其中小鼠IL-12序列連接至重鏈之C端。
T1.26m (序列19、序列301)為含有小鼠抗FAP序列之Fc融合蛋白二聚體,其中含有涉及肝素結合之胺基酸之突變(四個)的小鼠IL-12序列連接至重鏈之C端。
T1.27m (序列302)為含有小鼠IL-12序列之Fc融合蛋白二聚體,其中小鼠抗FAP序列之scFv連接至C端。
T1.28m (序列303)為由含有涉及肝素結合之胺基酸之突變(四個)的小鼠IL-12序列構成之Fc融合蛋白二聚體,其中小鼠抗FAP序列之scFv連接至C端。
[序列18]抗小鼠FAP HC小鼠IgG2a Fc杵DANG
QVQLQQSGAELARPGASVNLSCKASGYTFTNNGINWLKQRTGQGLEWIGEIYPRSTNTLYNEKFKGKATLTADRSSNTAYMELRSLTSEDSAVYFCARTLTAPFAFWGQGTLVTVSAAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVAVSEDDPDVQISWFVNNVEVHTAQTQTHREDYGSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLWCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK
[序列19]抗小鼠FAP LC
QIVLTQSPAIMSASPGEKVTMTCSASSGVNFMHWYQQKSGTSPKRWIFDTSKLASGVPARFSGSGSGTSYSLTISSMEAEDAATYYCQQWSFNPPTFGGGTKLEIKRADAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWK
IDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC
[序列20]小鼠scIL-12-小鼠IgG2a Fc臼DANG
MWELEKDVYVVEVDWTPDAPGETVNLTCDTPEEDDITWTSDQRHGVIGSGKTLTITVKEFLDAGQYTCHKGGETLSHSHLLLHKKENGIWSTEILKNFKNKTFLKCEAPNYSGRFTCSWLVQRNMDLKFNIKSSSSSPDSRAVTCGMASLSAEKVTLDQRDYEKYSVSCQEDVTCPTAEETLPIELALEARQQNKYENYSTSFFIRDIIKPDPPKNLQMKPLKNSQVEVSWEYPDSWSTPHSYFSLKFFVRIQRKKEKMKETEEGCNQKGAFLVEKTSTEVQCKGGNVCVQAQDRYYNSSCSKWACVPCRVRSGGGGSGGGGSGGGGSRVIPVSGPARCLSQSRNLLKTTDDMVKTAREKLKHYSCTAEDIDHEDITRDQTSTLKTCLPLELHKNESCLATRETSSTTRGSCLPPQKTSLMMTLCLGSIYEDLKMYQTEFQAINAALQNHNHQQIILDKGMLVAIDELMQSLNHNGETLRQKPPVGEADPYRVKMKLCILLHAFSTRVVTINRVMGYLSSAGGGGSGGGGSEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVAVSEDDPDVQISWFVNNVEVHTAQTQTHREDYGSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLSCAVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMVSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK
[序列21]小鼠scIL-12突變1-小鼠IgG2a Fc臼DANG
MWELEKDVYVVEVDWTPDAPGETVNLTCDTPEEDDITWTSDQRHGVIGSGKTLTITVKEFLDAGQYTCHKGGETLSHSHLLLHKKENGIWSTEILKNFKNKTFLKCEAPNYSGRFTCSWLVQRNMDLKFNIKSSSSSPDSRAVTCGMASLSAEKVTLDQRDYEKYSVSCQEDVTCPTAEETLPIELALEARQQNKYENYSTSFFIRDIIKPDPPKNLQMKPLKNSQVEVSWEYPDSWSTPHSYFSLKFFVRIQRAKEKMAETEEGCNQKGAFLVEKTSTEVQCKGGNVCVQAQDRYYNSSCSKWACVPCRVRSGGGGSGGGGSGGGGSRVIPVSGPARCLSQSRNLLKTTDDMVKTAREKLKHYSCTAEDIDHEDITRDQTSTLKTCLPLELHKNESCLATRETSSTTRGSCLPPQKTSLMMTLCLGSIYEDLKMYQTEFQAINAALQNHNHQQIILDKGMLVAIDELMQSLNHNGETLRQKPPVGEADPYRVKMKLCILLHAFSTRVVTINRVMGYLSSAGGGGSGGGGSEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVAVSEDDPDVQISWFVNNVEVHTAQTQTHREDYGSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLSCAVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMVSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK
[序列22]小鼠scIL-12突變2-小鼠IgG2a Fc臼DANG
MWELEKDVYVVEVDWTPDAPGETVNLTCDTPEEDDITWTSDQRHGVIGSGKTLTITVKEFLDAGQYTCHKGGETLSHSHLLLHKKENGIWSTEILKNFKNKTFLKCEAPNYSGRFTCSWLVQRNMDLKFNIKSSSSSPDSRAVTCGMASLSAEKVTLDQRDYEKYSVSCQEDVTCPTAEETLPIELALEARQQNKYENYSTSFFIRDIIKPDPPKNLQMKPLKNSQVEVSWEYPDSWSTPHSYFSLKFFVRIQAAAEKMAETEEGCNQKGAFLVEKTSTEVQCKGGNVCVQAQDRYYNSSCSKWACVPCRVRSGGGGSGGGGSGGGGSRVIPVSGPARCLSQSRNLLKTTDDMVKTAREKLKHYSCTAEDIDHEDITRDQTSTLKTCLPLELHKNESCLATRETSSTTRGSCLPPQKTSLMMTLCLGSIYEDLKMYQTEFQAINAALQNHNHQQIILDKGMLVAIDELMQSLNHNGETLRQKPPVGEADPYRVKMKLCILLHAFSTRVVTINRVMGYLSSAGGGGSGGGGSEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVAVSEDDPDVQISWFVNNVEVHTAQTQTHREDYGSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLSCAVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMVSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK
[序列23] (抗小鼠FAP VH)2、小鼠IgG2a Fc杵DANG
QVQLQQSGAELARPGASVNLSCKASGYTFTNNGINWLKQRTGQGLEWIGEIYPRSTNTLYNEKFKGKATLTADRSSNTAYMELRSLTSEDSAVYFCARTLTAPFAFWGQGTLVTVSAGGGGSGGGGSGGGGSQVQLQQSGAELARPGASVNLSCKASGYTFTNNGINWLKQRTGQGLEWIGEIYPRSTNTLYNEKFKGKATLTADRSSNTAYMELRSLTSEDSAVYFCARTLTAPFAFWGQGTLVTVSAAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVAVSEDDPDVQISWFVNNVEVHTAQTQTHREDYGSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLWCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK
[序列24] (抗小鼠FAP VL)2
QIVLTQSPAIMSASPGEKVTMTCSASSGVNFMHWYQQKSGTSPKRWIFDTSKLASGVPARFSGSGSGTSYSLTISSMEAEDAATYYCQQWSFNPPTFGGGTKLEIKGGGGSGGGGSGGGGSQIVLTQSPAIMSASPGEKVTMTCSASSGVNFMHWYQQKSGTSPKRWIFDTSKLASGVPARFSGSGSGTSYSLTISSMEAEDAATYYCQQWSFNPPTFGGGTKLEIKRADAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC
[序列25]抗小鼠FAP HC小鼠IgG2a Fc杵DANG-抗小鼠FAP scFv
QVQLQQSGAELARPGASVNLSCKASGYTFTNNGINWLKQRTGQGLEWIGEIYPRSTNTLYNEKFKGKATLTADRSSNTAYMELRSLTSEDSAVYFCARTLTAPFAFWGQGTLVTVSAAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVAVSEDDPDVQISWFVNNVEVHTAQTQTHREDYGSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLWCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGKGGGGSGGGGSGGGGSQVQLQQSGAELARPGASVNLSCKASGYTFTNNGINWLKQRTGQGLEWIGEIYPRSTNTLYNEKFKGKATLTADRSSNTAYMELRSLTSEDSAVYFCARTLTAPFAFWGQGTLVTVSAGGGGSGGGGSGGGGSGGGGSQIVLTQSPAIMSASPGEKVTMTCSASSGVNFMHWYQQKSGTSPKRWIFDTSKLASGVPARFSGSGSGTSYSLTISSMEAEDAATYYCQQWSFNPPTFGGGTKLEIK
[序列26]抗小鼠FAP LC-抗小鼠FAP scFv
QIVLTQSPAIMSASPGEKVTMTCSASSGVNFMHWYQQKSGTSPKRWIFDTSKLASGVPARFSGSGSGTSYSLTISSMEAEDAATYYCQQWSFNPPTFGGGTKLEIKRADAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNECGGGGSGGGGSGGGGSQVQLQQSGAELARPGASVNLSCKASGYTFTNNGINWLKQRTGQGLEWIGEIYPRSTNTLYNEKFKGKATLTADRSSNTAYMELRSLTSEDSAVYFCARTLTAPFAFWGQGTLVTVSAGGGGSGGGGSGGGGSGGGGSQIVLTQSPAIMSASPGEKVTMTCSASSGVNFMHWYQQKSGTSPKRWIFDTSKLASGVPARFSGSGSGTSYSLTISSMEAEDAATYYCQQWSFNPPTFGGGTKLEIK
[序列27]抗小鼠FAP HC小鼠IgG2a Fc臼DANG-小鼠scIL-12
QVQLQQSGAELARPGASVNLSCKASGYTFTNNGINWLKQRTGQGLEWIGEIYPRSTNTLYNEKFKGKATLTADRSSNTAYMELRSLTSEDSAVYFCARTLTAPFAFWGQGTLVTVSAAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVAVSEDDPDVQISWFVNNVEVHTAQTQTHREDYGSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLSCAVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMVSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGGGGGSGGGGSGGGGSMWELEKDVYVVEVDWTPDAPGETVNLTCDTPEEDDITWTSDQRHGVIGSGKTLTITVKEFLDAGQYTCHKGGETLSHSHLLLHKKENGIWSTEILKNFKNKTFLKCEAPNYSGRFTCSWLVQRNMDLKFNIKSSSSSPDSRAVTCGMASLSAEKVTLDQRDYEKYSVSCQEDVTCPTAEETLPIELALEARQQNKYENYSTSFFIRDIIKPDPPKNLQMKPLKNSQVEVSWEYPDSWSTPHSYFSLKFFVRIQRKKEKMKETEEGCNQKGAFLVEKTSTEVQCKGGNVCVQAQDRYYNSSCSKWACVPCRVRSGGGGSGGGGSGGGGSRVIPVSGPARCLSQSRNLLKTTDDMVKTAREKLKHYSCTAEDIDHEDITRDQTSTLKTCLPLELHKNESCLATRETSSTTRGSCLPPQKTSLMMTLCLGSIYEDLKMYQTEFQAINAALQNHNHQQIILDKGMLVAIDELMQSLNHNGETLRQKPPVGEADPYRVKMKLCILLHAFSTRVVTINRVMGYLSSA
[序列28]抗小鼠FAP HC小鼠IgG2a Fc臼DANG-小鼠scIL-12突變2
QVQLQQSGAELARPGASVNLSCKASGYTFTNNGINWLKQRTGQGLEWIGEIYPRSTNTLYNEKFKGKATLTADRSSNTAYMELRSLTSEDSAVYFCARTLTAPFAFWGQGTLVTVSAAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVAVSEDDPDVQISWFVNNVEVHTAQTQTHREDYGSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLSCAVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMVSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGGGGGSGGGGSGGGGSMWELEKDVYVVEVDWTPDAPGETVNLTCDTPEEDDITWTSDQRHGVIGSGKTLTITVKEFLDAGQYTCHKGGETLSHSHLLLHKKENGIWSTEILKNFKNKTFLKCEAPNYSGRFTCSWLVQRNMDLKFNIKSSSSSPDSRAVTCGMASLSAEKVTLDQRDYEKYSVSCQEDVTCPTAEETLPIELALEARQQNKYENYSTSFFIRDIIKPDPPKNLQMKPLKNSQVEVSWEYPDSWSTPHSYFSLKFFVRIQAAAEKMAETEEGCNQKGAFLVEKTSTEVQCKGGNVCVQAQDRYYNSSCSKWACVPCRVRSGGGGSGGGGSGGGGSRVIPVSGPARCLSQSRNLLKTTDDMVKTAREKLKHYSCTAEDIDHEDITRDQTSTLKTCLPLELHKNESCLATRETSSTTRGSCLPPQKTSLMMTLCLGSIYEDLKMYQTEFQAINAALQNHNHQQIILDKGMLVAIDELMQSLNHNGETLRQKPPVGEADPYRVKMKLCILLHAFSTRVVTINRVMGYLSSA
[序列29]小鼠IgG2a Fc臼DANG
EPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVAVSEDDPDVQISWFVNNVEVHTAQTQTHREDYGSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLSCAVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMVSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK
[序列30]小鼠IgG2a Fc杵DANG
EPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVAVSEDDPDVQISWFVNNVEVHTAQTQTHREDYGSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLWCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK
[序列31]抗小鼠FAP HC小鼠IgG2a Fc DANG
QVQLQQSGAELARPGASVNLSCKASGYTFTNNGINWLKQRTGQGLEWIGEIYPRSTNTLYNEKFKGKATLTADRSSNTAYMELRSLTSEDSAVYFCARTLTAPFAFWGQGTLVTVSAAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVAVSEDDPDVQISWFVNNVEVHTAQTQTHREDYGSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK
[序列32]小鼠scIL-12突變2-小鼠IgG2a Fc DANG
MWELEKDVYVVEVDWTPDAPGETVNLTCDTPEEDDITWTSDQRHGVIGSGKTLTITVKEFLDAGQYTCHKGGETLSHSHLLLHKKENGIWSTEILKNFKNKTFLKCEAPNYSGRFTCSWLVQRNMDLKFNIKSSSSSPDSRAVTCGMASLSAEKVTLDQRDYEKYSVSCQEDVTCPTAEETLPIELALEARQQNKYENYSTSFFIRDIIKPDPPKNLQMKPLKNSQVEVSWEYPDSWSTPHSYFSLKFFVRIQAAAEKMAETEEGCNQKGAFLVEKTSTEVQCKGGNVCVQAQDRYYNSSCSKWACVPCRVRSGGGGSGGGGSGGGGSRVIPVSGPARCLSQSRNLLKTTDDMVKTAREKLKHYSCTAEDIDHEDITRDQTSTLKTCLPLELHKNESCLATRETSSTTRGSCLPPQKTSLMMTLCLGSIYEDLKMYQTEFQAINAALQNHNHQQIILDKGMLVAIDELMQSLNHNGETLRQKPPVGEADPYRVKMKLCILLHAFSTRVVTINRVMGYLSSAGGGGSGGGGSEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVAVSEDDPDVQISWFVNNVEVHTAQTQTHREDYGSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK
[序列33]抗小鼠CD20 HC小鼠IgG2a Fc杵DANG
QVQLQQPGAELVRPGTSVKLSCKASGYTFTSYWMHWIKQRPGQGLEWIGVIDPSDNYTKYNQKFKGKATLTVDTSSSTAYMQLSSLTSEDSAVYFCAREGYYGSSPWFAYWGQGTLVTVSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVAVSEDDPDVQISWFVNNVEVHTAQTQTHREDYGSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLWCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK
[序列34]抗小鼠CD20 LC
QIVMSQSPAILSASPGEKVTMTCRARSSVSYIHWYQQKPGSSPKPWIYATSNLASGVPGRFSGSGSGTSYSLTITRVEAEDAATYYCQQWSSKPPTFGGGTKLEIKRTDAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC
[序列35]小鼠IgG2a Fc DANG
EPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVAVSEDDPDVQISWFVNNVEVHTAQTQTHREDYGSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK
[序列298]小鼠scIL-12-小鼠IgG2a Fc臼DANG-抗小鼠FAP scFv
MWELEKDVYVVEVDWTPDAPGETVNLTCDTPEEDDITWTSDQRHGVIGSGKTLTITVKEFLDAGQYTCHKGGETLSHSHLLLHKKENGIWSTEILKNFKNKTFLKCEAPNYSGRFTCSWLVQRNMDLKFNIKSSSSSPDSRAVTCGMASLSAEKVTLDQRDYEKYSVSCQEDVTCPTAEETLPIELALEARQQNKYENYSTSFFIRDIIKPDPPKNLQMKPLKNSQVEVSWEYPDSWSTPHSYFSLKFFVRIQRKKEKMKETEEGCNQKGAFLVEKTSTEVQCKGGNVCVQAQDRYYNSSCSKWACVPCRVRSGGGGSGGGGSGGGGSRVIPVSGPARCLSQSRNLLKTTDDMVKTAREKLKHYSCTAEDIDHEDITRDQTSTLKTCLPLELHKNESCLATRETSSTTRGSCLPPQKTSLMMTLCLGSIYEDLKMYQTEFQAINAALQNHNHQQIILDKGMLVAIDELMQSLNHNGETLRQKPPVGEADPYRVKMKLCILLHAFSTRVVTINRVMGYLSSAGGGGSGGGGSEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVAVSEDDPDVQISWFVNNVEVHTAQTQTHREDYGSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLSCAVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMVSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGGGGGSGGGGSGGGGSQVQLQQSGAELARPGASVNLSCKASGYTFTNNGINWLKQRTGQGLEWIGEIYPRSTNTLYNEKFKGKATLTADRSSNTAYMELRSLTSEDSAVYFCARTLTAPFAFWGQGTLVTVSAGGGGSGGGGSGGGGSGGGGSQIVLTQSPAIMSASPGEKVTMTCSASSGVNFMHWYQQKSGTSPKRWIFDTSKLASGVPARFSGSGSGTSYSLTISSMEAEDAATYYCQQWSFNPPTFGGGTKLEIK
[序列299]小鼠scIL-12突變2-小鼠IgG2a Fc臼DANG-抗小鼠FAP scFv
MWELEKDVYVVEVDWTPDAPGETVNLTCDTPEEDDITWTSDQRHGVIGSGKTLTITVKEFLDAGQYTCHKGGETLSHSHLLLHKKENGIWSTEILKNFKNKTFLKCEAPNYSGRFTCSWLVQRNMDLKFNIKSSSSSPDSRAVTCGMASLSAEKVTLDQRDYEKYSVSCQEDVTCPTAEETLPIELALEARQQNKYENYSTSFFIRDIIKPDPPKNLQMKPLKNSQVEVSWEYPDSWSTPHSYFSLKFFVRIQAAAEKMAETEEGCNQKGAFLVEKTSTEVQCKGGNVCVQAQDRYYNSSCSKWACVPCRVRSGGGGSGGGGSGGGGSRVIPVSGPARCLSQSRNLLKTTDDMVKTAREKLKHYSCTAEDIDHEDITRDQTSTLKTCLPLELHKNESCLATRETSSTTRGSCLPPQKTSLMMTLCLGSIYEDLKMYQTEFQAINAALQNHNHQQIILDKGMLVAIDELMQSLNHNGETLRQKPPVGEADPYRVKMKLCILLHAFSTRVVTINRVMGYLSSAGGGGSGGGGSEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVAVSEDDPDVQISWFVNNVEVHTAQTQTHREDYGSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLSCAVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMVSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGGGGGSGGGGSGGGGSQVQLQQSGAELARPGASVNLSCKASGYTFTNNGINWLKQRTGQGLEWIGEIYPRSTNTLYNEKFKGKATLTADRSSNTAYMELRSLTSEDSAVYFCARTLTAPFAFWGQGTLVTVSAGGGGSGGGGSGGGGSGGGGSQIVLTQSPAIMSASPGEKVTMTCSASSGVNFMHWYQQKSGTSPKRWIFDTSKLASGVPARFSGSGSGTSYSLTISSMEAEDAATYYCQQWSFNPPTFGGGTKLEIK
[序列300]抗小鼠FAP HC小鼠IgG2a Fc DANG-小鼠scIL-12
QVQLQQSGAELARPGASVNLSCKASGYTFTNNGINWLKQRTGQGLEWIGEIYPRSTNTLYNEKFKGKATLTADRSSNTAYMELRSLTSEDSAVYFCARTLTAPFAFWGQGTLVTVSAAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVAVSEDDPDVQISWFVNNVEVHTAQTQTHREDYGSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGGGGGSGGGGSGGGGSMWELEKDVYVVEVDWTPDAPGETVNLTCDTPEEDDITWTSDQRHGVIGSGKTLTITVKEFLDAGQYTCHKGGETLSHSHLLLHKKENGIWSTEILKNFKNKTFLKCEAPNYSGRFTCSWLVQRNMDLKFNIKSSSSSPDSRAVTCGMASLSAEKVTLDQRDYEKYSVSCQEDVTCPTAEETLPIELALEARQQNKYENYSTSFFIRDIIKPDPPKNLQMKPLKNSQVEVSWEYPDSWSTPHSYFSLKFFVRIQRKKEKMKETEEGCNQKGAFLVEKTSTEVQCKGGNVCVQAQDRYYNSSCSKWACVPCRVRSGGGGSGGGGSGGGGSRVIPVSGPARCLSQSRNLLKTTDDMVKTAREKLKHYSCTAEDIDHEDITRDQTSTLKTCLPLELHKNESCLATRETSSTTRGSCLPPQKTSLMMTLCLGSIYEDLKMYQTEFQAINAALQNHNHQQIILDKGMLVAIDELMQSLNHNGETLRQKPPVGEADPYRVKMKLCILLHAFSTRVVTINRVMGYLSSA
[序列301]抗小鼠FAP HC小鼠IgG2a Fc DANG-小鼠scIL-12突變2
QVQLQQSGAELARPGASVNLSCKASGYTFTNNGINWLKQRTGQGLEWIGEIYPRSTNTLYNEKFKGKATLTADRSSNTAYMELRSLTSEDSAVYFCARTLTAPFAFWGQGTLVTVSAAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVAVSEDDPDVQISWFVNNVEVHTAQTQTHREDYGSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGGGGGSGGGGSGGGGSMWELEKDVYVVEVDWTPDAPGETVNLTCDTPEEDDITWTSDQRHGVIGSGKTLTITVKEFLDAGQYTCHKGGETLSHSHLLLHKKENGIWSTEILKNFKNKTFLKCEAPNYSGRFTCSWLVQRNMDLKFNIKSSSSSPDSRAVTCGMASLSAEKVTLDQRDYEKYSVSCQEDVTCPTAEETLPIELALEARQQNKYENYSTSFFIRDIIKPDPPKNLQMKPLKNSQVEVSWEYPDSWSTPHSYFSLKFFVRIQAAAEKMAETEEGCNQKGAFLVEKTSTEVQCKGGNVCVQAQDRYYNSSCSKWACVPCRVRSGGGGSGGGGSGGGGSRVIPVSGPARCLSQSRNLLKTTDDMVKTAREKLKHYSCTAEDIDHEDITRDQTSTLKTCLPLELHKNESCLATRETSSTTRGSCLPPQKTSLMMTLCLGSIYEDLKMYQTEFQAINAALQNHNHQQIILDKGMLVAIDELMQSLNHNGETLRQKPPVGEADPYRVKMKLCILLHAFSTRVVTINRVMGYLSSA
[序列302]小鼠scIL-12-小鼠IgG2a Fc DANG-抗小鼠FAP scFv
MWELEKDVYVVEVDWTPDAPGETVNLTCDTPEEDDITWTSDQRHGVIGSGKTLTITVKEFLDAGQYTCHKGGETLSHSHLLLHKKENGIWSTEILKNFKNKTFLKCEAPNYSGRFTCSWLVQRNMDLKFNIKSSSSSPDSRAVTCGMASLSAEKVTLDQRDYEKYSVSCQEDVTCPTAEETLPIELALEARQQNKYENYSTSFFIRDIIKPDPPKNLQMKPLKNSQVEVSWEYPDSWSTPHSYFSLKFFVRIQRKKEKMKETEEGCNQKGAFLVEKTSTEVQCKGGNVCVQAQDRYYNSSCSKWACVPCRVRSGGGGSGGGGSGGGGSRVIPVSGPARCLSQSRNLLKTTDDMVKTAREKLKHYSCTAEDIDHEDITRDQTSTLKTCLPLELHKNESCLATRETSSTTRGSCLPPQKTSLMMTLCLGSIYEDLKMYQTEFQAINAALQNHNHQQIILDKGMLVAIDELMQSLNHNGETLRQKPPVGEADPYRVKMKLCILLHAFSTRVVTINRVMGYLSSAGGGGSGGGGSEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVAVSEDDPDVQISWFVNNVEVHTAQTQTHREDYGSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGGGGSGGGGSGGGGSQVQLQQSGAELARPGASVNLSCKASGYTFTNNGINWLKQRTGQGLEWIGEIYPRSTNTLYNEKFKGKATLTADRSSNTAYMELRSLTSEDSAVYFCARTLTAPFAFWGQGTLVTVSAGGGGSGGGGSGGGGSGGGGSQIVLTQSPAIMSASPGEKVTMTCSASSGVNFMHWYQQKSGTSPKRWIFDTSKLASGVPARFSGSGSGTSYSLTISSMEAEDAATYYCQQWSFNPPTFGGGTKLEIK
[序列303]小鼠scIL-12突變2-小鼠IgG2a Fc DANG-抗小鼠FAP scFv
MWELEKDVYVVEVDWTPDAPGETVNLTCDTPEEDDITWTSDQRHGVIGSGKTLTITVKEFLDAGQYTCHKGGETLSHSHLLLHKKENGIWSTEILKNFKNKTFLKCEAPNYSGRFTCSWLVQRNMDLKFNIKSSSSSPDSRAVTCGMASLSAEKVTLDQRDYEKYSVSCQEDVTCPTAEETLPIELALEARQQNKYENYSTSFFIRDIIKPDPPKNLQMKPLKNSQVEVSWEYPDSWSTPHSYFSLKFFVRIQAAAEKMAETEEGCNQKGAFLVEKTSTEVQCKGGNVCVQAQDRYYNSSCSKWACVPCRVRSGGGGSGGGGSGGGGSRVIPVSGPARCLSQSRNLLKTTDDMVKTAREKLKHYSCTAEDIDHEDITRDQTSTLKTCLPLELHKNESCLATRETSSTTRGSCLPPQKTSLMMTLCLGSIYEDLKMYQTEFQAINAALQNHNHQQIILDKGMLVAIDELMQSLNHNGETLRQKPPVGEADPYRVKMKLCILLHAFSTRVVTINRVMGYLSSAGGGGSGGGGSEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVAVSEDDPDVQISWFVNNVEVHTAQTQTHREDYGSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGGGGSGGGGSGGGGSQVQLQQSGAELARPGASVNLSCKASGYTFTNNGINWLKQRTGQGLEWIGEIYPRSTNTLYNEKFKGKATLTADRSSNTAYMELRSLTSEDSAVYFCARTLTAPFAFWGQGTLVTVSAGGGGSGGGGSGGGGSGGGGSQIVLTQSPAIMSASPGEKVTMTCSASSGVNFMHWYQQKSGTSPKRWIFDTSKLASGVPARFSGSGSGTSYSLTISSMEAEDAATYYCQQWSFNPPTFGGGTKLEIK
製造實例 1. 製造融合蛋白
試劑及設備描述於下表3及表4中。
[表3]
[表4]
試劑 | 製造商 | 目錄號 |
pTT5 | chempartner | |
In-Fusion HD選殖套組 | Clontech | 639648 |
Accuprime pfx DNA聚合酶 | Invitrogen | 12344-04 |
凝膠DNA片段純化套組(Gel DNA fragment purification Kit) | TaKaRa | D823A |
FastDigest®BamHI | Fermentas | FD0055 |
FastDigest®EcoRI | Fermentas | FD0275 |
設備及工具 | 製造商 | 型號名稱 |
生物安全櫃 | NUAIRE | LabGard類別± |
離心機 | Eppendorf | 5424 |
凝膠成像系統(Gel Imaging System) | Tanon | 2500R |
經由PCR擴增所合成之DNA片段,且藉由凝膠純化PCR產物。pTT5載體藉由限制酶EcoRI及BamHI裂解,且接著純化凝膠。各PCR產物及線性載體使用In-Fusion套組接合。將所產生載體轉型至ECOS101 DH5α勝任細胞中且在含有100 µg/ml安比西林之2xYT瓊脂盤上培養該細胞。所有操控方法均根據標準轉型方案進行。藉由菌落PCR鑑別陽性重組體,且對重組質體進行序列驗證定序。選擇單一菌落,且將種細胞培養物接種至5 ml含有100 μg/ml安比西林之2xYT培養基中。在37℃下在搖晃下將其培養8小時。
其後,將種細胞培養物以1:1,000之比率在200 ml選擇性2xYT培養基中稀釋。在37℃下在搖晃下將其培養16小時。藉由在4℃、4,700 rpm下離心10分鐘收集細菌細胞。使細菌球粒再懸浮於12 ml RES-EF緩衝液中。其後,添加12 ml LYS-EF緩衝液,且用力倒轉密封管以充分混合且接著在室溫下培育5分鐘。將12 ml NEU-EF緩衝液添加至裂解物中,且用力倒轉以充分且快速混合。
在注射裂解物至NucleoBond® Xtra管柱過濾器中之前,藉由將裂解物管倒轉3次來製備沈澱物之均質懸浮液,以防止過濾器堵塞。其後,用10 ml過濾器洗滌緩衝液FIL-EF洗滌NucleoBond® Xtra管柱過濾器及NucleoBond® Xtra管柱。藉由拉出或倒轉管柱來移除NucleoBond® Xtra管柱過濾器。用90 ml洗滌緩衝液ENDO洗滌NucleoBond® Xtra管柱。
用45 ml洗滌緩衝液WASH-EF洗滌NucleoBond® Xtra管柱。用15 ml溶離緩衝液ELU溶離質體DNA。將溶離液收集於50 ml離心管中。在室溫下添加10.5 ml異丙醇以使溶離之質體DNA沈澱。渦旋後,使混合物靜置2分鐘。
其後,將5 ml 70%乙醇添加至球粒中。使用移液管尖端自管小心且完全移出乙醇。在室溫(20℃)下乾燥球粒。其後,將DNA球粒用1,000 μl H
2O溶解。
製造實例 2. 細胞轉染及蛋白質表現製造實例2.1.細胞轉染
所使用之材料及試劑描述於下表5中。
[表5]
材料及試劑 | 製造商(產品號) |
293F細胞 | Invitrogen (R790-07) |
OPM 293 | OPM (81075-001) |
Pluronic®F-68,10% (100X) | Gibco (24040-032) |
1 mg/ml PEI | Polyscience (23966) |
OPTI MEM I | Gibco (31985088) |
蛋白腖(20×) | FLUKA (P0521-1KG) |
搖瓶 | |
ISF1-X培育箱震盪器 | Kuhner震盪器 |
在130 rpm、37℃及8% CO
2下將含有293F種菌株之完全培養基維持在培育箱震盪器中。將其以0.3至0.4×10
6個細胞/毫升之密度培養,且每2至3天更換培養基。在轉染之前二十四小時,以2.6×10
6個細胞/毫升製備新繼代數目之293F細胞。在130 rpm、37℃及8% CO
2下將所製備之細胞在培育箱震盪器中培養。在轉染當天,使用新鮮培養基將細胞密度調節至5.0×10
6個細胞/毫升之密度。此在3 L搖瓶中以1 L總體積進行。將0.4 mg HC及0.6 mg LC質體用50 ml OPTI MEM I稀釋,且經由0.22 μm過濾器過濾。其後,用50 ml OPTI MEM I稀釋2 mg PEI以製備轉染試劑。
將經稀釋之PEI添加至DNA混合物中,且接著立即混合。此後,將其在室溫下培養15分鐘。將DNA-PEI混合物添加至以2.6×10
6個細胞/毫升製備之293F細胞中。其後,在130 rpm、37℃及8% CO
2下將細胞在培育箱震盪器中連續培養24小時。在轉染之後二十四小時,將10%蛋白腖添加至培養溶液之1/20,使得最終濃度為0.5%。其後,在130 rpm、37℃及8% CO
2下將細胞在培育箱震盪器中連續培養。在轉染之後2至5天時段期間每天量測且記錄細胞密度/存活率。在轉染之後7天或在細胞存活率小於70%時收集細胞用於純化。
製造實例 2.2. 蛋白質純化
用於蛋白質純化之試劑、緩衝劑之組成及設備描述於下表6至表8中。
[表6]
[表7]
[表8]
試劑 | 製造商 | 目錄號 |
Mabselect SuRe | GE Healthcare | 11003493 |
Tris | SIGMA | 77-86-1 |
NaCl | ACROS ORGANIVS | 7647-14-5 |
檸檬酸鈉 | Adamas-beta | 76198B |
檸檬酸 | GENERAL-Reagent | G83162B |
精胺酸 | VETEC | V900343-500G |
丁二酸 | Sigma-Aldrich | S9512-500G |
曲拉通(Triton) X-100 | ABCONE | X10010-1L |
曲拉通X-114 | Sigma-Aldrich | X114 |
Millex-GP過濾器單元0.22 μm無菌 | MILLIPORE | SLGP033RS |
NaOH | Merck | B146369740 |
緩衝液A | 25 mM Tris、150 mM NaCl,pH 8.0 |
緩衝液B | 25 mM Tris、150 mM NaCl、0.1%曲拉通X-100、0.1%曲拉通X-114 pH 8.0 |
緩衝液C | 100 mM檸檬酸鈉、150 mM NaCl,pH 3.0 |
緩衝液D | 1 M精胺酸、400 mM丁二酸,pH 9.0 |
緩衝液E | 20 mM PB pH 6.5、1 M (NH 4) 2SO 4 |
緩衝液F | 20 mM PB pH 6.5、25%異丙醇 |
最終緩衝液 | 20 mM HEPES (pH 7.5)、240 mM蔗糖或20 mM his乙酸鹽pH 5.5、240 mM蔗糖 |
設備 | 製造商 | 型號名稱 |
AKTA Pure | GE Healthcare | 29-0182-24 |
離心機 | Beckman | J-26xp |
凝膠成像系統 | Tanon | 2500R |
Sartopore 2過濾器 | Sartorius | 5445307H9-OO-A |
使用Mabselect sure管柱純化蛋白質。特定言之,藉由在2,000×g、4℃下離心20分鐘收集上清液。其後,用Sartopore 2過濾器過濾上清液。用緩衝液A平衡之5 ml MabSelect Sure管柱負載有澄清上清液。其後,用緩衝液A洗滌管柱直至A280吸光度達到基線。用10 CV緩衝液B洗滌管柱。用10 CV緩衝液A洗滌管柱。將結合之蛋白質用6 CV緩衝液C溶離,且添加1/6體積之緩衝液D以中和溶離物質。進行SDS-PAGE及SEC-HPLC分析。其後,使用HIC管柱純化蛋白質。接著在4℃下蛋白質針對緩衝液E滲析隔夜。用緩衝液E平衡之HIC管柱負載有上清液。其後,用緩衝液E洗滌管柱直至A280吸光度達到基線。藉由梯度溶離(10 CV緩衝液F 0%-40%)來溶離結合之蛋白質。將結合之蛋白質用2 CV 100%緩衝液F溶離。進行SDS-PAGE分析。
收集經純化之蛋白質,且接著在4℃下針對最終緩衝液滲析蛋白質隔夜。其後,進行SDS-PAGE及SEC-HPLC分析。
因此,如圖1至圖6中所示,發現一個實施例之人類蛋白質及小鼠蛋白質經純化。
製造實例3. 雙特異性抗體之生產改良 製造實例3.1. 鑑定包含人類IL-12 之融合蛋白之生產的改良
下表9展示人類抗FAP/IL-12雙特異性抗體之產生根據人類IL-12突變的變化。圓括號指示蛋白質之生產規模,且單位為L。圓括號前方之數值為藉由將經純化蛋白質之量除以生產規模而獲得的每公升之產量。
[表9]
蛋白質 | 描述 | 在穿過蛋白A管柱之後蛋白質之量(mg) (生產規模,L) |
T1.01 | 抗人類FAP/人類IL-12、人類IgG1 DANG | 40 (1),132 (1) |
T1.02 | 抗人類FAP/人類IL-12突變1、人類IgG1 DANG | 45 (1),139.7 (2) |
T1.03 | 抗人類FAP/人類IL-12突變2、人類IgG1 DANG | 250 (1),220 (5) |
如上表9中所展示,隨著人類IL-12 p40 (β)區中涉及肝素結合之胺基酸的突變的數目增加,經由蛋白A管柱(MabSelect Sure管柱)純化之蛋白質的量增加。發現其中第280及第285胺基酸處之離胺酸(K)突變成丙胺酸(A)的雙特異性抗體T1.02與T1.01相比具有改良之產量。發現其中第280、第282、第285及第286胺基酸處之離胺酸(K)突變成丙胺酸(A)的雙特異性抗體T1.03與T1.01相比具有約2.5倍改良之產量。
製造實例 3.2. 鑑定包含小鼠 IL-12 之融合蛋白之生產的改良
下表10展示小鼠抗FAP/IL-12雙特異性抗體之產生根據小鼠IL-12突變的變化。
[表10]
蛋白質 | 描述 | 在穿過蛋白A管柱之後蛋白質之量(mg) (生產規模,L) |
T1.01m | 抗小鼠FAP/小鼠IL-12、小鼠IgG2a DANG | 5.725 (4),3.967 (12),3.667 (12) |
T1.02m | 抗小鼠FAP/小鼠IL-12突變1、小鼠IgG2a DANG | 5.825 (4),9.86 (2),5.74 (20) |
T1.03m | 抗小鼠FAP/小鼠IL-12突變2、小鼠IgG2a DANG | 9.54 (1),126.8 (1) |
如上表10中所展示,隨著小鼠IL-12 p40 (β)區中涉及肝素結合之胺基酸的突變的數目增加,經由蛋白A管柱(MabSelect Sure管柱)純化之蛋白質的量增加。
在各表中,藉由將總蛋白質產量除以生產規模來比較在穿過蛋白A管柱之後的蛋白質之量。發現與T1.01m及T1.02m相比,其中第277及第282胺基酸處之離胺酸(K)突變成丙胺酸(A)的雙特異性抗體T1.02m及其中第276胺基酸處之精胺酸(R)突變成丙胺酸(A)且第277、第278及第282胺基酸處之離胺酸(K)突變成丙胺酸(A)的雙特異性抗體T1.03m在蛋白質中之產量逐漸提高。另外,發現與使用HEK 293細胞株之生產相比,使用CHO細胞株之T1.03m之生產提高約13倍。
製造實例 4. 細胞株及細胞株之培養
經IL-12受體基因及STAT4誘導型SEAP報告基因轉型至HEK293細胞(其為人類胚胎腎纖維母細胞)中之HEK-Blue IL-12細胞株獲自Invivogen (San Diego, USA)。HEK-Blue IL-12細胞維持於含有10% FBS (GIBCO)、100 µg/ml Normocin及1X HEK-Blue selection之DMEM (GIBCO)中。
自ATCC (美國典型培養物保藏中心(American Type Culture Collection),Manassas, VA, USA)獲得人類胚胎腎纖維母細胞細胞株HEK293、小鼠大腸直腸癌細胞株CT26-WT、小鼠黑色素瘤細胞株B16F10及小鼠纖維母細胞細胞株NIH3T3。HEK293細胞、B16F10細胞及NIH3T3細胞維持於含有10% FBS (GIBCO)之DMEM (GIBCO)中。人類FAP(纖維母細胞活化蛋白α)在HEK293細胞中過度表現之細胞株(HEK293-hFAP)使用能夠遞送人類FAP基因之慢病毒來製備。HEK293-hFAP細胞維持於含有10% FBS (GIBCO)及5 µg/ml嘌呤黴素之DMEM (GIBCO)中。
小鼠FAP (纖維母細胞活化蛋白α)在CT26-WT細胞、B16F10細胞及NIH3T3細胞中過度表現的細胞株(CT26-mFAP、B16F10-mFAP及NIH3T3-mFAP)使用能夠遞送小鼠FAP基因之慢病毒製備。CT26-mFAP細胞維持於含有10% FBS (GIBCO)及10 µg/ml嘌呤黴素之RPMI-1640 (GIBCO)中。B16F10-mFAP細胞維持於含有10% FBS (GIBCO)及10 µg/ml嘌呤黴素之DMEM (GIBCO)中。NIH3T3-mFAP細胞維持於含有10% FBS (GIBCO)及5 µg/ml嘌呤黴素之DMEM (GIBCO)中。
製造實例 5. 分離及活化人類免疫細胞
血液包經機構審查委員會(IRB)批准獲自韓國之韓國紅十字會(Korean Red Cross, Korea),且分離及冷凍周邊血液單核細胞(PBMC)。對解凍之PBMC進行陽性選擇法,且用Easy sep (Stem cell,Vancouver, BC, CA)套組分離人類NK細胞。經分離之NK細胞經活化且維持於含有50 IU/ml重組人類IL-2 (rhIL-2,R&D systems,Minnesota, USA)之RPMI-1640 (GIBCO)及10% FBS中。
對解凍之PBMC進行負向選擇法,且用Easy sep (Stem cell)套組分離人類T細胞。人類T細胞在塗佈有1 µg/ml抗CD3 (OKT3,Invitrogen)之盤上培養且活化72小時。人類T細胞維持於含有10% FBS (GIBCO)之RPMI-1640 (GIBCO)中。
實例1. 鑑別融合蛋白之結合親和力 實例1.1. 鑑別融合蛋白與重組人類FAP 之結合
藉由表面電漿子共振(SPR)鑑別T1.01、T1.02及T1.03與重組人類FAP之結合。
特定言之,用50 nM NHS (N-羥基丁二醯亞胺)與200 nM EDC (1-乙基-3-(3-二甲胺基丙基)碳化二亞胺)之1:1混合物活化CM5晶片之表面,且以10 μl/min之速率使25 µg/ml抗人類IgG (Fc)抗體固定400秒。其餘活性酯基團用1 M乙醇胺封端。將T1.01、T1.02及T1.03稀釋至2 µg/ml且在固定有抗人類IgG (Fc)抗體之CM5晶片上反應。重組人類FAP在1×HBS-EP+緩衝溶液中稀釋至200 nM且藉由連續稀釋來稀釋。經稀釋之重組人類FAP以30 μl/min之速率反應。締合及解離時間分別為180秒及400秒。解離之後,進行穩定化60秒,且接著用10 mM甘胺酸pH 1.5溶液以30 μl/min之速率進行再生30秒。
因此,如圖7及圖8中所示,發現T1.01、T1.02及T1.03可特異性結合於重組人類FAP。
藉由表面電漿子共振(SPR)鑑別T1.04、T1.05、T1.06、T1.07、T1.08、T1.09、T1.10及T1.11與重組人類FAP之結合。用50 nM NHS (N-羥基丁二醯亞胺)與200 nM EDC (1-乙基-3-(3-二甲胺基丙基)碳化二亞胺)之1:1混合物活化CM5晶片之表面,且以10 μl/min之速率使25 µg/ml抗人類IgG (Fc)抗體固定400秒。其餘活性酯基團用1 M乙醇胺封端。
特定言之,將人類蛋白質T1.04、T1.05、T1.06、T1.07、T1.08、T1.09、T1.10及T1.11分別稀釋至1 µg/ml、1 µg/ml、1 µg/ml、1 µg/ml、0.5 µg/ml、0.5 µg/ml、0.5 µg/ml及1 µg/ml,且在固定有抗人類IgG (Fc)抗體之CM5晶片上反應。重組人類FAP在1×HBS-EP+緩衝溶液中稀釋至25 nM或50 nM且藉由連續稀釋來稀釋。經稀釋之重組人類FAP以30 μl/min之速率反應。締合及解離時間分別為180秒及400秒。解離之後,進行穩定化60秒,且接著用10 mM甘胺酸pH 1.5溶液以30 μl/min之速率進行再生30秒。
因此,如表11及圖9及圖10中所展示,發現T1.04、T1.05、T1.06及T1.07可結合於重組人類FAP以特異性靶向FAP。另外,如表12及圖11及圖12中所展示,發現T1.08、T1.09、T1.10及T1.11可結合於重組人類FAP以特異性靶向FAP。
[表11]
[表12]
實例 1.2. 鑑別小鼠蛋白與重組小鼠 FAP 之結合
動力學模型 | 捕捉物 1 溶液 | 分析物 1 溶液 | 動力學 Chi ² (RU ² ) | ka (1/Ms) | kd (1/s) | KD (M) |
1:1結合 | 1 µg/ml T1.04 | 人類FAP | 2.70E-01 | 5.83E+05 | 1.50E-05 | 2.57E-11 |
1:1結合 | 1 µg/ml T1.05 | 人類FAP | 2.80E-01 | 6.25E+05 | 5.83E-05 | 9.32E-11 |
1:1結合 | 1 µg/ml T1.06 | 人類FAP | 1.32E-01 | 1.04E+05 | 6.22E-05 | 5.96E-10 |
1:1結合 | 1 µg/ml T1.07 | 人類FAP | 2.33E-01 | 5.97E+05 | 7.64E-05 | 1.28E-10 |
動力學模型 | 捕捉物 1 溶液 | 分析物 1 溶液 | 動力學 Chi ² (RU ² ) | ka (1/Ms) | kd (1/s) | KD (M) |
1:1結合 | 0.5 µg/ml T1.08 | 人類FAP | 4.70E-01 | 4.46E+05 | 7.87E-05 | 1.77E-10 |
1:1結合 | 0.5 µg/ml T1.09 | 人類FAP | 3.31E-01 | 5.17E+05 | 1.11E-04 | 2.14E-10 |
1:1結合 | 0.5 µg/ml T1.10 | 人類FAP | 1.84E-01 | 1.56E+05 | 7.48E-05 | 4.79E-10 |
1:1結合 | 1 µg/ml T1.11 | 人類FAP | 2.85E-01 | 1.20E+05 | 3.19E-05 | 2.67E-10 |
藉由表面電漿子共振(SPR)鑑別T1.01m、T1.02m及T1.03m與重組小鼠FAP之結合。
用50 nM NHS (N-羥基丁二醯亞胺)與200 nM EDC (1-乙基-3-(3-二甲胺基丙基)碳化二亞胺)之1:1混合物活化CM5晶片之表面,且以10 μl/min之速率使25 µg/ml抗小鼠IgG (Fc)抗體固定400秒。其餘活性酯基團用1 M乙醇胺封端。將T1.01m、T1.02m及T1.03m稀釋至2 µg/ml且在固定有抗小鼠IgG (Fc)抗體之CM5晶片上反應。重組小鼠FAP在1×HBS-EP+緩衝溶液中稀釋至200 nM且藉由連續稀釋來稀釋。經稀釋之重組小鼠FAP以30 μl/min之速率反應。締合及解離時間分別為180秒及400秒。解離之後,進行穩定化60秒,且接著用10 mM甘胺酸pH 1.5溶液以30 μl/min之速率進行再生30秒。
因此,如圖13及圖14中所展示,發現T1.01m、T1.02m及T1.03m可結合於重組小鼠FAP以特異性靶向FAP。
實例 1.3. 鑑別與表現 FAP 之細胞的結合
鑑別T1.12、T1.01、T1.02及T1.03與HEK293及HEK293-hFAP細胞之結合程度。
特定言之,藉由以1×10
5個細胞/100 μl懸浮於FACS緩衝溶液中來製備細胞株,且用1 µg T1.12、T1.01、T1.02及T1.03中之每一者處理。用FACS緩衝溶液洗滌細胞二次。將細胞用抗人類IgG抗體(Biolegend)染色。將陰性對照僅用抗人類IgG抗體(Biolegend)染色。經染色細胞之表現速率使用BD LSR來量測且使用FlowJo軟體分析。
因此,如圖15中所展示,發現T1.12、T1.01、T1.02及T1.03以99%或更大結合於人類表現FAP之細胞株。此等結果指示一個實施例之融合蛋白可結合於人類表現FAP之細胞株以特異性靶向FAP。
另外,鑑別T1.12m、T1.01m、T1.02m及T1.03m與B16F10及B16F10-mFAP細胞之結合程度。
特定言之,藉由以1×10
5個細胞/100 μl懸浮於FACS緩衝溶液中來製備細胞株,且用1 µg T1.12m、T1.01m、T1.02m及T1.03m中之每一者處理。用FACS緩衝溶液洗滌細胞二次。將細胞用抗小鼠IgG2a抗體(Biolegend)染色。將陰性對照僅用抗小鼠IgG2a抗體(Biolegend)染色。經染色細胞之表現速率使用BD LSR來量測且使用FlowJo軟體分析。
因此,如圖16中所展示,發現T1.12m、T1.01m、T1.02m及T1.03m以99%或更大結合於表現FAP之細胞株。此等結果指示一個實施例之融合蛋白可結合於小鼠表現FAP之細胞株以特異性靶向FAP。
實例 1.4. 鑑別融合蛋白與重組人類 IL-12 受體之結合
考慮到出於作用融合蛋白之IL-12必須結合於IL-12受體,發現T1.01、T1.02、T1.03及T1.12結合於重組人類IL-12受體。
T1.01、T1.02及T1.03固定於盤上,且結合與辣根過氧化酶(HRP)結合之重組人類IL-12受體蛋白。特定言之,進行以下步驟:
(i)將T1.01、T1.02、T1.03及T1.12以5 µg/ml懸浮且藉由連續稀釋來稀釋。將經稀釋之T1.01、T1.02、T1.03及T1.12在96孔免疫盤中等分且處理24小時。
(ii)將孔用洗滌溶液洗滌,且接著用1% BSA(牛血清白蛋白,Sigma)溶液進行阻斷1小時。
(iii)將孔用洗滌溶液洗滌,且接著用1 nM IL-12受體β 1-生物素(IL-12Rβ1-生物素;Acrobiosystems,Newark, USA)處理2小時。
(iv)將孔用洗滌溶液洗滌,且接著用鏈黴抗生物素蛋白-HRP處理20分鐘。
(v)將孔用洗滌溶液洗滌,且接著用基質溶液處理20分鐘。
(vi)用停止溶液處理孔,且在450 nm下量測吸光度。
因此,如圖17中所展示,發現T1.01、T1.02及T1.03以濃度依賴性方式結合於重組人類IL-12受體蛋白。T1.12用作對照。
實例2. 鑑別融合蛋白誘導信號傳導之能力 實例2.1. IL-12 識別細胞中之信號傳導能力之鑑別
考慮到已知IL-12藉由誘導STAT4(信號轉導子及活化因子或轉錄4)(信號傳導介體)之磷酸化而起始信號傳導,當IL-12結合於IL-12受體時,評估一個實施例之融合蛋白在表現IL-12受體之IL-12識別細胞中的信號傳導能力。
特定言之,將HEK-Blue IL-12細胞株(其為IL-12識別細胞)稀釋至2.8×10
5個細胞/毫升且以180 μl/孔分配。將重組人類IL-12、T1.01m、T1.02m、T1.03m及T1.12m以4 nM懸浮且藉由連續稀釋來稀釋。用經稀釋之重組人類IL-12、T1.01m、T1.02m、T1.03m及T1.12m處理HEK-Blue IL-12細胞。在處理24小時之後,收集細胞上清液且在96孔盤中與QUANTI-Blue溶液(Invivogen)混合。報告子表現位準在620 nm下使用分光光度計(Thermo Fisher)量測。
因此,如圖18中所展示,其藉由620 nm吸光度鑑別,在IL-12、T1.01m、T1.02m及T1.03m處理組的情況下,IL-12被識別,且STAT4藉由誘導磷酸化表現報告基因。相比之下,鑑定到當IL-12識別細胞用T1.12m處理時,對照T1.12m未識別IL-12。此等結果指示一個實施例之融合蛋白特異性結合於IL-12受體以誘導信號傳導。
實例 2.2. 鑑別人類 T 細胞中之信號傳導能力
為鑑別當IL-12結合於人類T細胞之IL-12受體時IL-12是否藉由誘導STAT4 (信號傳導介體)之磷酸化起始信號傳導,使用AlphaLISA SureFire Ultra p-STAT4 (Tyr693)分析套組(PerkinElmer, Massachusetts, USA)分析經抗CD3 (OKT3,Invitrogen)活化之人類T細胞。
特定言之,將人類蛋白質IL-12、T1.01、T1.02、T1.03及T1.12以100 ng/ml懸浮且藉由連續稀釋來稀釋。將經抗CD3(OKT3,Invitrogen)活化之人類T細胞用經稀釋之重組人類IL-12、T1.01、T1.02、T1.03及T1.12處理。在處理2小時後,將細胞裂解且用偵測p-STAT4(磷酸化STAT4)之試劑(PerkinElmer)處理。藉由分光光度計在680 nm之激發波長及615 nm之發射波長下偵測p-STAT4。
因此,如圖19中所展示,鑑定出用重組人類IL-12處理之組的半最大有效濃度(EC50)為8.945 pM;用T1.01處理之組的EC50為14.48 pM;用T1.02處理之組的EC50為56.51 pM;及用T1.03處理之組的EC50為147.2 pM。相比之下,在用作為對照之T1.12處理之組中未偵測到磷酸化STAT4。
此等結果指示IL-12突變減弱T細胞信號傳導能力。
實例2.3. 鑑別融合蛋白在人類T 細胞中藉由低分子量肝素之信號傳導能力的變化
接下來,使用經抗CD3 (OKT3,Invitrogen)活化之人類T細胞及AlphaLISA SureFire Ultra p-STAT4 (Tyr693)分析套組鑑別IL-12突變(IL-12突變1)融合蛋白藉由低分子量肝素之信號傳導能力的增強。
特定言之,藉由觀測當減弱之IL-12突變2與人類T細胞之IL-12受體結合時STAT4(信號傳導介體)磷酸化之誘導是否減弱,鑑別人類T細胞中視低分子量肝素(LMWH)之存在或不存在而定的信號傳導能力。
特定言之,將重組人類IL-12、T1.01、T1.02及T1.03以100 ng/ml懸浮且藉由連續稀釋來稀釋。用經稀釋之重組人類IL-12、T1.01、T1.02及T1.03連同低分子量肝素處理經活化人類T細胞。在處理2小時之後,將細胞裂解且用用於偵測p-STAT4之試劑(PerkinElmer)處理。藉由分光光度計在680 nm之激發波長及615 nm之發射波長下偵測p-STAT4。
因此,如圖20中所展示,與用T1.01處理之組相比,用T1.01及低分子量肝素處理之組中的半最大有效濃度(EC50)增加9.4倍,與用T1.02處理之組相比,用T1.02及低分子量肝素處理之組中的半最大有效濃度(EC50)增加5.5倍,且與用T1.03處理之組相比,用T1.03及低分子量肝素處理之組中的半最大有效濃度(EC50)增加4倍。
此等結果指示當IL-12突變(IL-12突變2)添加至現有IL-12突變(IL-12突變1)中時,藉由添加低分子量肝素增強信號傳導能力的程度降低,因此IL-12被有效減弱。
實例3. 鑑別融合蛋白之細胞介素分泌能力 實例3.1. 用於細胞介素量測之酶聯免疫吸附分析
對於細胞介素量測,對儲存於-20℃下之上清液進行酶聯免疫吸附分析(ELISA,R&D systems),步驟如下:
(i)將捕捉抗體根據分析證書(Certificate of Analysis,CoA)稀釋且塗佈在96孔盤上維持24小時。
(ii)將孔用洗滌溶液洗滌,且接著用1% BSA(牛血清白蛋白,Sigma)溶液進行阻斷1小時。
(iii)用洗滌溶液洗滌孔,且接著處理樣品2小時。
(iv)用洗滌溶液洗滌孔,且接著根據分析證書稀釋偵測抗體且等分至該等孔中,且接著將該等孔與偵測抗體處理2小時。
(v)將孔用洗滌溶液洗滌,且接著用鏈黴抗生物素蛋白-HRP處理20分鐘。
(vi)將孔用洗滌溶液洗滌,且接著用基質溶液處理20分鐘。
(vii)用停止溶液處理孔,且在450 nm下量測吸光度。
實例 3.2. 鑑別人類 T 細胞中之細胞介素分泌能力
考慮到作為主要免疫反應之IFN-γ (干擾素-γ)分泌在人類T細胞用IL-12處理時發生,當用重組人類IL-12、T1.12、T1.01、T1.02及T1.03處理人類T細胞時評估IFN-γ分泌能力。
特定言之,將經抗CD3 (OKT3,Invitrogen)活化之人類T細胞稀釋至5×10
5個細胞/毫升且以200 μl/孔分配於96孔盤中。將重組人類IL-12、T1.12、T1.01、T1.02及T1.03稀釋至10 nM且以20 μl/孔分配。在處理48小時之後,收集細胞上清液,且將樣品儲存於-80℃下。
因此,如圖21中所展示,發現用重組人類IL-12處理之樣品平均具有1,640 pg/ml IFN-γ;用T1.01處理之樣品平均具有1,115 pg/ml IFN-γ;用T1.02處理之樣品平均具有845 pg/ml IFN-γ;且用T1.03處理之樣品平均具有607 pg/ml IFN-γ。相比之下,發現用作為對照之T1.12處理的樣品不具有IFN-γ。
此等結果指示T1.01、T1.02及T1.03作用於人類T細胞以誘導IFN-γ分泌。
實例 3.3. 鑑別人類 NK 細胞中之細胞介素分泌能力
考慮到作為主要免疫反應之IFN-γ (干擾素-γ)分泌在人類NK細胞用IL-12處理時發生,本發明人在經重組人類IL-2 (R&D systems)活化之人類NK細胞用重組人類IL-12、T1.12、T1.01、T1.02及T1.03處理時評估IFN-γ分泌能力。
特定言之,將經重組人類IL-2 (R&D Systems)活化之人類NK細胞稀釋至5×10
5個細胞/毫升且以200 μl/孔分配於96孔盤中。將重組人類IL-12、T1.12、T1.01、T1.02及T1.03稀釋至10 nM且以20 μl/孔分配。在處理24小時之後,收集細胞上清液,且將樣品儲存於-80℃下。
因此,如圖22中所展示,發現用重組人類IL-12處理之樣品平均具有180 pg/ml IFN-γ;用T1.01處理之樣品平均具有205 pg/ml IFN-γ;用T1.02處理之樣品平均具有133 pg/ml IFN-γ;且用T1.03處理之樣品平均具有80 pg/ml IFN-γ。相比之下,發現用作為對照之T1.12處理的樣品不具有IFN-γ。此等結果指示T1.01、T1.02及T1.03作用於人類NK細胞以誘導IFN-γ分泌。
實例4. 評估融合蛋白在大腸直腸癌動物模型中之抗癌功效 實例4.1. 經由共注射表現FAP 之纖維母細胞評估大腸直腸癌動物模型中之抗癌功效
考慮到融合蛋白呈具有抗FAP序列結構及IL-12序列結構之雙重抗體的形式,且FAP在存在於許多腫瘤微環境中之纖維母細胞中過度表現,在NIH3T3細胞(小鼠纖維母細胞細胞株)中過度表現小鼠FAP之後,在與CT26(小鼠大腸直腸癌細胞株)1:1共注射之腫瘤動物模型中評估腫瘤生長抑制能力。
使用CT26(小鼠大腸直腸癌細胞株)及NIH-3T3 (小鼠纖維母細胞細胞株)製備表現FAP之腫瘤動物模型。接著,將NIH-3T3製備為表現FAP之細胞株。
特定言之,將小鼠的過度表現FAP之NIH-3T3細胞及CT26細胞以培養物形式分別以1×10
6個細胞/50 μl之濃度再懸浮於漢克氏平衡鹽溶液(Hanks' Balanced salt solution) (HBSS,Gibco)中,且以1:1比率混合細胞,且接著使用1 cc針筒(25G)按各小鼠100 μl移植至6週齡BALB/c小鼠之右側腹之皮下區域中,以獲得表現FAP之纖維母細胞共注射動物模型。使用數位游標卡尺藉由量測腫瘤之短軸及長軸來量測腫瘤尺寸,且使用(短軸,mm)
2×(長軸,mm)×0.5之計算式一週二次量測腫瘤尺寸。
接下來,對於藥物功效評估,當腫瘤尺寸達到100 mm
3時,將小鼠隨機分成各組。各實驗組係由10隻動物組成,且作為對照,每100 μl之50 µg T1.24m以3天間隔腹膜內投予三次。在測試組中,每100 μl之10 µg及50 µg T1.02m及50 µg T1.01m分別以3天間隔腹膜內投予三次以評估腫瘤生長抑制能力。
因此,如圖23中所展示,當比較第14天之腫瘤尺寸時,發現與以50 µg T1.24m作為對照投予之組相比,以10 µg及50 µg T1.02m投予之組分別具有93.2%及92.7%之極佳腫瘤生長抑制能力。另外,觀測到與以50 µg T1.24m作為對照投予之組相比,以50 µg T1.01m投予之組具有91.9%之腫瘤生長抑制。
另外,如圖24中所展示,在投予之後第24天,與對照相比,在用T1.01m及T1.02m投予之組內觀測到完全反應之個體。
此等結果指示一個實施例之融合蛋白在大腸直腸癌動物模型中具有極佳抗癌功效。
實例 4.2. 評估表現 FAP 之大腸直腸癌動物模型中之抗癌功效
在大腸直腸癌之情況下,考慮腫瘤細胞本身中FAP之高表現,為評估抗癌效應,在CT26細胞(小鼠大腸直腸癌細胞株)中誘導小鼠FAP過度表現之腫瘤模型中評估腫瘤生長抑制能力。
為製備小鼠之表現FAP之腫瘤動物模型,在CT26(小鼠大腸直腸癌細胞株)中誘導FAP過度表現。特定言之,將過度表現FAP之CT26細胞以培養物形式再懸浮於漢克氏平衡鹽溶液(HBSS,Gibco)中,且接著使用1 cc針筒(25G)按各小鼠每100 μl之1×10
6個腫瘤細胞移植至6週齡BALB/c小鼠之左背側之皮下區域中,以獲得小鼠之表現FAP之大腸直腸癌動物模型。使用數位游標卡尺藉由量測腫瘤之短軸及長軸來量測腫瘤尺寸,且使用(短軸,mm)
2×(長軸,mm)×0.5之計算式一週二次量測腫瘤尺寸。
接下來,對於藥物功效評估,當腫瘤尺寸達到100 mm
3時,將小鼠隨機分成各組。各實驗組係由8隻動物組成,且作為對照,各100 μl之50 µg T1.24m以3天間隔腹膜內投予四次。在測試組中,每100 μl之10 µg及100 µg T1.01m以及2 µg、10 µg及100 µg T1.02m分別以3天間隔腹膜內投予四次以評估腫瘤生長抑制能力。
因此,如圖25中所展示,發現與用50 µg T1.24m作為對照投予之組相比,用10 µg及100 µg T1.01m投予之組分別具有84.9%及85.6%之高腫瘤生長抑制能力。另外,觀測到與用T1.24m作為對照投予之組相比,用T1.02m投予之組以劑量計分別具有80.1%、90.5%及89.8%之高腫瘤生長抑制能力。
另外,鑑定出在投予之後第30天各投予組中存在完全反應(CR)之個體以及腫瘤生長抑制,且在測試期間未觀測到根據投予之體重變化。此等結果指示一個實施例之融合蛋白在大腸直腸癌動物模型中具有極佳抗癌功效。
實例 4.3. 評估藉由融合蛋白對具有完全反應之小鼠中復發性實體癌症之生長抑制
為評估在融合蛋白治療之後是否可藉由誘導長期免疫反應來抑制腫瘤復發,在完全反應藉由在共注射有纖維母細胞NIH-3T3及CT26細胞之腫瘤模型中投予T1.01m來達成之個體中進行腫瘤再攻擊。無處理史之BALB/c小鼠用作對照小鼠。
將4T1細胞皮下注射至對照小鼠及藉由投予T1.01m達成完全反應之小鼠的左側腹中,且將CT26細胞皮下注射至其之右側腹中,以獲得腫瘤復發模型。
特定言之,在共注射有過度表現FAP之纖維母細胞NIH-3T3及CT26細胞之模型中,在藉由投予T1.01m展現完全反應的小鼠中誘導腫瘤復發模型。將CT26細胞及4T1細胞分別以1×10
6個細胞/100 μl之濃度懸浮於漢克氏平衡鹽溶液(HBSS, Gibco)中,且使用1 cc針筒(25G)將CT26細胞移植至小鼠之右側腹的皮下區域中。藉由將4T1細胞皮下移植至同一小鼠之左側腹中來評估腫瘤形成及生長。
因此,如圖26及27中所展示,發現經移植4T1腫瘤及CT26腫瘤二者在無處理史之對照小鼠中生長,而在投予T1.01m之後達成完全反應之小鼠中,4T1腫瘤生長,但CT26腫瘤之生長得到抑制。此等結果指示一個實施例之融合蛋白可抑制腫瘤復發。
實例 4.4. 評估根據融合蛋白之 IL-12 胺基酸突變的活性降低
為降低因IL-12過度活化免疫系統所致之活體內毒性,本發明人使用IL-12序列結構,其在與肝素結合之胺基酸序列中含有突變以藉由阻斷與IL-12受體之結合而誘導活性降低,且此經由腫瘤動物模型加以鑑別。
在抗FAP抗體中,其中涉及肝素結合之胺基酸經突變的T1.02m及T1.03m與T1.01m相比較,且使用磷酸鹽緩衝鹽水(PBS)作為對照。接著,T1.02m具有小鼠IL-12序列結構,其含有涉及肝素結合之胺基酸的突變(二個),以及抗FAP序列結構。T1.03m為一種融合蛋白,其具有含有涉及肝素結合之胺基酸之突變(四個)的IL-12序列結構以及抗FAP序列結構。
為評估IL-12活性根據胺基酸突變之存在及程度的變化,過度表現FAP之小鼠大腸直腸癌CT26藉由以5×10
5個細胞/100 μl之濃度再懸浮於PBS中來製備,且在藉由將細胞移植至5週齡雌性BALB/c小鼠中製備之腫瘤動物模型中評估腫瘤生長抑制能力。
特定言之,當模型中腫瘤尺寸達到100 mm
3時,將小鼠隨機分成各組。各實驗組係由8隻動物組成,且經由尾部靜脈注射對照投予一次100 μl磷酸鹽緩衝鹽水(PBS),且以10 µg之劑量靜脈內投予一次T1.01m、T1.02m及T1.03m中之每一者。
因此,如圖28中所展示,發現在投予之後15天,與對照相比,所有T1.01m、T1.02m及T1.03m投予組具有極佳腫瘤生長抑制能力。
另外,發現與用T1.01m投予之組相比,用T1.03m投予之組中的腫瘤生長抑制能力降低,該T1.03m具有含有涉及肝素結合之胺基酸的突變(四個)的IL-12以及小鼠抗FAP序列。此等結果指示與其他實驗組及對照相比,用T1.03m投予之組中IL-12活性降低,該T1.03m具有含有涉及肝素結合之胺基酸的突變(四個)的小鼠IL-12序列結構。
實例 4.5. 評估單次投予 IL-12 胺基酸突變融合蛋白後之抗癌功效
為評估由於含有涉及肝素結合之胺基酸之突變(四個)的序列結構而具有降低之IL-12活性的融合蛋白之抗癌效應,在移植有過度表現FAP之小鼠大腸直腸癌細胞株CT26之腫瘤模型中評估腫瘤生長抑制能力。
特定言之,將腫瘤細胞移植至6週齡BALB/c小鼠之右背側面,且當動物模型之腫瘤的尺寸達到70至100 mm
3時,將小鼠隨機分成各組且進行投予。作為對照,投予PBS,且作為測試組,以2 µg、10 µg及100 µg之劑量靜脈內投予一次100 μl T1.03m。以與實例4.1中相同之方式量測腫瘤尺寸。
因此,如圖29中所展示,觀測到與對照相比,用2 µg、10 µg及100 µg T1.03m投予之組具有高腫瘤生長抑制能力。在測試時段期間未觀測到體重變化。此等結果指示,由於含有涉及肝素結合之胺基酸之突變(四個)的序列結構而具有降低之IL-12活性的T1.03m在某一濃度或更高濃度下具有極佳抗癌功效。
實例 5. 評估融合蛋白在黑色素瘤動物模型中之抗癌功效
為鑑別經由融合蛋白之免疫活化的抗癌效應,小鼠FAP在已知具有極少免疫細胞浸潤之小鼠黑色素瘤細胞株B16F10中過度表現,且接著移植至C57BL/6J小鼠中,且評估腫瘤生長抑制能力。
特定言之,將細胞以培養物形式再懸浮於漢克氏平衡鹽溶液(HBSS,Gibco)中,且接著按每隻小鼠100 μl 1×10
6個腫瘤細胞移植至6週齡C57BL/6J小鼠之左側背側面之皮下區域中。
接下來,對於藥物功效評估,當腫瘤尺寸達到70至100 mm
3時,將小鼠隨機分成各組。作為對照,投予PBS,且作為測試組,以10 µg及100 µg之劑量靜脈內投予一次T1.03m。
因此,如圖30中所展示,觀測到與對照相比,用10 µg及100 µg T1.03m投予之二個組均具有高腫瘤生長抑制能力。在測試時段期間未觀測到體重變化。此等結果指示,由於含有涉及肝素結合之胺基酸之突變(四個)的序列結構而具有降低之IL-12活性的T1.03m即使在黑色素瘤動物模型中亦具有極佳抗癌功效。
實例 6. 評估融合蛋白在肺癌動物模型中之抗癌功效 實例6.1. 評估IL-12 胺基酸突變融合蛋白在肺癌動物模型中之抗癌功效
考慮到FAP在存在於圍繞腫瘤之微環境中的纖維母細胞中過度表現,使FAP在NIH-3T3(小鼠纖維母細胞細胞株)中過度表現,且接著以1:1比率與LLC1(小鼠肺癌細胞株)共注射以製備腫瘤動物模型,且評估腫瘤生長抑制能力。
特定言之,將過度表現FAP之NIH-3T3細胞株及LLC1細胞分別以1×10
6個細胞/50 μl之濃度再懸浮於漢克氏平衡鹽溶液(HBSS,Gibco)中,且以1:1比率混合細胞,且接著使用1 cc針筒(25G)將按每隻小鼠100 μl移植至6週齡C57BL/6J小鼠之右側腹之皮下區域中。
接下來,對於藥物功效評估,當腫瘤尺寸達到70至100 mm
3時,將小鼠隨機分成各組。作為對照,投予PBS,且作為測試組,以10 µg及100 µg之劑量靜脈內投予一次T1.03m。
因此,如圖31中所展示,與對照相比,用10 µg或100 µg T1.03m投予之二個組均具有極佳腫瘤生長抑制能力。在測試時段期間未觀測到體重變化。此等結果指示,由於含有涉及肝素結合之胺基酸之突變(四個)的序列結構而具有降低之IL-12活性的T1.03m識別腫瘤微環境之目標因子,由此即使在肺癌動物模型中亦具有極佳抗癌功效。
實例 6.2. 評估肺癌動物模型中經由共注射融合蛋白之癌症靶向功效
為比較根據其中抗FAP序列結構及IL-12序列結構形成杵-入-臼結構之雙重抗體型融合蛋白之癌症靶向的抗癌功效,在以1:1比率共注射有過度表現FAP之NIH-3T3(小鼠纖維母細胞細胞株)及LLC1(小鼠肺癌細胞株)的動物模型中鑑別腫瘤生長抑制能力。
特定言之,對於藥物功效評估,當腫瘤尺寸達到70至100 mm
3時,將小鼠隨機分成各組。作為對照,一週二次腹膜內投予PBS。將單獨投予T1.16m或T1.17m之組、組合投予T1.16m及T1.17m之組(T1.16m + T1.17m)及投予T1.03m之組用作測試組以評估腫瘤生長抑制能力。分別作為抗FAP與IL-12之二聚體的T1.16m及T1.17m以0.01 µg之劑量一週二次腹膜內投予,且作為單體融合蛋白之T1.03m以0.02 µg之劑量一週二次腹膜內投予以觀測腫瘤生長抑制能力。
因此,如圖32中所展示,觀測到與對照相比,在投予之後10天時間點時,用T1.03m投予之組具有極佳腫瘤生長抑制能力。比較單獨投予T1.16m或T1.17m之組及各組合投予組,且發現單獨投予T1.03m之組具有極佳腫瘤生長抑制能力。此等結果指示,一個實施例之融合蛋白之協同效應與其中僅靶向FAP之情況相比或在與無癌症目標之IL-12相比時顯著。
(無)
圖1說明藉由用SDS-PAGE根據一個實施例鑑別T1.01、T1.02、T1.03、T1.04、T1.05、T1.06及T1.07獲得之結果。
圖2說明藉由用SDS-PAGE根據一個實施例鑑別T1.08、T1.09、T1.10、T1.11、T1.12、T1.13、T1.14及T1.15獲得之結果。
圖3說明藉由用SDS-PAGE根據一個實施例鑑別T1.16、T1.17、T1.18、T1.19及T1.21獲得之結果。
圖4說明藉由用SDS-PAGE根據一個實施例鑑別T1.01m、T1.02m、T1.03m、T1.04m、T1.05m、T1.06m及T1.07m獲得之結果。
圖5說明藉由用SDS-PAGE根據一個實施例鑑別T1.08m、T1.09m、T1.10m、T1.11m、T1.12m、T1.13m及T1.15m獲得之結果。
圖6說明藉由用SDS-PAGE根據一個實施例鑑別T1.16m、T1.17m、T1.18m、T1.19m、T1.20m、T1.21m及T1.22m獲得之結果。
圖7說明展示經由表面電漿子共振分析方法,T1.01及T1.02對於重組人類FAP (rhFAP)之結合親和力的圖式。
圖8說明展示經由表面電漿子共振分析方法,T1.03對於重組人類FAP之結合親和力的圖式。
圖9說明展示經由表面電漿子共振分析方法,T1.04及T1.05對於重組人類FAP之結合親和力的圖式。
圖10說明展示經由表面電漿子共振分析方法,T1.06及T1.07對於重組人類FAP之結合親和力的圖式。
圖11說明展示經由表面電漿子共振分析方法,T1.08及T1.09對於重組人類FAP之結合親和力的圖式。
圖12說明展示經由表面電漿子共振分析方法,T1.10及T1.11對於重組人類FAP之結合親和力的圖式。
圖13說明展示經由表面電漿子共振分析方法,T1.01m及T1.02m對於重組小鼠FAP之結合親和力的圖式。
圖14說明展示經由表面電漿子共振分析方法,T1.03m對於重組小鼠FAP之結合親和力的圖式。
圖15說明展示經由流式細胞測量術,T1.12、T1.01、T1.02及T1.03對於HEK293-hFAP細胞及HEK293細胞之結合親和力的圖式。
圖16說明展示經由流式細胞測量術,T1.12m、T1.01m、T1.02m及T1.03m對於B16F10-mFAP細胞及B16F10細胞之結合親和力的圖式。
圖17說明展示經由酶聯免疫吸附分析,T1.01、T1.02、T1.03及T1.12對於IL-12受體β1之結合親和力的圖式。
圖18說明展示經由HEKblue報告細胞中之吸光度,鑑別T1.01m、T1.02m、T1.03m及T1.12m之IL-12活性獲得的結果的圖式。
圖19說明展示經由人類T細胞之信號傳導能力,T1.01、T1.02、T1.03及T1.12之IL-12活性之圖式。
圖20說明展示經由人類T細胞之信號傳導能力在低分子量肝素(LMWH)存在下T1.01、T1.02及T1.03之IL-12活性之圖式。
圖21說明展示藉由量測人類T細胞利用T1.12、T1.01、T1.02及T1.03分泌細胞介素IFN-γ之能力獲得之結果的圖式。
圖22說明展示藉由量測人類NK細胞利用T1.12、T1.01、T1.02及T1.03分泌細胞介素IFN-γ之能力獲得之結果的圖式。
圖23說明展示藉由量測共注射有小鼠FAP過度表現之纖維母細胞NIH-3T3及大腸直腸癌細胞株CT26之小鼠腫瘤模型之腫瘤尺寸變化,利用T1.01m及T1.02m之腫瘤生長抑制能力的圖式。
圖24說明展示藉由在共注射有小鼠FAP過度表現之纖維母細胞NIH-3T3及大腸直腸癌細胞株CT26之小鼠腫瘤模型中,量測各個體之腫瘤尺寸以便鑑別利用T1.01m及T1.02m之腫瘤生長抑制能力獲得的結果的圖式。
圖25說明展示藉由在植入小鼠FAP過度表現之大腸直腸癌細胞株CT26之小鼠腫瘤模型中量測各個體之腫瘤尺寸變化,利用針對各濃度投予T1.01m及T1.02m之腫瘤生長抑制能力的圖式。
圖26說明展示在藉由將CT26細胞及4T1細胞移殖至小鼠中構築腫瘤再攻擊模型之後CT26腫瘤尺寸之變化的圖式,其中藉由T1.01m治療在共注射有小鼠FAP過度表現之纖維母細胞NIH-3T3及大腸直腸癌細胞株CT26之小鼠腫瘤模型中實現完全反應。
圖27說明展示在藉由將CT26細胞及4T1細胞移殖至小鼠中構築腫瘤再攻擊模型之後4T1腫瘤尺寸之變化的圖式,其中藉由T1.01m治療在共注射有小鼠FAP過度表現之纖維母細胞NIH-3T3及大腸直腸癌細胞株CT26之小鼠腫瘤模型中實現完全反應。
圖28說明展示藉由在植入小鼠FAP過度表現之CT26細胞之小鼠模型中量測各個體之腫瘤尺寸,利用針對各個體投予T1.01m、T1.02m及T1.03m之腫瘤生長抑制能力的圖式。
圖29說明展示藉由在植入有小鼠FAP過度表現之CT26細胞之小鼠模型中量測各個體之腫瘤尺寸變化,利用針對各濃度投予T1.03m之對於各個體之腫瘤生長抑制能力的圖式。
圖30說明展示藉由在植入有小鼠FAP過度表現之B16F10細胞之小鼠模型中量測各個體之腫瘤尺寸變化,利用針對各濃度投予T1.03m之腫瘤生長抑制能力的圖式。
圖31說明展示藉由在共注射有小鼠FAP過度表現之纖維母細胞NIH-3T3及肺癌細胞株LLC1之小鼠模型中量測各個體之腫瘤尺寸變化,利用針對各濃度投予T1.03m之腫瘤生長抑制能力的圖式。
圖32說明展示藉由在共注射有小鼠FAP過度表現之纖維母細胞NIH-3T3及肺癌細胞株LLC1之小鼠模型中,在投予T1.16m、T1.17m、T1.03m或T1.16m與T1.17m之組合之後的時間點10天時量測腫瘤尺寸獲得之結果的圖式。
圖33說明以下之示意圖:抗FAP/IL-12融合蛋白(自左側之第一個;在該圖式中,左側為抗FAP單體,且右側為包含IL-12之單體)、具有雙可變區域之抗FAP/IL-12融合蛋白(第二個)、結合FAP特異性單鏈可變片段(scFv)之抗FAP/IL-12雙抗體(第三個及第四個),及其中IL-12結合於Fc之C端的抗FAP/IL-12融合蛋白(第五個)。
圖34說明以下之示意圖:FAP特異性Fab/FAP特異性單鏈可變片段(scFv)及IL-12融合蛋白(左側)、包含FAP特異性Fab及IL-12之融合蛋白二聚體(中間)及包含FAP特異性單鏈可變片段(scFv)及IL-12之融合蛋白二聚體(右側)。
序列表 <![CDATA[<110> 南韓商治納輔醫藥科技有限公司(KANAPH THERAPEUTICS INC.)]]> <![CDATA[<120> 包含IL-12及抗FAP抗體的融合蛋白及其用途]]> <![CDATA[<140> TW 110129665]]> <![CDATA[<141> 2021-08-11]]> <![CDATA[<150> KR 10-2020-0100229]]> <![CDATA[<151> 2020-08-11]]> <![CDATA[<160> 305]]> <![CDATA[<170> KoPatentIn 3.0]]> <![CDATA[<210> 1]]> <![CDATA[<211> 454]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗人類FAP HC人類IgG1 Fc杵DANG]]> <![CDATA[<400> 1]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr 20 25 30 Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile 35 40 45 Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 130 135 140 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 145 150 155 160 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 165 170 175 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 180 185 190 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 195 200 205 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro 210 215 220 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 245 250 255 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Ala 260 265 270 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 275 280 285 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly 290 295 300 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 305 310 315 320 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 325 330 335 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 340 345 350 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn 355 360 365 Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 370 375 380 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 385 390 395 400 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 405 410 415 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 420 425 430 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 435 440 445 Ser Leu Ser Pro Gly Lys 450 <![CDATA[<210> 2]]> <![CDATA[<211> 220]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗人類FAP LC]]> <![CDATA[<400> 2]]> Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser 20 25 30 Arg Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Phe Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Phe Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 85 90 95 Tyr Phe Ser Tyr Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile 100 105 110 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120 125 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 145 150 155 160 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 165 170 175 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 195 200 205 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220 <![CDATA[<210> 3]]> <![CDATA[<211> 755]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類scIL-12-人類IgG1 Fc臼DANG]]> <![CDATA[<400> 3]]> Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr 1 5 10 15 Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu 20 25 30 Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly 35 40 45 Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly 50 55 60 Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu 65 70 75 80 Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys 85 90 95 Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys 100 105 110 Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr 115 120 125 Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln 130 135 140 Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly 145 150 155 160 Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala 165 170 175 Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala 180 185 190 Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg 195 200 205 Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu 210 215 220 Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp 225 230 235 240 Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln 245 250 255 Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe Thr Asp Lys Thr 260 265 270 Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala 275 280 285 Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro 290 295 300 Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 305 310 315 320 Ser Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys 325 330 335 Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln 340 345 350 Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile 355 360 365 Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys 370 375 380 Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu 385 390 395 400 Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser 405 410 415 Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met 420 425 430 Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro 435 440 445 Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu 450 455 460 Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser 465 470 475 480 Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile 485 490 495 Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Met 500 505 510 Ser Tyr Leu Asn Ala Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 515 520 525 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 530 535 540 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 545 550 555 560 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Ala Val Ser His 565 570 575 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 580 585 590 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr 595 600 605 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 610 615 620 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 625 630 635 640 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 645 650 655 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 660 665 670 Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 675 680 685 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 690 695 700 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val 705 710 715 720 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 725 730 735 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 740 745 750 Pro Gly Lys 755 <![CDATA[<210> 4]]> <![CDATA[<211> 755]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類scIL-12突變1-人類IgG1 Fc臼DANG]]> <![CDATA[<400> 4]]> Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr 1 5 10 15 Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu 20 25 30 Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly 35 40 45 Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly 50 55 60 Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu 65 70 75 80 Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys 85 90 95 Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys 100 105 110 Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr 115 120 125 Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln 130 135 140 Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly 145 150 155 160 Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala 165 170 175 Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala 180 185 190 Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg 195 200 205 Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu 210 215 220 Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp 225 230 235 240 Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln 245 250 255 Gly Ala Ser Lys Arg Glu Ala Lys Asp Arg Val Phe Thr Asp Lys Thr 260 265 270 Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala 275 280 285 Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro 290 295 300 Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 305 310 315 320 Ser Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys 325 330 335 Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln 340 345 350 Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile 355 360 365 Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys 370 375 380 Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu 385 390 395 400 Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser 405 410 415 Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met 420 425 430 Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro 435 440 445 Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu 450 455 460 Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser 465 470 475 480 Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile 485 490 495 Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Met 500 505 510 Ser Tyr Leu Asn Ala Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 515 520 525 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 530 535 540 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 545 550 555 560 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Ala Val Ser His 565 570 575 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 580 585 590 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr 595 600 605 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 610 615 620 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 625 630 635 640 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 645 650 655 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 660 665 670 Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 675 680 685 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 690 695 700 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val 705 710 715 720 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 725 730 735 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 740 745 750 Pro Gly Lys 755 <![CDATA[<210> 5]]> <![CDATA[<211> 755]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類scIL-12突變2-人類IgG1 Fc臼DANG]]> <![CDATA[<400> 5]]> Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr 1 5 10 15 Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu 20 25 30 Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly 35 40 45 Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly 50 55 60 Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu 65 70 75 80 Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys 85 90 95 Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys 100 105 110 Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr 115 120 125 Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln 130 135 140 Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly 145 150 155 160 Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala 165 170 175 Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala 180 185 190 Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg 195 200 205 Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu 210 215 220 Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp 225 230 235 240 Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln 245 250 255 Gly Ala Ser Ala Arg Glu Ala Ala Asp Arg Val Phe Thr Asp Lys Thr 260 265 270 Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala 275 280 285 Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro 290 295 300 Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 305 310 315 320 Ser Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys 325 330 335 Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln 340 345 350 Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile 355 360 365 Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys 370 375 380 Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu 385 390 395 400 Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser 405 410 415 Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met 420 425 430 Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro 435 440 445 Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu 450 455 460 Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser 465 470 475 480 Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile 485 490 495 Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Met 500 505 510 Ser Tyr Leu Asn Ala Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 515 520 525 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 530 535 540 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 545 550 555 560 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Ala Val Ser His 565 570 575 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 580 585 590 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr 595 600 605 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 610 615 620 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 625 630 635 640 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 645 650 655 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 660 665 670 Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 675 680 685 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 690 695 700 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val 705 710 715 720 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 725 730 735 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 740 745 750 Pro Gly Lys 755 <![CDATA[<210> 6]]> <![CDATA[<211> 593]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> (抗人類FAP VH)2-人類IgG1 Fc杵DANG]]> <![CDATA[<400> 6]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr 20 25 30 Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile 35 40 45 Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly 115 120 125 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val 130 135 140 Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser 145 150 155 160 Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr Thr Ile His Trp Val 165 170 175 Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile Gly Gly Ile Asn Pro 180 185 190 Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe Lys Gly Arg Val Thr 195 200 205 Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr Met Glu Leu Ser Ser 210 215 220 Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Arg Arg Ile 225 230 235 240 Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp Tyr Trp Gly Gln Gly 245 250 255 Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 260 265 270 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 275 280 285 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 290 295 300 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 305 310 315 320 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 325 330 335 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 340 345 350 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 355 360 365 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 370 375 380 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 385 390 395 400 Arg Thr Pro Glu Val Thr Cys Val Val Val Ala Val Ser His Glu Asp 405 410 415 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 420 425 430 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Val 435 440 445 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 450 455 460 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 465 470 475 480 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 485 490 495 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp 500 505 510 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 515 520 525 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 530 535 540 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 545 550 555 560 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 565 570 575 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 580 585 590 Lys <![CDATA[<210> 7]]> <![CDATA[<211> 348]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> (抗人類FAP VL)2]]> <![CDATA[<400> 7]]> Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser 20 25 30 Arg Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Phe Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Phe Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 85 90 95 Tyr Phe Ser Tyr Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile 100 105 110 Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 130 135 140 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser 145 150 155 160 Arg Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 165 170 175 Pro Pro Lys Leu Leu Ile Phe Trp Ala Ser Thr Arg Glu Ser Gly Val 180 185 190 Pro Asp Arg Phe Ser Gly Ser Gly Phe Gly Thr Asp Phe Thr Leu Thr 195 200 205 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 210 215 220 Tyr Phe Ser Tyr Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile 225 230 235 240 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 245 250 255 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 260 265 270 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 275 280 285 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 290 295 300 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 305 310 315 320 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 325 330 335 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 340 345 <![CDATA[<210> 8]]> <![CDATA[<211> 726]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗人類FAP HC人類IgG1 Fc杵DANG-抗人類FAP scFv]]> <![CDATA[<400> 8]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr 20 25 30 Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile 35 40 45 Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 130 135 140 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 145 150 155 160 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 165 170 175 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 180 185 190 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 195 200 205 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro 210 215 220 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 245 250 255 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Ala 260 265 270 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 275 280 285 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly 290 295 300 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 305 310 315 320 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 325 330 335 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 340 345 350 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn 355 360 365 Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 370 375 380 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 385 390 395 400 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 405 410 415 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 420 425 430 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 435 440 445 Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 450 455 460 Gly Gly Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val 465 470 475 480 Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr 485 490 495 Thr Phe Thr Glu Tyr Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln 500 505 510 Arg Leu Glu Trp Ile Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn 515 520 525 Tyr Asn Gln Lys Phe Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser 530 535 540 Ala Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr 545 550 555 560 Ala Val Tyr Tyr Cys Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu 565 570 575 Gly His Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 580 585 590 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 595 600 605 Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu 610 615 620 Ala Val Ser Leu Gly Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln 625 630 635 640 Ser Leu Leu Tyr Ser Arg Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln 645 650 655 Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Phe Trp Ala Ser Thr 660 665 670 Arg Glu Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Phe Gly Thr 675 680 685 Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val 690 695 700 Tyr Tyr Cys Gln Gln Tyr Phe Ser Tyr Pro Leu Thr Phe Gly Gln Gly 705 710 715 720 Thr Lys Val Glu Ile Lys 725 <![CDATA[<210> 9]]> <![CDATA[<211> 492]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗人類FAP LC-抗人類FAP scFv]]> <![CDATA[<400> 9]]> Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser 20 25 30 Arg Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Phe Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Phe Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 85 90 95 Tyr Phe Ser Tyr Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile 100 105 110 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120 125 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 145 150 155 160 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 165 170 175 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 195 200 205 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys Gly Gly Gly Gly 210 215 220 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val 225 230 235 240 Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser 245 250 255 Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr Thr Ile His Trp Val 260 265 270 Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile Gly Gly Ile Asn Pro 275 280 285 Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe Lys Gly Arg Val Thr 290 295 300 Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr Met Glu Leu Ser Ser 305 310 315 320 Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Arg Arg Ile 325 330 335 Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp Tyr Trp Gly Gln Gly 340 345 350 Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 355 360 365 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr 370 375 380 Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr Ile 385 390 395 400 Asn Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser Arg Asn Gln Lys Asn 405 410 415 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu 420 425 430 Ile Phe Trp Ala Ser Thr Arg Glu Ser Gly Val Pro Asp Arg Phe Ser 435 440 445 Gly Ser Gly Phe Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln 450 455 460 Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Tyr Phe Ser Tyr Pro 465 470 475 480 Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 485 490 <![CDATA[<210> 10]]> <![CDATA[<211> 986]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗人類FAP HC人類IgG1 Fc臼DANG-人類scIL-12]]> <![CDATA[<400> 10]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr 20 25 30 Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile 35 40 45 Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 130 135 140 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 145 150 155 160 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 165 170 175 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 180 185 190 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 195 200 205 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro 210 215 220 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 245 250 255 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Ala 260 265 270 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 275 280 285 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly 290 295 300 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 305 310 315 320 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 325 330 335 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 340 345 350 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn 355 360 365 Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile 370 375 380 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 385 390 395 400 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys 405 410 415 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 420 425 430 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 435 440 445 Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 450 455 460 Gly Gly Gly Ser Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu 465 470 475 480 Leu Asp Trp Tyr Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys 485 490 495 Asp Thr Pro Glu Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser 500 505 510 Glu Val Leu Gly Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe 515 520 525 Gly Asp Ala Gly Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser 530 535 540 His Ser Leu Leu Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr 545 550 555 560 Asp Ile Leu Lys Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg 565 570 575 Cys Glu Ala Lys Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr 580 585 590 Thr Ile Ser Thr Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser 595 600 605 Ser Asp Pro Gln Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu 610 615 620 Arg Val Arg Gly Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln 625 630 635 640 Glu Asp Ser Ala Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val 645 650 655 Met Val Asp Ala Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser 660 665 670 Phe Phe Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln 675 680 685 Leu Lys Pro Leu Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr 690 695 700 Pro Asp Thr Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys 705 710 715 720 Val Gln Val Gln Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe 725 730 735 Thr Asp Lys Thr Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile 740 745 750 Ser Val Arg Ala Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp 755 760 765 Ala Ser Val Pro Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 770 775 780 Gly Gly Gly Gly Ser Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly 785 790 795 800 Met Phe Pro Cys Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser 805 810 815 Asn Met Leu Gln Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr 820 825 830 Ser Glu Glu Ile Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr 835 840 845 Val Glu Ala Cys Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu 850 855 860 Asn Ser Arg Glu Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser 865 870 875 880 Arg Lys Thr Ser Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu 885 890 895 Asp Leu Lys Met Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu 900 905 910 Leu Met Asp Pro Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala 915 920 925 Val Ile Asp Glu Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val 930 935 940 Pro Gln Lys Ser Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile 945 950 955 960 Lys Leu Cys Ile Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile 965 970 975 Asp Arg Val Met Ser Tyr Leu Asn Ala Ser 980 985 <![CDATA[<210> 11]]> <![CDATA[<211> 986]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗人類FAP HC人類IgG1 Fc臼DANG-人類scIL-12突變2]]> <![CDATA[<400> 11]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr 20 25 30 Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile 35 40 45 Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 130 135 140 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 145 150 155 160 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 165 170 175 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 180 185 190 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 195 200 205 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro 210 215 220 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 245 250 255 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Ala 260 265 270 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 275 280 285 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly 290 295 300 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 305 310 315 320 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 325 330 335 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 340 345 350 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn 355 360 365 Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile 370 375 380 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 385 390 395 400 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys 405 410 415 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 420 425 430 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 435 440 445 Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 450 455 460 Gly Gly Gly Ser Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu 465 470 475 480 Leu Asp Trp Tyr Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys 485 490 495 Asp Thr Pro Glu Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser 500 505 510 Glu Val Leu Gly Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe 515 520 525 Gly Asp Ala Gly Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser 530 535 540 His Ser Leu Leu Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr 545 550 555 560 Asp Ile Leu Lys Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg 565 570 575 Cys Glu Ala Lys Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr 580 585 590 Thr Ile Ser Thr Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser 595 600 605 Ser Asp Pro Gln Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu 610 615 620 Arg Val Arg Gly Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln 625 630 635 640 Glu Asp Ser Ala Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val 645 650 655 Met Val Asp Ala Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser 660 665 670 Phe Phe Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln 675 680 685 Leu Lys Pro Leu Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr 690 695 700 Pro Asp Thr Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys 705 710 715 720 Val Gln Val Gln Gly Ala Ser Ala Arg Glu Ala Ala Asp Arg Val Phe 725 730 735 Thr Asp Lys Thr Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile 740 745 750 Ser Val Arg Ala Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp 755 760 765 Ala Ser Val Pro Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 770 775 780 Gly Gly Gly Gly Ser Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly 785 790 795 800 Met Phe Pro Cys Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser 805 810 815 Asn Met Leu Gln Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr 820 825 830 Ser Glu Glu Ile Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr 835 840 845 Val Glu Ala Cys Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu 850 855 860 Asn Ser Arg Glu Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser 865 870 875 880 Arg Lys Thr Ser Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu 885 890 895 Asp Leu Lys Met Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu 900 905 910 Leu Met Asp Pro Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala 915 920 925 Val Ile Asp Glu Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val 930 935 940 Pro Gln Lys Ser Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile 945 950 955 960 Lys Leu Cys Ile Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile 965 970 975 Asp Arg Val Met Ser Tyr Leu Asn Ala Ser 980 985 <![CDATA[<210> 12]]> <![CDATA[<211> 227]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類IgG1 Fc臼DANG]]> <![CDATA[<400> 12]]> Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Ala Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Lys 225 <![CDATA[<210> 13]]> <![CDATA[<211> 227]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類IgG1 Fc杵DANG]]> <![CDATA[<400> 13]]> Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Ala Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Lys 225 <![CDATA[<210> 14]]> <![CDATA[<211> 454]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗人類FAP HC人類IgG1 Fc DANG]]> <![CDATA[<400> 14]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr 20 25 30 Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile 35 40 45 Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 130 135 140 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 145 150 155 160 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 165 170 175 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 180 185 190 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 195 200 205 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro 210 215 220 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 245 250 255 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Ala 260 265 270 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 275 280 285 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly 290 295 300 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 305 310 315 320 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 325 330 335 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 340 345 350 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn 355 360 365 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 370 375 380 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 385 390 395 400 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 405 410 415 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 420 425 430 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 435 440 445 Ser Leu Ser Pro Gly Lys 450 <![CDATA[<210> 15]]> <![CDATA[<211> 755]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類scIL-12突變2-人類IgG1 Fc DANG]]> <![CDATA[<400> 15]]> Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr 1 5 10 15 Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu 20 25 30 Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly 35 40 45 Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly 50 55 60 Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu 65 70 75 80 Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys 85 90 95 Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys 100 105 110 Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr 115 120 125 Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln 130 135 140 Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly 145 150 155 160 Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala 165 170 175 Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala 180 185 190 Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg 195 200 205 Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu 210 215 220 Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp 225 230 235 240 Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln 245 250 255 Gly Ala Ser Ala Arg Glu Ala Ala Asp Arg Val Phe Thr Asp Lys Thr 260 265 270 Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala 275 280 285 Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro 290 295 300 Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 305 310 315 320 Ser Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys 325 330 335 Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln 340 345 350 Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile 355 360 365 Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys 370 375 380 Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu 385 390 395 400 Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser 405 410 415 Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met 420 425 430 Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro 435 440 445 Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu 450 455 460 Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser 465 470 475 480 Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile 485 490 495 Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Met 500 505 510 Ser Tyr Leu Asn Ala Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 515 520 525 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 530 535 540 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 545 550 555 560 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Ala Val Ser His 565 570 575 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 580 585 590 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr 595 600 605 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 610 615 620 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 625 630 635 640 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 645 650 655 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 660 665 670 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 675 680 685 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 690 695 700 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 705 710 715 720 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 725 730 735 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 740 745 750 Pro Gly Lys 755 <![CDATA[<210> 16]]> <![CDATA[<211> 451]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗人類CD20 HC人類IgG1 Fc杵DANG ]]> <![CDATA[<400> 16]]> Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly 100 105 110 Ala Gly Thr Thr Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Ala Val Ser His 260 265 270 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr 290 295 300 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 305 310 315 320 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 355 360 365 Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445 Pro Gly Lys 450 <![CDATA[<210> 17]]> <![CDATA[<211> 213]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗人類CD20 LC]]> <![CDATA[<400> 17]]> Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Ile 20 25 30 His Trp Phe Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr 35 40 45 Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Thr Ser Asn Pro Pro Thr 85 90 95 Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro 100 105 110 Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125 Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu 145 150 155 160 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175 Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190 Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205 Asn Arg Gly Glu Cys 210 <![CDATA[<210> 18]]> <![CDATA[<211> 447]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗小鼠FAP HC小鼠IgG2a Fc杵DANG]]> <![CDATA[<400> 18]]> Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 1 5 10 15 Ser Val Asn Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Asn 20 25 30 Gly Ile Asn Trp Leu Lys Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Glu Ile Tyr Pro Arg Ser Thr Asn Thr Leu Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Arg Ser Ser Asn Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Thr Leu Thr Ala Pro Phe Ala Phe Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ala Ala Lys Thr Thr Ala Pro Ser Val Tyr Pro Leu 115 120 125 Ala Pro Val Cys Gly Asp Thr Thr Gly Ser Ser Val Thr Leu Gly Cys 130 135 140 Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu Thr Trp Asn Ser 145 150 155 160 Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175 Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr Ser Ser Thr Trp 180 185 190 Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr 195 200 205 Lys Val Asp Lys Lys Ile Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys 210 215 220 Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser 245 250 255 Pro Ile Val Thr Cys Val Val Val Ala Val Ser Glu Asp Asp Pro Asp 260 265 270 Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln 275 280 285 Thr Gln Thr His Arg Glu Asp Tyr Gly Ser Thr Leu Arg Val Val Ser 290 295 300 Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys 305 310 315 320 Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile 325 330 335 Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro 340 345 350 Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu Trp Cys Met 355 360 365 Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn 370 375 380 Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn 405 410 415 Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu 420 425 430 His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys 435 440 445 <![CDATA[<210> 19]]> <![CDATA[<211> 213]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗小鼠FAP LC]]> <![CDATA[<400> 19]]> Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Gly Val Asn Phe Met 20 25 30 His Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Phe 35 40 45 Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Phe Asn Pro Pro Thr 85 90 95 Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Ala Asp Ala Ala Pro 100 105 110 Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly Gly 115 120 125 Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile Asn 130 135 140 Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val Leu Asn 145 150 155 160 Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser Ser 165 170 175 Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr Thr 180 185 190 Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys Ser Phe 195 200 205 Asn Arg Asn Glu Cys 210 <![CDATA[<210> 20]]> <![CDATA[<211> 764]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 小鼠scIL-12-小鼠IgG2a Fc臼DANG]]> <![CDATA[<400> 20]]> Met Trp Glu Leu Glu Lys Asp Val Tyr Val Val Glu Val Asp Trp Thr 1 5 10 15 Pro Asp Ala Pro Gly Glu Thr Val Asn Leu Thr Cys Asp Thr Pro Glu 20 25 30 Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln Arg His Gly Val Ile Gly 35 40 45 Ser Gly Lys Thr Leu Thr Ile Thr Val Lys Glu Phe Leu Asp Ala Gly 50 55 60 Gln Tyr Thr Cys His Lys Gly Gly Glu Thr Leu Ser His Ser His Leu 65 70 75 80 Leu Leu His Lys Lys Glu Asn Gly Ile Trp Ser Thr Glu Ile Leu Lys 85 90 95 Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys Glu Ala Pro Asn Tyr Ser 100 105 110 Gly Arg Phe Thr Cys Ser Trp Leu Val Gln Arg Asn Met Asp Leu Lys 115 120 125 Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro Asp Ser Arg Ala Val Thr 130 135 140 Cys Gly Met Ala Ser Leu Ser Ala Glu Lys Val Thr Leu Asp Gln Arg 145 150 155 160 Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln Glu Asp Val Thr Cys Pro 165 170 175 Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu Ala Leu Glu Ala Arg Gln 180 185 190 Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser Phe Phe Ile Arg Asp Ile 195 200 205 Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Met Lys Pro Leu Lys Asn 210 215 220 Ser Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Ser Trp Ser Thr Pro 225 230 235 240 His Ser Tyr Phe Ser Leu Lys Phe Phe Val Arg Ile Gln Arg Lys Lys 245 250 255 Glu Lys Met Lys Glu Thr Glu Glu Gly Cys Asn Gln Lys Gly Ala Phe 260 265 270 Leu Val Glu Lys Thr Ser Thr Glu Val Gln Cys Lys Gly Gly Asn Val 275 280 285 Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn Ser Ser Cys Ser Lys Trp 290 295 300 Ala Cys Val Pro Cys Arg Val Arg Ser Gly Gly Gly Gly Ser Gly Gly 305 310 315 320 Gly Gly Ser Gly Gly Gly Gly Ser Arg Val Ile Pro Val Ser Gly Pro 325 330 335 Ala Arg Cys Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp 340 345 350 Met Val Lys Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala 355 360 365 Glu Asp Ile Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu 370 375 380 Lys Thr Cys Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala 385 390 395 400 Thr Arg Glu Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln 405 410 415 Lys Thr Ser Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp 420 425 430 Leu Lys Met Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln 435 440 445 Asn His Asn His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala 450 455 460 Ile Asp Glu Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg 465 470 475 480 Gln Lys Pro Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys 485 490 495 Leu Cys Ile Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn 500 505 510 Arg Val Met Gly Tyr Leu Ser Ser Ala Gly Gly Gly Gly Ser Gly Gly 515 520 525 Gly Gly Ser Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys 530 535 540 Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe 545 550 555 560 Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val 565 570 575 Thr Cys Val Val Val Ala Val Ser Glu Asp Asp Pro Asp Val Gln Ile 580 585 590 Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr 595 600 605 His Arg Glu Asp Tyr Gly Ser Thr Leu Arg Val Val Ser Ala Leu Pro 610 615 620 Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val 625 630 635 640 Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro 645 650 655 Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu 660 665 670 Glu Glu Met Thr Lys Lys Gln Val Thr Leu Ser Cys Ala Val Thr Asp 675 680 685 Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr 690 695 700 Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser 705 710 715 720 Tyr Phe Met Val Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu 725 730 735 Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His 740 745 750 His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys 755 760 <![CDATA[<210> 21]]> <![CDATA[<211> 764]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 小鼠scIL-12突變1-小鼠IgG2a Fc臼DANG]]> <![CDATA[<400> 21]]> Met Trp Glu Leu Glu Lys Asp Val Tyr Val Val Glu Val Asp Trp Thr 1 5 10 15 Pro Asp Ala Pro Gly Glu Thr Val Asn Leu Thr Cys Asp Thr Pro Glu 20 25 30 Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln Arg His Gly Val Ile Gly 35 40 45 Ser Gly Lys Thr Leu Thr Ile Thr Val Lys Glu Phe Leu Asp Ala Gly 50 55 60 Gln Tyr Thr Cys His Lys Gly Gly Glu Thr Leu Ser His Ser His Leu 65 70 75 80 Leu Leu His Lys Lys Glu Asn Gly Ile Trp Ser Thr Glu Ile Leu Lys 85 90 95 Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys Glu Ala Pro Asn Tyr Ser 100 105 110 Gly Arg Phe Thr Cys Ser Trp Leu Val Gln Arg Asn Met Asp Leu Lys 115 120 125 Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro Asp Ser Arg Ala Val Thr 130 135 140 Cys Gly Met Ala Ser Leu Ser Ala Glu Lys Val Thr Leu Asp Gln Arg 145 150 155 160 Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln Glu Asp Val Thr Cys Pro 165 170 175 Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu Ala Leu Glu Ala Arg Gln 180 185 190 Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser Phe Phe Ile Arg Asp Ile 195 200 205 Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Met Lys Pro Leu Lys Asn 210 215 220 Ser Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Ser Trp Ser Thr Pro 225 230 235 240 His Ser Tyr Phe Ser Leu Lys Phe Phe Val Arg Ile Gln Arg Ala Lys 245 250 255 Glu Lys Met Ala Glu Thr Glu Glu Gly Cys Asn Gln Lys Gly Ala Phe 260 265 270 Leu Val Glu Lys Thr Ser Thr Glu Val Gln Cys Lys Gly Gly Asn Val 275 280 285 Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn Ser Ser Cys Ser Lys Trp 290 295 300 Ala Cys Val Pro Cys Arg Val Arg Ser Gly Gly Gly Gly Ser Gly Gly 305 310 315 320 Gly Gly Ser Gly Gly Gly Gly Ser Arg Val Ile Pro Val Ser Gly Pro 325 330 335 Ala Arg Cys Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp 340 345 350 Met Val Lys Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala 355 360 365 Glu Asp Ile Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu 370 375 380 Lys Thr Cys Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala 385 390 395 400 Thr Arg Glu Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln 405 410 415 Lys Thr Ser Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp 420 425 430 Leu Lys Met Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln 435 440 445 Asn His Asn His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala 450 455 460 Ile Asp Glu Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg 465 470 475 480 Gln Lys Pro Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys 485 490 495 Leu Cys Ile Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn 500 505 510 Arg Val Met Gly Tyr Leu Ser Ser Ala Gly Gly Gly Gly Ser Gly Gly 515 520 525 Gly Gly Ser Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys 530 535 540 Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe 545 550 555 560 Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val 565 570 575 Thr Cys Val Val Val Ala Val Ser Glu Asp Asp Pro Asp Val Gln Ile 580 585 590 Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr 595 600 605 His Arg Glu Asp Tyr Gly Ser Thr Leu Arg Val Val Ser Ala Leu Pro 610 615 620 Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val 625 630 635 640 Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro 645 650 655 Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu 660 665 670 Glu Glu Met Thr Lys Lys Gln Val Thr Leu Ser Cys Ala Val Thr Asp 675 680 685 Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr 690 695 700 Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser 705 710 715 720 Tyr Phe Met Val Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu 725 730 735 Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His 740 745 750 His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys 755 760 <![CDATA[<210> 22]]> <![CDATA[<211> 764]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 小鼠scIL-12突變2-小鼠IgG2a Fc臼DANG]]> <![CDATA[<400> 22]]> Met Trp Glu Leu Glu Lys Asp Val Tyr Val Val Glu Val Asp Trp Thr 1 5 10 15 Pro Asp Ala Pro Gly Glu Thr Val Asn Leu Thr Cys Asp Thr Pro Glu 20 25 30 Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln Arg His Gly Val Ile Gly 35 40 45 Ser Gly Lys Thr Leu Thr Ile Thr Val Lys Glu Phe Leu Asp Ala Gly 50 55 60 Gln Tyr Thr Cys His Lys Gly Gly Glu Thr Leu Ser His Ser His Leu 65 70 75 80 Leu Leu His Lys Lys Glu Asn Gly Ile Trp Ser Thr Glu Ile Leu Lys 85 90 95 Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys Glu Ala Pro Asn Tyr Ser 100 105 110 Gly Arg Phe Thr Cys Ser Trp Leu Val Gln Arg Asn Met Asp Leu Lys 115 120 125 Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro Asp Ser Arg Ala Val Thr 130 135 140 Cys Gly Met Ala Ser Leu Ser Ala Glu Lys Val Thr Leu Asp Gln Arg 145 150 155 160 Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln Glu Asp Val Thr Cys Pro 165 170 175 Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu Ala Leu Glu Ala Arg Gln 180 185 190 Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser Phe Phe Ile Arg Asp Ile 195 200 205 Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Met Lys Pro Leu Lys Asn 210 215 220 Ser Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Ser Trp Ser Thr Pro 225 230 235 240 His Ser Tyr Phe Ser Leu Lys Phe Phe Val Arg Ile Gln Ala Ala Ala 245 250 255 Glu Lys Met Ala Glu Thr Glu Glu Gly Cys Asn Gln Lys Gly Ala Phe 260 265 270 Leu Val Glu Lys Thr Ser Thr Glu Val Gln Cys Lys Gly Gly Asn Val 275 280 285 Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn Ser Ser Cys Ser Lys Trp 290 295 300 Ala Cys Val Pro Cys Arg Val Arg Ser Gly Gly Gly Gly Ser Gly Gly 305 310 315 320 Gly Gly Ser Gly Gly Gly Gly Ser Arg Val Ile Pro Val Ser Gly Pro 325 330 335 Ala Arg Cys Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp 340 345 350 Met Val Lys Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala 355 360 365 Glu Asp Ile Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu 370 375 380 Lys Thr Cys Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala 385 390 395 400 Thr Arg Glu Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln 405 410 415 Lys Thr Ser Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp 420 425 430 Leu Lys Met Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln 435 440 445 Asn His Asn His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala 450 455 460 Ile Asp Glu Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg 465 470 475 480 Gln Lys Pro Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys 485 490 495 Leu Cys Ile Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn 500 505 510 Arg Val Met Gly Tyr Leu Ser Ser Ala Gly Gly Gly Gly Ser Gly Gly 515 520 525 Gly Gly Ser Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys 530 535 540 Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe 545 550 555 560 Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val 565 570 575 Thr Cys Val Val Val Ala Val Ser Glu Asp Asp Pro Asp Val Gln Ile 580 585 590 Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr 595 600 605 His Arg Glu Asp Tyr Gly Ser Thr Leu Arg Val Val Ser Ala Leu Pro 610 615 620 Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val 625 630 635 640 Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro 645 650 655 Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu 660 665 670 Glu Glu Met Thr Lys Lys Gln Val Thr Leu Ser Cys Ala Val Thr Asp 675 680 685 Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr 690 695 700 Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser 705 710 715 720 Tyr Phe Met Val Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu 725 730 735 Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His 740 745 750 His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys 755 760 <![CDATA[<210> 23]]> <![CDATA[<211> 579]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> (抗小鼠FAP VH)2,小鼠IgG2a Fc杵DANG]]> <![CDATA[<400> 23]]> Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 1 5 10 15 Ser Val Asn Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Asn 20 25 30 Gly Ile Asn Trp Leu Lys Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Glu Ile Tyr Pro Arg Ser Thr Asn Thr Leu Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Arg Ser Ser Asn Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Thr Leu Thr Ala Pro Phe Ala Phe Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 115 120 125 Gly Gly Gly Ser Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala 130 135 140 Arg Pro Gly Ala Ser Val Asn Leu Ser Cys Lys Ala Ser Gly Tyr Thr 145 150 155 160 Phe Thr Asn Asn Gly Ile Asn Trp Leu Lys Gln Arg Thr Gly Gln Gly 165 170 175 Leu Glu Trp Ile Gly Glu Ile Tyr Pro Arg Ser Thr Asn Thr Leu Tyr 180 185 190 Asn Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Arg Ser Ser 195 200 205 Asn Thr Ala Tyr Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala 210 215 220 Val Tyr Phe Cys Ala Arg Thr Leu Thr Ala Pro Phe Ala Phe Trp Gly 225 230 235 240 Gln Gly Thr Leu Val Thr Val Ser Ala Ala Lys Thr Thr Ala Pro Ser 245 250 255 Val Tyr Pro Leu Ala Pro Val Cys Gly Asp Thr Thr Gly Ser Ser Val 260 265 270 Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu 275 280 285 Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala 290 295 300 Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr 305 310 315 320 Ser Ser Thr Trp Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro 325 330 335 Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Glu Pro Arg Gly Pro Thr 340 345 350 Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly 355 360 365 Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met 370 375 380 Ile Ser Leu Ser Pro Ile Val Thr Cys Val Val Val Ala Val Ser Glu 385 390 395 400 Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val 405 410 415 His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Gly Ser Thr Leu 420 425 430 Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly 435 440 445 Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile 450 455 460 Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val 465 470 475 480 Tyr Val Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr 485 490 495 Leu Trp Cys Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu 500 505 510 Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro 515 520 525 Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val 530 535 540 Glu Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val 545 550 555 560 His Glu Gly Leu His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr 565 570 575 Pro Gly Lys <![CDATA[<210> 24]]> <![CDATA[<211> 334]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> (抗小鼠FAP VL)2]]> <![CDATA[<400> 24]]> Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Gly Val Asn Phe Met 20 25 30 His Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Phe 35 40 45 Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Phe Asn Pro Pro Thr 85 90 95 Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser Gly 100 105 110 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Ile Val Leu Thr Gln Ser 115 120 125 Pro Ala Ile Met Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys 130 135 140 Ser Ala Ser Ser Gly Val Asn Phe Met His Trp Tyr Gln Gln Lys Ser 145 150 155 160 Gly Thr Ser Pro Lys Arg Trp Ile Phe Asp Thr Ser Lys Leu Ala Ser 165 170 175 Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser 180 185 190 Leu Thr Ile Ser Ser Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys 195 200 205 Gln Gln Trp Ser Phe Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu 210 215 220 Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro 225 230 235 240 Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu 245 250 255 Asn Asn Phe Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly 260 265 270 Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser 275 280 285 Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp 290 295 300 Glu Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr 305 310 315 320 Ser Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys 325 330 <![CDATA[<210> 25]]> <![CDATA[<211> 705]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗小鼠FAP HC小鼠IgG2a Fc杵DANG-抗小鼠FAP scFv]]> <![CDATA[<400> 25]]> Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 1 5 10 15 Ser Val Asn Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Asn 20 25 30 Gly Ile Asn Trp Leu Lys Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Glu Ile Tyr Pro Arg Ser Thr Asn Thr Leu Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Arg Ser Ser Asn Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Thr Leu Thr Ala Pro Phe Ala Phe Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ala Ala Lys Thr Thr Ala Pro Ser Val Tyr Pro Leu 115 120 125 Ala Pro Val Cys Gly Asp Thr Thr Gly Ser Ser Val Thr Leu Gly Cys 130 135 140 Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu Thr Trp Asn Ser 145 150 155 160 Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175 Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr Ser Ser Thr Trp 180 185 190 Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr 195 200 205 Lys Val Asp Lys Lys Ile Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys 210 215 220 Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser 245 250 255 Pro Ile Val Thr Cys Val Val Val Ala Val Ser Glu Asp Asp Pro Asp 260 265 270 Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln 275 280 285 Thr Gln Thr His Arg Glu Asp Tyr Gly Ser Thr Leu Arg Val Val Ser 290 295 300 Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys 305 310 315 320 Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile 325 330 335 Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro 340 345 350 Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu Trp Cys Met 355 360 365 Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn 370 375 380 Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn 405 410 415 Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu 420 425 430 His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys Gly 435 440 445 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val 450 455 460 Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala Ser Val 465 470 475 480 Asn Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Asn Gly Ile 485 490 495 Asn Trp Leu Lys Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile Gly Glu 500 505 510 Ile Tyr Pro Arg Ser Thr Asn Thr Leu Tyr Asn Glu Lys Phe Lys Gly 515 520 525 Lys Ala Thr Leu Thr Ala Asp Arg Ser Ser Asn Thr Ala Tyr Met Glu 530 535 540 Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys Ala Arg 545 550 555 560 Thr Leu Thr Ala Pro Phe Ala Phe Trp Gly Gln Gly Thr Leu Val Thr 565 570 575 Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 580 585 590 Gly Ser Gly Gly Gly Gly Ser Gln Ile Val Leu Thr Gln Ser Pro Ala 595 600 605 Ile Met Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Ser Ala 610 615 620 Ser Ser Gly Val Asn Phe Met His Trp Tyr Gln Gln Lys Ser Gly Thr 625 630 635 640 Ser Pro Lys Arg Trp Ile Phe Asp Thr Ser Lys Leu Ala Ser Gly Val 645 650 655 Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr 660 665 670 Ile Ser Ser Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln 675 680 685 Trp Ser Phe Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile 690 695 700 Lys 705 <![CDATA[<210> 26]]> <![CDATA[<211> 471]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗小鼠FAP LC-抗小鼠FAP scFv]]> <![CDATA[<400> 26]]> Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Gly Val Asn Phe Met 20 25 30 His Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Phe 35 40 45 Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Phe Asn Pro Pro Thr 85 90 95 Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Ala Asp Ala Ala Pro 100 105 110 Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly Gly 115 120 125 Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile Asn 130 135 140 Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val Leu Asn 145 150 155 160 Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser Ser 165 170 175 Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr Thr 180 185 190 Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys Ser Phe 195 200 205 Asn Arg Asn Glu Cys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 210 215 220 Gly Gly Gly Ser Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala 225 230 235 240 Arg Pro Gly Ala Ser Val Asn Leu Ser Cys Lys Ala Ser Gly Tyr Thr 245 250 255 Phe Thr Asn Asn Gly Ile Asn Trp Leu Lys Gln Arg Thr Gly Gln Gly 260 265 270 Leu Glu Trp Ile Gly Glu Ile Tyr Pro Arg Ser Thr Asn Thr Leu Tyr 275 280 285 Asn Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Arg Ser Ser 290 295 300 Asn Thr Ala Tyr Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala 305 310 315 320 Val Tyr Phe Cys Ala Arg Thr Leu Thr Ala Pro Phe Ala Phe Trp Gly 325 330 335 Gln Gly Thr Leu Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly Gly 340 345 350 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Ile Val 355 360 365 Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly Glu Lys Val 370 375 380 Thr Met Thr Cys Ser Ala Ser Ser Gly Val Asn Phe Met His Trp Tyr 385 390 395 400 Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Phe Asp Thr Ser 405 410 415 Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly 420 425 430 Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu Asp Ala Ala 435 440 445 Thr Tyr Tyr Cys Gln Gln Trp Ser Phe Asn Pro Pro Thr Phe Gly Gly 450 455 460 Gly Thr Lys Leu Glu Ile Lys 465 470 <![CDATA[<210> 27]]> <![CDATA[<211> 982]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗小鼠FAP HC小鼠IgG2a Fc臼DANG-小鼠scIL-12]]> <![CDATA[<400> 27]]> Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 1 5 10 15 Ser Val Asn Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Asn 20 25 30 Gly Ile Asn Trp Leu Lys Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Glu Ile Tyr Pro Arg Ser Thr Asn Thr Leu Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Arg Ser Ser Asn Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Thr Leu Thr Ala Pro Phe Ala Phe Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ala Ala Lys Thr Thr Ala Pro Ser Val Tyr Pro Leu 115 120 125 Ala Pro Val Cys Gly Asp Thr Thr Gly Ser Ser Val Thr Leu Gly Cys 130 135 140 Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu Thr Trp Asn Ser 145 150 155 160 Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175 Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr Ser Ser Thr Trp 180 185 190 Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr 195 200 205 Lys Val Asp Lys Lys Ile Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys 210 215 220 Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser 245 250 255 Pro Ile Val Thr Cys Val Val Val Ala Val Ser Glu Asp Asp Pro Asp 260 265 270 Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln 275 280 285 Thr Gln Thr His Arg Glu Asp Tyr Gly Ser Thr Leu Arg Val Val Ser 290 295 300 Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys 305 310 315 320 Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile 325 330 335 Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro 340 345 350 Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu Ser Cys Ala 355 360 365 Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn 370 375 380 Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Tyr Phe Met Val Ser Lys Leu Arg Val Glu Lys Lys Asn 405 410 415 Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu 420 425 430 His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Gly Gly 435 440 445 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Met Trp Glu 450 455 460 Leu Glu Lys Asp Val Tyr Val Val Glu Val Asp Trp Thr Pro Asp Ala 465 470 475 480 Pro Gly Glu Thr Val Asn Leu Thr Cys Asp Thr Pro Glu Glu Asp Asp 485 490 495 Ile Thr Trp Thr Ser Asp Gln Arg His Gly Val Ile Gly Ser Gly Lys 500 505 510 Thr Leu Thr Ile Thr Val Lys Glu Phe Leu Asp Ala Gly Gln Tyr Thr 515 520 525 Cys His Lys Gly Gly Glu Thr Leu Ser His Ser His Leu Leu Leu His 530 535 540 Lys Lys Glu Asn Gly Ile Trp Ser Thr Glu Ile Leu Lys Asn Phe Lys 545 550 555 560 Asn Lys Thr Phe Leu Lys Cys Glu Ala Pro Asn Tyr Ser Gly Arg Phe 565 570 575 Thr Cys Ser Trp Leu Val Gln Arg Asn Met Asp Leu Lys Phe Asn Ile 580 585 590 Lys Ser Ser Ser Ser Ser Pro Asp Ser Arg Ala Val Thr Cys Gly Met 595 600 605 Ala Ser Leu Ser Ala Glu Lys Val Thr Leu Asp Gln Arg Asp Tyr Glu 610 615 620 Lys Tyr Ser Val Ser Cys Gln Glu Asp Val Thr Cys Pro Thr Ala Glu 625 630 635 640 Glu Thr Leu Pro Ile Glu Leu Ala Leu Glu Ala Arg Gln Gln Asn Lys 645 650 655 Tyr Glu Asn Tyr Ser Thr Ser Phe Phe Ile Arg Asp Ile Ile Lys Pro 660 665 670 Asp Pro Pro Lys Asn Leu Gln Met Lys Pro Leu Lys Asn Ser Gln Val 675 680 685 Glu Val Ser Trp Glu Tyr Pro Asp Ser Trp Ser Thr Pro His Ser Tyr 690 695 700 Phe Ser Leu Lys Phe Phe Val Arg Ile Gln Arg Lys Lys Glu Lys Met 705 710 715 720 Lys Glu Thr Glu Glu Gly Cys Asn Gln Lys Gly Ala Phe Leu Val Glu 725 730 735 Lys Thr Ser Thr Glu Val Gln Cys Lys Gly Gly Asn Val Cys Val Gln 740 745 750 Ala Gln Asp Arg Tyr Tyr Asn Ser Ser Cys Ser Lys Trp Ala Cys Val 755 760 765 Pro Cys Arg Val Arg Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 770 775 780 Gly Gly Gly Gly Ser Arg Val Ile Pro Val Ser Gly Pro Ala Arg Cys 785 790 795 800 Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp Met Val Lys 805 810 815 Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala Glu Asp Ile 820 825 830 Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu Lys Thr Cys 835 840 845 Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala Thr Arg Glu 850 855 860 Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln Lys Thr Ser 865 870 875 880 Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp Leu Lys Met 885 890 895 Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln Asn His Asn 900 905 910 His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala Ile Asp Glu 915 920 925 Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg Gln Lys Pro 930 935 940 Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys Leu Cys Ile 945 950 955 960 Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn Arg Val Met 965 970 975 Gly Tyr Leu Ser Ser Ala 980 <![CDATA[<210> 28]]> <![CDATA[<211> 982]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗小鼠FAP HC小鼠IgG2a Fc臼DANG-小鼠scIL-12突變2]]> <![CDATA[<400> 28]]> Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 1 5 10 15 Ser Val Asn Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Asn 20 25 30 Gly Ile Asn Trp Leu Lys Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Glu Ile Tyr Pro Arg Ser Thr Asn Thr Leu Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Arg Ser Ser Asn Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Thr Leu Thr Ala Pro Phe Ala Phe Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ala Ala Lys Thr Thr Ala Pro Ser Val Tyr Pro Leu 115 120 125 Ala Pro Val Cys Gly Asp Thr Thr Gly Ser Ser Val Thr Leu Gly Cys 130 135 140 Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu Thr Trp Asn Ser 145 150 155 160 Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175 Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr Ser Ser Thr Trp 180 185 190 Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr 195 200 205 Lys Val Asp Lys Lys Ile Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys 210 215 220 Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser 245 250 255 Pro Ile Val Thr Cys Val Val Val Ala Val Ser Glu Asp Asp Pro Asp 260 265 270 Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln 275 280 285 Thr Gln Thr His Arg Glu Asp Tyr Gly Ser Thr Leu Arg Val Val Ser 290 295 300 Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys 305 310 315 320 Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile 325 330 335 Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro 340 345 350 Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu Ser Cys Ala 355 360 365 Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn 370 375 380 Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Tyr Phe Met Val Ser Lys Leu Arg Val Glu Lys Lys Asn 405 410 415 Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu 420 425 430 His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Gly Gly 435 440 445 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Met Trp Glu 450 455 460 Leu Glu Lys Asp Val Tyr Val Val Glu Val Asp Trp Thr Pro Asp Ala 465 470 475 480 Pro Gly Glu Thr Val Asn Leu Thr Cys Asp Thr Pro Glu Glu Asp Asp 485 490 495 Ile Thr Trp Thr Ser Asp Gln Arg His Gly Val Ile Gly Ser Gly Lys 500 505 510 Thr Leu Thr Ile Thr Val Lys Glu Phe Leu Asp Ala Gly Gln Tyr Thr 515 520 525 Cys His Lys Gly Gly Glu Thr Leu Ser His Ser His Leu Leu Leu His 530 535 540 Lys Lys Glu Asn Gly Ile Trp Ser Thr Glu Ile Leu Lys Asn Phe Lys 545 550 555 560 Asn Lys Thr Phe Leu Lys Cys Glu Ala Pro Asn Tyr Ser Gly Arg Phe 565 570 575 Thr Cys Ser Trp Leu Val Gln Arg Asn Met Asp Leu Lys Phe Asn Ile 580 585 590 Lys Ser Ser Ser Ser Ser Pro Asp Ser Arg Ala Val Thr Cys Gly Met 595 600 605 Ala Ser Leu Ser Ala Glu Lys Val Thr Leu Asp Gln Arg Asp Tyr Glu 610 615 620 Lys Tyr Ser Val Ser Cys Gln Glu Asp Val Thr Cys Pro Thr Ala Glu 625 630 635 640 Glu Thr Leu Pro Ile Glu Leu Ala Leu Glu Ala Arg Gln Gln Asn Lys 645 650 655 Tyr Glu Asn Tyr Ser Thr Ser Phe Phe Ile Arg Asp Ile Ile Lys Pro 660 665 670 Asp Pro Pro Lys Asn Leu Gln Met Lys Pro Leu Lys Asn Ser Gln Val 675 680 685 Glu Val Ser Trp Glu Tyr Pro Asp Ser Trp Ser Thr Pro His Ser Tyr 690 695 700 Phe Ser Leu Lys Phe Phe Val Arg Ile Gln Ala Ala Ala Glu Lys Met 705 710 715 720 Ala Glu Thr Glu Glu Gly Cys Asn Gln Lys Gly Ala Phe Leu Val Glu 725 730 735 Lys Thr Ser Thr Glu Val Gln Cys Lys Gly Gly Asn Val Cys Val Gln 740 745 750 Ala Gln Asp Arg Tyr Tyr Asn Ser Ser Cys Ser Lys Trp Ala Cys Val 755 760 765 Pro Cys Arg Val Arg Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 770 775 780 Gly Gly Gly Gly Ser Arg Val Ile Pro Val Ser Gly Pro Ala Arg Cys 785 790 795 800 Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp Met Val Lys 805 810 815 Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala Glu Asp Ile 820 825 830 Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu Lys Thr Cys 835 840 845 Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala Thr Arg Glu 850 855 860 Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln Lys Thr Ser 865 870 875 880 Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp Leu Lys Met 885 890 895 Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln Asn His Asn 900 905 910 His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala Ile Asp Glu 915 920 925 Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg Gln Lys Pro 930 935 940 Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys Leu Cys Ile 945 950 955 960 Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn Arg Val Met 965 970 975 Gly Tyr Leu Ser Ser Ala 980 <![CDATA[<210> 29]]> <![CDATA[<211> 233]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 小鼠IgG2a Fc臼DANG]]> <![CDATA[<400> 29]]> Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro 1 5 10 15 Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys 20 25 30 Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val Thr Cys Val 35 40 45 Val Val Ala Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe 50 55 60 Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu 65 70 75 80 Asp Tyr Gly Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln His 85 90 95 Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys 100 105 110 Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser 115 120 125 Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu Glu Glu Met 130 135 140 Thr Lys Lys Gln Val Thr Leu Ser Cys Ala Val Thr Asp Phe Met Pro 145 150 155 160 Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn 165 170 175 Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Met 180 185 190 Val Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser 195 200 205 Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His His Thr Thr 210 215 220 Lys Ser Phe Ser Arg Thr Pro Gly Lys 225 230 <![CDATA[<210> 30]]> <![CDATA[<211> 233]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 小鼠IgG2a Fc杵DANG]]> <![CDATA[<400> 30]]> Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro 1 5 10 15 Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys 20 25 30 Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val Thr Cys Val 35 40 45 Val Val Ala Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe 50 55 60 Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu 65 70 75 80 Asp Tyr Gly Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln His 85 90 95 Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys 100 105 110 Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser 115 120 125 Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu Glu Glu Met 130 135 140 Thr Lys Lys Gln Val Thr Leu Trp Cys Met Val Thr Asp Phe Met Pro 145 150 155 160 Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn 165 170 175 Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Met 180 185 190 Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser 195 200 205 Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His His Thr Thr 210 215 220 Lys Ser Phe Ser Arg Thr Pro Gly Lys 225 230 <![CDATA[<210> 31]]> <![CDATA[<211> 447]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗小鼠FAP HC小鼠IgG2a Fc DANG]]> <![CDATA[<400> 31]]> Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 1 5 10 15 Ser Val Asn Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Asn 20 25 30 Gly Ile Asn Trp Leu Lys Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Glu Ile Tyr Pro Arg Ser Thr Asn Thr Leu Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Arg Ser Ser Asn Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Thr Leu Thr Ala Pro Phe Ala Phe Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ala Ala Lys Thr Thr Ala Pro Ser Val Tyr Pro Leu 115 120 125 Ala Pro Val Cys Gly Asp Thr Thr Gly Ser Ser Val Thr Leu Gly Cys 130 135 140 Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu Thr Trp Asn Ser 145 150 155 160 Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175 Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr Ser Ser Thr Trp 180 185 190 Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr 195 200 205 Lys Val Asp Lys Lys Ile Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys 210 215 220 Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser 245 250 255 Pro Ile Val Thr Cys Val Val Val Ala Val Ser Glu Asp Asp Pro Asp 260 265 270 Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln 275 280 285 Thr Gln Thr His Arg Glu Asp Tyr Gly Ser Thr Leu Arg Val Val Ser 290 295 300 Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys 305 310 315 320 Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile 325 330 335 Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro 340 345 350 Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu Thr Cys Met 355 360 365 Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn 370 375 380 Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn 405 410 415 Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu 420 425 430 His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys 435 440 445 <![CDATA[<210> 32]]> <![CDATA[<211> 764]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 小鼠scIL-12突變2-小鼠IgG2a Fc DANG]]> <![CDATA[<400> 32]]> Met Trp Glu Leu Glu Lys Asp Val Tyr Val Val Glu Val Asp Trp Thr 1 5 10 15 Pro Asp Ala Pro Gly Glu Thr Val Asn Leu Thr Cys Asp Thr Pro Glu 20 25 30 Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln Arg His Gly Val Ile Gly 35 40 45 Ser Gly Lys Thr Leu Thr Ile Thr Val Lys Glu Phe Leu Asp Ala Gly 50 55 60 Gln Tyr Thr Cys His Lys Gly Gly Glu Thr Leu Ser His Ser His Leu 65 70 75 80 Leu Leu His Lys Lys Glu Asn Gly Ile Trp Ser Thr Glu Ile Leu Lys 85 90 95 Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys Glu Ala Pro Asn Tyr Ser 100 105 110 Gly Arg Phe Thr Cys Ser Trp Leu Val Gln Arg Asn Met Asp Leu Lys 115 120 125 Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro Asp Ser Arg Ala Val Thr 130 135 140 Cys Gly Met Ala Ser Leu Ser Ala Glu Lys Val Thr Leu Asp Gln Arg 145 150 155 160 Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln Glu Asp Val Thr Cys Pro 165 170 175 Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu Ala Leu Glu Ala Arg Gln 180 185 190 Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser Phe Phe Ile Arg Asp Ile 195 200 205 Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Met Lys Pro Leu Lys Asn 210 215 220 Ser Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Ser Trp Ser Thr Pro 225 230 235 240 His Ser Tyr Phe Ser Leu Lys Phe Phe Val Arg Ile Gln Ala Ala Ala 245 250 255 Glu Lys Met Ala Glu Thr Glu Glu Gly Cys Asn Gln Lys Gly Ala Phe 260 265 270 Leu Val Glu Lys Thr Ser Thr Glu Val Gln Cys Lys Gly Gly Asn Val 275 280 285 Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn Ser Ser Cys Ser Lys Trp 290 295 300 Ala Cys Val Pro Cys Arg Val Arg Ser Gly Gly Gly Gly Ser Gly Gly 305 310 315 320 Gly Gly Ser Gly Gly Gly Gly Ser Arg Val Ile Pro Val Ser Gly Pro 325 330 335 Ala Arg Cys Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp 340 345 350 Met Val Lys Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala 355 360 365 Glu Asp Ile Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu 370 375 380 Lys Thr Cys Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala 385 390 395 400 Thr Arg Glu Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln 405 410 415 Lys Thr Ser Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp 420 425 430 Leu Lys Met Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln 435 440 445 Asn His Asn His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala 450 455 460 Ile Asp Glu Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg 465 470 475 480 Gln Lys Pro Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys 485 490 495 Leu Cys Ile Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn 500 505 510 Arg Val Met Gly Tyr Leu Ser Ser Ala Gly Gly Gly Gly Ser Gly Gly 515 520 525 Gly Gly Ser Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys 530 535 540 Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe 545 550 555 560 Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val 565 570 575 Thr Cys Val Val Val Ala Val Ser Glu Asp Asp Pro Asp Val Gln Ile 580 585 590 Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr 595 600 605 His Arg Glu Asp Tyr Gly Ser Thr Leu Arg Val Val Ser Ala Leu Pro 610 615 620 Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val 625 630 635 640 Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro 645 650 655 Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu 660 665 670 Glu Glu Met Thr Lys Lys Gln Val Thr Leu Thr Cys Met Val Thr Asp 675 680 685 Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr 690 695 700 Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser 705 710 715 720 Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu 725 730 735 Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His 740 745 750 His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys 755 760 <![CDATA[<210> 33]]> <![CDATA[<211> 451]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗小鼠CD20 HC小鼠IgG2a Fc杵DANG]]> <![CDATA[<400> 33]]> Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg Pro Gly Thr 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Trp Met His Trp Ile Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Val Ile Asp Pro Ser Asp Asn Tyr Thr Lys Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Glu Gly Tyr Tyr Gly Ser Ser Pro Trp Phe Ala Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Lys Thr Thr Ala Pro Ser 115 120 125 Val Tyr Pro Leu Ala Pro Val Cys Gly Asp Thr Thr Gly Ser Ser Val 130 135 140 Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu 145 150 155 160 Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr 180 185 190 Ser Ser Thr Trp Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro 195 200 205 Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Glu Pro Arg Gly Pro Thr 210 215 220 Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly 225 230 235 240 Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met 245 250 255 Ile Ser Leu Ser Pro Ile Val Thr Cys Val Val Val Ala Val Ser Glu 260 265 270 Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val 275 280 285 His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Gly Ser Thr Leu 290 295 300 Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly 305 310 315 320 Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile 325 330 335 Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val 340 345 350 Tyr Val Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr 355 360 365 Leu Trp Cys Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu 370 375 380 Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro 385 390 395 400 Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val 405 410 415 Glu Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val 420 425 430 His Glu Gly Leu His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr 435 440 445 Pro Gly Lys 450 <![CDATA[<210> 34]]> <![CDATA[<211> 213]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗小鼠CD20 LC]]> <![CDATA[<400> 34]]> Gln Ile Val Met Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Arg Ala Arg Ser Ser Val Ser Tyr Ile 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr 35 40 45 Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Gly Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Thr Arg Val Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Lys Pro Pro Thr 85 90 95 Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Asp Ala Ala Pro 100 105 110 Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly Gly 115 120 125 Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile Asn 130 135 140 Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val Leu Asn 145 150 155 160 Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser Ser 165 170 175 Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr Thr 180 185 190 Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys Ser Phe 195 200 205 Asn Arg Asn Glu Cys 210 <![CDATA[<210> 35]]> <![CDATA[<211> 233]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 小鼠IgG2a Fc DANG]]> <![CDATA[<400> 35]]> Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro 1 5 10 15 Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys 20 25 30 Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val Thr Cys Val 35 40 45 Val Val Ala Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe 50 55 60 Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu 65 70 75 80 Asp Tyr Gly Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln His 85 90 95 Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys 100 105 110 Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser 115 120 125 Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu Glu Glu Met 130 135 140 Thr Lys Lys Gln Val Thr Leu Thr Cys Met Val Thr Asp Phe Met Pro 145 150 155 160 Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn 165 170 175 Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Met 180 185 190 Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser 195 200 205 Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His His Thr Thr 210 215 220 Lys Ser Phe Ser Arg Thr Pro Gly Lys 225 230 <![CDATA[<210> 36]]> <![CDATA[<211> 1362]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗人類FAP HC人類IgG1 Fc杵DANG之DNA序列]]> <![CDATA[<400> 36]]> caggtgcagc tggtgcagtc cggagcagag gtgaagaagc caggagcctc tgtgaaggtg 60 agctgcaaga cctccagata caccttcaca gagtatacaa tccactgggt gcgccaggca 120 cctggacagc ggctggagtg gatcggaggc atcaacccca acaatggcat ccctaactac 180 aatcagaagt ttaagggcag agtgaccatc acagtggaca cctccgcctc tacagcctat 240 atggagctga gctccctgag gagcgaggat accgccgtgt actattgcgc ccggagaagg 300 atcgcctacg gctatgacga gggccacgcc atggattact ggggccaggg caccctggtg 360 acagtgtcta gcgcctctac caagggacca agcgtgttcc cactggcacc atcctctaag 420 agcacctccg gaggaacagc cgccctgggc tgtctggtga aggactattt cccagagccc 480 gtgacagtgt cctggaactc tggcgccctg acctccggag tgcacacatt tcctgccgtg 540 ctgcagagct ccggcctgta cagcctgtct agcgtggtga ccgtgccatc ctctagcctg 600 ggcacccaga catatatctg caacgtgaat cacaagccta gcaatacaaa ggtggacaag 660 aaggtggagc caaagtcctg tgataagacc cacacatgcc ccccttgtcc tgcaccagag 720 ctgctgggag gaccaagcgt gttcctgttt ccacccaagc ccaaggacac cctgatgatc 780 tctcgcaccc cagaggtgac atgcgtggtg gtggccgtga gccacgagga ccccgaggtg 840 aagtttaact ggtacgtgga tggcgtggag gtgcacaatg ccaagaccaa gccaagagag 900 gagcagtacg gctccaccta tagggtggtg tctgtgctga cagtgctgca ccaggattgg 960 ctgaacggca aggagtataa gtgcaaggtg tccaataagg ccctgcccgc ccctatcgag 1020 aagaccatct ctaaggcaaa gggacagcct agggagccac aggtgtacac cctgcctcca 1080 tcccgggacg agctgacaaa gaaccaggtg tctctgtggt gtctggtgaa gggcttctat 1140 ccctctgata tcgccgtgga gtgggagagc aatggccagc ctgagaacaa ttacaagacc 1200 acaccccctg tgctggacag cgatggctcc ttctttctgt atagcaagct gaccgtggat 1260 aagtcccggt ggcagcaggg caacgtgttt tcttgtagcg tgatgcacga ggccctgcac 1320 aatcactaca cacagaagtc cctgtctctg agccctggca ag 1362 <![CDATA[<210> 37]]> <![CDATA[<211> 660]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗人類FAP LC之DNA序列]]> <![CDATA[<400> 37]]> gacatcgtga tgacccagtc ccctgattct ctggccgtga gcctgggaga gagggcaaca 60 atcaactgca agagctccca gagcctgctg tactcccgca accagaagaa ttacctggcc 120 tggtatcagc agaagcccgg ccagccccct aagctgctga tcttctgggc atctaccagg 180 gagagcggag tgcctgacag attttctggc agcggcttcg gcacagactt caccctgaca 240 atctctagcc tgcaggccga ggacgtggcc gtgtactatt gccagcagta cttctcctat 300 cctctgacct ttggccaggg cacaaaggtg gagatcaaga ggaccgtggc agcaccaagc 360 gtgttcatct ttccaccctc cgacgagcag ctgaagtccg gcaccgcctc tgtggtgtgc 420 ctgctgaaca atttctaccc aagggaggcc aaggtgcagt ggaaggtgga taacgccctg 480 cagagcggca attcccagga gtctgtgacc gagcaggaca gcaaggattc cacatattct 540 ctgtcctcta ccctgacact gtctaaggcc gattacgaga agcacaaggt gtatgcatgc 600 gaggtgaccc accagggact gagctcccca gtgacaaagt cctttaatcg gggcgagtgt 660 660 <![CDATA[<210> 38]]> <![CDATA[<211> 2265]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類scIL-12-人類IgG1 Fc臼DANG之DNA序列]]> <![CDATA[<400> 38]]> atctgggagc tgaagaagga cgtgtacgtg gtggagctgg actggtatcc tgatgcccca 60 ggcgagatgg tggtgctgac ctgcgacaca cccgaggagg atggcatcac ctggacactg 120 gatcagagct ccgaggtgct gggcagcggc aagaccctga caatccaggt gaaggagttc 180 ggcgacgccg gccagtacac ctgtcacaag ggaggagagg tgctgagcca ctccctgctg 240 ctgctgcaca agaaggagga cggcatctgg agcacagaca tcctgaagga tcagaaggag 300 ccaaagaaca agaccttcct gcggtgcgag gccaagaatt attccggccg gttcacctgt 360 tggtggctga ccacaatctc caccgatctg acattttctg tgaagtctag caggggctcc 420 tctgaccccc agggagtgac atgcggagca gccaccctga gcgccgagcg ggtgagaggc 480 gataacaagg agtacgagta ttccgtggag tgccaggagg actctgcctg tcctgcagca 540 gaggagtccc tgccaatcga agtgatggtg gatgccgtgc acaagctgaa gtacgagaat 600 tatacaagct ccttctttat cagggacatc atcaagcctg atccccctaa gaacctgcag 660 ctgaagccac tgaagaatag ccgccaggtg gaggtgtcct gggagtaccc agacacctgg 720 tccacacccc actcttattt cagcctgacc ttttgcgtgc aggtgcaggg caagtccaag 780 agggagaaga aggaccgcgt gttcaccgat aagacatctg ccaccgtgat ctgtcggaag 840 aacgcctcta tcagcgtgcg ggcccaggat agatactatt ctagctcctg gagcgagtgg 900 gcctccgtgc cttgttctgg aggaggaggc agcggcggag gaggctccgg aggaggaggc 960 tctagaaatc tgccagtggc aacccctgac ccaggaatgt tcccttgcct gcaccactct 1020 cagaacctgc tgcgggccgt gagcaatatg ctgcagaagg ccagacagac actggagttt 1080 tacccctgta ccagcgagga gatcgaccac gaggatatca caaaggataa gacctccaca 1140 gtggaggcct gcctgcctct ggagctgacc aagaacgaga gctgtctgaa cagccgggag 1200 acatctttca tcaccaacgg cagctgcctg gcctccagaa agacatcttt tatgatggcc 1260 ctgtgcctgt ctagcatcta cgaggacctg aagatgtatc aggtggagtt caagaccatg 1320 aacgccaagc tgctgatgga cccaaagcgg cagatctttc tggatcagaa tatgctggcc 1380 gtgatcgacg agctgatgca ggccctgaac ttcaatagcg agacagtgcc ccagaagtcc 1440 tctctggagg agcctgactt ctacaagacc aagatcaagc tgtgcatcct gctgcacgcc 1500 ttccggatca gagccgtgac catcgataga gtgatgagct atctgaacgc aagcggcggc 1560 ggaggctctg gaggaggcgg cagcgacaag acccacacat gcccaccatg tccagcacct 1620 gagctgctgg gaggaccatc cgtgttcctg tttcctccaa agcccaagga tacactgatg 1680 atcagccgca cacctgaggt gacctgcgtg gtggtggccg tgtcccacga ggaccccgag 1740 gtgaagttta actggtacgt ggacggcgtg gaggtgcaca atgccaagac caagcccagg 1800 gaggagcagt acggctctac atatcgcgtg gtgagcgtgc tgaccgtgct gcaccaggac 1860 tggctgaacg gcaaggagta caagtgcaag gtgtctaata aggccctgcc agcccccatc 1920 gagaagacca tcagcaaggc aaagggacag ccaagggagc ctcaggtgta tacactgccc 1980 cctagccgcg atgagctgac caagaaccag gtgtccctgt cttgtgccgt gaagggcttc 2040 tacccatccg acatcgccgt ggagtgggag tctaatggcc agcccgagaa caattataag 2100 accacaccac ccgtgctgga ctccgatggc tctttctttc tggtgagcaa gctgacagtg 2160 gacaagtcca gatggcagca gggcaacgtg tttagctgct ccgtgatgca cgaggccctg 2220 cacaatcact acacccagaa gtctctgagc ctgtcccctg gcaag 2265 <![CDATA[<210> 39]]> <![CDATA[<211> 2265]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類scIL-12突變1-人類IgG1 Fc臼DANG之DNA序列]]> <![CDATA[<400> 39]]> atctgggagc tgaagaagga cgtgtacgtg gtggagctgg actggtatcc tgatgcccca 60 ggcgagatgg tggtgctgac ctgcgacaca cccgaggagg atggcatcac ctggacactg 120 gatcagagct ccgaggtgct gggcagcggc aagaccctga caatccaggt gaaggagttc 180 ggcgacgccg gccagtacac ctgtcacaag ggaggagagg tgctgagcca ctccctgctg 240 ctgctgcaca agaaggagga cggcatctgg agcacagaca tcctgaagga tcagaaggag 300 ccaaagaaca agaccttcct gcggtgcgag gccaagaatt attccggccg gttcacctgt 360 tggtggctga ccacaatctc caccgatctg acattttctg tgaagtctag caggggctcc 420 tctgaccccc agggagtgac atgcggagca gccaccctga gcgccgagcg ggtgagaggc 480 gataacaagg agtacgagta ttccgtggag tgccaggagg actctgcctg tcctgcagca 540 gaggagtccc tgccaatcga agtgatggtg gatgccgtgc acaagctgaa gtacgagaat 600 tatacaagct ccttctttat cagggacatc atcaagcctg atccccctaa gaacctgcag 660 ctgaagccac tgaagaatag ccgccaggtg gaggtgtcct gggagtaccc agacacctgg 720 tccacacccc actcttattt cagcctgacc ttttgcgtgc aggtgcaggg agcatccaag 780 agggaggcaa aggaccgcgt gttcaccgat aagacatctg ccaccgtgat ctgtcggaag 840 aacgcctcta tcagcgtgcg ggcccaggat agatactatt ctagctcctg gagcgagtgg 900 gcctccgtgc cttgttctgg aggaggaggc agcggcggag gaggctccgg aggaggaggc 960 tctagaaatc tgccagtggc aacccctgac ccaggaatgt tcccttgcct gcaccactct 1020 cagaacctgc tgcgggccgt gagcaatatg ctgcagaagg ccagacagac actggagttt 1080 tacccctgta ccagcgagga gatcgaccac gaggatatca caaaggataa gacctccaca 1140 gtggaggcct gcctgcctct ggagctgacc aagaacgaga gctgtctgaa cagccgggag 1200 acatctttca tcaccaacgg cagctgcctg gcctccagaa agacatcttt tatgatggcc 1260 ctgtgcctgt ctagcatcta cgaggacctg aagatgtatc aggtggagtt caagaccatg 1320 aacgccaagc tgctgatgga cccaaagcgg cagatctttc tggatcagaa tatgctggcc 1380 gtgatcgacg agctgatgca ggccctgaac ttcaatagcg agacagtgcc ccagaagtcc 1440 tctctggagg agcctgactt ctacaagacc aagatcaagc tgtgcatcct gctgcacgcc 1500 ttccggatca gagccgtgac catcgataga gtgatgagct atctgaacgc aagcggcggc 1560 ggaggctctg gaggaggcgg cagcgacaag acccacacat gcccaccatg tccagcacct 1620 gagctgctgg gaggaccatc cgtgttcctg tttcctccaa agcccaagga tacactgatg 1680 atcagccgca cacctgaggt gacctgcgtg gtggtggccg tgtcccacga ggaccccgag 1740 gtgaagttta actggtacgt ggacggcgtg gaggtgcaca atgccaagac caagcccagg 1800 gaggagcagt acggctctac atatcgcgtg gtgagcgtgc tgaccgtgct gcaccaggac 1860 tggctgaacg gcaaggagta caagtgcaag gtgtctaata aggccctgcc agcccccatc 1920 gagaagacca tcagcaaggc aaagggacag ccaagggagc ctcaggtgta tacactgccc 1980 cctagccgcg atgagctgac caagaaccag gtgtccctgt cttgtgccgt gaagggcttc 2040 tacccatccg acatcgccgt ggagtgggag tctaatggcc agcccgagaa caattataag 2100 accacaccac ccgtgctgga ctccgatggc tctttctttc tggtgagcaa gctgacagtg 2160 gacaagtcca gatggcagca gggcaacgtg tttagctgct ccgtgatgca cgaggccctg 2220 cacaatcact acacccagaa gtctctgagc ctgtcccctg gcaag 2265 <![CDATA[<210> 40]]> <![CDATA[<211> 2265]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類scIL-12突變2-人類IgG1 Fc臼DANG之DNA序列]]> <![CDATA[<400> 40]]> atctgggagc tgaagaagga cgtgtacgtg gtggagctgg actggtatcc tgatgcccca 60 ggcgagatgg tggtgctgac ctgcgacaca cccgaggagg atggcatcac ctggacactg 120 gatcagagct ccgaggtgct gggcagcggc aagaccctga caatccaggt gaaggagttc 180 ggcgacgccg gccagtacac ctgtcacaag ggaggagagg tgctgagcca ctccctgctg 240 ctgctgcaca agaaggagga cggcatctgg agcacagaca tcctgaagga tcagaaggag 300 ccaaagaaca agaccttcct gcggtgcgag gccaagaatt attccggccg gttcacctgt 360 tggtggctga ccacaatctc caccgatctg acattttctg tgaagtctag caggggctcc 420 tctgaccccc agggagtgac atgcggagca gccaccctga gcgccgagcg ggtgagaggc 480 gataacaagg agtacgagta ttccgtggag tgccaggagg actctgcctg tcctgcagca 540 gaggagtccc tgccaatcga agtgatggtg gatgccgtgc acaagctgaa gtacgagaat 600 tatacaagct ccttctttat cagggacatc atcaagcctg atccccctaa gaacctgcag 660 ctgaagccac tgaagaatag ccgccaggtg gaggtgtcct gggagtaccc agacacctgg 720 tccacacccc actcttattt cagcctgacc ttttgcgtgc aggtgcaggg cgcctccgct 780 agggaggccg ctgaccgcgt gttcaccgat aagacatctg ccaccgtgat ctgtcggaag 840 aacgcctcta tcagcgtgcg ggcccaggat agatactatt ctagctcctg gagcgagtgg 900 gcctccgtgc cttgttctgg aggaggaggc agcggcggag gaggctccgg aggaggaggc 960 tctagaaatc tgccagtggc aacccctgac ccaggaatgt tcccttgcct gcaccactct 1020 cagaacctgc tgcgggccgt gagcaatatg ctgcagaagg ccagacagac actggagttt 1080 tacccctgta ccagcgagga gatcgaccac gaggatatca caaaggataa gacctccaca 1140 gtggaggcct gcctgcctct ggagctgacc aagaacgaga gctgtctgaa cagccgggag 1200 acatctttca tcaccaacgg cagctgcctg gcctccagaa agacatcttt tatgatggcc 1260 ctgtgcctgt ctagcatcta cgaggacctg aagatgtatc aggtggagtt caagaccatg 1320 aacgccaagc tgctgatgga cccaaagcgg cagatctttc tggatcagaa tatgctggcc 1380 gtgatcgacg agctgatgca ggccctgaac ttcaatagcg agacagtgcc ccagaagtcc 1440 tctctggagg agcctgactt ctacaagacc aagatcaagc tgtgcatcct gctgcacgcc 1500 ttccggatca gagccgtgac catcgataga gtgatgagct atctgaacgc aagcggcggc 1560 ggaggctctg gaggaggcgg cagcgacaag acccacacat gcccaccatg tccagcacct 1620 gagctgctgg gaggaccatc cgtgttcctg tttcctccaa agcccaagga tacactgatg 1680 atcagccgca cacctgaggt gacctgcgtg gtggtggccg tgtcccacga ggaccccgag 1740 gtgaagttta actggtacgt ggacggcgtg gaggtgcaca atgccaagac caagcccagg 1800 gaggagcagt acggctctac atatcgcgtg gtgagcgtgc tgaccgtgct gcaccaggac 1860 tggctgaacg gcaaggagta caagtgcaag gtgtctaata aggccctgcc agcccccatc 1920 gagaagacca tcagcaaggc aaagggacag ccaagggagc ctcaggtgta tacactgccc 1980 cctagccgcg atgagctgac caagaaccag gtgtccctgt cttgtgccgt gaagggcttc 2040 tacccatccg acatcgccgt ggagtgggag tctaatggcc agcccgagaa caattataag 2100 accacaccac ccgtgctgga ctccgatggc tctttctttc tggtgagcaa gctgacagtg 2160 gacaagtcca gatggcagca gggcaacgtg tttagctgct ccgtgatgca cgaggccctg 2220 cacaatcact acacccagaa gtctctgagc ctgtcccctg gcaag 2265 <![CDATA[<210> 41]]> <![CDATA[<211> 1779]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> (抗人類FAP VH)2-人類IgG1 Fc杵DANG之DNA序列]]> <![CDATA[<400> 41]]> caagtgcagc tggtgcagag cggcgccgag gtgaaaaagc ctggcgcttc tgtgaaggtg 60 tcttgcaaga cctccagata cacattcacc gagtacacca tccactgggt gcggcaggcc 120 cctggacagc ggctggaatg gatcggaggc atcaacccca acaacggcat tccaaattac 180 aaccagaagt tcaagggcag agtgacaatc accgttgaca ccagcgccag caccgcttat 240 atggaactga gcagcctgag aagcgaggat acagccgtgt actactgtgc cagaagacgg 300 atcgcctacg gctacgacga gggccacgcc atggactact ggggccaggg cacactggtc 360 accgtgtcct ctggcggcgg cggcagcggc ggcggcggca gcggaggagg aggtagccag 420 gtccagctgg tgcagtctgg agcagaggtg aagaagccag gagcctctgt gaaggtgagc 480 tgcaagacct ccagatacac cttcacagag tatacaatcc actgggtgcg ccaggcacct 540 ggacagcggc tggagtggat cggaggcatc aaccccaaca atggcatccc taactacaat 600 cagaagttta agggcagagt gaccatcaca gtggacacct ccgcctctac agcctatatg 660 gagctgagct ccctgaggag cgaggatacc gccgtgtact attgcgcccg gagaaggatc 720 gcctacggct atgacgaggg ccacgccatg gattactggg gccagggcac cctggtgaca 780 gtgtctagcg cctctaccaa gggaccaagc gtgttcccac tggcaccatc ctctaagagc 840 acctccggag gaacagccgc cctgggctgt ctggtgaagg actatttccc agagcccgtg 900 acagtgtcct ggaactctgg cgccctgacc tccggagtgc acacatttcc tgccgtgctg 960 cagagctccg gcctgtacag cctgtctagc gtggtgaccg tgccatcctc tagcctgggc 1020 acccagacat atatctgcaa cgtgaatcac aagcctagca atacaaaggt ggacaagaag 1080 gtggagccaa agtcctgtga taagacccac acatgccccc cttgtcctgc accagagctg 1140 ctgggaggac caagcgtgtt cctgtttcca cccaagccca aggacaccct gatgatctct 1200 cgcaccccag aggtgacatg cgtggtggtg gccgtgagcc acgaggaccc cgaggtgaag 1260 tttaactggt acgtggatgg cgtggaggtg cacaatgcca agaccaagcc aagagaggag 1320 cagtacggct ccacctatag ggtggtgtct gtgctgacag tgctgcacca ggattggctg 1380 aacggcaagg agtataagtg caaggtgtcc aataaggccc tgcccgcccc tatcgagaag 1440 accatctcta aggcaaaggg acagcctagg gagccacagg tgtacaccct gcctccatcc 1500 cgggacgagc tgacaaagaa ccaggtgtct ctgtggtgtc tggtgaaggg cttctatccc 1560 tctgatatcg ccgtggagtg ggagagcaat ggccagcctg agaacaatta caagaccaca 1620 ccccctgtgc tggacagcga tggctccttc tttctgtata gcaagctgac cgtggataag 1680 tcccggtggc agcagggcaa cgtgttttct tgtagcgtga tgcacgaggc cctgcacaat 1740 cactacacac agaagtccct gtctctgagc cctggcaag 1779 <![CDATA[<210> 42]]> <![CDATA[<211> 1044]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> (抗人類FAP VL)2之DNA序列]]> <![CDATA[<400> 42]]> gatatcgtga tgacccagag ccccgacagc ctggccgtgt ccctgggcga acgggccaca 60 atcaactgca agtccagcca gtctctgctg tacagcagaa accagaagaa ttacctggct 120 tggtatcagc agaaacctgg ccaacctcca aagctgctga tcttctgggc cagcaccaga 180 gagagcggcg tgcctgatag attcagcggc agcggatttg gcaccgactt caccctgacc 240 atcagcagcc tccaggccga ggacgtggcc gtctactact gtcagcaata cttcagctac 300 cccctgacat tcggccaggg cacaaaggtg gaaatcaagg gcggcggagg ctctggcggc 360 ggcggatctg gaggtggcgg ctccgacatc gtgatgacac agtctcctga ttctctggcc 420 gtgagcctgg gagagagggc aacaatcaac tgcaagagct cccagagcct gctgtactcc 480 cgcaaccaga agaattacct ggcctggtat cagcagaagc ccggccagcc ccctaagctg 540 ctgatcttct gggcatctac cagggagagc ggagtgcctg acagattttc tggcagcggc 600 ttcggcacag acttcaccct gacaatctct agcctgcagg ccgaggacgt ggccgtgtac 660 tattgccagc agtacttctc ctatcctctg acctttggcc agggcacaaa ggtggagatc 720 aagaggaccg tggcagcacc aagcgtgttc atctttccac cctccgacga gcagctgaag 780 tccggcaccg cctctgtggt gtgcctgctg aacaatttct acccaaggga ggccaaggtg 840 cagtggaagg tggataacgc cctgcagagc ggcaattccc aggagtctgt gaccgagcag 900 gacagcaagg attccacata ttctctgtcc tctaccctga cactgtctaa ggccgattac 960 gagaagcaca aggtgtatgc atgcgaggtg acccaccagg gactgagctc cccagtgaca 1020 aagtccttta atcggggcga gtgt 1044 <![CDATA[<210> 43]]> <![CDATA[<211> 2178]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗人類FAP HC人類IgG1 Fc杵DANG-抗人類FAP scFv之DNA序列]]> <![CDATA[<400> 43]]> caggtgcagc tggtgcagtc cggagcagag gtgaagaagc caggagcctc tgtgaaggtg 60 agctgcaaga cctccagata caccttcaca gagtatacaa tccactgggt gcgccaggca 120 cctggacagc ggctggagtg gatcggaggc atcaacccca acaatggcat ccctaactac 180 aatcagaagt ttaagggcag agtgaccatc acagtggaca cctccgcctc tacagcctat 240 atggagctga gctccctgag gagcgaggat accgccgtgt actattgcgc ccggagaagg 300 atcgcctacg gctatgacga gggccacgcc atggattact ggggccaggg caccctggtg 360 acagtgtcta gcgcctctac caagggacca agcgtgttcc cactggcacc atcctctaag 420 agcacctccg gaggaacagc cgccctgggc tgtctggtga aggactattt cccagagccc 480 gtgacagtgt cctggaactc tggcgccctg acctccggag tgcacacatt tcctgccgtg 540 ctgcagagct ccggcctgta cagcctgtct agcgtggtga ccgtgccatc ctctagcctg 600 ggcacccaga catatatctg caacgtgaat cacaagccta gcaatacaaa ggtggacaag 660 aaggtggagc caaagtcctg tgataagacc cacacatgcc ccccttgtcc tgcaccagag 720 ctgctgggag gaccaagcgt gttcctgttt ccacccaagc ccaaggacac cctgatgatc 780 tctcgcaccc cagaggtgac atgcgtggtg gtggccgtga gccacgagga ccccgaggtg 840 aagtttaact ggtacgtgga tggcgtggag gtgcacaatg ccaagaccaa gccaagagag 900 gagcagtacg gctccaccta tagggtggtg tctgtgctga cagtgctgca ccaggattgg 960 ctgaacggca aggagtataa gtgcaaggtg tccaataagg ccctgcccgc ccctatcgag 1020 aagaccatct ctaaggcaaa gggacagcct agggagccac aggtgtacac cctgcctcca 1080 tcccgggacg agctgacaaa gaaccaggtg tctctgtggt gtctggtgaa gggcttctat 1140 ccctctgata tcgccgtgga gtgggagagc aatggccagc ctgagaacaa ttacaagacc 1200 acaccccctg tgctggacag cgatggctcc ttctttctgt atagcaagct gaccgtggat 1260 aagtcccggt ggcagcaggg caacgtgttt tcttgtagcg tgatgcacga ggccctgcac 1320 aatcactaca cacagaagtc cctgtctctg agccctggca agggcggcgg cggcagcggc 1380 ggcggcggca gcggaggagg aggtagccaa gtgcagctgg tgcagagcgg cgccgaggtg 1440 aaaaagcctg gcgcttctgt gaaggtgtct tgcaagacct ccagatacac attcaccgag 1500 tacaccatcc actgggtgcg gcaggcccct ggacagcggc tggaatggat cggaggcatc 1560 aaccccaaca acggcattcc aaattacaac cagaagttca agggcagagt gacaatcacc 1620 gttgacacca gcgccagcac cgcttatatg gaactgagca gcctgagaag cgaggataca 1680 gccgtgtact actgtgccag aagacggatc gcctacggct acgacgaggg ccacgccatg 1740 gactactggg gccagggcac actggtcacc gtgtcctctg gtggaggtgg ctcaggagga 1800 ggcggttctg gcggaggagg tagtggaggt ggcggctccg atatcgtgat gacccagagc 1860 cccgacagcc tggccgtgtc cctgggcgaa cgggccacaa tcaactgcaa gtccagccag 1920 tctctgctgt acagcagaaa ccagaagaat tacctggctt ggtatcagca gaaacctggc 1980 caacctccaa agctgctgat cttctgggcc agcaccagag agagcggcgt gcctgataga 2040 ttcagcggca gcggatttgg caccgacttc accctgacca tcagcagcct ccaggccgag 2100 gacgtggccg tctactactg tcagcaatac ttcagctacc ccctgacatt cggccagggc 2160 acaaaggtgg aaatcaag 2178 <![CDATA[<210> 44]]> <![CDATA[<211> 1476]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗人類FAP LC-抗人類FAP scFv之DNA序列]]> <![CDATA[<400> 44]]> gacatcgtga tgacccagtc ccctgattct ctggccgtga gcctgggaga gagggcaaca 60 atcaactgca agagctccca gagcctgctg tactcccgca accagaagaa ttacctggcc 120 tggtatcagc agaagcccgg ccagccccct aagctgctga tcttctgggc atctaccagg 180 gagagcggag tgcctgacag attttctggc agcggcttcg gcacagactt caccctgaca 240 atctctagcc tgcaggccga ggacgtggcc gtgtactatt gccagcagta cttctcctat 300 cctctgacct ttggccaggg cacaaaggtg gagatcaaga ggaccgtggc agcaccaagc 360 gtgttcatct ttccaccctc cgacgagcag ctgaagtccg gcaccgcctc tgtggtgtgc 420 ctgctgaaca atttctaccc aagggaggcc aaggtgcagt ggaaggtgga taacgccctg 480 cagagcggca attcccagga gtctgtgacc gagcaggaca gcaaggattc cacatattct 540 ctgtcctcta ccctgacact gtctaaggcc gattacgaga agcacaaggt gtatgcatgc 600 gaggtgaccc accagggact gagctcccca gtgacaaagt cctttaatcg gggcgagtgt 660 ggcggcggcg gcagcggcgg cggcggcagc ggaggaggag gtagccaagt gcagctggtg 720 cagagcggcg ccgaggtgaa aaagcctggc gcttctgtga aggtgtcttg caagacctcc 780 agatacacat tcaccgagta caccatccac tgggtgcggc aggcccctgg acagcggctg 840 gaatggatcg gaggcatcaa ccccaacaac ggcattccaa attacaacca gaagttcaag 900 ggcagagtga caatcaccgt tgacaccagc gccagcaccg cttatatgga actgagcagc 960 ctgagaagcg aggatacagc cgtgtactac tgtgccagaa gacggatcgc ctacggctac 1020 gacgagggcc acgccatgga ctactggggc cagggcacac tggtcaccgt gtcctctggt 1080 ggaggtggct caggaggagg cggttctggc ggaggaggta gtggaggtgg cggctccgat 1140 atcgtgatga cccagagccc cgacagcctg gccgtgtccc tgggcgaacg ggccacaatc 1200 aactgcaagt ccagccagtc tctgctgtac agcagaaacc agaagaatta cctggcttgg 1260 tatcagcaga aacctggcca acctccaaag ctgctgatct tctgggccag caccagagag 1320 agcggcgtgc ctgatagatt cagcggcagc ggatttggca ccgacttcac cctgaccatc 1380 agcagcctcc aggccgagga cgtggccgtc tactactgtc agcaatactt cagctacccc 1440 ctgacattcg gccagggcac aaaggtggaa atcaag 1476 <![CDATA[<210> 45]]> <![CDATA[<211> 2958]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗人類FAP HC人類IgG1 Fc臼DANG-人類scIL-12之DNA序列]]> <![CDATA[<400> 45]]> caggtgcagc tggtgcagtc cggagcagag gtgaagaagc caggagcctc tgtgaaggtg 60 agctgcaaga cctccagata caccttcaca gagtatacaa tccactgggt gcgccaggca 120 cctggacagc ggctggagtg gatcggaggc atcaacccca acaatggcat ccctaactac 180 aatcagaagt ttaagggcag agtgaccatc acagtggaca cctccgcctc tacagcctat 240 atggagctga gctccctgag gagcgaggat accgccgtgt actattgcgc ccggagaagg 300 atcgcctacg gctatgacga gggccacgcc atggattact ggggccaggg caccctggtg 360 acagtgtcta gcgcctctac caagggacca agcgtgttcc cactggcacc atcctctaag 420 agcacctccg gaggaacagc cgccctgggc tgtctggtga aggactattt cccagagccc 480 gtgacagtgt cctggaactc tggcgccctg acctccggag tgcacacatt tcctgccgtg 540 ctgcagagct ccggcctgta cagcctgtct agcgtggtga ccgtgccatc ctctagcctg 600 ggcacccaga catatatctg caacgtgaat cacaagccta gcaatacaaa ggtggacaag 660 aaggtggagc caaagtcctg tgacaagacc cacacatgcc caccatgtcc agcacctgag 720 ctgctgggag gaccatccgt gttcctgttt cctccaaagc ccaaggatac actgatgatc 780 agccgcacac ctgaggtgac ctgcgtggtg gtggccgtgt cccacgagga ccccgaggtg 840 aagtttaact ggtacgtgga cggcgtggag gtgcacaatg ccaagaccaa gcccagggag 900 gagcagtacg gctctacata tcgcgtggtg agcgtgctga ccgtgctgca ccaggactgg 960 ctgaacggca aggagtacaa gtgcaaggtg tctaataagg ccctgccagc ccccatcgag 1020 aagaccatca gcaaggcaaa gggacagcca agggagcctc aggtgtatac actgccccct 1080 agccgcgatg agctgaccaa gaaccaggtg tccctgtctt gtgccgtgaa gggcttctac 1140 ccatccgaca tcgccgtgga gtgggagtct aatggccagc ccgagaacaa ttataagacc 1200 acaccacccg tgctggactc cgatggctct ttctttctgg tgagcaagct gacagtggac 1260 aagtccagat ggcagcaggg caacgtgttt agctgctccg tgatgcacga ggccctgcac 1320 aatcactaca cccagaagtc tctgagcctg tcccctggcg gtggaggtgg ctcaggagga 1380 ggcggttctg gcggaggagg tagtatctgg gagctgaaga aggacgtgta cgtggtggag 1440 ctggactggt atcctgatgc cccaggcgag atggtggtgc tgacctgcga cacacccgag 1500 gaggatggca tcacctggac actggatcag agctccgagg tgctgggcag cggcaagacc 1560 ctgacaatcc aggtgaagga gttcggcgac gccggccagt acacctgtca caagggagga 1620 gaggtgctga gccactccct gctgctgctg cacaagaagg aggacggcat ctggagcaca 1680 gacatcctga aggatcagaa ggagccaaag aacaagacct tcctgcggtg cgaggccaag 1740 aattattccg gccggttcac ctgttggtgg ctgaccacaa tctccaccga tctgacattt 1800 tctgtgaagt ctagcagggg ctcctctgac ccccagggag tgacatgcgg agcagccacc 1860 ctgagcgccg agcgggtgag aggcgataac aaggagtacg agtattccgt ggagtgccag 1920 gaggactctg cctgtcctgc agcagaggag tccctgccaa tcgaagtgat ggtggatgcc 1980 gtgcacaagc tgaagtacga gaattataca agctccttct ttatcaggga catcatcaag 2040 cctgatcccc ctaagaacct gcagctgaag ccactgaaga atagccgcca ggtggaggtg 2100 tcctgggagt acccagacac ctggtccaca ccccactctt atttcagcct gaccttttgc 2160 gtgcaggtgc agggcaagtc caagagggag aagaaggacc gcgtgttcac cgataagaca 2220 tctgccaccg tgatctgtcg gaagaacgcc tctatcagcg tgcgggccca ggatagatac 2280 tattctagct cctggagcga gtgggcctcc gtgccttgtt ctggaggagg aggcagcggc 2340 ggaggaggct ccggaggagg aggctctaga aatctgccag tggcaacccc tgacccagga 2400 atgttccctt gcctgcacca ctctcagaac ctgctgcggg ccgtgagcaa tatgctgcag 2460 aaggccagac agacactgga gttttacccc tgtaccagcg aggagatcga ccacgaggat 2520 atcacaaagg ataagacctc cacagtggag gcctgcctgc ctctggagct gaccaagaac 2580 gagagctgtc tgaacagccg ggagacatct ttcatcacca acggcagctg cctggcctcc 2640 agaaagacat cttttatgat ggccctgtgc ctgtctagca tctacgagga cctgaagatg 2700 tatcaggtgg agttcaagac catgaacgcc aagctgctga tggacccaaa gcggcagatc 2760 tttctggatc agaatatgct ggccgtgatc gacgagctga tgcaggccct gaacttcaat 2820 agcgagacag tgccccagaa gtcctctctg gaggagcctg acttctacaa gaccaagatc 2880 aagctgtgca tcctgctgca cgccttccgg atcagagccg tgaccatcga tagagtgatg 2940 agctatctga acgcaagc 2958 <![CDATA[<210> 46]]> <![CDATA[<211> 2958]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗人類FAP HC人類IgG1 Fc臼DANG-人類scIL-12突變2之DNA序列]]> <![CDATA[<400> 46]]> caggtgcagc tggtgcagtc cggagcagag gtgaagaagc caggagcctc tgtgaaggtg 60 agctgcaaga cctccagata caccttcaca gagtatacaa tccactgggt gcgccaggca 120 cctggacagc ggctggagtg gatcggaggc atcaacccca acaatggcat ccctaactac 180 aatcagaagt ttaagggcag agtgaccatc acagtggaca cctccgcctc tacagcctat 240 atggagctga gctccctgag gagcgaggat accgccgtgt actattgcgc ccggagaagg 300 atcgcctacg gctatgacga gggccacgcc atggattact ggggccaggg caccctggtg 360 acagtgtcta gcgcctctac caagggacca agcgtgttcc cactggcacc atcctctaag 420 agcacctccg gaggaacagc cgccctgggc tgtctggtga aggactattt cccagagccc 480 gtgacagtgt cctggaactc tggcgccctg acctccggag tgcacacatt tcctgccgtg 540 ctgcagagct ccggcctgta cagcctgtct agcgtggtga ccgtgccatc ctctagcctg 600 ggcacccaga catatatctg caacgtgaat cacaagccta gcaatacaaa ggtggacaag 660 aaggtggagc caaagtcctg tgacaagacc cacacatgcc caccatgtcc agcacctgag 720 ctgctgggag gaccatccgt gttcctgttt cctccaaagc ccaaggatac actgatgatc 780 agccgcacac ctgaggtgac ctgcgtggtg gtggccgtgt cccacgagga ccccgaggtg 840 aagtttaact ggtacgtgga cggcgtggag gtgcacaatg ccaagaccaa gcccagggag 900 gagcagtacg gctctacata tcgcgtggtg agcgtgctga ccgtgctgca ccaggactgg 960 ctgaacggca aggagtacaa gtgcaaggtg tctaataagg ccctgccagc ccccatcgag 1020 aagaccatca gcaaggcaaa gggacagcca agggagcctc aggtgtatac actgccccct 1080 agccgcgatg agctgaccaa gaaccaggtg tccctgtctt gtgccgtgaa gggcttctac 1140 ccatccgaca tcgccgtgga gtgggagtct aatggccagc ccgagaacaa ttataagacc 1200 acaccacccg tgctggactc cgatggctct ttctttctgg tgagcaagct gacagtggac 1260 aagtccagat ggcagcaggg caacgtgttt agctgctccg tgatgcacga ggccctgcac 1320 aatcactaca cccagaagtc tctgagcctg tcccctggcg gtggaggtgg ctcaggagga 1380 ggcggttctg gcggaggagg tagtatctgg gagctgaaga aggacgtgta cgtggtggag 1440 ctggactggt atcctgatgc cccaggcgag atggtggtgc tgacctgcga cacacccgag 1500 gaggatggca tcacctggac actggatcag agctccgagg tgctgggcag cggcaagacc 1560 ctgacaatcc aggtgaagga gttcggcgac gccggccagt acacctgtca caagggagga 1620 gaggtgctga gccactccct gctgctgctg cacaagaagg aggacggcat ctggagcaca 1680 gacatcctga aggatcagaa ggagccaaag aacaagacct tcctgcggtg cgaggccaag 1740 aattattccg gccggttcac ctgttggtgg ctgaccacaa tctccaccga tctgacattt 1800 tctgtgaagt ctagcagggg ctcctctgac ccccagggag tgacatgcgg agcagccacc 1860 ctgagcgccg agcgggtgag aggcgataac aaggagtacg agtattccgt ggagtgccag 1920 gaggactctg cctgtcctgc agcagaggag tccctgccaa tcgaagtgat ggtggatgcc 1980 gtgcacaagc tgaagtacga gaattataca agctccttct ttatcaggga catcatcaag 2040 cctgatcccc ctaagaacct gcagctgaag ccactgaaga atagccgcca ggtggaggtg 2100 tcctgggagt acccagacac ctggtccaca ccccactctt atttcagcct gaccttttgc 2160 gtgcaggtgc agggcgcctc cgctagggag gccgctgacc gcgtgttcac cgataagaca 2220 tctgccaccg tgatctgtcg gaagaacgcc tctatcagcg tgcgggccca ggatagatac 2280 tattctagct cctggagcga gtgggcctcc gtgccttgtt ctggaggagg aggcagcggc 2340 ggaggaggct ccggaggagg aggctctaga aatctgccag tggcaacccc tgacccagga 2400 atgttccctt gcctgcacca ctctcagaac ctgctgcggg ccgtgagcaa tatgctgcag 2460 aaggccagac agacactgga gttttacccc tgtaccagcg aggagatcga ccacgaggat 2520 atcacaaagg ataagacctc cacagtggag gcctgcctgc ctctggagct gaccaagaac 2580 gagagctgtc tgaacagccg ggagacatct ttcatcacca acggcagctg cctggcctcc 2640 agaaagacat cttttatgat ggccctgtgc ctgtctagca tctacgagga cctgaagatg 2700 tatcaggtgg agttcaagac catgaacgcc aagctgctga tggacccaaa gcggcagatc 2760 tttctggatc agaatatgct ggccgtgatc gacgagctga tgcaggccct gaacttcaat 2820 agcgagacag tgccccagaa gtcctctctg gaggagcctg acttctacaa gaccaagatc 2880 aagctgtgca tcctgctgca cgccttccgg atcagagccg tgaccatcga tagagtgatg 2940 agctatctga acgcaagc 2958 <![CDATA[<210> 47]]> <![CDATA[<211> 681]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類IgG1 Fc臼DANG之DNA序列]]> <![CDATA[<400> 47]]> gacaagaccc acacatgccc accttgtcca gcaccagagc tgctgggagg accatccgtg 60 ttcctgtttc cacccaagcc caaggatacc ctgatgatca gcaggacccc agaggtgaca 120 tgcgtggtgg tggccgtgtc ccacgaggac cctgaggtga agttcaactg gtacgtggat 180 ggcgtggagg tgcacaatgc caagacaaag ccacgggagg agcagtacgg cagcacctat 240 agagtggtgt ccgtgctgac agtgctgcac caggactggc tgaacggcaa ggagtacaag 300 tgcaaggtgt ctaataaggc cctgcctgcc ccaatcgaga agaccatcag caaggcaaag 360 ggacagccaa gggagcctca ggtgtatacc ctgcctccaa gccgcgacga gctgacaaag 420 aaccaggtga gcctgtcctg tgccgtgaag ggcttctacc cttccgatat cgccgtggag 480 tgggagtcta atggccagcc agagaacaat tataagacca caccccctgt gctggactcc 540 gatggctctt tctttctggt gtctaagctg accgtggata agagcaggtg gcagcagggc 600 aacgtgtttt cttgtagcgt gatgcacgag gccctgcaca atcactatac acagaagtcc 660 ctgtctctga gccctggcaa g 681 <![CDATA[<210> 48]]> <![CDATA[<211> 681]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類IgG1 Fc杵DANG之DNA序列]]> <![CDATA[<400> 48]]> gacaagaccc acacatgccc accttgtcca gcaccagagc tgctgggagg accatccgtg 60 ttcctgtttc cacccaagcc caaggatacc ctgatgatca gcaggacccc agaggtgaca 120 tgcgtggtgg tggccgtgtc ccacgaggac cctgaggtga agttcaactg gtacgtggat 180 ggcgtggagg tgcacaatgc caagacaaag ccacgggagg agcagtacgg ctccacctat 240 agagtggtgt ctgtgctgac agtgctgcac caggactggc tgaacggcaa ggagtataag 300 tgcaaggtgt ctaataaggc cctgcctgcc ccaatcgaga agaccatcag caaggcaaag 360 ggacagccaa gggagcctca ggtgtacacc ctgcctccat cccgcgacga gctgacaaag 420 aaccaggtgt ctctgtggtg tctggtgaag ggcttctatc cttctgatat cgccgtggag 480 tgggagagca atggccagcc agagaacaat tacaagacca caccccctgt gctggactct 540 gatggcagct tctttctgta tagcaagctg accgtggata agtccaggtg gcagcagggc 600 aacgtgttta gctgttccgt gatgcacgag gccctgcaca atcactacac acagaagtct 660 ctgagcctgt cccctggcaa g 681 <![CDATA[<210> 49]]> <![CDATA[<211> 1365]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗人類FAP HC人類IgG1 Fc DANG之DNA序列]]> <![CDATA[<400> 49]]> caggtgcagc tggtgcagtc cggagcagag gtgaagaagc caggagcctc tgtgaaggtg 60 agctgcaaga cctccagata caccttcaca gagtatacaa tccactgggt gcgccaggca 120 cctggacagc ggctggagtg gatcggaggc atcaacccca acaatggcat ccctaactac 180 aatcagaagt ttaagggcag agtgaccatc acagtggaca cctccgcctc tacagcctat 240 atggagctga gctccctgag gagcgaggat accgccgtgt actattgcgc ccggagaagg 300 atcgcctacg gctatgacga gggccacgcc atggattact ggggccaggg caccctggtg 360 acagtgtcta gcgcctctac caagggacca agcgtgttcc cactggcacc atcctctaag 420 agcacctccg gaggaacagc cgccctgggc tgtctggtga aggactattt cccagagccc 480 gtgacagtgt cctggaactc tggcgccctg acctccggag tgcacacatt tcctgccgtg 540 ctgcagagct ccggcctgta cagcctgtct agcgtggtga ccgtgccatc ctctagcctg 600 ggcacccaga catatatctg caacgtgaat cacaagccta gcaatacaaa ggtggacaag 660 aaggtggagc caaagtcctg tgataagacc cacacatgcc ccccttgtcc tgcaccagag 720 ctgctgggag gaccaagcgt gttcctgttt ccacccaagc ccaaggacac cctgatgatc 780 tctcgcaccc cagaggtgac atgcgtggtg gtggccgtga gccacgagga ccccgaggtg 840 aagtttaact ggtacgtgga tggcgtggag gtgcacaatg ccaagaccaa gccaagagag 900 gagcagtacg gctccaccta tagggtggtg tctgtgctga cagtgctgca ccaggattgg 960 ctgaacggca aggagtataa gtgcaaggtg tccaataagg ccctgcccgc ccctatcgag 1020 aagaccatct ctaaggcaaa gggacagcct agggagccac aggtgtacac cctgcctcca 1080 tcccgggacg agctgacaaa gaaccaggtg tctctgacgt gtctggtgaa gggcttctat 1140 ccctctgata tcgccgtgga gtgggagagc aatggccagc ctgagaacaa ttacaagacc 1200 acaccccctg tgctggacag cgatggctcc ttctttctgt atagcaagct gaccgtggat 1260 aagtcccggt ggcagcaggg caacgtgttt tcttgtagcg tgatgcacga ggccctgcac 1320 aatcactaca cacagaagtc cctgtctctg agccctggca agtga 1365 <![CDATA[<210> 50]]> <![CDATA[<211> 2268]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類scIL-12突變2-人類IgG1 Fc DANG之DNA序列]]> <![CDATA[<400> 50]]> atctgggagc tgaagaagga cgtgtacgtg gtggagctgg actggtatcc tgatgcccca 60 ggcgagatgg tggtgctgac ctgcgacaca cccgaggagg atggcatcac ctggacactg 120 gatcagagct ccgaggtgct gggcagcggc aagaccctga caatccaggt gaaggagttc 180 ggcgacgccg gccagtacac ctgtcacaag ggaggagagg tgctgagcca ctccctgctg 240 ctgctgcaca agaaggagga cggcatctgg agcacagaca tcctgaagga tcagaaggag 300 ccaaagaaca agaccttcct gcggtgcgag gccaagaatt attccggccg gttcacctgt 360 tggtggctga ccacaatctc caccgatctg acattttctg tgaagtctag caggggctcc 420 tctgaccccc agggagtgac atgcggagca gccaccctga gcgccgagcg ggtgagaggc 480 gataacaagg agtacgagta ttccgtggag tgccaggagg actctgcctg tcctgcagca 540 gaggagtccc tgccaatcga agtgatggtg gatgccgtgc acaagctgaa gtacgagaat 600 tatacaagct ccttctttat cagggacatc atcaagcctg atccccctaa gaacctgcag 660 ctgaagccac tgaagaatag ccgccaggtg gaggtgtcct gggagtaccc agacacctgg 720 tccacacccc actcttattt cagcctgacc ttttgcgtgc aggtgcaggg cgcctccgct 780 agggaggccg ctgaccgcgt gttcaccgat aagacatctg ccaccgtgat ctgtcggaag 840 aacgcctcta tcagcgtgcg ggcccaggat agatactatt ctagctcctg gagcgagtgg 900 gcctccgtgc cttgttctgg aggaggaggc agcggcggag gaggctccgg aggaggaggc 960 tctagaaatc tgccagtggc aacccctgac ccaggaatgt tcccttgcct gcaccactct 1020 cagaacctgc tgcgggccgt gagcaatatg ctgcagaagg ccagacagac actggagttt 1080 tacccctgta ccagcgagga gatcgaccac gaggatatca caaaggataa gacctccaca 1140 gtggaggcct gcctgcctct ggagctgacc aagaacgaga gctgtctgaa cagccgggag 1200 acatctttca tcaccaacgg cagctgcctg gcctccagaa agacatcttt tatgatggcc 1260 ctgtgcctgt ctagcatcta cgaggacctg aagatgtatc aggtggagtt caagaccatg 1320 aacgccaagc tgctgatgga cccaaagcgg cagatctttc tggatcagaa tatgctggcc 1380 gtgatcgacg agctgatgca ggccctgaac ttcaatagcg agacagtgcc ccagaagtcc 1440 tctctggagg agcctgactt ctacaagacc aagatcaagc tgtgcatcct gctgcacgcc 1500 ttccggatca gagccgtgac catcgataga gtgatgagct atctgaacgc aagcggcggc 1560 ggaggctctg gaggaggcgg cagcgacaag acccacacat gcccaccatg tccagcacct 1620 gagctgctgg gaggaccatc cgtgttcctg tttcctccaa agcccaagga tacactgatg 1680 atcagccgca cacctgaggt gacctgcgtg gtggtggccg tgtcccacga ggaccccgag 1740 gtgaagttta actggtacgt ggacggcgtg gaggtgcaca atgccaagac caagcccagg 1800 gaggagcagt acggctctac atatcgcgtg gtgagcgtgc tgaccgtgct gcaccaggac 1860 tggctgaacg gcaaggagta caagtgcaag gtgtctaata aggccctgcc agcccccatc 1920 gagaagacca tcagcaaggc aaagggacag ccaagggagc ctcaggtgta tacactgccc 1980 cctagccgcg atgagctgac caagaaccag gtgtccctga cttgtctcgt gaagggcttc 2040 tacccatccg acatcgccgt ggagtgggag tctaatggcc agcccgagaa caattataag 2100 accacaccac ccgtgctgga ctccgatggc tctttctttc tgtacagcaa gctgacagtg 2160 gacaagtcca gatggcagca gggcaacgtg tttagctgct ccgtgatgca cgaggccctg 2220 cacaatcact acacccagaa gtctctgagc ctgtcccctg gcaagtga 2268 <![CDATA[<210> 51]]> <![CDATA[<211> 1353]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗人類CD20 HC人類IgG1 Fc杵DANG之DNA序列]]> <![CDATA[<400> 51]]> caggtgcagc tgcagcagcc aggagcagag ctggtgaagc ctggagcctc tgtgaagatg 60 agctgcaagg cctccggcta caccttcaca agctataaca tgcactgggt gaagcagacc 120 ccaggaaggg gactggagtg gatcggagcc atctaccctg gcaacggcga cacatcctat 180 aatcagaagt ttaagggcaa ggccaccctg acagccgata agagctcctc taccgcctac 240 atgcagctga gctccctgac aagcgaggac tccgccgtgt actattgcgc cagaagcacc 300 tactatggcg gcgattggta cttcaacgtg tggggagcag gaaccacagt gaccgtgtct 360 gccgccagca caaagggacc atccgtgttt ccactggcac catctagcaa gtctaccagc 420 ggaggaacag ccgccctggg atgtctggtg aaggactact tcccagagcc cgtgaccgtg 480 tcctggaact ctggcgccct gacctccgga gtgcacacat ttcccgccgt gctgcagtcc 540 tctggcctgt actctctgag ctccgtggtg accgtgcctt ctagctccct gggcacccag 600 acatatatct gcaacgtgaa tcacaagcct tccaatacaa aggtggacaa gaaggtggag 660 ccaaagtctt gtgataagac ccacacatgc cccccttgtc ctgcaccaga gctgctggga 720 ggaccaagcg tgttcctgtt tccacccaag cccaaggaca ccctgatgat cagcaggacc 780 cctgaggtga catgcgtggt ggtggccgtg tcccacgagg acccagaggt gaagttcaac 840 tggtacgtgg atggcgtgga ggtgcacaat gccaagacaa agccacggga ggagcagtac 900 ggctctacct atagagtggt gagcgtgctg acagtgctgc accaggattg gctgaacggc 960 aaggagtata agtgcaaggt gtctaataag gccctgcccg cccctatcga gaagaccatc 1020 agcaaggcca agggccagcc tagggagcca caggtgtaca ccctgcctcc atctcgcgac 1080 gagctgacaa agaaccaggt gagcctgtgg tgtctggtga agggcttcta tccaagcgat 1140 atcgccgtgg agtgggagtc caatggccag cccgagaaca attacaagac cacaccccct 1200 gtgctggaca gcgatggctc cttctttctg tattccaagc tgaccgtgga taagtctaga 1260 tggcagcagg gcaacgtgtt ttcctgttct gtgatgcacg aggccctgca caatcactac 1320 acacagaaga gcctgtccct gtctcctggc aag 1353 <![CDATA[<210> 52]]> <![CDATA[<211> 639]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗人類CD20 LC之DNA序列]]> <![CDATA[<400> 52]]> cagatcgtgc tgagccagtc cccagcaatc ctgtctgcca gccctggaga gaaggtgacc 60 atgacatgcc gggccagctc ctctgtgagc tacatccact ggttccagca gaagccaggc 120 agctccccta agccatggat ctatgccaca agcaacctgg catccggagt gcccgtgcgg 180 ttttccggct ctggcagcgg cacctcctac tctctgacaa tcagcagagt ggaggcagag 240 gacgcagcaa cctactattg ccagcagtgg acctccaatc cccctacatt cggcggcggc 300 accaagctgg agatcaagag gacagtggcc gccccttccg tgttcatctt tccaccctct 360 gacgagcagc tgaagtctgg caccgccagc gtggtgtgcc tgctgaacaa cttctaccca 420 cgcgaggcca aggtgcagtg gaaggtggat aacgccctgc agagcggcaa ttcccaggag 480 tctgtgacag agcaggacag caaggattcc acctattctc tgtctagcac cctgacactg 540 agcaaggccg attacgagaa gcacaaggtg tatgcctgcg aggtgacaca ccagggcctg 600 tcctctcccg tgaccaagtc cttcaacagg ggcgagtgt 639 <![CDATA[<210> 53]]> <![CDATA[<211> 1341]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗小鼠FAP HC小鼠IgG2a Fc杵DANG之DNA序列]]> <![CDATA[<400> 53]]> caggtgcagc tgcagcagtc cggagcagag ctggcaaggc ctggagcctc tgtgaacctg 60 agctgcaagg cctccggcta caccttcaca aacaatggca tcaattggct gaagcagagg 120 accggacagg gactggagtg gatcggcgag atctacccaa gatctaccaa cacactgtat 180 aatgagaagt tcaagggcaa ggccaccctg acagcagacc ggagctccaa caccgcctac 240 atggagctga gaagcctgac atccgaggat tctgccgtgt atttttgtgc acgcaccctg 300 acagcaccct tcgccttttg gggacagggc accctggtga cagtgagcgc cgccaagacc 360 acagcaccaa gcgtgtatcc actggcaccc gtgtgcggcg ataccacagg ctctagcgtg 420 accctgggct gtctggtgaa gggctacttc cctgagccag tgaccctgac atggaacagc 480 ggctctctgt cctctggcgt gcacaccttt cctgccgtgc tgcagtccga tctgtataca 540 ctgagctcct ctgtgaccgt gacaagctcc acctggccca gccagtccat cacatgcaac 600 gtggcccacc ctgcctctag caccaaggtg gacaagaaga tcgagccacg gggccccaca 660 atcaagccat gtccaccttg caagtgtcca gcacctaatc tgctgggagg acctagcgtg 720 ttcatctttc cacccaagat caaggacgtg ctgatgatct ctctgagccc tatcgtgacc 780 tgcgtggtgg tggccgtgtc tgaggacgat ccagatgtgc agatcagctg gttcgtgaac 840 aatgtggagg tgcacaccgc ccagacccag acacaccggg aggactacgg ctccacactg 900 agagtggtgt ctgccctgcc catccagcac caggactgga tgtccggcaa ggagtttaag 960 tgcaaggtga acaataagga tctgccagcc cccatcgaga ggaccatctc taagcctaag 1020 ggcagcgtgc gcgcaccaca ggtgtatgtg ctgcctccac ccgaggagga gatgaccaag 1080 aagcaggtga cactgtggtg tatggtgacc gacttcatgc cagaggatat ctacgtggag 1140 tggaccaaca atggcaagac agagctgaac tataagaata cagagcccgt gctggacagc 1200 gatggctcct actttatgta tagcaagctg agggtggaga agaagaactg ggtggagcgc 1260 aattcctact cttgtagcgt ggtgcacgag ggcctgcaca accaccacac cacaaagtcc 1320 ttttctagaa cccccggcaa g 1341 <![CDATA[<210> 54]]> <![CDATA[<211> 639]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗小鼠FAP LC之DNA序列]]> <![CDATA[<400> 54]]> cagatcgtgc tgacacagtc ccctgccatc atgtctgcca gcccaggcga gaaggtgacc 60 atgacatgct ctgccagctc cggcgtgaac ttcatgcact ggtaccagca gaagtctggc 120 acaagcccca agcggtggat cttcgacacc tccaagctgg cctctggcgt gcctgccaga 180 ttttccggct ctggcagcgg cacatcctat tctctgacca tctctagcat ggaggccgag 240 gacgccgcca cctactattg ccagcagtgg agcttcaatc cccctacatt tggcggcggc 300 accaagctgg agatcaagag ggcagatgca gcaccaacag tgtccatctt tccaccctcc 360 tctgagcagc tgaccagcgg aggagcatcc gtggtgtgct tcctgaacaa cttctacccc 420 aaggacatca acgtgaagtg gaagatcgat ggctctgaga ggcagaacgg cgtgctgaat 480 agctggacag accaggattc caaggactct acctatagca tgagctccac cctgacactg 540 accaaggatg agtacgagag gcacaatagc tatacatgcg aggccaccca caagacaagc 600 acctccccta tcgtgaagtc cttcaaccgc aatgagtgt 639 <![CDATA[<210> 55]]> <![CDATA[<211> 2292]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 小鼠scIL-12-小鼠IgG2a Fc臼DANG之DNA序列]]> <![CDATA[<400> 55]]> atgtgggagc tggagaagga cgtgtacgtg gtggaggtgg attggacacc tgacgccccc 60 ggcgagacag tgaacctgac atgcgatacc cctgaggagg atgatatcac atggacctcc 120 gatcagagac acggcgtgat cggcagcggc aagaccctga caatcaccgt gaaggagttt 180 ctggatgccg gccagtacac ctgtcacaag ggcggcgaga cactgagcca ctcccacctg 240 ctgctgcaca agaaggagaa tggcatctgg tccaccgaga tcctgaagaa cttcaagaac 300 aagaccttcc tgaagtgtga ggcccctaat tactccggca ggtttacatg ctcctggctg 360 gtgcagagaa acatggacct gaagtttaat atcaagagct cctcctccag ccccgatagc 420 agagccgtga cctgtggcat ggccagcctg agcgccgaga aggtgaccct ggatcagagg 480 gattacgaga agtactccgt gtcctgtcag gaggatgtga catgtcctac agccgaggag 540 acactgccta tcgagctggc cctggaggcc aggcagcaga ataagtacga gaactacagc 600 acaagctttt tcatcaggga catcatcaag cccgatcccc ccaagaacct gcagatgaag 660 cccctgaaga acagccaggt ggaggtgtcc tgggagtacc ctgatagctg gtccacccct 720 cactcctact tctccctgaa gttctttgtg agaatccaga gaaagaagga gaagatgaag 780 gagacagagg agggctgcaa tcagaagggc gccttcctgg tggagaagac atccaccgag 840 gtgcagtgta agggcggcaa cgtgtgcgtg caggcccagg acagatacta caattccagc 900 tgtagcaagt gggcctgtgt gccttgtaga gtgagatccg gcggcggcgg ctccggagga 960 ggaggaagcg gaggaggcgg ctccagagtg atccctgtgt ccggccctgc cagatgtctg 1020 tcccagagca gaaacctgct gaagaccaca gacgacatgg tgaagacagc cagagagaag 1080 ctgaagcact acagctgcac cgccgaggac atcgaccacg aggatatcac aagagaccag 1140 acatccaccc tgaagacatg tctgcctctg gagctgcaca agaatgagtc ctgcctggcc 1200 accagagaga cctccagcac caccaggggc agctgcctgc cccctcagaa gacctccctg 1260 atgatgacac tgtgcctggg cagcatctac gaggacctga agatgtacca gaccgagttc 1320 caggccatca atgccgccct gcagaaccac aaccaccagc agatcatcct ggataagggc 1380 atgctggtgg ccatcgacga gctgatgcag agcctgaacc acaatggcga gaccctgagg 1440 cagaagcctc ctgtgggcga ggccgatccc tacagagtga agatgaagct gtgtatcctg 1500 ctgcacgcct tttccacaag ggtggtgacc atcaacaggg tcatgggcta cctgtccagc 1560 gccggcggcg gcggcagcgg aggaggaggc tccgagccac gcggccccac aatcaagcca 1620 tgcccccctt gcaagtgtcc tgcaccaaat ctgctgggag gaccatccgt gttcatcttt 1680 ccacccaaga tcaaggacgt gctgatgatc agcctgtccc caatcgtgac ctgcgtggtc 1740 gtggccgtga gcgaggacga tcctgatgtg cagatctcct ggttcgtgaa caatgtggag 1800 gtgcacaccg cccagaccca gacacaccgg gaggactacg gctccacact gagagtggtg 1860 tctgccctgc ccatccagca ccaggactgg atgagcggca aggagtttaa gtgcaaggtg 1920 aacaataagg atctgcccgc ccctatcgag cggacaatct ctaagcctaa gggcagcgtg 1980 agagccccac aggtgtatgt gctgcctcca cccgaggagg agatgaccaa gaagcaggtg 2040 acactgtctt gtgccgtgac cgacttcatg cctgaggata tctatgtgga gtggaccaac 2100 aatggcaaga cagagctgaa ctacaagaat acagagccag tgctggactc cgatggctct 2160 tacttcatgg tgagcaagct gagggtggag aagaagaact gggtggagcg caattcttac 2220 agctgctccg tggtgcacga gggcctgcac aaccaccaca ccacaaagtc ttttagccgg 2280 acccctggca ag 2292 <![CDATA[<210> 56]]> <![CDATA[<211> 2292]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 小鼠scIL-12突變1-小鼠IgG2a Fc臼DANG之DNA序列]]> <![CDATA[<400> 56]]> atgtgggagc tggagaagga cgtgtacgtg gtggaggtgg attggacacc tgacgccccc 60 ggcgagacag tgaacctgac atgcgatacc cctgaggagg atgatatcac atggacctcc 120 gatcagagac acggcgtgat cggcagcggc aagaccctga caatcaccgt gaaggagttt 180 ctggatgccg gccagtacac ctgtcacaag ggcggcgaga cactgagcca ctcccacctg 240 ctgctgcaca agaaggagaa tggcatctgg tccaccgaga tcctgaagaa cttcaagaac 300 aagaccttcc tgaagtgtga ggcccctaat tactccggca ggtttacatg ctcctggctg 360 gtgcagagaa acatggacct gaagtttaat atcaagagct cctcctccag ccccgatagc 420 agagccgtga cctgtggcat ggccagcctg agcgccgaga aggtgaccct ggatcagagg 480 gattacgaga agtactccgt gtcctgtcag gaggatgtga catgtcctac agccgaggag 540 acactgccta tcgagctggc cctggaggcc aggcagcaga ataagtacga gaactacagc 600 acaagctttt tcatcaggga catcatcaag cccgatcccc ccaagaacct gcagatgaag 660 cccctgaaga acagccaggt ggaggtgtcc tgggagtacc ctgatagctg gtccacccct 720 cactcctact tctccctgaa gttctttgtg agaatccaga gagccaagga gaagatggcc 780 gagacagagg agggctgcaa tcagaagggc gccttcctgg tggagaagac atccaccgag 840 gtgcagtgta agggcggcaa cgtgtgcgtg caggcccagg acagatacta caattccagc 900 tgtagcaagt gggcctgtgt gccttgtaga gtgagatccg gcggcggcgg ctccggagga 960 ggaggaagcg gaggaggcgg ctccagagtg atccctgtgt ccggccctgc cagatgtctg 1020 tcccagagca gaaacctgct gaagaccaca gacgacatgg tgaagacagc cagagagaag 1080 ctgaagcact acagctgcac cgccgaggac atcgaccacg aggatatcac aagagaccag 1140 acatccaccc tgaagacatg tctgcctctg gagctgcaca agaatgagtc ctgcctggcc 1200 accagagaga cctccagcac caccaggggc agctgcctgc cccctcagaa gacctccctg 1260 atgatgacac tgtgcctggg cagcatctac gaggacctga agatgtacca gaccgagttc 1320 caggccatca atgccgccct gcagaaccac aaccaccagc agatcatcct ggataagggc 1380 atgctggtgg ccatcgacga gctgatgcag agcctgaacc acaatggcga gaccctgagg 1440 cagaagcctc ctgtgggcga ggccgatccc tacagagtga agatgaagct gtgtatcctg 1500 ctgcacgcct tttccacaag ggtggtgacc atcaacaggg tcatgggcta cctgtccagc 1560 gccggcggcg gcggcagcgg aggaggaggc tccgagccac gcggccccac aatcaagcca 1620 tgcccccctt gcaagtgtcc tgcaccaaat ctgctgggag gaccatccgt gttcatcttt 1680 ccacccaaga tcaaggacgt gctgatgatc agcctgtccc caatcgtgac ctgcgtggtc 1740 gtggccgtga gcgaggacga tcctgatgtg cagatctcct ggttcgtgaa caatgtggag 1800 gtgcacaccg cccagaccca gacacaccgg gaggactacg gctccacact gagagtggtg 1860 tctgccctgc ccatccagca ccaggactgg atgagcggca aggagtttaa gtgcaaggtg 1920 aacaataagg atctgcccgc ccctatcgag cggacaatct ctaagcctaa gggcagcgtg 1980 agagccccac aggtgtatgt gctgcctcca cccgaggagg agatgaccaa gaagcaggtg 2040 acactgtctt gtgccgtgac cgacttcatg cctgaggata tctatgtgga gtggaccaac 2100 aatggcaaga cagagctgaa ctacaagaat acagagccag tgctggactc cgatggctct 2160 tacttcatgg tgagcaagct gagggtggag aagaagaact gggtggagcg caattcttac 2220 agctgctccg tggtgcacga gggcctgcac aaccaccaca ccacaaagtc ttttagccgg 2280 acccctggca ag 2292 <![CDATA[<210> 57]]> <![CDATA[<211> 2292]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 小鼠scIL-12突變2-小鼠IgG2a Fc臼DANG之DNA序列]]> <![CDATA[<400> 57]]> atgtgggagc tggagaagga cgtgtacgtg gtggaggtgg attggacacc tgacgccccc 60 ggcgagacag tgaacctgac atgcgatacc cctgaggagg atgatatcac atggacctcc 120 gatcagagac acggcgtgat cggcagcggc aagaccctga caatcaccgt gaaggagttt 180 ctggatgccg gccagtacac ctgtcacaag ggcggcgaga cactgagcca ctcccacctg 240 ctgctgcaca agaaggagaa tggcatctgg tccaccgaga tcctgaagaa cttcaagaac 300 aagaccttcc tgaagtgtga ggcccctaat tactccggca ggtttacatg ctcctggctg 360 gtgcagagaa acatggacct gaagtttaat atcaagagct cctcctccag ccccgatagc 420 agagccgtga cctgtggcat ggccagcctg agcgccgaga aggtgaccct ggatcagagg 480 gattacgaga agtactccgt gtcctgtcag gaggatgtga catgtcctac agccgaggag 540 acactgccta tcgagctggc cctggaggcc aggcagcaga ataagtacga gaactacagc 600 acaagctttt tcatcaggga catcatcaag cccgatcccc ccaagaacct gcagatgaag 660 cccctgaaga acagccaggt ggaggtgtcc tgggagtacc ctgatagctg gtccacccct 720 cactcctact tctccctgaa gttctttgtg agaatccagg ctgccgccga gaagatggcc 780 gagacagagg agggctgcaa tcagaagggc gccttcctgg tggagaagac atccaccgag 840 gtgcagtgta agggcggcaa cgtgtgcgtg caggcccagg acagatacta caattccagc 900 tgtagcaagt gggcctgtgt gccttgtaga gtgagatccg gcggcggcgg ctccggagga 960 ggaggaagcg gaggaggcgg ctccagagtg atccctgtgt ccggccctgc cagatgtctg 1020 tcccagagca gaaacctgct gaagaccaca gacgacatgg tgaagacagc cagagagaag 1080 ctgaagcact acagctgcac cgccgaggac atcgaccacg aggatatcac aagagaccag 1140 acatccaccc tgaagacatg tctgcctctg gagctgcaca agaatgagtc ctgcctggcc 1200 accagagaga cctccagcac caccaggggc agctgcctgc cccctcagaa gacctccctg 1260 atgatgacac tgtgcctggg cagcatctac gaggacctga agatgtacca gaccgagttc 1320 caggccatca atgccgccct gcagaaccac aaccaccagc agatcatcct ggataagggc 1380 atgctggtgg ccatcgacga gctgatgcag agcctgaacc acaatggcga gaccctgagg 1440 cagaagcctc ctgtgggcga ggccgatccc tacagagtga agatgaagct gtgtatcctg 1500 ctgcacgcct tttccacaag ggtggtgacc atcaacaggg tcatgggcta cctgtccagc 1560 gccggcggcg gcggcagcgg aggaggaggc tccgagccac gcggccccac aatcaagcca 1620 tgcccccctt gcaagtgtcc tgcaccaaat ctgctgggag gaccatccgt gttcatcttt 1680 ccacccaaga tcaaggacgt gctgatgatc agcctgtccc caatcgtgac ctgcgtggtc 1740 gtggccgtga gcgaggacga tcctgatgtg cagatctcct ggttcgtgaa caatgtggag 1800 gtgcacaccg cccagaccca gacacaccgg gaggactacg gctccacact gagagtggtg 1860 tctgccctgc ccatccagca ccaggactgg atgagcggca aggagtttaa gtgcaaggtg 1920 aacaataagg atctgcccgc ccctatcgag cggacaatct ctaagcctaa gggcagcgtg 1980 agagccccac aggtgtatgt gctgcctcca cccgaggagg agatgaccaa gaagcaggtg 2040 acactgtctt gtgccgtgac cgacttcatg cctgaggata tctatgtgga gtggaccaac 2100 aatggcaaga cagagctgaa ctacaagaat acagagccag tgctggactc cgatggctct 2160 tacttcatgg tgagcaagct gagggtggag aagaagaact gggtggagcg caattcttac 2220 agctgctccg tggtgcacga gggcctgcac aaccaccaca ccacaaagtc ttttagccgg 2280 acccctggca ag 2292 <![CDATA[<210> 58]]> <![CDATA[<211> 1737]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> (抗小鼠FAP VH)2、小鼠IgG2a杵DANG之DNA序列]]> <![CDATA[<400> 58]]> caggtgcagc tgcagcagtc cggagcagag ctggcaaggc ctggagcctc tgtgaacctg 60 agctgcaagg cctccggcta caccttcaca aacaatggca tcaattggct gaagcagagg 120 accggacagg gactggagtg gatcggcgag atctacccaa gatctaccaa cacactgtat 180 aatgagaagt tcaagggcaa ggccaccctg acagcagacc ggagctccaa caccgcctac 240 atggagctga gaagcctgac atccgaggat tctgccgtgt atttttgtgc acgcaccctg 300 acagcaccct tcgccttttg gggacagggc accctggtga cagtgagcgc cggaggtgga 360 ggctcaggtg gtggcggatc tggaggaggc ggtagtcagg tgcagctgca gcagtccgga 420 gcagagctgg caaggcctgg agcctctgtg aacctgagct gcaaggcctc cggctacacc 480 ttcacaaaca atggcatcaa ttggctgaag cagaggaccg gacagggact ggagtggatc 540 ggcgagatct acccaagatc taccaacaca ctgtataatg agaagttcaa gggcaaggcc 600 accctgacag cagaccggag ctccaacacc gcctacatgg agctgagaag cctgacatcc 660 gaggattctg ccgtgtattt ttgtgcacgc accctgacag cacccttcgc cttttgggga 720 cagggcaccc tggtgacagt gagcgccgcc aagaccacag caccaagcgt gtatccactg 780 gcacccgtgt gcggcgatac cacaggctct agcgtgaccc tgggctgtct ggtgaagggc 840 tacttccctg agccagtgac cctgacatgg aacagcggct ctctgtcctc tggcgtgcac 900 acctttcctg ccgtgctgca gtccgatctg tatacactga gctcctctgt gaccgtgaca 960 agctccacct ggcccagcca gtccatcaca tgcaacgtgg cccaccctgc ctctagcacc 1020 aaggtggaca agaagatcga gccacggggc cccacaatca agccatgtcc accttgcaag 1080 tgtccagcac ctaatctgct gggaggacct agcgtgttca tctttccacc caagatcaag 1140 gacgtgctga tgatctctct gagccctatc gtgacctgcg tggtggtggc cgtgtctgag 1200 gacgatccag atgtgcagat cagctggttc gtgaacaatg tggaggtgca caccgcccag 1260 acccagacac accgggagga ctacggctcc acactgagag tggtgtctgc cctgcccatc 1320 cagcaccagg actggatgtc cggcaaggag tttaagtgca aggtgaacaa taaggatctg 1380 ccagccccca tcgagaggac catctctaag cctaagggca gcgtgcgcgc accacaggtg 1440 tatgtgctgc ctccacccga ggaggagatg accaagaagc aggtgacact gtggtgtatg 1500 gtgaccgact tcatgccaga ggatatctac gtggagtgga ccaacaatgg caagacagag 1560 ctgaactata agaatacaga gcccgtgctg gacagcgatg gctcctactt tatgtatagc 1620 aagctgaggg tggagaagaa gaactgggtg gagcgcaatt cctactcttg tagcgtggtg 1680 cacgagggcc tgcacaacca ccacaccaca aagtcctttt ctagaacccc cggcaag 1737 <![CDATA[<210> 59]]> <![CDATA[<211> 1002]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> (抗小鼠FAP VL)2之DNA序列]]> <![CDATA[<400> 59]]> cagatcgtgc tgacacagtc ccctgccatc atgtctgcca gcccaggcga gaaggtgacc 60 atgacatgct ctgccagctc cggcgtgaac ttcatgcact ggtaccagca gaagtctggc 120 acaagcccca agcggtggat cttcgacacc tccaagctgg cctctggcgt gcctgccaga 180 ttttccggct ctggcagcgg cacatcctat tctctgacca tctctagcat ggaggccgag 240 gacgccgcca cctactattg ccagcagtgg agcttcaatc cccctacatt tggcggcggc 300 accaagctgg agatcaaggg aggtggaggc tcaggtggtg gcggatctgg aggaggcggt 360 agtcagatcg tgctgacaca gtcccctgcc atcatgtctg ccagcccagg cgagaaggtg 420 accatgacat gctctgccag ctccggcgtg aacttcatgc actggtacca gcagaagtct 480 ggcacaagcc ccaagcggtg gatcttcgac acctccaagc tggcctctgg cgtgcctgcc 540 agattttccg gctctggcag cggcacatcc tattctctga ccatctctag catggaggcc 600 gaggacgccg ccacctacta ttgccagcag tggagcttca atccccctac atttggcggc 660 ggcaccaagc tggagatcaa gagggcagat gcagcaccaa cagtgtccat ctttccaccc 720 tcctctgagc agctgaccag cggaggagca tccgtggtgt gcttcctgaa caacttctac 780 cccaaggaca tcaacgtgaa gtggaagatc gatggctctg agaggcagaa cggcgtgctg 840 aatagctgga cagaccagga ttccaaggac tctacctata gcatgagctc caccctgaca 900 ctgaccaagg atgagtacga gaggcacaat agctatacat gcgaggccac ccacaagaca 960 agcacctccc ctatcgtgaa gtccttcaac cgcaatgagt gt 1002 <![CDATA[<210> 60]]> <![CDATA[<211> 2115]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗小鼠FAP HC小鼠IgG2a Fc杵DANG-抗小鼠FAP scFv之DNA序列]]> <![CDATA[<400> 60]]> caggtgcagc tgcagcagtc cggagcagag ctggcaaggc ctggagcctc tgtgaacctg 60 agctgcaagg cctccggcta caccttcaca aacaatggca tcaattggct gaagcagagg 120 accggacagg gactggagtg gatcggcgag atctacccaa gatctaccaa cacactgtat 180 aatgagaagt tcaagggcaa ggccaccctg acagcagacc ggagctccaa caccgcctac 240 atggagctga gaagcctgac atccgaggat tctgccgtgt atttttgtgc acgcaccctg 300 acagcaccct tcgccttttg gggacagggc accctggtga cagtgagcgc cgccaagacc 360 acagcaccaa gcgtgtatcc actggcaccc gtgtgcggcg ataccacagg ctctagcgtg 420 accctgggct gtctggtgaa gggctacttc cctgagccag tgaccctgac atggaacagc 480 ggctctctgt cctctggcgt gcacaccttt cctgccgtgc tgcagtccga tctgtataca 540 ctgagctcct ctgtgaccgt gacaagctcc acctggccca gccagtccat cacatgcaac 600 gtggcccacc ctgcctctag caccaaggtg gacaagaaga tcgagccacg gggccccaca 660 atcaagccat gtccaccttg caagtgtcca gcacctaatc tgctgggagg acctagcgtg 720 ttcatctttc cacccaagat caaggacgtg ctgatgatct ctctgagccc tatcgtgacc 780 tgcgtggtgg tggccgtgtc tgaggacgat ccagatgtgc agatcagctg gttcgtgaac 840 aatgtggagg tgcacaccgc ccagacccag acacaccggg aggactacgg ctccacactg 900 agagtggtgt ctgccctgcc catccagcac caggactgga tgtccggcaa ggagtttaag 960 tgcaaggtga acaataagga tctgccagcc cccatcgaga ggaccatctc taagcctaag 1020 ggcagcgtgc gcgcaccaca ggtgtatgtg ctgcctccac ccgaggagga gatgaccaag 1080 aagcaggtga cactgtggtg tatggtgacc gacttcatgc cagaggatat ctacgtggag 1140 tggaccaaca atggcaagac agagctgaac tataagaata cagagcccgt gctggacagc 1200 gatggctcct actttatgta tagcaagctg agggtggaga agaagaactg ggtggagcgc 1260 aattcctact cttgtagcgt ggtgcacgag ggcctgcaca accaccacac cacaaagtcc 1320 ttttctagaa cccccggcaa gggaggtgga ggctcaggtg gtggcggatc tggaggaggc 1380 ggtagtcagg tgcagctgca gcagtccgga gcagagctgg caaggcctgg agcctctgtg 1440 aacctgagct gcaaggcctc cggctacacc ttcacaaaca atggcatcaa ttggctgaag 1500 cagaggaccg gacagggact ggagtggatc ggcgagatct acccaagatc taccaacaca 1560 ctgtataatg agaagttcaa gggcaaggcc accctgacag cagaccggag ctccaacacc 1620 gcctacatgg agctgagaag cctgacatcc gaggattctg ccgtgtattt ttgtgcacgc 1680 accctgacag cacccttcgc cttttgggga cagggcaccc tggtgacagt gagcgccggt 1740 ggcggaggat caggaggagg cggtagtggc ggcggaggtt ctggtggagg aggtagccag 1800 atcgtgctga cacagtcccc tgccatcatg tctgccagcc caggcgagaa ggtgaccatg 1860 acatgctctg ccagctccgg cgtgaacttc atgcactggt accagcagaa gtctggcaca 1920 agccccaagc ggtggatctt cgacacctcc aagctggcct ctggcgtgcc tgccagattt 1980 tccggctctg gcagcggcac atcctattct ctgaccatct ctagcatgga ggccgaggac 2040 gccgccacct actattgcca gcagtggagc ttcaatcccc ctacatttgg cggcggcacc 2100 aagctggaga tcaag 2115 <![CDATA[<210> 61]]> <![CDATA[<211> 1413]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗小鼠FAP LC-抗小鼠FAP scFv之DNA序列]]> <![CDATA[<400> 61]]> cagatcgtgc tgacacagtc ccctgccatc atgtctgcca gcccaggcga gaaggtgacc 60 atgacatgct ctgccagctc cggcgtgaac ttcatgcact ggtaccagca gaagtctggc 120 acaagcccca agcggtggat cttcgacacc tccaagctgg cctctggcgt gcctgccaga 180 ttttccggct ctggcagcgg cacatcctat tctctgacca tctctagcat ggaggccgag 240 gacgccgcca cctactattg ccagcagtgg agcttcaatc cccctacatt tggcggcggc 300 accaagctgg agatcaagag ggcagatgca gcaccaacag tgtccatctt tccaccctcc 360 tctgagcagc tgaccagcgg aggagcatcc gtggtgtgct tcctgaacaa cttctacccc 420 aaggacatca acgtgaagtg gaagatcgat ggctctgaga ggcagaacgg cgtgctgaat 480 agctggacag accaggattc caaggactct acctatagca tgagctccac cctgacactg 540 accaaggatg agtacgagag gcacaatagc tatacatgcg aggccaccca caagacaagc 600 acctccccta tcgtgaagtc cttcaaccgc aatgagtgtg gaggtggagg ctcaggtggt 660 ggcggatctg gaggaggcgg tagtcaggtg cagctgcagc agtccggagc agagctggca 720 aggcctggag cctctgtgaa cctgagctgc aaggcctccg gctacacctt cacaaacaat 780 ggcatcaatt ggctgaagca gaggaccgga cagggactgg agtggatcgg cgagatctac 840 ccaagatcta ccaacacact gtataatgag aagttcaagg gcaaggccac cctgacagca 900 gaccggagct ccaacaccgc ctacatggag ctgagaagcc tgacatccga ggattctgcc 960 gtgtattttt gtgcacgcac cctgacagca cccttcgcct tttggggaca gggcaccctg 1020 gtgacagtga gcgccggtgg cggaggatca ggaggaggcg gtagtggcgg cggaggttct 1080 ggtggaggag gtagccagat cgtgctgaca cagtcccctg ccatcatgtc tgccagccca 1140 ggcgagaagg tgaccatgac atgctctgcc agctccggcg tgaacttcat gcactggtac 1200 cagcagaagt ctggcacaag ccccaagcgg tggatcttcg acacctccaa gctggcctct 1260 ggcgtgcctg ccagattttc cggctctggc agcggcacat cctattctct gaccatctct 1320 agcatggagg ccgaggacgc cgccacctac tattgccagc agtggagctt caatccccct 1380 acatttggcg gcggcaccaa gctggagatc aag 1413 <![CDATA[<210> 62]]> <![CDATA[<211> 2946]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗小鼠FAP HC小鼠IgG2a Fc臼DANG-小鼠scIL-12之DNA序列]]> <![CDATA[<400> 62]]> caggtgcagc tgcagcagtc cggagcagag ctggcaaggc ctggagcctc tgtgaacctg 60 agctgcaagg cctccggcta caccttcaca aacaatggca tcaattggct gaagcagagg 120 accggacagg gactggagtg gatcggcgag atctacccaa gatctaccaa cacactgtat 180 aatgagaagt tcaagggcaa ggccaccctg acagcagacc ggagctccaa caccgcctac 240 atggagctga gaagcctgac atccgaggat tctgccgtgt atttttgtgc acgcaccctg 300 acagcaccct tcgccttttg gggacagggc accctggtga cagtgagcgc cgccaagacc 360 acagcaccaa gcgtgtatcc actggcaccc gtgtgcggcg ataccacagg ctctagcgtg 420 accctgggct gtctggtgaa gggctacttc cctgagccag tgaccctgac atggaacagc 480 ggctctctgt cctctggcgt gcacaccttt cctgccgtgc tgcagtccga tctgtataca 540 ctgagctcct ctgtgaccgt gacaagctcc acctggccca gccagtccat cacatgcaac 600 gtggcccacc ctgcctctag caccaaggtg gacaagaaga tcgagccacg cggccccaca 660 atcaagccat gccccccttg caagtgtcct gcaccaaatc tgctgggagg accatccgtg 720 ttcatctttc cacccaagat caaggacgtg ctgatgatca gcctgtcccc aatcgtgacc 780 tgcgtggtcg tggccgtgag cgaggacgat cctgatgtgc agatctcctg gttcgtgaac 840 aatgtggagg tgcacaccgc ccagacccag acacaccggg aggactacgg ctccacactg 900 agagtggtgt ctgccctgcc catccagcac caggactgga tgagcggcaa ggagtttaag 960 tgcaaggtga acaataagga tctgcccgcc cctatcgagc ggacaatctc taagcctaag 1020 ggcagcgtga gagccccaca ggtgtatgtg ctgcctccac ccgaggagga gatgaccaag 1080 aagcaggtga cactgtcttg tgccgtgacc gacttcatgc ctgaggatat ctatgtggag 1140 tggaccaaca atggcaagac agagctgaac tacaagaata cagagccagt gctggactcc 1200 gatggctctt acttcatggt gagcaagctg agggtggaga agaagaactg ggtggagcgc 1260 aattcttaca gctgctccgt ggtgcacgag ggcctgcaca accaccacac cacaaagtct 1320 tttagccgga cccctggcgg tggaggtggc tcaggaggag gcggttctgg cggaggaggt 1380 agtatgtggg agctggagaa ggacgtgtac gtggtggagg tggattggac acctgacgcc 1440 cccggcgaga cagtgaacct gacatgcgat acccctgagg aggatgatat cacatggacc 1500 tccgatcaga gacacggcgt gatcggcagc ggcaagaccc tgacaatcac cgtgaaggag 1560 tttctggatg ccggccagta cacctgtcac aagggcggcg agacactgag ccactcccac 1620 ctgctgctgc acaagaagga gaatggcatc tggtccaccg agatcctgaa gaacttcaag 1680 aacaagacct tcctgaagtg tgaggcccct aattactccg gcaggtttac atgctcctgg 1740 ctggtgcaga gaaacatgga cctgaagttt aatatcaaga gctcctcctc cagccccgat 1800 agcagagccg tgacctgtgg catggccagc ctgagcgccg agaaggtgac cctggatcag 1860 agggattacg agaagtactc cgtgtcctgt caggaggatg tgacatgtcc tacagccgag 1920 gagacactgc ctatcgagct ggccctggag gccaggcagc agaataagta cgagaactac 1980 agcacaagct ttttcatcag ggacatcatc aagcccgatc cccccaagaa cctgcagatg 2040 aagcccctga agaacagcca ggtggaggtg tcctgggagt accctgatag ctggtccacc 2100 cctcactcct acttctccct gaagttcttt gtgagaatcc agagaaagaa ggagaagatg 2160 aaggagacag aggagggctg caatcagaag ggcgccttcc tggtggagaa gacatccacc 2220 gaggtgcagt gtaagggcgg caacgtgtgc gtgcaggccc aggacagata ctacaattcc 2280 agctgtagca agtgggcctg tgtgccttgt agagtgagat ccggcggcgg cggctccgga 2340 ggaggaggaa gcggaggagg cggctccaga gtgatccctg tgtccggccc tgccagatgt 2400 ctgtcccaga gcagaaacct gctgaagacc acagacgaca tggtgaagac agccagagag 2460 aagctgaagc actacagctg caccgccgag gacatcgacc acgaggatat cacaagagac 2520 cagacatcca ccctgaagac atgtctgcct ctggagctgc acaagaatga gtcctgcctg 2580 gccaccagag agacctccag caccaccagg ggcagctgcc tgccccctca gaagacctcc 2640 ctgatgatga cactgtgcct gggcagcatc tacgaggacc tgaagatgta ccagaccgag 2700 ttccaggcca tcaatgccgc cctgcagaac cacaaccacc agcagatcat cctggataag 2760 ggcatgctgg tggccatcga cgagctgatg cagagcctga accacaatgg cgagaccctg 2820 aggcagaagc ctcctgtggg cgaggccgat ccctacagag tgaagatgaa gctgtgtatc 2880 ctgctgcacg ccttttccac aagggtggtg accatcaaca gggtcatggg ctacctgtcc 2940 agcgcc 2946 <![CDATA[<210> 63]]> <![CDATA[<211> 2946]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗小鼠FAP HC小鼠IgG2a Fc臼DANG-小鼠scIL-12突變2之DNA序列]]> <![CDATA[<400> 63]]> caggtgcagc tgcagcagtc cggagcagag ctggcaaggc ctggagcctc tgtgaacctg 60 agctgcaagg cctccggcta caccttcaca aacaatggca tcaattggct gaagcagagg 120 accggacagg gactggagtg gatcggcgag atctacccaa gatctaccaa cacactgtat 180 aatgagaagt tcaagggcaa ggccaccctg acagcagacc ggagctccaa caccgcctac 240 atggagctga gaagcctgac atccgaggat tctgccgtgt atttttgtgc acgcaccctg 300 acagcaccct tcgccttttg gggacagggc accctggtga cagtgagcgc cgccaagacc 360 acagcaccaa gcgtgtatcc actggcaccc gtgtgcggcg ataccacagg ctctagcgtg 420 accctgggct gtctggtgaa gggctacttc cctgagccag tgaccctgac atggaacagc 480 ggctctctgt cctctggcgt gcacaccttt cctgccgtgc tgcagtccga tctgtataca 540 ctgagctcct ctgtgaccgt gacaagctcc acctggccca gccagtccat cacatgcaac 600 gtggcccacc ctgcctctag caccaaggtg gacaagaaga tcgagccacg cggccccaca 660 atcaagccat gccccccttg caagtgtcct gcaccaaatc tgctgggagg accatccgtg 720 ttcatctttc cacccaagat caaggacgtg ctgatgatca gcctgtcccc aatcgtgacc 780 tgcgtggtcg tggccgtgag cgaggacgat cctgatgtgc agatctcctg gttcgtgaac 840 aatgtggagg tgcacaccgc ccagacccag acacaccggg aggactacgg ctccacactg 900 agagtggtgt ctgccctgcc catccagcac caggactgga tgagcggcaa ggagtttaag 960 tgcaaggtga acaataagga tctgcccgcc cctatcgagc ggacaatctc taagcctaag 1020 ggcagcgtga gagccccaca ggtgtatgtg ctgcctccac ccgaggagga gatgaccaag 1080 aagcaggtga cactgtcttg tgccgtgacc gacttcatgc ctgaggatat ctatgtggag 1140 tggaccaaca atggcaagac agagctgaac tacaagaata cagagccagt gctggactcc 1200 gatggctctt acttcatggt gagcaagctg agggtggaga agaagaactg ggtggagcgc 1260 aattcttaca gctgctccgt ggtgcacgag ggcctgcaca accaccacac cacaaagtct 1320 tttagccgga cccctggcgg tggaggtggc tcaggaggag gcggttctgg cggaggaggt 1380 agtatgtggg agctggagaa ggacgtgtac gtggtggagg tggattggac acctgacgcc 1440 cccggcgaga cagtgaacct gacatgcgat acccctgagg aggatgatat cacatggacc 1500 tccgatcaga gacacggcgt gatcggcagc ggcaagaccc tgacaatcac cgtgaaggag 1560 tttctggatg ccggccagta cacctgtcac aagggcggcg agacactgag ccactcccac 1620 ctgctgctgc acaagaagga gaatggcatc tggtccaccg agatcctgaa gaacttcaag 1680 aacaagacct tcctgaagtg tgaggcccct aattactccg gcaggtttac atgctcctgg 1740 ctggtgcaga gaaacatgga cctgaagttt aatatcaaga gctcctcctc cagccccgat 1800 agcagagccg tgacctgtgg catggccagc ctgagcgccg agaaggtgac cctggatcag 1860 agggattacg agaagtactc cgtgtcctgt caggaggatg tgacatgtcc tacagccgag 1920 gagacactgc ctatcgagct ggccctggag gccaggcagc agaataagta cgagaactac 1980 agcacaagct ttttcatcag ggacatcatc aagcccgatc cccccaagaa cctgcagatg 2040 aagcccctga agaacagcca ggtggaggtg tcctgggagt accctgatag ctggtccacc 2100 cctcactcct acttctccct gaagttcttt gtgagaatcc aggctgccgc cgagaagatg 2160 gccgagacag aggagggctg caatcagaag ggcgccttcc tggtggagaa gacatccacc 2220 gaggtgcagt gtaagggcgg caacgtgtgc gtgcaggccc aggacagata ctacaattcc 2280 agctgtagca agtgggcctg tgtgccttgt agagtgagat ccggcggcgg cggctccgga 2340 ggaggaggaa gcggaggagg cggctccaga gtgatccctg tgtccggccc tgccagatgt 2400 ctgtcccaga gcagaaacct gctgaagacc acagacgaca tggtgaagac agccagagag 2460 aagctgaagc actacagctg caccgccgag gacatcgacc acgaggatat cacaagagac 2520 cagacatcca ccctgaagac atgtctgcct ctggagctgc acaagaatga gtcctgcctg 2580 gccaccagag agacctccag caccaccagg ggcagctgcc tgccccctca gaagacctcc 2640 ctgatgatga cactgtgcct gggcagcatc tacgaggacc tgaagatgta ccagaccgag 2700 ttccaggcca tcaatgccgc cctgcagaac cacaaccacc agcagatcat cctggataag 2760 ggcatgctgg tggccatcga cgagctgatg cagagcctga accacaatgg cgagaccctg 2820 aggcagaagc ctcctgtggg cgaggccgat ccctacagag tgaagatgaa gctgtgtatc 2880 ctgctgcacg ccttttccac aagggtggtg accatcaaca gggtcatggg ctacctgtcc 2940 agcgcc 2946 <![CDATA[<210> 64]]> <![CDATA[<211> 699]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 小鼠IgG2a Fc臼DANG之DNA序列]]> <![CDATA[<400> 64]]> gagccaaggg gccccaccat caagccatgc cccccttgca agtgtcctgc accaaacctg 60 ctgggaggac caagcgtgtt catctttcca cccaagatca aggacgtgct gatgatcagc 120 ctgtccccca tcgtgacatg cgtggtggtg gccgtgtccg aggacgatcc tgatgtgcag 180 atctcttggt tcgtgaacaa tgtggaggtg cacaccgccc agacccagac acaccgggag 240 gactatggct ctacactgag agtggtgagc gccctgccca tccagcacca ggactggatg 300 agcggcaagg agtttaagtg caaggtgaac aataaggatc tgcccgcccc tatcgagcgg 360 accatcagca agcctaaggg ctccgtgaga gccccacagg tgtacgtgct gcctccaccc 420 gaggaggaga tgaccaagaa gcaggtgaca ctgagctgtg ccgtgaccga cttcatgcct 480 gaggatatct acgtggagtg gaccaacaat ggcaagacag agctgaacta taagaataca 540 gagccagtgc tggactccga tggctcttac tttatggtgt ccaagctgag ggtggagaag 600 aagaactggg tggagcgcaa ttcttatagc tgctccgtgg tgcacgaggg cctgcacaat 660 caccacacca caaagtcttt cagcagaacc cctggcaag 699 <![CDATA[<210> 65]]> <![CDATA[<211> 699]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 小鼠IgG2a Fc杵DANG之DNA序列]]> <![CDATA[<400> 65]]> gagccaaggg gccccaccat caagccatgc cccccttgca agtgtcctgc accaaacctg 60 ctgggaggac caagcgtgtt catctttcca cccaagatca aggacgtgct gatgatcagc 120 ctgtccccca tcgtgacatg cgtggtggtg gccgtgtccg aggacgatcc tgatgtgcag 180 atctcttggt tcgtgaacaa tgtggaggtg cacaccgccc agacccagac acaccgggag 240 gactacggct ctacactgag agtggtgagc gccctgccca tccagcacca ggactggatg 300 tccggcaagg agtttaagtg caaggtgaac aataaggatc tgcccgcccc tatcgagcgg 360 accatcagca agcctaaggg ctccgtgaga gccccacagg tgtatgtgct gcctccaccc 420 gaggaggaga tgaccaagaa gcaggtgaca ctgtggtgta tggtgaccga cttcatgcct 480 gaggatatct acgtggagtg gaccaacaat ggcaagacag agctgaacta taagaataca 540 gagccagtgc tggactccga tggctcttac tttatgtatt ctaagctgag ggtggagaag 600 aagaactggg tggagcgcaa ttcttacagc tgctccgtgg tgcacgaggg cctgcacaat 660 caccacacca caaagtcttt cagcagaacc cctggcaag 699 <![CDATA[<210> 66]]> <![CDATA[<211> 1344]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗小鼠FAP HC小鼠IgG2a Fc DANG之DNA序列]]> <![CDATA[<400> 66]]> caggtgcagc tgcagcagtc cggagcagag ctggcaaggc ctggagcctc tgtgaacctg 60 agctgcaagg cctccggcta caccttcaca aacaatggca tcaattggct gaagcagagg 120 accggacagg gactggagtg gatcggcgag atctacccaa gatctaccaa cacactgtat 180 aatgagaagt tcaagggcaa ggccaccctg acagcagacc ggagctccaa caccgcctac 240 atggagctga gaagcctgac atccgaggat tctgccgtgt atttttgtgc acgcaccctg 300 acagcaccct tcgccttttg gggacagggc accctggtga cagtgagcgc cgccaagacc 360 acagcaccaa gcgtgtatcc actggcaccc gtgtgcggcg ataccacagg ctctagcgtg 420 accctgggct gtctggtgaa gggctacttc cctgagccag tgaccctgac atggaacagc 480 ggctctctgt cctctggcgt gcacaccttt cctgccgtgc tgcagtccga tctgtataca 540 ctgagctcct ctgtgaccgt gacaagctcc acctggccca gccagtccat cacatgcaac 600 gtggcccacc ctgcctctag caccaaggtg gacaagaaga tcgagccacg gggccccaca 660 atcaagccat gtccaccttg caagtgtcca gcacctaatc tgctgggagg acctagcgtg 720 ttcatctttc cacccaagat caaggacgtg ctgatgatct ctctgagccc tatcgtgacc 780 tgcgtggtgg tggccgtgtc tgaggacgat ccagatgtgc agatcagctg gttcgtgaac 840 aatgtggagg tgcacaccgc ccagacccag acacaccggg aggactacgg ctccacactg 900 agagtggtgt ctgccctgcc catccagcac caggactgga tgtccggcaa ggagtttaag 960 tgcaaggtga acaataagga tctgccagcc cccatcgaga ggaccatctc taagcctaag 1020 ggcagcgtgc gcgcaccaca ggtgtatgtg ctgcctccac ccgaggagga gatgaccaag 1080 aagcaggtga cactgacgtg tatggtgacc gacttcatgc cagaggatat ctacgtggag 1140 tggaccaaca atggcaagac agagctgaac tataagaata cagagcccgt gctggacagc 1200 gatggctcct actttatgta tagcaagctg agggtggaga agaagaactg ggtggagcgc 1260 aattcctact cttgtagcgt ggtgcacgag ggcctgcaca accaccacac cacaaagtcc 1320 ttttctagaa cccccggcaa gtga 1344 <![CDATA[<210> 67]]> <![CDATA[<211> 2292]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 小鼠scIL-12突變2-小鼠IgG2a Fc DANG之DNA序列]]> <![CDATA[<400> 67]]> atgtgggagc tggagaagga cgtgtacgtg gtggaggtgg attggacacc tgacgccccc 60 ggcgagacag tgaacctgac atgcgatacc cctgaggagg atgatatcac atggacctcc 120 gatcagagac acggcgtgat cggcagcggc aagaccctga caatcaccgt gaaggagttt 180 ctggatgccg gccagtacac ctgtcacaag ggcggcgaga cactgagcca ctcccacctg 240 ctgctgcaca agaaggagaa tggcatctgg tccaccgaga tcctgaagaa cttcaagaac 300 aagaccttcc tgaagtgtga ggcccctaat tactccggca ggtttacatg ctcctggctg 360 gtgcagagaa acatggacct gaagtttaat atcaagagct cctcctccag ccccgatagc 420 agagccgtga cctgtggcat ggccagcctg agcgccgaga aggtgaccct ggatcagagg 480 gattacgaga agtactccgt gtcctgtcag gaggatgtga catgtcctac agccgaggag 540 acactgccta tcgagctggc cctggaggcc aggcagcaga ataagtacga gaactacagc 600 acaagctttt tcatcaggga catcatcaag cccgatcccc ccaagaacct gcagatgaag 660 cccctgaaga acagccaggt ggaggtgtcc tgggagtacc ctgatagctg gtccacccct 720 cactcctact tctccctgaa gttctttgtg agaatccagg ctgccgccga gaagatggcc 780 gagacagagg agggctgcaa tcagaagggc gccttcctgg tggagaagac atccaccgag 840 gtgcagtgta agggcggcaa cgtgtgcgtg caggcccagg acagatacta caattccagc 900 tgtagcaagt gggcctgtgt gccttgtaga gtgagatccg gcggcggcgg ctccggagga 960 ggaggaagcg gaggaggcgg ctccagagtg atccctgtgt ccggccctgc cagatgtctg 1020 tcccagagca gaaacctgct gaagaccaca gacgacatgg tgaagacagc cagagagaag 1080 ctgaagcact acagctgcac cgccgaggac atcgaccacg aggatatcac aagagaccag 1140 acatccaccc tgaagacatg tctgcctctg gagctgcaca agaatgagtc ctgcctggcc 1200 accagagaga cctccagcac caccaggggc agctgcctgc cccctcagaa gacctccctg 1260 atgatgacac tgtgcctggg cagcatctac gaggacctga agatgtacca gaccgagttc 1320 caggccatca atgccgccct gcagaaccac aaccaccagc agatcatcct ggataagggc 1380 atgctggtgg ccatcgacga gctgatgcag agcctgaacc acaatggcga gaccctgagg 1440 cagaagcctc ctgtgggcga ggccgatccc tacagagtga agatgaagct gtgtatcctg 1500 ctgcacgcct tttccacaag ggtggtgacc atcaacaggg tcatgggcta cctgtccagc 1560 gccggcggcg gcggcagcgg aggaggaggc tccgagccac gcggccccac aatcaagcca 1620 tgcccccctt gcaagtgtcc tgcaccaaat ctgctgggag gaccatccgt gttcatcttt 1680 ccacccaaga tcaaggacgt gctgatgatc agcctgtccc caatcgtgac ctgcgtggtc 1740 gtggccgtga gcgaggacga tcctgatgtg cagatctcct ggttcgtgaa caatgtggag 1800 gtgcacaccg cccagaccca gacacaccgg gaggactacg gctccacact gagagtggtg 1860 tctgccctgc ccatccagca ccaggactgg atgagcggca aggagtttaa gtgcaaggtg 1920 aacaataagg atctgcccgc ccctatcgag cggacaatct ctaagcctaa gggcagcgtg 1980 agagccccac aggtgtatgt gctgcctcca cccgaggagg agatgaccaa gaagcaggtg 2040 acactgactt gtatggtgac cgacttcatg cctgaggata tctatgtgga gtggaccaac 2100 aatggcaaga cagagctgaa ctacaagaat acagagccag tgctggactc cgatggctct 2160 tacttcatgt acagcaagct gagggtggag aagaagaact gggtggagcg caattcttac 2220 agctgctccg tggtgcacga gggcctgcac aaccaccaca ccacaaagtc ttttagccgg 2280 acccctggca ag 2292 <![CDATA[<210> 68]]> <![CDATA[<211> 1353]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗小鼠CD20 HC小鼠IgG2a Fc杵DANG之DNA序列]]> <![CDATA[<400> 68]]> caggtgcagc tgcagcagcc aggagcagag ctggtgaggc caggcacctc tgtgaagctg 60 agctgcaagg cctccggcta caccttcaca tcttattgga tgcactggat caagcagagg 120 ccaggacagg gactggagtg gatcggcgtg atcgacccct ccgataacta caccaagtac 180 aaccagaagt ttaagggcaa ggccaccctg acagtggaca ccagctcctc tacagcctac 240 atgcagctga gctccctgac atccgaggat tctgccgtgt atttctgtgc ccgggagggc 300 tactatggct ctagcccatg gtttgcctac tggggccagg gcaccctggt gacagtgtcc 360 tctgccaaga ccacagcccc cagcgtgtat cctctggccc cagtgtgcgg cgataccaca 420 ggcagctccg tgaccctggg ctgtctggtg aagggctact tccctgagcc agtgaccctg 480 acatggaact ctggcagcct gtctagcgga gtgcacacct ttccagccgt gctgcagtcc 540 gatctgtata cactgtcctc tagcgtgacc gtgacatcct ctacctggcc ctcccagtct 600 atcacatgca acgtggccca ccctgccagc tccaccaagg tggacaagaa gatcgagccc 660 cggggcccta caatcaagcc atgtccacct tgcaagtgtc cagcacctaa tctgctggga 720 ggacctagcg tgttcatctt tccacccaag atcaaggacg tgctgatgat cagcctgtcc 780 cctatcgtga cctgcgtggt ggtggccgtg agcgaggacg atccagatgt gcagatctcc 840 tggttcgtga acaatgtgga ggtgcacacc gcccagaccc agacacaccg ggaggactac 900 ggctccacac tgagagtggt gtctgccctg cctatccagc accaggactg gatgtccggc 960 aaggagttta agtgcaaggt gaacaataag gatctgccag cccccatcga gcggaccatc 1020 tctaagccta agggcagcgt gagagcccca caggtgtatg tgctgcctcc acccgaggag 1080 gagatgacca agaagcaggt gacactgtgg tgtatggtga ccgacttcat gcctgaggat 1140 atctacgtgg agtggaccaa caatggcaag acagagctga actataagaa tacagagcca 1200 gtgctggaca gcgatggctc ctactttatg tatagcaagc tgagggtgga gaagaagaac 1260 tgggtggagc gcaattctta cagctgttcc gtggtgcacg agggcctgca caatcaccac 1320 accacaaagt ctttcagcag aacccccggc aag 1353 <![CDATA[<210> 69]]> <![CDATA[<211> 639]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗小鼠CD20 LC之DNA序列]]> <![CDATA[<400> 69]]> cagatcgtga tgagccagtc ccctgccatc ctgtccgcca gccctggcga gaaggtgaca 60 atgacctgca gggccagatc ctccgtgtcc tacatccact ggtaccagca gaagcccggc 120 agcagcccta agccctggat ctacgccacc agcaacctgg ccagcggcgt gcctggcaga 180 ttttccggct ccggcagcgg caccagctac agcctgacaa tcacaagggt ggaggccgag 240 gatgccgcca catactactg ccagcagtgg agctccaagc ctcccacctt cggcggcggc 300 accaagctgg agatcaagag gaccgacgcc gcccccaccg tgtccatctt tcccccttcc 360 tccgagcagc tgacctccgg cggcgcttcc gtggtgtgtt tcctgaataa tttctaccct 420 aaggatatca acgtgaagtg gaagatcgat ggcagcgaga ggcagaatgg cgtgctgaat 480 agctggaccg accaggacag caaggatagc acctacagca tgagctccac actgaccctg 540 acaaaggacg agtacgagag gcacaattcc tacacatgtg aggccacaca caagacctcc 600 acctccccta tcgtgaagtc cttcaacagg aacgagtgc 639 <![CDATA[<210> 70]]> <![CDATA[<211> 702]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 小鼠IgG2a Fc DANG之DNA序列]]> <![CDATA[<400> 70]]> gagcccagag gccccacaat caagccttgc cccccttgca aatgtcccgc ccccaatctg 60 ctgggaggcc cttccgtctt catcttcccc cccaagatca aggacgtgct gatgatctct 120 ctgagcccca tcgtgacatg cgtggtggtg gccgtgagcg aggacgatcc cgacgtgcag 180 atcagctggt tcgtcaacaa cgtggaggtg cataccgccc aaacacagac ccatagagag 240 gactacggct ccacactgag agtggtgtcc gctctgccca tccagcatca agactggatg 300 agcggcaagg agttcaagtg caaggtgaac aacaaggatc tgcccgcccc tatcgagagg 360 accatctcca agcccaaagg ctccgtgaga gctccccaag tgtatgtgct gcctcccccc 420 gaggaggaga tgaccaagaa gcaagtgaca ctgacatgca tggtgaccga tttcatgccc 480 gaagacatct acgtggagtg gaccaacaac ggcaagaccg agctcaacta caagaacacc 540 gagcccgtgc tcgacagcga cggcagctac ttcatgtaca gcaagctgag ggtcgagaag 600 aaaaactggg tggagaggaa cagctacagc tgtagcgtgg tgcacgaggg actgcacaac 660 caccatacca ccaagagctt ctccagaaca cccggcaagt ga 702 <![CDATA[<210> 71]]> <![CDATA[<211> 222]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗人類FAP HC]]> <![CDATA[<400> 71]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr 20 25 30 Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile 35 40 45 Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 130 135 140 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 145 150 155 160 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 165 170 175 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 180 185 190 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 195 200 205 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val 210 215 220 <![CDATA[<210> 72]]> <![CDATA[<211> 257]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗人類FAP scFv]]> <![CDATA[<400> 72]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr 20 25 30 Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile 35 40 45 Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly 115 120 125 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 130 135 140 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 145 150 155 160 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser 165 170 175 Arg Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 180 185 190 Pro Pro Lys Leu Leu Ile Phe Trp Ala Ser Thr Arg Glu Ser Gly Val 195 200 205 Pro Asp Arg Phe Ser Gly Ser Gly Phe Gly Thr Asp Phe Thr Leu Thr 210 215 220 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 225 230 235 240 Tyr Phe Ser Tyr Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile 245 250 255 Lys <![CDATA[<210> 73]]> <![CDATA[<211> 518]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類scIL-12]]> <![CDATA[<400> 73]]> Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr 1 5 10 15 Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu 20 25 30 Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly 35 40 45 Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly 50 55 60 Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu 65 70 75 80 Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys 85 90 95 Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys 100 105 110 Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr 115 120 125 Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln 130 135 140 Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly 145 150 155 160 Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala 165 170 175 Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala 180 185 190 Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg 195 200 205 Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu 210 215 220 Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp 225 230 235 240 Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln 245 250 255 Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe Thr Asp Lys Thr 260 265 270 Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala 275 280 285 Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro 290 295 300 Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 305 310 315 320 Ser Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys 325 330 335 Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln 340 345 350 Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile 355 360 365 Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys 370 375 380 Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu 385 390 395 400 Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser 405 410 415 Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met 420 425 430 Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro 435 440 445 Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu 450 455 460 Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser 465 470 475 480 Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile 485 490 495 Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Met 500 505 510 Ser Tyr Leu Asn Ala Ser 515 <![CDATA[<210> 74]]> <![CDATA[<211> 306]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類scIL-12 p40]]> <![CDATA[<400> 74]]> Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr 1 5 10 15 Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu 20 25 30 Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly 35 40 45 Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly 50 55 60 Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu 65 70 75 80 Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys 85 90 95 Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys 100 105 110 Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr 115 120 125 Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln 130 135 140 Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly 145 150 155 160 Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala 165 170 175 Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala 180 185 190 Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg 195 200 205 Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu 210 215 220 Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp 225 230 235 240 Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln 245 250 255 Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe Thr Asp Lys Thr 260 265 270 Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala 275 280 285 Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro 290 295 300 Cys Ser 305 <![CDATA[<210> 75]]> <![CDATA[<211> 197]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類scIL-12 p35]]> <![CDATA[<400> 75]]> Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys Leu 1 5 10 15 His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln Lys 20 25 30 Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile Asp 35 40 45 His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys Leu 50 55 60 Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu Thr 65 70 75 80 Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser Phe 85 90 95 Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met Tyr 100 105 110 Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro Lys 115 120 125 Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu Leu 130 135 140 Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser Ser 145 150 155 160 Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile Leu 165 170 175 Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Met Ser 180 185 190 Tyr Leu Asn Ala Ser 195 <![CDATA[<210> 76]]> <![CDATA[<211> 518]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類scIL-12突變1]]> <![CDATA[<400> 76]]> Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr 1 5 10 15 Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu 20 25 30 Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly 35 40 45 Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly 50 55 60 Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu 65 70 75 80 Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys 85 90 95 Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys 100 105 110 Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr 115 120 125 Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln 130 135 140 Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly 145 150 155 160 Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala 165 170 175 Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala 180 185 190 Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg 195 200 205 Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu 210 215 220 Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp 225 230 235 240 Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln 245 250 255 Gly Ala Ser Lys Arg Glu Ala Lys Asp Arg Val Phe Thr Asp Lys Thr 260 265 270 Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala 275 280 285 Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro 290 295 300 Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 305 310 315 320 Ser Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys 325 330 335 Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln 340 345 350 Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile 355 360 365 Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys 370 375 380 Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu 385 390 395 400 Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser 405 410 415 Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met 420 425 430 Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro 435 440 445 Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu 450 455 460 Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser 465 470 475 480 Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile 485 490 495 Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Met 500 505 510 Ser Tyr Leu Asn Ala Ser 515 <![CDATA[<210> 77]]> <![CDATA[<211> 306]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類scIL-12突變1 p40]]> <![CDATA[<400> 77]]> Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr 1 5 10 15 Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu 20 25 30 Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly 35 40 45 Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly 50 55 60 Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu 65 70 75 80 Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys 85 90 95 Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys 100 105 110 Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr 115 120 125 Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln 130 135 140 Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly 145 150 155 160 Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala 165 170 175 Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala 180 185 190 Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg 195 200 205 Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu 210 215 220 Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp 225 230 235 240 Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln 245 250 255 Gly Ala Ser Lys Arg Glu Ala Lys Asp Arg Val Phe Thr Asp Lys Thr 260 265 270 Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala 275 280 285 Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro 290 295 300 Cys Ser 305 <![CDATA[<210> 78]]> <![CDATA[<211> 518]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類scIL-12突變2]]> <![CDATA[<400> 78]]> Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr 1 5 10 15 Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu 20 25 30 Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly 35 40 45 Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly 50 55 60 Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu 65 70 75 80 Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys 85 90 95 Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys 100 105 110 Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr 115 120 125 Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln 130 135 140 Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly 145 150 155 160 Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala 165 170 175 Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala 180 185 190 Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg 195 200 205 Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu 210 215 220 Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp 225 230 235 240 Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln 245 250 255 Gly Ala Ser Ala Arg Glu Ala Ala Asp Arg Val Phe Thr Asp Lys Thr 260 265 270 Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala 275 280 285 Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro 290 295 300 Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 305 310 315 320 Ser Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys 325 330 335 Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln 340 345 350 Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile 355 360 365 Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys 370 375 380 Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu 385 390 395 400 Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser 405 410 415 Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met 420 425 430 Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro 435 440 445 Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu 450 455 460 Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser 465 470 475 480 Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile 485 490 495 Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Met 500 505 510 Ser Tyr Leu Asn Ala Ser 515 <![CDATA[<210> 79]]> <![CDATA[<211> 306]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類scIL-12突變2 p40]]> <![CDATA[<400> 79]]> Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr 1 5 10 15 Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu 20 25 30 Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly 35 40 45 Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly 50 55 60 Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu 65 70 75 80 Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys 85 90 95 Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys 100 105 110 Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr 115 120 125 Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln 130 135 140 Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly 145 150 155 160 Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala 165 170 175 Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala 180 185 190 Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg 195 200 205 Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu 210 215 220 Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp 225 230 235 240 Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln 245 250 255 Gly Ala Ser Ala Arg Glu Ala Ala Asp Arg Val Phe Thr Asp Lys Thr 260 265 270 Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala 275 280 285 Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro 290 295 300 Cys Ser 305 <![CDATA[<210> 80]]> <![CDATA[<211> 224]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗人類CD20 HC]]> <![CDATA[<400> 80]]> Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly 100 105 110 Ala Gly Thr Thr Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 <![CDATA[<210> 81]]> <![CDATA[<211> 361]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> (抗人類FAP VH)2]]> <![CDATA[<400> 81]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr 20 25 30 Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile 35 40 45 Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly 115 120 125 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val 130 135 140 Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser 145 150 155 160 Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr Thr Ile His Trp Val 165 170 175 Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile Gly Gly Ile Asn Pro 180 185 190 Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe Lys Gly Arg Val Thr 195 200 205 Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr Met Glu Leu Ser Ser 210 215 220 Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Arg Arg Ile 225 230 235 240 Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp Tyr Trp Gly Gln Gly 245 250 255 Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 260 265 270 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 275 280 285 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 290 295 300 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 305 310 315 320 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 325 330 335 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 340 345 350 Ser Asn Thr Lys Val Asp Lys Lys Val 355 360 <![CDATA[<210> 82]]> <![CDATA[<211> 209]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類IgG1 Fc DANG]]> <![CDATA[<400> 82]]> Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 1 5 10 15 Arg Thr Pro Glu Val Thr Cys Val Val Val Ala Val Ser His Glu Asp 20 25 30 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 35 40 45 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Val 50 55 60 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 65 70 75 80 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 85 90 95 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 100 105 110 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 115 120 125 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 130 135 140 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 145 150 155 160 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 165 170 175 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 180 185 190 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 195 200 205 Lys <![CDATA[<210> 83]]> <![CDATA[<211> 214]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗小鼠FAP HC]]> <![CDATA[<400> 83]]> Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 1 5 10 15 Ser Val Asn Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Asn 20 25 30 Gly Ile Asn Trp Leu Lys Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Glu Ile Tyr Pro Arg Ser Thr Asn Thr Leu Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Arg Ser Ser Asn Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Thr Leu Thr Ala Pro Phe Ala Phe Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ala Ala Lys Thr Thr Ala Pro Ser Val Tyr Pro Leu 115 120 125 Ala Pro Val Cys Gly Asp Thr Thr Gly Ser Ser Val Thr Leu Gly Cys 130 135 140 Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu Thr Trp Asn Ser 145 150 155 160 Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175 Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr Ser Ser Thr Trp 180 185 190 Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr 195 200 205 Lys Val Asp Lys Lys Ile 210 <![CDATA[<210> 84]]> <![CDATA[<211> 243]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗小鼠FAP scFv]]> <![CDATA[<400> 84]]> Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 1 5 10 15 Ser Val Asn Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Asn 20 25 30 Gly Ile Asn Trp Leu Lys Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Glu Ile Tyr Pro Arg Ser Thr Asn Thr Leu Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Arg Ser Ser Asn Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Thr Leu Thr Ala Pro Phe Ala Phe Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 115 120 125 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Ile Val Leu Thr Gln Ser 130 135 140 Pro Ala Ile Met Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys 145 150 155 160 Ser Ala Ser Ser Gly Val Asn Phe Met His Trp Tyr Gln Gln Lys Ser 165 170 175 Gly Thr Ser Pro Lys Arg Trp Ile Phe Asp Thr Ser Lys Leu Ala Ser 180 185 190 Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser 195 200 205 Leu Thr Ile Ser Ser Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys 210 215 220 Gln Gln Trp Ser Phe Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu 225 230 235 240 Glu Ile Lys <![CDATA[<210> 85]]> <![CDATA[<211> 521]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 小鼠scIL-12]]> <![CDATA[<400> 85]]> Met Trp Glu Leu Glu Lys Asp Val Tyr Val Val Glu Val Asp Trp Thr 1 5 10 15 Pro Asp Ala Pro Gly Glu Thr Val Asn Leu Thr Cys Asp Thr Pro Glu 20 25 30 Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln Arg His Gly Val Ile Gly 35 40 45 Ser Gly Lys Thr Leu Thr Ile Thr Val Lys Glu Phe Leu Asp Ala Gly 50 55 60 Gln Tyr Thr Cys His Lys Gly Gly Glu Thr Leu Ser His Ser His Leu 65 70 75 80 Leu Leu His Lys Lys Glu Asn Gly Ile Trp Ser Thr Glu Ile Leu Lys 85 90 95 Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys Glu Ala Pro Asn Tyr Ser 100 105 110 Gly Arg Phe Thr Cys Ser Trp Leu Val Gln Arg Asn Met Asp Leu Lys 115 120 125 Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro Asp Ser Arg Ala Val Thr 130 135 140 Cys Gly Met Ala Ser Leu Ser Ala Glu Lys Val Thr Leu Asp Gln Arg 145 150 155 160 Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln Glu Asp Val Thr Cys Pro 165 170 175 Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu Ala Leu Glu Ala Arg Gln 180 185 190 Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser Phe Phe Ile Arg Asp Ile 195 200 205 Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Met Lys Pro Leu Lys Asn 210 215 220 Ser Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Ser Trp Ser Thr Pro 225 230 235 240 His Ser Tyr Phe Ser Leu Lys Phe Phe Val Arg Ile Gln Arg Lys Lys 245 250 255 Glu Lys Met Lys Glu Thr Glu Glu Gly Cys Asn Gln Lys Gly Ala Phe 260 265 270 Leu Val Glu Lys Thr Ser Thr Glu Val Gln Cys Lys Gly Gly Asn Val 275 280 285 Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn Ser Ser Cys Ser Lys Trp 290 295 300 Ala Cys Val Pro Cys Arg Val Arg Ser Gly Gly Gly Gly Ser Gly Gly 305 310 315 320 Gly Gly Ser Gly Gly Gly Gly Ser Arg Val Ile Pro Val Ser Gly Pro 325 330 335 Ala Arg Cys Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp 340 345 350 Met Val Lys Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala 355 360 365 Glu Asp Ile Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu 370 375 380 Lys Thr Cys Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala 385 390 395 400 Thr Arg Glu Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln 405 410 415 Lys Thr Ser Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp 420 425 430 Leu Lys Met Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln 435 440 445 Asn His Asn His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala 450 455 460 Ile Asp Glu Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg 465 470 475 480 Gln Lys Pro Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys 485 490 495 Leu Cys Ile Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn 500 505 510 Arg Val Met Gly Tyr Leu Ser Ser Ala 515 520 <![CDATA[<210> 86]]> <![CDATA[<211> 313]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 小鼠scIL-12 p40]]> <![CDATA[<400> 86]]> Met Trp Glu Leu Glu Lys Asp Val Tyr Val Val Glu Val Asp Trp Thr 1 5 10 15 Pro Asp Ala Pro Gly Glu Thr Val Asn Leu Thr Cys Asp Thr Pro Glu 20 25 30 Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln Arg His Gly Val Ile Gly 35 40 45 Ser Gly Lys Thr Leu Thr Ile Thr Val Lys Glu Phe Leu Asp Ala Gly 50 55 60 Gln Tyr Thr Cys His Lys Gly Gly Glu Thr Leu Ser His Ser His Leu 65 70 75 80 Leu Leu His Lys Lys Glu Asn Gly Ile Trp Ser Thr Glu Ile Leu Lys 85 90 95 Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys Glu Ala Pro Asn Tyr Ser 100 105 110 Gly Arg Phe Thr Cys Ser Trp Leu Val Gln Arg Asn Met Asp Leu Lys 115 120 125 Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro Asp Ser Arg Ala Val Thr 130 135 140 Cys Gly Met Ala Ser Leu Ser Ala Glu Lys Val Thr Leu Asp Gln Arg 145 150 155 160 Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln Glu Asp Val Thr Cys Pro 165 170 175 Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu Ala Leu Glu Ala Arg Gln 180 185 190 Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser Phe Phe Ile Arg Asp Ile 195 200 205 Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Met Lys Pro Leu Lys Asn 210 215 220 Ser Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Ser Trp Ser Thr Pro 225 230 235 240 His Ser Tyr Phe Ser Leu Lys Phe Phe Val Arg Ile Gln Arg Lys Lys 245 250 255 Glu Lys Met Lys Glu Thr Glu Glu Gly Cys Asn Gln Lys Gly Ala Phe 260 265 270 Leu Val Glu Lys Thr Ser Thr Glu Val Gln Cys Lys Gly Gly Asn Val 275 280 285 Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn Ser Ser Cys Ser Lys Trp 290 295 300 Ala Cys Val Pro Cys Arg Val Arg Ser 305 310 <![CDATA[<210> 87]]> <![CDATA[<211> 193]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 小鼠scIL-12 p35]]> <![CDATA[<400> 87]]> Arg Val Ile Pro Val Ser Gly Pro Ala Arg Cys Leu Ser Gln Ser Arg 1 5 10 15 Asn Leu Leu Lys Thr Thr Asp Asp Met Val Lys Thr Ala Arg Glu Lys 20 25 30 Leu Lys His Tyr Ser Cys Thr Ala Glu Asp Ile Asp His Glu Asp Ile 35 40 45 Thr Arg Asp Gln Thr Ser Thr Leu Lys Thr Cys Leu Pro Leu Glu Leu 50 55 60 His Lys Asn Glu Ser Cys Leu Ala Thr Arg Glu Thr Ser Ser Thr Thr 65 70 75 80 Arg Gly Ser Cys Leu Pro Pro Gln Lys Thr Ser Leu Met Met Thr Leu 85 90 95 Cys Leu Gly Ser Ile Tyr Glu Asp Leu Lys Met Tyr Gln Thr Glu Phe 100 105 110 Gln Ala Ile Asn Ala Ala Leu Gln Asn His Asn His Gln Gln Ile Ile 115 120 125 Leu Asp Lys Gly Met Leu Val Ala Ile Asp Glu Leu Met Gln Ser Leu 130 135 140 Asn His Asn Gly Glu Thr Leu Arg Gln Lys Pro Pro Val Gly Glu Ala 145 150 155 160 Asp Pro Tyr Arg Val Lys Met Lys Leu Cys Ile Leu Leu His Ala Phe 165 170 175 Ser Thr Arg Val Val Thr Ile Asn Arg Val Met Gly Tyr Leu Ser Ser 180 185 190 Ala <![CDATA[<210> 88]]> <![CDATA[<211> 521]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 小鼠scIL-12突變1]]> <![CDATA[<400> 88]]> Met Trp Glu Leu Glu Lys Asp Val Tyr Val Val Glu Val Asp Trp Thr 1 5 10 15 Pro Asp Ala Pro Gly Glu Thr Val Asn Leu Thr Cys Asp Thr Pro Glu 20 25 30 Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln Arg His Gly Val Ile Gly 35 40 45 Ser Gly Lys Thr Leu Thr Ile Thr Val Lys Glu Phe Leu Asp Ala Gly 50 55 60 Gln Tyr Thr Cys His Lys Gly Gly Glu Thr Leu Ser His Ser His Leu 65 70 75 80 Leu Leu His Lys Lys Glu Asn Gly Ile Trp Ser Thr Glu Ile Leu Lys 85 90 95 Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys Glu Ala Pro Asn Tyr Ser 100 105 110 Gly Arg Phe Thr Cys Ser Trp Leu Val Gln Arg Asn Met Asp Leu Lys 115 120 125 Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro Asp Ser Arg Ala Val Thr 130 135 140 Cys Gly Met Ala Ser Leu Ser Ala Glu Lys Val Thr Leu Asp Gln Arg 145 150 155 160 Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln Glu Asp Val Thr Cys Pro 165 170 175 Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu Ala Leu Glu Ala Arg Gln 180 185 190 Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser Phe Phe Ile Arg Asp Ile 195 200 205 Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Met Lys Pro Leu Lys Asn 210 215 220 Ser Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Ser Trp Ser Thr Pro 225 230 235 240 His Ser Tyr Phe Ser Leu Lys Phe Phe Val Arg Ile Gln Arg Ala Lys 245 250 255 Glu Lys Met Ala Glu Thr Glu Glu Gly Cys Asn Gln Lys Gly Ala Phe 260 265 270 Leu Val Glu Lys Thr Ser Thr Glu Val Gln Cys Lys Gly Gly Asn Val 275 280 285 Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn Ser Ser Cys Ser Lys Trp 290 295 300 Ala Cys Val Pro Cys Arg Val Arg Ser Gly Gly Gly Gly Ser Gly Gly 305 310 315 320 Gly Gly Ser Gly Gly Gly Gly Ser Arg Val Ile Pro Val Ser Gly Pro 325 330 335 Ala Arg Cys Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp 340 345 350 Met Val Lys Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala 355 360 365 Glu Asp Ile Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu 370 375 380 Lys Thr Cys Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala 385 390 395 400 Thr Arg Glu Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln 405 410 415 Lys Thr Ser Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp 420 425 430 Leu Lys Met Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln 435 440 445 Asn His Asn His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala 450 455 460 Ile Asp Glu Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg 465 470 475 480 Gln Lys Pro Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys 485 490 495 Leu Cys Ile Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn 500 505 510 Arg Val Met Gly Tyr Leu Ser Ser Ala 515 520 <![CDATA[<210> 89]]> <![CDATA[<211> 313]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 小鼠scIL-12突變1 p40]]> <![CDATA[<400> 89]]> Met Trp Glu Leu Glu Lys Asp Val Tyr Val Val Glu Val Asp Trp Thr 1 5 10 15 Pro Asp Ala Pro Gly Glu Thr Val Asn Leu Thr Cys Asp Thr Pro Glu 20 25 30 Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln Arg His Gly Val Ile Gly 35 40 45 Ser Gly Lys Thr Leu Thr Ile Thr Val Lys Glu Phe Leu Asp Ala Gly 50 55 60 Gln Tyr Thr Cys His Lys Gly Gly Glu Thr Leu Ser His Ser His Leu 65 70 75 80 Leu Leu His Lys Lys Glu Asn Gly Ile Trp Ser Thr Glu Ile Leu Lys 85 90 95 Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys Glu Ala Pro Asn Tyr Ser 100 105 110 Gly Arg Phe Thr Cys Ser Trp Leu Val Gln Arg Asn Met Asp Leu Lys 115 120 125 Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro Asp Ser Arg Ala Val Thr 130 135 140 Cys Gly Met Ala Ser Leu Ser Ala Glu Lys Val Thr Leu Asp Gln Arg 145 150 155 160 Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln Glu Asp Val Thr Cys Pro 165 170 175 Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu Ala Leu Glu Ala Arg Gln 180 185 190 Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser Phe Phe Ile Arg Asp Ile 195 200 205 Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Met Lys Pro Leu Lys Asn 210 215 220 Ser Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Ser Trp Ser Thr Pro 225 230 235 240 His Ser Tyr Phe Ser Leu Lys Phe Phe Val Arg Ile Gln Arg Ala Lys 245 250 255 Glu Lys Met Ala Glu Thr Glu Glu Gly Cys Asn Gln Lys Gly Ala Phe 260 265 270 Leu Val Glu Lys Thr Ser Thr Glu Val Gln Cys Lys Gly Gly Asn Val 275 280 285 Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn Ser Ser Cys Ser Lys Trp 290 295 300 Ala Cys Val Pro Cys Arg Val Arg Ser 305 310 <![CDATA[<210> 90]]> <![CDATA[<211> 521]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 小鼠scIL-12突變2]]> <![CDATA[<400> 90]]> Met Trp Glu Leu Glu Lys Asp Val Tyr Val Val Glu Val Asp Trp Thr 1 5 10 15 Pro Asp Ala Pro Gly Glu Thr Val Asn Leu Thr Cys Asp Thr Pro Glu 20 25 30 Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln Arg His Gly Val Ile Gly 35 40 45 Ser Gly Lys Thr Leu Thr Ile Thr Val Lys Glu Phe Leu Asp Ala Gly 50 55 60 Gln Tyr Thr Cys His Lys Gly Gly Glu Thr Leu Ser His Ser His Leu 65 70 75 80 Leu Leu His Lys Lys Glu Asn Gly Ile Trp Ser Thr Glu Ile Leu Lys 85 90 95 Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys Glu Ala Pro Asn Tyr Ser 100 105 110 Gly Arg Phe Thr Cys Ser Trp Leu Val Gln Arg Asn Met Asp Leu Lys 115 120 125 Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro Asp Ser Arg Ala Val Thr 130 135 140 Cys Gly Met Ala Ser Leu Ser Ala Glu Lys Val Thr Leu Asp Gln Arg 145 150 155 160 Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln Glu Asp Val Thr Cys Pro 165 170 175 Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu Ala Leu Glu Ala Arg Gln 180 185 190 Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser Phe Phe Ile Arg Asp Ile 195 200 205 Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Met Lys Pro Leu Lys Asn 210 215 220 Ser Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Ser Trp Ser Thr Pro 225 230 235 240 His Ser Tyr Phe Ser Leu Lys Phe Phe Val Arg Ile Gln Ala Ala Ala 245 250 255 Glu Lys Met Ala Glu Thr Glu Glu Gly Cys Asn Gln Lys Gly Ala Phe 260 265 270 Leu Val Glu Lys Thr Ser Thr Glu Val Gln Cys Lys Gly Gly Asn Val 275 280 285 Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn Ser Ser Cys Ser Lys Trp 290 295 300 Ala Cys Val Pro Cys Arg Val Arg Ser Gly Gly Gly Gly Ser Gly Gly 305 310 315 320 Gly Gly Ser Gly Gly Gly Gly Ser Arg Val Ile Pro Val Ser Gly Pro 325 330 335 Ala Arg Cys Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp 340 345 350 Met Val Lys Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala 355 360 365 Glu Asp Ile Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu 370 375 380 Lys Thr Cys Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala 385 390 395 400 Thr Arg Glu Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln 405 410 415 Lys Thr Ser Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp 420 425 430 Leu Lys Met Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln 435 440 445 Asn His Asn His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala 450 455 460 Ile Asp Glu Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg 465 470 475 480 Gln Lys Pro Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys 485 490 495 Leu Cys Ile Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn 500 505 510 Arg Val Met Gly Tyr Leu Ser Ser Ala 515 520 <![CDATA[<210> 91]]> <![CDATA[<211> 313]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 小鼠scIL-12突變2 p40]]> <![CDATA[<400> 91]]> Met Trp Glu Leu Glu Lys Asp Val Tyr Val Val Glu Val Asp Trp Thr 1 5 10 15 Pro Asp Ala Pro Gly Glu Thr Val Asn Leu Thr Cys Asp Thr Pro Glu 20 25 30 Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln Arg His Gly Val Ile Gly 35 40 45 Ser Gly Lys Thr Leu Thr Ile Thr Val Lys Glu Phe Leu Asp Ala Gly 50 55 60 Gln Tyr Thr Cys His Lys Gly Gly Glu Thr Leu Ser His Ser His Leu 65 70 75 80 Leu Leu His Lys Lys Glu Asn Gly Ile Trp Ser Thr Glu Ile Leu Lys 85 90 95 Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys Glu Ala Pro Asn Tyr Ser 100 105 110 Gly Arg Phe Thr Cys Ser Trp Leu Val Gln Arg Asn Met Asp Leu Lys 115 120 125 Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro Asp Ser Arg Ala Val Thr 130 135 140 Cys Gly Met Ala Ser Leu Ser Ala Glu Lys Val Thr Leu Asp Gln Arg 145 150 155 160 Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln Glu Asp Val Thr Cys Pro 165 170 175 Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu Ala Leu Glu Ala Arg Gln 180 185 190 Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser Phe Phe Ile Arg Asp Ile 195 200 205 Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Met Lys Pro Leu Lys Asn 210 215 220 Ser Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Ser Trp Ser Thr Pro 225 230 235 240 His Ser Tyr Phe Ser Leu Lys Phe Phe Val Arg Ile Gln Ala Ala Ala 245 250 255 Glu Lys Met Ala Glu Thr Glu Glu Gly Cys Asn Gln Lys Gly Ala Phe 260 265 270 Leu Val Glu Lys Thr Ser Thr Glu Val Gln Cys Lys Gly Gly Asn Val 275 280 285 Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn Ser Ser Cys Ser Lys Trp 290 295 300 Ala Cys Val Pro Cys Arg Val Arg Ser 305 310 <![CDATA[<210> 92]]> <![CDATA[<211> 218]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗小鼠CD20 HC]]> <![CDATA[<400> 92]]> Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg Pro Gly Thr 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Trp Met His Trp Ile Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Val Ile Asp Pro Ser Asp Asn Tyr Thr Lys Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Glu Gly Tyr Tyr Gly Ser Ser Pro Trp Phe Ala Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Lys Thr Thr Ala Pro Ser 115 120 125 Val Tyr Pro Leu Ala Pro Val Cys Gly Asp Thr Thr Gly Ser Ser Val 130 135 140 Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu 145 150 155 160 Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr 180 185 190 Ser Ser Thr Trp Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro 195 200 205 Ala Ser Ser Thr Lys Val Asp Lys Lys Ile 210 215 <![CDATA[<210> 93]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 連接子1]]> <![CDATA[<400> 93]]> Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1 5 10 <![CDATA[<210> 94]]> <![CDATA[<211> 15]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 連接子2]]> <![CDATA[<400> 94]]> Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1 5 10 15 <![CDATA[<210> 95]]> <![CDATA[<211> 20]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 連接子3]]> <![CDATA[<400> 95]]> Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 1 5 10 15 Gly Gly Gly Ser 20 <![CDATA[<210> 96]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗人類FAP HCDR1]]> <![CDATA[<400> 96]]> Glu Tyr Thr Ile His 1 5 <![CDATA[<210> 97]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗人類FAP HCDR2]]> <![CDATA[<400> 97]]> Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe Lys 1 5 10 15 Gly <![CDATA[<210> 98]]> <![CDATA[<211> 15]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗人類FAP HCDR3]]> <![CDATA[<400> 98]]> Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp Tyr 1 5 10 15 <![CDATA[<210> 99]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗人類FAP LCDR1]]> <![CDATA[<400> 99]]> Lys Ser Ser Gln Ser Leu Leu Tyr Ser Arg Asn Gln Lys Asn Tyr Leu 1 5 10 15 Ala <![CDATA[<210> 100]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗人類FAP LCDR2]]> <![CDATA[<400> 100]]> Trp Ala Ser Thr Arg Glu Ser 1 5 <![CDATA[<210> 101]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗人類FAP LCDR3]]> <![CDATA[<400> 101]]> Gln Gln Tyr Phe Ser Tyr Pro Leu Thr 1 5 <![CDATA[<210> 102]]> <![CDATA[<211> 124]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗人類FAP HCVR]]> <![CDATA[<400> 102]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr 20 25 30 Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile 35 40 45 Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <![CDATA[<210> 103]]> <![CDATA[<211> 113]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗人類FAP LCVR]]> <![CDATA[<400> 103]]> Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser 20 25 30 Arg Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Phe Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Phe Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 85 90 95 Tyr Phe Ser Tyr Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile 100 105 110 Lys <![CDATA[<210> 104]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗小鼠FAP HCDR1]]> <![CDATA[<400> 104]]> Asn Asn Gly Ile Asn 1 5 <![CDATA[<210> 105]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗小鼠FAP HCDR2]]> <![CDATA[<400> 105]]> Glu Ile Tyr Pro Arg Ser Thr Asn Thr Leu Tyr Asn Glu Lys Phe Lys 1 5 10 15 Gly <![CDATA[<210> 106]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗小鼠FAP HCDR3]]> <![CDATA[<400> 106]]> Thr Leu Thr Ala Pro Phe Ala Phe 1 5 <![CDATA[<210> 107]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗小鼠FAP LCDR1]]> <![CDATA[<400> 107]]> Ser Ala Ser Ser Gly Val Asn Phe Met His 1 5 10 <![CDATA[<210> 108]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗小鼠FAP LCDR2]]> <![CDATA[<400> 108]]> Asp Thr Ser Lys Leu Ala Ser 1 5 <![CDATA[<210> 109]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗小鼠FAP LCDR3]]> <![CDATA[<400> 109]]> Gln Gln Trp Ser Phe Asn Pro Pro Thr 1 5 <![CDATA[<210> 110]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗小鼠FAP HCVR]]> <![CDATA[<400> 110]]> Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 1 5 10 15 Ser Val Asn Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Asn 20 25 30 Gly Ile Asn Trp Leu Lys Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Glu Ile Tyr Pro Arg Ser Thr Asn Thr Leu Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Arg Ser Ser Asn Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Thr Leu Thr Ala Pro Phe Ala Phe Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ala 115 <![CDATA[<210> 111]]> <![CDATA[<211> 107]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗小鼠FAP LCVR]]> <![CDATA[<400> 111]]> Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Gly Val Asn Phe Met 20 25 30 His Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Phe 35 40 45 Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Phe Asn Pro Pro Thr 85 90 95 Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg 100 105 <![CDATA[<210> 112]]> <![CDATA[<211> 23]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類IgG1鉸鏈]]> <![CDATA[<400> 112]]> Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala 1 5 10 15 Pro Glu Leu Leu Gly Gly Pro 20 <![CDATA[<210> 113]]> <![CDATA[<211> 14]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類IgG1鉸鏈-核心1]]> <![CDATA[<400> 113]]> Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 1 5 10 <![CDATA[<210> 114]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類IgG1鉸鏈-核心2]]> <![CDATA[<400> 114]]> Asp Lys Thr His Thr Cys Pro Pro Cys 1 5 <![CDATA[<210> 115]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類IgG1鉸鏈-核心3]]> <![CDATA[<400> 115]]> Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro 1 5 10 <![CDATA[<210> 116]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類IgG1鉸鏈-核心4]]> <![CDATA[<400> 116]]> Cys Pro Pro Cys Pro 1 5 <![CDATA[<210> 117]]> <![CDATA[<211> 4]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類IgG1鉸鏈-核心5]]> <![CDATA[<400> 117]]> Cys Pro Pro Cys 1 <![CDATA[<210> 118]]> <![CDATA[<211> 28]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類IgG1鉸鏈連接子]]> <![CDATA[<400> 118]]> Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys 1 5 10 15 Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 20 25 <![CDATA[<210> 119]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 小鼠IgG2a鉸鏈]]> <![CDATA[<400> 119]]> Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro 1 5 10 15 <![CDATA[<210> 120]]> <![CDATA[<211> 26]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 小鼠IgG2a鉸鏈連接子]]> <![CDATA[<400> 120]]> Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Arg Gly Pro Thr 1 5 10 15 Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro 20 25 <![CDATA[<210> 121]]> <![CDATA[<211> 328]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類IL-12 p40野生型_AAD56386]]> <![CDATA[<400> 121]]> Met Cys His Gln Gln Leu Val Ile Ser Trp Phe Ser Leu Val Phe Leu 1 5 10 15 Ala Ser Pro Leu Val Ala Ile Trp Glu Leu Lys Lys Asp Val Tyr Val 20 25 30 Val Glu Leu Asp Trp Tyr Pro Asp Ala Pro Gly Glu Met Val Val Leu 35 40 45 Thr Cys Asp Thr Pro Glu Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln 50 55 60 Ser Ser Glu Val Leu Gly Ser Gly Lys Thr Leu Thr Ile Gln Val Lys 65 70 75 80 Glu Phe Gly Asp Ala Gly Gln Tyr Thr Cys His Lys Gly Gly Glu Val 85 90 95 Leu Ser His Ser Leu Leu Leu Leu His Lys Lys Glu Asp Gly Ile Trp 100 105 110 Ser Thr Asp Ile Leu Lys Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe 115 120 125 Leu Arg Cys Glu Ala Lys Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp 130 135 140 Leu Thr Thr Ile Ser Thr Asp Leu Thr Phe Ser Val Lys Ser Ser Arg 145 150 155 160 Gly Ser Ser Asp Pro Gln Gly Val Thr Cys Gly Ala Ala Thr Leu Ser 165 170 175 Ala Glu Arg Val Arg Gly Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu 180 185 190 Cys Gln Glu Asp Ser Ala Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile 195 200 205 Glu Val Met Val Asp Ala Val His Lys Leu Lys Tyr Glu Asn Tyr Thr 210 215 220 Ser Ser Phe Phe Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn 225 230 235 240 Leu Gln Leu Lys Pro Leu Lys Asn Ser Arg Gln Val Glu Val Ser Trp 245 250 255 Glu Tyr Pro Asp Thr Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Thr 260 265 270 Phe Cys Val Gln Val Gln Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg 275 280 285 Val Phe Thr Asp Lys Thr Ser Ala Thr Val Ile Cys Arg Lys Asn Ala 290 295 300 Ser Ile Ser Val Arg Ala Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser 305 310 315 320 Glu Trp Ala Ser Val Pro Cys Ser 325 <![CDATA[<210> 122]]> <![CDATA[<211> 219]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類IL-12 p35野生型_AAK84425]]> <![CDATA[<400> 122]]> Met Cys Pro Ala Arg Ser Leu Leu Leu Val Ala Thr Leu Val Leu Leu 1 5 10 15 Asp His Leu Ser Leu Ala Arg Asn Leu Pro Val Ala Thr Pro Asp Pro 20 25 30 Gly Met Phe Pro Cys Leu His His Ser Gln Asn Leu Leu Arg Ala Val 35 40 45 Ser Asn Met Leu Gln Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys 50 55 60 Thr Ser Glu Glu Ile Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser 65 70 75 80 Thr Val Glu Ala Cys Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys 85 90 95 Leu Asn Ser Arg Glu Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala 100 105 110 Ser Arg Lys Thr Ser Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr 115 120 125 Glu Asp Leu Lys Met Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys 130 135 140 Leu Leu Met Asp Pro Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu 145 150 155 160 Ala Val Ile Asp Glu Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr 165 170 175 Val Pro Gln Lys Ser Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys 180 185 190 Ile Lys Leu Cys Ile Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr 195 200 205 Ile Asp Arg Val Met Ser Tyr Leu Asn Ala Ser 210 215 <![CDATA[<210> 123]]> <![CDATA[<211> 335]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 小鼠IL-12 p40野生型_AAA39296]]> <![CDATA[<400> 123]]> Met Cys Pro Gln Lys Leu Thr Ile Ser Trp Phe Ala Ile Val Leu Leu 1 5 10 15 Val Ser Pro Leu Met Ala Met Trp Glu Leu Glu Lys Asp Val Tyr Val 20 25 30 Val Glu Val Asp Trp Thr Pro Asp Ala Pro Gly Glu Thr Val Asn Leu 35 40 45 Thr Cys Asp Thr Pro Glu Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln 50 55 60 Arg His Gly Val Ile Gly Ser Gly Lys Thr Leu Thr Ile Thr Val Lys 65 70 75 80 Glu Phe Leu Asp Ala Gly Gln Tyr Thr Cys His Lys Gly Gly Glu Thr 85 90 95 Leu Ser His Ser His Leu Leu Leu His Lys Lys Glu Asn Gly Ile Trp 100 105 110 Ser Thr Glu Ile Leu Lys Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys 115 120 125 Glu Ala Pro Asn Tyr Ser Gly Arg Phe Thr Cys Ser Trp Leu Val Gln 130 135 140 Arg Asn Met Asp Leu Lys Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro 145 150 155 160 Asp Ser Arg Ala Val Thr Cys Gly Met Ala Ser Leu Ser Ala Glu Lys 165 170 175 Val Thr Leu Asp Gln Arg Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln 180 185 190 Glu Asp Val Thr Cys Pro Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu 195 200 205 Ala Leu Glu Ala Arg Gln Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser 210 215 220 Phe Phe Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln 225 230 235 240 Met Lys Pro Leu Lys Asn Ser Gln Val Glu Val Ser Trp Glu Tyr Pro 245 250 255 Asp Ser Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Lys Phe Phe Val 260 265 270 Arg Ile Gln Arg Lys Lys Glu Lys Met Lys Glu Thr Glu Glu Gly Cys 275 280 285 Asn Gln Lys Gly Ala Phe Leu Val Glu Lys Thr Ser Thr Glu Val Gln 290 295 300 Cys Lys Gly Gly Asn Val Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn 305 310 315 320 Ser Ser Cys Ser Lys Trp Ala Cys Val Pro Cys Arg Val Arg Ser 325 330 335 <![CDATA[<210> 124]]> <![CDATA[<211> 215]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 小鼠IL-12 p35野生型_AAK39292]]> <![CDATA[<400> 124]]> Met Cys Gln Ser Arg Tyr Leu Leu Phe Leu Ala Thr Leu Ala Leu Leu 1 5 10 15 Asn His Leu Ser Leu Ala Arg Val Ile Pro Val Ser Gly Pro Ala Arg 20 25 30 Cys Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp Met Val 35 40 45 Lys Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala Glu Asp 50 55 60 Ile Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu Lys Thr 65 70 75 80 Cys Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala Thr Arg 85 90 95 Glu Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln Lys Thr 100 105 110 Ser Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp Leu Lys 115 120 125 Met Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln Asn His 130 135 140 Asn His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala Ile Asp 145 150 155 160 Glu Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg Gln Lys 165 170 175 Pro Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys Leu Cys 180 185 190 Ile Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn Arg Val 195 200 205 Met Gly Tyr Leu Ser Ser Ala 210 215 <![CDATA[<210> 125]]> <![CDATA[<211> 252]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類IL-12 p40_X1]]> <![CDATA[<400> 125]]> Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr 1 5 10 15 Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu 20 25 30 Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly 35 40 45 Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly 50 55 60 Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu 65 70 75 80 Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys 85 90 95 Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys 100 105 110 Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr 115 120 125 Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln 130 135 140 Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly 145 150 155 160 Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala 165 170 175 Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala 180 185 190 Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg 195 200 205 Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu 210 215 220 Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp 225 230 235 240 Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys 245 250 <![CDATA[<210> 126]]> <![CDATA[<211> 42]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類IL-12 p40_X2]]> <![CDATA[<400> 126]]> Asp Arg Val Phe Thr Asp Lys Thr Ser Ala Thr Val Ile Cys Arg Lys 1 5 10 15 Asn Ala Ser Ile Ser Val Arg Ala Gln Asp Arg Tyr Tyr Ser Ser Ser 20 25 30 Trp Ser Glu Trp Ala Ser Val Pro Cys Ser 35 40 <![CDATA[<210> 127]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> NG-641 HCDR1]]> <![CDATA[<400> 127]]> Glu Tyr Thr Ile His 1 5 <![CDATA[<210> 128]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> NG-641 HCDR2]]> <![CDATA[<400> 128]]> Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe Lys 1 5 10 15 Gly <![CDATA[<210> 129]]> <![CDATA[<211> 15]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> NG-641 HCDR3]]> <![CDATA[<400> 129]]> Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp Tyr 1 5 10 15 <![CDATA[<210> 130]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> NG-641 LCDR1]]> <![CDATA[<400> 130]]> Lys Ser Ser Gln Ser Leu Leu Tyr Ser Arg Asn Gln Lys Asn Tyr Leu 1 5 10 15 Ala <![CDATA[<210> 131]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> NG-641 LCDR2]]> <![CDATA[<400> 131]]> Trp Ala Ser Thr Arg Glu Ser 1 5 <![CDATA[<210> 132]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> NG-641 LCDR3]]> <![CDATA[<400> 132]]> Gln Gln Tyr Phe Ser Tyr Pro Leu Thr 1 5 <![CDATA[<210> 133]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 28H1 HCDR1]]> <![CDATA[<400> 133]]> Ser His Ala Met Ser 1 5 <![CDATA[<210> 134]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 28H1 HCDR2]]> <![CDATA[<400> 134]]> Ala Ile Trp Ala Ser Gly Glu Gln Tyr Tyr Ala Asp Ser Val Lys Gly 1 5 10 15 <![CDATA[<210> 135]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 28H1 HCDR3]]> <![CDATA[<400> 135]]> Gly Trp Leu Gly Asn Phe Asp Tyr 1 5 <![CDATA[<210> 136]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 28H1 LCDR1]]> <![CDATA[<400> 136]]> Arg Ala Ser Gln Ser Val Ser Arg Ser Tyr Leu Ala 1 5 10 <![CDATA[<210> 137]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 28H1 LCDR2]]> <![CDATA[<400> 137]]> Gly Ala Ser Thr Arg Ala Thr 1 5 <![CDATA[<210> 138]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 28H1 LCDR3]]> <![CDATA[<400> 138]]> Gln Gln Gly Gln Val Ile Pro Pro Thr 1 5 <![CDATA[<210> 139]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 4B9 HCDR1]]> <![CDATA[<400> 139]]> Ser Tyr Ala Met Ser 1 5 <![CDATA[<210> 140]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 4B9 HCDR2]]> <![CDATA[<400> 140]]> Ala Ile Ile Gly Ser Gly Ala Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <![CDATA[<210> 141]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 4B9 HCDR3]]> <![CDATA[<400> 141]]> Gly Trp Phe Gly Gly Phe Asn Tyr 1 5 <![CDATA[<210> 142]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 4B9 LCDR1]]> <![CDATA[<400> 142]]> Arg Ala Ser Gln Ser Val Thr Ser Ser Tyr Leu Ala 1 5 10 <![CDATA[<210> 143]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 4B9 LCDR2]]> <![CDATA[<400> 143]]> Val Gly Ser Arg Arg Ala Thr 1 5 <![CDATA[<210> 144]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 4B9 LCDR3]]> <![CDATA[<400> 144]]> Gln Gln Gly Ile Met Leu Pro Pro Thr 1 5 <![CDATA[<210> 145]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> OMTX-705 HCDR1]]> <![CDATA[<400> 145]]> Glu Asn Ile Ile His 1 5 <![CDATA[<210> 146]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> OMTX-705 HCDR2]]> <![CDATA[<400> 146]]> Trp Phe His Pro Gly Ser Gly Ser Ile Lys Tyr Asn Glu Lys Phe Lys 1 5 10 15 Asp <![CDATA[<210> 147]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> OMTX-705 HCDR3]]> <![CDATA[<400> 147]]> His Gly Gly Thr Gly Arg Gly Ala Met Asp Tyr 1 5 10 <![CDATA[<210> 148]]> <![CDATA[<211> 15]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> OMTX-705 LCDR1]]> <![CDATA[<400> 148]]> Arg Ala Ser Lys Ser Val Ser Thr Ser Ala Tyr Ser Tyr Met His 1 5 10 15 <![CDATA[<210> 149]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> OMTX-705 LCDR2]]> <![CDATA[<400> 149]]> Leu Ala Ser Asn Leu Glu Ser 1 5 <![CDATA[<210> 150]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> OMTX-705 LCDR3]]> <![CDATA[<400> 150]]> Gln His Ser Arg Glu Leu Pro Tyr Thr 1 5 <![CDATA[<210> 151]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 3F2 HCDR1]]> <![CDATA[<400> 151]]> Ser Tyr Ala Met Ser 1 5 <![CDATA[<210> 152]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 3F2 HCDR2]]> <![CDATA[<400> 152]]> Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 <![CDATA[<210> 153]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 3F2 HCDR3]]> <![CDATA[<400> 153]]> Tyr Cys Ala Lys Gly Trp Phe Gly 1 5 <![CDATA[<210> 154]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 3F2 LCDR1]]> <![CDATA[<400> 154]]> Arg Ala Ser Gln Ser Val Thr Ser Ser Tyr Leu 1 5 10 <![CDATA[<210> 155]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 3F2 LCDR2]]> <![CDATA[<400> 155]]> Asn Val Gly Ser Arg Arg Ala 1 5 <![CDATA[<210> 156]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 3F2 LCDR3]]> <![CDATA[<400> 156]]> Cys Gln Gln Gly Ile Met Leu Pro Pro 1 5 <![CDATA[<210> 157]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 4G8 HCDR1]]> <![CDATA[<400> 157]]> Ser Tyr Ala Met Ser 1 5 <![CDATA[<210> 158]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 4G8 HCDR2]]> <![CDATA[<400> 158]]> Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 <![CDATA[<210> 159]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 4G8 HCDR3]]> <![CDATA[<400> 159]]> Tyr Cys Ala Lys Gly Trp Leu Gly 1 5 <![CDATA[<210> 160]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 4G8 LCDR1]]> <![CDATA[<400> 160]]> Arg Ala Ser Gln Ser Val Ser Arg Ser Tyr Leu 1 5 10 <![CDATA[<210> 161]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 4G8 LCDR2]]> <![CDATA[<400> 161]]> Ile Gly Ala Ser Thr Arg Ala 1 5 <![CDATA[<210> 162]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 4G8 LCDR3]]> <![CDATA[<400> 162]]> Cys Gln Gln Gly Gln Val Ile Pro Pro 1 5 <![CDATA[<210> 163]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 3D9 HCDR1]]> <![CDATA[<400> 163]]> Ser Tyr Ala Met Ser 1 5 <![CDATA[<210> 164]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 3D9 HCDR2]]> <![CDATA[<400> 164]]> Ala Ile Gly Val Ser Thr Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 <![CDATA[<210> 165]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 3D9 HCDR3]]> <![CDATA[<400> 165]]> Tyr Cys Ala Lys Gly Trp Leu Gly 1 5 <![CDATA[<210> 166]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 3D9 LCDR1]]> <![CDATA[<400> 166]]> Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu 1 5 10 <![CDATA[<210> 167]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 3D9 LCDR2]]> <![CDATA[<400> 167]]> Tyr Gly Ala Ser Ser Arg Ala 1 5 <![CDATA[<210> 168]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 3D9 LCDR3]]> <![CDATA[<400> 168]]> Cys Gln Gln Gly Gln Leu Ile Pro Pro 1 5 <![CDATA[<210> 169]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 4B3 HCDR1]]> <![CDATA[<400> 169]]> Ser Tyr Ala Met Ser 1 5 <![CDATA[<210> 170]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 4B3 HCDR2]]> <![CDATA[<400> 170]]> Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 <![CDATA[<210> 171]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 4B3 HCDR3]]> <![CDATA[<400> 171]]> Tyr Cys Ala Lys Gly Trp Leu Gly 1 5 <![CDATA[<210> 172]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 4B3 LCDR1]]> <![CDATA[<400> 172]]> Arg Ala Ser Gln Ser Val Ser Ser Asn Tyr Leu 1 5 10 <![CDATA[<210> 173]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 4B3 LCDR2]]> <![CDATA[<400> 173]]> Tyr Gly Ala Tyr Ile Arg Ala 1 5 <![CDATA[<210> 174]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 4B3 LCDR3]]> <![CDATA[<400> 174]]> Cys Gln Gln Gly Gln Val Ile Pro Pro 1 5 <![CDATA[<210> 175]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 19G1 HCDR1]]> <![CDATA[<400> 175]]> Ser Tyr Ala Met Ser 1 5 <![CDATA[<210> 176]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 19G1 HCDR2]]> <![CDATA[<400> 176]]> Ala Ile Ile Ser Ser Gly Gly Leu Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 <![CDATA[<210> 177]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 19G1 HCDR3]]> <![CDATA[<400> 177]]> Tyr Cys Ala Lys Gly Trp Phe Gly 1 5 <![CDATA[<210> 178]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 19G1 LCDR1]]> <![CDATA[<400> 178]]> Arg Ala Ser Gln Ser Val Thr Ser Ser Tyr Leu 1 5 10 <![CDATA[<210> 179]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 19G1 LCDR2]]> <![CDATA[<400> 179]]> Asn Val Gly Ser Arg Arg Ala 1 5 <![CDATA[<210> 180]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 19G1 LCDR3]]> <![CDATA[<400> 180]]> Cys Gln Gln Gly Ile Met Leu Pro Pro 1 5 <![CDATA[<210> 181]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 20G8 HCDR1]]> <![CDATA[<400> 181]]> Ser Tyr Ala Met Ser 1 5 <![CDATA[<210> 182]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 20G8 HCDR2]]> <![CDATA[<400> 182]]> Ala Ile Ile Gly Ser Gly Ser Arg Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 <![CDATA[<210> 183]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 20G8 HCDR3]]> <![CDATA[<400> 183]]> Tyr Cys Ala Lys Gly Trp Phe Gly 1 5 <![CDATA[<210> 184]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 20G8 LCDR1]]> <![CDATA[<400> 184]]> Arg Ala Ser Gln Ser Val Thr Ser Ser Tyr Leu 1 5 10 <![CDATA[<210> 185]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 20G8 LCDR2]]> <![CDATA[<400> 185]]> Asn Val Gly Ser Arg Arg Ala 1 5 <![CDATA[<210> 186]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 20G8 LCDR3]]> <![CDATA[<400> 186]]> Cys Gln Gln Gly Ile Met Leu Pro Pro 1 5 <![CDATA[<210> 187]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 5B8 HCDR1]]> <![CDATA[<400> 187]]> Ser Tyr Ala Met Ser 1 5 <![CDATA[<210> 188]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 5B8 HCDR2]]> <![CDATA[<400> 188]]> Ala Ile Trp Gly Gly Gly Arg Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 <![CDATA[<210> 189]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 5B8 HCDR3]]> <![CDATA[<400> 189]]> Tyr Cys Ala Lys Gly Trp Phe Gly 1 5 <![CDATA[<210> 190]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 5B8 LCDR1]]> <![CDATA[<400> 190]]> Arg Ala Ser Gln Ser Val Thr Ser Ser Tyr Leu 1 5 10 <![CDATA[<210> 191]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 5B8 LCDR2]]> <![CDATA[<400> 191]]> Asn Val Gly Ser Arg Arg Ala 1 5 <![CDATA[<210> 192]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 5B8 LCDR3]]> <![CDATA[<400> 192]]> Cys Gln Gln Gly Ile Met Leu Pro Pro 1 5 <![CDATA[<210> 193]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 5F1 HCDR1]]> <![CDATA[<400> 193]]> Ser Tyr Ala Met Ser 1 5 <![CDATA[<210> 194]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 5F1 HCDR2]]> <![CDATA[<400> 194]]> Ala Ile Ile Ser Ser Gly Ala Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 <![CDATA[<210> 195]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 5F1 HCDR3]]> <![CDATA[<400> 195]]> Tyr Cys Ala Lys Gly Trp Phe Gly 1 5 <![CDATA[<210> 196]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 5F1 LCDR1]]> <![CDATA[<400> 196]]> Arg Ala Ser Gln Ser Val Thr Ser Ser Tyr Leu 1 5 10 <![CDATA[<210> 197]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 5F1 LCDR2]]> <![CDATA[<400> 197]]> Asn Val Gly Ser Arg Arg Ala 1 5 <![CDATA[<210> 198]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 5F1 LCDR3]]> <![CDATA[<400> 198]]> Cys Gln Gln Gly Ile Met Leu Pro Pro 1 5 <![CDATA[<210> 199]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 14B3 HCDR1]]> <![CDATA[<400> 199]]> Ser Tyr Ala Met Ser 1 5 <![CDATA[<210> 200]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 14B3 HCDR2]]> <![CDATA[<400> 200]]> Ala Ile Leu Ala Ser Gly Ala Ile Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 <![CDATA[<210> 201]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 14B3 HCDR3]]> <![CDATA[<400> 201]]> Tyr Cys Ala Lys Gly Trp Phe Gly 1 5 <![CDATA[<210> 202]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 14B3 LCDR1]]> <![CDATA[<400> 202]]> Arg Ala Ser Gln Ser Val Thr Ser Ser Tyr Leu 1 5 10 <![CDATA[<210> 203]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 14B3 LCDR2]]> <![CDATA[<400> 203]]> Asn Val Gly Ser Arg Arg Ala 1 5 <![CDATA[<210> 204]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 14B3 LCDR3]]> <![CDATA[<400> 204]]> Cys Gln Gln Gly Ile Met Leu Pro Pro 1 5 <![CDATA[<210> 205]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 16F1 HCDR1]]> <![CDATA[<400> 205]]> Ser Tyr Ala Met Ser 1 5 <![CDATA[<210> 206]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 16F1 HCDR2]]> <![CDATA[<400> 206]]> Gly Ile Ile Gly Ser Gly Gly Ile Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 <![CDATA[<210> 207]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 16F1 HCDR3]]> <![CDATA[<400> 207]]> Tyr Cys Ala Lys Gly Trp Phe Gly 1 5 <![CDATA[<210> 208]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 16F1 LCDR1]]> <![CDATA[<400> 208]]> Arg Ala Ser Gln Ser Val Thr Ser Ser Tyr Leu 1 5 10 <![CDATA[<210> 209]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 16F1 LCDR2]]> <![CDATA[<400> 209]]> Asn Val Gly Ser Arg Arg Ala 1 5 <![CDATA[<210> 210]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 16F1 LCDR3]]> <![CDATA[<400> 210]]> Cys Gln Gln Gly Ile Met Leu Pro Pro 1 5 <![CDATA[<210> 211]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 16F8 HCDR1]]> <![CDATA[<400> 211]]> Ser Tyr Ala Met Ser 1 5 <![CDATA[<210> 212]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 16F8 HCDR2]]> <![CDATA[<400> 212]]> Ala Ile Leu Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 <![CDATA[<210> 213]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 16F8 HCDR3]]> <![CDATA[<400> 213]]> Tyr Cys Ala Lys Gly Trp Phe Gly 1 5 <![CDATA[<210> 214]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 16F8 LCDR1]]> <![CDATA[<400> 214]]> Arg Ala Ser Gln Ser Val Thr Ser Ser Tyr Leu 1 5 10 <![CDATA[<210> 215]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 16F8 LCDR2]]> <![CDATA[<400> 215]]> Asn Val Gly Ser Arg Arg Ala 1 5 <![CDATA[<210> 216]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 16F8 LCDR3]]> <![CDATA[<400> 216]]> Cys Gln Gln Gly Ile Met Leu Pro Pro 1 5 <![CDATA[<210> 217]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> O3C9 HCDR1]]> <![CDATA[<400> 217]]> Ser Phe Ala Met Ser 1 5 <![CDATA[<210> 218]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> O3C9 HCDR2]]> <![CDATA[<400> 218]]> Ala Ile Ile Gly Ser Gly Ser Asn Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 <![CDATA[<210> 219]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> O3C9 HCDR3]]> <![CDATA[<400> 219]]> Tyr Cys Ala Lys Gly Trp Phe Gly 1 5 <![CDATA[<210> 220]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> O3C9 LCDR1]]> <![CDATA[<400> 220]]> Arg Ala Ser Gln Ser Val Thr Ser Ser Tyr Leu 1 5 10 <![CDATA[<210> 221]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> O3C9 LCDR2]]> <![CDATA[<400> 221]]> Asn Val Gly Ser Arg Arg Ala 1 5 <![CDATA[<210> 222]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> O3C9 LCDR3]]> <![CDATA[<400> 222]]> Cys Gln Gln Gly Ile Met Leu Pro Pro 1 5 <![CDATA[<210> 223]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 22A3 HCDR1]]> <![CDATA[<400> 223]]> Ser Tyr Ala Met Ser 1 5 <![CDATA[<210> 224]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 22A3 HCDR2]]> <![CDATA[<400> 224]]> Ala Ile Ile Gly Ser Gly Ser Ile Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 <![CDATA[<210> 225]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 22A3 HCDR3]]> <![CDATA[<400> 225]]> Tyr Cys Ala Lys Gly Trp Phe Gly 1 5 <![CDATA[<210> 226]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 22A3 LCDR1]]> <![CDATA[<400> 226]]> Arg Ala Ser Gln Ser Val Thr Ser Ser Tyr Leu 1 5 10 <![CDATA[<210> 227]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 22A3 LCDR2]]> <![CDATA[<400> 227]]> Asn Val Gly Ser Arg Arg Ala 1 5 <![CDATA[<210> 228]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 22A3 LCDR3]]> <![CDATA[<400> 228]]> Cys Gln Gln Gly Ile Met Leu Pro Pro 1 5 <![CDATA[<210> 229]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 29B11 HCDR1]]> <![CDATA[<400> 229]]> Ser Tyr Ala Met Ser 1 5 <![CDATA[<210> 230]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 29B11 HCDR2]]> <![CDATA[<400> 230]]> Ala Ile Ile Gly Ser Gly Gly Ile Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 <![CDATA[<210> 231]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 29B11 HCDR3]]> <![CDATA[<400> 231]]> Tyr Cys Ala Lys Gly Trp Phe Gly 1 5 <![CDATA[<210> 232]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 29B11 LCDR1]]> <![CDATA[<400> 232]]> Arg Ala Ser Gln Ser Val Thr Ser Ser Tyr Leu 1 5 10 <![CDATA[<210> 233]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 29B11 LCDR2]]> <![CDATA[<400> 233]]> Asn Val Gly Ser Arg Arg Ala 1 5 <![CDATA[<210> 234]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 29B11 LCDR3]]> <![CDATA[<400> 234]]> Cys Gln Gln Gly Ile Met Leu Pro Pro 1 5 <![CDATA[<210> 235]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> O2D7 HCDR1]]> <![CDATA[<400> 235]]> Ser Tyr Ala Met Ser 1 5 <![CDATA[<210> 236]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> O2D7 HCDR2]]> <![CDATA[<400> 236]]> Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 <![CDATA[<210> 237]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> O2D7 HCDR3]]> <![CDATA[<400> 237]]> Tyr Cys Ala Lys Gly Trp Phe Gly 1 5 <![CDATA[<210> 238]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> O2D7 LCDR1]]> <![CDATA[<400> 238]]> Arg Ala Ser Gln Ser Val Thr Ser Ser Tyr Leu 1 5 10 <![CDATA[<210> 239]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> O2D7 LCDR2]]> <![CDATA[<400> 239]]> Asn Val Gly Ser Arg Arg Ala 1 5 <![CDATA[<210> 240]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> O2D7 LCDR3]]> <![CDATA[<400> 240]]> Cys Gln Gln Ala Ile Met Leu Pro Pro 1 5 <![CDATA[<210> 241]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 23C10 HCDR1]]> <![CDATA[<400> 241]]> Ser Ser Ala Met Ser 1 5 <![CDATA[<210> 242]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 23C10 HCDR2]]> <![CDATA[<400> 242]]> Ala Ile Ser Thr Asn Gly Asn Tyr Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 <![CDATA[<210> 243]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 23C10 HCDR3]]> <![CDATA[<400> 243]]> Tyr Cys Ala Lys Gly Trp Leu Gly 1 5 <![CDATA[<210> 244]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 23C10 LCDR1]]> <![CDATA[<400> 244]]> Arg Ala Ser Gln Ser Val Ser Arg Ser Tyr Leu 1 5 10 <![CDATA[<210> 245]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 23C10 LCDR2]]> <![CDATA[<400> 245]]> Ile Gly Ala Ser Thr Arg Ala 1 5 <![CDATA[<210> 246]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 23C10 LCDR3]]> <![CDATA[<400> 246]]> Cys Gln Gln Gly Gln Val Ile Pro Pro 1 5 <![CDATA[<210> 247]]> <![CDATA[<211> 157]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> DARPin AMG-506/MP-0310]]> <![CDATA[<400> 247]]> Asp Leu Gly Lys Lys Leu Leu Glu Ala Ala Arg Ala Gly Gln Asp Asp 1 5 10 15 Glu Val Arg Glu Leu Leu Lys Ala Gly Ala Asp Val Asn Ala Lys Asp 20 25 30 Val Leu Gly Trp Thr Pro Leu His Leu Ala Ala Phe Glu Gly His Leu 35 40 45 Glu Ile Val Glu Val Leu Leu Lys Ala Gly Ala Asp Val Asn Ala Lys 50 55 60 Asp Lys Lys Gly Trp Thr Pro Leu Gln Leu Ala Ala Arg Thr Gly His 65 70 75 80 Leu Glu Ile Val Glu Val Leu Leu Lys Ala Gly Ala Asp Val Asn Ala 85 90 95 Lys Asp His Ile Gly Ala Thr Pro Leu His Leu Ala Ala Trp Gln Gly 100 105 110 His Pro Glu Ile Val Glu Val Leu Leu Lys Ala Gly Ala Asp Val Asn 115 120 125 Ala Gln Asp Lys Ser Gly Lys Thr Pro Ala Asp Leu Ala Ala Asp Ala 130 135 140 Gly His Glu Asp Ile Ala Glu Val Leu Gln Lys Ala Ala 145 150 155 <![CDATA[<210> 248]]> <![CDATA[<211> 124]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> NG-641之VH]]> <![CDATA[<400> 248]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr 20 25 30 Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile 35 40 45 Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <![CDATA[<210> 249]]> <![CDATA[<211> 113]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> NG-641之VL]]> <![CDATA[<400> 249]]> Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser 20 25 30 Arg Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Phe Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Phe Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 85 90 95 Tyr Phe Ser Tyr Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile 100 105 110 Lys <![CDATA[<210> 250]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 28H1之VH]]> <![CDATA[<400> 250]]> Glu Val Gln Leu Leu 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 Ser His 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Trp Ala Ser Gly Glu Gln Tyr Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu 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 Lys Gly Trp Leu Gly Asn Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <![CDATA[<210> 251]]> <![CDATA[<211> 108]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 28H1之VL]]> <![CDATA[<400> 251]]> Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Arg Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Ile Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Gln Val Ile Pro 85 90 95 Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <![CDATA[<210> 252]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 4B9之VH]]> <![CDATA[<400> 252]]> Glu Val Gln Leu Leu 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 Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ile Gly Ser Gly Ala Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Gly Trp Phe Gly Gly Phe Asn Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <![CDATA[<210> 253]]> <![CDATA[<211> 108]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 4B9之VL]]> <![CDATA[<400> 253]]> Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Asn Val Gly Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Ile Met Leu Pro 85 90 95 Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <![CDATA[<210> 254]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> OMTX-705之VH]]> <![CDATA[<400> 254]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Glu Asn 20 25 30 Ile Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Phe His Pro Gly Ser Gly Ser Ile Lys Tyr Asn Glu Lys Phe 50 55 60 Lys Asp Arg Val Thr Met Thr Thr Ala Asp Thr Ser Thr Ser Thr Val 65 70 75 80 Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg His Gly Gly Thr Gly Arg Gly Ala Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <![CDATA[<210> 255]]> <![CDATA[<211> 112]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> OMTX-705之VL]]> <![CDATA[<400> 255]]> Asp Ile Gln Met Ile Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Lys Ser Val Ser Thr Ser 20 25 30 Ala Tyr Ser Tyr Met His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro 35 40 45 Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser Gly Val Pro Ser 50 55 60 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Ile Leu Thr Ile Ser 65 70 75 80 Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His Ser Arg 85 90 95 Glu Leu Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg 100 105 110 <![CDATA[<210> 256]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 3F2之VH]]> <![CDATA[<400> 256]]> Glu Val Gln Leu Leu 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 Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Gly Trp Phe Gly Gly Phe Asn Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <![CDATA[<210> 257]]> <![CDATA[<211> 108]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 3F2之VL]]> <![CDATA[<400> 257]]> Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Tyr Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Asn Val Gly Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Ile Met Leu Pro 85 90 95 Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <![CDATA[<210> 258]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 4G8之VH]]> <![CDATA[<400> 258]]> Glu Val Gln Leu Leu 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 Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Gly Trp Leu Gly Asn Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <![CDATA[<210> 259]]> <![CDATA[<211> 108]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 4G8之VL]]> <![CDATA[<400> 259]]> Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Arg Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Ile Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Gln Val Ile Pro 85 90 95 Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <![CDATA[<210> 260]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 3D9之VH]]> <![CDATA[<400> 260]]> Glu Val Gln Leu Leu 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 Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Thr Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Gly Val Ser Thr Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Gly Trp Leu Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <![CDATA[<210> 261]]> <![CDATA[<211> 108]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 3D9之VL]]> <![CDATA[<400> 261]]> Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Lys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Gln Leu Ile Pro 85 90 95 Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <![CDATA[<210> 262]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 4B3之VH]]> <![CDATA[<400> 262]]> Glu Val Gln Leu Leu 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 Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Gly Trp Leu Gly Asn Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <![CDATA[<210> 263]]> <![CDATA[<211> 108]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 4B3之VL]]> <![CDATA[<400> 263]]> Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Tyr Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Gln Val Ile Pro 85 90 95 Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <![CDATA[<210> 264]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 19G1之VH]]> <![CDATA[<400> 264]]> Glu Val Gln Leu Leu 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 Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ile Ser Ser Gly Gly Leu Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Gly Trp Phe Gly Gly Phe Asn Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <![CDATA[<210> 265]]> <![CDATA[<211> 108]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 19G1之VL]]> <![CDATA[<400> 265]]> Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Gly Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Asn Val Gly Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Ile Met Leu Pro 85 90 95 Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <![CDATA[<210> 266]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 20G8之VH]]> <![CDATA[<400> 266]]> Glu Val Gln Leu Leu 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 Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Lys Leu Glu Trp Val 35 40 45 Ser Ala Ile Ile Gly Ser Gly Ser Arg Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Gly Trp Phe Gly Gly Phe Asn Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <![CDATA[<210> 267]]> <![CDATA[<211> 108]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 20G8之VL]]> <![CDATA[<400> 267]]> Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Asn Val Gly Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Ile Met Leu Pro 85 90 95 Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <![CDATA[<210> 268]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 5B8之VH]]> <![CDATA[<400> 268]]> Glu Val Gln Leu Leu 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 Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Trp Gly Gly Gly Arg Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Gly Trp Phe Gly Gly Phe Asn Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <![CDATA[<210> 269]]> <![CDATA[<211> 108]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 5B8之VL]]> <![CDATA[<400> 269]]> Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Asn Val Gly Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Ile Met Leu Pro 85 90 95 Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <![CDATA[<210> 270]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 5F1之VH]]> <![CDATA[<400> 270]]> Glu Val Gln Leu Leu 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 Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ile Ser Ser Gly Ala Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Gly Trp Phe Gly Gly Phe Asn Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <![CDATA[<210> 271]]> <![CDATA[<211> 108]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 5F1之VL]]> <![CDATA[<400> 271]]> Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Asn Val Gly Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Ile Met Leu Pro 85 90 95 Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <![CDATA[<210> 272]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 14B3之VH]]> <![CDATA[<400> 272]]> Glu Val Gln Leu Leu 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 Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Leu Ala Ser Gly Ala Ile Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Gly Trp Phe Gly Gly Phe Asn Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <![CDATA[<210> 273]]> <![CDATA[<211> 108]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 14B3之VL]]> <![CDATA[<400> 273]]> Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Gly Pro Gly Gly Ala Pro Arg Leu Leu 35 40 45 Ile Asn Val Gly Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Ile Met Leu Pro 85 90 95 Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <![CDATA[<210> 274]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 16F1之VH]]> <![CDATA[<400> 274]]> Glu Val Gln Leu Leu 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 Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ile Gly Ser Gly Gly Ile Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Asp Phe Thr Ile Ser Arg Asp Asn Ser Gly Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Gly Trp Phe Gly Gly Phe Asn Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <![CDATA[<210> 275]]> <![CDATA[<211> 108]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 16F1之VL]]> <![CDATA[<400> 275]]> Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Asn Val Gly Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Ile Met Leu Pro 85 90 95 Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <![CDATA[<210> 276]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 16F8之VH]]> <![CDATA[<400> 276]]> Glu Val Gln Leu Leu 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 Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Leu Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Gly Trp Phe Gly Gly Phe Asn Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <![CDATA[<210> 277]]> <![CDATA[<211> 108]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 16F8之VL]]> <![CDATA[<400> 277]]> Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Asn Val Gly Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Ile Met Leu Pro 85 90 95 Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <![CDATA[<210> 278]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> O3C9之VH]]> <![CDATA[<400> 278]]> Glu Val Gln Leu Leu 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 Ser Phe 20 25 30 Ala Met Ser Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ile Gly Ser Gly Ser Asn Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Gly Trp Phe Gly Gly Phe Asn Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <![CDATA[<210> 279]]> <![CDATA[<211> 108]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> O3C9之VL]]> <![CDATA[<400> 279]]> Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Asn Val Gly Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Ile Met Leu Pro 85 90 95 Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <![CDATA[<210> 280]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 22A3之VH]]> <![CDATA[<400> 280]]> Glu Val Gln Leu Leu 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 Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ile Gly Ser Gly Ser Ile Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Gly Trp Phe Gly Gly Phe Asn Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <![CDATA[<210> 281]]> <![CDATA[<211> 108]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 22A3之VL]]> <![CDATA[<400> 281]]> Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Asn Val Gly Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Ile Met Leu Pro 85 90 95 Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <![CDATA[<210> 282]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 29B11之VH]]> <![CDATA[<400> 282]]> Glu Val Gln Leu Leu 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 Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ile Gly Ser Gly Gly Ile Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Gly Trp Phe Gly Gly Phe Asn Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <![CDATA[<210> 283]]> <![CDATA[<211> 108]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 29B11之VL]]> <![CDATA[<400> 283]]> Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Asn Val Gly Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Ile Met Leu Pro 85 90 95 Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <![CDATA[<210> 284]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> O2D7之VH]]> <![CDATA[<400> 284]]> Glu Val Gln Leu Leu 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 Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Gly Trp Phe Gly Gly Phe Asn Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <![CDATA[<210> 285]]> <![CDATA[<211> 108]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> O2D7之VL]]> <![CDATA[<400> 285]]> Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Asn Val Gly Ser Arg Arg Ala Thr Gly Thr Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ala Ile Met Leu Pro 85 90 95 Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <![CDATA[<210> 286]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 23C10之VH]]> <![CDATA[<400> 286]]> Glu Val Gln Leu Leu 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 Ser Ser 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Thr Asn Gly Asn Tyr Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Gly Trp Leu Gly Asn Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <![CDATA[<210> 287]]> <![CDATA[<211> 108]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 23C10之VL]]> <![CDATA[<400> 287]]> Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Arg Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Ile Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Gln Val Ile Pro 85 90 95 Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <![CDATA[<210> 288]]> <![CDATA[<211> 227]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類IgG1 Fc杵]]> <![CDATA[<400> 288]]> Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Lys 225 <![CDATA[<210> 289]]> <![CDATA[<211> 227]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類IgG1 Fc臼]]> <![CDATA[<400> 289]]> Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Lys 225 <![CDATA[<210> 290]]> <![CDATA[<211> 233]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 小鼠IgG2a Fc杵]]> <![CDATA[<400> 290]]> Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro 1 5 10 15 Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys 20 25 30 Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val Thr Cys Val 35 40 45 Val Val Asp Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe 50 55 60 Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu 65 70 75 80 Asp Tyr Asn Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln His 85 90 95 Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys 100 105 110 Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser 115 120 125 Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu Glu Glu Met 130 135 140 Thr Lys Lys Gln Val Thr Leu Trp Cys Met Val Thr Asp Phe Met Pro 145 150 155 160 Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn 165 170 175 Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Met 180 185 190 Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser 195 200 205 Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His His Thr Thr 210 215 220 Lys Ser Phe Ser Arg Thr Pro Gly Lys 225 230 <![CDATA[<210> 291]]> <![CDATA[<211> 233]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 小鼠IgG2a Fc臼]]> <![CDATA[<400> 291]]> Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro 1 5 10 15 Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys 20 25 30 Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val Thr Cys Val 35 40 45 Val Val Asp Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe 50 55 60 Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu 65 70 75 80 Asp Tyr Asn Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln His 85 90 95 Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys 100 105 110 Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser 115 120 125 Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu Glu Glu Met 130 135 140 Thr Lys Lys Gln Val Thr Leu Ser Cys Ala Val Thr Asp Phe Met Pro 145 150 155 160 Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn 165 170 175 Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Met 180 185 190 Val Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser 195 200 205 Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His His Thr Thr 210 215 220 Lys Ser Phe Ser Arg Thr Pro Gly Lys 225 230 <![CDATA[<210> 292]]> <![CDATA[<211> 1026]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類scIL-12-人類IgG1 Fc臼DANG-抗人類FAP scFv]]> <![CDATA[<400> 292]]> Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr 1 5 10 15 Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu 20 25 30 Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly 35 40 45 Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly 50 55 60 Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu 65 70 75 80 Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys 85 90 95 Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys 100 105 110 Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr 115 120 125 Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln 130 135 140 Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly 145 150 155 160 Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala 165 170 175 Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala 180 185 190 Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg 195 200 205 Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu 210 215 220 Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp 225 230 235 240 Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln 245 250 255 Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe Thr Asp Lys Thr 260 265 270 Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala 275 280 285 Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro 290 295 300 Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 305 310 315 320 Ser Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys 325 330 335 Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln 340 345 350 Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile 355 360 365 Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys 370 375 380 Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu 385 390 395 400 Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser 405 410 415 Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met 420 425 430 Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro 435 440 445 Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu 450 455 460 Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser 465 470 475 480 Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile 485 490 495 Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Met 500 505 510 Ser Tyr Leu Asn Ala Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 515 520 525 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 530 535 540 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 545 550 555 560 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Ala Val Ser His 565 570 575 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 580 585 590 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr 595 600 605 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 610 615 620 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 625 630 635 640 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 645 650 655 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 660 665 670 Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 675 680 685 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 690 695 700 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val 705 710 715 720 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 725 730 735 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 740 745 750 Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 755 760 765 Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly 770 775 780 Ala Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu 785 790 795 800 Tyr Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp 805 810 815 Ile Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys 820 825 830 Phe Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala 835 840 845 Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr 850 855 860 Cys Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met 865 870 875 880 Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly 885 890 895 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 900 905 910 Ser Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu 915 920 925 Gly Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Tyr 930 935 940 Ser Arg Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly 945 950 955 960 Gln Pro Pro Lys Leu Leu Ile Phe Trp Ala Ser Thr Arg Glu Ser Gly 965 970 975 Val Pro Asp Arg Phe Ser Gly Ser Gly Phe Gly Thr Asp Phe Thr Leu 980 985 990 Thr Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln 995 1000 1005 Gln Tyr Phe Ser Tyr Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu 1010 1015 1020 Ile Lys 1025 <![CDATA[<210> 293]]> <![CDATA[<211> 1026]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類scIL-12突變2-人類IgG1 Fc臼DANG-抗人類FAP scFv]]> <![CDATA[<400> 293]]> Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr 1 5 10 15 Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu 20 25 30 Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly 35 40 45 Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly 50 55 60 Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu 65 70 75 80 Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys 85 90 95 Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys 100 105 110 Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr 115 120 125 Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln 130 135 140 Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly 145 150 155 160 Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala 165 170 175 Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala 180 185 190 Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg 195 200 205 Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu 210 215 220 Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp 225 230 235 240 Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln 245 250 255 Gly Ala Ser Ala Arg Glu Ala Ala Asp Arg Val Phe Thr Asp Lys Thr 260 265 270 Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala 275 280 285 Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro 290 295 300 Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 305 310 315 320 Ser Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys 325 330 335 Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln 340 345 350 Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile 355 360 365 Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys 370 375 380 Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu 385 390 395 400 Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser 405 410 415 Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met 420 425 430 Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro 435 440 445 Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu 450 455 460 Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser 465 470 475 480 Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile 485 490 495 Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Met 500 505 510 Ser Tyr Leu Asn Ala Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 515 520 525 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 530 535 540 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 545 550 555 560 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Ala Val Ser His 565 570 575 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 580 585 590 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr 595 600 605 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 610 615 620 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 625 630 635 640 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 645 650 655 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 660 665 670 Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 675 680 685 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 690 695 700 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val 705 710 715 720 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 725 730 735 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 740 745 750 Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 755 760 765 Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly 770 775 780 Ala Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu 785 790 795 800 Tyr Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp 805 810 815 Ile Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys 820 825 830 Phe Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala 835 840 845 Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr 850 855 860 Cys Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met 865 870 875 880 Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly 885 890 895 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 900 905 910 Ser Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu 915 920 925 Gly Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Tyr 930 935 940 Ser Arg Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly 945 950 955 960 Gln Pro Pro Lys Leu Leu Ile Phe Trp Ala Ser Thr Arg Glu Ser Gly 965 970 975 Val Pro Asp Arg Phe Ser Gly Ser Gly Phe Gly Thr Asp Phe Thr Leu 980 985 990 Thr Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln 995 1000 1005 Gln Tyr Phe Ser Tyr Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu 1010 1015 1020 Ile Lys 1025 <![CDATA[<210> 294]]> <![CDATA[<211> 986]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗人類FAP HC人類IgG1 Fc DANG-人類scIL-12]]> <![CDATA[<400> 294]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr 20 25 30 Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile 35 40 45 Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 130 135 140 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 145 150 155 160 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 165 170 175 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 180 185 190 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 195 200 205 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro 210 215 220 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 245 250 255 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Ala 260 265 270 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 275 280 285 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly 290 295 300 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 305 310 315 320 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 325 330 335 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 340 345 350 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn 355 360 365 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 370 375 380 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 385 390 395 400 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 405 410 415 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 420 425 430 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 435 440 445 Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 450 455 460 Gly Gly Gly Ser Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu 465 470 475 480 Leu Asp Trp Tyr Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys 485 490 495 Asp Thr Pro Glu Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser 500 505 510 Glu Val Leu Gly Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe 515 520 525 Gly Asp Ala Gly Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser 530 535 540 His Ser Leu Leu Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr 545 550 555 560 Asp Ile Leu Lys Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg 565 570 575 Cys Glu Ala Lys Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr 580 585 590 Thr Ile Ser Thr Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser 595 600 605 Ser Asp Pro Gln Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu 610 615 620 Arg Val Arg Gly Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln 625 630 635 640 Glu Asp Ser Ala Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val 645 650 655 Met Val Asp Ala Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser 660 665 670 Phe Phe Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln 675 680 685 Leu Lys Pro Leu Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr 690 695 700 Pro Asp Thr Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys 705 710 715 720 Val Gln Val Gln Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe 725 730 735 Thr Asp Lys Thr Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile 740 745 750 Ser Val Arg Ala Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp 755 760 765 Ala Ser Val Pro Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 770 775 780 Gly Gly Gly Gly Ser Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly 785 790 795 800 Met Phe Pro Cys Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser 805 810 815 Asn Met Leu Gln Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr 820 825 830 Ser Glu Glu Ile Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr 835 840 845 Val Glu Ala Cys Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu 850 855 860 Asn Ser Arg Glu Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser 865 870 875 880 Arg Lys Thr Ser Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu 885 890 895 Asp Leu Lys Met Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu 900 905 910 Leu Met Asp Pro Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala 915 920 925 Val Ile Asp Glu Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val 930 935 940 Pro Gln Lys Ser Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile 945 950 955 960 Lys Leu Cys Ile Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile 965 970 975 Asp Arg Val Met Ser Tyr Leu Asn Ala Ser 980 985 <![CDATA[<210> 295]]> <![CDATA[<211> 986]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗人類FAP HC人類IgG1 Fc DANG-人類scIL-12突變2]]> <![CDATA[<400> 295]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr 20 25 30 Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile 35 40 45 Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125 Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 130 135 140 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 145 150 155 160 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 165 170 175 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 180 185 190 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 195 200 205 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro 210 215 220 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 225 230 235 240 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 245 250 255 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Ala 260 265 270 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 275 280 285 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly 290 295 300 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 305 310 315 320 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 325 330 335 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 340 345 350 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn 355 360 365 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 370 375 380 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 385 390 395 400 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 405 410 415 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 420 425 430 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 435 440 445 Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 450 455 460 Gly Gly Gly Ser Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu 465 470 475 480 Leu Asp Trp Tyr Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys 485 490 495 Asp Thr Pro Glu Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser 500 505 510 Glu Val Leu Gly Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe 515 520 525 Gly Asp Ala Gly Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser 530 535 540 His Ser Leu Leu Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr 545 550 555 560 Asp Ile Leu Lys Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg 565 570 575 Cys Glu Ala Lys Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr 580 585 590 Thr Ile Ser Thr Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser 595 600 605 Ser Asp Pro Gln Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu 610 615 620 Arg Val Arg Gly Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln 625 630 635 640 Glu Asp Ser Ala Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val 645 650 655 Met Val Asp Ala Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser 660 665 670 Phe Phe Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln 675 680 685 Leu Lys Pro Leu Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr 690 695 700 Pro Asp Thr Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys 705 710 715 720 Val Gln Val Gln Gly Ala Ser Ala Arg Glu Ala Ala Asp Arg Val Phe 725 730 735 Thr Asp Lys Thr Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile 740 745 750 Ser Val Arg Ala Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp 755 760 765 Ala Ser Val Pro Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 770 775 780 Gly Gly Gly Gly Ser Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly 785 790 795 800 Met Phe Pro Cys Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser 805 810 815 Asn Met Leu Gln Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr 820 825 830 Ser Glu Glu Ile Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr 835 840 845 Val Glu Ala Cys Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu 850 855 860 Asn Ser Arg Glu Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser 865 870 875 880 Arg Lys Thr Ser Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu 885 890 895 Asp Leu Lys Met Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu 900 905 910 Leu Met Asp Pro Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala 915 920 925 Val Ile Asp Glu Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val 930 935 940 Pro Gln Lys Ser Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile 945 950 955 960 Lys Leu Cys Ile Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile 965 970 975 Asp Arg Val Met Ser Tyr Leu Asn Ala Ser 980 985 <![CDATA[<210> 296]]> <![CDATA[<211> 1026]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類scIL-12-人類IgG1 Fc DANG-抗人類FAP scFv]]> <![CDATA[<400> 296]]> Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr 1 5 10 15 Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu 20 25 30 Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly 35 40 45 Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly 50 55 60 Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu 65 70 75 80 Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys 85 90 95 Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys 100 105 110 Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr 115 120 125 Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln 130 135 140 Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly 145 150 155 160 Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala 165 170 175 Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala 180 185 190 Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg 195 200 205 Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu 210 215 220 Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp 225 230 235 240 Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln 245 250 255 Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe Thr Asp Lys Thr 260 265 270 Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala 275 280 285 Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro 290 295 300 Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 305 310 315 320 Ser Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys 325 330 335 Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln 340 345 350 Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile 355 360 365 Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys 370 375 380 Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu 385 390 395 400 Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser 405 410 415 Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met 420 425 430 Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro 435 440 445 Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu 450 455 460 Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser 465 470 475 480 Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile 485 490 495 Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Met 500 505 510 Ser Tyr Leu Asn Ala Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 515 520 525 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 530 535 540 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 545 550 555 560 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Ala Val Ser His 565 570 575 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 580 585 590 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr 595 600 605 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 610 615 620 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 625 630 635 640 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 645 650 655 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 660 665 670 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 675 680 685 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 690 695 700 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 705 710 715 720 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 725 730 735 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 740 745 750 Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 755 760 765 Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly 770 775 780 Ala Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu 785 790 795 800 Tyr Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp 805 810 815 Ile Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys 820 825 830 Phe Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala 835 840 845 Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr 850 855 860 Cys Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met 865 870 875 880 Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly 885 890 895 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 900 905 910 Ser Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu 915 920 925 Gly Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Tyr 930 935 940 Ser Arg Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly 945 950 955 960 Gln Pro Pro Lys Leu Leu Ile Phe Trp Ala Ser Thr Arg Glu Ser Gly 965 970 975 Val Pro Asp Arg Phe Ser Gly Ser Gly Phe Gly Thr Asp Phe Thr Leu 980 985 990 Thr Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln 995 1000 1005 Gln Tyr Phe Ser Tyr Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu 1010 1015 1020 Ile Lys 1025 <![CDATA[<210> 297]]> <![CDATA[<211> 1026]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類scIL-12突變2-人類IgG1 Fc DANG-抗人類FAP scFv]]> <![CDATA[<400> 297]]> Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr 1 5 10 15 Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu 20 25 30 Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly 35 40 45 Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly 50 55 60 Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu 65 70 75 80 Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys 85 90 95 Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys 100 105 110 Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr 115 120 125 Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln 130 135 140 Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly 145 150 155 160 Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala 165 170 175 Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala 180 185 190 Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg 195 200 205 Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu 210 215 220 Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp 225 230 235 240 Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln 245 250 255 Gly Ala Ser Ala Arg Glu Ala Ala Asp Arg Val Phe Thr Asp Lys Thr 260 265 270 Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala 275 280 285 Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro 290 295 300 Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 305 310 315 320 Ser Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys 325 330 335 Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln 340 345 350 Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile 355 360 365 Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys 370 375 380 Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu 385 390 395 400 Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser 405 410 415 Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met 420 425 430 Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro 435 440 445 Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu 450 455 460 Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser 465 470 475 480 Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile 485 490 495 Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Met 500 505 510 Ser Tyr Leu Asn Ala Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 515 520 525 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 530 535 540 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 545 550 555 560 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Ala Val Ser His 565 570 575 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 580 585 590 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr 595 600 605 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 610 615 620 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 625 630 635 640 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 645 650 655 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 660 665 670 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 675 680 685 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 690 695 700 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 705 710 715 720 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 725 730 735 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 740 745 750 Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 755 760 765 Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly 770 775 780 Ala Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu 785 790 795 800 Tyr Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp 805 810 815 Ile Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys 820 825 830 Phe Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala 835 840 845 Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr 850 855 860 Cys Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met 865 870 875 880 Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly 885 890 895 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 900 905 910 Ser Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu 915 920 925 Gly Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Tyr 930 935 940 Ser Arg Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly 945 950 955 960 Gln Pro Pro Lys Leu Leu Ile Phe Trp Ala Ser Thr Arg Glu Ser Gly 965 970 975 Val Pro Asp Arg Phe Ser Gly Ser Gly Phe Gly Thr Asp Phe Thr Leu 980 985 990 Thr Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln 995 1000 1005 Gln Tyr Phe Ser Tyr Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu 1010 1015 1020 Ile Lys 1025 <![CDATA[<210> 298]]> <![CDATA[<211> 1021]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 小鼠scIL-12-小鼠IgG2a Fc臼DANG-抗小鼠FAP scFv]]> <![CDATA[<400> 298]]> Met Trp Glu Leu Glu Lys Asp Val Tyr Val Val Glu Val Asp Trp Thr 1 5 10 15 Pro Asp Ala Pro Gly Glu Thr Val Asn Leu Thr Cys Asp Thr Pro Glu 20 25 30 Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln Arg His Gly Val Ile Gly 35 40 45 Ser Gly Lys Thr Leu Thr Ile Thr Val Lys Glu Phe Leu Asp Ala Gly 50 55 60 Gln Tyr Thr Cys His Lys Gly Gly Glu Thr Leu Ser His Ser His Leu 65 70 75 80 Leu Leu His Lys Lys Glu Asn Gly Ile Trp Ser Thr Glu Ile Leu Lys 85 90 95 Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys Glu Ala Pro Asn Tyr Ser 100 105 110 Gly Arg Phe Thr Cys Ser Trp Leu Val Gln Arg Asn Met Asp Leu Lys 115 120 125 Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro Asp Ser Arg Ala Val Thr 130 135 140 Cys Gly Met Ala Ser Leu Ser Ala Glu Lys Val Thr Leu Asp Gln Arg 145 150 155 160 Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln Glu Asp Val Thr Cys Pro 165 170 175 Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu Ala Leu Glu Ala Arg Gln 180 185 190 Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser Phe Phe Ile Arg Asp Ile 195 200 205 Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Met Lys Pro Leu Lys Asn 210 215 220 Ser Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Ser Trp Ser Thr Pro 225 230 235 240 His Ser Tyr Phe Ser Leu Lys Phe Phe Val Arg Ile Gln Arg Lys Lys 245 250 255 Glu Lys Met Lys Glu Thr Glu Glu Gly Cys Asn Gln Lys Gly Ala Phe 260 265 270 Leu Val Glu Lys Thr Ser Thr Glu Val Gln Cys Lys Gly Gly Asn Val 275 280 285 Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn Ser Ser Cys Ser Lys Trp 290 295 300 Ala Cys Val Pro Cys Arg Val Arg Ser Gly Gly Gly Gly Ser Gly Gly 305 310 315 320 Gly Gly Ser Gly Gly Gly Gly Ser Arg Val Ile Pro Val Ser Gly Pro 325 330 335 Ala Arg Cys Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp 340 345 350 Met Val Lys Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala 355 360 365 Glu Asp Ile Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu 370 375 380 Lys Thr Cys Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala 385 390 395 400 Thr Arg Glu Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln 405 410 415 Lys Thr Ser Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp 420 425 430 Leu Lys Met Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln 435 440 445 Asn His Asn His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala 450 455 460 Ile Asp Glu Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg 465 470 475 480 Gln Lys Pro Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys 485 490 495 Leu Cys Ile Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn 500 505 510 Arg Val Met Gly Tyr Leu Ser Ser Ala Gly Gly Gly Gly Ser Gly Gly 515 520 525 Gly Gly Ser Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys 530 535 540 Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe 545 550 555 560 Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val 565 570 575 Thr Cys Val Val Val Ala Val Ser Glu Asp Asp Pro Asp Val Gln Ile 580 585 590 Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr 595 600 605 His Arg Glu Asp Tyr Gly Ser Thr Leu Arg Val Val Ser Ala Leu Pro 610 615 620 Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val 625 630 635 640 Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro 645 650 655 Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu 660 665 670 Glu Glu Met Thr Lys Lys Gln Val Thr Leu Ser Cys Ala Val Thr Asp 675 680 685 Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr 690 695 700 Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser 705 710 715 720 Tyr Phe Met Val Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu 725 730 735 Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His 740 745 750 His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Gly Gly Gly Gly Ser 755 760 765 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Gln 770 775 780 Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala Ser Val Asn Leu Ser Cys 785 790 795 800 Lys Ala Ser Gly Tyr Thr Phe Thr Asn Asn Gly Ile Asn Trp Leu Lys 805 810 815 Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile Gly Glu Ile Tyr Pro Arg 820 825 830 Ser Thr Asn Thr Leu Tyr Asn Glu Lys Phe Lys Gly Lys Ala Thr Leu 835 840 845 Thr Ala Asp Arg Ser Ser Asn Thr Ala Tyr Met Glu Leu Arg Ser Leu 850 855 860 Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys Ala Arg Thr Leu Thr Ala 865 870 875 880 Pro Phe Ala Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala Gly 885 890 895 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 900 905 910 Gly Gly Ser Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala 915 920 925 Ser Pro Gly Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Gly Val 930 935 940 Asn Phe Met His Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg 945 950 955 960 Trp Ile Phe Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe 965 970 975 Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met 980 985 990 Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Phe Asn 995 1000 1005 Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 1010 1015 1020 <![CDATA[<210> 299]]> <![CDATA[<211> 1021]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 小鼠scIL-12突變2-小鼠IgG2a Fc臼DANG-抗小鼠FAP scFv]]> <![CDATA[<400> 299]]> Met Trp Glu Leu Glu Lys Asp Val Tyr Val Val Glu Val Asp Trp Thr 1 5 10 15 Pro Asp Ala Pro Gly Glu Thr Val Asn Leu Thr Cys Asp Thr Pro Glu 20 25 30 Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln Arg His Gly Val Ile Gly 35 40 45 Ser Gly Lys Thr Leu Thr Ile Thr Val Lys Glu Phe Leu Asp Ala Gly 50 55 60 Gln Tyr Thr Cys His Lys Gly Gly Glu Thr Leu Ser His Ser His Leu 65 70 75 80 Leu Leu His Lys Lys Glu Asn Gly Ile Trp Ser Thr Glu Ile Leu Lys 85 90 95 Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys Glu Ala Pro Asn Tyr Ser 100 105 110 Gly Arg Phe Thr Cys Ser Trp Leu Val Gln Arg Asn Met Asp Leu Lys 115 120 125 Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro Asp Ser Arg Ala Val Thr 130 135 140 Cys Gly Met Ala Ser Leu Ser Ala Glu Lys Val Thr Leu Asp Gln Arg 145 150 155 160 Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln Glu Asp Val Thr Cys Pro 165 170 175 Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu Ala Leu Glu Ala Arg Gln 180 185 190 Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser Phe Phe Ile Arg Asp Ile 195 200 205 Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Met Lys Pro Leu Lys Asn 210 215 220 Ser Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Ser Trp Ser Thr Pro 225 230 235 240 His Ser Tyr Phe Ser Leu Lys Phe Phe Val Arg Ile Gln Ala Ala Ala 245 250 255 Glu Lys Met Ala Glu Thr Glu Glu Gly Cys Asn Gln Lys Gly Ala Phe 260 265 270 Leu Val Glu Lys Thr Ser Thr Glu Val Gln Cys Lys Gly Gly Asn Val 275 280 285 Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn Ser Ser Cys Ser Lys Trp 290 295 300 Ala Cys Val Pro Cys Arg Val Arg Ser Gly Gly Gly Gly Ser Gly Gly 305 310 315 320 Gly Gly Ser Gly Gly Gly Gly Ser Arg Val Ile Pro Val Ser Gly Pro 325 330 335 Ala Arg Cys Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp 340 345 350 Met Val Lys Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala 355 360 365 Glu Asp Ile Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu 370 375 380 Lys Thr Cys Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala 385 390 395 400 Thr Arg Glu Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln 405 410 415 Lys Thr Ser Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp 420 425 430 Leu Lys Met Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln 435 440 445 Asn His Asn His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala 450 455 460 Ile Asp Glu Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg 465 470 475 480 Gln Lys Pro Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys 485 490 495 Leu Cys Ile Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn 500 505 510 Arg Val Met Gly Tyr Leu Ser Ser Ala Gly Gly Gly Gly Ser Gly Gly 515 520 525 Gly Gly Ser Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys 530 535 540 Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe 545 550 555 560 Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val 565 570 575 Thr Cys Val Val Val Ala Val Ser Glu Asp Asp Pro Asp Val Gln Ile 580 585 590 Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr 595 600 605 His Arg Glu Asp Tyr Gly Ser Thr Leu Arg Val Val Ser Ala Leu Pro 610 615 620 Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val 625 630 635 640 Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro 645 650 655 Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu 660 665 670 Glu Glu Met Thr Lys Lys Gln Val Thr Leu Ser Cys Ala Val Thr Asp 675 680 685 Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr 690 695 700 Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser 705 710 715 720 Tyr Phe Met Val Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu 725 730 735 Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His 740 745 750 His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Gly Gly Gly Gly Ser 755 760 765 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Gln 770 775 780 Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala Ser Val Asn Leu Ser Cys 785 790 795 800 Lys Ala Ser Gly Tyr Thr Phe Thr Asn Asn Gly Ile Asn Trp Leu Lys 805 810 815 Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile Gly Glu Ile Tyr Pro Arg 820 825 830 Ser Thr Asn Thr Leu Tyr Asn Glu Lys Phe Lys Gly Lys Ala Thr Leu 835 840 845 Thr Ala Asp Arg Ser Ser Asn Thr Ala Tyr Met Glu Leu Arg Ser Leu 850 855 860 Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys Ala Arg Thr Leu Thr Ala 865 870 875 880 Pro Phe Ala Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala Gly 885 890 895 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 900 905 910 Gly Gly Ser Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala 915 920 925 Ser Pro Gly Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Gly Val 930 935 940 Asn Phe Met His Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg 945 950 955 960 Trp Ile Phe Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe 965 970 975 Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met 980 985 990 Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Phe Asn 995 1000 1005 Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 1010 1015 1020 <![CDATA[<210> 300]]> <![CDATA[<211> 982]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗小鼠FAP HC小鼠IgG2a Fc DANG-小鼠scIL-12]]> <![CDATA[<400> 300]]> Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 1 5 10 15 Ser Val Asn Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Asn 20 25 30 Gly Ile Asn Trp Leu Lys Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Glu Ile Tyr Pro Arg Ser Thr Asn Thr Leu Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Arg Ser Ser Asn Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Thr Leu Thr Ala Pro Phe Ala Phe Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ala Ala Lys Thr Thr Ala Pro Ser Val Tyr Pro Leu 115 120 125 Ala Pro Val Cys Gly Asp Thr Thr Gly Ser Ser Val Thr Leu Gly Cys 130 135 140 Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu Thr Trp Asn Ser 145 150 155 160 Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175 Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr Ser Ser Thr Trp 180 185 190 Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr 195 200 205 Lys Val Asp Lys Lys Ile Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys 210 215 220 Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser 245 250 255 Pro Ile Val Thr Cys Val Val Val Ala Val Ser Glu Asp Asp Pro Asp 260 265 270 Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln 275 280 285 Thr Gln Thr His Arg Glu Asp Tyr Gly Ser Thr Leu Arg Val Val Ser 290 295 300 Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys 305 310 315 320 Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile 325 330 335 Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro 340 345 350 Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu Thr Cys Met 355 360 365 Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn 370 375 380 Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn 405 410 415 Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu 420 425 430 His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Gly Gly 435 440 445 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Met Trp Glu 450 455 460 Leu Glu Lys Asp Val Tyr Val Val Glu Val Asp Trp Thr Pro Asp Ala 465 470 475 480 Pro Gly Glu Thr Val Asn Leu Thr Cys Asp Thr Pro Glu Glu Asp Asp 485 490 495 Ile Thr Trp Thr Ser Asp Gln Arg His Gly Val Ile Gly Ser Gly Lys 500 505 510 Thr Leu Thr Ile Thr Val Lys Glu Phe Leu Asp Ala Gly Gln Tyr Thr 515 520 525 Cys His Lys Gly Gly Glu Thr Leu Ser His Ser His Leu Leu Leu His 530 535 540 Lys Lys Glu Asn Gly Ile Trp Ser Thr Glu Ile Leu Lys Asn Phe Lys 545 550 555 560 Asn Lys Thr Phe Leu Lys Cys Glu Ala Pro Asn Tyr Ser Gly Arg Phe 565 570 575 Thr Cys Ser Trp Leu Val Gln Arg Asn Met Asp Leu Lys Phe Asn Ile 580 585 590 Lys Ser Ser Ser Ser Ser Pro Asp Ser Arg Ala Val Thr Cys Gly Met 595 600 605 Ala Ser Leu Ser Ala Glu Lys Val Thr Leu Asp Gln Arg Asp Tyr Glu 610 615 620 Lys Tyr Ser Val Ser Cys Gln Glu Asp Val Thr Cys Pro Thr Ala Glu 625 630 635 640 Glu Thr Leu Pro Ile Glu Leu Ala Leu Glu Ala Arg Gln Gln Asn Lys 645 650 655 Tyr Glu Asn Tyr Ser Thr Ser Phe Phe Ile Arg Asp Ile Ile Lys Pro 660 665 670 Asp Pro Pro Lys Asn Leu Gln Met Lys Pro Leu Lys Asn Ser Gln Val 675 680 685 Glu Val Ser Trp Glu Tyr Pro Asp Ser Trp Ser Thr Pro His Ser Tyr 690 695 700 Phe Ser Leu Lys Phe Phe Val Arg Ile Gln Arg Lys Lys Glu Lys Met 705 710 715 720 Lys Glu Thr Glu Glu Gly Cys Asn Gln Lys Gly Ala Phe Leu Val Glu 725 730 735 Lys Thr Ser Thr Glu Val Gln Cys Lys Gly Gly Asn Val Cys Val Gln 740 745 750 Ala Gln Asp Arg Tyr Tyr Asn Ser Ser Cys Ser Lys Trp Ala Cys Val 755 760 765 Pro Cys Arg Val Arg Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 770 775 780 Gly Gly Gly Gly Ser Arg Val Ile Pro Val Ser Gly Pro Ala Arg Cys 785 790 795 800 Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp Met Val Lys 805 810 815 Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala Glu Asp Ile 820 825 830 Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu Lys Thr Cys 835 840 845 Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala Thr Arg Glu 850 855 860 Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln Lys Thr Ser 865 870 875 880 Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp Leu Lys Met 885 890 895 Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln Asn His Asn 900 905 910 His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala Ile Asp Glu 915 920 925 Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg Gln Lys Pro 930 935 940 Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys Leu Cys Ile 945 950 955 960 Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn Arg Val Met 965 970 975 Gly Tyr Leu Ser Ser Ala 980 <![CDATA[<210> 301]]> <![CDATA[<211> 982]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 抗小鼠FAP HC小鼠IgG2a Fc DANG-小鼠scIL-12突變2]]> <![CDATA[<400> 301]]> Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 1 5 10 15 Ser Val Asn Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Asn 20 25 30 Gly Ile Asn Trp Leu Lys Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Glu Ile Tyr Pro Arg Ser Thr Asn Thr Leu Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Arg Ser Ser Asn Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Thr Leu Thr Ala Pro Phe Ala Phe Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ala Ala Lys Thr Thr Ala Pro Ser Val Tyr Pro Leu 115 120 125 Ala Pro Val Cys Gly Asp Thr Thr Gly Ser Ser Val Thr Leu Gly Cys 130 135 140 Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu Thr Trp Asn Ser 145 150 155 160 Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175 Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr Ser Ser Thr Trp 180 185 190 Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr 195 200 205 Lys Val Asp Lys Lys Ile Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys 210 215 220 Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser 245 250 255 Pro Ile Val Thr Cys Val Val Val Ala Val Ser Glu Asp Asp Pro Asp 260 265 270 Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln 275 280 285 Thr Gln Thr His Arg Glu Asp Tyr Gly Ser Thr Leu Arg Val Val Ser 290 295 300 Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys 305 310 315 320 Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile 325 330 335 Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro 340 345 350 Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu Thr Cys Met 355 360 365 Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn 370 375 380 Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn 405 410 415 Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu 420 425 430 His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Gly Gly 435 440 445 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Met Trp Glu 450 455 460 Leu Glu Lys Asp Val Tyr Val Val Glu Val Asp Trp Thr Pro Asp Ala 465 470 475 480 Pro Gly Glu Thr Val Asn Leu Thr Cys Asp Thr Pro Glu Glu Asp Asp 485 490 495 Ile Thr Trp Thr Ser Asp Gln Arg His Gly Val Ile Gly Ser Gly Lys 500 505 510 Thr Leu Thr Ile Thr Val Lys Glu Phe Leu Asp Ala Gly Gln Tyr Thr 515 520 525 Cys His Lys Gly Gly Glu Thr Leu Ser His Ser His Leu Leu Leu His 530 535 540 Lys Lys Glu Asn Gly Ile Trp Ser Thr Glu Ile Leu Lys Asn Phe Lys 545 550 555 560 Asn Lys Thr Phe Leu Lys Cys Glu Ala Pro Asn Tyr Ser Gly Arg Phe 565 570 575 Thr Cys Ser Trp Leu Val Gln Arg Asn Met Asp Leu Lys Phe Asn Ile 580 585 590 Lys Ser Ser Ser Ser Ser Pro Asp Ser Arg Ala Val Thr Cys Gly Met 595 600 605 Ala Ser Leu Ser Ala Glu Lys Val Thr Leu Asp Gln Arg Asp Tyr Glu 610 615 620 Lys Tyr Ser Val Ser Cys Gln Glu Asp Val Thr Cys Pro Thr Ala Glu 625 630 635 640 Glu Thr Leu Pro Ile Glu Leu Ala Leu Glu Ala Arg Gln Gln Asn Lys 645 650 655 Tyr Glu Asn Tyr Ser Thr Ser Phe Phe Ile Arg Asp Ile Ile Lys Pro 660 665 670 Asp Pro Pro Lys Asn Leu Gln Met Lys Pro Leu Lys Asn Ser Gln Val 675 680 685 Glu Val Ser Trp Glu Tyr Pro Asp Ser Trp Ser Thr Pro His Ser Tyr 690 695 700 Phe Ser Leu Lys Phe Phe Val Arg Ile Gln Ala Ala Ala Glu Lys Met 705 710 715 720 Ala Glu Thr Glu Glu Gly Cys Asn Gln Lys Gly Ala Phe Leu Val Glu 725 730 735 Lys Thr Ser Thr Glu Val Gln Cys Lys Gly Gly Asn Val Cys Val Gln 740 745 750 Ala Gln Asp Arg Tyr Tyr Asn Ser Ser Cys Ser Lys Trp Ala Cys Val 755 760 765 Pro Cys Arg Val Arg Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 770 775 780 Gly Gly Gly Gly Ser Arg Val Ile Pro Val Ser Gly Pro Ala Arg Cys 785 790 795 800 Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp Met Val Lys 805 810 815 Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala Glu Asp Ile 820 825 830 Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu Lys Thr Cys 835 840 845 Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala Thr Arg Glu 850 855 860 Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln Lys Thr Ser 865 870 875 880 Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp Leu Lys Met 885 890 895 Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln Asn His Asn 900 905 910 His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala Ile Asp Glu 915 920 925 Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg Gln Lys Pro 930 935 940 Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys Leu Cys Ile 945 950 955 960 Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn Arg Val Met 965 970 975 Gly Tyr Leu Ser Ser Ala 980 <![CDATA[<210> 302]]> <![CDATA[<211> 1020]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 小鼠scIL-12-小鼠IgG2a Fc DANG-抗小鼠FAP scFv]]> <![CDATA[<400> 302]]> Met Trp Glu Leu Glu Lys Asp Val Tyr Val Val Glu Val Asp Trp Thr 1 5 10 15 Pro Asp Ala Pro Gly Glu Thr Val Asn Leu Thr Cys Asp Thr Pro Glu 20 25 30 Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln Arg His Gly Val Ile Gly 35 40 45 Ser Gly Lys Thr Leu Thr Ile Thr Val Lys Glu Phe Leu Asp Ala Gly 50 55 60 Gln Tyr Thr Cys His Lys Gly Gly Glu Thr Leu Ser His Ser His Leu 65 70 75 80 Leu Leu His Lys Lys Glu Asn Gly Ile Trp Ser Thr Glu Ile Leu Lys 85 90 95 Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys Glu Ala Pro Asn Tyr Ser 100 105 110 Gly Arg Phe Thr Cys Ser Trp Leu Val Gln Arg Asn Met Asp Leu Lys 115 120 125 Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro Asp Ser Arg Ala Val Thr 130 135 140 Cys Gly Met Ala Ser Leu Ser Ala Glu Lys Val Thr Leu Asp Gln Arg 145 150 155 160 Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln Glu Asp Val Thr Cys Pro 165 170 175 Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu Ala Leu Glu Ala Arg Gln 180 185 190 Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser Phe Phe Ile Arg Asp Ile 195 200 205 Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Met Lys Pro Leu Lys Asn 210 215 220 Ser Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Ser Trp Ser Thr Pro 225 230 235 240 His Ser Tyr Phe Ser Leu Lys Phe Phe Val Arg Ile Gln Arg Lys Lys 245 250 255 Glu Lys Met Lys Glu Thr Glu Glu Gly Cys Asn Gln Lys Gly Ala Phe 260 265 270 Leu Val Glu Lys Thr Ser Thr Glu Val Gln Cys Lys Gly Gly Asn Val 275 280 285 Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn Ser Ser Cys Ser Lys Trp 290 295 300 Ala Cys Val Pro Cys Arg Val Arg Ser Gly Gly Gly Gly Ser Gly Gly 305 310 315 320 Gly Gly Ser Gly Gly Gly Gly Ser Arg Val Ile Pro Val Ser Gly Pro 325 330 335 Ala Arg Cys Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp 340 345 350 Met Val Lys Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala 355 360 365 Glu Asp Ile Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu 370 375 380 Lys Thr Cys Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala 385 390 395 400 Thr Arg Glu Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln 405 410 415 Lys Thr Ser Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp 420 425 430 Leu Lys Met Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln 435 440 445 Asn His Asn His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala 450 455 460 Ile Asp Glu Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg 465 470 475 480 Gln Lys Pro Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys 485 490 495 Leu Cys Ile Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn 500 505 510 Arg Val Met Gly Tyr Leu Ser Ser Ala Gly Gly Gly Gly Ser Gly Gly 515 520 525 Gly Gly Ser Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys 530 535 540 Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe 545 550 555 560 Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val 565 570 575 Thr Cys Val Val Val Ala Val Ser Glu Asp Asp Pro Asp Val Gln Ile 580 585 590 Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr 595 600 605 His Arg Glu Asp Tyr Gly Ser Thr Leu Arg Val Val Ser Ala Leu Pro 610 615 620 Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val 625 630 635 640 Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro 645 650 655 Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu 660 665 670 Glu Glu Met Thr Lys Lys Gln Val Thr Leu Thr Cys Met Val Thr Asp 675 680 685 Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr 690 695 700 Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser 705 710 715 720 Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu 725 730 735 Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His 740 745 750 His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Gly Gly Gly Ser Gly 755 760 765 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Gln Ser 770 775 780 Gly Ala Glu Leu Ala Arg Pro Gly Ala Ser Val Asn Leu Ser Cys Lys 785 790 795 800 Ala Ser Gly Tyr Thr Phe Thr Asn Asn Gly Ile Asn Trp Leu Lys Gln 805 810 815 Arg Thr Gly Gln Gly Leu Glu Trp Ile Gly Glu Ile Tyr Pro Arg Ser 820 825 830 Thr Asn Thr Leu Tyr Asn Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr 835 840 845 Ala Asp Arg Ser Ser Asn Thr Ala Tyr Met Glu Leu Arg Ser Leu Thr 850 855 860 Ser Glu Asp Ser Ala Val Tyr Phe Cys Ala Arg Thr Leu Thr Ala Pro 865 870 875 880 Phe Ala Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala Gly Gly 885 890 895 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 900 905 910 Gly Ser Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser 915 920 925 Pro Gly Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Gly Val Asn 930 935 940 Phe Met His Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp 945 950 955 960 Ile Phe Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser 965 970 975 Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu 980 985 990 Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Phe Asn Pro 995 1000 1005 Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 1010 1015 1020 <![CDATA[<210> 303]]> <![CDATA[<211> 1020]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 小鼠scIL-12突變2-小鼠IgG2a Fc DANG-抗小鼠FAP scFv]]> <![CDATA[<400> 303]]> Met Trp Glu Leu Glu Lys Asp Val Tyr Val Val Glu Val Asp Trp Thr 1 5 10 15 Pro Asp Ala Pro Gly Glu Thr Val Asn Leu Thr Cys Asp Thr Pro Glu 20 25 30 Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln Arg His Gly Val Ile Gly 35 40 45 Ser Gly Lys Thr Leu Thr Ile Thr Val Lys Glu Phe Leu Asp Ala Gly 50 55 60 Gln Tyr Thr Cys His Lys Gly Gly Glu Thr Leu Ser His Ser His Leu 65 70 75 80 Leu Leu His Lys Lys Glu Asn Gly Ile Trp Ser Thr Glu Ile Leu Lys 85 90 95 Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys Glu Ala Pro Asn Tyr Ser 100 105 110 Gly Arg Phe Thr Cys Ser Trp Leu Val Gln Arg Asn Met Asp Leu Lys 115 120 125 Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro Asp Ser Arg Ala Val Thr 130 135 140 Cys Gly Met Ala Ser Leu Ser Ala Glu Lys Val Thr Leu Asp Gln Arg 145 150 155 160 Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln Glu Asp Val Thr Cys Pro 165 170 175 Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu Ala Leu Glu Ala Arg Gln 180 185 190 Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser Phe Phe Ile Arg Asp Ile 195 200 205 Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Met Lys Pro Leu Lys Asn 210 215 220 Ser Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Ser Trp Ser Thr Pro 225 230 235 240 His Ser Tyr Phe Ser Leu Lys Phe Phe Val Arg Ile Gln Ala Ala Ala 245 250 255 Glu Lys Met Ala Glu Thr Glu Glu Gly Cys Asn Gln Lys Gly Ala Phe 260 265 270 Leu Val Glu Lys Thr Ser Thr Glu Val Gln Cys Lys Gly Gly Asn Val 275 280 285 Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn Ser Ser Cys Ser Lys Trp 290 295 300 Ala Cys Val Pro Cys Arg Val Arg Ser Gly Gly Gly Gly Ser Gly Gly 305 310 315 320 Gly Gly Ser Gly Gly Gly Gly Ser Arg Val Ile Pro Val Ser Gly Pro 325 330 335 Ala Arg Cys Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp 340 345 350 Met Val Lys Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala 355 360 365 Glu Asp Ile Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu 370 375 380 Lys Thr Cys Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala 385 390 395 400 Thr Arg Glu Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln 405 410 415 Lys Thr Ser Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp 420 425 430 Leu Lys Met Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln 435 440 445 Asn His Asn His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala 450 455 460 Ile Asp Glu Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg 465 470 475 480 Gln Lys Pro Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys 485 490 495 Leu Cys Ile Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn 500 505 510 Arg Val Met Gly Tyr Leu Ser Ser Ala Gly Gly Gly Gly Ser Gly Gly 515 520 525 Gly Gly Ser Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys 530 535 540 Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe 545 550 555 560 Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val 565 570 575 Thr Cys Val Val Val Ala Val Ser Glu Asp Asp Pro Asp Val Gln Ile 580 585 590 Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr 595 600 605 His Arg Glu Asp Tyr Gly Ser Thr Leu Arg Val Val Ser Ala Leu Pro 610 615 620 Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val 625 630 635 640 Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro 645 650 655 Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu 660 665 670 Glu Glu Met Thr Lys Lys Gln Val Thr Leu Thr Cys Met Val Thr Asp 675 680 685 Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr 690 695 700 Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser 705 710 715 720 Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu 725 730 735 Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His 740 745 750 His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Gly Gly Gly Ser Gly 755 760 765 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Gln Ser 770 775 780 Gly Ala Glu Leu Ala Arg Pro Gly Ala Ser Val Asn Leu Ser Cys Lys 785 790 795 800 Ala Ser Gly Tyr Thr Phe Thr Asn Asn Gly Ile Asn Trp Leu Lys Gln 805 810 815 Arg Thr Gly Gln Gly Leu Glu Trp Ile Gly Glu Ile Tyr Pro Arg Ser 820 825 830 Thr Asn Thr Leu Tyr Asn Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr 835 840 845 Ala Asp Arg Ser Ser Asn Thr Ala Tyr Met Glu Leu Arg Ser Leu Thr 850 855 860 Ser Glu Asp Ser Ala Val Tyr Phe Cys Ala Arg Thr Leu Thr Ala Pro 865 870 875 880 Phe Ala Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala Gly Gly 885 890 895 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 900 905 910 Gly Ser Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser 915 920 925 Pro Gly Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Gly Val Asn 930 935 940 Phe Met His Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp 945 950 955 960 Ile Phe Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser 965 970 975 Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu 980 985 990 Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Phe Asn Pro 995 1000 1005 Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 1010 1015 1020 <![CDATA[<210> 304]]> <![CDATA[<211> 227]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類IgG1 Fc]]> <![CDATA[<400> 304]]> Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Lys 225 <![CDATA[<210> 305]]> <![CDATA[<211> 233]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 小鼠IgG2a Fc]]> <![CDATA[<400> 305]]> Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro 1 5 10 15 Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys 20 25 30 Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val Thr Cys Val 35 40 45 Val Val Asp Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe 50 55 60 Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu 65 70 75 80 Asp Tyr Asn Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln His 85 90 95 Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys 100 105 110 Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser 115 120 125 Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu Glu Glu Met 130 135 140 Thr Lys Lys Gln Val Thr Leu Thr Cys Met Val Thr Asp Phe Met Pro 145 150 155 160 Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn 165 170 175 Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Met 180 185 190 Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser 195 200 205 Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His His Thr Thr 210 215 220 Lys Ser Phe Ser Arg Thr Pro Gly Lys 225 230
(無)
Claims (34)
- 一種融合蛋白,其包含: 包含IL-12或其一變體之一第一單體;及 包含特異性結合於FAP (纖維母細胞活化蛋白α)之一抗原結合位點的一第二單體。
- 如請求項1之融合蛋白,其中該IL-12或其之該變體包含IL-12A (p35)或其一變體;及IL-12B (p40)或其一變體。
- 如請求項2之融合蛋白,其中該IL-12或其之該變體包含以下結構式(I)或(II): N'-Y-[連接子(1)]o-Z-C' (I) N'-Z-[連接子(1)]o-Y-C' (II) 在該結構式(I)及該結構式(II)中, N'為該融合蛋白之N端, C'為該融合蛋白之C端, Y為該IL-12A或其之該變體, Z為該IL-12B或其之該變體, 該連接子(1)為一肽連接子,及 o為0或1。
- 如請求項2之融合蛋白,其中該IL-12B (p40)之該變體包含在SEQ ID NO: 74之胺基酸序列中藉由至少一個選自由K258A、K260A、K263A及K264A組成之群之取代獲得的一胺基酸序列。
- 如請求項2之融合蛋白,其中該IL-12B (p40)包含SEQ ID NO: 74或SEQ ID NO: 86之胺基酸序列。
- 如請求項4之融合蛋白,其中該IL-12B (p40)之該變體包含SEQ ID NO: 77、SEQ ID NO: 79、SEQ ID NO: 89或SEQ ID NO: 91之胺基酸序列。
- 如請求項2之融合蛋白,其中該IL-12A (p35)包含SEQ ID NO: 75或SEQ ID NO: 87之胺基酸序列。
- 如請求項1之融合蛋白,其中該IL-12包含SEQ ID NO: 73、SEQ ID NO: 76、SEQ ID NO: 78、SEQ ID NO: 85、SEQ ID NO: 88或SEQ ID NO: 90之胺基酸序列。
- 如請求項1之融合蛋白,其中特異性結合於FAP之該抗原結合位點包含: 一重鏈可變區,該重鏈可變區包含SEQ ID NO: 96之HCDR1、SEQ ID NO: 97之HCDR2及SEQ ID NO: 98之HCDR3;及一輕鏈可變區,該輕鏈可變區包含SEQ ID NO: 99之LCDR1、SEQ ID NO: 100之LCDR2及SEQ ID NO: 101之LCDR3; 一重鏈可變區,該重鏈可變區包含SEQ ID NO: 104之HCDR1、SEQ ID NO: 105之HCDR2及SEQ ID NO: 106之HCDR3;及一輕鏈可變區,該輕鏈可變區包含SEQ ID NO: 107之LCDR1、SEQ ID NO: 108之LCDR2及SEQ ID NO: 109之LCDR3; 一重鏈可變區,該重鏈可變區包含SEQ ID NO: 127之HCDR1、SEQ ID NO: 128之HCDR2及SEQ ID NO: 129之HCDR3;及一輕鏈可變區,該輕鏈可變區包含SEQ ID NO: 130之LCDR1、SEQ ID NO: 131之LCDR2及SEQ ID NO: 132之LCDR3; 一重鏈可變區,該重鏈可變區包含SEQ ID NO: 133之HCDR1、SEQ ID NO: 134之HCDR2及SEQ ID NO: 135之HCDR3;及一輕鏈可變區,該輕鏈可變區包含SEQ ID NO: 136之LCDR1、SEQ ID NO: 137之LCDR2及SEQ ID NO: 138之LCDR3; 一重鏈可變區,該重鏈可變區包含SEQ ID NO: 139之HCDR1、SEQ ID NO: 140之HCDR2及SEQ ID NO: 141之HCDR3;及一輕鏈可變區,該輕鏈可變區包含SEQ ID NO: 142之LCDR1、SEQ ID NO: 143之LCDR2及SEQ ID NO: 144之LCDR3; 一重鏈可變區,該重鏈可變區包含SEQ ID NO: 145之HCDR1、SEQ ID NO: 146之HCDR2及SEQ ID NO: 147之HCDR3;及一輕鏈可變區,該輕鏈可變區包含SEQ ID NO: 148之LCDR1、SEQ ID NO: 149之LCDR2及SEQ ID NO: 150之LCDR3; 一重鏈可變區,該重鏈可變區包含SEQ ID NO: 151之HCDR1、SEQ ID NO: 152之HCDR2及SEQ ID NO: 153之HCDR3;及一輕鏈可變區,該輕鏈可變區包含SEQ ID NO: 154之LCDR1、SEQ ID NO: 155之LCDR2及SEQ ID NO: 156之LCDR3; 一重鏈可變區,該重鏈可變區包含SEQ ID NO: 157之HCDR1、SEQ ID NO: 158之HCDR2及SEQ ID NO: 159之HCDR3;及一輕鏈可變區,該輕鏈可變區包含SEQ ID NO: 160之LCDR1、SEQ ID NO: 161之LCDR2及SEQ ID NO: 162之LCDR3; 一重鏈可變區,該重鏈可變區包含SEQ ID NO: 163之HCDR1、SEQ ID NO: 164之HCDR2及SEQ ID NO: 165之HCDR3;及一輕鏈可變區,該輕鏈可變區包含SEQ ID NO: 166之LCDR1、SEQ ID NO: 167之LCDR2及SEQ ID NO: 168之LCDR3; 一重鏈可變區,該重鏈可變區包含SEQ ID NO: 169之HCDR1、SEQ ID NO: 170之HCDR2及SEQ ID NO: 171之HCDR3;及一輕鏈可變區,該輕鏈可變區包含SEQ ID NO: 172之LCDR1、SEQ ID NO: 173之LCDR2及SEQ ID NO: 174之LCDR3; 一重鏈可變區,該重鏈可變區包含SEQ ID NO: 175之HCDR1、SEQ ID NO: 176之HCDR2及SEQ ID NO: 177之HCDR3;及一輕鏈可變區,該輕鏈可變區包含SEQ ID NO: 178之LCDR1、SEQ ID NO: 179之LCDR2及SEQ ID NO: 180之LCDR3; 一重鏈可變區,該重鏈可變區包含SEQ ID NO: 181之HCDR1、SEQ ID NO: 182之HCDR2及SEQ ID NO: 183之HCDR3;及一輕鏈可變區,該輕鏈可變區包含SEQ ID NO: 184之LCDR1、SEQ ID NO: 185之LCDR2及SEQ ID NO: 186之LCDR3; 一重鏈可變區,該重鏈可變區包含SEQ ID NO: 187之HCDR1、SEQ ID NO: 188之HCDR2及SEQ ID NO: 189之HCDR3;及一輕鏈可變區,該輕鏈可變區包含SEQ ID NO: 190之LCDR1、SEQ ID NO: 191之LCDR2及SEQ ID NO: 192之LCDR3; 一重鏈可變區,該重鏈可變區包含SEQ ID NO: 193之HCDR1、SEQ ID NO: 194之HCDR2及SEQ ID NO: 195之HCDR3;及一輕鏈可變區,該輕鏈可變區包含SEQ ID NO: 196之LCDR1、SEQ ID NO: 197之LCDR2及SEQ ID NO: 198之LCDR3; 一重鏈可變區,該重鏈可變區包含SEQ ID NO: 199之HCDR1、SEQ ID NO: 200之HCDR2及SEQ ID NO: 201之HCDR3;及一輕鏈可變區,該輕鏈可變區包含SEQ ID NO: 202之LCDR1、SEQ ID NO: 203之LCDR2及SEQ ID NO: 204之LCDR3; 一重鏈可變區,該重鏈可變區包含SEQ ID NO: 205之HCDR1、SEQ ID NO: 206之HCDR2及SEQ ID NO: 207之HCDR3;及一輕鏈可變區,該輕鏈可變區包含SEQ ID NO: 208之LCDR1、SEQ ID NO: 209之LCDR2及SEQ ID NO: 210之LCDR3; 一重鏈可變區,該重鏈可變區包含SEQ ID NO: 211之HCDR1、SEQ ID NO: 212之HCDR2及SEQ ID NO: 213之HCDR3;及一輕鏈可變區,該輕鏈可變區包含SEQ ID NO: 214之LCDR1、SEQ ID NO: 215之LCDR2及SEQ ID NO: 216之LCDR3; 一重鏈可變區,該重鏈可變區包含SEQ ID NO: 217之HCDR1、SEQ ID NO: 218之HCDR2及SEQ ID NO: 219之HCDR3;及一輕鏈可變區,該輕鏈可變區包含SEQ ID NO: 220之LCDR1、SEQ ID NO: 221之LCDR2及SEQ ID NO: 222之LCDR3; 一重鏈可變區,該重鏈可變區包含SEQ ID NO: 223之HCDR1、SEQ ID NO: 224之HCDR2及SEQ ID NO: 225之HCDR3;及一輕鏈可變區,該輕鏈可變區包含SEQ ID NO: 226之LCDR1、SEQ ID NO: 227之LCDR2及SEQ ID NO: 228之LCDR3; 一重鏈可變區,該重鏈可變區包含SEQ ID NO: 229之HCDR1、SEQ ID NO: 230之HCDR2及SEQ ID NO: 231之HCDR3;及一輕鏈可變區,該輕鏈可變區包含SEQ ID NO: 232之LCDR1、SEQ ID NO: 233之LCDR2及SEQ ID NO: 234之LCDR3; 一重鏈可變區,該重鏈可變區包含SEQ ID NO: 235之HCDR1、SEQ ID NO: 236之HCDR2及SEQ ID NO: 237之HCDR3;及一輕鏈可變區,該輕鏈可變區包含SEQ ID NO: 238之LCDR1、SEQ ID NO: 239之LCDR2及SEQ ID NO: 240之LCDR3;或 一重鏈可變區,該重鏈可變區包含SEQ ID NO: 241之HCDR1、SEQ ID NO: 242之HCDR2及SEQ ID NO: 243之HCDR3;及一輕鏈可變區,該輕鏈可變區包含SEQ ID NO: 244之LCDR1、SEQ ID NO: 245之LCDR2及SEQ ID NO: 246之LCDR3。
- 如請求項1之融合蛋白,其中特異性結合於FAP之該抗原結合位點包含: SEQ ID NO: 102之一重鏈可變區及SEQ ID NO: 103之一輕鏈可變區; SEQ ID NO: 110之一重鏈可變區及SEQ ID NO: 111之一輕鏈可變區; SEQ ID NO: 248之一重鏈可變區及SEQ ID NO: 249之一輕鏈可變區; SEQ ID NO: 250之一重鏈可變區及SEQ ID NO: 251之一輕鏈可變區; SEQ ID NO: 252之一重鏈可變區及SEQ ID NO: 253之一輕鏈可變區; SEQ ID NO: 254之一重鏈可變區及SEQ ID NO: 255之一輕鏈可變區; SEQ ID NO: 256之一重鏈可變區及SEQ ID NO: 257之一輕鏈可變區; SEQ ID NO: 258之一重鏈可變區及SEQ ID NO: 259之一輕鏈可變區; SEQ ID NO: 260之一重鏈可變區及SEQ ID NO: 261之一輕鏈可變區; SEQ ID NO: 262之一重鏈可變區及SEQ ID NO: 263之一輕鏈可變區; SEQ ID NO: 264之一重鏈可變區及SEQ ID NO: 265之一輕鏈可變區; SEQ ID NO: 266之一重鏈可變區及SEQ ID NO: 267之一輕鏈可變區; SEQ ID NO: 268之一重鏈可變區及SEQ ID NO: 269之一輕鏈可變區; SEQ ID NO: 270之一重鏈可變區及SEQ ID NO: 271之一輕鏈可變區; SEQ ID NO: 272之一重鏈可變區及SEQ ID NO: 273之一輕鏈可變區; SEQ ID NO: 274之一重鏈可變區及SEQ ID NO: 275之一輕鏈可變區; SEQ ID NO: 276之一重鏈可變區及SEQ ID NO: 277之一輕鏈可變區; SEQ ID NO: 278之一重鏈可變區及SEQ ID NO: 279之一輕鏈可變區; SEQ ID NO: 280之一重鏈可變區及SEQ ID NO: 281之一輕鏈可變區; SEQ ID NO: 282之一重鏈可變區及SEQ ID NO: 283之一輕鏈可變區; SEQ ID NO: 284之一重鏈可變區及SEQ ID NO: 285之一輕鏈可變區; SEQ ID NO: 286之一重鏈可變區及SEQ ID NO: 287之一輕鏈可變區; SEQ ID NO: 72之scFv;或 SEQ ID NO: 84之scFv。
- 如請求項1之融合蛋白,其中該第一單體進一步包含特異性結合於FAP之一抗原結合位點。
- 如請求項3之融合蛋白,其中該第一單體包含以下結構式(III)或(IV): N'-X-[連接子(2)]p-Fc區片段或其變體-[連接子(3)]q-(T)r-C' (III) N'-(T)r-[連接子(2)]q-Fc區片段或其變體-[連接子(3)]p-X-C' (IV) 在該結構式(III)及該結構式(IV)中, N'為該融合蛋白之該N端, C'為該融合蛋白之該C端, X為該結構式(I)或(II), T為特異性結合於FAP之該抗原結合位點, 該等連接子(2)及(3)為肽連接子,及 p、q及r各自獨立地為0或1。
- 如請求項3或12之融合蛋白,其中該連接子包含一(G 4S) n連接子,其中n為1至10之整數中的任一個。
- 如請求項12之融合蛋白,其中該第一單體之該Fc區衍生自人類IgG1或小鼠IgG2a。
- 如請求項12之融合蛋白,其中該第一單體之該Fc包含一杵結構或一臼結構。
- 如請求項1之融合蛋白,其中該第二單體進一步包含特異性結合於FAP之一抗原結合位點。
- 如請求項16之融合蛋白,其中特異性結合於FAP之該抗原結合位點為Fab、scFv、Fv或其一片段。
- 如請求項16之融合蛋白,其中特異性結合於FAP之額外結合之抗原結合位點結合於該第二單體之N端或C端。
- 如請求項3之融合蛋白,其中該第二單體包含以下結構式(V): N'-(R)s-[連接子(4)]t-Q-[連接子(5)]u-Fc區片段或其變體-[連接子(6)]v-(W)a-C' (V) 在該結構式(V)中, N'為該融合蛋白之該N端, C'為該融合蛋白之該C端, R為特異性結合於FAP之該抗原結合位點, Q為特異性結合於FAP之該抗原結合位點, W為特異性結合於FAP之scFv;或具有結構式(I)或(II)之該IL-12或其之該變體, 該等連接子(4)至(6)為肽連接子,及 s、t、u及v各自獨立地為0或1。
- 如請求項19之融合蛋白,其中該結構式(V)包含以下結構式(V')及(V''): N'-(R')s-[連接子(4)]t-Q'-[連接子(5)]u-Fc區片段或其變體-[連接子(6)]p-(W)a-C' (V') N'-(R'')s-[連接子(4)]t-Q''-[連接子(7)]x-(W)b-C' (V'') 在該結構式(V')及該結構式(V'')中, R'為一特異性結合於FAP之抗體之一重鏈區,包含一可變區及一CH1區;或為該抗體之一輕鏈區; R''為一特異性結合於FAP之抗體之一輕鏈區;或為該抗體之一重鏈區,包含一可變區及一CH1區; 其中R'與R''彼此結合以形成該抗體之一可變區,其中該可變區特異性結合於FAP; Q'為一特異性結合於FAP之抗體之一重鏈區,包含一可變區及一CH1區;或為該抗體之一輕鏈區; Q''為一特異性結合於FAP之抗體之一輕鏈區;或為該抗體之一重鏈區,包含一可變區及一CH1區; 其中Q'與Q''彼此結合以形成該抗體之一可變區,其中該可變區特異性結合於FAP, R'及Q'各自為該抗體之一重鏈區,包含一可變區及一CH1區;或為該抗體之一輕鏈區; R''及Q''各自為該抗體之一輕鏈區;或為該抗體之一重鏈區,包含一可變區及一CH1區; 其中R'與R''以及Q'與Q''彼此結合以形成該抗體之一可變區,其中該可變區特異性結合於FAP, W為特異性結合於FAP之scFv, 該等連接子(4)、(5)及(7)為肽連接子,及 s、t、u、x、a及b各自獨立地為0或1。
- 如請求項1之融合蛋白,其中該融合蛋白包含結構式(III)及結構式(V);結構式(IV)及結構式(V);結構式(III)及結構式(III);結構式(IV)及結構式(IV);或結構式(V)及結構式(V)。
- 如請求項1之融合蛋白,其中該第二單體包含由SEQ ID NO: 102之胺基酸序列組成之一重鏈及由SEQ ID NO: 103之胺基酸序列組成之一輕鏈;或由SEQ ID NO: 110之胺基酸序列組成之一重鏈及由SEQ ID NO: 111之胺基酸序列組成之一輕鏈。
- 如請求項2之融合蛋白,其中該第二單體之該Fc包含一杵結構或一臼結構。
- 一種用於預防或治療癌症之醫藥組成物,其包含如請求項1至23中任一項之融合蛋白作為一活性成分。
- 如請求項24之醫藥組成物,其中該癌症為選自由以下組成之群中之任一者:胃癌、肝癌、肺癌、大腸直腸癌、乳癌、前列腺癌、皮膚癌、骨癌、多發性骨髓瘤、神經膠質瘤、卵巢癌、胰臟癌、子宮頸癌、甲狀腺癌、喉癌、急性骨髓性白血病、慢性骨髓性白血病、急性淋巴母細胞性白血病、慢性淋巴母細胞性白血病、腦瘤、神經母細胞瘤、視網膜母細胞瘤、頭頸癌、唾液腺癌及淋巴瘤。
- 一種多核苷酸,其編碼如請求項1之第一單體。
- 一種載體,其包含如請求項26之多核苷酸。
- 一種多核苷酸,其編碼如請求項1之第二單體。
- 一種載體,其包含如請求項28之多核苷酸。
- 一種轉型細胞,其中已引入如請求項27或29之載體。
- 一種產生一融合蛋白之方法,其包含: i)培養如請求項30之轉型細胞;及 ii)回收包含該第一單體及該第二單體之一融合蛋白。
- 一種用於治療或預防癌症之方法,其包含: 向一個體投予一融合蛋白,該融合蛋白包含第一單體及第二單體,該第一單體包含IL-12或其一變體,且該第二單體包含特異性結合於FAP之一抗原結合位點。
- 一種一融合蛋白用於治療癌症之用途,該融合蛋白包含第一單體及第二單體,該第一單體包含IL-12或其一變體,且該第二單體包含特異性結合於FAP之一抗原結合位點。
- 一種一融合蛋白用於製造供治療癌症用之一藥劑之用途,該融合蛋白包含第一單體及第二單體,該第一單體包含IL-12或其一變體,且該第二單體包含特異性結合於FAP之一抗原結合位點。
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US3924445A (en) | 1973-09-28 | 1975-12-09 | Toyota Motor Co Ltd | Flow rate measuring system with calibration means |
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- 2021-08-10 KR KR1020210105643A patent/KR20220020227A/ko not_active Application Discontinuation
- 2021-08-10 JP JP2023501232A patent/JP2023533042A/ja active Pending
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US20230295258A1 (en) | 2023-09-21 |
JP2023533042A (ja) | 2023-08-01 |
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IL300534A (en) | 2023-04-01 |
BR112022026577A2 (pt) | 2023-02-23 |
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CN116390937A (zh) | 2023-07-04 |
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EP4198051A1 (en) | 2023-06-21 |
EP4198050A1 (en) | 2023-06-21 |
AU2021324738A1 (en) | 2023-03-23 |
KR20220020229A (ko) | 2022-02-18 |
AU2021324738B2 (en) | 2024-05-09 |
WO2022035201A1 (ko) | 2022-02-17 |
CN116323672A (zh) | 2023-06-23 |
US20230295327A1 (en) | 2023-09-21 |
TWI819352B (zh) | 2023-10-21 |
CA3191454A1 (en) | 2022-02-17 |
EP4198050A4 (en) | 2024-05-01 |
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