TW202309089A - 抗體 - Google Patents
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- TW202309089A TW202309089A TW111116603A TW111116603A TW202309089A TW 202309089 A TW202309089 A TW 202309089A TW 111116603 A TW111116603 A TW 111116603A TW 111116603 A TW111116603 A TW 111116603A TW 202309089 A TW202309089 A TW 202309089A
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Abstract
本發明係關於與TREM1結合且抑制其與其天然配位體中之一或多者之相互作用的抗體。提供此類抗體之特定實例。亦提供該等抗體之治療性用途及產生此類抗體之方法。
Description
本發明係關於抗TREM1抗體及其用於治療神經病症之用途,且更特定言之,用於治療肌肉萎縮性脊髓側索硬化症(ALS)及阿茲海默氏病(Alzheimer's disease)之用途。
表現於骨髓細胞上之觸發受體(TREM)為包括免疫活化性及免疫抑制性同功異型物的受體,由定位至人類染色體6p21及小鼠染色體17之MHC基因簇編碼。TREM為免疫球蛋白(Ig)超家族之成員,其主要表現在髓系細胞中,包括周邊之單核球、嗜中性白血球及樹突狀細胞以及中樞神經系統(CNS)之微神經膠質細胞。表現於骨髓細胞上之觸發受體-1 (TREM1),另稱為分化簇354,為TREM家族中第一個經鑑別之成員且其與Ig超家族之其他受體的同源性有限。TREM1為一種跨膜醣蛋白,其具有單一Ig樣域、具有與其信號傳導搭配物DAP12上之帶負電天冬胺酸相互作用的帶(+)電離胺酸殘基之跨膜區及不具有任何信號傳導域之短胞質尾區。
已提出TREM1經由與其所提出之配位體肽聚糖識別蛋白1 (PGLYRP1)、高遷移率基團B1 (HMGB1)、可溶性CD177、熱休克蛋白70 (HSP70)、胞外冷誘導RNA-結合蛋白(eCIRP)相互作用之活化會誘導形成「頭尾相接(head-to-tail)」均二聚體。二聚體交聯觸發所募集之DAP12上基於免疫受體酪胺酸之活化基元(ITAM)的磷酸化,其為脾臟酪胺酸激酶(SYK)及其下游信號傳導搭配物(包括ζ鏈相關蛋白激酶70 (ZAP70)、casitas b系淋巴瘤(Cbl)、無七子(son of sevenless;SOS)及生長因子受體結合蛋白2 (GRB2))提供對接位點來實現信號傳導及功能。此等相互作用經由磷脂醯肌醇3-激酶(PI3K)、磷脂酶-C-γ 2 (PLC-γ2)及ERK路徑觸發下游信號轉導。此等事件之後為鈣動員,轉錄因子之活化,該等轉錄因子包括含ETS之蛋白(ELK1)、活化T細胞之核因子(NFAT)、AP1、c-fos、c-Jun及NF-κB。此路徑與TREM家族之另一成員TREM2共用。
不同於明確為免疫活化劑之TREM1,TREM2在分別結合於高親和力配位體及低親和力配位體時可充當促炎劑及消炎劑兩者。在穩態條件下,TREM2與低親和力配位體的相互作用使路徑處於受控狀態,從而維持穩態(Konishi H.等人. Frontiers Cellular Neuroscience 2018)。
在神經發炎性神經退化性病狀中,胞內因子(尤其TREM1配位體),另稱為損傷相關分子模式(DAMP),自垂死神經元溢出且經由TREM1及其他模式識別受體活化監測微神經膠質細胞。TREM1-DAMP相互作用超過TREM2活性,導致微神經膠質細胞/先天性免疫活化、直接神經毒性及經由異常吞噬對突觸架構之破壞。除其在路徑調節中與TREM2之「陰及陽(Yin and Yang)」動力學以外,TREM1作為先天性免疫反應之其他關鍵調節因子(包括鐸樣(TLR)及NOD樣受體家族)之增強劑攜帶獨特且不同的功能。此等受體之擴增經由TREM1誘導之TLR(其下游節點,諸如MYD88及IKk)過度表現或經由在TLR促效劑與TREM1配位體之間形成的TREM1配位體複合物直接交聯而發生,如同PGN (TLR2/TLR4刺激劑)及PGLYRP1 (TREM1配位體)。
TREM1多路徑活化之結果引起先天性免疫/微神經膠質細胞促發炎反應增強,包括細胞介素及趨化介素釋放,共刺激分子/抗原呈遞之上調及下游異常吞噬活性(Buchon等人, 2000)。此等過程為各種神經退化性、神經發育性及自體免疫性中樞神經系統病症之病理學的共同之處。包括全基因體關聯研究(GWAS)之人類遺傳學已表明TREM2,TREM1/TREM2路徑下游的若干節點,諸如DAP12、Syk、PLCγ2及TLR作為各種神經退化性疾病中之風險基因。
US 9,000,127提供破壞TREM1與其配位體之相互作用的抗TREM1抗體。提供所揭示之抗體用於治療患有發炎性疾病,諸如類風濕性關節炎及發炎性腸病之個體。
WO 2017/152102揭示與TREM1蛋白結合且調節或增強一或多種TREM1活性之抗體。
本發明藉由提供具有如本文所描述之功能及結構特性的抗TREM1抗體來解決對神經病症之新治療的需要。
特定言之,本發明提供一種與人類TREM1結合之抗體,其包含:
輕鏈可變區,該輕鏈可變區包含:
包含SEQ ID NO:11之CDR-L1,
包含SEQ ID NO:12之CDR-L2,及
包含SEQ ID NO:13之CDR-L3;
以及重鏈可變區,該重鏈可變區包含:
包含SEQ ID NO:14之CDR-H1,
包含SEQ ID NO:15之CDR-H2,及
包含SEQ ID NO:16之CDR-H3。
縮寫
表
1.
在整個本說明書中使用之縮寫
ADCC | 抗體依賴性細胞毒性 |
CDC | 補體依賴性細胞毒性 |
CDR | 互補決定區 |
CH1、CH2、CH3 | 恆定重鏈域1、2、3 |
CL | 恆定輕鏈域 |
dsscFv | 二硫鍵穩定之scFv |
Fab | 抗原結合片段 |
Fc | 可結晶片段 |
FR1、FR2、FR3、FR4 | 構架區1、2、3、4 |
Fv | 可變域片段 |
HVR | 高變區 |
KD | 解離常數 |
mAb | 單株抗體 |
scFv | 單鏈可變片段 |
VH | 重鏈可變區 |
VHH | 單域抗體(或駱駝科) |
VL | 輕鏈可變區 |
VNAR | IgNAR之可變域 |
表
2.
胺基酸縮寫
定義
縮寫 | 1 字母縮寫 | 胺基酸名稱 |
Ala | A | 丙胺酸 |
Arg | R | 精胺酸 |
Asn | N | 天冬醯胺 |
Asp | D | 天冬胺酸 |
Cys | C | 半胱胺酸 |
Gln | Q | 麩醯胺酸 |
Glu | E | 麩胺酸 |
Gly | G | 甘胺酸 |
His | H | 組胺酸 |
Ile | I | 異白胺酸 |
Leu | L | 白胺酸 |
Lys | K | 離胺酸 |
Met | M | 甲硫胺酸 |
Phe | F | 苯丙胺酸 |
Pro | P | 脯胺酸 |
Pyl | O | 吡咯離胺酸 |
Ser | S | 絲胺酸 |
Sec | U | 硒半胱胺酸 |
Thr | T | 蘇胺酸 |
Trp | W | 色胺酸 |
Tyr | Y | 酪胺酸 |
Val | V | 纈胺酸 |
在整個本說明書中使用以下術語。
如本文中所使用之術語「受體人類構架」為來源於人類免疫球蛋白構架或人類共同構架的包含輕鏈可變域(VL)構架或重鏈可變域(VH)構架之胺基酸序列之構架。來源於人類免疫球蛋白構架或人類共同構架之受體人類構架可包含與人類免疫球蛋白構架或人類共同構架相同的胺基酸序列,或其可含有胺基酸序列變化。
術語「親和力」係指抗體與其目標蛋白質之間的所有非共價相互作用之強度。如本文中所使用,除非另外指明,否則術語「結合親和力」係指固有結合親和力,其反映結合對(例如,抗體與抗原)中之成員之間的1:1相互作用。分子針對其結合搭配物之親和力通常可由解離常數(KD)表示。可藉由此項技術中已知之常用方法(包括本文所描述之彼等方法)來量測親和力。
在抗體之情形下,術語「親和力成熟」係指與不具有高變區中之一或多種變化之親本抗體相比,在高變區中具有一或多種此類變化之抗體,其中此類變化引起抗體針對抗原之親和力之改良。
在本文中,術語「抗體」係以最廣泛含義使用且涵蓋各種抗體結構,包括(但不限於)單株抗體、多株抗體及多特異性抗體,只要其呈現所需抗原結合活性即可。如本文中所使用,術語抗體係指完全(全長)抗體(亦即,包含兩條重鏈及兩條輕鏈之元件)及其功能活性片段(亦即,含有特異性結合於抗原之抗原結合域之分子,亦稱為抗體片段或抗原結合片段)。除非上下文另外規定,否則本文中關於抗體所描述之特徵亦適用於抗體片段。術語「抗體」涵蓋單價抗體,亦即,僅包含一個抗原結合域之抗體(例如,包含互連的全長重鏈及全長輕鏈之單臂抗體,亦稱為「半抗體」),及多價抗體,亦即,包含超過一個抗原結合域之抗體,例如,二價抗體。
術語「與參考抗體結合於相同抗原決定基之抗體」係指滿足以下條件之抗體:在競爭分析法中阻斷參考抗體與其抗原之結合達50%或更多,且相反,在競爭分析法中參考抗體阻斷該抗體與其抗原之結合達50%或更多。
術語「抗體依賴性細胞毒性」或「ADCC」為誘導細胞死亡之機制,其依賴於經抗體塗佈之目標細胞與具有裂解活性之效應細胞(諸如自然殺手細胞、單核球、巨噬細胞及嗜中性白血球)經由表現於效應細胞上之Fcγ受體(FcγR)進行之相互作用。
如本文中所使用,術語「抗原結合片段」係指功能活性抗體結合片段,包括(但不限於) Fab、經修飾之Fab、Fab'、經修飾之Fab'、F(ab')2、Fv、單域抗體、scFv、Fv、二價抗體、三價抗體或四價抗體、雙scFv、雙功能抗體、三功能抗體、四功能抗體及以上中之任一者之抗原決定基結合片段(參見例如Holliger及Hudson, 2005, Nature Biotech. 23(9): 1126-1136;Adair及Lawson, 2005, Drug Design Reviews - Online 2(3), 209-217)。如本文中所使用,「結合片段」係指滿足以下條件之片段:能夠以足以將該片段表徵為對肽或抗原具有特異性的親和力結合於目標肽或抗原。
術語「抗體變異體」係指多肽,舉例而言,具有本文中所描述之所需特徵且包含與參考抗體之VH及/或VL具有至少約80%胺基酸序列一致性之VH及/或VL之抗體。此類抗體變異體包括例如其中一或多個胺基酸殘基添加至VH及/或VL域中或自VH及/或VL域缺失之抗體。通常,抗體變異體將與本文中所描述之抗體具有至少約80%胺基酸序列一致性,或者至少約85%、90%、95%、96%、97%、98%或99%胺基酸序列一致性。視情況地,變異體抗體與本文所提供之抗體序列相比將具有不超過一個保守性胺基酸取代,或者與本文所提供之抗體序列相比不超過約2、3、4、5、6、7、8、9或10個保守性胺基酸取代中之任一者。在實施例中,「抗體變異體」係指包含VH及/或VL之抗體或其抗原結合片段,其中抗體或其抗原結合片段之非CDR區與本文所描述之抗體具有至少約85%、90%、95%、96%、97%、98%或99%胺基酸序列一致性。
如本文中所使用之術語「抗原結合域」係指抗體中之與目標抗原特異性相互作用之部分,其包含一或多個可變域之一部分或全部,例如一對可變域VH及VL之一部分或全部。結合域可包含單域抗體。各結合域可為單價的。各結合域可包含不超過一個VH及一個VL。
如本文中所使用,術語「雙特異性」或「雙特異性抗體」係指具有兩種抗原特異性之抗體。
術語「互補決定區」或「CDR」通常係指包含六個CDR之抗體:三個在VH中(H1、H2、H3)且三個在VL中(L1、L2、L3)。根據Kabat編號系統,重鏈可變域之CDR位於殘基31-35 (CDR-H1)、殘基50-65 (CDR-H2)及殘基95-102 (CDR-H3)處。然而,根據Chothia (Chothia, C.及Lesk, A.M. J. Mol. Biol., 196, 901-917 (1987)),等效於CDR-H1的環自殘基26延伸至殘基32。因此,除非另外規定,否則如Kabat編號系統與Chothia拓樸環定義之組合所描述,如本文中所使用之「CDR-H1」意欲指殘基26至35。根據Kabat編號系統,輕鏈可變域之CDR位於殘基24-34 (CDR-L1)、殘基50-56 (CDR-L2)及殘基89-97 (CDR-L3)處。除非另外指明,否則本文中之可變域中之CDR殘基及其他殘基(例如,FR殘基)係根據Kabat編號。
術語「嵌合」抗體係指滿足以下條件之抗體:重鏈及/或輕鏈之可變域(或其至少一部分)係來源於特定來源或物種,而重鏈及/或輕鏈之其餘部分(亦即,恆定域)係來源於不同來源或物種(Morrison; PNAS 81, 6851 (1984))。舉例而言,嵌合抗體可包含非人類可變域及人類恆定域。通常使用重組DNA方法製備嵌合抗體。「嵌合抗體」之子類別為「人類化抗體」。
抗體之「類別」係指其重鏈所具有之恆定域或恆定區的類型。存在五個主要抗體類別:IgA、IgD、IgE、IgG及IgM,且此等類別中之若干個類別可進一步分成子類(同型),例如IgG1、IgG2、IgG3、IgG4、IgA1及IgA2。對應於不同類別之免疫球蛋白之重鏈恆定域分別稱為α、δ、ε、γ及μ。
術語「補體依賴性細胞毒性」或「CDC」係指誘導細胞死亡之機制,其中與目標結合的抗體之Fc效應子域結合於且活化補體組分C1q,其又活化補體級聯,引起目標細胞死亡。
如本文中所使用,術語「恆定域」或「恆定區」可互換地用於指抗體之位於可變區外部之域。恆定域在相同同型之所有抗體中一致,但在同型之間係不同的。通常,重鏈恆定區自N端至C端由包含三個或四個恆定域之CH1-鉸鏈-CH2-CH3-視情況CH4形成。
術語「競爭抗體」或「交叉競爭抗體」應解釋為意謂所主張之抗體結合於(i)抗原上之與由參考抗體所結合之位置相同的位置,或(ii)抗原上之抗體在空間上阻礙參考抗體與抗原結合之位置。
如本文中所使用,術語「衍生物」意欲包括反應性衍生物,例如硫醇選擇性反應性基團,諸如順丁烯二醯亞胺及其類似物。反應性基團可直接地或經由連接子區段連接至聚合物。應瞭解此類基團之殘基在一些情況下將作為抗體片段與聚合物之間的鍵聯基團形成產物之一部分。
在產生可變序列之情形下,術語「來源於」係指以下事實:所使用之序列或與所使用之序列極類似之序列係自原始遺傳物質(諸如抗體之輕鏈或重鏈)獲得。
如本文中所使用,術語「雙功能抗體」係指兩個Fv對,第一VH/VL對及另一個VH/VL對,其具有兩個Fv間連接子,使得第一Fv之VH連接至第二Fv之VL且第一Fv之VL連接至第二Fv之VH。
如本文中所使用,術語「DiFab」係指經由重鏈之C端連接之兩個Fab分子。
如本文中所使用,術語「DiFab'」係指經由鉸鏈區中之一或多個二硫鍵連接之兩個Fab'分子。
如本文中所使用,術語「dsscFv」或「二硫鍵穩定化之單鏈可變片段」係指藉由VH與VL可變域之間的肽連接子穩定化且亦包括VH與VL之間的域間二硫鍵的單鏈可變片段。(參見例如Weatherill等人, Protein Engineering, Design & Selection, 25 (321-329), 2012, WO2007109254。)
術語「DVD-Ig」(亦稱為雙重V域IgG)係指具有4個額外可變域(每條重鏈及每條輕鏈之N端上具有一個)之全長抗體。
術語「效應功能」係指可歸因於抗體之Fc區之生物活性,其隨抗體同型而變化。抗體效應功能之實例包括:C1q結合及補體依賴性細胞毒性(CDC);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)之下調;及B細胞活化。
如本文中所使用,術語「效應分子」包括例如抗腫瘤劑、藥物、毒素、生物活性蛋白質(例如,酶)、其他抗體或抗體片段、合成或天然存在之聚合物、核酸及其片段(例如,DNA、RNA及其片段)、放射性核種(尤其放射性碘)、放射性同位素、螯合金屬、奈米粒子及報導基團,諸如螢光化合物或可藉由NMR或ESR光譜法偵測的化合物。
在抗體之情形下,術語「抗原決定基」或「結合位點」係指抗原上之由抗體之互補位結合或識別之位點(或部分)。抗原決定基可由相鄰胺基酸形成(亦通常稱為「線形抗原決定基」)或由蛋白質之三級摺疊形成之非相鄰胺基酸形成(通常稱為「構形抗原決定基」)。由相鄰胺基酸形成的抗原決定基通常在暴露於變性溶劑後保留,而藉由摺疊形成的抗原決定基通常在變性溶劑處理後消失。抗原決定基通常在獨特空間構形中包括至少3個,且更通常至少5-10個胺基酸。抗原決定基通常由分子之化學活性表面基團(諸如胺基酸、糖側鏈)組成且通常具有特定3D結構及電荷特徵。
「EU索引」或「如Kabat中之EU索引」或「EU編號方案」係指EU抗體之編號(Edelman等人, 1969, Proc Natl Acad Sci USA 63:78-85)。此類編號通常在參考抗體重鏈恆定區中之殘基時使用(例如,如Kabat等人中所報告)。除非另外陳述,否則EU編號方案係用於指本文中所描述之抗體重鏈恆定區中之殘基。
如本文中所使用,術語「Fab」係指包含有包含輕鏈之VL (可變輕鏈)域及恆定域(CL)的輕鏈片段以及重鏈之VH (可變重鏈)域及第一恆定域(CH1)的抗體片段。根據本發明之Fab'之二聚體產生F(ab')2,其中例如二聚可經由鉸鏈。
如本文中所使用,術語「Fab'-Fv」與FabFv類似,其中Fab部分由Fab'置換。該型式可以其聚乙二醇化版本形式提供。
如本文中所使用,術語「Fab'-scFv」為具有在輕鏈或重鏈之C端上附接之scFv之Fab'分子。
如本文中所使用,術語「Fab-dsFv」係指其中Fv內二硫鍵使附接之C端可變區穩定之FabFv。該型式可以其聚乙二醇化版本形式提供。
如本文中所使用,術語「Fab-Fv」係指具有附接以下中之每一者之C端的可變區之Fab片段:重鏈之CH1及輕鏈之CL。該型式可以其聚乙二醇化版本形式提供。
如本文中所使用,術語「Fab-scFv」為具有在輕鏈或重鏈之C端上附接之scFv之Fab分子。
術語「Fc」、「Fc片段」及「Fc區」可互換地用於指抗體之包含除第一恆定區免疫球蛋白域以外的抗體之恆定區之C端區。因此,Fc係指IgA、IgD及IgG之最後兩個恆定域CH2及CH3,或IgE及IgM之最後三個恆定域,及此等域之N端之可撓性鉸鏈。人類IgG1重鏈Fc區在本文中定義為包含殘基C226至其羧基端,其中編號係根據EU索引。在人類IgG1之情形下,根據EU索引,下部鉸鏈係指位置226-236,CH2域係指位置237-340且CH3域係指位置341-447。其他免疫球蛋白之相對應Fc區可藉由序列比對來識別。
術語「構架」或「FR」係指除高變區殘基以外的可變域殘基。可變域之FR一般由四個FR域組成:FR1、FR2、FR3及FR4。因此,在VH (或VL)中,HVR及FR序列一般依以下序列呈現:FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4。
術語「全長抗體」在本文中用於指具有與原生抗體結構實質上類似之結構或具有含有如本文中所定義之Fc區之重鏈之抗體。各輕鏈包含輕鏈可變區(本文中縮寫為VL)及輕鏈恆定區(CL)。視Ig類別而定,各重鏈包含重鏈可變區(本文中縮寫為VH)及由三個恆定域CH1、CH2及CH3或四個恆定域CH1、CH2、CH3及CH4構成之重鏈恆定區(CH)。抗體之恆定區可介導免疫球蛋白結合於宿主組織或因子,包括免疫系統之各種細胞(例如效應細胞)及經典補體系統之第一組分(Clq)。
術語「Fv」係指全長抗體之兩個可變域,例如共同操作性可變域,諸如同源對或親和力成熟可變域,亦即,VH及VL對。
如在胺基酸序列之情形下所使用,術語「極類似」意指在全長範圍內達到95%類似或更高,諸如96%、97%、98%或99%類似之胺基酸序列。
術語「人類抗體」係指滿足以下條件之抗體:具有對應於由人類或人類細胞產生或來源於非人類來源之抗體的胺基酸序列之胺基酸序列,該非人類來源利用人類抗體譜系或其他人類抗體編碼序列。人類抗體之此定義特定排除包含非人類抗原結合殘基之人類化抗體。
術語「人類共同構架」係指表示一系列人類免疫球蛋白VL或VH構架序列中最常出現之胺基酸殘基的構架。一般而言,人類免疫球蛋白VL或VH序列係選自可變域序列之子組。通常,序列子組為如Kabat等人, Sequences of Proteins of Immunological Interest, 第五版, NIH公開案91-3242, Bethesda MD (1991), 第1-3卷中之子組。在一些實施例中,對於VL,子組為如Kabat等人, 同前文獻中之子組κI。在一些實施例中,對於VH,子組為如Kabat等人中之子組III。在一些實施例中,對於VH,子組為如Kabat等人中之子組IV。
術語「人類化」抗體係指包含來自非人類HVR之胺基酸殘基及來自人類FR之胺基酸殘基之抗體。典型地,重鏈及/或輕鏈含有一或多個來自供體抗體(例如非人類抗體,諸如鼠類或兔單株抗體)之CDR (包括必要時一或多個經修飾之CDR)且移植至接受體抗體(例如人類抗體)之重鏈及/或輕鏈可變區構架中。(參見例如Vaughan等人, Nature Biotechnology, 16, 535-539, 1998)。此類人類化抗體之優點係降低針對人類之免疫原性,同時保留親本非人類抗體之特異性及親和力。可僅將來自上文所描述之任一CDR之一或多個特異性決定殘基轉移至人類抗體構架中,而非轉移整個CDR (參見例如Kashmiri等人, 2005, Methods, 36, 25-34)。「人類化」抗體係指包含來自非人類HVR之胺基酸殘基及來自人類FR之胺基酸殘基的嵌合抗體。抗體(例如非人類抗體)之「人類化形式」係指已經歷人類化之抗體。
如本文中所使用,術語「高變區」或「HVR」係指抗體可變域中之滿足以下條件之各區域:在序列方面具有高變性(「互補決定區」或「CDR」),及/或形成結構上定義之環(「高變環」),及/或含有抗原接觸殘基(「抗原接觸點」)。
如本文中所使用,術語「IC50」係指半最大抑制濃度,其為物質(諸如抗體)抑制特定生物或生物化學功能之有效性之量度。IC50係定量量度,其指示抑制既定生物過程達50%所需之特定物質之量。
序列中之胺基酸之間的「一致性」指示在所比對之序列中之任何特定位置,序列之間的胺基酸殘基係一致的。
如本文中所使用,術語「IgG-scFv」為在各重鏈或各輕鏈之C端上具有scFv之全長抗體。
如本文中所使用,術語「IgG-V」為在各重鏈或各輕鏈之C端上具有可變域之全長抗體。
術語「IgG1 LALA」或「hIgG1 LALA」係指已在IgG1恆定區中引入胺基酸取代L234A/L235A的野生型人類IgG1同功異型物的突變體。
如例如Angal等人, Molecular Immunology, 1993, 30 (1), 105-108中所描述,術語「IgG4P」或「hIgG4P」係指其中胺基酸228(根據EU編號)經脯胺酸置換之野生型人類IgG4同功異型物的突變體。
在本說明書通篇中,術語「經分離」意謂視具體情況而定,抗體或聚核苷酸存在於與其在自然界中所存在於之物理環境不同的物理環境中。術語「經分離」之核酸係指已自其天然環境分離或以合成方式產生之核酸分子。經分離之核酸可包含合成DNA(例如,藉由化學處理產生)、cDNA、基因體DNA或其任何組合。
術語「Kabat殘基名稱」或「Kabat」係指通常用於抗體之殘基編號方案。此類編號並非始終與胺基酸殘基之線形編號直接對應。對應於基本可變域結構的縮短或插入結構組分、是否為構架或互補決定區(CDR),實際線性胺基酸序列含有的胺基酸可比嚴格Kabat編號少或含有其他胺基酸。對於給定抗體,可藉由比對抗體序列與「標準」Kabat編號序列之同源殘基來確定殘基之正確Kabat編號。關於詳情,參見Kabat等人, Sequences of Proteins of Immunological Interest, 第5版. Public Health Service, National Institutes of Health, Bethesda, MD (1991)。除非另外指明,否則在整個本說明書中使用Kabat編號。
如本文所使用,術語「KD」係指解離常數,由Kd與Ka之比率(亦即,Kd/Ka)得到且以莫耳濃度(M)表示。Kd及Ka分別係指特定抗原-抗體相互作用之解離速率及締合速率。抗體之KD值可使用此項技術中沿用已久之方法測定。
術語「單株抗體」(或「mAb」)係指自實質上均質的抗體群體獲得之抗體,亦即,除可能少量存在之可能的突變(例如,天然存在之突變)以外,各個別單株抗體製劑係一致的。然而,存在於組合物中之各種不同的抗體分子之間可存在與轉譯後修飾(例如,重鏈C端離胺酸之裂解、天冬醯胺殘基之去醯胺化及/或天冬胺酸殘基之異構化)有關的蛋白質序列之某些差異。與多株抗體製劑不同,單株抗體製劑中之各單株抗體係針對抗原上之單一決定子。
如本文中所使用,術語「多互補位抗體」係指包含兩個或更多個不同互補位之如本文中所描述之抗體,該等互補位與來自相同抗原或兩種不同抗原之不同抗原決定基相互作用。本文中所描述之多互補位抗體可為雙互補位、三互補位、四互補位。
如本文中所使用之術語「多特異性」或「多特異性抗體」係指具有至少兩個結合域(亦即,兩個或更多個結合域,例如兩個或三個結合域)之如本文中所描述之抗體,其中該至少兩個結合域獨立地結合兩種不同抗原或相同抗原上之兩種不同抗原決定基。多特異性抗體對於各特異性(抗原)而言通常為單價的。本文所描述之多特異性抗體涵蓋單價及多價,例如二價、三價、四價多特異性抗體。舉例而言,抗體可包含連接至兩個scFv或dsscFv之Fab,各scFv或dsscFv結合相同或不同的目標(例如,一個scFv或dsscFv結合治療目標且一個scFv或dsscFv藉由結合於例如白蛋白來延長半衰期)。此類抗體描述於WO2015/197772中。
在抗體之情形下,術語「中和(neutralizing)」(或「中和(neutralize)」)描述能夠抑制或減弱其目標(目標蛋白)之生物信號傳導活性的抗體。
術語「互補位」係指抗體中之識別且結合於抗原之區域。
術語相對於多肽及抗體序列之「序列一致性(或類似性)百分比(%)」定義為在比對序列且視需要引入空位以實現最大序列一致性百分比且不將任何保守性取代視為序列一致性之一部分之後,候選序列中之與所比較之多肽中之胺基酸殘基一致(或類似)的胺基酸殘基之百分比。
「醫藥學上可接受之載劑」係指藥物調配物中除活性成分以外之對受試者無毒的成分。醫藥學上可接受之載劑包括(但不限於)緩衝液、賦形劑、穩定劑或防腐劑。
術語「多株抗體」係指與抗原之超過一種抗原決定基結合(或以其他方式相互作用)之不同抗體分子之混合物。
在抗體之情形下,術語「預防」在本文中可與術語「抑制」互換地使用且指示根據本發明之抗體對特定生物過程或分子相互作用之作用。
術語「sc雙功能抗體」係指包含Fv內連接子之雙功能抗體,使得分子包含三個連接子且形成VH及VL端各自連接至另一對Fv之一個可變區之正常scFv。
如本文中所使用之術語「sc雙功能抗體-CH3」係指各自例如經由鉸鏈連接至CH3域之兩個sc雙功能抗體分子。
如本文中所使用,術語「sc雙功能抗體-Fc」為兩個sc雙功能抗體,其中各sc雙功能抗體例如經由鉸鏈附接至恆定區片段-CH2CH3之CH2域之N端。
如本文中所使用,術語「單鏈可變片段」或「scFv」係指由VH與VL可變域之間的肽連接子穩定化之單鏈可變片段。
如本文中所使用,術語「ScFv-Fc-scFv」係指四個scFv,其中各scFv中之一者附接至CH2CH3片段之兩條重鏈之N端及C端。
如本文中所使用之術語「scFv-IgG」為在各重鏈或各輕鏈上具有N端之scFv的全長抗體。
如本文中所使用之術語「類似性」指示在比對序列中之任何特定位置處,胺基酸殘基在序列之間屬於類似類型。舉例而言,白胺酸可取代異白胺酸或纈胺酸。通常可彼此間取代的其他胺基酸包括但不限於:
- 苯丙胺酸、酪胺酸及色胺酸(具有芳族側鏈之胺基酸);
- 離胺酸、精胺酸及組胺酸(具有鹼性側鏈之胺基酸);
- 天冬胺酸及麩胺酸(具有酸性側鏈之胺基酸);
- 天冬醯胺酸及麩醯胺酸(具有醯胺側鏈之胺基酸);及
- 半胱胺酸及甲硫胺酸(具有含硫側鏈之胺基酸)。
如本文中所使用,術語「單域抗體」係指由單一單體可變域組成之抗體片段。單域抗體之實例包括VH或VL或VHH或V-NAR。
在抗體之情形下,如本文所使用之術語「特異性」意指僅識別特異性抗原之抗體,或相比於與非特異性抗原之結合,對特異性抗原具有明顯更高的結合親和力(例如,至少5、6、7、8、9、10倍更高的結合親和力)之抗體。
如本文中所使用,術語「空間上阻斷」或「空間上阻止」意指藉由結合於第一蛋白質之第三蛋白質來阻斷第一蛋白質與第二蛋白質之間的相互作用之方法。歸因於第二蛋白質與第三蛋白質之間的不適當的凡得瓦爾力(van der Waals)或靜電相互作用,第一蛋白質與第三蛋白質之間的結合阻止第二蛋白質結合於第一蛋白質。
在治療及診斷之情形下,術語「受試者」或「個體」通常係指哺乳動物。哺乳動物包括(但不限於)家養動物(例如牛、羊、貓、狗及馬)、靈長類動物(例如人類及非人類靈長類動物,諸如猴)、兔及嚙齒動物(例如小鼠及大鼠)。更特定言之,個體或受試者為人類。
如本文中所使用之術語「串聯scFv」係指經由單一連接子連接,使得存在單一Fv間連接子之至少兩個scFv。
如本文中所使用,術語「串聯scFv-Fc」係指至少兩個串聯scFv,其中各scFv例如經由鉸鏈附接至恆定區片段-CH2CH3之CH2域之N端。
如本文中所使用,術語「目標」或「抗體目標」係指抗體結合之目標抗原。
如本文中所使用,術語「四功能抗體」係指包含四個Fv及四個Fv間連接子之與雙功能抗體類似的型式。
術語「治療有效量」係指當向受試者投與以用於治療疾病時,足以實現此類疾病之治療的抗體之量。治療有效量將視抗體、所治療之受試者之疾病及其嚴重程度以及年齡、體重等而變化。
如本文中所使用之術語「三功能抗體」(亦稱為Fab(scFv)
2)係指具有附接至輕鏈之C端之第一scFv及附接至重鏈之C端之第二scFv的Fab片段。
如本文中所使用,術語「三特異性或三特異性抗體」係指具有三種抗原結合特異性之抗體。舉例而言,抗體為具有三個抗原結合域(三價)之抗體,該等三個抗原結合域獨立地結合同一抗原上之三個不同抗原或三個不同抗原決定基,亦即各結合域對於各抗原為單價的。三特異性抗體型式之實例中之一者為TrYbe。
術語「預防(prevent/preventing)」及其類似術語係指實現完全或部分預防疾病或其症狀方面之預防性作用。因此,預防涵蓋在可能易患疾病,但尚未診斷為罹患疾病之受試者中停止疾病之發生。
術語「治療(treatment/treating)」及其類似術語係指實現所需藥理學及/或生理學效應。該作用就部分或完成治癒疾病及/或由疾病引起之不良作用而言可為治療性的。因此,治療涵蓋(a)抑制疾病,亦即,遏制其發展;及(b)緩解疾病,亦即,引起疾病消退。
如本文中所使用,術語「TrYbe」係指包含兩個dsscFv之三功能抗體。如本文中所使用,dsFab係指具有可變區內二硫鍵之Fab。
術語「可變區」或「可變域」係指抗體重鏈或輕鏈中之涉及抗體與抗原之結合之域。全長抗體之重鏈(VH)及輕鏈(VL)之可變域一般具有類似結構,其中各域包含四個保守構架區(FR)及三個CDR。(參見例如Kindt等人. Kuby Immunology, 第6版, W.H. Freeman and Co., 第91頁 (2007)。)單一VH或VL域可足以賦予抗原結合特異性。各VH及VL由三個CDR及四個FR構成,自胺基端至羧基端按以下順序排列:FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。CDR及FR共同形成可變區。按照慣例,抗體之重鏈可變區中之CDR稱為CDR-H1、CDR-H2及CDR-H3且輕鏈可變區中之CDR稱為CDR-L1、CDR-L2及CDR-L3。其在自各鏈之N端至C端之方向上依序編號。習知地根據由Kabat設計之系統來將CDR編號。
如本文所用,術語「載體」係指一種核酸分子,其能夠傳送其所連接之另一核酸。該術語包括呈自我複製核酸結構之載體以及併入其已引入之宿主細胞之基因體中的載體。某些載體能夠導引可操作地連接其之核酸的表現。此類載體在本文中稱為「表現載體」。術語「載體」包括「表現載體」。
術語「VH」係指重鏈之可變域(或序列)。
如本文中所使用,術語「V-IgG」為在各重鏈或各輕鏈之N端上具有可變域的全長抗體。
術語「VL」係指輕鏈之可變域(或序列)。
TREM1
術語「TREM1」係指「表現於骨髓細胞上之觸發受體1」(亦稱為TREM-1及CD354),係指表現於單核球、巨噬細胞、嗜中性白血球及其他類型的細胞上之受體。用於TREM1之初級配位體包括屬於肽聚糖(PGN)結合蛋白(PGRP)家族之肽聚糖識別蛋白1 (PGLYRP1)。術語「TREM1」包括由細胞自然表現之TREM1之任何變異體或同功異型物。
已識別出三種人類TREM1之同功異型物。同功異型物1 (寄存編號NP 061113.1;SEQ ID NO: 1)由234種胺基酸組成且表示典型序列。同功異型物2 (寄存編號NP 001229518.1;SEQ ID NO: 2)由225種胺基酸組成且不同於胺基酸殘基201-234處之典型序列。胺基酸殘基編碼部分跨膜域及細胞質域。同功異型物3 (寄存編號NP 001229519;SEQ ID NO: 3)由150種胺基酸組成且為可溶的。其缺乏編碼跨膜域、細胞質域及部分細胞外域之胺基酸殘基151-234。胺基酸殘基138-150亦不同於上文所描述之典型序列。
識別抗 TREM1 抗體之方法
為了識別與TREM1上之不同於PGLYRP1配位體之胺基酸殘基相互作用且中和一或多種TREM1活性的抗體,必須開發出特定篩選及測試策略,其涉及量測測試抗體之與TREM1之結合及功能特性,以及結合結構態樣(目標抗原決定基殘基)的高通量量測。藉由確定涉及與PGLYRP1之相互作用的TREM1殘基,此方法允許進行快速測試及選擇抗體以供進一步開發,該等抗體將結合於不同於PGLYRP1之TREM1上的位點。此類抗體可提供防止與不同TREM1位點相互作用之其他可能配位體結合的額外益處。
因此,本文提供一種識別與TREM1上之不同於PGLYRP1之胺基酸殘基相互作用且中和人類TREM1活性之抗體的方法,該方法包含:
a) 用短暫表現人類TREM1之細胞使動物免疫;
b) 自該動物回收B細胞;
c) 基於其以下之能力,選擇由該等B細胞產生之該等抗體:
i. 以至少1 nM之親和力結合於人類TREM1;及
ii. 在THP1單核球TREM1/DAP12 NF-κB螢光素酶報導細胞分析中阻斷PGLYRP1介導之信號傳導;及
iii. 結合於人類TREM1上之不同於PGLYRP1的位點。
為識別結合於與PGLYRP1不同的位點之抗體,已研發一種使用突變TREM1蛋白陣列之方法,其允許快速測試TREM1蛋白上之結合位點(涉及與測試抗體相互作用之TREM1殘基)。使用同一方法測定PGLYRP1配位體之結合位點。此類識別TREM1上形成測試抗體(或PGLYRP1)之結合位點的胺基酸殘基之方法包含:
a) 獲得TREM1之3D結構資訊;
b) 使用所獲得之3D結構資料識別可及表面積內之胺基酸殘基;
c) 對於所識別之胺基酸中之每一者而言,選擇在距所識別之胺基酸預定距離內且在可及表面積內之1或2個胺基酸,藉此此類胺基酸殘基組合形成2或3個胺基酸之區塊(patch)(區塊);
d) 自大量所產生之可能區塊中選擇覆蓋大部分TREM1可及表面積之一組代表性區塊,同時使很可能引起TREM1蛋白質摺疊異常之區塊數目減至最小;
e) 產生一組突變蛋白,其中突變蛋白中之每一者包含目標蛋白之突變序列,其中突變序列中之每一者包含在步驟(c)中識別之胺基酸之單一突變區塊,且其中該區塊之胺基酸中之每一者經另一胺基酸取代;
f) 量測突變蛋白中之每一者之結合特性;及
g) 識別展現抗體與包含此類區塊之相應突變TREM1蛋白之結合特性降低的區塊,其中該等區塊中之殘基經識別為抗體之結合位點之一部分。
在一較佳實施例中,若抗體與人類TREM1之殘基E26、E27、K28、Y29、E30、L31、K32及Q35(其中編號係根據SEQ ID NO: 1)相互作用,則選擇抗體。
為了識別用於產生TREM1之突變型式的胺基酸殘基,需要獲得TREM1之3D結構資料。此類資料可以PDB結構(PDB碼:1SMO,A鏈)之形式獲得。替代地,此類結構資料可使用熟習此項技術者已知之技術獲得。此類技術包括X射線分析或NMR資料。較佳地,此類3D資料具有足以允許識別目標殘基之空間解析度。
特定言之,各區塊之殘基之間的預定距離為4、5、6或7 Å。較佳地,此類距離為6 Å。較佳地,不選擇丙胺酸及甘胺酸進行取代。視3D結構中之Cys殘基之相關性而定,此類可經取代或未經選擇用於取代。Cys通常涉及蛋白質中S-S鍵之形成且對於三級結構而言為重要的。Gly為極可撓性胺基酸且經諸如Ala之較大胺基酸取代此類胺基酸亦可具有結構效應。視情況,Pro殘基亦可排除在分析之外,因此其通常涉及二級結構形成。
更特定言之,基於側鏈之所計算溶劑可及表面積來選擇可及表面積內之胺基酸。可應用計算溶劑可及性之標準方法。在一典型實例中,1.4 Å之探針用於計算(簡化形式之H
2O分子,其中此類探針具有與H
2O分子類似之大小)。在此類計算中,將接觸探針之胺基酸殘基之原子歸類為表面可及原子。以A
2為單位計算各胺基酸之表面可及性。隨後,計算實際表面暴露面積(以Å
2為單位)與理論可能表面暴露(以Å
2為單位)之間的比率。不同截止值可視蛋白質之所需精確性及大小而選擇。此類截止值可選自0.5、0.2,較佳此類截止值在0.05-0.1之間,更佳此類截止值為0.07。此類過濾步驟適用於消除潛在摺疊異常蛋白質。
可進行減少最終陣列中摺疊異常TREM1蛋白質之量的其他步驟。舉例而言,較佳避免引起各突變區塊之原始殘基中之任一者(2或3個殘基)與蛋白質之其餘部分之間超過一個氫鍵斷裂的殘基。類似地,亦應較佳避免鹽橋中之任何斷裂。另外,亦避免使蛋白質之較大疏水性區域暴露之殘基突變。在另一實施例中,亦避免引起蛋白質內之超過兩個氫鍵斷裂的殘基。類似地,亦應較佳避免鹽橋中之任何斷裂。
因此,在該方法之一較佳實施例中,方法排除或過濾出1)導致氫鍵斷裂(較佳允許最大2個斷裂鍵)之區塊及2)鹽橋(較佳允許最大1個斷裂鍵),以及3)使大疏水性區塊(較佳允許最大15Å 2個暴露疏水性表面)暴露。用以界定區塊之距離臨限值可設定在6與6.5 Å之間且最小側鏈表面暴露可設定為7%。
視情況,另一粒度可藉由利用任何廣泛使用之模擬封裝(例如AMBER、GROMACS、DESMOND等)執行分子動力學模擬,隨後分析相互作用持久性來達成。存在於大部分模擬軌跡中的氫鍵及鹽橋可視為「必需」且不應被Ala突變破壞,而僅在小部分模擬中觀察到的鍵可能對蛋白質之穩定性具有極小影響。
另外,在已識別出殘基之所有區塊之後,藉由消除產生冗餘之區塊來消除此類區塊中之任何冗餘。此步驟為視情況選用的,因為在可及表面積之覆蓋範圍中具有一些冗餘可能為有益的,然而,具有此類冗餘可能在隨後產生突變純系方面提供技術困難。因此,此類冗餘應在蛋白質大小、複雜性及設計對應突變蛋白質之技術限制的情形下考慮。
理想地,針對整個蛋白質表面進行上述步驟以確保最大表面可及面積由所識別區塊覆蓋。較佳避免表面可及面積具有一些未由此類區塊覆蓋之部分。目的為覆蓋溶劑可及表面,同時使所產生之摺疊異常蛋白質之數目降至最低。
若例如使用2個取代之區塊將不能覆蓋整個表面可及面積,則可設計由3個取代組成之額外區塊。亦可使用大於3個取代之較大區塊,然而超過3個取代可導致突變TREM1蛋白摺疊異常。因此,較佳使用含有2或3個Ala取代之區塊。若需要,亦可選擇額外單Ala取代。然而,相較於2或3個取代,此可能不提供所需敏感度。
遵循此策略之具有2或3個Ala區塊之突變TREM1蛋白陣列提供於實例中。
隨後產生所產生之突變TREM1蛋白序列用於實驗測試。產生此類序列之典型方式為藉由將序列選殖至適合表現載體中。作為對照,亦選殖所關注目標蛋白之野生型序列。
突變TREM1蛋白陣列可使用熟習此項技術者已知之技術產生。可使用用於在目標細胞中表現蛋白質之任何適合表現系統。較佳地,哺乳動物細胞系統用於表現選殖之突變肽。哺乳動物細胞將允許突變多肽自此類細胞中分泌且使得測試此類肽更容易。可使用任何哺乳動物細胞或細胞株,只要其允許突變肽中之每一者之表現充分即可。在此類哺乳動物系統中,可使用適合表現載體。許多哺乳動物表現載體為可商購的。此類載體通常將包含組成型啟動子,諸如細胞巨大病毒(CMV)啟動子。
突變TREM1蛋白中之每一者可融合至Fc區,較佳人類Fc域。在此類融合蛋白中使用Fc域提供實際優點,諸如在偵測中的穩固性較高及易於在表面上捕獲此類融合蛋白。視情況,可將一或多個連接子序列引入Fc域與目標突變蛋白之間的融合蛋白序列中,必要時諸如三重Ala連接子。
較佳地,包含人類Fc域之此類融合蛋白表現於哺乳動物Expi293細胞或可產生足夠濃度之蛋白質的任何其他細胞中。
視情況,可藉由使用針對TREM1之多株抗體(靶向多個抗原決定基)或適用於ELISA分析之具有已知抗原決定基之任何商業單株抗體(因而抗體將識別結構抗原決定基)預篩選陣列而自陣列移除可能潛在地摺疊異常之TREM1蛋白。
最後,量測抗體與陣列上之突變目標蛋白中之每一者的結合特性。可使用任何合適的可用方法來執行此類量測。較佳地,使用高通量方法來執行此類量測。
所關注分子之親和力以及此類分子抑制與目標蛋白之結合的程度可由一般熟習此項技術者使用習知技術,例如由Scatchard等人(Ann. KY. Acad. Sci. 51:660-672 (1949))描述之技術或藉由表面電漿子共振(SPR),使用諸如BIAcore之系統測定。對於表面電漿子共振,將突變蛋白固定於固相上且在沿流通槽流動之移動相中暴露於所關注配位體及/或分子。若發生配位體與固定目標之結合,則局部折射率改變,引起SPR角之變化,其可藉由偵測反射光強度之變化而進行即時監測。可分析SPR信號之變化速率以針對結合反應之締合及解離相產生表觀速率常數。此等值之比率產生表觀平衡常數(親和力)
(參見例如Wolff等人, Cancer Res. 53:2560-65 (1993))。
使用類似於SPR之技術的替代平台由諸如Carterra LSA平台之Cartera(carterra-bio.com)提供。其為合併流動印刷微流體與高通量表面電漿子共振(SPR)偵測技術之高通量抗體表徵平台。
其他類型之平台包括利用細胞表面表現陣列之技術。此類平台之實例為LigandTracer (ligandtracer.com),其尤其適合於跟蹤與細胞表面受體結合之蛋白質且允許量測締合速率及解離速率以及親和力。
為了簡化量測,陣列之突變蛋白中之每一者可與分子或蛋白質融合以允許在表面上捕獲此類融合蛋白用於更容易地偵測結合特性。
較佳地,使用作為無標記技術之生物層干涉法(BLI)測定與突變蛋白中之每一者的結合。該技術為分析由兩個表面反射之白光之干涉圖案的光學分析技術,該兩個表面亦即生物感測器尖端上之固定蛋白質層及內部參考層。結合至生物感測器尖端之分子數目的任何變化導致可即時量測之干涉圖案的轉移(REF)。
通常使用30種、60種經選殖之突變蛋白之陣列。然而,此類陣列之大小視目標蛋白之大小及溶劑可及面積之所需覆蓋度而定。較佳地,突變蛋白提供於96孔盤或384孔盤上。一般而言,BLI儀器可處置96孔或384孔盤進行量測。
當使用BLI技術時,各感測器通常暴露於含有所關注分子(諸如抗體或配位體)的溶液,對其測定結合位點。BLI技術之優點為幾乎與正常BIACore一樣敏感,其為高通量(可同時測試96個純系)且使用可拋棄式感測器尖端,因此不需要如您將通常用BIACore所進行來更新表面且再使用晶片。
測試抗體與突變TREM1蛋白之結合的不同量測可用於確定何等突變蛋白展現減少的結合。典型地,量測解離常數或結合常數。典型地,可量測結合之完全損失或所關注分子離開突變蛋白之快速程度。在量測抗體之結合特性時,一般使用適當對照。通常,將結合特性與目標蛋白之親本序列(野生型,WT)相比。典型地,大部分突變蛋白將展示與WT相同之K
d。應考慮展示結合差異之突變蛋白。典型地,考慮與野生型TREM1相比至少2、3、4、5、6、7、8、9或10倍或更多倍之任何解離常數差異。較佳,至少3倍之任何差異視為顯著的。忽略或重新量測產生具有低雜訊-信號解析度之結果的突變TREM1蛋白。
若所需突變蛋白包含不同大小之區塊,諸如2或3個取代之區塊,可在陣列上使用。若需要較高精確度,則亦可另外測試包含單一取代之突變蛋白的結合特性,其限制條件為此類蛋白提供足夠敏感度以獲得可量測效應。
結合於 TREM1 之抗體
本發明提供抗TREM1抗體,其結合於人類TREM1 (目標多肽)且具有如本文進一步描述之功能及結構特性。
在本發明之上下文中,抗體包括完整抗體及功能活性抗體片段(亦即含有特異性結合抗原之抗原結合域的分子,亦稱為抗原結合片段)。除非上下文另外規定,否則本文所描述之特徵亦適用於抗體片段。抗體可為(或衍生自)多株、單株、多價、多特異性、雙特異性、完全人類、人類化或嵌合抗體。
進一步描述之抗體為特異性抗體類型且不限制本發明之範疇。
根據本發明使用之抗體可為單株抗體或多株抗體,且較佳為單株抗體。根據本發明使用之抗體可為嵌合抗體、CDR移植抗體(例如,根據衍生CDR之供體抗體之類別/類型,可使用任何適當受體可變區構架序列,包括小鼠、靈長類動物及人類構架區)、奈米抗體、人類或人類化抗體。對於單株及多株抗體之產生,用於產生此類抗體之動物通常為非人類哺乳動物,諸如山羊、兔、大鼠或鼠,但亦可在其他物種中產生抗體。
可藉由常規方法產生多株抗體,諸如用所關注抗原對適合的動物進行免疫接種。隨後,可自此類動物移出血液且將所產生之抗體純化。
可藉由多種技術製備單株抗體,包括(但不限於)融合瘤方法、重組DNA方法、噬菌體呈現方法及使用含有全部或一部分人類免疫球蛋白基因座之轉基因動物之方法。本文中描述用於製備單株抗體之一些例示性方法。
舉例而言,可使用融合瘤技術(Kohler及Milstein, 1975, Nature, 256:495-497)、三源融合瘤技術、人類B細胞融合瘤技術(Kozbor等人, 1983, Immunology Today, 4:72)及EBV融合瘤技術(Cole等人, Monoclonal Antibodies and Cancer Therapy, 第77-96頁, Alan R Liss, Inc., 1985)製備單株抗體。
亦可藉由例如WO9202551、WO2004051268及WO2004106377中所描述之方法,使用單一淋巴球抗體方法,藉由選殖及表現由經選擇以用於製備特異性抗體之單一淋巴球所產生之免疫球蛋白可變區cDNA來產生抗體。
在需要對動物進行免疫接種之情況下,可使用熟知及常規的方案,藉由向動物、較佳非人類動物投與多肽來獲得針對目標多肽所產生的抗體,參見例如Handbook of Experimental Immunology, D. M. Weir (編), 第4卷, Blackwell Scientific Publishers, Oxford, England, 1986)。可對許多動物進行免疫接種,諸如兔、小鼠、大鼠、羊、牛、駱駝或豬。然而,通常使用小鼠、兔、豬及大鼠。
單株抗體亦可使用此項技術中已知之各種噬菌體呈現方法產生且包括由Brinkman等人(J. Immunol. Methods, 1995, 182: 41-50)、Ames等人(J. Immunol. Methods, 1995, 184:177-186)、Kettleborough等人(Eur. J. Immunol. 1994, 24:952-958)、Persic等人(Gene, 1997 187 9-18)、Burton等人(Advances in Immunology, 1994, 57:191-280)所揭示之方法。在某些噬菌體呈現方法中,VH及VL基因之譜系分別藉由聚合酶鏈反應(PCR)選殖且在噬菌體庫中隨機重組,其接著可針對抗原結合噬菌體進行篩檢,如Winter等人, Ann. Rev. Immunol, 12: 433-455 (1994)中所描述。噬菌體典型地以單鏈Fv (scFv)片段或Fab片段形式呈現抗體片段。來自免疫來源之庫提供抗免疫原之高親和力抗體而無需構築融合瘤。或者,可選殖(例如,自人類)天然譜系以提供針對廣泛範圍之非自體抗原以及自體抗原之單一抗體來源而無需任何免疫接種,如Griffiths等人, EMBO J 12: 725-734 (1993)所描述。最後,天然庫亦可以合成方式藉由以下來製備:自幹細胞選殖未重排V基因區段,且使用含有隨機序列以編碼高度可變CDR3區及實現活體外重排之PCR引子,如藉由Hoogenboom及Winter, J. Mol. Biol, 227: 381-388 (1992)所描述。描述人類抗體噬菌體庫之專利公開案包括例如:US 5,750,373及US 2005/0079574、US2005/0119455、US2005/0266000、US2007/0117126、US2007/0160598、US2007/0237764、US2007/0292936及US2009/0002360。
可使用用於量測與目標多肽之結合之分析法及/或用於量測抗體阻斷特定相互作用之能力之分析法進行抗體篩選。結合分析法之實例為ELISA,舉例而言,使用固定在盤上之目標多肽之融合蛋白且使用經結合之二級抗體以偵測抗體與目標之結合。阻斷分析法之實例為基於流式細胞測量術之分析法,其量測與目標多肽結合之配位體蛋白質之阻斷。使用經螢光標記之二級抗體偵測結合於目標多肽之此類配位體蛋白質之量。
可藉由針對具有一或多種所需活性之抗體篩檢組合庫來分離抗體。舉例而言,用於生成噬菌體呈現庫及篩選具有所需結合特徵之抗體的此類庫之各種方法在此項技術中已知。
自人類抗體庫分離之抗體或抗體片段視為人類抗體或人類抗體片段。
抗體可為全長抗體。更特定言之,抗體可具有IgG同型。更特定言之,抗體可為IgG1或IgG4。
可根據所提出的抗體分子之功能且特定言之,可能需要的效應功能來選擇抗體之恆定區域(若存在)。舉例而言,恆定區域可為人類IgA、IgD、IgE、IgG或IgM域。特定言之,當抗體分子意圖用於治療用途且需要抗體效應功能時,可使用人類IgG恆定區域,尤其IgG1及IgG3同型。或者,當抗體分子意圖用於達成治療目的且不需要抗體效應功能時可使用IgG2及IgG4同型。應瞭解,亦可使用此等恆定區域之序列變異體。熟習此項技術者亦已知抗體可經歷各種轉譯後修飾。此等修飾之類型及程度通常視用於表現抗體的宿主細胞株以及細胞培養條件而定。此類修飾可包括糖基化變化、甲硫胺酸氧化、二酮哌𠯤形成、天冬胺酸異構化及天冬醯胺酸去醯胺。常見修飾為由於羧基肽酶作用而損失羧基端鹼性殘基(諸如離胺酸或精胺酸)(如Harris, RJ. Journal of Chromatography 705:129-134, 1995中所述)。因此,可不存在抗體重鏈之C端離胺酸。
或者,抗體為抗原結合片段。
關於某些抗原結合片段之評述,參見Hudson等人 Nat. Med. 9: 129-134 (2003)。關於scFv片段之評述,參見例如Plückthun, The Pharmacology of Monoclonal Antibodies, 第113卷, Rosenburg及Moore編, (Springer- Verlag, New York), 第269-315頁 (1994);亦參見WO 93/16185;及US 5,571,894及US 5,587,458。包含救助受體結合抗原決定基殘基且具有延長之活體內半衰期之Fab及F(ab')2片段揭示於US 5,869,046中。
抗原結合片段及其製備方法為此項技術中熟知的,參見例如Verma等人, 1998, Journal of Immunological Methods, 216, 165-181;Adair及Lawson, 2005. Therapeutic antibodies. Drug Design Reviews-Online 2(3): 209-217。Fab-Fv型式首先揭示於WO2009/040562中且其二硫鍵穩定之版本,亦即Fab-dsFv,首先揭示於WO2010/035012中,且TrYbe型式揭示於WO2015/197772中。
已開發出用於產生抗體片段的多種技術。此類片段可經由完整抗體之蛋白水解消化產生(參見例如Morimoto等人, Journal of Biochemical and Biophysical Methods 24: 107-117 (1992)及Brennan等人, Science 229:81 (1985))。然而,亦可藉由重組宿主細胞直接產生抗體片段。舉例而言,可自上文所論述之抗體噬菌體庫分離抗體片段。或者,Fab'-SH片段可直接自大腸桿菌回收且以化學方式偶合以形成F(ab')
2片段(Carter等人, Bio/Technology 10: 163-167 (1992))。
可直接自重組宿主細胞培養物分離F(ab')
2片段。抗體可為單鏈Fv片段(scFv)。此類片段描述於WO 93/16185、US 5,571,894及US 5,587,458中。抗體片段亦可為「線性抗體」,例如如US 5,641,870中所描述。此類線性抗體片段可具有單特異性或雙特異性。
抗體可為Fab、Fab'、F(ab')
2、Fv、dsFv、scFv或dsscFv。抗體可為單域抗體或奈米抗體,例如VH或VL或VHH或VNAR。抗體可為WO2011/117648、WO2005/003169、WO2005/003170及WO2005/003171中所描述之Fab或Fab'片段。
抗體可為二硫鍵穩定之單鏈可變片段(dsscFv)。
可變域VH與VL之間的二硫鍵可位於兩個以下列舉之殘基之間:
● V
H37 + V
L95,參見例如Protein Science 6, 781-788 Zhu等人(1997);
● V
H44 + V
L100,參見例如Weatherill等人, Protein Engineering, Design & Selection, 25 (321-329), 2012;
● V
H44 + V
L105,參見例如J Biochem. 118, 825-831 Luo等人(1995);
● V
H45 + V
L87,參見例如Protein Science 6, 781-788 Zhu等人(1997);
● V
H55 + V
L101,參見例如FEBS Letters 377 135-139 Young等人(1995);
● V
H100 + V
L50,參見例如Biochemistry 29 1362-1367 Glockshuber等人(1990);
● V
H100b + V
L49;參見例如Biochemistry 29 1362-1367 Glockshuber等人(1990);
● V
H98 + V
L46,參見例如Protein Science 6, 781-788 Zhu等人(1997);
● V
H101 + V
L46;參見例如Protein Science 6, 781-788 Zhu等人(1997);
● V
H105 + V
L43,參見例如Proc. Natl. Acad. Sci. USA 第90卷 第7538-7542頁 Brinkmann等人(1993);或Proteins 19, 35-47 Jung等人(1994),
● V
H106 + V
L57,參見例如FEBS Letters 377 135-139 Young等人(1995)
及與其相應的位於分子中之可變區對中之一或多個位置。
可在位置VH44與VL100之間形成二硫鍵。
熟習此項技術者應瞭解,本文中所描述之抗原結合片段亦可表徵為單株、嵌合、人類化、完全人類、多特異性、雙特異性等,且此等術語之論述亦係關於此類片段。
多特異性抗體
本發明之抗體可為多特異性抗體。
亦預期在本發明之情形下使用之多特異性抗體或其抗原結合片段之實例包括二價抗體、三價抗體或四價抗體、雙scFv、雙功能抗體、三功能抗體、四功能抗體、雙體(bibody)及三體(tribody)(參見例如Holliger及Hudson, 2005, Nature Biotech 23(9): 1126-1136;Schoonjans等人. 2001, Biomolecular Engineering, 17(6), 193-202)。
已產生多種多特異性抗體型式。已提出不同分類,但多特異性IgG抗體型式大體上包括雙特異性IgG、附接IgG、多特異性(例如,雙特異性)抗體片段、多特異性(例如,雙特異性)融合蛋白及多特異性(例如,雙特異性)抗體結合物,如例如Spiess等人, Alternative molecular formats and therapeutic applications for bispecific antibodies. Mol Immunol. 67(2015):95-106中所描述。
抗體可為雙特異性抗體。在一個實施例中,抗體包含兩個抗原結合域,其中一個結合域結合TREM1且另一結合域結合另一抗原,亦即,各結合域對於各抗原為單價的。在一個實施例中,抗體為四價雙特異性抗體,亦即,抗體包含四個抗原結合域,其中例如兩個結合域結合TREM1且另外兩個結合域結合另一抗原。在一個實施例中,抗體為三價雙特異性抗體。
用於製備雙特異性抗體之技術包括(但不限於)CrossMab技術(Klein等人, Engineering therapeutic bispecific antibodies using CrossMab technology, Methods 154 (2019) 21-31)、杵臼工程改造(Knobs-in-holes engineering)(例如,WO1996027011、WO1998050431)、DuoBody技術(例如,WO2011131746)、Azymetric技術(例如,WO2012058768)。其他用於製備雙特異性抗體之技術已描述於例如Godar等人, 2018, Therapeutic bispecific antibody formats: a patent applications review (1994-2017), Expert Opinion on Therapeutic Patents, 28:3, 251-276中。雙特異性抗體尤其包括CrossMab抗體、DAF (二合一)、DAF (四合一)、DutaMab、DT-lgG、杵臼常見LC、杵臼組合件、電荷對(Charge pair)、Fab臂交換、SEED體、三功能單抗、LUZ-Y、Fcab、κλ-體及正交Fab。
抗體構築體可為三特異性抗體。
抗體可為多互補位抗體。
在一個實施例中,各結合域為單價的。較佳地,各結合域包含不超過一個VH及一個VL。
附接IgG通常包含藉由將額外抗原結合域或抗原結合片段附接至IgG之重鏈及/或輕鏈之N端及/或C端而工程改造之全長IgG。此類額外抗原結合片段之實例包括sdAb抗體(例如,VH或VL)、Fv、scFv、dsscFv、Fab、scFab。附接IgG抗體型式尤其包括DVD-IgG、IgG(H)-scFv、scFv-(H)lgG、IgG(L)-scFv、scFv-(L)IgG、lgG(L,H)-Fv、IgG(H)-V、V(H)-IgG、IgC(L)-V、V(L)-IgG、KIH IgG-scFab、2scFv-IgG、lgG-2scFv、scFv4-Ig、Zybody及DVI-IgG(四合一),例如如Spiess等人, Alternative molecular formats and therapeutic applications for bispecific antibodies. Mol Immunol. 67(2015):95-106中所述。
多特異性抗體片段包括奈米抗體、奈米抗體-HAS、BiTE、雙功能抗體、DART、TandAb、sc雙功能抗體、sc-雙功能抗體-CH3、雙功能抗體-CH3、三功能抗體(Triple Body)、微型抗體(Miniantibody);微型抗體(Minibody)、三聚體雙特異性微型抗體(Tri Bi minibody)、scFv-CH3 KIH、Fab-scFv、scFv-CH-CL-scFv、F(ab')
2、F(ab')
2-scFv
2、scFv-KIH、Fab-scFv-Fc、四價HCAb、sc雙功能抗體-Fc、雙功能抗體-Fc、串聯scFv-Fc;及胞內抗體,如例如Spiess等人, Alternative molecular formats and therapeutic applications for bispecific antibodies. Mol Immunol. 67(2015):95-106所描述。
多特異性融合蛋白包括鎖鑰結構(Dock and Lock)、ImmTAC、HSAbody、sc雙功能抗體-HSA及串聯scFv-毒素。
多特異性抗體結合物包括IgG-IgG;Cov-X體;及scFv1-PEG-scFv
2。
已於例如Brinkmann等人, The making of bispecific antibodies, mAbs, 9:2, 182-212 (2017)中,尤其在圖2中描述額外多特異性抗體型式,例如串聯scFv、三功能抗體、Fab-VHH、taFv-Fc、scFv4-Ig、scFv2-Fcab、scFv4-IgG。雙功能抗體、三功能抗體及用於產生此類抗體之方法揭示於例如WO99/37791中。
用於本發明之抗體可為連接至兩個scFv或dsscFv之Fab,各scFv或dsscFv結合相同或不同目標(例如,一個scFv或dsscFv結合治療目標且一個scFv或dsscFv藉由結合例如白蛋白來延長半衰期)。此類抗體片段描述於WO2015/197772中。用於本發明片段之另一較佳抗體包含僅連接至一個scFv或dsscFv之Fab,如例如WO2013/068571及Dave等人, Mabs, 8(7) 1319-1335 (2016)中所描述。
用於本發明中之另一抗體為杵-臼抗體(「KiH」)。其為由重鏈均二聚體組成之多特異性抗體型式,其用於雜二聚化(例如用於有效產生雙特異性抗體、多特異性抗體或單臂抗體)。通常,此類技術涉及在第一多肽之界面(諸如第一抗體重鏈中之第一CH3域)中引入突起(「杵」)且在第二多肽之界面(諸如第二抗體重鏈中之第二CH3域)中引入相應的凹穴(「臼」),使得突起可位於凹穴中以便促進雜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(諸如第一抗體重鏈中之第一CH3域)之較小胺基酸側鏈來構築突起。藉由用較小胺基酸側鏈(例如,丙胺酸、絲胺酸、纈胺酸或蘇胺酸)置換較大胺基酸側鏈來在第二多肽之界面(諸如第二抗體重鏈中之第二CH3域)中產生具有與突起相同或類似的大小之補償性凹穴。突起及凹穴可藉由改變編碼多肽之核酸,例如藉由定點突變誘發或藉由肽合成產生。其他關於「杵-臼」技術之詳細說明描述於例如US 5,731,168;U.S 7,695,936;WO 2009/089004;US 2009/0182127;Marvin md Z u, Acta Pharmacologica Sincia (2005) 26(6):649-658;Kontermann Acta Pharmacologica Sincia (2005) 26: 1-9;Ridgway等人, Prot Eng 9, 617-621 (1996);及Carter, J Immunol Meth 248, 7-15 (2001)中。
人類化、人類及嵌合抗體以及其製備方法
本發明之抗體可為(但不限於)人類化、完全人類或嵌合抗體。
在一個實施例中,抗體經人類化。更特定言之,抗體為嵌合、人類或人類化抗體。
在某些實施例中,本文所提供之抗體為嵌合抗體。嵌合抗體之實例描述於例如US 4,816,567;及Morrison等人, Proc. Natl. Acad. Sci. USA, 81 :6851-6855 (1984))中。在一個實例中,嵌合抗體包含非人類可變區(例如,來源於小鼠、大鼠、倉鼠、兔或非人類靈長類動物(諸如猴)之可變區)及人類恆定區。在另一實例中,嵌合抗體為「類別切換」抗體,其中類別或子類別已自親本抗體之類別或子類別改變。嵌合抗體包括其抗原結合片段。
在一個實施例中,抗體為人類化抗體。
人類化抗體可視情況進一步包含一或多個來源於衍生CDR之非人類物種的構架殘基。應瞭解,可能僅需要轉移CDR之特異性決定殘基而非整個CDR (參見例如Kashmiri等人, 2005, Methods, 36, 25-34)。
適當地,根據本發明之人類化抗體具有可變域,其包含人類受體構架區以及一或多個CDR且視情況進一步包括一或多個供體構架殘基。
因此,在一個實施例中提供人類化抗體,其中可變域包含人類受體構架區及非人類供體CDR。
當移植CDR或特異性決定殘基時,根據衍生CDR之供體抗體之類別/類型,可使用任何適當的受體可變區構架序列,包括小鼠、靈長類動物及人類構架區。
可用於本發明中之人類構架之實例為KOL、NEWM、REI、EU、TUR、TEI、LAY及POM (Kabat等人)。舉例而言,KOL及NEWM可用於重鏈,REI可用於輕鏈且EU、LAY及POM可用於重鏈及輕鏈。或者,可使用人類生殖系序列;此等序列可在www.imgt.org獲得。在實施例中,受體構架為IGKV1-9人類生殖系及/或IGHV3-66人類生殖系。在實施例中,人類構架含有1-5、1-4、1-3或1-2個供體抗體胺基酸殘基。
在本發明之人類化抗體中,受體重鏈及輕鏈無需來源於相同抗體且可視需要包含具有來源於不同鏈之構架區之複合鏈。
在某些實施例中,本文所提供之抗體為人類抗體。可使用此項技術中已知之各種技術產生人類抗體。
若抗體之可變區或全長鏈係自使用人類生殖系免疫球蛋白基因之系統獲得,則人類抗體包含作為特定生殖系序列之「產物」或「來源於」特定生殖系序列之重鏈或輕鏈可變區或全長重鏈或輕鏈。此類系統包括用所關注之抗原使攜帶人類免疫球蛋白基因之轉殖基因小鼠免疫或用所關注之抗原篩選呈現在噬菌體上之人類免疫球蛋白基因庫。作為人類生殖系免疫球蛋白序列之「產物」或「來源於」人類生殖系免疫球蛋白序列之人類抗體或其片段可藉由將人類抗體之胺基酸序列與人類生殖系免疫球蛋白之胺基酸序列進行比較且選擇按序列最接近人類抗體序列(亦即最大一致性%)之人類生殖系免疫球蛋白序列來如此識別。作為特定人類生殖系免疫球蛋白序列之「產物」或「來源於」特定人類生殖系免疫球蛋白序列的人類抗體可含有與生殖系序列相比因例如天然存在之體細胞突變或有意引入之定點突變所致的胺基酸差異。然而,所選擇的人類抗體通常在胺基酸序列方面與由人類生殖系免疫球蛋白基因編碼之胺基酸序列至少90%一致,且含有當與其他物種之生殖系免疫球蛋白胺基酸序列(例如,鼠類生殖系序列)相比時識別人類抗體為人類的胺基酸殘基。在某些情況下,人類抗體在胺基酸序列方面可與由生殖系免疫球蛋白基因編碼之胺基酸序列至少60%、70%、80%、90%,或至少95%,或甚至至少96%、97%、98%或99%一致。通常,來源於特定人類生殖系序列之人類抗體將呈現與由人類生殖系免疫球蛋白基因編碼之胺基酸序列相比不超過10個胺基酸差異。在某些情況下,人類抗體可呈現與由生殖系免疫球蛋白基因編碼之胺基酸序列相比不超過5個,或甚至不超過4、3、2或1個胺基酸差異。
抗體之結構特徵
本發明之抗體包含結合域。結合域一般將包含6個CDR,三個來自重鏈且三個來自輕鏈。在一個實施例中,CDR位於一個構架中且一起形成可變區。因此,抗體具有對抗原具有特異性之結合域,該結合域包含輕鏈可變區及重鏈可變區。
在一個實施例中,抗體包含重鏈及輕鏈,其中重鏈包含CH1域且輕鏈包含CL域,κ或λ。
如本發明之實例所證明,已產生重鏈及輕鏈之可變區之不同變異體且測試其結合親和力。彼等變異體包含同一組CDR序列且展現類似結合親和力範圍。所選抗體變異體之不同結構元件的概述呈現於表3中。
表
3.
抗
TREM1
抗體之胺基酸序列
構件 | 12172 gL2gH11 SEQ ID NO | 12172 gL6gH6 SEQ ID NO |
CDR-L1 | 11 | 11 |
CDR-L2 | 12 | 12 |
CDR-L3 | 13 | 13 |
CDR-H1 | 14 | 14 |
CDR-H2 | 15 | 15 |
CDR-H3 | 16 | 16 |
輕鏈V區 | 29 | 33 |
重鏈V區 | 79 | 57 |
輕鏈 | 31 | 35 |
重鏈IgG1 | 85 | 63 |
重鏈IgG1 LALA | 87 | 65 |
重鏈IgG4P | 81 | 59 |
重鏈IgG4P FALA | 83 | 61 |
在一個實施例中,本發明提供一種結合於人類TREM1之抗體,其包含有包含以下中之至少一者的輕鏈可變域:
包含SEQ ID NO:11之CDR-L1,
包含SEQ ID NO:12之CDR-L2,及
包含SEQ ID NO:13之CDR-L3。
在一個實施例中,本發明提供一種結合於人類TREM1之抗體,其包含有包含以下的輕鏈可變域:
包含SEQ ID NO:11之CDR-L1,
包含SEQ ID NO:12之CDR-L2,及
包含SEQ ID NO:13之CDR-L3。
在一個實施例中,本發明提供一種結合於人類TREM1之抗體,其包含有包含以下中之至少一者的重鏈可變域:
包含SEQ ID NO:14之CDR-H1,
包含SEQ ID NO:15之CDR-H2,及
包含SEQ ID NO:16之CDR-H3。
在一個實施例中,本發明提供一種結合於人類TREM1之抗體,其包含有包含以下的重鏈可變域:
包含SEQ ID NO:14之CDR-H1,
包含SEQ ID NO:15之CDR-H2,及
包含SEQ ID NO:16之CDR-H3。
本發明之抗體分子可分別包含互補輕鏈或互補重鏈。
因此,在一個實施例中,本發明提供一種結合於人類TREM1之抗體,其包含:
輕鏈可變區,該輕鏈可變區包含:
包含SEQ ID NO:11之CDR-L1,
包含SEQ ID NO:12之CDR-L2,及
包含SEQ ID NO:13之CDR-L3;
以及重鏈可變區,該重鏈可變區包含:
包含SEQ ID NO:14之CDR-H1,
包含SEQ ID NO:15之CDR-H2,及
包含SEQ ID NO:16之CDR-H3。
在一個實施例中,本發明之抗體包含輕鏈可變區,其包含SEQ ID NO:29或SEQ ID NO:33中給出之序列。
在一個實施例中,本發明之抗體包含重鏈可變區,其包含以SEQ ID NO:57或SEQ ID NO:79中給出之序列。
在一個實施例中,本發明之抗體包含有包含SEQ ID NO:33中給出之序列之輕鏈可變區及包含SEQ ID NO:57中給出之序列之重鏈可變區。
在一替代實施例中,本發明之抗體包含有包含SEQ ID NO:29中給出之序列之輕鏈可變區及包含SEQ ID NO:79中給出之序列之重鏈可變區。
在一個實施例中,本發明之抗體為全長抗體,其包含
輕鏈可變區,該輕鏈可變區包含:
包含SEQ ID NO:11之CDR-L1,
包含SEQ ID NO:12之CDR-L2,及
包含SEQ ID NO:13之CDR-L3;
以及重鏈可變區,該重鏈可變區包含:
包含SEQ ID NO:14之CDR-H1,
包含SEQ ID NO:15之CDR-H2,及
包含SEQ ID NO:16之CDR-H3。
在一個實施例中,本發明之抗體為IgG1 LALA,其包含
輕鏈可變區,該輕鏈可變區包含:
包含SEQ ID NO:11之CDR-L1,
包含SEQ ID NO:12之CDR-L2,及
包含SEQ ID NO:13之CDR-L3;
以及重鏈可變區,該重鏈可變區包含:
包含SEQ ID NO:14之CDR-H1,
包含SEQ ID NO:15之CDR-H2,及
包含SEQ ID NO:16之CDR-H3。
在另一實施例中,本發明之抗體為IgG1 LALA,其包含有包含SEQ ID NO: 35中給出之序列的輕鏈及包含SEQ ID NO: 65中給出之序列的重鏈。
在另一實施例中,本發明之抗體為IgG1 LALA,其包含有包含SEQ ID NO: 31中給出之序列的輕鏈及包含SEQ ID NO: 87中給出之序列的重鏈。
在另一實施例中,IgG4P為較佳的。在多種分析法中測試本文所述之12172抗體之若干變異體以測定其物理化學特性,其皆顯示出極類似的可顯影性概況,其中IgG4P變異體具有與其他變異體相比不佳的特性。然而,IgG4P變異體展現出人意料的生物特性而在其他變異體情況下未觀測到,且因此為其中此類特性為有益之應用的較佳變異體。舉例而言,在治療病狀時,此類特性提供治療效應。
IgG4P在鉸鏈區中含有Ser-228-Pro突變,其中編號係根據EU編號(根據Kabat編號之Ser-241-Pro)以改良鉸鏈穩定性(Angal S等人, (1993), Mol Immunol, 30(1), 105-108)。
因此,在一個實施例中,本發明之抗體為包含以下之IgG4P:
輕鏈可變區,該輕鏈可變區包含:
包含SEQ ID NO:11之CDR-L1,
包含SEQ ID NO:12之CDR-L2,及
包含SEQ ID NO:13之CDR-L3;
以及重鏈可變區,該重鏈可變區包含:
包含SEQ ID NO:14之CDR-H1,
包含SEQ ID NO:15之CDR-H2,及
包含SEQ ID NO:16之CDR-H3。
在又另一實施例中,本發明之抗體為IgG4P,其包含有包含SEQ ID NO: 35中給出之序列的輕鏈及包含SEQ ID NO: 59中給出之序列的重鏈。
在一更特定實施例中,本發明之抗體為IgG4P,其包含有包含SEQ ID NO: 31中給出之序列的輕鏈及包含SEQ ID NO: 81中給出之序列的重鏈。
抗 TREM1 抗體之功能特性
在一個實施例中,本發明之抗體為中和抗體。較佳地,根據本發明之抗體中和一或多種TREM1活性。
本發明之抗體特異性結合人類TREM1,且更特定言之,特異性結合人類TREM1胞外域內之特定區。在一些實施例中,抗體特異性結合至TREM1上之TREM1配位體(例如PGLYRP1)所結合之不同或最低限度重疊位點。在一些實施例中,抗體為拮抗性抗體,亦即其抑制或遏制細胞上TREM1之活性。此類細胞可為單核球、巨噬細胞及/或嗜中性白血球。在一些實施例中,抗體可特異性異位結合於TREM1而非正位結合於單一配位體,且因此對在不同於PGLYRP1之TREM1上的位點處結合之其他配位體的結合提供更有效抑制。
如藉由實例所證明,PGLYRP1結合於TREM1上之抗原決定基,該抗原決定基包含選自由人類TREM1 (SEQ ID NO: 1)之E27、D42-E46、A49、Y90-L95及F126組成之清單的殘基,由在小於4 Å接觸距離處所測定。
在一個特定實施例中,本發明提供結合於TREM1上不同於PGLYRP1結合位點之區域使得結合仍阻止TREM1與PGLYRP1之間的相互作用之抗體。
在一些實施例中,抗TREM1抗體展示極弱的與食蟹獼猴TREM1之結合。在一些實施例中,抗TREM1抗體展示不可偵測的與小鼠、大鼠、豬或犬TREM1之結合。
在一些實施例中,抗TREM1抗體減少多種細胞介素及趨化介素自活化人類單核球之釋放,該等細胞介素及趨化介素諸如CCL-3、CCL-20、CXCL-9、GM-CSF、IFN-γ、IL-1α、IL-1β、IL-6、IL-10、IL-12p40、IL-15、IL-18、IL-27、TNF-α及TNF-β。
在一些實施例中,抗TREM1抗體為IgG4P且顯著增加IL-1R拮抗劑(IL-1RA) (IL-1路徑之消炎負調節劑)自初級人類單核球之釋放。
根據本發明之抗體對人類TREM1具有特異性。
在一些實施例中,抗體以足夠親和力及特異性結合於人類TREM1。在某些實施例中,抗體以約以下中之任一者的KD結合人類TREM1:l µM、100 nM、50 nM、40 nM、30 nM、20nM、10 nM、5nM、l nM、0.5 nM,包括此等值之間的任何範圍。在一個實施例中,根據本發明之抗體以小於600 pM之KD結合人類TREM1。在更特定實施例中,根據本發明之抗體以300-1200 pM、更佳300-600 pM之間的KD結合人類TREM1。
熟習此項技術者可使用習知技術(例如由Scatchard等人(Ann. KY. Acad. Sci. 51:660-672 (1949))描述之技術或使用諸如BIAcore之系統藉由表面電漿子共振(SPR)來測定抗體之親和力及抗體抑制結合之程度。對於表面電漿子共振,目標分子係固定於固相上且在沿流通槽流動之移動相中暴露於配位體。若發生配位體與固定目標之結合,則局部折射率改變,引起SPR角之變化,其可藉由偵測反射光強度之變化而進行即時監測。可分析SPR信號之變化速率以針對結合反應之締合及解離相產生表觀速率常數。此等值之比率產生表觀平衡常數(親和力)(參見例如Wolff等人, Cancer Res. 53:2560-65 (1993))。
較佳地,根據本發明之抗體對人類TREM1具有特異性。
本文中本發明關於抗體,尤其就結合親和力及特異性及活性而言,亦適用於抗原結合片段及抗體樣分子。
結合於相同抗原決定基之抗體
在輕鏈、重鏈、輕鏈可變區(LCVR)、重鏈可變區(HCVR)或CDR序列方面,抗體可與如上文所定義之抗體競爭結合於TREM1或結合於相同抗原決定基。
特定言之,本發明提供一種抗體,其與包含SEQ ID NO: 11/12/13/14/15/16之CDR-L1/CDR-L2/CDR-L3/CDR-H1/CDR-H2/CDR-H3序列組合之抗體競爭結合於TREM1或結合於相同抗原決定基。抗體可與包含SEQ ID NO: 29/79之LCVR及HCVR序列對的抗體競爭結合於TREM1或結合於相同抗原決定基。抗體可與包含SEQ ID NO: 11/12/13/14/15/16之CDR-L1/CDR-L2/CDR-L3/CDR-H1/CDR-H2/CDR-H3序列組合的IgG4P競爭結合於TREM1或結合於相同抗原決定基。
在一些實施例中,抗TREM1抗體結合於人類TREM1上之抗原決定基,該抗原決定基包含殘基E26、E27、K28、Y29、E30、L31、K32及Q35 (其中編號係根據SEQ ID NO: 1)。此類抗原決定基可使用本文所揭示之方法來確定,該方法涉及設計突變TREM1蛋白之陣列及量測該抗體與突變TREM1蛋白之結合,該突變TREM1蛋白包含突變成較小胺基酸(諸如Ala)之2或3個該等殘基。
在一個實施例中,本發明提供一種與人類TREM1之抗原決定基結合的IgG4P抗體,該抗原決定基包含人類TREM1 (SEQ ID NO: 1)之殘基E26、E27、K28、Y29、E30、L31、K32及Q35。
在一個實施例中,本發明提供一種結合於TREM1上之抗原決定基的抗TREM1抗體,該抗原決定基包含選自由以下組成之清單的至少3個、至少4個、至少5個、至少6個、至少7個、至少8個、至少9個、至少10個或所有殘基:人類TREM1 (SEQ ID NO: 1)之E26、E27、K28、Y29、E30、L31、K32、Q35、T36、D38、K40、D42、R97、D127、T134及G136,由在小於4 Å接觸距離處所測定。
在一個實施例中,本發明提供一種結合於人類TREM1之抗原決定基的IgG4P抗體,該抗原決定基包含選自由以下組成之清單的至少3個、至少4個、至少5個、至少6個、至少7個、至少8個、至少9個、至少10個或所有殘基:人類TREM1 (SEQ ID NO: 1)之E26、E27、K28、Y29、E30、L31、K32、Q35、T36、D38、K40、D42、R97、D127、T134及G136,由在小於4 Å接觸距離處所測定。
在一些實施例中,本發明提供一種抗TREM1抗體,其結合於不同於PGLYRP1之抗原決定基。在一些實施例中,本發明提供一種結合於TREM1上之抗原決定基的抗TREM1抗體,該抗原決定基包含選自由以下組成之清單的不超過1或2個殘基:人類TREM1 (SEQ ID NO: 1)之E27、D42 - E46、A49、Y90 - L95及F126,由在小於4 Å接觸距離處所測定。
可藉由此項技術中已知之任何適合的結合位點定位方法與由本發明所提供之抗體中之任一者之組合識別抗原決定基。本發明提供一種特異性方法,其依賴於突變TREM1蛋白陣列以確定何等突變殘基對於結合特定抗體而言為重要的。使用此類方法,可識別與本發明所提供之抗體結合於基本上相同的胺基酸殘基之抗體。抗原決定基定位方法之其他實例包括篩選衍生自全長目標蛋白之不同長度的肽以結合至本發明之抗體或其片段及識別可特異性結合於抗體的片段,該抗體含有抗體所識別之抗原決定基的序列。可以合成方式製備目標肽。結合抗體之肽可藉由例如質譜分析來識別。在另一實例中,可使用NMR光譜法或X射線結晶學識別本發明之抗體所結合之抗原決定基。典型地,在藉由X射線結晶學進行抗原決定基測定時,來自CDR之在4Å內之抗原的胺基酸殘基視為抗原決定基之胺基酸殘基部分。在識別後,抗原決定基可用於製備結合本發明之抗體之片段且視需要用作免疫原以獲得結合相同抗原決定基之額外抗體。
在一個實施例中,藉由X射線結晶學測定抗體之抗原決定基。
藉由使用此項技術中已知之常規方法,可容易地測定抗體是否與參考抗體結合於相同抗原決定基或競爭結合。舉例而言,為確定測試抗體是否結合於與本發明之參考抗體相同的抗原決定基,使參考抗體在飽和條件下與蛋白質或肽結合。接著,評估測試抗體結合於蛋白質或肽之能力。若在飽和結合參考抗體之後測試抗體能夠結合於蛋白質或肽,則可得出以下結論:測試抗體與參考抗體結合於不同抗原決定基。另一方面,若在飽和結合參考抗體之後測試抗體不能結合於蛋白質或肽,則測試抗體可結合於與由本發明之參考抗體所結合之抗原決定基相同的抗原決定基或參考抗體引起抗原之構形變化且因此阻止測試抗體之結合。
為測定抗體是否與參考抗體競爭結合,以兩種不同實驗設置來進行上述結合方法論。在第一設置中,使參考抗體在飽和條件下結合於抗原,接著評估測試抗體與抗原之結合。在第二設置中,使測試抗體在飽和條件下結合於抗原,接著評估參考抗體與蛋白質/肽之結合。在兩種實驗性設置中,若僅第一(飽和)抗體能夠結合於蛋白質/肽,則得出以下結論:測試抗體及參考抗體競爭結合於抗原。如熟習此項技術者將瞭解,與參考抗體競爭結合之抗體可能未必與參考抗體結合於相同抗原決定基,但可藉由結合重疊或相鄰抗原決定基而在空間上阻斷參考抗體之結合或引起構形變化,該構形變化引起結合不足。
若兩種抗體中之一者競爭性地抑制(阻斷)另一者與抗原之結合,則該兩種抗體結合於相同或重疊抗原決定基。或者,若抗原中之減少或消除一種抗體之結合的基本上所有胺基酸突變減少或消除另一種抗體之結合,則兩種抗體具有相同抗原決定基。若減少或消除一種抗體之結合的一些胺基酸突變減少或消除另一種抗體之結合,則兩種抗體具有重疊抗原決定基。
接著,可進行其他常規實驗(例如,肽突變及結合分析)以確認所觀測到的測試抗體之結合不足是否確實係歸因於與參考抗體結合於相同抗原部分或空間阻斷(或另一種現象)是否引起所觀測到的結合不足。此類實驗可使用ELISA、RIA、表面電漿子共振、流式細胞測量術或此項技術中可用的任何其他定量或定性抗體結合分析法來進行。
抗體變異體
在某些實施例中,提供具有一或多個胺基酸取代、插入及/或缺失之抗體變異體。用於取代型突變誘發之所關注位點包括CDR及FR。胺基酸取代可引入所關注抗體中,且針對如下所需活性篩選產物:例如保留/改進之抗原結合、降低之免疫原性或改進之ADCC或CDC。
在某些實施例中,涵蓋本文中所描述之抗體之胺基酸序列變異體。舉例而言,可能需要改進抗體之結合親和力及/或其他生物特性。抗TREM1抗體之胺基酸序列變異體可藉由將適當修飾引入編碼蛋白質之核苷酸序列或藉由肽合成來製備。此類修飾包括例如抗TREM1抗體之胺基酸序列內(諸如一或多個CDR及/或構架序列中或VH及/或VL域中)的殘基缺失及/或插入該等殘基及/或取代該等殘基。可進行缺失、插入及取代之任何組合以獲得最終構築體,其限制條件為最終構築體具有所需特徵。
在本文所提供之變異型VH及VL序列之某些實施例中,各HVR未改變或含有不超過一個、兩個或三個胺基酸取代。
亦應理解,可對由本發明提供之CDR進行一或多個胺基酸取代、添加及/或缺失而不顯著改變抗體結合於TREM1及中和TREM1活性之能力。熟習此項技術者可例如藉由使用本文所描述之方法,尤其實例中所說明之方法,容易地測試任何胺基酸取代、添加及/或缺失之作用,以測定TREM1結合及TREM1與其天然配位體之相互作用的抑制。
因此,在變異型VH及VL序列之某些實施例中,各CDR含有不超過一個、兩個或三個胺基酸取代,其中此類胺基酸取代為保守性的,且其中抗體保持其結合於TREM1之特性。
因此,本發明提供一種抗TREM1抗體,其包含一或多個選自以下之CDR:CDR-L1 (包含SEQ ID NO:11)、CDR-L2 (包含SEQ ID NO:12)、CDR-L3 (包含SEQ ID NO:13)、CDR-H1 (包含SEQ ID NO:14)、CDR-H2 (包含SEQ ID NO:15)及CDR-H3 (包含SEQ ID NO:16),其中一或多個CDR中之一或多個胺基酸已經被另一胺基酸,例如如本文下文所定義之類似胺基酸取代。
在一個實施例中,本發明提供一種抗TREM1抗體,其包含CDR-L1 (包含SEQ ID NO:11)、CDR-L2 (包含SEQ ID NO:12)、CDR-L3 (包含SEQ ID NO:13)、CDR-H1 (包含SEQ ID NO:14)、CDR-H2 (包含SEQ ID NO:15)及CDR-H3 (包含SEQ ID NO:16),例如其中一或多個CDR中之一或多個胺基酸已經被另一胺基酸,諸如如本文下文所定義之類似胺基酸取代。
在一個實施例中,本發明提供一種抗TREM1抗體CDR-L2 (包含SEQ ID NO:12),其中SEQ ID NO:12之第一胺基酸已經被另一胺基酸取代。更特定言之,K經S取代。
在一個實施例中,本發明之抗TREM1抗體包含輕鏈可變域,其包含三個CDR,其中CDR-L1之序列包含與SEQ ID NO:11中給出之序列具有至少70%、80%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%一致性或相似性之序列,CDR-L2包含與SEQ ID NO:12中給出之序列具有至少70%、80%、90%、95%或98%一致性或相似性之序列,及/或CDR-L3包含與SEQ ID NO:13中給出之序列具有至少70%、80%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%一致性或相似性之序列。
在一個實施例中,本發明之抗TREM1抗體包含重鏈可變域,其包含三個CDR,其中CDR-H1之序列包含與SEQ ID NO:14中給出之序列具有至少70%、80%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%一致性或相似性之序列,CDR-H2包含與SEQ ID NO:15中給出之序列具有至少70%、80%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%一致性或相似性之序列,及/或CDR-H3包含與SEQ ID NO:16中給出之序列具有至少70%、80%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%一致性或相似性之序列。
在一個實施例中,本發明之抗TREM1抗體包含輕鏈可變區,其包含與SEQ ID NO:29中給出之序列具有至少70%、80%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%一致性或相似性的序列。
在一個實施例中,本發明之抗體包含重鏈可變區,其包含與SEQ ID NO:79中給出之序列具有至少70%、80%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%一致性或相似性的序列。
在一個實施例中,本發明之抗TREM1抗體包含輕鏈可變區及重鏈可變區,其中輕鏈可變區包含與以SEQ ID NO:29所提供具有至少70%、80%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%一致性或相似性的序列;及/或重鏈可變區包含與SEQ ID NO:79所提供具有至少70%、80%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%一致性或相似性的序列。
在一個實施例中,本發明之抗TREM1抗體包含分別包含SEQ ID NO:11/12/13/14/15/16之CDR-L1/CDR-L2/CDR-L3/CDR-H1/CDR-H2/CDR-H3序列,且輕鏈及重鏈可變區之其餘部分分別與SEQ ID NO:29及79具有至少70%、80%、90%、91%、92%、93%、94、95%、96%、97%、98%或99%一致性或相似性。
在一個實施例中,本發明之抗TREM1抗體為包含輕鏈及重鏈之IgG4P,該輕鏈包含與SEQ ID NO:31中給出之序列具有至少70%、80%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%一致性或相似性的序列,該重鏈包含與SEQ ID NO:81中給出之序列具有至少70%、80%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%一致性或相似性的序列。
在一個實施例中,本發明之抗TREM1抗體為IgG4P,其包含SEQ ID NO:11/12/13/14/15/16中分別提供之CDR-L1/CDR-L2/CDR-L3/CDR-H1/CDR-H2/CDR-H3序列,且輕鏈及重鏈之其餘部分分別與SEQ ID No: 31及81具有至少70%、80%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%一致性或相似性。
在一個實施例中,本發明之抗體包含輕鏈可變區及重鏈可變區,其中輕鏈可變區包含SEQ ID NO:29中給出之序列,其中位置1、2、3、18及50處之一或多個殘基已經被另一胺基酸取代;且重鏈可變區包含SEQ ID NO:79中給出之序列,其中位置23、48、49、71、73、75及78處之一或多個殘基已經被另一胺基酸取代。
序列一致性及相似性
可容易地計算序列之間的一致性及類似性之程度。「序列一致性%」(或「序列相似性%」)係藉由以下計算:(1)在比較窗口(例如,較長序列之長度、較短序列之長度、指定窗口等)內比較兩個最佳比對之序列,(2)測定含有一致(或類似)胺基酸(例如,兩個序列中存在之一致胺基酸、兩個序列中存在之類似胺基酸)之位置數,得到匹配位置數,(3)將匹配位置數除以比較窗口(例如,較長序列之長度、較短序列之長度、指定窗口)中之總位置數,及(4)將結果乘以100,得到序列一致性%或序列相似性%。
用於比較之序列比對的方法為此項技術中熟知的。用於比較之最佳序列比對可藉由以下方式執行:例如Smith及Waterman, Adv. Appl. Math. 2:482 (1981)之局部同源演算法;Needleman及Wunsch, J. Mol. Biol. 48:443 (1970)之同源比對演算法;Pearson及Lipman, Proc. Nat'l. Acad. Sci. USA 85:2444 (1988)之相似性搜尋方法;此等演算法之電腦化實施方式(Wisconsin Genetics套裝軟體中的GAP、BESTFIT、FASTA及TFASTA, Genetics Computer Group, 575 Science Dr., Madison, Wis.);或人工比對及目視檢查(參見例如Current Protocols in Molecular Biology (Ausubel等人編. 1995增刊))。
適用於測定序列一致性及序列相似性百分比之演算法之較佳實例包括BLAST及BLAST 2.0演算法,其描述於Altschul等人, Nuc. Acids Res. 25:3389-3402 (1977)及Altschul等人, J. Mol. Biol. 215:403-410 (1990)中。亦可使用FASTA,使用預設或建議參數比較多肽序列。FASTA (例如FASTA2及FASTA3)提供查詢及檢索序列之間的最佳重疊區域的比對及序列一致性百分比。
在某些實施例中,一或多個CDR內可存在取代、插入或缺失,只要此類變化不實質上降低抗體結合目標之能力即可。
舉例而言,可在CDR中進行不實質上降低結合親和力之保守性變化。可在CDR中之抗原接觸殘基之外部進行此類變化。
保守性取代以及更多的實質性「例示性取代」展示於表4中。
表
4.
胺基酸取代之實例
初始殘基 | 例示性取代 | 保守取代 |
Ala (A) | Val;Leu;Ile | Val |
Arg (R) | Lys;Gln;Asn | Lys |
Asn (N) | Gln;His;Asp、Lys;Arg | Gln |
Asp (D) | Glu;Asn | Glu |
Cys(C) | Ser;Ala | Ser |
Gln (Q) | Asn;Glu | Asn |
Glu (E) | Asp;Gln | Asp |
Gly (G) | Ala | Ala |
His (H) | Asn;Gln;Lys;Arg | Arg |
Ile (I) | Leu;Val;Met;Ala;Phe | Leu |
Leu (L) | Ile;Val;Met;Ala;Phe | Ile |
Lys (K) | Arg;Gln;Asn | Arg |
Met (M) | Leu;Phe;Ile | Leu |
Phe (F) | Trp;Leu;Val;Ile;Ala;Tyr | Tyr |
Pro (P) | Ala | Ala |
Ser (S) | Thr | Thr |
Thr (T) | Val;Ser | Ser |
Trp (W) | Tyr;Phe | Tyr |
Tyr (Y) | Trp;Phe;Thr;Ser | Phe |
Val (V) | Ile;Leu;Met;Phe;Ala; | Leu |
可藉由選擇在保持取代區域中之多肽主鏈之結構、目標位點處的分子之電荷或疏水性或側鏈之主體之作用方面顯著不同的取代來實現抗體變異體之生物特性之實質性修飾。可根據胺基酸側鏈之特性之類似性將胺基酸分組(A. L. Lehninger, Biochemistry第二版, 第73-75頁, Worth Publishers, New York (1975))。
一種類型之取代型變異體涉及取代親本抗體(人類化或人類抗體)之一或多個CDR區殘基。通常,選擇用於進一步研究之所得變異體與親本抗體相比將具有某些生物特性之變化(例如,增加之親和力、降低之免疫原性)及/或將實質上保留親本抗體之某些生物特性。例示性取代型變異體為親和力成熟抗體,其可例如使用基於噬菌體呈現之親和力成熟技術便利地產生。簡言之,使一或多個CDR殘基突變,且在噬菌體上呈現變異體抗體且針對特定生物活性(例如結合親和力)進行篩選。
改變(例如取代)可於CDR中進行以例如改善抗體親和力。此類變化可在HVR「熱點」中進行,該等熱點亦即,由在體細胞成熟過程期間經歷高頻突變之密碼子編碼之殘基(參見例如Chowdhury, Methods Mol. Biol. 207: 179-196 (2008)),及/或使抗原與測試結合親和力之所得變異型VH或VL接觸之殘基。藉由構築二級庫及自二級庫再選擇來達成親和力成熟已描述於例如Hoogenboom等人. Methods in Molecular Biology 178: 1-37 (O'Brien等人編, Human Press, Totowa, NJ, (2001))。在親和力成熟之一些實施例中,藉由多種方法(例如易錯PCR、鏈改組或寡核苷酸定向突變誘發)中之任一種將多樣性引入出於成熟所選之可變基因中。接著產生二級庫。接著篩選該庫以識別具有所需親和力之任何抗體變異體。
一種可用於識別可作為突變誘發之目標的抗體之殘基或區域之方法為丙胺酸掃描突變誘發(Cunningham及Wells (1989) Science, 244: 1081-1085)。在此方法中,識別殘基或多個目標殘基且用丙胺酸置換以測定抗體與抗原之相互作用是否受影響。或者或另外,可使用抗原-抗體複合物之X射線結構識別抗體與其抗原之間的接觸點。可篩選變異體以確定其是否含有所需特性。
恆定區變異體
在一些實施例中,可將一或多個胺基酸修飾引入至本文所提供之抗體之Fc區中,進而產生Fc區變異體。Fc區變異體可包含在一或多個胺基酸位置處包含胺基酸修飾(例如取代)之人類Fc區序列(例如,人類IgG1、IgG2、IgG3或IgG4 Fc區)。
描述具有提高或降低之與FcR之結合的某些抗體變異體。(參見例如US 6,737,056;WO 2004/056312及Shields等人, J. Biol. Chem. 9(2): 6591-6604 (2001))。
具有延長之半衰期及改良之與新生兒Fc受體(FcRn)之結合之抗體描述於US2005/0014934A1中。彼等抗體包含其中具有一或多個取代之Fc區,該一或多個取代改良Fc區與FcRn的結合。
在某些實施例中,抗體變異體包含Fc區,其具有改良ADCC的一或多個胺基酸取代,例如Fc區之位置298、333及/或334 (殘基之EU編號)處的取代。
效應功能降低之抗體包括具有Fc區殘基234、235、237、238、265、269、270、297、327及329中之一或多者之取代的抗體(參見例如US. 6,737,056)。此類Fc突變體包括具有胺基酸位置265、269、270、297及327中之兩者或更多者處的取代之Fc突變體,其中胺基酸殘基係根據EU編號系統編號。
可進行活體外及/或活體內細胞毒性分析以確認CDC及/或ADCC活性之降低/消耗。舉例而言,可進行Fc受體(FcR)結合分析以確保抗體不具有FcγR結合能力(因此可能不具有ADCC活性),但保留FcRn結合能力。用於介導ADCC之初級細胞NK細胞僅表現FcγRIII,而單核球表現FcRI、FcγRII及FcγRIII。造血細胞上之FcR表現概述於Ravetch及Kinet, Annu. Rev. Immunol. 9:457-492 (1991)中。用於評估所關注分子之ADCC活性之活體外分析法的非限制性實例描述於US5,500,362、US5,821,337中。或者或另外,可活體內評估所關注分子之ADCC活性,例如在動物模型中,諸如Clynes等人 Proc. Nat l Acad. Sci. USA 95:652-656 (1998)中所揭示之彼等動物模型。亦可進行Clq結合分析法以證實抗體不能結合Clq且因此不具有CDC活性。參見例如WO 2006/029879及WO 2005/100402中之Clq及C3c結合ELISA。為評估補體活化,可進行CDC分析法(參見例如Gazzano-Santoro等人, J. Immunol. Methods 202: 163 (1996);Cragg, M.S.等人, Blood 101: 1045-1052 (2003);及Cragg, M.S.及M.I Glennie, Blood 103:2738-2743 (2004))。亦可使用此項技術中已知之方法進行FcRn結合及活體內清除/半衰期測定(參見例如Petkova, S.B.等人, Int l. Immunol. 18(12): 1759-1769 (2006))。
本發明之抗體分子之恆定區域若存在則可根據抗體分子之所提出功能及尤其可能需要的效應功能來選擇。舉例而言,恆定區域可為人類IgA、IgD、IgE、IgG或IgM域。特定言之,當抗體分子意圖用於治療用途且需要抗體效應功能時,可使用人類IgG恆定區域,尤其IgG1及IgG3同型。或者,當抗體分子意圖用於達成治療目的且不需要抗體效應功能時可使用IgG2及IgG4同型。應瞭解,亦可使用此等恆定區域之序列變異體。
在一些實施例中,抗體為IgG1 LALA,一種野生型人類IgG1同功異型物突變體,其中已在IgG1恆定區中引入胺基酸取代L234A/L235A(根據EU編號)。
在一些實施例中,抗體為IgG4P,一種野生型人類IgG4同功異型物突變體,其中胺基酸228 (根據EU編號)由脯胺酸置換,如例如Angal等人, Molecular Immunology, 1993, 30 (1), 105-108中所描述。
糖基化變異體
在某些實施例中,對本文所提供之抗體進行改變以增加或降低該抗體經糖基化之程度。向抗體中添加糖基化位點或使抗體缺失糖基化位點可藉由改變胺基酸序列以便產生或移除一或多個糖基化位點來便利地實現。
人類化、人類及嵌合抗體
本發明之抗體可為(但不限於)人類化、完全人類或嵌合抗體。
在一個實施例中,抗體經人類化。更特定言之,抗TREM1抗體為嵌合、人類或人類化抗體。
在某些實施例中,本文所提供之抗體為嵌合抗體。嵌合抗體之實例描述於例如US4,816,567;及Morrison等人, Proc. Natl. Acad. Sci. USA, 81 :6851-6855 (1984))中。在一個實例中,嵌合抗體包含非人類可變區(例如,來源於小鼠、大鼠、倉鼠、兔或非人類靈長類動物(諸如猴)之可變區)及人類恆定區。在另一實例中,嵌合抗體為「類別切換」抗體,其中類別或子類別已自親本抗體之類別或子類別改變。
嵌合抗體係由來源於兩種不同物種之元件構成,使得該元件保留衍生其之物種之特徵。一般而言,嵌合抗體將包含來自一個物種之可變區,例如來自另一物種(諸如人類)之小鼠、大鼠、兔或類似及恆定區。
在某些實施例中,嵌合抗體為人類化抗體。
應瞭解,可能僅需要轉移CDR之特異性決定殘基而非整個CDR (參見例如Kashmiri等人, 2005, Methods, 36, 25-34)。人類化抗體可視情況進一步包含一或多個來源於衍生CDR之非人類物種的構架殘基。
適當地,根據本發明之人類化抗體具有可變域,其包含人類受體構架區以及一或多個CDR且視情況進一步包括一或多個供體構架殘基。
在一個實施例中,抗體為人類化抗體,其中可變域包含人類受體構架區及非人類供體CDR。
在移植CDR時,根據衍生CDR之供體抗體之類別/類型,可使用任何合適的受體可變區構架序列,包括小鼠、靈長類動物及人類構架區。
可用於本發明中之人類構架之實例為KOL、NEWM、REI、EU、TUR、TEI、LAY及POM (Kabat等人)。舉例而言,KOL及NEWM可用於重鏈,REI可用於輕鏈且EU、LAY及POM可用於重鏈及輕鏈。或者,可使用人類生殖系序列;此等序列可在www.imgt.org獲得。在實施例中,受體構架為IGKV1-9人類生殖系及/或IGHV3-66人類生殖系。在實施例中,人類構架含有1-5、1-4、1-3或1-2個供體抗體胺基酸殘基。
在本發明之人類化抗體中,受體重鏈及輕鏈無需來源於相同抗體且可視需要包含具有來源於不同鏈之構架區之複合鏈。
在一些實施例中,抗體為人類抗體。可使用此項技術中已知之各種技術產生人類抗體。更特定言之,抗TREM1抗體包含人類抗體重鏈恆定區及人類輕鏈恆定區。
人類抗體包含重鏈或輕鏈可變區或全長重鏈或輕鏈,若抗體之可變區或全長鏈獲自使用人生殖系免疫球蛋白基因之系統,則其來源於特定生殖系序列。此類系統包括用所關注之抗原使攜帶人類免疫球蛋白基因之轉殖基因小鼠免疫或用所關注之抗原篩選呈現在噬菌體上之人類免疫球蛋白基因庫。來源於人類生殖系免疫球蛋白序列之人類抗體可藉由將人類抗體之胺基酸序列與人類生殖系免疫球蛋白之胺基酸序列進行比較且選擇序列最接近(亦即最大一致性%)人類抗體序列之人類生殖系免疫球蛋白序列來如此識別。來源於特定人類生殖系免疫球蛋白序列的人類抗體可含有與生殖系序列相比因例如天然存在之體細胞突變或有意引入之定點突變所致的胺基酸差異。然而,所選擇的人類抗體通常在胺基酸序列方面與由人類生殖系免疫球蛋白基因編碼之胺基酸序列至少90%一致,且含有當與其他物種之生殖系免疫球蛋白胺基酸序列(例如,鼠類生殖系序列)相比時識別人類抗體為人類的胺基酸殘基。在某些情況下,人類抗體在胺基酸序列方面可與由生殖系免疫球蛋白基因編碼之胺基酸序列至少60%、70%、80%、90%,或至少95%,或甚至至少96%、97%、98%或99%一致。通常,來源於特定人類生殖系序列之人類抗體將呈現與由人類生殖系免疫球蛋白基因編碼之胺基酸序列相比不超過10個胺基酸差異。在某些情況下,人類抗體可呈現與由生殖系免疫球蛋白基因編碼之胺基酸序列相比不超過5個,或甚至不超過4、3、2或1個胺基酸差異。
人類抗體可藉由熟習此項技術者已知的多種方法產生。人類抗體可藉由融合瘤方法使用人類骨髓瘤或小鼠-人類融合骨髓瘤細胞株製得(Kozbor, J Immunol; (1984) 133:3001;Brodeur, Monoclonal Isolated Antibody Production Techniques and Applications, 第51-63頁, Marcel Dekker Inc, 1987)。替代方法包括使用噬菌體庫或轉殖基因小鼠,兩者均利用人類可變區庫(Winter G; (1994) Annu Rev Immunol 12:433-455, Green LL, (1999) J Immunol Methods 231 :1 1-23)。人類抗體可例如由小鼠產生,其中鼠類免疫球蛋白可變區基因及視情況選用之恆定區基因已如例如US 5,545,806、US 5,569,825、US 5,625,126、US 5,633,425、US 5,661,016及US 5,770,429中所描述經其人類對應物置換。
效應分子
必要時,根據本發明之抗體可與一或多種效應分子結合。在一個實施例中,抗體不與效應分子連接。
應瞭解效應分子可包含單個效應分子或兩個或更多個連接成用於形成可連接至本發明抗體之單一部分的分子。在需要獲得連接至效應分子之抗體片段的情況下,此可藉由其中抗體片段直接或經由偶合劑連接至效應分子的標準化學或重組DNA程序來製備。用於此類效應分子結合於抗體之技術為此項技術中所熟知(參見Hellstrom等人, Controlled Drug Delivery, 第2版, Robinson等人編, 1987, 第623-53頁;Thorpe等人, 1982, Immunol. Rev., 62:119-58及Dubowchik等人, 1999, Pharmacology and Therapeutics, 83, 67-123)。特定化學程序包括例如WO 93/06231、WO 92/22583、WO 89/00195、WO 89/01476及WO 03/031581中所描述之程序。或者,在效應分子為蛋白質或多肽之情況下,連接可使用重組DNA程序,例如如WO 86/01533及EP0392745中所描述來實現。
效應分子之實例可包括細胞毒素或細胞毒性劑,包括任何對細胞不利(例如殺死)之試劑。實例包括康普瑞汀(combrestatin)、海兔毒素(dolastatin)、埃博黴素(epothilone)、星形孢菌素(staurosporin)、類美登素(maytansinoid)、海綿素(spongistatin)、根瘤菌素(rhizoxin)、軟海綿素(halichondrin)、桿孢菌素(roridin)、海米斯林(hemiasterlin)、紫杉醇(taxol)、細胞遲緩素B (cytochalasin B)、短桿菌素D (gramicidin D)、溴化乙錠(ethidium bromide)、吐根素(emetine)、絲裂黴素(mitomycin)、依託泊苷(etoposide)、特諾波賽(tenoposide)、長春新鹼(vincristine)、長春鹼(vinblastine)、秋水仙鹼(colchicin)、小紅莓(doxorubicin)、道諾比星、二羥基炭疽菌素二酮(dihydroxy anthracin dione)、米托蒽醌(mitoxantrone)、光神黴素(mithramycin)、放線菌素D (actinomycin D)、1-去氫睪固酮、糖皮質激素、普魯卡因(procaine)、四卡因(tetracaine)、利多卡因(lidocaine)、普萘洛爾(propranolol)及嘌呤黴素(puromycin)及其類似物或同源物。
效應分子亦包括(但不限於)抗代謝物(例如甲胺喋呤(methotrexate)、6-巰基嘌呤(6-mercaptopurine)、6-硫代鳥嘌呤(6-thioguanine)、阿糖胞苷(cytarabine)、5-氟尿嘧啶、達卡巴𠯤(decarbazine))、烷基化劑(例如甲氮芥(mechlorethamine)、噻替派(thiotepa)、苯丁酸氮芥(chlorambucil)、美法侖(melphalan)、卡莫司汀(carmustine) (BSNU)及洛莫司汀(lomustine) (CCNU)、環磷醯胺(cyclophosphamide)、白消安(busulfan)、二溴甘露醇(dibromomannitol)、鏈佐黴素(streptozotocin)、絲裂黴素C及順式-二氯二胺鉑(II)(DDP)、順鉑(cisplatin))、蒽環黴素(anthracycline)(例如道諾比星(以前為道諾黴素(daunomycin))及小紅莓(doxorubicin))、抗生素(例如放線菌素(以前為放射菌素)、博萊黴素(bleomycin)、光神黴素、安麴黴素(anthramycin) (AMC)、卡奇黴素(calicheamicin)或倍癌黴素(duocarmycin))及抗有絲分裂劑(例如長春新鹼及長春鹼)。
其他效應分子可包括螯合放射性核素,諸如111In及90Y、Lu177、鉍213、鐦252、銥192及鎢188/錸188;或藥物,諸如(但不限於)烷基磷酸膽鹼、拓樸異構酶I抑制劑、類紫杉醇及蘇拉明(suramin)。
其他效應分子包括蛋白質、肽及酶。所關注酶包括但不限於蛋白水解酶、水解酶、裂解酶、異構酶、轉移酶。所關注蛋白質、多肽及肽包括(但不限於)免疫球蛋白、毒素(諸如相思子毒素、蓖麻毒素A、綠膿桿菌外毒素或白喉毒素)、蛋白質(諸如胰島素、腫瘤壞死因子、α-干擾素、β-干擾素、神經生長因子、血小板衍生生長因子或組織纖維蛋白溶酶原活化因子)、血栓劑或抗血管生成劑(例如血管生長抑素或內皮生長抑素)或生物反應調節劑(諸如淋巴激素、介白素-1 (IL-1)、介白素-2 (IL-2)、顆粒球巨噬細胞群落刺激因子(GM-CSF)、顆粒球群落刺激因子(G-CSF)、神經生長因子(NGF)或其他生長因子及免疫球蛋白)。
其他效應分子可包括適用於例如診斷之可偵測物質。可偵測物質之實例包括各種酶、輔基、螢光材料、發光材料、生物發光材料、放射性核種、正電子發射金屬(用於正電子發射斷層攝影術)及非放射性順磁性金屬離子。關於可結合於抗體以用於診斷學之金屬離子,通常參見US4,741,900。適合酶包括辣根過氧化酶、鹼性磷酸酶、β半乳糖苷酶或乙醯膽鹼酯酶;適合輔基包括鏈黴抗生物素蛋白、鏈黴抗生物素蛋白及生物素;適合螢光物質包括傘酮、螢光素、異硫氰酸螢光素、若丹明(rhodamine)、二氯三𠯤基胺螢光素、丹磺醯氯及藻紅素;適合發光物質包括魯米諾(luminol);適合生物發光物質包括螢光素酶、螢光素及水母素(aequorin);且適合放射性核素包括125I、131I、111In及99Tc。
在另一實例中,效應分子可延長抗體的活體內半衰期,及/或降低抗體之免疫原性及/或增強抗體跨越上皮障壁至免疫系統之遞送。此類型之適合的效應分子之實例包括聚合物、白蛋白、白蛋白結合蛋白質或白蛋白結合化合物,諸如WO2005/117984中所描述之化合物。
在效應分子為聚合物之情況下,其一般可以為合成或天然存在之聚合物,例如視情況經取代之直鏈或分支鏈聚伸烷基、聚伸烯基或聚氧化烯聚合物,或分支或未分支多醣,例如同多醣或雜多醣。
可存在於上述合成聚合物上的視情況存在之特定取代基包括一或多個羥基、甲基或甲氧基。
合成聚合物之特定實例包括視情況經取代之直鏈或分支鏈聚(乙二醇)、聚(丙二醇)、聚(乙烯醇)或其衍生物,尤其視情況經取代之聚(乙二醇),諸如甲氧基聚(乙二醇)或其衍生物。
特定天然存在的聚合物包括乳糖、直鏈澱粉、聚葡萄糖、肝糖或其衍生物。
在一個實施例中,聚合物為白蛋白或其片段,諸如人類血清白蛋白或其片段。
聚合物之大小可根據需要變化,但平均分子量將通常在500 Da至50000 Da之範圍內,例如5000 Da至40000 Da,諸如20000 Da至40000 Da。聚合物大小可尤其基於產物之意圖用途,例如定位至某些組織,諸如腫瘤或延長循環半衰期之能力而選擇(評述參見Chapman, 2002, Advanced Drug Delivery Reviews, 54, 531-545)。因此,舉例而言,在產物意欲離開循環且滲透組織,例如用於治療腫瘤之情況下,宜使用例如分子量為大約5000 Da之小分子量聚合物。對於產物仍然在循環中之應用,宜使用例如分子量在20000 Da至40000 Da範圍內之較高分子量聚合物。
適合聚合物包括聚伸烷基聚合物,諸如聚(乙二醇)或尤其甲氧基聚(乙二醇)或其衍生物,且尤其分子量在約15000 Da至約40000 Da範圍內的聚合物。
在一個實例中,根據本發明之抗體附接於聚(乙二醇) (PEG)部分。在一個特定實施例中,根據本發明之抗原結合片段及PEG分子可經由定位於抗體片段中之任何可用胺基酸側鏈或末端胺基酸官能基(例如,任何游離胺基、亞胺基、巰基、羥基或羧基)連接。此類胺基酸可天然存在於抗體片段中或可使用重組DNA方法經工程改造至片段中(參見例如US 5,219,996;US 5,667,425;WO98/25971、WO2008/038024)。在一個實例中,本發明之抗體分子係經修飾之Fab片段,其中該修飾係將一或多個胺基酸添加至其重鏈之C端以允許附接效應分子。適當地,額外的胺基酸形成含有效應分子可連接的一或多個半胱胺酸殘基的經修飾鉸鏈區。可以使用多個位點連接兩個或更多個PEG分子。
PEG分子宜經由位於抗體片段中的至少一個半胱胺酸殘基之巰基共價連接。連接至經修飾抗體片段的各聚合物分子可共價連接於位於片段中的半胱胺酸殘基之硫原子。共價鍵一般為二硫鍵或尤其為硫-碳鍵。在巰基用作連接點的情況下,可使用適當活化的效應分子,例如巰基選擇性衍生物,諸如順丁烯二醯亞胺及半胱胺酸衍生物。在如上所述之經聚合物修飾的抗體片段之製備中,可使用活化聚合物作為起始物質。活化聚合物可為含有硫醇反應基之任何聚合物,諸如α-鹵基羧酸或酯,例如碘乙醯胺、醯亞胺(例如順丁烯二醯亞胺)、乙烯基碸或二硫化物。此類起始物質可商購(例如購自Nektar,以前為Shearwater Polymers Inc., Huntsville, AL, USA)或可使用習知化學程序由可商購的起始物質製備。特定PEG分子包括20K甲氧基-PEG-胺(可獲自Nektar,以前為Shearwater;Rapp Polymere;及SunBio)及M-PEG-SPA (可獲自Nektar,以前為Shearwater)。
在一個實施例中,抗體為經聚乙二醇化的經修飾Fab片段、Fab'片段或二Fab (diFab),亦即具有PEG (聚(乙二醇))共價連接於其上,例如根據揭示於EP0948544或EP1090037中之方法[亦參見「Poly(ethyleneglycol) Chemistry, Biotechnical and Biomedical Applications」, 1992, J. Milton Harris (編), Plenum Press, New York;「Poly(ethyleneglycol) Chemistry and Biological Applications」, 1997, J. Milton Harris及S. Zalipsky (編), American Chemical Society, Washington DC及「Bioconjugation Protein Coupling Techniques for the Biomedical Sciences」, 1998, M. Aslam及A. Dent, Grove Publishers, New York;Chapman, A. 2002, Advanced Drug Delivery Reviews 2002, 54:531-545]。在一個實例中,PEG連接至鉸鏈區中之半胱胺酸。在一個實例中,經PEG修飾之Fab片段具有共價連接於經修飾之鉸鏈區中單一巰基的順丁烯二醯亞胺基團。離胺酸殘基可共價連接於順丁烯二醯亞胺基團且離胺酸殘基上之各胺基可連接分子量為大約20,000 Da的甲氧基聚(乙二醇)聚合物。因此,連接至Fab片段之PEG的總分子量可為約40,000 Da。
在一個實施例中,抗體為經修飾之Fab'片段,其在其重鏈之C端具有經修飾之鉸鏈區,該經修飾之鉸鏈區含有至少一個效應分子所連接之半胱胺酸殘基。適當地,效應分子為PEG且使用WO 98/25971及WO 2004072116或WO 2007/003898中所描述之方法連接。可使用國際專利申請案WO 2005/003169、WO 2005/003170及WO 2005/003171中所描述之方法將效應分子連接至抗體片段。
在一個實施例中,抗體不與效應分子連接。
聚核苷酸及載體
本發明亦提供一種經分離之聚核苷酸,其編碼根據本發明之抗體或其一部分(諸如表5中所列之胺基酸SEQ ID)。根據本發明之經分離之聚核苷酸可包含例如藉由化學處理產生的合成DNA、cDNA、基因體DNA或其任何組合。
表
5.
抗
TREM1
抗體之胺基酸序列及其相應核酸序列
抗體序列 | 胺基酸SEQ ID NO | 核酸SEQ ID NO |
12172 gL6gH6輕鏈V區 | 33 | 34 |
12172 gL6gH6重鏈V區 | 57 | 58 |
12172 gL6gH6輕鏈 | 35 | 36 |
12172 gL6gH6重鏈IgG1 | 63 | 64 |
12172 gL6gH6重鏈IgG1 LALA | 65 | 66 |
12172 gL6gH6重鏈IgG4P | 59 | 60 |
12172 gL6gH6重鏈IgG4P FALA | 61 | 62 |
12172 gL2gH11輕鏈V區 | 29 | 30 |
12172 gL2gH11重鏈V區 | 79 | 80 |
12172 gL2gH11輕鏈 | 31 | 32 |
12172 gL2gH11重鏈IgG1 | 85 | 86 |
12172 gL2gH11重鏈IgG1 LALA | 87 | 88 |
12172 gL2gH11重鏈IgG4P | 81 | 82 |
12172 gL2gH11重鏈IgG4P FALA | 83 | 84 |
本文中提供適合的序列之實例。因此,在一個實施例中,本發明提供編碼抗體之經分離聚核苷酸,其包含SEQ ID NO 34、58、36、64、66、60、62、30、80、32、86、88、82或84中給出之序列。
在一個實施例中,本發明提供一種經分離之聚核苷酸,其編碼本發明之IgG1 LALA或IgG4P抗體之重鏈,該重鏈分別包含SEQ ID NO: 88或82中給出之序列。
亦提供一種經分離之聚核苷酸,其編碼本發明之IgG1 LALA或IgG4P抗體之輕鏈,該輕鏈包含SEQ ID NO: 32中給出之序列。
在另一實施例中,本發明提供一種經分離之聚核苷酸,其編碼本發明之IgG4P抗體之重鏈及輕鏈,其中編碼重鏈之聚核苷酸包含SEQ ID NO: 82中給出之序列且編碼輕鏈之聚核苷酸包含SEQ ID NO: 32中給出之序列。
本發明亦提供選殖或表現載體,其包含一或多種本文中所描述之聚核苷酸。在一個實例中,根據本發明之選殖或表現載體包含一或多種經分離之聚核苷酸,其包含選自SEQ ID NO: 34、58、36、64、66、60、62、30、80、32、86、88、82或84之序列。
分子生物學之標準技術可用於製備編碼本發明之抗體或其抗原結合片段之DNA序列。所需DNA序列可使用寡核苷酸合成技術完全或部分合成。適當時可使用定點突變誘發及聚合酶鏈反應(PCR)技術。
可用於構築載體之一般方法、轉染方法及培養方法為熟習此項技術者熟知的。在此方面,參考「Current Protocols in Molecular Biology」, 1999, F. M. Ausubel (編), Wiley Interscience, New York及由Cold Spring Harbor Publishing出版的Maniatis Manual。
產生抗體及其抗原結合片段之宿主細胞
亦提供一種宿主細胞,其包含根據本發明之一或多種經分離聚核苷酸序列或包含編碼本發明之抗體之一或多種經分離聚核苷酸序列的一或多種選殖或表現載體。任何適合的宿主細胞/載體系統皆可用於表現編碼本發明之抗體或其抗原結合片段之聚核苷酸序列。可使用細菌,例如大腸桿菌及其他微生物系統,或亦可使用真核,例如哺乳動物、宿主細胞表現系統。適合哺乳動物宿主細胞包括CHO、骨髓瘤或融合瘤細胞。
在另一實施例中,提供包含此類核酸或載體之宿主細胞。在一個此類實施例中,宿主細胞包含(例如,已經以下轉型):(1)包含核酸之載體,該核酸編碼包含抗TREM1抗體之VL的胺基酸序列及包含抗TREM1抗體之VH的胺基酸序列;或(2)包含核酸之第一載體,該核酸編碼包含抗TREM1抗體之VL的胺基酸序列,及包含核酸之第二載體,該核酸編碼包含抗TREM1抗體之VH的胺基酸序列。在一個實施例中,宿主細胞為真核細胞,例如中國倉鼠卵巢(CHO)細胞或淋巴細胞(例如Y0、NS0、Sp20細胞)。在一個實施例中,宿主細胞為原核細胞,例如大腸桿菌細胞。在一個實施例中,提供一種製備抗TREM1抗體之方法,其中該方法包含在適合於表現抗體之條件下培養如上文所提供之包含編碼抗體之核酸的宿主細胞,且視情況自宿主細胞(或宿主細胞培養基)回收抗體。
適合於選殖或表現編碼抗體之載體的宿主細胞包括本文所描述之原核或真核細胞。舉例而言,抗體可於細菌中產生,在不需要糖基化及Fc效應功能時尤其如此。對於細菌中抗體片段及多肽之表現,參見例如U.S. 5,648,237、5,789,199及5,840,523(亦參見Charlton, Methods in Molecular Biology, 第248卷 (B.K.C. Lo編, Humana Press, Totowa, NJ, 2003), 第245-254頁,其描述大腸桿菌中抗體片段之表現)。在表現之後,抗體可以可溶性溶離份自細菌細胞糊狀物分離在且可進一步進行純化。
除原核生物外,諸如絲狀真菌或酵母之真核微生物為抗體編碼載體之適合選殖或表現宿主,包括糖基化路徑已經「人類化」,從而使得所產生之抗體具有部分或完全人類糖基化型態的真菌及酵母菌株。參見Gerngross, Nat. Biotech. 22: 1409-1414 (2004),及Li等人, Nat. Biotech. 24:210-215 (2006)。
用於本發明中之中國倉鼠卵巢(CHO細胞)的適合類型可包括CHO及CHO-K1細胞,包括dhfr-CHO細胞,諸如可與DHFR可選標記一起使用之CHO-DG44細胞及CHO-DXB11細胞或可與麩醯胺酸合成酶可選標記一起使用之CHOK1-SV細胞。用於表現抗體之其他細胞類型包括淋巴球性細胞株,例如NS0骨髓瘤細胞及SP2細胞、COS細胞。宿主細胞可用根據本發明之經分離之聚核苷酸序列或表現載體穩定轉型或轉染。
用於產生抗體之方法
本發明亦提供一種用於產生根據本發明之抗體的方法,其包含在適合於產生根據本發明之抗體之條件下培養根據本發明之宿主細胞及分離抗體。
抗體可僅包含重鏈或輕鏈多肽,在此情況下,僅需使用重鏈或輕鏈多肽編碼序列即可轉染宿主細胞。為了產生包含重鏈及輕鏈兩者之抗體或其抗原結合片段,細胞株可用兩種載體轉染,第一載體編碼輕鏈多肽且第二載體編碼重鏈多肽。或者,可使用單一載體,載體包括編碼輕鏈及重鏈多肽之序列。
因此,提供一種培養宿主細胞且表現抗體,分離抗體且視情況純化抗體以提供分離之抗體的方法。在一個實施例中,該方法進一步包含使效應分子與經分離之抗體結合之步驟。
本發明亦提供用於產生根據本發明之抗體之方法,其包含在適於引起自編碼本發明之抗體分子之DNA表現蛋白質的條件下培養含有本發明之載體之宿主細胞,及分離抗體分子。
抗體分子可僅包含重鏈或輕鏈多肽,在此情況下,僅需使用重鏈或輕鏈多肽編碼序列即可轉染宿主細胞。為產生包含重鏈及輕鏈之產物,細胞株可以用兩個載體轉染,第一載體編碼輕鏈多肽且第二載體編碼重鏈多肽。或者,可使用單一載體,載體包括編碼輕鏈及重鏈多肽之序列。
根據本發明之抗體由宿主細胞以優良含量表現。因此,抗體之特性似乎經最佳化用於商業加工。
經純化抗體
在一個實施例中,提供經純化之抗體,例如人類化抗體,尤其本發明之抗體,其呈實質上純化形式,尤其不含或實質上不含內毒素及/或宿主細胞蛋白質或DNA。
實質上不含內毒素一般意指每毫克抗體產物內毒素含量為1 EU或更低,諸如每毫克產物0.5或0.1 EU。
實質上不含宿主細胞蛋白質或DNA一般意指每毫克抗體產物宿主細胞蛋白質及/或DNA含量為400 µg或更低,諸如100 µg/mg或更低,尤其適當時20 µg/mg。
抗體之治療性用途
可投與本發明之抗體、其調配物或醫藥組合物以用於預防性及/或治療性治療。
本發明提供一種本發明之抗TREM1抗體或其醫藥組合物,其用作藥劑。
在預防性應用中,向處於如本文中所描述之病症或病狀之風險下的受試者投與足以阻止或減少病狀或其一或多種症狀之後續作用的量之抗體、調配物或組合物。
在治療性應用中,向已罹患如本文中所描述之病症或病狀之受試者投與足以治癒、緩解或部分抑制病狀或其一或多種症狀的量之抗體。此類治療性治療可導致疾病症狀之嚴重程度降低,或無症狀時期之頻率或持續時間增加。
所治療之受試者可為動物。較佳地,根據本發明之醫藥組合物經調適以用於向人類受試者投與。
本發明提供一種在有需要之受試者中治療如本文所描述之病症或病狀之方法,該方法包含向受試者投與根據本發明之抗體。以治療有效量投與此類抗體。
本發明亦提供本發明之抗體,其用於治療如本文所描述之病症或病狀。
治療適應症
本發明之抗體可用於治療、預防或改善與TREM1活性相關之任何病狀;例如完全或部分地引起經由TREM1之信號傳導的任何病狀。
TREM1及其多種路徑與多種神經、神經發育、精神、全身性及自體免疫性發炎病狀有關。可使用本發明之抗體及組合物治療的病狀之一些實例包括肌肉萎縮性脊髓側索硬化症、阿茲海默氏病(AD)、帕金森氏症(PD)、tau蛋白病、失智症、額顳葉型失智症、血管性失智症、混合型失智症、多系統萎縮、癲癇(包括結節性硬化症及局灶性皮質發育不良)、亨丁頓氏病、脊髓損傷、創傷性腦損傷、慢性創傷性腦病變、缺血性中風、多發性硬化症、自體免疫性神經炎、精神分裂症、泛自閉症障礙、重度憂鬱症、躁鬱症、遺傳性病狀或其任何組合。
本發明之抗體及組合物可用於治療神經病症。更特定言之,該神經病症為肌肉萎縮性脊髓側索硬化症(ALS)或阿茲海默氏病。
抗體及其抗原結合片段之診斷用途
本發明亦提供本發明之抗體作為診斷活性劑或在診斷分析中之用途,例如用於診斷疾病或其嚴重程度。
較佳可對生物樣品進行診斷。「生物樣品」涵蓋獲自個體之多種樣品類型且可用於診斷或監測分析。該定義涵蓋腦脊髓液,諸如血漿及血清之血液,及生物來源之其他液體樣品,諸如尿液及唾液,固體組織樣品,諸如活檢樣本或自其及其子代衍生之組織培養物或細胞。定義亦包括在獲取之後已以任何方式操控的樣品,諸如藉由試劑處理、增溶,或富集某些組分,諸如聚核苷酸。
診斷測試較佳可對不與人類或動物身體接觸的生物樣品進行。此類診斷測試亦稱為活體外測試。活體外診斷測試可依賴於活體外偵測已自受試者獲得之生物樣品中的TREM1之方法。
醫藥及診斷組合物
本發明之抗體可以醫藥組合物形式提供。醫藥組合物將通常為無菌的且可另外包含醫藥學上可接受之佐劑及/或載劑。
由於本發明之抗體適用於治療、診斷及/或預防如本文中所描述之病症或病狀,因此本發明亦提供醫藥或診斷組合物,其包含根據本發明之抗體或其抗原結合片段與醫藥學上可接受之載劑、賦形劑或稀釋劑中之一或多者之組合。
特定言之,以包含醫藥學上可接受之賦形劑、稀釋劑或載劑中之一或多者之醫藥組合物形式提供抗體或其抗原結合片段。
除治療活性成分以外,此等組合物可包含醫藥學上可接受之賦形劑、載劑、稀釋劑、緩衝液、穩定劑或熟習此項技術者熟知的其他材料。此類物質應為無毒的且不應干擾活性成分之功效。
亦提供組合物,其包括醫藥調配物,該等醫藥調配物包含本發明之抗TREM1抗體或包含編碼本發明抗體之序列之聚核苷酸。在某些實施例中,組合物包含一或多種本發明抗體或一或多種包含編碼本發明之一或多種抗體之序列的聚核苷酸。此等組合物可進一步包含此項技術中熟知的適合的載劑,諸如醫藥學上可接受之賦形劑及/或佐劑,包括緩衝液。
本發明之抗體之醫藥組合物係藉由將具有所需純度之此類抗體與一或多種視情況選用之醫藥學上可接受之載劑以凍乾調配物或水性溶液之形式混合來製備。
上文所提及之技術及方案之實例可見於Remington's Pharmaceutical Sciences, 第20版, 2000, 出版社Lippincott, Williams & Wilkins。
醫藥學上可接受之載劑在所採用之劑量及濃度下一般對接受者無毒性,且包括但不限於:緩衝液,諸如磷酸鹽、檸檬酸鹽及其他有機酸;抗氧化劑,包括抗壞血酸及甲硫胺酸;防腐劑(諸如十八烷基二甲基苯甲基氯化銨;氯化六羥季銨;氯化苄烷銨;氯化苯索銨;苯酚、丁基或苯甲醇;對羥基苯甲酸烷酯,諸如對羥基苯甲酸甲酯或對羥基苯甲酸丙酯;兒茶酚;間苯二酚;環己醇;3-戊醇;及間甲酚);低分子量(小於約10個殘基)多肽;蛋白質,諸如血清白蛋白、明膠或免疫球蛋白;親水性聚合物,諸如聚乙烯吡咯烷酮;胺基酸,諸如甘胺酸、麩醯胺酸、天冬醯胺、組胺酸、精胺酸或離胺酸;單醣、雙醣及其他碳水化合物,包括葡萄糖、甘露糖或糊精;螯合劑,諸如EDTA;糖,諸如蔗糖、甘露醇、海藻糖或山梨醇;成鹽相對離子,諸如鈉;金屬複合物(例如,Zn-蛋白質複合物);及/或非離子界面活性劑,諸如聚乙二醇(PEG)。本文中之例示性醫藥學上可接受之載劑進一步包括間質藥物分散劑,諸如可溶性中性活性玻糖醛酸酶醣蛋白(sHASEGP),例如人類可溶性PH-20玻糖醛酸酶蛋白,諸如rHuPH20 (HYLENEX®, Baxter International, Inc.)。某些例示性sHASEGP及使用方法(包括rHuPH20)描述於US 2005/0260186及2006/0104968中。在一個態樣中,sHASEGP與一或多種其他葡萄糖胺聚糖酶,諸如軟骨素酶組合。
活性成分可包覆於微膠囊中,例如藉由凝聚技術或藉由界面聚合法所製備之微膠囊,例如分別為羥基甲基纖維素或明膠微膠囊及聚(甲基丙烯酸甲酯)微膠囊;包覆於膠態藥物遞送系統(例如脂質體、白蛋白微球體、微乳液、奈米顆粒及奈米膠囊)中或巨乳液中。此類技術揭示於Remington's Pharmaceutical Sciences 第16版, Osol, A.編(1980)中。
亦可製備持續釋放製劑。持續釋放製劑之適合實例包括含有抗體之固體疏水性聚合物之半滲透基質,該等基質呈成形物品形式,例如膜或微膠囊。
用於活體內投與之調配物通常為無菌的。無菌性可容易地藉由例如經由無菌過濾膜過濾來實現。
本發明之醫藥組合物可包括一或多種醫藥學上可接受之鹽。
醫藥學上可接受之載劑包含水性載劑或稀釋劑。可用於本發明之醫藥組合物之適合之水性載劑的實例包括水、緩衝水及生理鹽水。其他載劑之實例包括乙醇、多元醇(諸如甘油、丙二醇、聚乙二醇及其類似物)及其適合的混合物、植物油(諸如橄欖油)及可注射的有機酯(諸如油酸乙酯)。在許多情況下,組合物中需要包括等張劑(例如糖)、多元醇(諸如甘露醇、山梨醇)或氯化鈉。
醫藥組合物通常必須在製造及儲存條件下為無菌且穩定的。組合物可調配為溶液、微乳液、脂質體或適合於高藥物濃度之其他有序結構。
在一個實施例中,本發明之抗體為唯一活性成分。在另一實施例中,本發明之抗體與一或多種額外活性成分組合。或者,醫藥組合物包含本發明之抗體,其為唯一活性成分且其可與其他藥劑、藥物或激素組合(例如同時、依序或分開)單獨地向患者投與。
載劑或其他材料之確切性質可視投與途徑而定,例如經口、靜脈內、皮膚或皮下、經鼻、肌肉內及腹膜內途徑。舉例而言,固體口服形式可含有活性物質以及稀釋劑,例如乳糖、右旋糖、蔗糖、纖維素、玉米澱粉或馬鈴薯澱粉;潤滑劑,例如二氧化矽、滑石、硬脂酸、硬脂酸鎂或硬脂酸鈣及/或聚乙二醇;黏合劑,例如澱粉、阿拉伯膠、明膠、甲基纖維素、羧基甲基纖維素或聚乙烯吡咯烷酮;崩解劑,例如澱粉、褐藻酸、海藻酸鹽或羥基乙酸澱粉鈉;發泡混合物;染料;甜味劑;濕潤劑,諸如卵磷脂、聚山梨醇酯、十二烷磺酸酯;及通常用於醫藥調配物中之無毒且藥理學上非活性物質。可以已知方式,例如藉由混合、粒化、製錠、糖包覆或膜包覆過程來製造此類醫藥製劑。
口服調配物包括常用賦形劑,例如醫藥級甘露醇、乳糖、澱粉、硬脂酸鎂、糖精鈉、纖維素、碳酸鎂及其類似物。此等組合物呈溶液、懸浮液、錠劑、丸劑、膠囊、持續釋放調配物或散劑形式且含有10%至95%,較佳25%至70%之活性成分。當將醫藥組合物凍乾時,可在投與之前將凍乾材料復原,例如懸浮液。較佳在緩衝液中進行復原。
用於靜脈內投與或輸注之溶液可含有例如無菌水作為載劑或較佳其可呈無菌水性、等張生理鹽水溶液形式。
較佳地,醫藥或診斷組合物包含根據本發明之人類化抗體。
治療有效量及劑量確定
根據本發明之抗體及醫藥組合物宜可適當地向患者投與以識別所需之治療有效量。關於任何抗體,治療有效量可最初在細胞培養分析中或在動物模型中,通常在嚙齒動物、兔、狗、豬或靈長類中估算。動物模型亦可用於確定投與之適當濃度範圍及途徑。此類資訊可接著用於確定適用於在人體內投與之劑量及途徑。
用於人類受試者之精確治療有效量將取決於疾病狀態之嚴重程度、受試者之整體健康狀況、受試者之年齡、體重及性別、飲食、投與之時間及頻率、藥物組合、反應敏感性及對療法之耐受性/反應。組合物宜以每劑量含有預定量之本發明之活性劑的單位劑型存在。本文所描述之任何實施例之劑量範圍及方案包括(但不限於)在1 mg-1000 mg單位劑量範圍內之劑量。
本發明之抗體或醫藥組合物之適合的劑量可由熟練的開業醫師確定。本發明之醫藥組合物中的活性成分之實際劑量含量可變化,以獲得在對患者無毒性之情況下有效實現特定患者、組合物及投與模式之所需治療反應的活性成分之量。所選劑量含量將視多種藥物動力學因素而定,該等因素包括所採用之本發明之特定組合物的活性;投與途徑;投與時間;待採用之特定化合物之排泄速率;治療持續時間;與所採用之特定組合物組合使用的其他藥物、化合物及/或材料;待治療之患者的年齡、性別、體重、病狀、一般健康狀況及先前病史;及醫學技術中熟知之類似因素。
適合劑量可例如介於待治療患者之約0.01 µg/kg至約1000 mg/kg體重、通常約0.1 µg/kg至約100 mg/kg體重範圍內。
可調節給藥方案以提供最佳所需反應(例如治療反應)。舉例而言,可投與單次劑量、可隨時間推移而投與若干多次劑量,或可如治療情況之緊急需要所指示而按比例減少或增加劑量。如本文所用之單位劑型係指適合作為用於待治療之受試者之單位劑量的物理離散單位;各單元含有經計算以與所要求之醫藥載劑結合產生所需治療作用的預定量之活性化合物。
醫藥組合物或調配物之投與
可投與本文所描述之抗體或其調配物或組合物以用於預防性及/或治療性治療。
本發明之抗體或醫藥組合物可使用此項技術中已知之多種方法中之一或多者經由一或多種投與途徑投與。如熟習此項技術者應瞭解,投與途徑及/或模式將視所需結果而變化。本發明之抗體或醫藥組合物之投與途徑的實例包括靜脈內、肌內、皮內、眼內、腹膜內、皮下、脊椎或其他非經腸投與途徑,例如經注射或輸注。或者,本發明之抗體或醫藥組合物可經由非經腸以外之途徑,諸如局部、表皮或黏膜投與途徑來投與。本發明之抗體或醫藥組合物可用於經口投與。
適合的投與形式包括適用於非經腸投與之形式,例如藉由注射或輸注,例如藉由彈丸注射或連續輸注,以靜脈內、可吸入或皮下形式。在產品用於注射或輸注的情況下,其可呈於油性或水性媒劑中之懸浮液、溶液或乳液的形式且其可含有其他試劑,諸如懸浮劑、防腐劑、穩定劑及/或分散劑。或者,根據本發明之抗體或其抗原結合片段可呈無水形式,以在使用之前用適合的無菌液體復原。亦可製備適合於在注射前溶解或懸浮於液體媒劑中之固體形式。
在調配之後,可將本發明之醫藥組合物直接投與至受試者。因此,本文中提供根據本發明之抗體或其抗原結合片段之用途,其用於製造藥劑。
製品及套組
本發明亦提供套組,其包含本發明之抗TREM1抗體及使用說明書。套組可進一步含有一或多種其他試劑,諸如上文所論述之其他治療劑或預防劑。
本發明提供根據本發明之抗體或其醫藥組合物之用途,其用於製造藥劑。
本發明亦提供本發明之抗體之用途,其用於製造用以治療如本文所描述之病症或病狀之藥劑。
在某些實施例中,製品或套組包含含有一或多種本發明之抗體或本文所描述之組合物的容器。在某些實施例中,製品或套組包含含有編碼一(或多種)本文所描述之抗體或組合物之核酸的容器。在一些實施例中,套組包括產生如本文所描述之抗體之細胞或細胞株。
在某些實施例中,製品或套組包含容器及容器上或容器隨附之標籤或藥品說明書。適合的容器包括例如瓶子、小瓶、注射器、IV溶液袋等。容器可由各種材料形成,諸如玻璃或塑膠。容器收納單獨的組合物或其與可有效用於治療、預防及/或診斷之另一種組合物之組合且可具有無菌接取口。組合物中之至少一種藥劑為本發明之抗體。標籤或藥品說明書指示組合物用於治療如本文所描述之病症或病狀。
應注意,上文所提及之實施例說明而非限制本發明,且熟習此項技術者將能夠在不偏離申請專利範圍之範疇的情況下設計許多替代性實施例。在申請專利範圍中,置放於圓括號之間的任何參考標識不應被視為限制請求項。
本發明中所包括的序列展示於表6及表7中:
表
6
.
TREM1
之序列
名稱 | 序列 | SEQ ID NO |
人類 TREM1 同功異型物 1 ( 寄存編號 NP _ 061113 . 1 ) SwissProt: Q9NP99 | MRKTRLWGLLWMLFVSELRAATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKGFSGTPGSNENSTQNVYKIPPTTTKALCPLYTSPRTVTQAPPKSTADVSTPDSEINLTNVTDIIRVPVFNIVILLAGGFLSKSLVFSVLFAVTLRSFVP | 1 |
人類 TREM1 同功異型物 1 (21-234) 不具有信號肽 | ATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKGFSGTPGSNENSTQNVYKIPPTTTKALCPLYTSPRTVTQAPPKSTADVSTPDSEINLTNVTDIIRVPVFNIVILLAGGFLSKSLVFSVLFAVTLRSFVP | 2 |
人類 TREM1 同功異型物 2 ( 寄存編號 NP_001229518.1) | MRKTRLWGLLWMLFVSELRAATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKGFSGTPGSNENSTQNVYKIPPTTTKALCPLYTSPRTVTQAPPKSTADVSTPDSEINLTNVTDIIRYSFQVPGPLVWTLSPLFPSLCAERM | 3 |
人類 TREM1 同功異型物 3 ( 寄存編號 NP_001229519) | MRKTRLWGLLWMLFVSELRAATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKGFRCSTLSFSWLVDS | 4 |
食蟹獼猴 TREM1 蛋白 (XP_001082517) | MRKTRLWGLLWMLFVSELRATTELTEEKYEYKEGQTLEVKCDYALEKYANSRKAWQKMEGKMPKILAKTERPSENSHPVQVGRITLEDYPDHGLLQVQMTNLQVEDSGLYQCVIYQHPKESHVLFNPICLVVTKGSSGTPGSSENSTQNVYRTPSTTAKALGPRYTSPRTVTQAPPESTVVVSTPGSEINLTNVTDIIRVPVFNIVIIVAGGFLSKSLVFSVLFAVTLRSFGP | 5 |
PGLYRP1 (NP_005082.1) | MSRRSMLLAWALPSLLRLGAAQETEDPACCSPIVPRNEWKALASECAQHLSLPLRYVVVSHTAGSSCNTPASCQQQARNVQHYHMKTLGWCDVGYNFLIGEDGLVYEGRGWNFTGAHSGHLWNPMSIGISFMGNYMDRVPTPQAIRAAQGLLACGVAQGALRSNYVLKGHRDVQRTLSPGNQLYHLIQNWPHYRSP | 6 |
CID101904 hTREM1_1-200-Avi-Tev-HKH | MRKTRLWGLLWMLFVSELRAATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKGFSGTPGSNENSTQNVYKIPPTTTKALCPLYTSPRTVTQAPPKSTADVSTPDSEINLTNVTDIIRLEGGGSGGSGGLNDIFEAQKIEWHENLYFQGGSHHHHHHKAKGSKGKGSKKAGHHHHHHHHHH | 7 |
CID101953 cTREM1_1-201-Avi-Tev-HKH | MRKTRLWGLLWMLFVSELRATTELTEEKYEYKEGQTLEVKCDYALEKYANSRKAWQKMEGKMPKILAKTERPSENSHPVQVGRITLEDYPDHGLLQVRMTNLQVEDSGLYQCVIYQHPKESHVLFNPICLVVTKGSSGTPGSSENSTQNVYRTPSTTAKALGPRYTSPRTVTQAPPESTVVVSTPGSEINLTNVTDIIRVPLEGGGSGGSGGLNDIFEAQKIEWHENLYFQGGSHHHHHHKAKGSKGKGSKKAGHHHHHHHHHH | 8 |
CID101907 hTREM1 IgV (His-Smt-TREM1_21-139) | MGHHHHHHSGEVKPEVKPETHINLKVSDGSSEIFFKIKKTTPLRRLMEAFAKRQGKEMDSLRFLYDGIRIQADQTPEDLDMEDNDIIEAHREQIGGATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKGFSG | 9 |
CID101951 hPGLYRP1_1-196-His | MSRRSMLLAWALPSLLRLGAAQETEDPACCSPIVPRNEWKALASECAQHLSLPLRYVVVSHTAGSSCNTPASCQQQARNVQHYHMKTLGWCDVGYNFLIGEDGLVYEGRGWNFTGAHSGHLWNPMSIGISFMGNYMDRVPTPQAIRAAQGLLACGVAQGALRSNYVLKGHRDVQRTLSPGNQLYHLIQNWPHYRSPHHHHHH | 10 |
表
7
.
12172
抗體及相關變異體之序列
實例
實例
1
:
TREM1
蛋白之產生
名稱 | 序列 | SEQ ID NO |
CDRL1 | QASQNIGSDLA | 11 |
CDRL2 | KAATLAS | 12 |
CDRL3 | QQYYYGSAGADTDT | 13 |
CDRH1 | GFSLSSYAMT | 14 |
CDRH2 | IIYAGGSPSYASWAKG | 15 |
CDRH3 | GTGDTVYTYFNI | 16 |
兔 Ab 12172 VL 區 | AVVLTQTASPVSAPVGGTVTIKCQASQNIGSDLAWYQQEPGQPPKLLIYKAATLASGVPSRFKGSGSGTEFTLTISGVQCEDGATYYCQQYYYGSAGADTDTFGGGTEVVVK | 17 |
兔 Ab 12172 VL 區 | gccgtcgtgctgacccagactgcatcccccgtgtctgcacctgtgggaggcacagtcaccatcaagtgccaggccagtcagaacattggtagcgacttagcctggtatcagcaggaaccagggcagccacccaagctcctgatctacaaggcagccactctggcatctggggtcccatcgcggttcaaaggcagtggatctgggacagagttcactctcaccatcagtggcgtgcagtgtgaagatggtgccacttactactgtcaacagtattattatggtagtgctggtgctgatacggatactttcggcggagggaccgaggtggtggtcaaa | 18 |
CID102770 :兔 Ab 12172 輕鏈 (Fab) | AVVLTQTASPVSAPVGGTVTIKCQASQNIGSDLAWYQQEPGQPPKLLIYKAATLASGVPSRFKGSGSGTEFTLTISGVQCEDGATYYCQQYYYGSAGADTDTFGGGTEVVVKRTPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC | 19 |
兔 Ab 12172 輕鏈 | gccgtcgtgctgacccagactgcatcccccgtgtctgcacctgtgggaggcacagtcaccatcaagtgccaggccagtcagaacattggtagcgacttagcctggtatcagcaggaaccagggcagccacccaagctcctgatctacaaggcagccactctggcatctggggtcccatcgcggttcaaaggcagtggatctgggacagagttcactctcaccatcagtggcgtgcagtgtgaagatggtgccacttactactgtcaacagtattattatggtagtgctggtgctgatacggatactttcggcggagggaccgaggtggtggtcaaacgtacgccagttgcacctactgtcctcatcttcccaccagctgctgatcaggtggcaactggaacagtcaccatcgtgtgtgtggcgaataaatactttcccgatgtcaccgtcacctgggaggtggatggcaccacccaaacaactggcatcgagaacagtaaaacaccgcagaattctgcagattgtacctacaacctcagcagcactctgacactgaccagcacacagtacaacagccacaaagagtacacctgcaaggtgacccagggcacgacctcagtcgtccagagcttcaataggggtgactgt | 20 |
兔 Ab 12172 VH 區 | QSLEESGGRLVTPGTPLTLTCTASGFSLSSYAMTWVRQAPGKGLEWIGIIYAGGSPSYASWAKGRFTISKTSTTVDLKMTSPTTEDTATYFCARGTGDTVYTYFNIWGPGTLVTVSS | 21 |
兔 Ab 12172 VH 區 | cagtcgctggaggagtccgggggtcgcctggtcacgcctgggacacccctgacactcacctgcacagcctctggattctccctcagtagctatgcaatgacctgggtccgccaggctccagggaaggggctggaatggatcggaatcatttatgctggtggtagcccatcctacgcgagctgggcgaaaggccgattcaccatctccaaaacctcgaccacggtggatctgaaaatgaccagtccgacaaccgaggacacggccacctatttctgtgccagagggactggtgatactgtttatacctactttaatatttggggcccaggcaccctggtcaccgtctcgagt | 22 |
CID120769 :兔 Ab 12172 重鏈 (Fab) | QSLEESGGRLVTPGTPLTLTCTASGFSLSSYAMTWVRQAPGKGLEWIGIIYAGGSPSYASWAKGRFTISKTSTTVDLKMTSPTTEDTATYFCARGTGDTVYTYFNIWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTVAPSTCSKP | 23 |
兔 Ab 12172 重鏈 (Fab) | cagtcgctggaggagtccgggggtcgcctggtcacgcctgggacacccctgacactcacctgcacagcctctggattctccctcagtagctatgcaatgacctgggtccgccaggctccagggaaggggctggaatggatcggaatcatttatgctggtggtagcccatcctacgcgagctgggcgaaaggccgattcaccatctccaaaacctcgaccacggtggatctgaaaatgaccagtccgacaaccgaggacacggccacctatttctgtgccagagggactggtgatactgtttatacctactttaatatttggggcccaggcaccctggtcaccgtctcgagtgggcaacctaaggctccatcagtcttcccactggccccctgctgcggggacacacccagctccacggtgaccctgggctgcctggtcaaaggctacctcccggagccagtgaccgtgacctggaactcgggcaccctcaccaatggggtacgcaccttcccgtccgtccggcagtcctcaggcctctactcgctgagcagcgtggtgagcgtgacctcaagcagccagcccgtcacctgcaacgtggcccacccagccaccaacaccaaagtggacaagaccgttgcgccctcgacatgcagcaagccc | 24 |
12172gL1 V 區 | AVVLTQSPSFLSASVGDRVTITCQASQNIGSDLAWYQQKPGKAPKLLIYKAATLASGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQYYYGSAGADTDTFGGGTKVEIK | 25 |
12172gL1 V 區 | gccgtggtgctgactcagtccccctccttcctgagcgcctcagtgggagatcgcgtgaccatcacctgtcaagccagccagaacattgggtccgacttggcctggtatcagcagaagcctggcaaagcgccgaagctgctgatctacaaggccgctactctcgcgtcgggagtgccatcccggttttccggttcgggaagcgggaccgagttcacccttaccatttcctcgctccaaccggaggacttcgccacgtactactgccagcagtactactacggttcagccggagcagacactgataccttcggcggaggcaccaaggtcgaaatcaag | 26 |
12172gL1 輕鏈 | AVVLTQSPSFLSASVGDRVTITCQASQNIGSDLAWYQQKPGKAPKLLIYKAATLASGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQYYYGSAGADTDTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC | 27 |
12172gL1 輕鏈 | gccgtggtgctgactcagtccccctccttcctgagcgcctcagtgggagatcgcgtgaccatcacctgtcaagccagccagaacattgggtccgacttggcctggtatcagcagaagcctggcaaagcgccgaagctgctgatctacaaggccgctactctcgcgtcgggagtgccatcccggttttccggttcgggaagcgggaccgagttcacccttaccatttcctcgctccaaccggaggacttcgccacgtactactgccagcagtactactacggttcagccggagcagacactgataccttcggcggaggcaccaaggtcgaaatcaagcgtacggtagcggccccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgt | 28 |
12172gL2 V 區 | DIQLTQSPSFLSASVGDRVTITCQASQNIGSDLAWYQQKPGKAPKLLIYKAATLASGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQYYYGSAGADTDTFGGGTKVEIK | 29 |
12172gL2 V 區 | gacatccagctgactcagtccccctccttcctgagcgcctcagtgggagatcgcgtgaccatcacctgtcaagccagccagaacattgggtccgacttggcctggtatcagcagaagcctggcaaagcgccgaagctgctgatctacaaggccgctactctcgcgtcgggagtgccatcccggttttccggttcgggaagcgggaccgagttcacccttaccatttcctcgctccaaccggaggacttcgccacgtactactgccagcagtactactacggttcagccggagcagacactgataccttcggcggaggcaccaaggtcgaaatcaag | 30 |
12172gL2 輕鏈 | DIQLTQSPSFLSASVGDRVTITCQASQNIGSDLAWYQQKPGKAPKLLIYKAATLASGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQYYYGSAGADTDTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC | 31 |
12172gL2 輕鏈 | gacatccagctgactcagtccccctccttcctgagcgcctcagtgggagatcgcgtgaccatcacctgtcaagccagccagaacattgggtccgacttggcctggtatcagcagaagcctggcaaagcgccgaagctgctgatctacaaggccgctactctcgcgtcgggagtgccatcccggttttccggttcgggaagcgggaccgagttcacccttaccatttcctcgctccaaccggaggacttcgccacgtactactgccagcagtactactacggttcagccggagcagacactgataccttcggcggaggcaccaaggtcgaaatcaagcgtacggtggccgctccctccgtgttcatcttcccaccctccgacgagcagctgaagtccggcaccgcctccgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaggtgcagtggaaggtggacaacgccctgcagtccggcaactcccaggaatccgtcaccgagcaggactccaaggacagcacctactccctgtcctccaccctgaccctgtccaaggccgactacgagaagcacaaggtgtacgcctgcgaagtgacccaccagggcctgtccagccccgtgaccaagtccttcaaccggggcgagtgc | 32 |
12172gL6 V 區 | DIVLTQSPSFLSASVGDRVTITCQASQNIGSDLAWYQQKPGKAPKLLIYKAATLASGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQYYYGSAGADTDTFGGGTKVEIK | 33 |
12172gL6 V 區 | gacatcgtgctgactcagtccccctccttcctgagcgcctcagtgggagatcgcgtgaccatcacctgtcaagccagccagaacattgggtccgacttggcctggtatcagcagaagcctggcaaagcgccgaagctgctgatctacaaggccgctactctcgcgtcgggagtgccatcccggttttccggttcgggaagcgggaccgagttcacccttaccatttcctcgctccaaccggaggacttcgccacgtactactgccagcagtactactacggttcagccggagcagacactgataccttcggcggaggcaccaaggtcgaaatcaag | 34 |
12172gL6 輕鏈 | DIVLTQSPSFLSASVGDRVTITCQASQNIGSDLAWYQQKPGKAPKLLIYKAATLASGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQYYYGSAGADTDTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC | 35 |
12172gL6 輕鏈 | gacatcgtgctgactcagtccccctccttcctgagcgcctcagtgggagatcgcgtgaccatcacctgtcaagccagccagaacattgggtccgacttggcctggtatcagcagaagcctggcaaagcgccgaagctgctgatctacaaggccgctactctcgcgtcgggagtgccatcccggttttccggttcgggaagcgggaccgagttcacccttaccatttcctcgctccaaccggaggacttcgccacgtactactgccagcagtactactacggttcagccggagcagacactgataccttcggcggaggcaccaaggtcgaaatcaagcgtacggtggccgctccctccgtgttcatcttcccaccctccgacgagcagctgaagtccggcaccgcctccgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaggtgcagtggaaggtggacaacgccctgcagtccggcaactcccaggaatccgtcaccgagcaggactccaaggacagcacctactccctgtcctccaccctgaccctgtccaaggccgactacgagaagcacaaggtgtacgcctgcgaagtgacccaccagggcctgtccagccccgtgaccaagtccttcaaccggggcgagtgc | 36 |
12172gL9 V 區 | DIQLTQSPSFLSASVGDSVTITCQASQNIGSDLAWYQQKPGKAPKLLIYKAATLASGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQYYYGSAGADTDTFGGGTKVEIK | 37 |
12172gL9 V 區 | gacatccagctgactcagtccccctccttcctgagcgcctcagtgggagatagcgtgaccatcacctgtcaagccagccagaacattgggtccgacttggcctggtatcagcagaagcctggcaaagcgccgaagctgctgatctacaaggccgctactctcgcgtcgggagtgccatcccggttttccggttcgggaagcgggaccgagttcacccttaccatttcctcgctccaaccggaggacttcgccacgtactactgccagcagtactactacggttcagccggagcagacactgataccttcggcggaggcaccaaggtcgaaatcaag | 38 |
12172gL9 輕鏈 | DIQLTQSPSFLSASVGDSVTITCQASQNIGSDLAWYQQKPGKAPKLLIYKAATLASGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQYYYGSAGADTDTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC | 39 |
12172gL9 輕鏈 | gacatccagctgactcagtccccctccttcctgagcgcctcagtgggagatagcgtgaccatcacctgtcaagccagccagaacattgggtccgacttggcctggtatcagcagaagcctggcaaagcgccgaagctgctgatctacaaggccgctactctcgcgtcgggagtgccatcccggttttccggttcgggaagcgggaccgagttcacccttaccatttcctcgctccaaccggaggacttcgccacgtactactgccagcagtactactacggttcagccggagcagacactgataccttcggcggaggcaccaaggtcgaaatcaagcgtacggtagcggccccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgt | 40 |
12172gL11 V 區 | DIQLTQSPSFLSASVGDRVTITCQASQNIGSDLAWYQQKPGKAPKLLIYSAATLASGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQYYYGSAGADTDTFGGGTKVEIK | 41 |
12172gL11 V 區 | gacatccagctgactcagtccccctccttcctgagcgcctcagtgggagatcgcgtgaccatcacctgtcaagccagccagaacattgggtccgacttggcctggtatcagcagaagcctggcaaagcgccgaagctgctgatctacagcgccgctactctcgcgtcgggagtgccatcccggttttccggttcgggaagcgggaccgagttcacccttaccatttcctcgctccaaccggaggacttcgccacgtactactgccagcagtactactacggttcagccggagcagacactgataccttcggcggaggcaccaaggtcgaaatcaag | 42 |
12172gL11 輕鏈 | DIQLTQSPSFLSASVGDRVTITCQASQNIGSDLAWYQQKPGKAPKLLIYSAATLASGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQYYYGSAGADTDTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC | 43 |
12172gL11 輕鏈 | gacatccagctgactcagtccccctccttcctgagcgcctcagtgggagatcgcgtgaccatcacctgtcaagccagccagaacattgggtccgacttggcctggtatcagcagaagcctggcaaagcgccgaagctgctgatctacagcgccgctactctcgcgtcgggagtgccatcccggttttccggttcgggaagcgggaccgagttcacccttaccatttcctcgctccaaccggaggacttcgccacgtactactgccagcagtactactacggttcagccggagcagacactgataccttcggcggaggcaccaaggtcgaaatcaagcgtacggtagcggccccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgt | 44 |
12172gH1 V 區 | EVQLVESGGGLVQPGGSLRLSCTASGFSLSSYAMTWVRQAPGKGLEWIGIIYAGGSPSYASWAKGRFTISKDSSKNTVYLQMNSLRAEDTAVYYCARGTGDTVYTYFNIWGQGTLVTVSS | 45 |
12172gH1 V 區 | gaagtgcagctcgtggagtcgggcggaggtctggtgcagcccggaggaagcctgcgcctgtcatgcaccgccagcgggttctcgctttcctcctacgccatgacctgggtcagacaggcaccgggaaagggcctcgaatggattggcattatctatgcgggtggcagcccttcctacgcctcctgggctaaagggcggttcaccatctcgaaggactcctccaagaacacggtgtacttgcaaatgaactcactgagggccgaggacactgcggtgtactactgtgcccggggaactggagataccgtgtacacctactttaacatctggggccagggaaccctggtcactgtctcgagc | 46 |
12172gH1 重鏈 (IgG4P) | EVQLVESGGGLVQPGGSLRLSCTASGFSLSSYAMTWVRQAPGKGLEWIGIIYAGGSPSYASWAKGRFTISKDSSKNTVYLQMNSLRAEDTAVYYCARGTGDTVYTYFNIWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 47 |
12172gH1 重鏈 (IgG4P) | gaagtgcagctcgtggagtcgggcggaggtctggtgcagcccggaggaagcctgcgcctgtcatgcaccgccagcgggttctcgctttcctcctacgccatgacctgggtcagacaggcaccgggaaagggcctcgaatggattggcattatctatgcgggtggcagcccttcctacgcctcctgggctaaagggcggttcaccatctcgaaggactcctccaagaacacggtgtacttgcaaatgaactcactgagggccgaggacactgcggtgtactactgtgcccggggaactggagataccgtgtacacctactttaacatctggggccagggaaccctggtcactgtctcgagcgcttctacaaagggcccatccgtcttccccctggcgccctgctccaggagcacctccgagagcacagccgccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacgaagacctacacctgcaacgtagatcacaagcccagcaacaccaaggtggacaagagagttgagtccaaatatggtcccccatgcccaccatgcccagcacctgagttcctggggggaccatcagtcttcctgttccccccaaaacccaaggacactctcatgatctcccggacccctgaggtcacgtgcgtggtggtggacgtgagccaggaagaccccgaggtccagttcaactggtacgtggatggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagttcaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaacggcaaggagtacaagtgcaaggtctccaacaaaggcctcccgtcctccatcgagaaaaccatctccaaagccaaagggcagccccgagagccacaggtgtacaccctgcccccatcccaggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctaccccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaggctaaccgtggacaagagcaggtggcaggaggggaatgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacacagaagagcctctccctgtctctgggtaaa | 48 |
12172gH2 V 區 | EVQLVESGGGLVQPGGSLRLSCAASGFSLSSYAMTWVRQAPGKGLEWVGIIYAGGSPSYASWAKGRFTISKDSSKNTVYLQMNSLRAEDTAVYYCARGTGDTVYTYFNIWGQGTLVTVSS | 49 |
12172gH2 V 區 | gaagtgcagctcgtggagtcgggcggaggtctggtgcagcccggaggaagcctgcgcctgtcatgcgctgccagcgggttctcgctttcctcctacgccatgacctgggtcagacaggcaccgggaaagggcctcgaatgggtcggcattatctatgcgggtggcagcccttcctacgcctcctgggctaaagggcggttcaccatctcgaaggactcctccaagaacacggtgtacttgcaaatgaactcactgagggccgaggacactgcggtgtactactgtgcccggggaactggagataccgtgtacacctactttaacatctggggccagggaaccctggtcactgtctcgagc | 50 |
12172gH2 重鏈 (IgG4P) | EVQLVESGGGLVQPGGSLRLSCAASGFSLSSYAMTWVRQAPGKGLEWVGIIYAGGSPSYASWAKGRFTISKDSSKNTVYLQMNSLRAEDTAVYYCARGTGDTVYTYFNIWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 51 |
12172gH2 重鏈 (IgG4P) | gaagtgcagctcgtggagtcgggcggaggtctggtgcagcccggaggaagcctgcgcctgtcatgcgctgccagcgggttctcgctttcctcctacgccatgacctgggtcagacaggcaccgggaaagggcctcgaatgggtcggcattatctatgcgggtggcagcccttcctacgcctcctgggctaaagggcggttcaccatctcgaaggactcctccaagaacacggtgtacttgcaaatgaactcactgagggccgaggacactgcggtgtactactgtgcccggggaactggagataccgtgtacacctactttaacatctggggccagggaaccctggtcactgtctcgagcgcttctacaaagggcccatccgtcttccccctggcgccctgctccaggagcacctccgagagcacagccgccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacgaagacctacacctgcaacgtagatcacaagcccagcaacaccaaggtggacaagagagttgagtccaaatatggtcccccatgcccaccatgcccagcacctgagttcctggggggaccatcagtcttcctgttccccccaaaacccaaggacactctcatgatctcccggacccctgaggtcacgtgcgtggtggtggacgtgagccaggaagaccccgaggtccagttcaactggtacgtggatggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagttcaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaacggcaaggagtacaagtgcaaggtctccaacaaaggcctcccgtcctccatcgagaaaaccatctccaaagccaaagggcagccccgagagccacaggtgtacaccctgcccccatcccaggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctaccccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaggctaaccgtggacaagagcaggtggcaggaggggaatgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacacagaagagcctctccctgtctctgggtaaa | 52 |
12172gH4 V 區 | EVQLVESGGGLVQPGGSLRLSCTASGFSLSSYAMTWVRQAPGKGLEWIGIIYAGGSPSYASWAKGRFTISRDSSKNTVYLQMNSLRAEDTAVYYCARGTGDTVYTYFNIWGQGTLVTVSS | 53 |
12172gH4 V 區 | gaagtgcagctcgtggagtcgggcggaggtctggtgcagcccggaggaagcctgcgcctgtcatgcaccgccagcgggttctcgctttcctcctacgccatgacctgggtcagacaggcaccgggaaagggcctcgaatggattggcattatctatgcgggtggcagcccttcctacgcctcctgggctaaagggcggttcaccatctcgcgcgactcctccaagaacacggtgtacttgcaaatgaactcactgagggccgaggacactgcggtgtactactgtgcccggggaactggagataccgtgtacacctactttaacatctggggccagggaaccctggtcactgtctcgagc | 54 |
12172gH4 重鏈 (IgG4P) | EVQLVESGGGLVQPGGSLRLSCTASGFSLSSYAMTWVRQAPGKGLEWIGIIYAGGSPSYASWAKGRFTISRDSSKNTVYLQMNSLRAEDTAVYYCARGTGDTVYTYFNIWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 55 |
12172gH4 重鏈 (IgG4P) | gaagtgcagctcgtggagtcgggcggaggtctggtgcagcccggaggaagcctgcgcctgtcatgcaccgccagcgggttctcgctttcctcctacgccatgacctgggtcagacaggcaccgggaaagggcctcgaatggattggcattatctatgcgggtggcagcccttcctacgcctcctgggctaaagggcggttcaccatctcgcgcgactcctccaagaacacggtgtacttgcaaatgaactcactgagggccgaggacactgcggtgtactactgtgcccggggaactggagataccgtgtacacctactttaacatctggggccagggaaccctggtcactgtctcgagcgcttctacaaagggcccatccgtcttccccctggcgccctgctccaggagcacctccgagagcacagccgccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacgaagacctacacctgcaacgtagatcacaagcccagcaacaccaaggtggacaagagagttgagtccaaatatggtcccccatgcccaccatgcccagcacctgagttcctggggggaccatcagtcttcctgttccccccaaaacccaaggacactctcatgatctcccggacccctgaggtcacgtgcgtggtggtggacgtgagccaggaagaccccgaggtccagttcaactggtacgtggatggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagttcaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaacggcaaggagtacaagtgcaaggtctccaacaaaggcctcccgtcctccatcgagaaaaccatctccaaagccaaagggcagccccgagagccacaggtgtacaccctgcccccatcccaggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctaccccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaggctaaccgtggacaagagcaggtggcaggaggggaatgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacacagaagagcctctccctgtctctgggtaaa | 56 |
12172gH6 V 區 | EVQLVESGGGLVQPGGSLRLSCTASGFSLSSYAMTWVRQAPGKGLEWIGIIYAGGSPSYASWAKGRFTISKDSSKNTLYLQMNSLRAEDTAVYYCARGTGDTVYTYFNIWGQGTLVTVSS | 57 |
12172gH6 V 區 | gaagtgcagctcgtggagtcgggcggaggtctggtgcagcccggaggaagcctgcgcctgtcatgcaccgccagcgggttctcgctttcctcctacgccatgacctgggtcagacaggcaccgggaaagggcctcgaatggattggcattatctatgcgggtggcagcccttcctacgcctcctgggctaaagggcggttcaccatctcgaaggactcctccaagaacacgctgtacttgcaaatgaactcactgagggccgaggacactgcggtgtactactgtgcccggggaactggagataccgtgtacacctactttaacatctggggccagggaaccctggtcactgtctcgagc | 58 |
12172gH6 重鏈 (IgG4P) | EVQLVESGGGLVQPGGSLRLSCTASGFSLSSYAMTWVRQAPGKGLEWIGIIYAGGSPSYASWAKGRFTISKDSSKNTLYLQMNSLRAEDTAVYYCARGTGDTVYTYFNIWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 59 |
12172gH6 重鏈 (IgG4P) | gaagtgcagctcgtggagtcgggcggaggtctggtgcagcccggaggaagcctgcgcctgtcatgcaccgccagcgggttctcgctttcctcctacgccatgacctgggtcagacaggcaccgggaaagggcctcgaatggattggcattatctatgcgggtggcagcccttcctacgcctcctgggctaaagggcggttcaccatctcgaaggactcctccaagaacacgctgtacttgcaaatgaactcactgagggccgaggacactgcggtgtactactgtgcccggggaactggagataccgtgtacacctactttaacatctggggccagggaaccctggtcactgtctcgagcgcttctacaaagggcccatccgtcttccccctggcgccctgctccaggagcacctccgagagcacagccgccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacgaagacctacacctgcaacgtagatcacaagcccagcaacaccaaggtggacaagagagttgagtccaaatatggtcccccatgcccaccatgcccagcacctgagttcctggggggaccatcagtcttcctgttccccccaaaacccaaggacactctcatgatctcccggacccctgaggtcacgtgcgtggtggtggacgtgagccaggaagaccccgaggtccagttcaactggtacgtggatggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagttcaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaacggcaaggagtacaagtgcaaggtctccaacaaaggcctcccgtcctccatcgagaaaaccatctccaaagccaaagggcagccccgagagccacaggtgtacaccctgcccccatcccaggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctaccccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaggctaaccgtggacaagagcaggtggcaggaggggaatgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacacagaagagcctctccctgtctctgggtaaa | 60 |
12172gH6 重鏈 (IgG4P F234A L235A) | EVQLVESGGGLVQPGGSLRLSCTASGFSLSSYAMTWVRQAPGKGLEWIGIIYAGGSPSYASWAKGRFTISKDSSKNTLYLQMNSLRAEDTAVYYCARGTGDTVYTYFNIWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 61 |
12172gH6 重鏈 (IgG4P F234A L235A) | gaagtgcagctcgtggagtcgggcggaggtctggtgcagcccggaggaagcctgcgcctgtcatgcaccgccagcgggttctcgctttcctcctacgccatgacctgggtcagacaggcaccgggaaagggcctcgaatggattggcattatctatgcgggtggcagcccttcctacgcctcctgggctaaagggcggttcaccatctcgaaggactcctccaagaacacgctgtacttgcaaatgaactcactgagggccgaggacactgcggtgtactactgtgcccggggaactggagataccgtgtacacctactttaacatctggggccagggaaccctggtcactgtctcgagcgcttctacaaagggcccatccgtcttccccctggcgccctgctccaggagcacctccgagagcacagccgccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacgaagacctacacctgcaacgtagatcacaagcccagcaacaccaaggtggacaagagagttgagtccaaatatggtcccccatgcccaccatgcccagcacctgaagccgcggggggaccgtcagtcttcctgttccccccaaaacccaaggacactctcatgatctcccggacccctgaggtcacgtgcgtggtggtggacgtgagccaggaagaccccgaggtccagttcaactggtacgtggatggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagttcaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaacggcaaggagtacaagtgcaaggtctccaacaaaggcctcccgtcctccatcgagaaaaccatctccaaagccaaagggcagccccgagagccacaggtgtacaccctgcccccatcccaggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctaccccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaggctaaccgtggacaagagcaggtggcaggaggggaatgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacacagaagagcctctccctgtctctgggtaaa | 62 |
12172gH6 重鏈 (IgG1) | EVQLVESGGGLVQPGGSLRLSCTASGFSLSSYAMTWVRQAPGKGLEWIGIIYAGGSPSYASWAKGRFTISKDSSKNTLYLQMNSLRAEDTAVYYCARGTGDTVYTYFNIWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK | 63 |
12172gH6 重鏈 (IgG1) | gaagtgcagctcgtggagtcgggcggaggtctggtgcagcccggaggaagcctgcgcctgtcatgcaccgccagcgggttctcgctttcctcctacgccatgacctgggtcagacaggcaccgggaaagggcctcgaatggattggcattatctatgcgggtggcagcccttcctacgcctcctgggctaaagggcggttcaccatctcgaaggactcctccaagaacacgctgtacttgcaaatgaactcactgagggccgaggacactgcggtgtactactgtgcccggggaactggagataccgtgtacacctactttaacatctggggccagggaaccctggtcactgtctcgagcgcttctacaaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggatgagctgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa | 64 |
12172gH6 重鏈 (IgG1 L234A L235A) | EVQLVESGGGLVQPGGSLRLSCTASGFSLSSYAMTWVRQAPGKGLEWIGIIYAGGSPSYASWAKGRFTISKDSSKNTLYLQMNSLRAEDTAVYYCARGTGDTVYTYFNIWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK | 65 |
12172gH6 重鏈 (IgG1 L234A L235A) | gaagtgcagctcgtggagtcgggcggaggtctggtgcagcccggaggaagcctgcgcctgtcatgcaccgccagcgggttctcgctttcctcctacgccatgacctgggtcagacaggcaccgggaaagggcctcgaatggattggcattatctatgcgggtggcagcccttcctacgcctcctgggctaaagggcggttcaccatctcgaaggactcctccaagaacacgctgtacttgcaaatgaactcactgagggccgaggacactgcggtgtactactgtgcccggggaactggagataccgtgtacacctactttaacatctggggccagggaaccctggtcactgtctcgagcgcttctacaaagggcccctccgtgttcccgctcgctccatcatcgaagtctaccagcggaggcactgcggctctcggttgcctcgtgaaggactacttcccggagccggtgaccgtgtcgtggaacagcggagccctgaccagcggggtgcacacctttccggccgtcttgcagtcaagcggcctttactccctgtcatcagtggtgactgtcccgtccagctcattgggaacccaaacctacatctgcaatgtgaatcacaaacctagcaacaccaaggttgacaagaaagtcgagcccaaatcgtgtgacaagactcacacttgtccgccgtgcccggcacccgaagccgcaggaggtcccagcgtctttctgttccctccaaagccgaaagacacgctgatgatctcccgcaccccggaggtcacttgcgtggtcgtggacgtgtcacatgaggacccagaggtgaagttcaattggtacgtggatggcgtcgaagtccacaatgccaaaactaagcccagagaagaacagtacaattcgacctaccgcgtcgtgtccgtgctcacggtgttgcatcaggattggctgaacgggaaggaatacaagtgcaaagtgtccaacaaggcgctgccggcaccgatcgagaaaactatctccaaagcgaagggacagcctagggaacctcaagtctacacgctgccaccatcacgggatgaactgactaagaatcaagtctcactgacttgtctggtgaaggggttttaccctagcgacattgccgtggagtgggaatccaacggccagccagagaacaactacaagactacccctccagtgctcgactcggatggatcgttcttcctttactcgaagctcaccgtggataagtcccggtggcagcagggaaacgtgttctcctgctcggtgatgcatgaagccctccataaccactatacccaaaagtcgctgtccctgtcgccgggaaag | 66 |
12172gH8 V 區 | EVQLVESGGGLVQPGGSLRLSCAASGFSLSSYAMTWVRQAPGKGLEWIGIIYAGGSPSYASWAKGRFTISKDSSKNTVYLQMNSLRAEDTAVYYCARGTGDTVYTYFNIWGQGTLVTVSS | 67 |
12172gH8 V 區 | gaagtgcagctcgtggagtcgggcggaggtctggtgcagcccggaggaagcctgcgcctgtcatgcgctgccagcgggttctcgctttcctcctacgccatgacctgggtcagacaggcaccgggaaagggcctcgaatggattggcattatctatgcgggtggcagcccttcctacgcctcctgggctaaagggcggttcaccatctcgaaggactcctccaagaacacggtgtacttgcaaatgaactcactgagggccgaggacactgcggtgtactactgtgcccggggaactggagataccgtgtacacctactttaacatctggggccagggaaccctggtcactgtctcgagc | 68 |
12172gH8 重鏈 (IgG4P) | EVQLVESGGGLVQPGGSLRLSCAASGFSLSSYAMTWVRQAPGKGLEWIGIIYAGGSPSYASWAKGRFTISKDSSKNTVYLQMNSLRAEDTAVYYCARGTGDTVYTYFNIWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 69 |
12172gH8 重鏈 (IgG4P) | gaagtgcagctcgtggagtcgggcggaggtctggtgcagcccggaggaagcctgcgcctgtcatgcgctgccagcgggttctcgctttcctcctacgccatgacctgggtcagacaggcaccgggaaagggcctcgaatggattggcattatctatgcgggtggcagcccttcctacgcctcctgggctaaagggcggttcaccatctcgaaggactcctccaagaacacggtgtacttgcaaatgaactcactgagggccgaggacactgcggtgtactactgtgcccggggaactggagataccgtgtacacctactttaacatctggggccagggaaccctggtcactgtctcgagcgcttctacaaagggcccatccgtcttccccctggcgccctgctccaggagcacctccgagagcacagccgccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacgaagacctacacctgcaacgtagatcacaagcccagcaacaccaaggtggacaagagagttgagtccaaatatggtcccccatgcccaccatgcccagcacctgagttcctggggggaccatcagtcttcctgttccccccaaaacccaaggacactctcatgatctcccggacccctgaggtcacgtgcgtggtggtggacgtgagccaggaagaccccgaggtccagttcaactggtacgtggatggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagttcaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaacggcaaggagtacaagtgcaaggtctccaacaaaggcctcccgtcctccatcgagaaaaccatctccaaagccaaagggcagccccgagagccacaggtgtacaccctgcccccatcccaggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctaccccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaggctaaccgtggacaagagcaggtggcaggaggggaatgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacacagaagagcctctccctgtctctgggtaaa | 70 |
12172gH9 V 區 | EVQLVESGGGLVQPGGSLRLSCAASGFSLSSYAMTWVRQAPGKGLEWIGIIYAGGSPSYASWAKGRFTISRDNSKNTVYLQMNSLRAEDTAVYYCARGTGDTVYTYFNIWGQGTLVTVSS | 71 |
12172gH9 V 區 | gaagtgcagctcgtggagtcgggcggaggtctggtgcagcccggaggaagcctgcgcctgtcatgcgctgccagcgggttctcgctttcctcctacgccatgacctgggtcagacaggcaccgggaaagggcctcgaatggattggcattatctatgcgggtggcagcccttcctacgcctcctgggctaaagggcggttcaccatctcgcgcgacaattccaagaacacggtgtacttgcaaatgaactcactgagggccgaggacactgcggtgtactactgtgcccggggaactggagataccgtgtacacctactttaacatctggggccagggaaccctggtcactgtctcgagc | 72 |
12172gH9 重鏈 (IgG4P) | EVQLVESGGGLVQPGGSLRLSCAASGFSLSSYAMTWVRQAPGKGLEWIGIIYAGGSPSYASWAKGRFTISRDNSKNTVYLQMNSLRAEDTAVYYCARGTGDTVYTYFNIWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 73 |
12172gH9 重鏈 (IgG4P) | gaagtgcagctcgtggagtcgggcggaggtctggtgcagcccggaggaagcctgcgcctgtcatgcgctgccagcgggttctcgctttcctcctacgccatgacctgggtcagacaggcaccgggaaagggcctcgaatggattggcattatctatgcgggtggcagcccttcctacgcctcctgggctaaagggcggttcaccatctcgcgcgacaattccaagaacacggtgtacttgcaaatgaactcactgagggccgaggacactgcggtgtactactgtgcccggggaactggagataccgtgtacacctactttaacatctggggccagggaaccctggtcactgtctcgagcgcttctacaaagggcccatccgtcttccccctggcgccctgctccaggagcacctccgagagcacagccgccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacgaagacctacacctgcaacgtagatcacaagcccagcaacaccaaggtggacaagagagttgagtccaaatatggtcccccatgcccaccatgcccagcacctgagttcctggggggaccatcagtcttcctgttccccccaaaacccaaggacactctcatgatctcccggacccctgaggtcacgtgcgtggtggtggacgtgagccaggaagaccccgaggtccagttcaactggtacgtggatggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagttcaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaacggcaaggagtacaagtgcaaggtctccaacaaaggcctcccgtcctccatcgagaaaaccatctccaaagccaaagggcagccccgagagccacaggtgtacaccctgcccccatcccaggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctaccccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaggctaaccgtggacaagagcaggtggcaggaggggaatgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacacagaagagcctctccctgtctctgggtaaa | 74 |
12172gH10 V 區 | EVQLVESGGGLVQPGGSLRLSCAASGFSLSSYAMTWVRQAPGKGLEWIGIIYAGGSPSYASWAKGRFTISRDSSKNTLYLQMNSLRAEDTAVYYCARGTGDTVYTYFNIWGQGTLVTVSS | 75 |
12172gH10 V 區 | gaagtgcagctcgtggagtcgggcggaggtctggtgcagcccggaggaagcctgcgcctgtcatgcgctgccagcgggttctcgctttcctcctacgccatgacctgggtcagacaggcaccgggaaagggcctcgaatggattggcattatctatgcgggtggcagcccttcctacgcctcctgggctaaagggcggttcaccatctcgcgcgactcctccaagaacacgctgtacttgcaaatgaactcactgagggccgaggacactgcggtgtactactgtgcccggggaactggagataccgtgtacacctactttaacatctggggccagggaaccctggtcactgtctcgagc | 76 |
12172gH10 重鏈 (IgG4P) | EVQLVESGGGLVQPGGSLRLSCAASGFSLSSYAMTWVRQAPGKGLEWIGIIYAGGSPSYASWAKGRFTISRDSSKNTLYLQMNSLRAEDTAVYYCARGTGDTVYTYFNIWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 77 |
12172gH10 重鏈 (IgG4P) | gaagtgcagctcgtggagtcgggcggaggtctggtgcagcccggaggaagcctgcgcctgtcatgcgctgccagcgggttctcgctttcctcctacgccatgacctgggtcagacaggcaccgggaaagggcctcgaatggattggcattatctatgcgggtggcagcccttcctacgcctcctgggctaaagggcggttcaccatctcgcgcgactcctccaagaacacgctgtacttgcaaatgaactcactgagggccgaggacactgcggtgtactactgtgcccggggaactggagataccgtgtacacctactttaacatctggggccagggaaccctggtcactgtctcgagcgcttctacaaagggcccatccgtcttccccctggcgccctgctccaggagcacctccgagagcacagccgccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacgaagacctacacctgcaacgtagatcacaagcccagcaacaccaaggtggacaagagagttgagtccaaatatggtcccccatgcccaccatgcccagcacctgagttcctggggggaccatcagtcttcctgttccccccaaaacccaaggacactctcatgatctcccggacccctgaggtcacgtgcgtggtggtggacgtgagccaggaagaccccgaggtccagttcaactggtacgtggatggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagttcaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaacggcaaggagtacaagtgcaaggtctccaacaaaggcctcccgtcctccatcgagaaaaccatctccaaagccaaagggcagccccgagagccacaggtgtacaccctgcccccatcccaggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctaccccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaggctaaccgtggacaagagcaggtggcaggaggggaatgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacacagaagagcctctccctgtctctgggtaaa | 78 |
12172gH11 V 區 | EVQLVESGGGLVQPGGSLRLSCAASGFSLSSYAMTWVRQAPGKGLEWIGIIYAGGSPSYASWAKGRFTISKDNSKNTLYLQMNSLRAEDTAVYYCARGTGDTVYTYFNIWGQGTLVTVSS | 79 |
12172gH11 V 區 | gaagtgcagctcgtggagtcgggcggaggtctggtgcagcccggaggaagcctgcgcctgtcatgcgctgccagcgggttctcgctttcctcctacgccatgacctgggtcagacaggcaccgggaaagggcctcgaatggattggcattatctatgcgggtggcagcccttcctacgcctcctgggctaaagggcggttcaccatctcgaaggacaattccaagaacacgctgtacttgcaaatgaactcactgagggccgaggacactgcggtgtactactgtgcccggggaactggagataccgtgtacacctactttaacatctggggccagggaaccctggtcactgtctcgagc | 80 |
12172gH11 重鏈 (IgG4P) | EVQLVESGGGLVQPGGSLRLSCAASGFSLSSYAMTWVRQAPGKGLEWIGIIYAGGSPSYASWAKGRFTISKDNSKNTLYLQMNSLRAEDTAVYYCARGTGDTVYTYFNIWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 81 |
12172gH11 重鏈 (IgG4P) | gaagtgcagctcgtggagtcgggcggaggtctggtgcagcccggaggaagcctgcgcctgtcatgcgctgccagcgggttctcgctttcctcctacgccatgacctgggtcagacaggcaccgggaaagggcctcgaatggattggcattatctatgcgggtggcagcccttcctacgcctcctgggctaaagggcggttcaccatctcgaaggacaattccaagaacacgctgtacttgcaaatgaactcactgagggccgaggacactgcggtgtactactgtgcccggggaactggagataccgtgtacacctactttaacatctggggccagggaaccctggtcactgtctcgagcgcttctacaaagggcccctccgtgttccctctggccccttgctcccggtccacctccgagtctaccgccgctctgggctgcctggtcaaggactacttccccgagcccgtgacagtgtcctggaactctggcgccctgacctccggcgtgcacaccttccctgccgtgctgcagtcctccggcctgtactccctgtcctccgtcgtgaccgtgccctcctccagcctgggcaccaagacctacacctgtaacgtggaccacaagccctccaacaccaaggtggacaagcgggtggaatctaagtacggccctccctgccccccctgccctgcccctgaatttctgggcggaccttccgtgttcctgttccccccaaagcccaaggacaccctgatgatctcccggacccccgaagtgacctgcgtggtggtggacgtgtcccaggaagatcccgaggtccagttcaattggtacgtggacggcgtggaagtgcacaatgccaagaccaagcccagagaggaacagttcaactccacctaccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagagtacaagtgcaaggtgtccaacaagggcctgccctccagcatcgaaaagaccatctccaaggccaagggccagccccgcgagccccaggtgtacaccctgccccctagccaggaagagatgaccaagaaccaggtgtccctgacctgtctggtcaagggcttctacccctccgacattgccgtggaatgggagtccaacggccagcccgagaacaactacaagaccaccccccctgtgctggacagcgacggctccttcttcctgtactctcggctgaccgtggacaagtcccggtggcaggaaggcaacgtcttctcctgctccgtgatgcacgaggccctgcacaaccactacacccagaagtccctgtccctgagcctgggcaag | 82 |
12172gH11 重鏈 (IgG4P F234A L235A) | EVQLVESGGGLVQPGGSLRLSCAASGFSLSSYAMTWVRQAPGKGLEWIGIIYAGGSPSYASWAKGRFTISKDNSKNTLYLQMNSLRAEDTAVYYCARGTGDTVYTYFNIWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 83 |
12172gH11 重鏈 (IgG4P F234A L235A) | gaagtgcagctcgtggagtcgggcggaggtctggtgcagcccggaggaagcctgcgcctgtcatgcgctgccagcgggttctcgctttcctcctacgccatgacctgggtcagacaggcaccgggaaagggcctcgaatggattggcattatctatgcgggtggcagcccttcctacgcctcctgggctaaagggcggttcaccatctcgaaggacaattccaagaacacgctgtacttgcaaatgaactcactgagggccgaggacactgcggtgtactactgtgcccggggaactggagataccgtgtacacctactttaacatctggggccagggaaccctggtcactgtctcgagcgcttctacaaagggcccatccgtcttccccctggcgccctgctccaggagcacctccgagagcacagccgccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacgaagacctacacctgcaacgtagatcacaagcccagcaacaccaaggtggacaagagagttgagtccaaatatggtcccccatgcccaccatgcccagcacctgaagccgcggggggaccgtcagtcttcctgttccccccaaaacccaaggacactctcatgatctcccggacccctgaggtcacgtgcgtggtggtggacgtgagccaggaagaccccgaggtccagttcaactggtacgtggatggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagttcaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaacggcaaggagtacaagtgcaaggtctccaacaaaggcctcccgtcctccatcgagaaaaccatctccaaagccaaagggcagccccgagagccacaggtgtacaccctgcccccatcccaggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctaccccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaggctaaccgtggacaagagcaggtggcaggaggggaatgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacacagaagagcctctccctgtctctgggtaaa | 84 |
12172gH11 重鏈 (IgG1) | EVQLVESGGGLVQPGGSLRLSCAASGFSLSSYAMTWVRQAPGKGLEWIGIIYAGGSPSYASWAKGRFTISKDNSKNTLYLQMNSLRAEDTAVYYCARGTGDTVYTYFNIWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK | 85 |
12172gH11 重鏈 (IgG1) | gaagtgcagctcgtggagtcgggcggaggtctggtgcagcccggaggaagcctgcgcctgtcatgcgctgccagcgggttctcgctttcctcctacgccatgacctgggtcagacaggcaccgggaaagggcctcgaatggattggcattatctatgcgggtggcagcccttcctacgcctcctgggctaaagggcggttcaccatctcgaaggacaattccaagaacacgctgtacttgcaaatgaactcactgagggccgaggacactgcggtgtactactgtgcccggggaactggagataccgtgtacacctactttaacatctggggccagggaaccctggtcactgtctcgagcgcttctacaaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggatgagctgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa | 86 |
12172gH11 重鏈 (IgG1 L234A L235A) | EVQLVESGGGLVQPGGSLRLSCAASGFSLSSYAMTWVRQAPGKGLEWIGIIYAGGSPSYASWAKGRFTISKDNSKNTLYLQMNSLRAEDTAVYYCARGTGDTVYTYFNIWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK | 87 |
12172gH11 重鏈 (IgG1 L234A L235A) | gaagtgcagctcgtggagtcgggcggaggtctggtgcagcccggaggaagcctgcgcctgtcatgcgctgccagcgggttctcgctttcctcctacgccatgacctgggtcagacaggcaccgggaaagggcctcgaatggattggcattatctatgcgggtggcagcccttcctacgcctcctgggctaaagggcggttcaccatctcgaaggacaattccaagaacacgctgtacttgcaaatgaactcactgagggccgaggacactgcggtgtactactgtgcccggggaactggagataccgtgtacacctactttaacatctggggccagggaaccctggtcactgtctcgagcgcttctacaaagggcccctccgtgttcccgctcgctccatcatcgaagtctaccagcggaggcactgcggctctcggttgcctcgtgaaggactacttcccggagccggtgaccgtgtcgtggaacagcggagccctgaccagcggggtgcacacctttccggccgtcttgcagtcaagcggcctttactccctgtcatcagtggtgactgtcccgtccagctcattgggaacccaaacctacatctgcaatgtgaatcacaaacctagcaacaccaaggttgacaagaaagtcgagcccaaatcgtgtgacaagactcacacttgtccgccgtgcccggcacccgaagccgcaggaggtcccagcgtctttctgttccctccaaagccgaaagacacgctgatgatctcccgcaccccggaggtcacttgcgtggtcgtggacgtgtcacatgaggacccagaggtgaagttcaattggtacgtggatggcgtcgaagtccacaatgccaaaactaagcccagagaagaacagtacaattcgacctaccgcgtcgtgtccgtgctcacggtgttgcatcaggattggctgaacgggaaggaatacaagtgcaaagtgtccaacaaggcgctgccggcaccgatcgagaaaactatctccaaagcgaagggacagcctagggaacctcaagtctacacgctgccaccatcacgggatgaactgactaagaatcaagtctcactgacttgtctggtgaaggggttttaccctagcgacattgccgtggagtgggaatccaacggccagccagagaacaactacaagactacccctccagtgctcgactcggatggatcgttcttcctttactcgaagctcaccgtggataagtcccggtggcagcagggaaacgtgttctcctgctcggtgatgcatgaagccctccataaccactatacccaaaagtcgctgtccctgtcgccgggaaag | 88 |
12172gH12 V 區 | EVQLVESGGGLVQPGGSLRLSCAASGFSLSSYAMTWVRQAPGKGLEWIGIIYAGGSPSYASWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGTGDTVYTYFNIWGQGTLVTVSS | 89 |
12172gH12 V 區 | gaagtgcagctcgtggagtcgggcggaggtctggtgcagcccggaggaagcctgcgcctgtcatgcgctgccagcgggttctcgctttcctcctacgccatgacctgggtcagacaggcaccgggaaagggcctcgaatggattggcattatctatgcgggtggcagcccttcctacgcctcctgggctaaagggcggttcaccatctcgcgcgacaattccaagaacacgctgtacttgcaaatgaactcactgagggccgaggacactgcggtgtactactgtgcccggggaactggagataccgtgtacacctactttaacatctggggccagggaaccctggtcactgtctcgagc | 90 |
12172gH12 重鏈 (IgG4P) | EVQLVESGGGLVQPGGSLRLSCAASGFSLSSYAMTWVRQAPGKGLEWIGIIYAGGSPSYASWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGTGDTVYTYFNIWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 91 |
12172gH12 重鏈 (IgG4P) | gaagtgcagctcgtggagtcgggcggaggtctggtgcagcccggaggaagcctgcgcctgtcatgcgctgccagcgggttctcgctttcctcctacgccatgacctgggtcagacaggcaccgggaaagggcctcgaatggattggcattatctatgcgggtggcagcccttcctacgcctcctgggctaaagggcggttcaccatctcgcgcgacaattccaagaacacgctgtacttgcaaatgaactcactgagggccgaggacactgcggtgtactactgtgcccggggaactggagataccgtgtacacctactttaacatctggggccagggaaccctggtcactgtctcgagcgcttctacaaagggcccatccgtcttccccctggcgccctgctccaggagcacctccgagagcacagccgccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacgaagacctacacctgcaacgtagatcacaagcccagcaacaccaaggtggacaagagagttgagtccaaatatggtcccccatgcccaccatgcccagcacctgagttcctggggggaccatcagtcttcctgttccccccaaaacccaaggacactctcatgatctcccggacccctgaggtcacgtgcgtggtggtggacgtgagccaggaagaccccgaggtccagttcaactggtacgtggatggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagttcaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaacggcaaggagtacaagtgcaaggtctccaacaaaggcctcccgtcctccatcgagaaaaccatctccaaagccaaagggcagccccgagagccacaggtgtacaccctgcccccatcccaggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctaccccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaggctaaccgtggacaagagcaggtggcaggaggggaatgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacacagaagagcctctccctgtctctgggtaaa | 92 |
12172gH26 V 區 | EVQLVESGGGLVQPGGSLRLSCAASGFSLSSYAMTWVRQAPGKGLEWIGIIYAGGSPSYASWAKGRFTISKDNSSNTLYLQMNSLRAEDTAVYYCARGTGDTVYTYFNIWGQGTLVTVSS | 93 |
12172gH26 V 區 | gaagtgcagctcgtggagtcgggcggaggtctggtgcagcccggaggaagcctgcgcctgtcatgcgctgccagcgggttctcgctttcctcctacgccatgacctgggtcagacaggcaccgggaaagggcctcgaatggattggcattatctatgcgggtggcagcccttcctacgcctcctgggctaaagggcggttcaccatctcgaaggacaattccagcaacacgctgtacttgcaaatgaactcactgagggccgaggacactgcggtgtactactgtgcccggggaactggagataccgtgtacacctactttaacatctggggccagggaaccctggtcactgtctcgagc | 94 |
12172gH26 重鏈 (hIgG4P) | EVQLVESGGGLVQPGGSLRLSCAASGFSLSSYAMTWVRQAPGKGLEWIGIIYAGGSPSYASWAKGRFTISKDNSSNTLYLQMNSLRAEDTAVYYCARGTGDTVYTYFNIWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 95 |
12172gH26 重鏈 (hIgG4P) | gaagtgcagctcgtggagtcgggcggaggtctggtgcagcccggaggaagcctgcgcctgtcatgcgctgccagcgggttctcgctttcctcctacgccatgacctgggtcagacaggcaccgggaaagggcctcgaatggattggcattatctatgcgggtggcagcccttcctacgcctcctgggctaaagggcggttcaccatctcgaaggacaattccagcaacacgctgtacttgcaaatgaactcactgagggccgaggacactgcggtgtactactgtgcccggggaactggagataccgtgtacacctactttaacatctggggccagggaaccctggtcactgtctcgagcgcttctacaaagggcccatccgtcttccccctggcgccctgctccaggagcacctccgagagcacagccgccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacgaagacctacacctgcaacgtagatcacaagcccagcaacaccaaggtggacaagagagttgagtccaaatatggtcccccatgcccaccatgcccagcacctgagttcctggggggaccatcagtcttcctgttccccccaaaacccaaggacactctcatgatctcccggacccctgaggtcacgtgcgtggtggtggacgtgagccaggaagaccccgaggtccagttcaactggtacgtggatggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagttcaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaacggcaaggagtacaagtgcaaggtctccaacaaaggcctcccgtcctccatcgagaaaaccatctccaaagccaaagggcagccccgagagccacaggtgtacaccctgcccccatcccaggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctaccccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaggctaaccgtggacaagagcaggtggcaggaggggaatgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacacagaagagcctctccctgtctctgggtaaa | 96 |
12172gH48 V 區 | EVQLVESGGGLVQPGGSLRLSCAASGFSLSSYAMTWVRQAPGKGLEWIGIIYAGGSPSYASWAKGRFTISKDNSQNTLYLQMNSLRAEDTAVYYCARGTGDTVYTYFNIWGQGTLVTVSS | 97 |
12172gH48 V 區 | gaagtgcagctcgtggagtcgggcggaggtctggtgcagcccggaggaagcctgcgcctgtcatgcgctgccagcgggttctcgctttcctcctacgccatgacctgggtcagacaggcaccgggaaagggcctcgaatggattggcattatctatgcgggtggcagcccttcctacgcctcctgggctaaagggcggttcaccatctcgaaggacaattcccagaacacgctgtacttgcaaatgaactcactgagggccgaggacactgcggtgtactactgtgcccggggaactggagataccgtgtacacctactttaacatctggggccagggaaccctggtcactgtctcgagc | 98 |
12172gH48 重鏈 (hIgG4P) | EVQLVESGGGLVQPGGSLRLSCAASGFSLSSYAMTWVRQAPGKGLEWIGIIYAGGSPSYASWAKGRFTISKDNSQNTLYLQMNSLRAEDTAVYYCARGTGDTVYTYFNIWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 99 |
12172gH48 重鏈 (hIgG4P) | gaagtgcagctcgtggagtcgggcggaggtctggtgcagcccggaggaagcctgcgcctgtcatgcgctgccagcgggttctcgctttcctcctacgccatgacctgggtcagacaggcaccgggaaagggcctcgaatggattggcattatctatgcgggtggcagcccttcctacgcctcctgggctaaagggcggttcaccatctcgaaggacaattcccagaacacgctgtacttgcaaatgaactcactgagggccgaggacactgcggtgtactactgtgcccggggaactggagataccgtgtacacctactttaacatctggggccagggaaccctggtcactgtctcgagcgcttctacaaagggcccatccgtcttccccctggcgccctgctccaggagcacctccgagagcacagccgccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacgaagacctacacctgcaacgtagatcacaagcccagcaacaccaaggtggacaagagagttgagtccaaatatggtcccccatgcccaccatgcccagcacctgagttcctggggggaccatcagtcttcctgttccccccaaaacccaaggacactctcatgatctcccggacccctgaggtcacgtgcgtggtggtggacgtgagccaggaagaccccgaggtccagttcaactggtacgtggatggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagttcaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaacggcaaggagtacaagtgcaaggtctccaacaaaggcctcccgtcctccatcgagaaaaccatctccaaagccaaagggcagccccgagagccacaggtgtacaccctgcccccatcccaggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctaccccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaggctaaccgtggacaagagcaggtggcaggaggggaatgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacacagaagagcctctccctgtctctgggtaaa | 100 |
12172gH49 V 區 | EVQLVESGGGLVQPGGSLRLSCAASGFSLSSYAMTWVRQAPGKGLEWIGIIYAGGSPSYASWAKGRFTISKDNSENTLYLQMNSLRAEDTAVYYCARGTGDTVYTYFNIWGQGTLVTVSS | 101 |
12172gH49 V 區 | gaagtgcagctcgtggagtcgggcggaggtctggtgcagcccggaggaagcctgcgcctgtcatgcgctgccagcgggttctcgctttcctcctacgccatgacctgggtcagacaggcaccgggaaagggcctcgaatggattggcattatctatgcgggtggcagcccttcctacgcctcctgggctaaagggcggttcaccatctcgaaggacaattccgagaacacgctgtacttgcaaatgaactcactgagggccgaggacactgcggtgtactactgtgcccggggaactggagataccgtgtacacctactttaacatctggggccagggaaccctggtcactgtctcgagc | 102 |
12172gH49 重鏈 (hIgG4P) | EVQLVESGGGLVQPGGSLRLSCAASGFSLSSYAMTWVRQAPGKGLEWIGIIYAGGSPSYASWAKGRFTISKDNSENTLYLQMNSLRAEDTAVYYCARGTGDTVYTYFNIWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 103 |
12172gH49 重鏈 (hIgG4P) | gaagtgcagctcgtggagtcgggcggaggtctggtgcagcccggaggaagcctgcgcctgtcatgcgctgccagcgggttctcgctttcctcctacgccatgacctgggtcagacaggcaccgggaaagggcctcgaatggattggcattatctatgcgggtggcagcccttcctacgcctcctgggctaaagggcggttcaccatctcgaaggacaattccgagaacacgctgtacttgcaaatgaactcactgagggccgaggacactgcggtgtactactgtgcccggggaactggagataccgtgtacacctactttaacatctggggccagggaaccctggtcactgtctcgagcgcttctacaaagggcccatccgtcttccccctggcgccctgctccaggagcacctccgagagcacagccgccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacgaagacctacacctgcaacgtagatcacaagcccagcaacaccaaggtggacaagagagttgagtccaaatatggtcccccatgcccaccatgcccagcacctgagttcctggggggaccatcagtcttcctgttccccccaaaacccaaggacactctcatgatctcccggacccctgaggtcacgtgcgtggtggtggacgtgagccaggaagaccccgaggtccagttcaactggtacgtggatggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagttcaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaacggcaaggagtacaagtgcaaggtctccaacaaaggcctcccgtcctccatcgagaaaaccatctccaaagccaaagggcagccccgagagccacaggtgtacaccctgcccccatcccaggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctaccccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaggctaaccgtggacaagagcaggtggcaggaggggaatgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacacagaagagcctctccctgtctctgggtaaa | 104 |
人類 IGKV1-9 IGKJ4 受體構架 | DIQLTQSPSFLSASVGDRVTITCRASQGISSYLAWYQQKPGKAPKLLIYAASTLQSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQLNSYPLTFGGGTKVEIK | 105 |
人類 IGKV1-9 IGKJ4 受體構架 | gacatccagttgacccagtctccatccttcctgtctgcatctgtaggagacagagtcaccatcacttgccgggccagtcagggcattagcagttatttagcctggtatcagcaaaaaccagggaaagcccctaagctcctgatctatgctgcatccactttgcaaagtggggtcccatcaaggttcagcggcagtggatctgggacagaattcactctcacaatcagcagcctgcagcctgaagattttgcaacttattactgtcaacagcttaatagttaccctctcactttcggcggagggaccaaggtggagatcaaa | 106 |
人類 IGHV3-66 IGHJ4 受體構架 | EVQLVESGGGLVQPGGSLRLSCAASGFTVSSNYMSWVRQAPGKGLEWVSVIYSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARYFDYWGQGTLVTVSS | 107 |
人類 IGHV3-66 IGHJ4 受體構架 | gaggtgcagctggtggagtctgggggaggcttggtccagcctggggggtccctgagactctcctgtgcagcctctggattcaccgtcagtagcaactacatgagctgggtccgccaggctccagggaaggggctggagtgggtctcagttatttatagcggtggtagcacatactacgcagactccgtgaagggcagattcaccatctccagagacaattccaagaacacgctgtatcttcaaatgaacagcctgagagccgaggacacggctgtgtattactgtgcgagatactttgactactggggccaaggaaccctggtcaccgtctcctca | 108 |
與N端六聚組胺酸SUMO(小泛素相關修飾因子)溶解度標籤融合之人類TREM1 IgV樣域(CID101907)表現於大腸桿菌(
Escherichia coli) BL21 (DE3)中。藉由離心收穫細菌,再懸浮於100 mM Tris pH 8、300 mM NaCl、250U核酸酶、1 PI tab中且藉由音波處理裂解。將裂解物藉由在42,000 RPM (Ti45)、4℃下離心45分鐘進行澄清且施加至5ml HiTrap Ni螯合管柱。用100 mM Tris pH 8、300 mM NaCl洗滌管柱持續5CV。用線性梯度2-60% 100 mM Tris pH 8、300 mM NaCl、500mM咪唑緩衝液持續15 CV接著用100%緩衝液B持續4CV溶離所結合之TREM1蛋白。彙集含有TREM1之溶離份,透析(10 kDa MWCO)至100 mM Tris pH 8、300 mM NaCl中,且在4℃下用ULP-1消化隔夜。 將經裂解之蛋白質施加至5ml HiTrap Ni螯合管柱上,且收集流過物溶離份且在Vivaspin PES Turbo (10 kDa MWCO濃縮器)中濃縮。接著使用superdex s75管柱(GE Healthcare)拋光經裂解之IgV蛋白質且使緩衝液更換成100mM Tris pH 8.0、300mM NaCl、0.5mM EDTA。藉由使用Nanodrop UV光譜儀量測280 nm吸光度測定最終蛋白質濃度。藉由十二烷基硫酸鈉聚丙烯醯胺凝膠電泳(sodium dodecyl sulfate polyacrylamide gel electrophoresis;SDS-PAGE)評估蛋白質純度。
含有天然N端信號序列及C端抗生物素蛋白親和標籤(AVI)、TEV蛋白酶裂解位點及HKH親和標籤之人類(CID101904)及獼猴(CID101953) TREM1胞外域(ECD)均表現於哺乳動物HEK細胞中。介質通過切向流過濾(TFF)且施加至HiTrap Ni螯合管柱(5 mL)且用100 mM HEPES pH 7.0、300 mM NaCl洗滌。將所結合之TREM1蛋白分別用2-60%,接著100% 100 mM HEPES pH 7.0、300 mM NaCl、500 mM咪唑線性梯度經4 CV溶離。彙集含有TREM1之溶離份且在Vivaspin PES Turbo (10 kDa MWCO濃縮器)中濃縮。接著使用丙烯葡聚糖凝膠s300管柱拋光蛋白質且使緩衝液更換成50 mM HEPES pH 7.0、250 mM NaCl。如先前所描述評估最終蛋白質濃度及純度。
含有天然N端信號序列及不可裂解C端his標籤之人類PGLYRP1 (CID101951)表現於哺乳動物HEK細胞中。將介質施加至HiTrap Ni Excel 2×5 mL管柱且用100 mM HEPES pH 7.0、300 mM NaCl洗滌。將所結合之PGLYRP1蛋白質分別用0-60%、接著100% 100 mM HEPES pH 7.0、300 mM NaCl、500 mM咪唑線性梯度經4 CV溶離。彙集含有PGLYRP1之溶離份且在Vivaspin PES Turbo (10 kDa MWCO濃縮器)中濃縮。接著使用superdex S200管柱拋光蛋白質且使緩衝液更換成PBS pH 7.0。如先前所描述評估最終蛋白質濃度及純度。
實例 2. 治療性抗 TREM1 抗體 12172 之產生及選擇
用在細胞表面上短暫表現人類TREM1之3×10
7個兔纖維母細胞皮下免疫接種一隻雌性紐西蘭白兔。細胞經由電穿孔轉染且使用抗TREM1抗體(R&D FAB1278P)藉由流式細胞測量術驗證TREM1表現。在與用細胞免疫接種的同時,在不同位置將等體積之完全弗氏佐劑(complete Freunds adjuvant)皮下注射至該兔中。
將兔以14天時間間隔給與兩次追加注射,其中兔纖維母細胞在細胞表面上短暫表現人類TREM1。在每次免疫接種之前,自耳靜脈獲取肝素出血(200 µl)。在台上型離心機中在以10,000 rpm旋轉5分鐘之後自出血收集血清且在-20℃下冷凍。在最後一次增強免疫之後14天終止,其中在-80℃下在10% DMSO/FCS中製備脾臟、淋巴結、骨髓及周邊血液單核細胞之單細胞懸浮液且冷凍,直至需要用於B細胞發現目的為止。亦在終止時取血及如先前所描述製備血清。
使用Tickle等人
(2015)在J Biomol Screen 20(4):492-7中描述之方法設定記憶B細胞培養物,且首先在基於細胞的分析中在TTP Labtech Mirrorball系統上針對結合人類及食蟹獼猴TREM1之能力篩選上清液。基於細胞之分析為使用經人類TREM1或食蟹獼猴TREM1 DNA短暫轉染之HEK 293細胞進行的均質多重分析,且相對於經不相關DNA短暫轉染之HEK 293細胞反向篩選。將細胞用Vybrant
TMDIO或DIL標籤(ThermoFisher)及山羊抗兔Fc-AF647結合物作為顯色劑染色。
由總共20×200盤B培養物實驗,在初始Mirrorball篩選中識別約7000個TREM1特異性陽性命中。接著藉由在BIAcore中進行型態分析以估算解離速率,對來自此分析之陽性上清液進行進一步表徵。
使用螢光焦點法以及單細胞反轉錄(RT)及PCR (RT-PCR),對在300s解離步驟的查詢期間具有導致結合性損失小於25%的解離速率的孔進行V區基因回收。
在對所挑選之細胞進行反轉錄(RT)及PCR之後,產生編碼抗體之V區之『轉錄活性PCR』(TAP)產物且用於短暫轉染HEK-293細胞。測試含有重組抗體之所得TAP上清液之以下能力:藉由ELISA測試其結合人類(CID101904;SEQ ID NO: 7)及食蟹獼猴(CID101953;SEQ ID NO : 8) TREM1胞外域(如實例1中所描述產生)的能力;在BIAcore中測試其以至少1000 pM之親和力結合於人類TREM1的能力;及在THP1單核球TREM1/DAP12 NF-κB螢光素酶報導細胞分析中測試其阻斷PGLYRP1介導之信號傳導的能力。
根據抗體經由人類TREM1抑制PGLYRP1/PGN介導之NF-κB信號傳導活化之能力評估功能。為此,使用THP1單核球TREM1/DAP12 NF-κB螢光素酶報導細胞(在UCB中產生)。此等細胞穩定地表現人類TREM1、人類DAP12及NF-κB螢光素酶報導基因。PGLYRP1與來自大腸桿菌之可溶性肽聚糖(PGN)複合,用作TREM1配位體,其藉由結合於TREM1來誘導NF-κB活化。不與TREM1結合之PGN亦誘導NF-κB活化,但程度較低,且經由替代性信號傳導路徑誘導。螢光素酶活性之抑制證實此系統中抗體之功能性阻斷活性。
使用標準組織培養技術,由THP1單核球TREM1/DAP12 NF-κB螢光素酶報導細胞在含有選擇抗生素(RPMI + 10% FBS + 50 µM 2-巰基乙醇+ 10 µg/ml殺稻瘟菌素(blasticidin)+ 1 µg/ml嘌呤黴素+ 200 µg/ml遺傳黴素)之完全培養基中培養。在分析設定之前三天,在平放於培育箱中之T175燒瓶中之50 ml完全培養基(200,000個細胞/毫升)中接種細胞,10×10
6個細胞。在分析當天,自燒瓶移出細胞且轉移至50 ml法爾康離心管(falcon)且以300×g離心五分鐘。移除培養基且將細胞再懸浮於5-10 ml完全培養基中且計數。接著藉由添加細胞懸浮液至完全培養基,細胞依1×10
6個細胞/毫升再懸浮,且將10 µl/孔添加至分析盤(Corning #3570)。在384孔稀釋盤(Greiner #781281)中之完全培養基中連續稀釋抗體。接著將抗體之連續稀釋液轉移至分析盤(10 µl/孔)且在37℃/5% CO
2下培育分析盤1小時。將重組人類PGLYRP1 (R&D Systems #2590-PGB)與PGN (Invivogen #tlrl-ksspgn)在室溫下在無菌DPBS中複合一小時。在一小時之後,在完全培養基中稀釋溶液,接著轉移至分析盤(10 µl/孔)直至2.5 µg/ml PGLYRP1及10 µg/ml PGN之最終分析濃度。對照盤(未添加抗體)分別包括PGLYRP1/PGN複合物及單獨PGN,作為分析最大值及最小值。將分析盤接著在37℃/5% CO
2下培育16小時±2小時。在培育之後,使用SteadyGlo螢光素酶分析系統(Promega #E2520)量測螢光素酶活性。根據製造商說明書製備Steady-Glo試劑且將30 µl/孔添加至分析盤中。將盤接著以200×g離心三分鐘且接著在室溫下再培育兩分鐘,以使得用SteadyGlo試劑之總培育時間為五分鐘。接著使用Synergy Neo 2盤式讀取器量測發光且使用原始發光值以確定相比於對照孔之相對抑制百分比。使用ActivityBase v9.4進行4PL曲線擬合及IC
50值之計算。
接著,以兔IgG抗體形式選殖來自感興趣的TAP產物之重鏈及輕鏈可變區基因對且在HEK-293短暫表現系統中再表現。總共選殖144個V區。接著再測試重組型選殖抗體以下之能力:藉由ELISA再測試其結合人類及食蟹獼猴TREM1之能力;在BIAcore中再測試其結合之能力;及在NF-κB螢光素酶報導細胞分析中再測試其抑制PGLYRP1+PGN介導之信號傳導的能力。在使用人類TREM1丙胺酸突變陣列(與下文關於抑制TREM1抗體進一步描述之相同方法)表徵已知TREM1配位體PGLYRP1之配位體結合位點之後,假定結合於同一結合位點之抗體經由直接配位體阻斷而調節TREM1功能。為識別TREM1上賦予功能之替代抗體結合位點,使用人類TREM1丙胺酸突變陣列評估在NF-κB螢光素酶報導細胞分析中經證實抑制TREM1活性的抗體之抗原決定基位置。
產生人類TREM1 IgV域突變體純系之陣列。其由以下組成:58個純系,各自具有三個緊密接近的突變成丙胺酸之表面殘基;65個純系,各自具有兩個緊密接近的突變成丙胺酸之表面殘基;或63個純系,各自具有突變成丙胺酸的單一表面殘基。所有陣列包括野生型人類TREM1純系。包括野生型之突變人類TREM1陣列純系之序列展示於表8、表9及表10中。
表 8.用於設計三丙胺酸突變陣列之TREM1蛋白質序列清單
ID | SEQ ID NO | TREM1 多肽序列 |
01_WT | 109 | MELRAATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
02_6 | 110 | MELRAAAKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
03_6_7 | 111 | MELRAAAALTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
04_6_7_9 | 112 | MELRAAAALAEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
05_7_8_9 | 113 | MELRAATAAAEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
06_9_10_111 | 114 | MELRAATKLAAEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFARIRLVVTLE |
07_9_10_11 | 115 | MELRAATKLAAAKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
08_10_11_12 | 116 | MELRAATKLTAAAYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
09_11_12_13 | 117 | MELRAATKLTEAAAELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
10_16_118_119 | 118 | MELRAATKLTEEKYELAEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVAAE |
11_19_20_85 | 119 | MELRAATKLTEEKYELKEGAALDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMANLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
12_22_24_26 | 120 | MELRAATKLTEEKYELKEGQTLAVACAYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
13_24_26_28 | 121 | MELRAATKLTEEKYELKEGQTLDVACAYALEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
14_26_28_29 | 122 | MELRAATKLTEEKYELKEGQTLDVKCAYAAEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
15_28_29_30 | 123 | MELRAATKLTEEKYELKEGQTLDVKCDYAAAKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
16_29_30_31 | 124 | MELRAATKLTEEKYELKEGQTLDVKCDYTAAAFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
17_31_32_35 | 125 | MELRAATKLTEEKYELKEGQTLDVKCDYTLEAAASAQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
18_30_34 | 126 | MELRAATKLTEEKYELKEGQTLDVKCDYTLAKFAASQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
19_34_35_57 | 127 | MELRAATKLTEEKYELKEGQTLDVKCDYTLEKFAAAQKAWQIIRDGEMPKTLACTERASKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
20_35_36_56 | 128 | MELRAATKLTEEKYELKEGQTLDVKCDYTLEKFASAAKAWQIIRDGEMPKTLACTEAPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
21_40_49_50 | 129 | MELRAATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWAIIRDGEMPAALACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
22_43_44_47 | 130 | MELRAATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIAAGEAPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
23_43_44_45 | 131 | MELRAATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIAAAEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
24_44_45_46 | 132 | MELRAATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRAAAMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
25_45_46_47 | 133 | MELRAATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDAAAPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
26_43_46_47 | 134 | MELRAATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIADGAAPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
27_47_48_49 | 135 | MELRAATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEAAATLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
28_47_49_50 | 136 | MELRAATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEAPAALACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
29_49_50_53 | 137 | MELRAATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPAALAATERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
30_50_53_55 | 138 | MELRAATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKALAATARPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
31_55_56_57 | 139 | MELRAATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTAAASKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
32_34_56_57 | 140 | MELRAATKLTEEKYELKEGQTLDVKCDYTLEKFAASQKAWQIIRDGEMPKTLACTEAASKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
33_57_59_60 | 141 | MELRAATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERASAASHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
34_59_60_61 | 142 | MELRAATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSAAAHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
35_60_61_62 | 143 | MELRAATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKAAAPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
36_61_62_63 | 144 | MELRAATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNAAAVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
37_62_63_64 | 145 | MELRAATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSAAAQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
38_63_64_65 | 146 | MELRAATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHAAAVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
39_64_65_66 | 147 | MELRAATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPAAAGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
40_60_74_76 | 148 | MELRAATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKASHPVQVGRIILEDAHAHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
41_60_75_76 | 149 | MELRAATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKASHPVQVGRIILEDYAAHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
42_60_76_77 | 150 | MELRAATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKASHPVQVGRIILEDYHAAGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
43_28_76_77 | 151 | MELRAATKLTEEKYELKEGQTLDVKCDYALEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHAAGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
44_28_77_78 | 152 | MELRAATKLTEEKYELKEGQTLDVKCDYALEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDAALLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
45_96_109_111 | 153 | MELRAATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYACVIYQPPKEPHMAFARIRLVVTLE |
46_98_100_109 | 154 | MELRAATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCAIAQPPKEPHMAFDRIRLVVTLE |
47_35_100_102 | 155 | MELRAATKLTEEKYELKEGQTLDVKCDYTLEKFASAQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIAQAPKEPHMLFDRIRLVVTLE |
48_102_103_104 | 156 | MELRAATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQAAAEPHMLFDRIRLVVTLE |
49_103_104_105 | 157 | MELRAATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPAAAPHMLFDRIRLVVTLE |
50_104_105_106 | 158 | MELRAATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPAAAHMLFDRIRLVVTLE |
51_105_106_107 | 159 | MELRAATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKAAAMLFDRIRLVVTLE |
52_106_107_108 | 160 | MELRAATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEAAALFDRIRLVVTLE |
53_107_108_109 | 161 | MELRAATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPAAAFDRIRLVVTLE |
54_109_110_111 | 162 | MELRAATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMAAARIRLVVTLE |
55_11_113_114 | 163 | MELRAATKLTEAKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRAALVVTLE |
56_10_12_114 | 164 | MELRAATKLTAEAYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIALVVTLE |
57_118_119_120 | 165 | MELRAATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVAAA |
58_16_119_120 | 166 | MELRAATKLTEEKYELAEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTAA |
表 9.用於設計二丙胺酸突變陣列之TREM1蛋白質序列清單
ID | SEQ ID NO | TREM1 多肽序列 |
01_WT | 167 | AATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKG |
02_2_3 | 168 | AAAALTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKG |
03_3_4 | 169 | AATAATEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKG |
04_4_5 | 170 | AATKAAEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKG |
05_5_104 | 171 | AATKLAEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHALFDRIRLVVTKG |
06_5_106 | 172 | AATKLAEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLADRIRLVVTKG |
07_5_107 | 173 | AATKLAEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFARIRLVVTKG |
08_7_9 | 174 | AATKLTEAKAELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKG |
09_7_107 | 175 | AATKLTEAKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFARIRLVVTKG |
10_8_10 | 176 | AATKLTEEAYALKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKG |
11_11_12 | 177 | AATKLTEEKYEAAEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKG |
12_12_13 | 178 | AATKLTEEKYELAAGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKG |
13_12_15 | 179 | AATKLTEEKYELAEGATLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKG |
14_13_85 | 180 | AATKLTEEKYELKAGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQAEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKG |
15_16_81 | 181 | AATKLTEEKYELKEGQALDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMANLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKG |
16_20_75 | 182 | AATKLTEEKYELKEGQTLDVACDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGALRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKG |
17_24_25 | 183 | AATKLTEEKYELKEGQTLDVKCDYAAEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKG |
18_24_26 | 184 | AATKLTEEKYELKEGQTLDVKCDYALAKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKG |
19_24_27 | 185 | AATKLTEEKYELKEGQTLDVKCDYALEAFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKG |
20_25_26 | 186 | AATKLTEEKYELKEGQTLDVKCDYTAAKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKG |
21_26_27 | 187 | AATKLTEEKYELKEGQTLDVKCDYTLAAFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKG |
22_30_31 | 188 | AATKLTEEKYELKEGQTLDVKCDYTLEKFAAAQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKG |
23_30_53 | 189 | AATKLTEEKYELKEGQTLDVKCDYTLEKFAASQKAWQIIRDGEMPKTLACTERASKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKG |
24_37_38 | 190 | AATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQAARDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKG |
25_37_39 | 191 | AATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQAIADGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKG |
26_37_45 | 192 | AATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQAIRDGEMPATLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKG |
27_37_47 | 193 | AATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQAIRDGEMPKTAACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKG |
28_38_44 | 194 | AATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIARDGEMAKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKG |
29_38_90 | 195 | AATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIARDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGAYQCVIYQPPKEPHMLFDRIRLVVTKG |
30_42_43 | 196 | AATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGAAPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKG |
31_42_45 | 197 | AATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGAMPATLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKG |
32_43_44 | 198 | AATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEAAKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKG |
33_43_101 | 199 | AATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEAPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKAPHMLFDRIRLVVTKG |
34_44_45 | 200 | AATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMAATLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKG |
35_45_47 | 201 | AATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPATAACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKG |
36_47_65 | 202 | AATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTAACTERPSKNSHPVQVGRAILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKG |
37_51_55 | 203 | AATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTARPSANSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKG |
38_56_57 | 204 | AATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKAAHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKG |
39_58_59 | 205 | AATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSAAVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKG |
40_59_60 | 206 | AATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHAAQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKG |
41_59_61 | 207 | AATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHAVAVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKG |
42_59_66 | 208 | AATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHAVQVGRIALEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKG |
43_60_61 | 209 | AATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPAAVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKG |
44_60_62 | 210 | AATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPAQAGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKG |
45_61_62 | 211 | AATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVAAGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKG |
46_61_66 | 212 | AATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVAVGRIALEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKG |
47_62_65 | 213 | AATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQAGRAILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKG |
48_65_66 | 214 | AATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRAALEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKG |
49_66_81 | 215 | AATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIALEDYHDHGLLRVRMANLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKG |
50_72_73 | 216 | AATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHAAGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKG |
51_73_75 | 217 | AATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDAGALRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKG |
52_81_82 | 218 | AATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMAALQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKG |
53_85_86 | 219 | AATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQAADSGLYQCVIYQPPKEPHMLFDRIRLVVTKG |
54_98_99 | 220 | AATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQAAKEPHMLFDRIRLVVTKG |
55_99_100 | 221 | AATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPAAEPHMLFDRIRLVVTKG |
56_100_101 | 222 | AATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPAAPHMLFDRIRLVVTKG |
57_101_102 | 223 | AATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKAAHMLFDRIRLVVTKG |
58_102_103 | 224 | AATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEAAMLFDRIRLVVTKG |
59_103_104 | 225 | AATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPAALFDRIRLVVTKG |
60_104_106 | 226 | AATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHALADRIRLVVTKG |
61_106_107 | 227 | AATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLAARIRLVVTKG |
62_8_10_112 | 228 | AATKLTEEAYALKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLAVTKG |
63_37_39_40 | 229 | AATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQAIAAGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKG |
64_40 | 230 | AATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRAGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKG |
65_112 | 231 | AATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLAVTKG |
表 10.用於設計單丙胺酸突變陣列之TREM1蛋白質序列清單
ID | SEQ ID NO | TREM1 多肽序列 |
01_WT | 232 | ATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
02_1 | 233 | AAKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
03_2 | 234 | ATALTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
04_4 | 235 | ATKLAEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
05_5 | 236 | ATKLTAEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
06_6 | 237 | ATKLTEAKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
07_7 | 238 | ATKLTEEAYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
08_8 | 239 | ATKLTEEKAELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
09_9 | 240 | ATKLTEEKYALKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
10_11 | 241 | ATKLTEEKYELAEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
11_14 | 242 | ATKLTEEKYELKEGATLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
12_17 | 243 | ATKLTEEKYELKEGQTLAVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
13_19 | 244 | ATKLTEEKYELKEGQTLDVACDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
14_21 | 245 | ATKLTEEKYELKEGQTLDVKCAYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
15_23 | 246 | ATKLTEEKYELKEGQTLDVKCDYALEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
16_24 | 247 | ATKLTEEKYELKEGQTLDVKCDYTAEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
17_25 | 248 | ATKLTEEKYELKEGQTLDVKCDYTLAKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
18_26 | 249 | ATKLTEEKYELKEGQTLDVKCDYTLEAFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
19_29 | 250 | ATKLTEEKYELKEGQTLDVKCDYTLEKFAASQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
20_30 | 251 | ATKLTEEKYELKEGQTLDVKCDYTLEKFASAQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
21_38 | 252 | ATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIADGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
22_39 | 253 | ATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRAGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
23_41 | 254 | ATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGAMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
24_42 | 255 | ATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEAPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
25_44 | 256 | ATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPATLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
26_45 | 257 | ATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKALACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
27_50 | 258 | ATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTARPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
28_51 | 259 | ATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTEAPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
29_52 | 260 | ATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERASKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
30_54 | 261 | ATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSANSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
31_55 | 262 | ATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKASHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
32_56 | 263 | ATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNAHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
33_57 | 264 | ATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSAPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
34_58 | 265 | ATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHAVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
35_59 | 266 | ATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPAQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
36_60 | 267 | ATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVAVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
37_61 | 268 | ATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQAGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
38_63 | 269 | ATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGAIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
39_65 | 270 | ATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIALEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
40_71 | 271 | ATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHAHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
41_72 | 272 | ATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDAGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
42_78 | 273 | ATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVAMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
43_80 | 274 | ATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMANLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
44_81 | 275 | ATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVALQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
45_83 | 276 | ATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLAVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
46_84 | 277 | ATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQAEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
47_85 | 278 | ATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVADSGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
48_87 | 279 | ATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDAGLYQCVIYQPPKEPHMLFDRIRLVVTLE |
49_95 | 280 | ATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIAQPPKEPHMLFDRIRLVVTLE |
50_97 | 281 | ATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQAPKEPHMLFDRIRLVVTLE |
51_98 | 282 | ATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPAKEPHMLFDRIRLVVTLE |
52_99 | 283 | ATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPAEPHMLFDRIRLVVTLE |
53_100 | 284 | ATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKAPHMLFDRIRLVVTLE |
54_101 | 285 | ATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEAHMLFDRIRLVVTLE |
55_102 | 286 | ATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPAMLFDRIRLVVTLE |
56_103 | 287 | ATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHALFDRIRLVVTLE |
57_104 | 288 | ATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMAFDRIRLVVTLE |
58_106 | 289 | ATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFARIRLVVTLE |
59_109 | 290 | ATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIALVVTLE |
60_111 | 291 | ATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLAVTLE |
61_113 | 292 | ATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVALE |
62_114 | 293 | ATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTAE |
63_115 | 294 | ATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTLA |
以上純系中之每一者表現為由TREM1 IgV域繼之以與人類Fc域融合之三丙胺酸連接子組成之融合蛋白。將各純系捕獲至塗佈有抗人類Fc抗體之感測器上。隨後將感測器浸漬於含有所關注抗體之溶液中。使用生物膜層干涉術(BLI)儀器(Octet RED384或Octet HTX,ForteBio)監測結合動力學。
藉由監測抗體與各突變TREM1純系之結合動力學且將其與針對野生型蛋白質之動力學進行比較,可推斷抗原決定基。抗體解離速率常數的增加或抗體結合於蛋白質之損失指示該純系中之突變殘基對於抗體結合而言為重要的,且因此為其抗原決定基之一部分。
12172抗體經選擇為TREM1活性之強力抑制劑。有趣地,丙胺酸掃描方法證實此分子具有遠離經識別PGLYRP1配位體結合位點之抗原決定基。此隨後經選擇作為鉛分子。
使用以上方法且考慮全部三個陣列,12172抗體之關鍵抗原決定基殘基經測定為殘基E26、E27、K28、Y29、E30、L31、K32及Q35(其中編號係根據SEQ ID NO: 1)。
實例 3 : 抗體人類化
藉由將來自兔V區之CDR移植至人類生殖系抗體V區構架上來對抗體12172進行人類化。為了恢復抗體活性,來自兔V區之許多構架殘基亦保留於人類化序列中。使用由Adair等人 (1991) (WO91/09967)概述之方案選擇此等殘基。兔抗體(供體) V區序列與人類生殖系(受體) V區序列之比對以及所設計之人類化序列展示於圖1及圖2中。除在CDR-H1中使用組合型Chothia/Kabat定義(參見Adair等人, WO91/09967)以外,自供體移植至受體序列之CDR係由Kabat (Kabat等人, 1987)定義。
選擇人類V區IGKV1-9加IGKJ4 J區(IMGT,http://www.imgt.org/)作為抗體12172輕鏈CDR之受體。除其中分別保留供體殘基丙胺酸(A1)、纈胺酸(V2)及纈胺酸(V3)之來自包含殘基1、2及3 (參考SEQ ID NO:25)之群的零個、一個、兩個或三個殘基以外,人類化移植物變異體中之輕鏈構架殘基皆來自人類生殖系基因(圖1及表11)。
選擇人類V區IGHV3-66加IGHJ4 J區(IMGT,http://www.imgt.org/)作為抗體12172之重鏈CDR之受體。與許多兔抗體相同,抗體12172之VH基因比所選人類受體短。在與人類受體序列比對時,抗體12172之VH區之構架1缺乏人類化抗體中所保留之N端殘基(圖2)。12172兔VH區之構架3亦缺乏位於β摺疊股D與E之間的環中的兩個殘基(75及76,參考SEQ ID NO:45):在人類化移植物變異體中,空位由來自所選擇的人類受體序列之相應殘基(離胺酸75,K75;天冬醯胺76,N76)填充(圖2)。除其中分別保留供體殘基蘇胺酸(T23)、異白胺酸(I48)、甘胺酸(G49)、離胺酸(K71)、絲胺酸(S73)及纈胺酸(V78)之來自包含殘基23、48、49、71、73及78 (參考SEQ ID NO:45)之群的一或多個殘基以外,人類化移植物變異體中之重鏈構架殘基皆來自人類生殖系基因。
藉由ATUM (CA, USA)之自動化合成方法,設計且構築編碼多個變異體重鏈及輕鏈V區序列的基因。藉由寡核苷酸定向突變誘發修飾VH及VK基因產生重鏈及輕鏈V區之其他變異體。為了在哺乳動物細胞中短暫表現,將人類化輕鏈V區基因選殖至UCB輕鏈表現載體pMhCK中,該表現載體含有編碼人類κ鏈恆定區的DNA (Km3異型)。將人類化重鏈V區基因選殖至UCB人類γ-4重鏈表現載體pMhγ4PFL中,該表現載體含有編碼具有鉸鏈穩定化突變S228P之人類γ-4重鏈恆定區的DNA(Angal S., King D.J., Bodmer M.W., Turner A., Lawson A.D.G., Roberts G., Pedley B.及Adair J.R. A single amino acid substitution abolishes the heterogeneity of chimeric mouse/human (IgG4) antibody. Mol. Immunol.1993, 30 (1):105-8),或選殖至UCB γ-1 LALA重鏈表現載體pMhγ1 L234A L235A中,該表現載體含有編碼具有突變L234A及L235A之人類γ-1重鏈恆定區之DNA以減少與Fc γ受體(FcγR)之結合(Canfield S.M.及Morrison S.L. The Binding affinity of Human IgG for its High Affinity Fc Receptor Is Determined by Multiple Amino Acids in the CH2 Domain and Is Modulated by the Hinge Region. J. Exp. Med. 1991, 173:1483-1491)。將所得重鏈及輕鏈載體共轉染至Expi293
TM懸浮細胞中係使用ExpiFectamine
TM293轉染劑(A14525,ThermoFisher Scientific)實現,且得到人類化、重組IgG4P及IgG1 LALA抗體之表現。
表現變異人類化抗體鏈及其組合,且評估其相對於親本抗體對人類TREM1之結合親和力,藉由基於螢光之熱偏移分析評估其熱穩定性(如實例13中所描述)及藉由親和力捕獲自相互作用奈米粒子光譜法(AC-SINS,如實例17中所描述)評估自相互作用之傾向。如藉由表面電漿子共振所量測,保留移植物gH11中之VH構架供體殘基I48、G49及K71對於與人類TREM1之最高親和力結合係必要的(表11)。移植物gL2中之輕鏈構架殘基均來自人類生殖系基因。如藉由AC-SINS分析所量測,在移植物gL6中保留VL供體殘基V3減少自相互作用之傾向(表22)。
對熱去摺疊(變性)之抗性為構形穩定性及長期儲存穩定性之指標。人類化IgG4P抗體具有良好熱穩定性,其中Fab域之去摺疊中點(Tm)在73.5 - 74.6℃範圍內(表11)。
分子自相互作用可引起天然狀態聚集及不良溶解度,尤其在用於皮下投與治療性mAb之高蛋白質濃度下。已顯示抗體Fv域之淨電荷以同型特異性方式影響人類IgG在pH 7.4及pH 5.0下之天然狀態聚集(Heads JT, Lamb R, Kelm S, Adams R, Elliott P, Tyson K, Topia S, West S, Nan R, Turner A, Lawson ADG. Electrostatic interactions modulate the differential aggregation propensities of IgG1 and IgG4P antibodies and inform charged residue substitutions for improved developability. Protein Eng Des Sel. 2019年12月31日;32(6):277-288. doi: 10.1093/protein/gzz046. PMID: 31868219; PMCID: PMC7036597)。為了減少人類化12172 hIgG4P抗體之自相互作用傾向,如由藉由AC-SINS分析所量測之高Δλmax值指示(在此實例中為表12及在實例17中為表22),Fv域之淨正電荷藉由將帶正電殘基突變成中性或帶負電殘基來減少。此等殘基使用Heads等人(2019) (WO2019/234094)所概述之基本原理來選擇。人類化輕鏈移植物12712gL2 (SEQ ID NO: 29)之殘基18及50分別在移植物gL9及gL11中由精胺酸(R18)突變成絲胺酸(S18)及由離胺酸(K50)突變成絲胺酸(S50)。人類化重鏈移植物12172gH11 (SEQ ID NO: 79)中之殘基75分別在移植物gH26、gH48及gH49中由離胺酸(K75)突變成絲胺酸(S75)、麩醯胺酸(Q75)或麩胺酸(E75)。經修飾之重鏈及輕鏈基因以組合形式短暫表現於Expi293
TM懸浮細胞中,且評估重組IgG4P抗體對人類TREM1之結合親和力、熱穩定性及自相互作用之傾向(表12)。人類化12172電荷突變體保留對人類TREM1之親和力,且展現減少之自相互作用傾向,如藉由AC-SINS分析法量測之Δλmax降低所指示。
人類化12172 gL2gH11及12172 gL6gH6 (hIgG4P及hIgG1 LALA型式)之生物物理表徵使用不同應力條件進行以評估可顯影性,如實例12-20中所描述。另外,藉由液相層析質譜分析(LC-MS)分析所有分子以證實經預測序列分子量(MW)與實驗資料一致。
人類化12172gL2gH11 IgG4P抗體在THP1單核球TREM1/DAP12 NF-κB螢光素酶報導細胞分析(實例2中所述)中展示相對於兔親本12172抗體類似的NF-κB抑制(參見表13)。
表 11.各種12172抗體變異體之親和力及Tm。
抗體12172 變異體 | 輕鏈供體殘基 | 重鏈供體殘基 | 親和力 (KD ) pM | Tm ( ℃) |
12172 | - | - | 519/461 | |
12172gL1gH1 | A1、V2、V3 | T23、I48、G49、K71、S73、V78 | 437 | 73.5 |
12172gL2gH1 | - | T23、I48、G49、K71、S73、V78 | 442 | 74.1 |
12172gL2gH4 | - | T23、I48、G49、S73、V78 | 693 | 74.3 |
12172gL2gH6 | - | T23、I48、G49、K71、S73 | 581 | 73.9 |
12172gL2gH8 | - | I48、G49、K71、S73、V78 | 476 | 74.2 |
12172gL6gH4 | V3 | T23、I48、G49、S73、V78 | 619 | 74.1 |
12172gL6gH6 | V3 | T23、I48、G49、K71、S73 | 463 | 74.5 |
12172gL6gH11 | V3 | I48、G49、K71 | 336 | 74.5 |
12172gL2gH2 | - | G49、K71、S73、V78 | 989 | 73.6 |
12172gL2gH9 | - | I48、G49、V78 | 362 | 74.6 |
12172gL2gH10 | - | I48、G49、S73 | 1970 | 74.1 |
12172gL2gH11 | - | I48、G49、K71 | 453 | 74.4 |
12172gL2gH12 | - | I48、G49 | 718 | 74.1 |
表 12.各種12172抗體變異體之親和力、Tm及AC-SINS (一些變異體提供重複值)
抗體12172 變異體 | 輕鏈供體殘基 | 輕鏈突變 | 重鏈供體殘基 | 重鏈 突變 | 親和力(KD) pM | Fab Tm | AC-SINS |
12172 | - | - | - | - | 570 | ||
12172gL2gH11 | - | - | I48、G49、K71 | - | 445 | 74.4 | 10.2 |
12172gL2gH26 | - | - | I48、G49、K71 | K75S | 624/672 | 74.1 | 1.98/1.17 |
12172gL9gH11 | - | R18S | I48、G49、K71 | - | 550 | ND | 9.38 |
12172gL11gH11 | - | K50S | I48、G49、K71 | - | 550 | 73.8 | 7.02/10.56 |
12172gL9gH26 | - | R18S | I48、G49、K71 | K75S | 559/616 | 73.8 | 1.73/0.68 |
12172gL10gH26 | - | K42Q | I48、G49、K71 | K75S | 578/659 | 73.8 | 2.06/1.33 |
12172gL11gH26 | - | K50S | I48、G49、K71 | K75S | 532/633 | 74 | 2.03/1.36 |
12172gL9gH48 | - | R18S | I48、G49、K71 | K75Q | 370 | 73.6 | 10.46 |
12172gL9gH49 | - | R18S | I48、G49、K71 | K75E | 394 | 73.6 | 6.45 |
表 13.12172gL2gH11 IgG4P及12172兔IgG1之效能、功效及希爾斜率值之概述
*根據三個獨立實驗計算各分子之值。
實例 4. 兔 12172 Fab 之表現及純化
抗體 | 幾何平均IC50 (pM) ± SD | 平均Emax (%) ± SD | 平均 斜率± SD | N* |
12172gL2gH11 IgG4P | 64 ± 36 | 72 ± 4 | 2.1 ± 0.9 | 3 |
12172兔IgG1 | 84 ± 40 | 89 ± 6 | 2.7 ± 1.2 | 3 |
將重鏈及輕鏈載體CID102769及CID102770共轉染至Expi293
TM懸浮細胞中係使用ExpiFectamine
TM293轉染試劑(A14525,ThermoFisher Scientific)實現,且得到兔重組12172 Fab之表現。將培養基經由PALL 0.4/0.2µm膠囊過濾器過濾且施加於在XK16/60管柱中沈降之Protein G GammaBind Plus樹脂(7 mL)且用10CV 1×PBS pH 7.4洗滌。將所結合之Fab複合物蛋白質用50 mL 100mM甘胺酸pH 2.7溶離且立即用10% 1M Tris pH 8中和。彙集含有12172 Fab複合物之溶離份且在Vivaspin PES 20 (10 kDa MWCO濃縮器)中濃縮。接著使用superdex s200 16/60管柱(GE Healthcare)拋光且使緩衝液更換成1×PBS pH 7.4。如先前實例1中所描述評估最終蛋白質濃度及純度。
實例 5. 12172 gL2gH11 / gL6gH6 hIgG4P 及 hIgG1 LALA 之表現及純化 短暫哺乳動物表現, CHOSXE 培養
懸浮CHOSXE細胞預適應於補充有2 mM (100x) Glutamax之CDCHO無血清培養基(Invitrogen)。
將細胞維持在對數生長期,在振盪培育箱(Kuhner AG, Birsfelden, Switzerland)中以190 rpm攪拌且在補充有8% CO
2情況下在37℃下培養。
電穿孔轉染
在轉染之前,使用Vi-Cell™XR細胞活力分析儀(Beckman Coulter)測定細胞數目及活力,且將99%活力之所需細胞數目(2.3×10
8個細胞/毫升)轉移至離心機錐形管中且以1500 rpm旋轉15分鐘。將集結細胞在Hyclone™ MaxCyte®緩衝液(Thermo Scientific)中洗滌,且再離心15分鐘。將集結粒以2.3×10
8個細胞/毫升再懸浮於新鮮緩衝液中。
以400 µg/ml添加使用Qiagen Plasmid
PlusGiga Kit®純化之質體DNA。在使用MaxCyte STx®流式電穿孔儀器進行電穿孔之後,將細胞轉移至ProCHO™ 5無蛋白質CHO培養基(Lonza),其含有2 mM Glutamax、0.75 mM丁酸鈉(正丁酸鈉鹽,Sigma B-5887)、抗生素抗有絲分裂100x溶液(1/500)及在第0天添加之彈丸饋料。
接著將經轉染細胞直接轉移至通風燒瓶中且在設定為37℃、8% CO
2及190 rpm振盪之Kuhner振盪培育箱中培養。在轉染後24小時將溫度下降至32℃且再培養細胞11-13天。
在第12-14天,將培養物轉移至離心管中,且在以4000 rpm旋轉30分鐘之後將上清液與細胞分離。保留的上清液藉由經由0.22 µm Sartobran® P Millipore濾筒繼之以0.22 µm Millipak® Gamma Gold過濾器過濾來進一步澄清。藉由蛋白質G定量HPLC分析,使用1 mg/ml之A33 hIgG1作為標準物、0.8 ml POROS™ G 20 µm管柱及Agilent 1100系列HPLC系統來測定最終表現效價。將澄清的細胞培養收穫物在純化之前儲存在4℃下。
抗體純化及分析
使澄清的細胞培養收穫物升溫至室溫,隨後使用ÄKTA Pure 25L層析系統(Cytiva)裝載至預平衡至Hyclone™磷酸鹽緩衝鹽水(PBS) pH 7.4中的215 ml MabSelect™ SuRe™管柱(Cytiva)上。在PBS pH 7.4中洗滌之後,對於人類IgG1同型,藉由將pH值降低至3.4 (0.1 M檸檬酸鈉緩衝液)或對於人類IgG4P同型,將pH值降低至pH 3.7 (30 mM乙酸鈉)繼之至pH 3.6 (0.1 M檸檬酸鈉緩衝液)來溶離所結合物質。溶離後,將管柱用0.1 M檸檬酸pH 2.0洗提以移除任何強結合的聚集體。彙集親和力捕獲溶離峰溶離份且藉由添加2M Tris-HCl pH 8.5來中和至pH 5.5-7.5。藉由使用nanodrop讀取在280 nm處之吸光度測定蛋白質濃度且藉由分析型尺寸排阻HPLC (方法如下)測定純度。
使用離心過濾裝置(Centricon® Plus-70或Amicon® Ultra-15)或具有10 KDa或30 KDa MWCO膜(視體積而定)之加壓攪拌細胞室(Amicon®)濃縮親和力池(Affinity pool),以裝載至HiLoad Superdex 200 26/60 (Cytiva)或50/60製備級管柱(由Cytiva定製封裝)上。在使用ÄKTA層析系統(Cytiva)裝載樣品之前,將HiLoad Superdex 200 26/60或50/60管柱平衡至50 mM乙酸鈉、125 mM氯化鈉緩衝液pH5.0中。進行等度溶離,且在0.3 CV之後收集溶離份。藉由在分析型尺寸排阻HPLC上操作溶離份或模擬池來識別含有單體之溶離份。彙集溶離份以獲得>98%單體含量。使用離心過濾裝置(Centricon® Plus-70或Amicon® Ultra-15)或具有10 KDa或30 KDa MWCO膜(視體積而定)之加壓攪拌細胞室(Amicon®)將池濃縮至10-15 mg/ml,接著回收且使用Stericup®過濾單元或Millex GV針筒過濾器進行0.22 µm無菌過濾。
藉由使用nanodrop讀取280 nm處之吸光度來測定最終蛋白質濃度。藉由分析型尺寸排阻HPLC測定單體含量。校正條帶型態藉由使用Invitrogen Novex™ WedgeWell™ 4-20% Tris-甘胺酸及XCell SureLock™微型細胞電泳系統進行SDS-PAGE以及庫馬斯染色來測定。使用Charles River Endosafe® LAL試劑濾筒技術及Endosafe® nexgen-PTS讀取器測定內毒素含量,其中含量< 1 EU/mg具有可接受品質。藉由完整質譜分析來分析樣品以確認重鏈及輕鏈質量、預期修飾及一致性。
分析型尺寸排阻 HPLC
使用Agilent 1100或1200系列HPLC將TSKgel G3000SWXL HPLC管柱(Tosoh)平衡至Hyclone磷酸鹽緩衝鹽水(PBS) pH 7.4中。注射20-50 µg樣品且在等度溶離條件(PBS pH 7.4)下以1 ml/min操作16分鐘。將資料與BioRad分子量標記標準比較。報告單體以及高及低分子量產物相關雜質之滯留時間及百分比。
實例 6. 12172gL2gH11 hIgG4P 與人類及食蟹獼猴 TREM1 之結合動力學
在25℃下在Biacore T200儀器及Biacore 8k儀器上藉由表面電漿子共振來量測12172gL2gH11 hIgG4P與人類及食蟹獼猴TREM1之結合的動力學。
山羊抗人類IgG亦即Fc片段特異性抗體(F(ab')2片段,Jackson ImmunoResearch 109-006-098)經由胺偶合化學反應固定於CM5感測器晶片上達到約5000 RU之含量。以相同方式處理參考細胞。在胺偶合完成之後,除捕獲溶液以外,所有後續溶液連續流經參考細胞及樣品細胞,且在整個操作中自樣品細胞減去參考細胞之反應。
各分析循環係由以下組成:將約250 RU之12172gL2gH11 hIgG4P捕獲至抗Fc表面,注射分析物180 s (在25℃下,以30 µl/分鐘之流速),解離分析物600 s,繼之進行表面再生(注射50 mM HCl 60 s、注射5 mM NaOH 30 s及再注射50 mM HCl 60 s)。 將人類TREM1 ECD分析物(自製,加His標籤)以3倍連續稀釋度注射於在T200上之濃度為200 nM至2.5 nM的HBS-EP+操作緩衝液(GE Healthcare)中,及注射於在8k上之濃度為500 nM至2 nM的該操作緩衝液中。將獼猴TREM1 ECD分析物(自製,加His標籤)以3倍連續稀釋度注射於濃度為4100 nM至17 nM之HBS-EP+操作緩衝液(GE Healthcare)中-此僅在T200上操作。包括緩衝液空白注射液以減除儀器雜訊及漂移。
視需要使用1:1結合模型,使用Biacore T200評估軟體(3.0版)或Biacore Insight評估軟體(3.0版)來測定動力學參數。12172gL2gH11 hIgG4P展示對人類TREM1具有0.52 nM之親和力及對獼猴TREM1具有870 nM之親和力。動力學參數概述於表14中。
表 14.12172gL2gH11 hIgG4P與人類及食蟹獼猴TREM1結合之動力學參數
實例 7. 12172gL2gH11 hIgG4P 與不同物種之 TREM1 的結合
物種 | k a (1/Ms) | k d (1/s) | K D (nM) | n= |
人類 | 1.8E+05 | 9.2E-05 | 0.52 | 2 |
食蟹獼猴 | 1.2E+05 | 1.0E-01 | 870 | 1 |
在25℃下在Biacore T200儀器上藉由表面電漿子共振來量測12172gL2gH11 hIgG4P與各種物種之TREM1結合的動力學。所測試之物種為人類、食蟹獼猴、恆河猴、狨猴、大鼠、小鼠、狗及豬。
山羊抗人類IgG亦即Fc片段特異性抗體(F(ab')2片段,Jackson ImmunoResearch 109-006-098)經由胺偶合化學反應固定於CM5感測器晶片上達到約5000 RU之含量。以相同方式處理參考細胞。在胺偶合完成之後,除捕獲溶液以外,所有後續溶液連續流經參考細胞及樣品細胞,且在整個操作中自樣品細胞減去參考細胞之反應。
各分析循環係由以下組成:將約250 RU之12172gL2gH11 hIgG4P捕獲至抗Fc表面,注射分析物180 s (在25℃下,以30 µl/分鐘之流速),解離分析物600 s,繼之進行表面再生(注射50 mM HCl 60 s、注射5 mM NaOH 30 s及再注射50 mM HCl 60 s)。將TREM1 ECD分析物(自製,加His標籤)以3倍連續稀釋度注射於HBS-EP+操作緩衝液(GE Healthcare)中,最高濃度顯示於表15中,且進行三倍連續稀釋直至底部濃度為2 nM。包括緩衝液空白注射液以減除儀器雜訊及漂移。
使用1:1結合模型,使用Biacore Insight評估軟體(3.0版)來測定動力學參數。12172 gL2gH11 hIgG4P在此實驗中展示對於人類TREM1具有0.54 nM之親和力(動力學參數概述於表15中)。觀察到食蟹獼猴及恆河猴之極小結合反應,但不足以測定結合動力學。未偵測到12172gL2gH11 hIgG4P與任何其他物種之TREM1的結合(如表16中所概述)。
表 15.12172gL2gH11 hIgG4P與人類TREM1結合之動力學參數
物種 | k a (1/Ms) | k d (1/s) | K D (nM) | n= |
人類 | 1.7E+05 | 9.1E-05 | 0.54 | 1 |
表 16.報告顯示TREM1物種與12172gL2gH11 hIgG4P之結合的點資料。BL指示結合晚期:TREM1注射結束之前的平均信號7.5 - 12.5 s,自此注射開始之前的平均信號7.5 - 12.5 s減去。SE指示早期穩定性:TREM1注射結束之後的平均信號7.5 - 12.5 s自此注射開始之前的平均信號7.5 - 12.5 s減去。理論Rmax為若所有捕獲抗體(150 kDa)完全結合至TREM1之2個分子則將產生之信號。SR_BL為BL除以理論Rmax,SR_SE為SE除以理論Rmax。
實例 8. 藉由 12172gL2gH11 hIgG4P 阻斷 TREM1 / PGLYRP1 相互作用
物種 | 濃度 (nM) | BL (RU) | SE (RU) | 捕獲量 (RU) | TREM1 MW (kDa) | 理論 Rmax (RU) | SR_BL | SR_SE |
人類 | 490 | 78 | 78 | 223 | 21 | 62 | 1.3 | 1.3 |
食蟹獼猴 | 460 | 26 | 16 | 231 | 21 | 65 | 0.4 | 0.3 |
恆河猴 | 450 | 12 | 5 | 229 | 21 | 64 | 0.2 | 0.1 |
狨猴 | 510 | 0 | 0 | 224 | 22 | 66 | 0.0 | 0.0 |
小鼠 | 520 | 0 | 0 | 228 | 21 | 64 | 0.0 | 0.0 |
大鼠 | 470 | 0 | 0 | 233 | 21 | 65 | 0.0 | 0.0 |
豬 | 490 | 0 | 0 | 233 | 22 | 68 | 0.0 | 0.0 |
狗 | 460 | 0 | 0 | 226 | 22 | 66 | 0.0 | 0.0 |
12172gL2gH11 hIgG4P在25℃下在Biacore T200儀器上藉由表面電漿子共振展現阻斷人類TREM1與人類PGLYRP1之間的相互作用。
山羊抗人類IgG亦即Fc片段特異性抗體(F(ab')
2片段,Jackson ImmunoResearch 109-006-098)經由胺偶合化學反應固定於HC30M感測器晶片(XanTec Bioanalytics)之所有四個流通槽上達到約4000 RU之含量。在整個操作中自流通槽2之反應減去流通槽1之反應,類似地在整個操作中自流通槽4之反應減去流通槽3之反應。
各分析循環係由以下組成:將約100 RU之TREM1-Fc (R&D 1278-TR批次GZF0220071)捕獲至流通槽2之表面,將約150 RU 12172gL2gH11 hIgG4P捕獲至流通槽4之表面,且使TREM1 ECD分析物(自製,加His標籤)流經流通槽3及流通槽4之表面持續180 s。使PGLYRP1 (R&D 2590-PGB,NLC1520031)及PGN (Invivogen tlrl-ksspgn批次KSS-41-01)之混合物流經所有表面持續180 s且監測結合,繼之為300 s解離時段。接著再生表面(注射50 mM HCl 60 s、注射5 mM NaOH 30 s及再注射50 mM HCl 60 s)。
12172gL2gH11 hIgG4P在存在及不存在PGN下阻斷PGLYRP1與TREM1之相互作用(參見表17)。
表 17.結合晚期報告點處之相對反應。此在PGLYRP1及PGN之注射期間計算:注射結束之前的平均信號7.5 - 12.5 s自此注射開始之前的平均信號7.5 - 12.5 s減去。接著將此值自無捕獲之配位體之等效循環中之值減去。此展示TREM1-Fc結合5 RU之單獨的PGLYRP1,且其結合12 RU之PGLYPR1及PGN之混合物,然而,PGLYRP1不結合TREM1,其已捕獲至以12172gL2gH11 hIgG4P塗佈之表面。
實例 9 : 藉由結晶學測定人類 PGLYRP1 與人類 TREM1 之結合界面 結晶學
所有流通槽 | 流通槽 2 | 流通槽 4 | ||||
PGLYRP1 濃度 (nM) | PGN 濃度 (µg/ml) | 配位體 | 結合晚期 (RU) | 配位體 | TREM1 之濃度 (nM) | 結合晚期 (RU) |
0 | 0 | TREM1-Fc | 0 | 12172 gL2gH11 hIgG4P | 552 | -1.8 |
30 | 0 | TREM1-Fc | 4.5 | 12172 gL2gH11 hIgG4P | 552 | -1.8 |
0 | 0.55 | TREM1-Fc | -0.5 | 12172 gL2gH11 hIgG4P | 552 | -1.9 |
30 | 0.55 | TREM1-Fc | 11.8 | 12172 gL2gH11 hIgG4P | 552 | -1.7 |
將人類TREM1 IgV域與全長人類PGLYRP1 (1:1莫耳比)在PBS pH 7.0下以15 mg/ml複合且在4℃下培育一小時。將蛋白質以懸滴共結晶,蒸氣擴散由0.2 ul蛋白質及0.2 ul儲集器Molecular Dimensions ProPlex螢幕D7 (15% (w/V) PEG 6000、100mM檸檬酸三鈉/氫氧化鈉pH 5.5)組成。20%乙二醇用於低溫保護。
X 射線繞射、資料收集、結構確定及改進
在APS 21-ID-F處遠端收集低溫(100K) X射線繞射資料。使用XDS對原始資料框進行索引、積分且按比例調整。晶體之空間群為P21,其中單位晶胞參數為:a = 58.68 Å,b= 98.73 Å,c = 60.43 Å,α= 90°,β= 109.145°,γ= 90° (相對於2.55 Å之解析度)。結構之品質參數良好,其中結構之總R因子= 17.9%且自由R因子= 22.9%。在COOT中模型化蛋白質複合物結構且使用PHENIX (包括TLS方案)改進。添加水分子且藉由COOT檢驗。
人類TREM1 IgV域(位置21-139) (SEQ ID NO: 9)與全長PGLYRP1 (SEQ ID NO: 10)複合。儘管等莫耳混合,但晶體複合物之化學計量為1:2,其中單一hTREM1分子結合於二聚合之PGLYRP1分子。使用CCP4程式套中之程式NCONT對人類TREM1與hPGLYRP1之IgV樣域之間的小於或等於4Å的分子間距離進行分析。抗原決定基已以結晶學方式確定如下:殘基E27、D42 - E46、A49、Y90 - L95及F126(位置對應於SEQ ID NO: 1)。圖3A展示hTREM1: PDBPDB 1SMO上PGLYRP1配位體結合位點之結構定位。
實例 10 : 藉由 X 射線結晶學測定 12172 兔親本 Fab 人類 TREM1 抗原決定基 結晶學
為識別12172抗體之確切抗原決定基,使用X射線結晶學。使人類TREM1 IgV域(SEQ ID NO: 9)與兔親本Fab (1:1莫耳比)在PBS pH 7.4中複合且應用於尺寸排阻。將伴護蛋白Fab 11994與hTREM1: Fab複合物以15 mg/ml混合且在4℃下培育一小時。將蛋白質以懸滴共結晶,蒸氣擴散由0.2 ul蛋白質及0.1 ul儲集器Molecular Dimensions ProPlex螢幕A6 (25% (w/V) PEG 1000、200 mM氯化鈉、100 m磷酸氫二鉀/磷酸二氫鈉pH 6.5)組成。20%乙二醇用於低溫保護。
X 射線繞射、資料收集、結構確定及改進
在APS 21-ID-F處遠端收集低溫(100K) X射線繞射資料。使用XDS對原始資料框進行索引、積分且按比例調整。晶體之空間群為I222,其中單位晶胞參數為:a = 91.98 Å,b= 139.10 Å,c = 224.81 Å,α= 90°,β= 90°,γ= 90° (相對於2.60 Å之解析度)。結構之品質參數良好,其中結構之總R因子= 19.3%且自由R因子= 22.6%。在COOT中模型化蛋白質複合物結構且使用PHENIX (包括TLS方案)改進。添加水分子且藉由COOT檢驗。
在伴護蛋白Fab分子(11994)存在下獲得與兔親本Fab (12172) (SEQ ID NO: 19及23)複合之人類TREM1 IgV域(位置21-139) (SEQ ID NO: 9)。使用氫氘交換質譜分析(HDX-MS),已證實用於12172兔親本Fab之結晶學的11994 Fab伴護蛋白不影響12172與TREM1之結合。晶體複合物之化學計量為1:1:1,其中Fab抗原決定基結合於hTREM1分子上之相對側。使用CCP4程式套中之程式NCONT對人類TREM1與Fab 12172之IgV樣域之間的小於或等於4Å的分子間距離進行分析。抗原決定基以晶體學方式確定如下:殘基E26 - K32、Q35、T36、D38、K40、D42、R97、D127、T134及G136 (位置對應於SEQ ID NO: 1)。圖3B展示hTREM1: PDBPDB 1SMO上Fab 12172抗原決定基之結構定位。該抗原決定基經確認與PGLYRP1之抗原決定基不同(參見實例9)。
實例 11. 全長抗體 12172gL2gH11 hIgG4P - 哺乳動物細胞株研發。
為了證明12172gL2gH11 hIgG4P之穩定表現,產生穩定表現型哺乳動物細胞株。用質體載體12172_gL2_ckappa_gH11_IgG4(p)轉染CHO細胞株。將細胞株選殖且評估對適合的製造方法之適用度。為了評估所關注蛋白質之品質及數量以及確保選擇最佳細胞株,在製造分批進料生物反應器之小規模模型中評估細胞株。選擇以可接受含量表現12172gL2gH11 hIgG4P且含有超過95%單體之純系CHO細胞株。
實例 12. 藉由液體層析 - 質譜分析 ( LC - MS ) 表徵抗體分子。
使用具有Xevo G2 Q-ToF質譜儀之Waters ACQUITY UPLC系統藉由LC-MS量測完整分子(非還原性)及單獨重鏈及輕鏈(還原性)兩者上之所產生的12172 gL2gH11 (hIgG4P及hIG1 LALA)以及12172 gL6gH6 (hIgG4P及hIgG1 LALA)抗體分子的分子量(MW)。在37℃下用含5 mM參(2-羧基乙基)膦(TCEP)之150 mM乙酸銨還原樣品(約5 µg) 40分鐘。對於非還原性(完整)量測,將樣品用PBS pH 7.4稀釋至相同濃度且如上培育,隨後分析。LC管柱為Waters BioResolve ™RP mAb聚苯基,450 Å,2.7 µm,保持在80℃下,經95%溶劑A (水/0.02%三氟乙酸(TFA)/0.08%甲酸)及5%溶劑B (95%乙腈/5%水/0.02% TFA/0.08%甲酸)平衡,流速為0.6毫升/分鐘。將蛋白質用自5%至50%溶劑B之梯度經8.8分鐘溶離,繼之以95%溶劑B洗滌及再平衡。在280 nm處獲取UV資料。MS條件如下:離子模式:ESI正離子,解析模式,質量範圍:400-5000m/z及用NaI外部校準。
使用Waters MassLynx™及MaxEnt軟體分析資料。
如表18及表19中所示,根據12172 gL2gH11 (hIgG4P及hIgG1 LALA)以及12172 gL6gH6 (hIgG4P及hIgG1 LALA)抗體分子之序列的預測MW與藉由LC-MS量測之完整分子以及重鏈及輕鏈的MW一致。
表 18. 12172 gL2gH11及12172 gL6gH6 (hIgG4P及hIgG1 LALA)抗體分子之完整(非還原性)LC-MS資料。
移植物 | 型式 | 完整抗體MW (Da ) | ||
預期 | 所觀測 | Δm | ||
12172 gL2gH11 | hIgG4P | 147482.6 | 147485.0 | 2.4 |
hIgG1 LALA | 147624.9 | 147628.0 | 3.1 | |
12172 gL6gH6 | hIgG4P | 147430.6 | 147433.0 | 2.4 |
hIgG1 LALA | 147572.9 | 147578.5 | 5.6 |
表 19. 12172 gL2gH11及12172 gL6gH6 (hIgG4P及hIgG1 LALA)抗體分子之還原性LC-MS資料。
實例 13. 熱穩定性 ( Tm ) 量測。
移植物 | 型式 | 輕鏈MW (Da) | 重鏈MW (Da) | ||||
預期 | 所觀測 | Δm | 預期 | 所觀測 | Δm | ||
12172 gL2gH11 | hIgG4P | 23651.2 | 23650.8 | -0.4 | 50094.1 | 50095.4 | 1.3 |
hIgG1 LALA | 23651.2 | 23650.6 | -0.6 | 50165.3 | 50166.4 | 1.1 | |
12172 gL6gH6 | hIgG4P | 23622.2 | 23621.6 | -0.6 | 50097.1 | 50098.2 | 1.1 |
hIgG1 LALA | 23622.21 | 23621.8 | -0.4 | 50168.3 | 50169.4 | 1.1 |
使用(i)熱轉移分析或(ii)差示掃描熱量測定(DSC)來測定在去摺疊中點處之熔融溫度(Tm)或溫度以評估分子之構形穩定性且因此評估製造穩固性及長期穩定性。
熱轉移分析
基於早期移植物篩選及選擇進行熱轉移分析,參見實例3。
使用螢光染料SYPRO®橙,根據對隨著溫度升高而暴露之疏水區的結合來監測蛋白質去摺疊過程。反應混合物含有5 µL之30x SYPRO®橙蛋白凝膠染色劑(Thermofisher scientific,S6651),用測試緩衝液自5000x濃縮物稀釋。將0.2 mg/mL於常見預調配儲存緩衝液(pH 7.4)中之45 µL樣品添加至染料中且混合。將10 µl之此溶液一式四份分配於384 PCR光學孔盤中且在QuantStudio 7即時PCR系統(Thermofisher™)上運作。PCR系統加熱裝置設定在20℃下且以1.1℃/min之速率升高至99℃。電荷耦合裝置監測孔中的螢光變化。標繪螢光強度之增加,使用斜率之反曲點產生表觀中點溫度(Tm)。資料展示於表11及表12中(參見實例3)。
差示掃描熱量測定 ( DSC )
差示掃描熱量測定用於評估熱穩定性。將所有樣品在400 µL總體積之常見預調配儲存緩衝液(pH 7.4或pH 5.0)中稀釋至10 µM,添加至96孔盤中且以4,000×g離心5分鐘以移除氣泡。將盤在自動化MicroCal VP DSC (Malvern Panalytical)上自10-100℃以1℃/min之速率,用預掃描恆溫器操作15 min,經8s之過濾時段且以被動反饋模式操作。自資料中減去緩衝區,進行手動基線校正且在Origin 7.0中將資料擬合至非2態模型。轉移中點(Tm)及去摺疊起始展示於下表20及圖4中。
IgG4P同型相對於三種轉移擬合,而IgG1 LALA相對於兩種轉移擬合,其中Fab及CH3去摺疊不能區分。對於各同型,熱穩定性在預期範圍內。
表 20.常見預調配儲存緩衝液pH 7.4中12172 gL2gH11及12172 gL6gH6 (hIgG4P及hIgG1 LALA)之熱穩定性資料之概述。Tm1=CH2去摺疊,Tm2=Fab去摺疊,Tm3=CH3去摺疊
實例 14. 實驗等電點 ( pI ) 量測。
移植物 | 型式 | 熱穩定性pH 7.4 ( ℃) | |||
Tm1 | Tm2 | Tm3 | 起始 | ||
gL2gH11 | hIgG4P | 69.94 | 74.30 | 76.84 | 60.93 |
hIgG1 LALA | 72.86 | 80.81 | 65.76 | ||
gL6gH6 | hIgG4P | 69.72 | 74.08 | 76.67 | 61.20 |
hIgG1 LALA | 73.12 | 80.65 | 66.05 |
發現呈hIgG4P型式之12172 gL2gH11及12172 gL6gH6的實驗pI類似。亦觀測到hIgG1 LALA分子之此情況。pI在預期適合於製造步驟及調配物緩衝液之範圍內。不同帶電物種之存在與其他治療分子之觀測結果一致且歸因於常見轉譯後修飾,諸如離胺酸之C端重鏈移除。
實例 15. 疏水相互作用層析 ( HIC ) 。
疏水相互作用層析(HIC)用於量測呈hIgG4P型式之12172 gL2gH11及12172 gL6gH6的疏水性。HIC按增加之疏水性的次序使分子分離。分子在高濃度極性鹽存在下結合於疏水性固定相且隨著鹽濃度降低而解吸附於移動相中。較長之滯留時間等效於較高疏水性。
所有分子均顯示低表觀疏水性(少於15分鐘滯留時間)。12172 gL2gH11與12172 gL6gH6 hIgG4P分子之間不存在有意義的差異。類似地,hIgG1 LALA樣品之疏水性滯留時間不存在有意義的差異。hIgG4P分子展示與對應hIgG1 LALA分子相比稍微較晚的滯留時間。
實例 16. 使用聚乙二醇 ( PEG ) 聚集分析進行溶解度量測。
PEG聚集分析用作高濃度溶解度模擬分析。PEG為非吸附、非變性聚合物,且由於其惰性性質,已用於主要經由排除體積效應來促進蛋白質沈澱。使樣品暴露於增加濃度之PEG 3350;藉由標繪A280 nm處之吸光度測定溶液中剩餘之樣品量。對一半樣品已沈澱之PEG濃度%進行測定產生PEG中點(PEGmdpnt)評分。此評分允許測試分子以表觀天然狀態聚集傾向評級,低PEGmdpnt評分(例如≤ 10)指示天然狀態聚集之傾向更大。
儲備40% PEG 3350 (Merck,202444)溶液(w/v)在常見預調配儲存緩衝液pH 7.4及5.0以及常見預調配緩衝液pH 5.5中製備。藉由ASSIST PLUS液體搬運機器人(INTEGRA 4505)進行連續滴定,產生40%至15.4%範圍內之PEG 3350。為將非平衡沈澱降至最少,樣品製劑係由以1:1體積比混合之抗體及PEG溶液組成。藉由液體搬運機器人將35 µL PEG 3350儲備溶液添加至96孔v底PCR盤(A1至H1)中。將35 µL之2 mg/mL樣品溶液添加至PEG儲備溶液中,產生1 mg/mL測試濃度及20%至7.7%之最終PEG 3350濃度。此溶液藉由自動化緩慢重複移液而混合且在37℃下培育0.5小時以再溶解任何非平衡聚集體。接著,在20℃下培育樣品24小時。隨後以4000×g在20℃下使樣品盤離心1小時。將50 µL上清液分配至UV-Star®半區96孔μClear®微定量盤(Greiner,675801)中。藉由在280 nm處使用FLUOstar ®Omega多偵測微定量盤式讀取器(BMG LABTECH)進行UV分光光度法來測定蛋白質濃度。使用Graphpad prism (7.04版)標繪所得值;自S形劑量-反應(可變斜率)擬合之中點處衍生PEG中點(PEG
mdpnt)評分。
資料展示於表21中,其中較高PEG中點(%)等於較大溶解度。
觀測所測試分子之緩衝液依賴性溶解度。在常見預調配儲存緩衝液pH 7.4中,12172 gL2gH11及12172 gL6gH6之同型(hIgG4P及hIgG1 LALA)均展現低PEG中點評分,指示高濃度下之溶解度低。在常見預調配儲存緩衝液pH 5緩衝液中觀測到增加之PEG中點評分。值得注意地,所有樣品在調配於常見預調配緩衝液pH 5.5中時均展示實質上改良之PEG中點評分。hIgG1 LALA樣品在PEG 3350之最高測試濃度下不沈澱於此緩衝液中。
表 21.常見預調配儲存緩衝液pH 7.4及5.5以及常見預調配緩衝液pH 5.5中12172 gL2gH11及12172 gL6gH6 (hIgG4P及hIgG1 LALA)之PEG聚集分析資料。較高PEG中點% =較大高濃度溶解度。NB*樣品展示在PEG 3350之最低測試濃度(7.7%)下之聚集跡象,因此可能不會產生精確PEG中點。
實例 17. 使用 AC - SINS ( 親和力捕獲自相互作用奈米粒子光譜法 ) 評估蛋白質 - 蛋白質自相互作用。
移植物 | 型式 | 中點% | ||
常見預調配儲存緩衝液 pH7.4 | 常見預調配緩衝液 pH 5.5 | 常見預調配儲存緩衝液 pH 5 | ||
gL2gH11 | hIgG4P | *<7.7 | 13.0 | 10.0 |
hIgG1 LALA | *<7.7 | >20 | 12.2 | |
gL6gH6 | hIgG4P | *<7.7 | 14.4 | 10.7 |
hIgG1 LALA | *<7.7 | >20 | 12.9 |
AC-SINS分析用於藉由測定蛋白質-蛋白質自相互作用傾向來篩選包括12172 gL2gH11及12172 gL6gH6 (呈hIgG4P及hIgG1 LALA;亦參見實例3)之人類化分子的可顯影性,因此告知潛在聚集穩定性。此在常見預調配儲存緩衝液pH 7.4中進行。
對山羊抗人類Fcγ特異性捕獲抗體(Jackson ImmunoResearch)使緩衝液更換成20 mM乙酸鈉pH 4.3,稀釋至0.4 mg/mL,且將50 µL添加至450 µL檸檬酸鹽穩定之20 nm金奈米粒子(TedPella, USA)中,且在室溫下靜置隔夜。將結合之奈米粒子用55 µL PEG甲基醚硫醇(平均Mn = 2,000) (Sigma #729140)阻斷1小時,以21,000×
g離心6分鐘,移除上清液且再懸浮於20 mM乙酸鈉pH4.3中直至最終體積為150 µL。
將抗體樣品在常見預調配儲存緩衝液pH 7.4 (180 µL)中稀釋至22 µg/mL且添加至20 µL模擬上清液及200 µL非特異性全IgG (222 µg/mL)(Jackson ImmunoResearch)中,短暫渦旋且將72 µL添加至96孔盤中。將8 µL奈米粒子添加至各孔(n=4)。在BMG盤式讀取器上自500-600 nm讀取吸光度,擬合於Lorenzian曲線(RShiny)及僅自樣品減去常見預調配儲存緩衝液以得到Δλmax。
資料概述於表22中,其中較高Δλ max (nm)值等於較高蛋白質-蛋白質自相互作用傾向。發現12172 gL2gH11及12172 gL6gH6兩者之hIgG1 LALA分子展示與相應hIgG4P分子相比較低之自相互作用,如較低Δλ max (nm)所示。另外,12172 gL6gH6 (hIgG4P及hIgG1 LALA)分子展示與12172 gL2gH11 (hIgG4P及hIgG1 LALA)分子相比稍低的Δλ max (nm)值。
表 22. 12172 gL2gH11及12172 gL6gH6 (hIgG4P及hIgG1)之自相互作用量測值(AC SINS)。低值=較少蛋白質-蛋白質自相互作用。
實例 18. kD 相互作用參數量測 ( 膠體穩定性 )
移植物 | 型式 | Δλ max (nm) | |
gL2gH11 | hIgG4P | 13.15 | |
hIgG1 LALA | 5.970 | ||
gL6gH6 | hIgG4P | 8.58 | |
hIgG1 LALA | 3.93 |
kD相互作用參數用於評估膠體穩定性,其中正值及負值分別與排斥性及吸引性分子間力相關。
動態光散射(DLS)在DynaPro III盤式讀取器(Wyatt Technology Corp,美國加利福尼亞州聖巴巴拉(Santa Barbara, CA, USA))上進行。將樣品稀釋於常見預調配儲存緩衝液pH 7.4中或使緩衝液更換成常見預調配儲存緩衝液pH 5.0且以1 mg/mL增量自7 mg/mL稀釋至1 mg/mL。選擇含有緩衝液之孔作為溶劑補償且在25℃下進行量測,其中雷射功率設定為20%且啟動自動衰減。各量測值為五次5s掃描重複三次(5×3)的平均值。量測擴散係數(
Dm)且根據以下等式計算相互作用參數(kD),其中
D
0 表示無限稀釋時之擴散係數。
等式:D
0藉由Debye曲線在Y-截距處給出。斜率=kD*D
0。
擴散係數依據蛋白質濃度量測且kD用於評估膠體穩定性,其中正值及負值分別表明排斥性及吸引性分子間力。對於展示吸引力/自締合之樣品,擴散係數隨蛋白質濃度而變大且此以負kD值反映。資料展示於表23中。
與常見預調配儲存緩衝液pH 7.4中所獲得之資料相比,針對常見預調配儲存緩衝液pH 5中之hIgG4P及hIgG1 LALA分子兩者,kD相互作用參數展示為較不負的負值(更為膠體穩定)。hIgG1 LALA分子展示比相應hIgG4P分子更穩定。另外,12172 gL6gH6 (hIgG4P及hIgG1 LALA)分子展現比12172 gL2gH11 (hIgG4P及hIgG1 LALA)稍微更大的膠體穩定性。此資料證實自AC-SINS分析產生之資料(參見實例17)。
表 23. 12172 gL2gH11及12172 gH6gL6 (hIgG4P及hIgG1 LALA)之kD相互作用參數資料。負值愈負=吸引愈大(蛋白質-蛋白質自相互作用愈高)。
實例 19. 機械應力對聚集穩定性之影響 ( 聚集分析 ) 。
移植物 | 型式 | ml/g | |
PBS | Ac pH 5 | ||
gL2gH11 | hIgG4P | -14.7 | -7.6 |
hIgG1 LALA | -10.8 | -5.1 | |
gL6gH6 | hIgG4P | -12.4 | -5.5 |
hIgG1 LALA | -9.8 | -4.1 |
蛋白質在暴露於空氣-液體界面時傾向於去摺疊,其中向疏水環境(空氣)呈現疏水性表面且向親水環境(水)呈現親水性表面。攪拌蛋白質溶液可實現可驅動聚集之大型空氣-液體界面。此分析用以模仿分子在製造(例如超過濾)期間將經受之應力且提供嚴格條件以便試圖區分不同的抗體分子。
常見預調配儲存緩衝液pH 7.4或pH 5中之樣品使用Eppendorf Thermomixer Comfort™藉由渦旋來施加應力。在渦旋之前,使用合適的消光係數(分別對於hIgG1 LALA及hIgG4P為1.42及1.43 Abs 280 nm,1 mg/mL,1 cm路徑長度)將濃度調節至1 mg/mL且使用Varian Cary® 50-Bio分光光度計獲得595 nm下之吸光度以建立零時間讀數。將各樣品再等分至1.5 mL錐形Eppendorf®型加蓋管(3×250 μL)中且在1400 rpm下在25℃下進行渦旋24小時。在使用Varian Cary® 50-Bio分光光度計渦旋後3小時及24小時時量測595 nm下之樣品來監測聚集(濁度)。資料概述於表24中。
12172 gL2gH11及12172 gL6gH6 (hIgG4P及hIgG1 LALA)在渦旋後3小時時在兩種緩衝液(常見預調配儲存緩衝液pH 7.4及pH 5)中展示良好聚集穩定性,亦即在595 nm下未觀測到濁度。在24小時時,有可能區分其中12172 gL2gH11及12172 gL6gH6 (hIgG1 LALA)與兩種緩衝液中之相應hIgG4P分子相比展示更大聚集穩定性的分子。對於hIgG4P分子,在pH 7.4下之常見預調配物儲存緩衝液中與在pH 5下相比觀測到更大聚集穩定性。將設想12172 gL2gH11及12172 gL6gH6 (作為hIgG4P及hIgG1 LALA)在製造期間對剪應力條件(例如超濾)將為聚集穩定的。
表 24.空氣-液體界面處(在595 nm下之濁度)之應力對常見預調配物儲存緩衝液pH 7.4及pH 5中之12172 gL2gH11及12172 gL6gH6 (hIgG4P及hIgG1)的影響。
實例 20. 12172 gL2gH11 ( hIgG4P 及 hIgG1 LALA ) 在不同濃度下之黏度評估。
移植物 | 型式 | OD 595nm | |||
pH 7.4 | pH 5 | ||||
3h | 24h | 3h | 24h | ||
gL2gH11 | hIgG4P | 0.06 | 0.87 | 0.21 | 1.48 |
hIgG1 LALA | 0.00 | 0.06 | 0.00 | 0.06 | |
gL6gH6 | hIgG4P | 0.01 | 0.67 | 0.20 | 1.68 |
hIgG1 LALA | 0.00 | 0.13 | 0.01 | 0.03 |
高抗體濃度下之低黏度對於皮下投與治療分子而言為重要的,因此獲得在常見預調配緩衝液pH 5中濃度提高時之黏度以評估用於皮下投與之適合性。此對於12172 gL2gH11 (hIgG4P及hIgG1 LALA)加以測定。
研究藉由(i)初始濃度之樣品及(ii)如下詳述之黏度量測來進行。
12172 gL2gH11 ( hIgG4P 及 hIgG1 LALA ) 之濃度。
在20℃下使用Vivaspin 20 MWCO 30kDa離心過濾器(Z14637,Sigma-Aldrich)以4000×g濃縮常見預調配儲存緩衝液pH 5.0中之12 mL 12172 gL2gH11 hIgG4P (15.2 mg/mL)及11 mL 12172 gL2 gH11 IgG1 LALA (15.5 mg/mL)。將樣品離心直至獲得約750 µL之體積。回收滯留物溶液且使用UV吸光度量測(NanoDrop
TM1000)在280 nm處測定所得抗體濃度。使用12172gL2gH11 hIgG4P之1.43 mL/(mg cm)及12172 gL2gH11 IgG1 LALA之1.42 mL/(mg cm)消光係數。
接著使用常見預調配儲存緩衝液pH 5.0稀釋抗體樣品,得到適合於黏度測試之一系列濃度。藉由在280 nm處再量測UV吸光度來確認經稀釋之抗體的濃度。發現12172 gL2gH11 hIgG4P之濃度為158 mg/mL、94 mg/mL及52 mg/mL,且12172 gL2gH11 hIgG1 LALA之濃度為144 mg/mL、100 mg/mL及45 mg/mL。
12172 gL2gH11 ( hIgG4P 及 hIgG1 LALA ) 之黏度量測。
各濃度下之黏度係使用Discovery Hybrid Rheometer-1 (DHR-1,TA Instruments),利用帕耳帖盤(Peltier plate)及液體冷卻系統進行溫度控制及20 mm不鏽鋼平行盤幾何結構進行量測來量測。將樣品(80 μL)置放於帕爾貼盤之中心上,且在自2.87918至287.918 s
- 1之不同剪切速率下在設定於20℃下之穩態流掃描程序下量測黏度(以mPa·s或cP為單位)。當各剪切速率點處之值恆定(SD±5%)時,求量測之黏度之平均值。使用儀器量測不同濃度下之12172 gL2gH11 hIgG4P及12172 hIgG1 LALA分子,以觀測黏度關於樣品濃度之變化。結果概述於表25中。
12172 gL2gH11 hIgG4P及12172 hIgG1 LALA分子均展示濃度與黏度係數之間的增加趨勢。對於12172 hIgG4P,黏度自1.2 cP增加至4.1 cP,而濃度自52 mg/mL增加至158 mg/ml。類似地,IgG1 LALA分子之黏度自1.4 cP增加至5.4 cP,而濃度自45 mg/mL增加至144 mg/ml。所有此等樣品在不同剪切速率下展示恆定黏度係數(變化率小於5%)。此結果顯示,12172 hIgG4P及12172 hIgG1 LALA在較高濃度下展現低黏度水準,且因此可設想適於皮下投與。
表 25.在20℃下在常見預調配儲存緩衝液pH 5中之12172 gL2gH11 (hIgG4P及hIgG1 LALA)在不同濃度下的平均黏度(厘泊(cP))。
實例 21. 使用人類 TREM1 THP1 NF - κ B 報導細胞株評估 12172 gL2gH11 hIgG4P 之功能活性
gL2gH11 IgG4P | gL2gH11 IgG1 LALA | ||
濃度(mg/mL) | 黏度(cP) | 濃度(mg/mL) | 黏度(cP) |
52 | 1.2 | 45 | 1.4 |
94 | 2.1 | 100 | 2.4 |
158 | 4.1 | 144 | 5.4 |
此研究之目的為評估12172 gL2gH11 hIgG4P經由人類TREM1抑制PGLYRP1/PGN介導的NF-κB信號傳導活化之能力。為此,使用THP1單核球TREM1/DAP12 NF-κB螢光素酶報導細胞。此等細胞穩定地表現人類TREM1、人類DAP12及NF-κB螢光素酶報導基因。PGLYRP1與來自大腸桿菌之可溶性肽聚糖(PGN)複合,用作TREM1配位體,其藉由結合於TREM1來誘導NF-κB活化。不與TREM1結合之PGN亦誘導NF-κB活化,但在較低程度上且經由替代性信號傳導路徑誘導。螢光素酶活性之抑制表明此系統中12172 gL2gH11 hIgG4P之功能性阻斷活性。
使用標準組織培養技術將THP1單核球TREM1/DAP12 NF-κB螢光素酶報導細胞在含有選擇抗生素(RPMI + 10% FBS + 50 µM 2-巰基乙醇+ 10 µg/ml殺稻瘟菌素+ 1 µg/ml嘌呤黴素+ 200 µg/ml遺傳黴素)之完全培養基中培養。在分析設定之前三天,將細胞在平坦置放於培育箱中之T175燒瓶中之50 ml完全培養基(200,000個細胞/毫升)中以10×10
6個細胞接種。在分析當天,自燒瓶移出細胞且轉移至50 ml法爾康(falcon)且以300×g離心五分鐘。移除培養基且將細胞再懸浮於5-10 ml完全培養基中且計數。接著藉由添加細胞懸浮液至完全培養基來以1×10
6個細胞/毫升再懸浮細胞,且將10 µl/孔添加至分析盤(Corning #3570)。將12172 gL2gH11 hIgG4P在384孔稀釋盤(Greiner #781281)中之完全培養基中連續稀釋直至最終分析濃度範圍為33.3 nM至1.69 pM。接著將12172 gL2gH11 hIgG4P之連續稀釋液轉移至分析盤(10 µl/孔)且在37℃/5% CO
2下培育分析盤1小時。將重組人類PGLYRP1 (R&D Systems #2590-PGB)與PGN (Invivogen #tlrl-ksspgn)在室溫下在無菌DPBS中複合一小時。在一小時之後,在完全培養基中稀釋溶液,接著轉移至分析盤(10 µl/孔)直至2.5 µg/ml PGLYRP1及10 µg/ml PGN之最終分析濃度。盤對照(未添加抗體)分別包括PGLYRP1/PGN複合物及單獨PGN作為分析最大值及最小值。接著將分析盤在37℃/5% CO
2下培育16小時±2小時。在培育之後,使用SteadyGlo螢光素酶分析系統(Promega #E2520)量測螢光素酶活性。根據製造商說明書製備Steady-Glo試劑且將30 µl/孔添加至分析盤中。將盤接著以200×g離心三分鐘且接著在室溫下再培育兩分鐘,以使得用SteadyGlo試劑之總培育時間為五分鐘。接著使用Synergy Neo 2盤式讀取器量測發光且使用原始發光值以確定相比於對照孔之相對抑制百分比。使用ActivityBase v9.4進行4PL曲線擬合及IC
50值之計算。
表 26.12172 gL2gH11 hIgG4P之效能、功效及希爾斜率值之概述
*根據三個獨立實驗計算值。
實例 22. 12172 抗體在阻斷 TREM1 介導之自初級人類單核球釋放促炎性細胞介素及趨化介素方面的功效及效能
幾何平均IC 50(pM) ± SD | 平均Emax (%) ± SD | 平均斜率± SD | N* |
64 ± 36 | 72 ± 4 | 2.1 ± 0.9 | 3 |
為了評估抗TREM1 12172變異抗體阻斷TREM1信號傳導之能力,在12172抗體處理之後量測促炎性細胞介素及趨化介素自活化初級人類單核球之釋放。藉由負向選擇自健康人類供體之冷凍保存周邊血液單核細胞(PBMC)分離單核球(Miltenyi,130-117-337)。藉由流式細胞測量術評估單核球存活率及純度,且超過≥ 90%。將單核球以5×10
4個細胞/孔之密度接種於96孔盤(Falcon)中且用來自枯草桿菌(
Bacillus subtilis)之預複合肽聚糖(PGN-BS;3 µg/ml;Invivogen,tlrl-pgnb3)及重組人類肽聚糖識別蛋白1 (PGLYRP1;1 µg/ml;R&D Systems,2590-PGB)刺激以活化TREM1。24小時後收集細胞上清液以藉由均相時間解析螢光
®技術(HTRF
®;Cisbio)量測促炎性細胞介素釋放(TNF-α、IL-6、IL-1β)。
如
表 27中所示,12172 gL2gH11 hIgG4P變異體在抑制TREM1介導之自初級人類單核球釋放TNF-α (幾何平均IC
50= 15 pM)、IL-6 (幾何平均IC
50= 27 pM)及IL-1β (幾何平均IC
50= 5 pM)方面為最有效的。如
圖 5中所示,在整個供體中觀測到12172 gL2gH11 hIgG4P在初級人類單核球中之效能。
為進一步評估抗TREM1 12172變異抗體在阻斷TREM1介導之促炎性細胞介素及趨化介素釋放方面之能力,使用以下兩種多重免疫分析定量地分析來自用抗TREM1抗體(1 nM)處理且用預複合PGN-BS/PGLYRP1活化之初級人類單核球的上清液:MILLIPLEX
®人類細胞介素/趨化介素/生長因子面板A (Merck Millipore,HCYTA-60K-PX48)及定製LegendPlex面板(Biolegend)。
如
表 28中所示,在不同12172抗體變異體情況下抑制TREM1很大程度上減少多種細胞介素及趨化介素(CCL-3、CCL-20、CXCL-9、G-CSF、GM-CSF、IFN-γ、IL-1α、IL-1β、IL-6、IL-10、IL-12p40、IL-15、IL-18、IL-27、TNF-α、TNF-β)自活化初級人類單核球(n=4個供體)之釋放。12172 gL2gH11 hIgG4P變異體為抑制百分比值在57%-110%之間變化的最有效12172變異體。如
圖 6中所示,12172 gL2gH11 hIgG4P顯著增加供體中IL-1R拮抗劑(IL-1RA) (IL-1路徑之負調節劑)自初級單核球之釋放。IL-1RA與嚴重全身性自體免疫疾病以單基因方式(引起低IL-1RA含量之突變)相關。已在ALS患者中識別出IL-1RN (編碼IL-1RA)的單核苷酸多型性。較高循環IL-1RA含量與ALS之較低風險顯著相關(Yuan等人 2020 Eur J Neurol)。相比於健康對照,AD患者之腦脊髓液中的IL-1RA含量亦顯著降低(Tarkowski等人 2001 Dement Geriatr Cogn Disord)。相比於12172 gL2gH11 hIgG4P,先前技術抗TREM1抗體(0318-IgG1.3f)對IL-1RA自初級單核球之釋放無影響。
表 27.不同12172變異體對TNF-α、IL-6及IL-1β釋放之效力
TNF-α (n = 4) | IL-6 (n = 4) | IL-1β (n = 2) | |
描述 | 幾何平均IC50 (pM) | 幾何平均IC50 (pM) | 幾何平均IC50 (pM) |
12172 gL2gH11 hIgG4P | 15 | 27 | 5 |
12172 gL6gH6 hIgG4P | 26 | 36 | 28 |
12172 gL2gH11 hIgG1 LALA | 43 | 112 | 32 |
12172 gL6gH6 hIgG1 LALA | 54 | 178 | 25 |
表 28.不同12172抗體變異體對細胞介素及趨化介素之釋放的功效(抑制百分比)
實例 23 : 12172 gL2gH11 hIgG4P 在增加 IL - 1RA 自未經刺激之初級人類單核球釋放方面的功效及效力
12172 gL2gH11 hIgG4P | 12172 gL6gH6 hIgG4P | 12172 gL2gH11 hIgG1 LALA | 12172 gL6gH6 hIgG1 LALA | ||
CCL-3 | 57 | 38 | 48 | 26 | |
CCL-20 | 69 | 56 | 65 | 66 | |
CXCL-9 | 77 | 73 | 72 | 68 | |
G-CSF | 92 | 88 | 89 | 86 | |
GM-CSF | 91 | 89 | 91 | 89 | |
IFN-γ | 59 | 57 | 60 | 53 | |
IL-1α | 110 | 107 | 112 | 110 | |
IL-1β | 98 | 96 | 96 | 97 | |
IL-6 | 64 | 57 | 58 | 55 | |
IL-10 | 86 | 83 | 77 | 73 | |
IL-12p40 | 96 | 96 | 96 | 95 | |
IL-15 | 78 | 69 | 86 | 92 | |
IL-18 | 87 | 78 | 85 | 81 | |
IL-27 | 81 | 57 | 88 | 74 | |
TNF-α | 94 | 93 | 94 | 94 | |
TNF-β | 65 | 63 | 62 | 60 |
已觀測到12172 gL2gH11 hIgG4P顯著增加IL-1RA自經TREM1配位體刺激之人類單核球的釋放,亦評估其對IL-1RA自未經刺激之人類單核球釋放的影響。如先前實例22中所述分離且接種人類單核球,且添加抗體維持24小時,隨後收集上清液以使用IL-1RA Quantikine ELISA套組(R&D Systems)進行IL-1RA量測。
如
表 29及
圖 7中所示,12172 gL2gH11 hIgG4P以劑量依賴性方式增加未經刺激之初級人類單核球中IL-1RA之釋放。相比於12172 gL2gH11 hIgG4P,另一先前技術抗TREM1抗體(0318-IgG1.3f)對IL-1RA自未經刺激之初級人類單核球釋放無影響。
表 29 :12172 gL2gH11 hIgG4P及0318-IgG1.3f在增加IL-1RA自未經刺激之初級人類單核球釋放方面的功效及效力。
* n.d.=不可偵測
實例 24. 12172 gL2gH11 hIgG4P 在阻斷 TREM1 介導之自 阿茲海默氏病 ( AD ) 及肌肉萎縮性脊髓側索硬化症 ( ALS ) 患者之 PBMC 釋放促炎性細胞介素及趨化介素方面的功效
12172 gL2gH11 hIgG4P | 0318-IgG1.3f | |||
增加 % | IC50 (pM) | 增加% | IC50 (pM) | |
供體A | n.d. | n.d. | ||
供體B | 50 | 54 | n.d. | |
供體C | 83 | 624 | n.d. | |
供體D | 35 | 30 | n.d. |
AD及ALS中之神經退化及神經發炎與患者之CSF及血液中之多種促炎性細胞介素及趨化介素之含量升高相關。舉例而言,在ALS患者之血液中TNF-α、IL-6及IL-1β之含量顯著增加(Hu等人 2017 Sci Rep),同時在ALS患者之CSF中CCL-3、G-CSF及TNF-α升高(Chen等人 2018 Front Immunol),吾人觀測到之所有因子均因人類單核球中之TREM1抑制而減少。
為評估抗TREM1 12172 gL2gH11 hIgG4P阻斷患者源細胞中之TREM1信號傳導的功效,在TREM1活化之後量測來自AD及ALS患者之PBMC中促炎性細胞介素及趨化介素的釋放。藉由密度梯度離心自AD及ALS患者之全血及對應匹配的健康對照分離PBMC。將PBMC以1×10
5個細胞/孔之密度接種於96孔盤(Falcon)中,用12172 gL2gH11 hIgG4P (1 nM)預處理1小時且用來自枯草桿菌之預複合肽聚糖(PGN-BS;3 µg/ml;Invivogen,tlrl-pgnb3)及重組人類肽聚糖識別蛋白1 (PGLYRP1;1 µg/ml;R&D Systems,2590-PGB)刺激以活化TREM1。24小時後收集細胞上清液以使用均相時間解析螢光
®技術(HTRF
®;Cisbio)及MILLIPLEX
®人類細胞介素/趨化介素/生長因子面板A (Merck Millipore,HCYTA-60K-PX48)量測促炎性細胞介素及趨化介素釋放。
如圖8及表30中所示,12172 gL2gH11 hIgG4P有效抑制TREM1介導之自AD患者之PBMC的TNF-α釋放(抑制率為66% ± 15)及IL-6釋放(70% ± 17)。如圖9及表31中所示,12172 gL2gH11 hIgG4P亦有效抑制TREM1介導之自ALS患者之PBMC的TNF-α釋放(抑制率為72% ± 7)及IL-6釋放(69% ± 9)。如圖10中所示,使用12172 gL2gH11 hIgG4P對TREM1之抑制亦在很大程度上減少多種細胞介素及趨化介素(CCL-3、CCL-4、CCL-20、CCL-22、CXCL-9、G-CSF、GM-CSF、GRO-α、IL-1α、IL-1β、IL-6、IL-10、IL-12p40、TNF-α)自ALS PBMC(代表n=4個供體)及AD PBMC(代表n=5個供體)之釋放。
表 30 :12172 gL2gH11 hIgG4P在自健康對照及AD PBMC釋放TNF-α及IL-6方面之功效。
TNF-α | IL-6 | |||
抑制% | S.D. | 抑制% | S.D. | |
健康對照(HC) n = 8 | 79 | 16 | 85 | 18 |
阿茲海默氏病(AD) n = 8 | 66 | 15 | 70 | 17 |
表 31 :12172 gL2gH11 hIgG4P在自健康對照及ALS PBMC釋放TNF-α及IL-6方面之功效。
實例 25. 在用 TREM1 配位體複合物或凋亡 iPSC 衍生之人類運動神經元刺激及用 12172 抗體變異體處理之後 , 人類單核球之轉錄概況
TNF-α | IL-6 | |||
抑制% | S.D. | 抑制% | S.D. | |
健康對照(HC) n = 4 | 59 | 13 | 56 | 19 |
肌肉萎縮性脊髓側索硬化症(ALS) n = 4 | 72 | 7 | 69 | 9 |
為進一步表徵抗TREM1 12172抗體變異體之細胞概況,對經TREM1配位體複合物或凋亡誘導性富潛能幹細胞(iPSC)衍生之人類運動神經元(一種ALS疾病相關配位體)刺激之人類單核球進行轉錄組分析。藉由負向選擇自健康人類供體(n = 8)之冷凍保存周邊血液單核細胞(PBMC)分離單核球(Miltenyi,130-117-337)。藉由流式細胞測量術評估單核球存活率及純度,且超過≥ 90%。將單核球以2×10
6個細胞/孔之密度接種於6孔盤(Falcon)中且用12172抗體變異體(1 nM)預處理1小時。接著將單核球用以下刺激4小時:(i)用來自枯草桿菌之預複合肽聚糖(PGN-BS;3 µg/ml;Invivogen,tlrl-pgnb3)及重組人類肽聚糖識別蛋白1 (PGLYRP1;1 µg/ml;R&D Systems,2590-PGB)刺激以活化TREM1,或(ii)用紫外光誘導之凋亡iPSC衍生之人類運動神經元刺激。使用RNeasy Plus Mini套組(Qiagen)分離RNA且使用Experion™ RNA分析套組(Bio-Rad)評估RNA品質。使用NEBNext Ultra II Directional RNA庫製備型套組(New England BioLabs)製備定序庫且使用Illumina NovaSeq6000定序樣品。
如圖11 (A及B)及表32中所示,在TREM1配位體複合物刺激之後,在12172 gL2gH11及12172 gL6gH6之hIgG4P型式下觀測到最高數目的顯著差異化表現基因(DEG)。在頂部DEG中,兩個12172 hIgG4P抗體亦展示類似轉錄組概況(例如
HERC5、
OAS1、
DDX58、
TNF - α下調)。此等概況與先前技術抗TREM1抗體(0318-IgG1.3f) (圖11C)形成對比。另外,如表33中所示,與經0318-IgG1.3f處理之單核球相比,經12172 gL2gH11 hIgG4P處理之單核球中存在111個顯著上調之基因及121個顯著下調之基因。
表 32.考慮到0.05之偽發現率(FDR),在用12172抗體變異體處理人類單核球及用TREM1配位體複合物刺激之後的差異化表現基因(DEG)之數目(相比於配位體或同型對照)。
經上調之基因 | 經下調之基因 | ||||
Ab/配位體 | Ab/同型 | Ab/配位體 | Ab/同型 | ||
12172 gL2gH11 | hIgG4P | 6 | 19 | 4 | 86 |
hIgG1 LALA | 0 | 0 | 0 | 0 | |
12172 gL6gH6 | hIgG4P | 20 | 71 | 63 | 255 |
hIgG1 LALA | 9 | 10 | 47 | 9 | |
0318-IgG1.3f | 9 | 99 | 38 | 82 |
表 33.考慮到0.05之FDR,在用TREM1配位體複合物刺激人類單核球之後的12172 gL2gH11 hIgG4P與0318-IgG1.3f之間的DEG數目。
12172 gL2gH11 hIgG4P:0318-IgG1.3f | |
經上調之基因 | 經下調之基因 |
111 | 121 |
如圖12 (A及B)及表34中所示,相較於TREM1配位體複合物刺激,用凋亡iPSC衍生之人類運動神經元刺激之後的DEG數目更高。在頂部DEG中,兩個12172 hIgG4P抗體展示一些重疊,包括例如
CCR2下調及
IL - 1RN(編碼IL-1RA之基因)上調。相比之下,頂部DEG在先前技術抗TREM1抗體(0318-IgG1.3f)情況下不同(圖12C)且在此抗體情況下未觀測到
IL - 1RN顯著上調。另外,如表35中所示,與經0318-IgG1.3f處理之單核球相比,經12172 gL2gH11 hIgG4P處理之單核球中存在598個顯著上調之基因及808個顯著下調之基因。
表 34.考慮到0.05之FDR,在用12172抗體變異體處理人類單核球及用凋亡iPSC衍生之人類運動神經元刺激之後的DEG數目(相比於配位體或同型對照)。
經上調之基因 | 經下調之基因 | ||||
Ab/配位體 | Ab/同型 | Ab/配位體 | Ab/同型 | ||
12172 gL2gH11 | hIgG4P | 420 | 221 | 453 | 151 |
hIgG1 LALA | 563 | 64 | 728 | 19 | |
12172 gL6gH6 | hIgG4P | 484 | 183 | 253 | 69 |
hIgG1 LALA | 836 | 280 | 725 | 29 | |
0318-IgG1.3f | 674 | 623 | 545 | 139 |
表 35.考慮到0.05之FDR,在用凋亡iPSC衍生之人類運動神經元刺激人類單核球之後的12172 gL2gH11 hIgG4P與0318-IgG1.3f之間的DEG數目。
實例 26. 12172 抗體在阻斷 TREM1 介導之初級人類單核球及嗜中性白血球的吞噬作用及活性含氧物 ( ROS ) 生產方面之功效
12172 gL2gH11 hIgG4P:0318-IgG1.3f | |
經上調之基因 | 經下調之基因 |
598 | 808 |
為評估阻斷TREM1信號傳導對抗微生物免疫反應之影響,藉由流式細胞測量術評估全血中活化初級人類單核球及嗜中性白血球之吞噬作用及ROS生產兩者。為檢驗ROS產生,將二氫羅丹明-123 (5 µg/ml)添加至健康人類供體之血液(25 µl)中持續5分鐘,之後再與12172 gL2gH11 hIgG4P或0318-IgG1.3f抗體(10 µg/ml)一起預培育30分鐘。接著將全血樣品與1×10
6個mCherry表現細菌一起培養1小時。洗滌樣品,用CD45及CD14表面抗體染色以藉由流式細胞測量術區分嗜中性白血球及單核球。
如圖13中所示,12172 gL2gH11 hIgG4P變異體不削弱嗜中性白血球或單核球之細菌清除,亦不影響其產生活性含氧物之能力。相比之下,0318-IgG1.3f之分析揭示藉由嗜中性白血球及單核球產生的大腸桿菌誘導之ROS顯著減少。兩種免疫細胞類型之吞噬能力均不受0318-IgG1.3f顯著影響。
實例 27 : 12172 抗體在阻斷 TREM1 介導之脾臟酪胺酸激酶 ( SYK ) 活化方面的功效及效力
TREM1與其轉接蛋白DAP-12之締合引起DAP-12磷酸化及後續脾臟酪胺酸激酶之募集及磷酸化(SYK;Carrasco等人 2018 Cell Mol Immunol)。SYK先前已涉及驅動TREM1介導之神經發炎性損傷(Xu等人 2019 Cell Death Dis)且已知在澱粉樣蛋白-β沈積及病理性tau蛋白物質形成之後活化(Schweig等人 2017 Acta Neuropathol Commun)。為評估抗TREM1 12172變異抗體阻斷TREM1介導之SYK活化的能力,量測穩定表現人類TREM1及人類DAP-12之Flp-In™ 293細胞中的磷酸化SYK (pSYK)含量。將細胞以25,000個細胞/孔之密度接種於384孔盤(Greiner)中,用12172變異抗體或同型抗體預處理1小時且用來自大腸桿菌之預複合肽聚糖(PGN-EC;5 µg/ml;Invivogen,tlrl-pgnb3)及重組人類肽聚糖識別蛋白1 (PGLYRP1;2.5 µg/ml;R&D Systems,2590-PGB)刺激以活化TREM1。30分鐘後收集蛋白質裂解物以使用AlphaLISA SureFire Ultra p-SYK (Tyr525/526)分析套組
®(PerkinElmer)量測pSYK含量。
如
表 36及圖
14中所示,所有四種12172變異抗體在TREM1活化之後在阻斷SYK活化方面均有效(Emax = 57-72%)且強效(357-1015 pM),而A33同型抗體未展示活性。
表 36.12172變異抗TREM1抗體在阻斷hTREM1/hDAP-12 Flp-In 293細胞中之SYK活化方面的功效及效能(ND-不可偵測)
實例 28 : 12172 gL2gH11 hIgG4P 細胞表面 TREM1 親和力量測
hTREM1/hDAP-12 Flp-In 293 :pSYK 抑制 | ||
描述 | Emax (%) | IC50 (pM) |
12172 gL2gH11 hIgG4P | 63 | 1015 |
12172 gL6gH6 hIgG4P | 57 | 357 |
12172 gL2gH11 hIgG1 LALA | 72 | 372 |
12172 gL6gH6 hIgG1 LALA | 79 | 960 |
A33 hIgG1 | ND | ND |
A33 hIgG4P | ND | ND |
在25℃下使用LigandTracer量測表現於活細胞上之12172 gL2gH11 hIgG4P與人類或食蟹獼猴TREM1結合的動力學。內部研發出兩個HEK293多株細胞株以表現人類或食蟹獼猴TREM1,且將親本正常黏附HEK293用作對照細胞。所有三種細胞類型均維持在補充有胎牛血清(Invitrogen,10082)、GlutaMAX (Gibco,35050061)之生長培養基DMEM (Gibco,21969-035)中,且為維持TREM1多株細胞株之選擇,另外包括0.5 mg/ml遺傳黴素(Gibco,10131-027)。在實驗前一天,將1.4×10
6個細胞接種於先前根據製造商說明塗佈有聚D-離胺酸(Gibco,A38904-01)之LigandTracer MultiDish 2 × 2 (Ridgeview,1-04-204-5)之各四分之一中,且在37℃/5% CO
2下培育隔夜。將表現TREM1之細胞接種於各皿隔室之四分之一中且在另一隔室中接種陰性表現對照細胞。次日早晨,在各皿隔室(一半)中將培養基更換為確切1.8 ml新製生長培養基(不含遺傳黴素),且置於LigandTracer儀器中。開始旋轉以記錄基線讀數持續約20分鐘或直至穩定。停止旋轉且以0.5 nM之濃度添加經AlexaFluor647標記之12172 gL2gH11 hIgG4P(自製),濃度接近預期12172 gL2gH11 hIgG4P K
D。重新開始旋轉,且記錄表示抗體與細胞之即時結合的螢光量測值直至曲率指示觀測到平衡度(耗費約2小時)。以此方式,在1.5 nM及5 nM下再進行兩次抗體添加,每次均比上一次高約3倍。最後,移除所有含有抗體之培養基,且用新製培養基置換。持續旋轉及量測直至解離信號下降至少10%,或若解離緩慢,則持續隔夜。在LigandTracer 「TraceDrawer」軟體(1.9.2版)內分析親和力量測值且計算。12172 gL2gH11 hIgG4P與表現TREM1之細胞結合的原始資料讀數首先藉由減去與對照細胞結合的等效讀數進行正規化。使用該軟體之1:1結合模型評估減去之跡線。若1:1模型並不適用於資料跡線,則考慮替代模型。12172 gL2gH11 hIgG4P展示出對於人類TREM1具有16.5 pM之親和力及對於獼猴TREM1具有約300倍較弱之較弱親和力。動力學參數概述於
表 37 及表 38中。12172 gL2gH11 hIgG4P展示由1:1模型充分表示之結合。LigandTracer儀器難以量測緩慢解離速率,趨向精確範圍之限值,但五次重複實驗得到了類似資料。12172 gL2gH11 hIgG4P與食蟹獼猴TREM1之結合明顯更為複雜且不適應1:1結合模型。1:2模型或1:1-二狀態模型更好地表示資料且得到類似親和力值(並未展示所有資料),但將需要其他實驗以確定此等替代模型中之何者恰當地適合描述該結合。然而,一般而言,12172 gL2gH11 hIgG4P對食蟹獼猴TREM1之親和力與對人類TREM1之親和力相比明顯降低了約300倍。總之,由於對細胞之結合親合力,與可溶性人類TREM1 ECD (實例6)相比,12172gL2gH11 hIgG4P顯示對細胞表面人類TREM1之較強親和力,兩種方法(Biacore及LigandTracer)展示與人類TREM1相比,12172gL2gH11 hIgG4P對食蟹獼猴TREM1之親和力顯著較弱。
表 37.12172 gL2gH11 hIgG4P與人類TREM1結合之動力學參數。U值表示擬合模型相對於資料之品質。小於10%之低U值被視為良好擬合,值>20%被視為不佳。
1:1 擬合模型 | ka (1/(M*s)) | kd (1/s) | K D(pM) | U 值:kd (%) |
N=1 | 3.50E+05 | 6.80E-06 | 19.4 | 3.6 |
N=2 | 3.56E+05 | 8.89E-06 | 25.0 | 4.3 |
N=3 | 2.44E+05 | 3.71E-06 | 15.2 | 10.4 |
N=4 | 2.38E+05 | 2.97E-06 | 12.5 | 3.8 |
N=5 | 4.43E+05 | 5.88E-06 | 13.3 | 5.7 |
平均值 | 3.26E+05 | 5.65E-06 | 17.1 | |
SD | 8.61E+04 | 2.39E-06 | 5.2 | |
幾何平均值 | 3.17E+05 | 5.23E-06 | 16.5 |
表 38.12172 gL2gH11 hIgG4P與食蟹獼猴TREM1結合之動力學參數。U值表示擬合模型相對於資料之品質。小於10%之低U值被視為良好擬合,值>20%被視為不佳。1:2模型產生兩組親和力值,描述兩種促成結合事件。
1:2 擬合模型 | ka 1 (1/(M*s)) | kd 1 (1/s) | K D1 (pM) | ka 2 (1/(M*s)) | kd 2 (1/s) | K D2 (pM) | U 值:kd (%) |
N=1 | 8.87E+05 | 7.58E-03 | 8550 | 1.08E+05 | 8.69E-06 | 80.8 | 17.7 |
N=2 | 3.12 E+05 | 1.84 E-03 | 5910 | 7.27 E+04 | 3.08 E-05 | 423 | 4 |
N=3 | 4.69E+05 | 1.92E-03 | 4090 | 5.97E+04 | 3.13E-05 | 524 | 3.6 |
N=4 | 3.00 E+05 | 1.78 E-03 | 5940 | 5.97 E+04 | 2.36 E-06 | 39.5 | 11.8 |
N=5 | 7.06 E+05 | 1.90 E-03 | 2690 | 3.27 E+04 | 4.03 E-06 | 124 | 6.5 |
平均值 | 6.78E+05 | 4.75E-03 | 5436 | 8.39E+04 | 2.00E-05 | 238 | |
SD | 2.96E+05 | 4.00E-03 | 2210 | 3.42E+04 | 1.60E-05 | 220 | |
幾何平均值 | 6.45E+05 | 3.81E-03 | 5055 | 8.03E+04 | 1.65E-05 | 154 |
本文中所引用之所有參考文獻(包括專利案、專利申請案、論文、教科書及其類似物)及其中引用的參考文獻(就尚未引用而言)以全文引用之方式併入本文中。
下文中藉由參考以下圖式來描述本發明,其中:
圖 1展示抗體12172輕鏈之人類化。亦展示所產生之該鏈之不同變異體。CDR序列加有下劃線。
圖 2展示抗體12172重鏈之人類化。亦展示所產生之該鏈之不同變異體。CDR序列加有下劃線。
圖 3A 及圖 3B展示人類TREM1結合於PGLYRP1及12172兔Fab之晶體結構。(3A)人類TREM1結合於PGLYRP1之晶體結構。具有屬於PGLYRP1之任一原子在4埃內之原子的TREM1殘基以黑色突出顯示。(3B)人類TREM1結合於12172兔Fab之晶體結構。具有屬於12172之任一原子在4埃內之原子的TREM1殘基以黑色突出顯示。
圖 4展示12172抗體之不同變異體之熱穩定性。在常見預調配儲存緩衝液pH7.4中量測12172 gL2gH11及12172 gL6gH6 (hIgG4P及hIgG1 LALA)之熱分析圖。
圖 5展示對TREM1介導之藉由12172 gL2gH11 hIgG4P自初級人類單核球釋放TNF-α、IL-6及IL-1β的抑制。
圖 6展示藉由各種12172變異體及參考抗體自初級人類單核球釋放IL-1R拮抗劑的增加。
圖 7展示12172 gL2gH11 hIgG4P及0318-IgG1.3f在自未經刺激之初級人類單核球增加IL-1RA釋放方面的效應。
圖 8展示12172 gL2gH11 hIgG4P在自健康對照及阿茲海默氏病(AD) PBMC釋放TNF-α及IL-6方面之功效。
圖 9展示12172 gL2gH11 hIgG4P在自健康對照及ALS PBMC釋放TNF-α及IL-6方面之功效。
圖 10展示12172 gL2gH11 hIgG4P在自ALS及AD PBMC釋放促炎性細胞介素及趨化介素方面之功效。
圖 11A - 圖 11C展示火山圖,其示出在用12172抗體變異體(11A及11B)或0318-IgG1.3f (11C)處理人類單核球及用TREM1配位體複合物刺激之後的差異性表現基因(DEG)(考慮0.05之FDR)(相比於同型對照)。
圖 12A - 圖 12C展示火山圖,其示出在用12172抗體變異體(12A及12B)或0318-IgG1.3f (12C)處理人類單核球及用凋亡、人類iPSC衍生之運動神經元刺激之後的DEG(考慮0.05之FDR)(相比於同型對照)。
圖 13展示12172 gL2gH11 hIgG4P不影響活體外人類嗜中性白血球及單核球對大腸桿菌(
E. coli)之清除。資料代表12172 gL2gH11 hIgG4P v同種型之3個個別供體及包括0318-IgG1.3f (Ab 318)分子之一個供體用於比較。進行統計分析,亦即單因子變異數分析Dunnet事後檢驗以比較針對同型對照****之抗TREM1抗體(p<0.0001)
圖 14展示12172抗體變異體在hTREM1/hDAP-12 Flp-In 293細胞中阻斷SYK活化方面之功效及效力。
<![CDATA[<110> 比利時商UCB生物製藥公司(UCB Biopharma SRL)]]> <![CDATA[<120> 抗體]]> <![CDATA[<130> PF0303-TW-NP]]> <![CDATA[<150> US 63/183,280]]> <![CDATA[<151> 2022-05-03]]> <![CDATA[<160> 294 ]]> <![CDATA[<170> PatentIn version 3.5]]> <![CDATA[<210> 1]]> <![CDATA[<211> 234]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 1]]> Met Arg Lys Thr Arg Leu Trp Gly Leu Leu Trp Met Leu Phe Val Ser 1 5 10 15 Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys 20 25 30 Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe 35 40 45 Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro 50 55 60 Lys Thr Leu Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val 65 70 75 80 Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu 85 90 95 Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln 100 105 110 Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg 115 120 125 Ile Arg Leu Val Val Thr Lys Gly Phe Ser Gly Thr Pro Gly Ser Asn 130 135 140 Glu Asn Ser Thr Gln Asn Val Tyr Lys Ile Pro Pro Thr Thr Thr Lys 145 150 155 160 Ala Leu Cys Pro Leu Tyr Thr Ser Pro Arg Thr Val Thr Gln Ala Pro 165 170 175 Pro Lys Ser Thr Ala Asp Val Ser Thr Pro Asp Ser Glu Ile Asn Leu 180 185 190 Thr Asn Val Thr Asp Ile Ile Arg Val Pro Val Phe Asn Ile Val Ile 195 200 205 Leu Leu Ala Gly Gly Phe Leu Ser Lys Ser Leu Val Phe Ser Val Leu 210 215 220 Phe Ala Val Thr Leu Arg Ser Phe Val Pro 225 230 <![CDATA[<210> 2]]> <![CDATA[<211> 214]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 2]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Lys Gly Phe Ser Gly Thr Pro Gly Ser Asn Glu Asn Ser Thr 115 120 125 Gln Asn Val Tyr Lys Ile Pro Pro Thr Thr Thr Lys Ala Leu Cys Pro 130 135 140 Leu Tyr Thr Ser Pro Arg Thr Val Thr Gln Ala Pro Pro Lys Ser Thr 145 150 155 160 Ala Asp Val Ser Thr Pro Asp Ser Glu Ile Asn Leu Thr Asn Val Thr 165 170 175 Asp Ile Ile Arg Val Pro Val Phe Asn Ile Val Ile Leu Leu Ala Gly 180 185 190 Gly Phe Leu Ser Lys Ser Leu Val Phe Ser Val Leu Phe Ala Val Thr 195 200 205 Leu Arg Ser Phe Val Pro 210 <![CDATA[<210> 3]]> <![CDATA[<211> 225]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 3]]> Met Arg Lys Thr Arg Leu Trp Gly Leu Leu Trp Met Leu Phe Val Ser 1 5 10 15 Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys 20 25 30 Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe 35 40 45 Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro 50 55 60 Lys Thr Leu Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val 65 70 75 80 Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu 85 90 95 Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln 100 105 110 Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg 115 120 125 Ile Arg Leu Val Val Thr Lys Gly Phe Ser Gly Thr Pro Gly Ser Asn 130 135 140 Glu Asn Ser Thr Gln Asn Val Tyr Lys Ile Pro Pro Thr Thr Thr Lys 145 150 155 160 Ala Leu Cys Pro Leu Tyr Thr Ser Pro Arg Thr Val Thr Gln Ala Pro 165 170 175 Pro Lys Ser Thr Ala Asp Val Ser Thr Pro Asp Ser Glu Ile Asn Leu 180 185 190 Thr Asn Val Thr Asp Ile Ile Arg Tyr Ser Phe Gln Val Pro Gly Pro 195 200 205 Leu Val Trp Thr Leu Ser Pro Leu Phe Pro Ser Leu Cys Ala Glu Arg 210 215 220 Met 225 <![CDATA[<210> 4]]> <![CDATA[<211> 150]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 4]]> Met Arg Lys Thr Arg Leu Trp Gly Leu Leu Trp Met Leu Phe Val Ser 1 5 10 15 Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys 20 25 30 Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe 35 40 45 Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro 50 55 60 Lys Thr Leu Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val 65 70 75 80 Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu 85 90 95 Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln 100 105 110 Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg 115 120 125 Ile Arg Leu Val Val Thr Lys Gly Phe Arg Cys Ser Thr Leu Ser Phe 130 135 140 Ser Trp Leu Val Asp Ser 145 150 <![CDATA[<210> 5]]> <![CDATA[<211> 233]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 恆河獼猴]]> <![CDATA[<400> 5]]> Met Arg Lys Thr Arg Leu Trp Gly Leu Leu Trp Met Leu Phe Val Ser 1 5 10 15 Glu Leu Arg Ala Thr Thr Glu Leu Thr Glu Glu Lys Tyr Glu Tyr Lys 20 25 30 Glu Gly Gln Thr Leu Glu Val Lys Cys Asp Tyr Ala Leu Glu Lys Tyr 35 40 45 Ala Asn Ser Arg Lys Ala Trp Gln Lys Met Glu Gly Lys Met Pro Lys 50 55 60 Ile Leu Ala Lys Thr Glu Arg Pro Ser Glu Asn Ser His Pro Val Gln 65 70 75 80 Val Gly Arg Ile Thr Leu Glu Asp Tyr Pro Asp His Gly Leu Leu Gln 85 90 95 Val Gln Met Thr Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys 100 105 110 Val Ile Tyr Gln His Pro Lys Glu Ser His Val Leu Phe Asn Pro Ile 115 120 125 Cys Leu Val Val Thr Lys Gly Ser Ser Gly Thr Pro Gly Ser Ser Glu 130 135 140 Asn Ser Thr Gln Asn Val Tyr Arg Thr Pro Ser Thr Thr Ala Lys Ala 145 150 155 160 Leu Gly Pro Arg Tyr Thr Ser Pro Arg Thr Val Thr Gln Ala Pro Pro 165 170 175 Glu Ser Thr Val Val Val Ser Thr Pro Gly Ser Glu Ile Asn Leu Thr 180 185 190 Asn Val Thr Asp Ile Ile Arg Val Pro Val Phe Asn Ile Val Ile Ile 195 200 205 Val Ala Gly Gly Phe Leu Ser Lys Ser Leu Val Phe Ser Val Leu Phe 210 215 220 Ala Val Thr Leu Arg Ser Phe Gly Pro 225 230 <![CDATA[<210> 6]]> <![CDATA[<211> 196]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 6]]> Met Ser Arg Arg Ser Met Leu Leu Ala Trp Ala Leu Pro Ser Leu Leu 1 5 10 15 Arg Leu Gly Ala Ala Gln Glu Thr Glu Asp Pro Ala Cys Cys Ser Pro 20 25 30 Ile Val Pro Arg Asn Glu Trp Lys Ala Leu Ala Ser Glu Cys Ala Gln 35 40 45 His Leu Ser Leu Pro Leu Arg Tyr Val Val Val Ser His Thr Ala Gly 50 55 60 Ser Ser Cys Asn Thr Pro Ala Ser Cys Gln Gln Gln Ala Arg Asn Val 65 70 75 80 Gln His Tyr His Met Lys Thr Leu Gly Trp Cys Asp Val Gly Tyr Asn 85 90 95 Phe Leu Ile Gly Glu Asp Gly Leu Val Tyr Glu Gly Arg Gly Trp Asn 100 105 110 Phe Thr Gly Ala His Ser Gly His Leu Trp Asn Pro Met Ser Ile Gly 115 120 125 Ile Ser Phe Met Gly Asn Tyr Met Asp Arg Val Pro Thr Pro Gln Ala 130 135 140 Ile Arg Ala Ala Gln Gly Leu Leu Ala Cys Gly Val Ala Gln Gly Ala 145 150 155 160 Leu Arg Ser Asn Tyr Val Leu Lys Gly His Arg Asp Val Gln Arg Thr 165 170 175 Leu Ser Pro Gly Asn Gln Leu Tyr His Leu Ile Gln Asn Trp Pro His 180 185 190 Tyr Arg Ser Pro 195 <![CDATA[<210> 7]]> <![CDATA[<211> 263]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> CID101904 hTREM1_1-200-Avi-Tev-HKH]]> <![CDATA[<400> 7]]> Met Arg Lys Thr Arg Leu Trp Gly Leu Leu Trp Met Leu Phe Val Ser 1 5 10 15 Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys 20 25 30 Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe 35 40 45 Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro 50 55 60 Lys Thr Leu Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val 65 70 75 80 Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu 85 90 95 Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln 100 105 110 Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg 115 120 125 Ile Arg Leu Val Val Thr Lys Gly Phe Ser Gly Thr Pro Gly Ser Asn 130 135 140 Glu Asn Ser Thr Gln Asn Val Tyr Lys Ile Pro Pro Thr Thr Thr Lys 145 150 155 160 Ala Leu Cys Pro Leu Tyr Thr Ser Pro Arg Thr Val Thr Gln Ala Pro 165 170 175 Pro Lys Ser Thr Ala Asp Val Ser Thr Pro Asp Ser Glu Ile Asn Leu 180 185 190 Thr Asn Val Thr Asp Ile Ile Arg Leu Glu Gly Gly Gly Ser Gly Gly 195 200 205 Ser Gly Gly Leu Asn Asp Ile Phe Glu Ala Gln Lys Ile Glu Trp His 210 215 220 Glu Asn Leu Tyr Phe Gln Gly Gly Ser His His His His His His Lys 225 230 235 240 Ala Lys Gly Ser Lys Gly Lys Gly Ser Lys Lys Ala Gly His His His 245 250 255 His His His His His His His 260 <![CDATA[<210> 8]]> <![CDATA[<211> 264]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> CID101953 cTREM1_1-201-Avi-Tev-HKH]]> <![CDATA[<400> 8]]> Met Arg Lys Thr Arg Leu Trp Gly Leu Leu Trp Met Leu Phe Val Ser 1 5 10 15 Glu Leu Arg Ala Thr Thr Glu Leu Thr Glu Glu Lys Tyr Glu Tyr Lys 20 25 30 Glu Gly Gln Thr Leu Glu Val Lys Cys Asp Tyr Ala Leu Glu Lys Tyr 35 40 45 Ala Asn Ser Arg Lys Ala Trp Gln Lys Met Glu Gly Lys Met Pro Lys 50 55 60 Ile Leu Ala Lys Thr Glu Arg Pro Ser Glu Asn Ser His Pro Val Gln 65 70 75 80 Val Gly Arg Ile Thr Leu Glu Asp Tyr Pro Asp His Gly Leu Leu Gln 85 90 95 Val Arg Met Thr Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys 100 105 110 Val Ile Tyr Gln His Pro Lys Glu Ser His Val Leu Phe Asn Pro Ile 115 120 125 Cys Leu Val Val Thr Lys Gly Ser Ser Gly Thr Pro Gly Ser Ser Glu 130 135 140 Asn Ser Thr Gln Asn Val Tyr Arg Thr Pro Ser Thr Thr Ala Lys Ala 145 150 155 160 Leu Gly Pro Arg Tyr Thr Ser Pro Arg Thr Val Thr Gln Ala Pro Pro 165 170 175 Glu Ser Thr Val Val Val Ser Thr Pro Gly Ser Glu Ile Asn Leu Thr 180 185 190 Asn Val Thr Asp Ile Ile Arg Val Pro Leu Glu Gly Gly Gly Ser Gly 195 200 205 Gly Ser Gly Gly Leu Asn Asp Ile Phe Glu Ala Gln Lys Ile Glu Trp 210 215 220 His Glu Asn Leu Tyr Phe Gln Gly Gly Ser His His His His His His 225 230 235 240 Lys Ala Lys Gly Ser Lys Gly Lys Gly Ser Lys Lys Ala Gly His His 245 250 255 His His His His His His His His 260 <![CDATA[<210> 9]]> <![CDATA[<211> 215]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> CID101907 hTREM1 IgV (His-Smt-TREM1_21-139)]]> <![CDATA[<400> 9]]> Met Gly His His His His His His Ser Gly Glu Val Lys Pro Glu Val 1 5 10 15 Lys Pro Glu Thr His Ile Asn Leu Lys Val Ser Asp Gly Ser Ser Glu 20 25 30 Ile Phe Phe Lys Ile Lys Lys Thr Thr Pro Leu Arg Arg Leu Met Glu 35 40 45 Ala Phe Ala Lys Arg Gln Gly Lys Glu Met Asp Ser Leu Arg Phe Leu 50 55 60 Tyr Asp Gly Ile Arg Ile Gln Ala Asp Gln Thr Pro Glu Asp Leu Asp 65 70 75 80 Met Glu Asp Asn Asp Ile Ile Glu Ala His Arg Glu Gln Ile Gly Gly 85 90 95 Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 100 105 110 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 115 120 125 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 130 135 140 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 145 150 155 160 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 165 170 175 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 180 185 190 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 195 200 205 Val Thr Lys Gly Phe Ser Gly 210 215 <![CDATA[<210> 10]]> <![CDATA[<211> 202]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> CID101951 hPGLYRP1_1-196-His]]> <![CDATA[<400> 10]]> Met Ser Arg Arg Ser Met Leu Leu Ala Trp Ala Leu Pro Ser Leu Leu 1 5 10 15 Arg Leu Gly Ala Ala Gln Glu Thr Glu Asp Pro Ala Cys Cys Ser Pro 20 25 30 Ile Val Pro Arg Asn Glu Trp Lys Ala Leu Ala Ser Glu Cys Ala Gln 35 40 45 His Leu Ser Leu Pro Leu Arg Tyr Val Val Val Ser His Thr Ala Gly 50 55 60 Ser Ser Cys Asn Thr Pro Ala Ser Cys Gln Gln Gln Ala Arg Asn Val 65 70 75 80 Gln His Tyr His Met Lys Thr Leu Gly Trp Cys Asp Val Gly Tyr Asn 85 90 95 Phe Leu Ile Gly Glu Asp Gly Leu Val Tyr Glu Gly Arg Gly Trp Asn 100 105 110 Phe Thr Gly Ala His Ser Gly His Leu Trp Asn Pro Met Ser Ile Gly 115 120 125 Ile Ser Phe Met Gly Asn Tyr Met Asp Arg Val Pro Thr Pro Gln Ala 130 135 140 Ile Arg Ala Ala Gln Gly Leu Leu Ala Cys Gly Val Ala Gln Gly Ala 145 150 155 160 Leu Arg Ser Asn Tyr Val Leu Lys Gly His Arg Asp Val Gln Arg Thr 165 170 175 Leu Ser Pro Gly Asn Gln Leu Tyr His Leu Ile Gln Asn Trp Pro His 180 185 190 Tyr Arg Ser Pro His His His His His His 195 200 <![CDATA[<210> 11]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> CDRL1]]> <![CDATA[<400> 11]]> Gln Ala Ser Gln Asn Ile Gly Ser Asp Leu Ala 1 5 10 <![CDATA[<210> 12]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> CDRL2]]> <![CDATA[<400> 12]]> Lys Ala Ala Thr Leu Ala Ser 1 5 <![CDATA[<210> 13]]> <![CDATA[<211> 14]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> CDRL3]]> <![CDATA[<400> 13]]> Gln Gln Tyr Tyr Tyr Gly Ser Ala Gly Ala Asp Thr Asp Thr 1 5 10 <![CDATA[<210> 14]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> CDRH1]]> <![CDATA[<400> 1]]>4 Gly Phe Ser Leu Ser Ser Tyr Ala Met Thr 1 5 10 <![CDATA[<210> 15]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> CDRH2]]> <![CDATA[<400> 15]]> Ile Ile Tyr Ala Gly Gly Ser Pro Ser Tyr Ala Ser Trp Ala Lys Gly 1 5 10 15 <![CDATA[<210> 16]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> CDRH3]]> <![CDATA[<400> 16]]> Gly Thr Gly Asp Thr Val Tyr Thr Tyr Phe Asn Ile 1 5 10 <![CDATA[<210> 17]]> <![CDATA[<211> 112]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 兔Ab 12172 VL區]]> <![CDATA[<400> 17]]> Ala Val Val Leu Thr Gln Thr Ala Ser Pro Val Ser Ala Pro Val Gly 1 5 10 15 Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Gln Asn Ile Gly Ser Asp 20 25 30 Leu Ala Trp Tyr Gln Gln Glu Pro Gly Gln Pro Pro Lys Leu Leu Ile 35 40 45 Tyr Lys Ala Ala Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Lys Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Gly Val Gln Cys 65 70 75 80 Glu Asp Gly Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Tyr Gly Ser Ala 85 90 95 Gly Ala Asp Thr Asp Thr Phe Gly Gly Gly Thr Glu Val Val Val Lys 100 105 110 <![CDATA[<210> 18]]> <![CDATA[<211> 336]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 兔Ab 12172 VL區]]> <![CDATA[<400> 18]]> gccgtcgtgc tgacccagac tgcatccccc gtgtctgcac ctgtgggagg cacagtcacc 60 atcaagtgcc aggccagtca gaacattggt agcgacttag cctggtatca gcaggaacca 120 gggcagccac ccaagctcct gatctacaag gcagccactc tggcatctgg ggtcccatcg 180 cggttcaaag gcagtggatc tgggacagag ttcactctca ccatcagtgg cgtgcagtgt 240 gaagatggtg ccacttacta ctgtcaacag tattattatg gtagtgctgg tgctgatacg 300 gatactttcg gcggagggac cgaggtggtg gtcaaa 336 <![CDATA[<210> 19]]> <![CDATA[<211> 216]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> CID102770:兔Ab 12172輕鏈(Fab)]]> <![CDATA[<400> 19]]> Ala Val Val Leu Thr Gln Thr Ala Ser Pro Val Ser Ala Pro Val Gly 1 5 10 15 Gly Thr Val Thr Ile Lys Cys Gln Ala Ser Gln Asn Ile Gly Ser Asp 20 25 30 Leu Ala Trp Tyr Gln Gln Glu Pro Gly Gln Pro Pro Lys Leu Leu Ile 35 40 45 Tyr Lys Ala Ala Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Lys Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Gly Val Gln Cys 65 70 75 80 Glu Asp Gly Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Tyr Gly Ser Ala 85 90 95 Gly Ala Asp Thr Asp Thr Phe Gly Gly Gly Thr Glu Val Val Val Lys 100 105 110 Arg Thr Pro Val Ala Pro Thr Val Leu Ile Phe Pro Pro Ala Ala Asp 115 120 125 Gln Val Ala Thr Gly Thr Val Thr Ile Val Cys Val Ala Asn Lys Tyr 130 135 140 Phe Pro Asp Val Thr Val Thr Trp Glu Val Asp Gly Thr Thr Gln Thr 145 150 155 160 Thr Gly Ile Glu Asn Ser Lys Thr Pro Gln Asn Ser Ala Asp Cys Thr 165 170 175 Tyr Asn Leu Ser Ser Thr Leu Thr Leu Thr Ser Thr Gln Tyr Asn Ser 180 185 190 His Lys Glu Tyr Thr Cys Lys Val Thr Gln Gly Thr Thr Ser Val Val 195 200 205 Gln Ser Phe Asn Arg Gly Asp Cys 210 215 <![CDATA[<210> 20]]> <![CDATA[<211> 648]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 兔Ab 12172輕鏈]]> <![CDATA[<400> 20]]> gccgtcgtgc tgacccagac tgcatccccc gtgtctgcac ctgtgggagg cacagtcacc 60 atcaagtgcc aggccagtca gaacattggt agcgacttag cctggtatca gcaggaacca 120 gggcagccac ccaagctcct gatctacaag gcagccactc tggcatctgg ggtcccatcg 180 cggttcaaag gcagtggatc tgggacagag ttcactctca ccatcagtgg cgtgcagtgt 240 gaagatggtg ccacttacta ctgtcaacag tattattatg gtagtgctgg tgctgatacg 300 gatactttcg gcggagggac cgaggtggtg gtcaaacgta cgccagttgc acctactgtc 360 ctcatcttcc caccagctgc tgatcaggtg gcaactggaa cagtcaccat cgtgtgtgtg 420 gcgaataaat actttcccga tgtcaccgtc acctgggagg tggatggcac cacccaaaca 480 actggcatcg agaacagtaa aacaccgcag aattctgcag attgtaccta caacctcagc 540 agcactctga cactgaccag cacacagtac aacagccaca aagagtacac ctgcaaggtg 600 acccagggca cgacctcagt cgtccagagc ttcaataggg gtgactgt 648 <![CDATA[<210> 21]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 兔Ab 12172 VH區]]> <![CDATA[<400> 21]]> Gln Ser Leu Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro 1 5 10 15 Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Ser Tyr Ala 20 25 30 Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly 35 40 45 Ile Ile Tyr Ala Gly Gly Ser Pro Ser Tyr Ala Ser Trp Ala Lys Gly 50 55 60 Arg Phe Thr Ile Ser Lys Thr Ser Thr Thr Val Asp Leu Lys Met Thr 65 70 75 80 Ser Pro Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Gly Thr 85 90 95 Gly Asp Thr Val Tyr Thr Tyr Phe Asn Ile Trp Gly Pro Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <![CDATA[<210> 22]]> <![CDATA[<211> 351]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 兔Ab 12172 VH區]]> <![CDATA[<400> 22]]> cagtcgctgg aggagtccgg gggtcgcctg gtcacgcctg ggacacccct gacactcacc 60 tgcacagcct ctggattctc cctcagtagc tatgcaatga cctgggtccg ccaggctcca 120 gggaaggggc tggaatggat cggaatcatt tatgctggtg gtagcccatc ctacgcgagc 180 tgggcgaaag gccgattcac catctccaaa acctcgacca cggtggatct gaaaatgacc 240 agtccgacaa ccgaggacac ggccacctat ttctgtgcca gagggactgg tgatactgtt 300 tatacctact ttaatatttg gggcccaggc accctggtca ccgtctcgag t 351 <![CDATA[<210> 23]]> <![CDATA[<211> 220]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> CID120769:兔Ab 12172重鏈(Fab)]]> <![CDATA[<400> 23]]> Gln Ser Leu Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro 1 5 10 15 Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Ser Tyr Ala 20 25 30 Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly 35 40 45 Ile Ile Tyr Ala Gly Gly Ser Pro Ser Tyr Ala Ser Trp Ala Lys Gly 50 55 60 Arg Phe Thr Ile Ser Lys Thr Ser Thr Thr Val Asp Leu Lys Met Thr 65 70 75 80 Ser Pro Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Gly Thr 85 90 95 Gly Asp Thr Val Tyr Thr Tyr Phe Asn Ile Trp Gly Pro Gly Thr Leu 100 105 110 Val Thr Val Ser Ser Gly Gln Pro Lys Ala Pro Ser Val Phe Pro Leu 115 120 125 Ala Pro Cys Cys Gly Asp Thr Pro Ser Ser Thr Val Thr Leu Gly Cys 130 135 140 Leu Val Lys Gly Tyr Leu Pro Glu Pro Val Thr Val Thr Trp Asn Ser 145 150 155 160 Gly Thr Leu Thr Asn Gly Val Arg Thr Phe Pro Ser Val Arg Gln Ser 165 170 175 Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Ser Val Thr Ser Ser Ser 180 185 190 Gln Pro Val Thr Cys Asn Val Ala His Pro Ala Thr Asn Thr Lys Val 195 200 205 Asp Lys Thr Val Ala Pro Ser Thr Cys Ser Lys Pro 210 215 220 <![CDATA[<210> 24]]> <![CDATA[<211> 660]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 兔Ab 12172重鏈(Fab)]]> <![CDATA[<400> 24]]> cagtcgctgg aggagtccgg gggtcgcctg gtcacgcctg ggacacccct gacactcacc 60 tgcacagcct ctggattctc cctcagtagc tatgcaatga cctgggtccg ccaggctcca 120 gggaaggggc tggaatggat cggaatcatt tatgctggtg gtagcccatc ctacgcgagc 180 tgggcgaaag gccgattcac catctccaaa acctcgacca cggtggatct gaaaatgacc 240 agtccgacaa ccgaggacac ggccacctat ttctgtgcca gagggactgg tgatactgtt 300 tatacctact ttaatatttg gggcccaggc accctggtca ccgtctcgag tgggcaacct 360 aaggctccat cagtcttccc actggccccc tgctgcgggg acacacccag ctccacggtg 420 accctgggct gcctggtcaa aggctacctc ccggagccag tgaccgtgac ctggaactcg 480 ggcaccctca ccaatggggt acgcaccttc ccgtccgtcc ggcagtcctc aggcctctac 540 tcgctgagca gcgtggtgag cgtgacctca agcagccagc ccgtcacctg caacgtggcc 600 cacccagcca ccaacaccaa agtggacaag accgttgcgc cctcgacatg cagcaagccc 660 <![CDATA[<210> 25]]> <![CDATA[<211> 112]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gL1 V區]]> <![CDATA[<400> 25]]> Ala Val Val Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asn Ile Gly Ser Asp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Lys Ala Ala Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Tyr Gly Ser Ala 85 90 95 Gly Ala Asp Thr Asp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110 <![CDATA[<210> 26]]> <![CDATA[<211> 336]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gL1 V區]]> <![CDATA[<400> 26]]> gccgtggtgc tgactcagtc cccctccttc ctgagcgcct cagtgggaga tcgcgtgacc 60 atcacctgtc aagccagcca gaacattggg tccgacttgg cctggtatca gcagaagcct 120 ggcaaagcgc cgaagctgct gatctacaag gccgctactc tcgcgtcggg agtgccatcc 180 cggttttccg gttcgggaag cgggaccgag ttcaccctta ccatttcctc gctccaaccg 240 gaggacttcg ccacgtacta ctgccagcag tactactacg gttcagccgg agcagacact 300 gataccttcg gcggaggcac caaggtcgaa atcaag 336 <![CDATA[<210> 27]]> <![CDATA[<211> 219]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gL1輕鏈]]> <![CDATA[<400> 27]]> Ala Val Val Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asn Ile Gly Ser Asp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Lys Ala Ala Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Tyr Gly Ser Ala 85 90 95 Gly Ala Asp Thr Asp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 145 150 155 160 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <![CDATA[<210> 28]]> <![CDATA[<211> 657]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gL1輕鏈]]> <![CDATA[<400> 28]]> gccgtggtgc tgactcagtc cccctccttc ctgagcgcct cagtgggaga tcgcgtgacc 60 atcacctgtc aagccagcca gaacattggg tccgacttgg cctggtatca gcagaagcct 120 ggcaaagcgc cgaagctgct gatctacaag gccgctactc tcgcgtcggg agtgccatcc 180 cggttttccg gttcgggaag cgggaccgag ttcaccctta ccatttcctc gctccaaccg 240 gaggacttcg ccacgtacta ctgccagcag tactactacg gttcagccgg agcagacact 300 gataccttcg gcggaggcac caaggtcgaa atcaagcgta cggtagcggc cccatctgtc 360 ttcatcttcc cgccatctga tgagcagttg aaatctggaa ctgcctctgt tgtgtgcctg 420 ctgaataact tctatcccag agaggccaaa gtacagtgga aggtggataa cgccctccaa 480 tcgggtaact cccaggagag tgtcacagag caggacagca aggacagcac ctacagcctc 540 agcagcaccc tgacgctgag caaagcagac tacgagaaac acaaagtcta cgcctgcgaa 600 gtcacccatc agggcctgag ctcgcccgtc acaaagagct tcaacagggg agagtgt 657 <![CDATA[<210> 29]]> <![CDATA[<211> 112]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gL2 V區]]> <![CDATA[<400> 29]]> Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asn Ile Gly Ser Asp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Lys Ala Ala Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Tyr Gly Ser Ala 85 90 95 Gly Ala Asp Thr Asp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110 <![CDATA[<210> 30]]> <![CDATA[<211> 336]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gL2 V區]]> <![CDATA[<400> 30]]> gacatccagc tgactcagtc cccctccttc ctgagcgcct cagtgggaga tcgcgtgacc 60 atcacctgtc aagccagcca gaacattggg tccgacttgg cctggtatca gcagaagcct 120 ggcaaagcgc cgaagctgct gatctacaag gccgctactc tcgcgtcggg agtgccatcc 180 cggttttccg gttcgggaag cgggaccgag ttcaccctta ccatttcctc gctccaaccg 240 gaggacttcg ccacgtacta ctgccagcag tactactacg gttcagccgg agcagacact 300 gataccttcg gcggaggcac caaggtcgaa atcaag 336 <![CDATA[<210> 31]]> <![CDATA[<211> 219]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gL2輕鏈]]> <![CDATA[<400> 31]]> Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asn Ile Gly Ser Asp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Lys Ala Ala Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Tyr Gly Ser Ala 85 90 95 Gly Ala Asp Thr Asp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 145 150 155 160 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <![CDATA[<210> 32]]> <![CDATA[<211> 657]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gL2輕鏈]]> <![CDATA[<400> 32]]> gacatccagc tgactcagtc cccctccttc ctgagcgcct cagtgggaga tcgcgtgacc 60 atcacctgtc aagccagcca gaacattggg tccgacttgg cctggtatca gcagaagcct 120 ggcaaagcgc cgaagctgct gatctacaag gccgctactc tcgcgtcggg agtgccatcc 180 cggttttccg gttcgggaag cgggaccgag ttcaccctta ccatttcctc gctccaaccg 240 gaggacttcg ccacgtacta ctgccagcag tactactacg gttcagccgg agcagacact 300 gataccttcg gcggaggcac caaggtcgaa atcaagcgta cggtggccgc tccctccgtg 360 ttcatcttcc caccctccga cgagcagctg aagtccggca ccgcctccgt cgtgtgcctg 420 ctgaacaact tctacccccg cgaggccaag gtgcagtgga aggtggacaa cgccctgcag 480 tccggcaact cccaggaatc cgtcaccgag caggactcca aggacagcac ctactccctg 540 tcctccaccc tgaccctgtc caaggccgac tacgagaagc acaaggtgta cgcctgcgaa 600 gtgacccacc agggcctgtc cagccccgtg accaagtcct tcaaccgggg cgagtgc 657 <![CDATA[<210> 33]]> <![CDATA[<211> 112]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gL6 V區]]> <![CDATA[<400> 33]]> Asp Ile Val Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asn Ile Gly Ser Asp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Lys Ala Ala Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Tyr Gly Ser Ala 85 90 95 Gly Ala Asp Thr Asp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110 <![CDATA[<210> 34]]> <![CDATA[<211> 336]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gL6 V區]]> <![CDATA[<400> 34]]> gacatcgtgc tgactcagtc cccctccttc ctgagcgcct cagtgggaga tcgcgtgacc 60 atcacctgtc aagccagcca gaacattggg tccgacttgg cctggtatca gcagaagcct 120 ggcaaagcgc cgaagctgct gatctacaag gccgctactc tcgcgtcggg agtgccatcc 180 cggttttccg gttcgggaag cgggaccgag ttcaccctta ccatttcctc gctccaaccg 240 gaggacttcg ccacgtacta ctgccagcag tactactacg gttcagccgg agcagacact 300 gataccttcg gcggaggcac caaggtcgaa atcaag 336 <![CDATA[<210> 35]]> <![CDATA[<211> 219]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gL6輕鏈]]> <![CDATA[<400> 35]]> Asp Ile Val Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asn Ile Gly Ser Asp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Lys Ala Ala Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Tyr Gly Ser Ala 85 90 95 Gly Ala Asp Thr Asp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 145 150 155 160 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <![CDATA[<210> 36]]> <![CDATA[<211> 657]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gL6輕鏈]]> <![CDATA[<400> 36]]> gacatcgtgc tgactcagtc cccctccttc ctgagcgcct cagtgggaga tcgcgtgacc 60 atcacctgtc aagccagcca gaacattggg tccgacttgg cctggtatca gcagaagcct 120 ggcaaagcgc cgaagctgct gatctacaag gccgctactc tcgcgtcggg agtgccatcc 180 cggttttccg gttcgggaag cgggaccgag ttcaccctta ccatttcctc gctccaaccg 240 gaggacttcg ccacgtacta ctgccagcag tactactacg gttcagccgg agcagacact 300 gataccttcg gcggaggcac caaggtcgaa atcaagcgta cggtggccgc tccctccgtg 360 ttcatcttcc caccctccga cgagcagctg aagtccggca ccgcctccgt cgtgtgcctg 420 ctgaacaact tctacccccg cgaggccaag gtgcagtgga aggtggacaa cgccctgcag 480 tccggcaact cccaggaatc cgtcaccgag caggactcca aggacagcac ctactccctg 540 tcctccaccc tgaccctgtc caaggccgac tacgagaagc acaaggtgta cgcctgcgaa 600 gtgacccacc agggcctgtc cagccccgtg accaagtcct tcaaccgggg cgagtgc 657 <![CDATA[<210> 37]]> <![CDATA[<211> 112]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gL9 V區]]> <![CDATA[<400> 37]]> Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Ser Val Thr Ile Thr Cys Gln Ala Ser Gln Asn Ile Gly Ser Asp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Lys Ala Ala Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Tyr Gly Ser Ala 85 90 95 Gly Ala Asp Thr Asp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110 <![CDATA[<210> 38]]> <![CDATA[<211> 336]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gL9 V區]]> <![CDATA[<400> 38]]> gacatccagc tgactcagtc cccctccttc ctgagcgcct cagtgggaga tagcgtgacc 60 atcacctgtc aagccagcca gaacattggg tccgacttgg cctggtatca gcagaagcct 120 ggcaaagcgc cgaagctgct gatctacaag gccgctactc tcgcgtcggg agtgccatcc 180 cggttttccg gttcgggaag cgggaccgag ttcaccctta ccatttcctc gctccaaccg 240 gaggacttcg ccacgtacta ctgccagcag tactactacg gttcagccgg agcagacact 300 gataccttcg gcggaggcac caaggtcgaa atcaag 336 <![CDATA[<210> 39]]> <![CDATA[<211> 219]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gL9輕鏈]]> <![CDATA[<400> 39]]> Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Ser Val Thr Ile Thr Cys Gln Ala Ser Gln Asn Ile Gly Ser Asp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Lys Ala Ala Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Tyr Gly Ser Ala 85 90 95 Gly Ala Asp Thr Asp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 145 150 155 160 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <![CDATA[<210> 40]]> <![CDATA[<211> 657]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gL9輕鏈]]> <![CDATA[<400> 40]]> gacatccagc tgactcagtc cccctccttc ctgagcgcct cagtgggaga tagcgtgacc 60 atcacctgtc aagccagcca gaacattggg tccgacttgg cctggtatca gcagaagcct 120 ggcaaagcgc cgaagctgct gatctacaag gccgctactc tcgcgtcggg agtgccatcc 180 cggttttccg gttcgggaag cgggaccgag ttcaccctta ccatttcctc gctccaaccg 240 gaggacttcg ccacgtacta ctgccagcag tactactacg gttcagccgg agcagacact 300 gataccttcg gcggaggcac caaggtcgaa atcaagcgta cggtagcggc cccatctgtc 360 ttcatcttcc cgccatctga tgagcagttg aaatctggaa ctgcctctgt tgtgtgcctg 420 ctgaataact tctatcccag agaggccaaa gtacagtgga aggtggataa cgccctccaa 480 tcgggtaact cccaggagag tgtcacagag caggacagca aggacagcac ctacagcctc 540 agcagcaccc tgacgctgag caaagcagac tacgagaaac acaaagtcta cgcctgcgaa 600 gtcacccatc agggcctgag ctcgcccgtc acaaagagct tcaacagggg agagtgt 657 <![CDATA[<210> 41]]> <![CDATA[<211> 112]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gL11 V區]]> <![CDATA[<400> 41]]> Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asn Ile Gly Ser Asp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ala Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Tyr Gly Ser Ala 85 90 95 Gly Ala Asp Thr Asp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110 <![CDATA[<210> 42]]> <![CDATA[<211> 336]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gL11 V區]]> <![CDATA[<400> 42]]> gacatccagc tgactcagtc cccctccttc ctgagcgcct cagtgggaga tcgcgtgacc 60 atcacctgtc aagccagcca gaacattggg tccgacttgg cctggtatca gcagaagcct 120 ggcaaagcgc cgaagctgct gatctacagc gccgctactc tcgcgtcggg agtgccatcc 180 cggttttccg gttcgggaag cgggaccgag ttcaccctta ccatttcctc gctccaaccg 240 gaggacttcg ccacgtacta ctgccagcag tactactacg gttcagccgg agcagacact 300 gataccttcg gcggaggcac caaggtcgaa atcaag 336 <![CDATA[<210> 43]]> <![CDATA[<211> 219]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gL11輕鏈]]> <![CDATA[<400]]>> 43]]> <br/> <br/><![CDATA[Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asn Ile Gly Ser Asp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ala Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Tyr Gly Ser Ala 85 90 95 Gly Ala Asp Thr Asp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 145 150 155 160 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <![CDATA[<210> 44]]> <![CDATA[<211> 657]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gL11輕鏈]]> <![CDATA[<400> 44]]> gacatccagc tgactcagtc cccctccttc ctgagcgcct cagtgggaga tcgcgtgacc 60 atcacctgtc aagccagcca gaacattggg tccgacttgg cctggtatca gcagaagcct 120 ggcaaagcgc cgaagctgct gatctacagc gccgctactc tcgcgtcggg agtgccatcc 180 cggttttccg gttcgggaag cgggaccgag ttcaccctta ccatttcctc gctccaaccg 240 gaggacttcg ccacgtacta ctgccagcag tactactacg gttcagccgg agcagacact 300 gataccttcg gcggaggcac caaggtcgaa atcaagcgta cggtagcggc cccatctgtc 360 ttcatcttcc cgccatctga tgagcagttg aaatctggaa ctgcctctgt tgtgtgcctg 420 ctgaataact tctatcccag agaggccaaa gtacagtgga aggtggataa cgccctccaa 480 tcgggtaact cccaggagag tgtcacagag caggacagca aggacagcac ctacagcctc 540 agcagcaccc tgacgctgag caaagcagac tacgagaaac acaaagtcta cgcctgcgaa 600 gtcacccatc agggcctgag ctcgcccgtc acaaagagct tcaacagggg agagtgt 657 <![CDATA[<210> 45]]> <![CDATA[<211> 120]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH1 V區]]> <![CDATA[<400> 45]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Ile Ile Tyr Ala Gly Gly Ser Pro Ser Tyr Ala Ser Trp Ala Lys 50 55 60 Gly Arg Phe Thr Ile Ser Lys Asp Ser Ser Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Gly Thr Gly Asp Thr Val Tyr Thr Tyr Phe Asn Ile Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <![CDATA[<210> 46]]> <![CDATA[<211> 360]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH1 V區]]> <![CDATA[<400> 46]]> gaagtgcagc tcgtggagtc gggcggaggt ctggtgcagc ccggaggaag cctgcgcctg 60 tcatgcaccg ccagcgggtt ctcgctttcc tcctacgcca tgacctgggt cagacaggca 120 ccgggaaagg gcctcgaatg gattggcatt atctatgcgg gtggcagccc ttcctacgcc 180 tcctgggcta aagggcggtt caccatctcg aaggactcct ccaagaacac ggtgtacttg 240 caaatgaact cactgagggc cgaggacact gcggtgtact actgtgcccg gggaactgga 300 gataccgtgt acacctactt taacatctgg ggccagggaa ccctggtcac tgtctcgagc 360 <![CDATA[<210> 47]]> <![CDATA[<211> 447]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH1重鏈(IgG4P)]]> <![CDATA[<400> 47]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Ile Ile Tyr Ala Gly Gly Ser Pro Ser Tyr Ala Ser Trp Ala Lys 50 55 60 Gly Arg Phe Thr Ile Ser Lys Asp Ser Ser Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Gly Thr Gly Asp Thr Val Tyr Thr Tyr Phe Asn Ile Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys 435 440 445 <![CDATA[<210> 48]]> <![CDATA[<211> 1341]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH1重鏈(IgG4P)]]> <![CDATA[<400> 48]]> gaagtgcagc tcgtggagtc gggcggaggt ctggtgcagc ccggaggaag cctgcgcctg 60 tcatgcaccg ccagcgggtt ctcgctttcc tcctacgcca tgacctgggt cagacaggca 120 ccgggaaagg gcctcgaatg gattggcatt atctatgcgg gtggcagccc ttcctacgcc 180 tcctgggcta aagggcggtt caccatctcg aaggactcct ccaagaacac ggtgtacttg 240 caaatgaact cactgagggc cgaggacact gcggtgtact actgtgcccg gggaactgga 300 gataccgtgt acacctactt taacatctgg ggccagggaa ccctggtcac tgtctcgagc 360 gcttctacaa agggcccatc cgtcttcccc ctggcgccct gctccaggag cacctccgag 420 agcacagccg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 480 tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 540 ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacgaagacc 600 tacacctgca acgtagatca caagcccagc aacaccaagg tggacaagag agttgagtcc 660 aaatatggtc ccccatgccc accatgccca gcacctgagt tcctgggggg accatcagtc 720 ttcctgttcc ccccaaaacc caaggacact ctcatgatct cccggacccc tgaggtcacg 780 tgcgtggtgg tggacgtgag ccaggaagac cccgaggtcc agttcaactg gtacgtggat 840 ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagttcaa cagcacgtac 900 cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaacggcaa ggagtacaag 960 tgcaaggtct ccaacaaagg cctcccgtcc tccatcgaga aaaccatctc caaagccaaa 1020 gggcagcccc gagagccaca ggtgtacacc ctgcccccat cccaggagga gatgaccaag 1080 aaccaggtca gcctgacctg cctggtcaaa ggcttctacc ccagcgacat cgccgtggag 1140 tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 1200 gacggctcct tcttcctcta cagcaggcta accgtggaca agagcaggtg gcaggagggg 1260 aatgtcttct catgctccgt gatgcatgag gctctgcaca accactacac acagaagagc 1320 ctctccctgt ctctgggtaa a 1341 <![CDATA[<210> 49]]> <![CDATA[<211> 120]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH2 V區]]> <![CDATA[<400> 49]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Ile Ile Tyr Ala Gly Gly Ser Pro Ser Tyr Ala Ser Trp Ala Lys 50 55 60 Gly Arg Phe Thr Ile Ser Lys Asp Ser Ser Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Gly Thr Gly Asp Thr Val Tyr Thr Tyr Phe Asn Ile Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <![CDATA[<210> 50]]> <![CDATA[<211> 360]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH2 V區]]> <![CDATA[<400> 50]]> gaagtgcagc tcgtggagtc gggcggaggt ctggtgcagc ccggaggaag cctgcgcctg 60 tcatgcgctg ccagcgggtt ctcgctttcc tcctacgcca tgacctgggt cagacaggca 120 ccgggaaagg gcctcgaatg ggtcggcatt atctatgcgg gtggcagccc ttcctacgcc 180 tcctgggcta aagggcggtt caccatctcg aaggactcct ccaagaacac ggtgtacttg 240 caaatgaact cactgagggc cgaggacact gcggtgtact actgtgcccg gggaactgga 300 gataccgtgt acacctactt taacatctgg ggccagggaa ccctggtcac tgtctcgagc 360 <![CDATA[<210> 51]]> <![CDATA[<211> 447]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH2重鏈(IgG4P)]]> <![CDATA[<400> 51]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Ile Ile Tyr Ala Gly Gly Ser Pro Ser Tyr Ala Ser Trp Ala Lys 50 55 60 Gly Arg Phe Thr Ile Ser Lys Asp Ser Ser Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Gly Thr Gly Asp Thr Val Tyr Thr Tyr Phe Asn Ile Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys 435 440 445 <![CDATA[<210> 52]]> <![CDATA[<211> 1341]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH2重鏈(IgG4P)]]> <![CDATA[<400> 52]]> gaagtgcagc tcgtggagtc gggcggaggt ctggtgcagc ccggaggaag cctgcgcctg 60 tcatgcgctg ccagcgggtt ctcgctttcc tcctacgcca tgacctgggt cagacaggca 120 ccgggaaagg gcctcgaatg ggtcggcatt atctatgcgg gtggcagccc ttcctacgcc 180 tcctgggcta aagggcggtt caccatctcg aaggactcct ccaagaacac ggtgtacttg 240 caaatgaact cactgagggc cgaggacact gcggtgtact actgtgcccg gggaactgga 300 gataccgtgt acacctactt taacatctgg ggccagggaa ccctggtcac tgtctcgagc 360 gcttctacaa agggcccatc cgtcttcccc ctggcgccct gctccaggag cacctccgag 420 agcacagccg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 480 tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 540 ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacgaagacc 600 tacacctgca acgtagatca caagcccagc aacaccaagg tggacaagag agttgagtcc 660 aaatatggtc ccccatgccc accatgccca gcacctgagt tcctgggggg accatcagtc 720 ttcctgttcc ccccaaaacc caaggacact ctcatgatct cccggacccc tgaggtcacg 780 tgcgtggtgg tggacgtgag ccaggaagac cccgaggtcc agttcaactg gtacgtggat 840 ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagttcaa cagcacgtac 900 cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaacggcaa ggagtacaag 960 tgcaaggtct ccaacaaagg cctcccgtcc tccatcgaga aaaccatctc caaagccaaa 1020 gggcagcccc gagagccaca ggtgtacacc ctgcccccat cccaggagga gatgaccaag 1080 aaccaggtca gcctgacctg cctggtcaaa ggcttctacc ccagcgacat cgccgtggag 1140 tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 1200 gacggctcct tcttcctcta cagcaggcta accgtggaca agagcaggtg gcaggagggg 1260 aatgtcttct catgctccgt gatgcatgag gctctgcaca accactacac acagaagagc 1320 ctctccctgt ctctgggtaa a 1341 <![CDATA[<210> 53]]> <![CDATA[<211> 120]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH4 V區]]> <![CDATA[<400> 53]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Ile Ile Tyr Ala Gly Gly Ser Pro Ser Tyr Ala Ser Trp Ala Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Ser Ser Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Gly Thr Gly Asp Thr Val Tyr Thr Tyr Phe Asn Ile Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <![CDATA[<210> 54]]> <![CDATA[<211> 360]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH4 V區]]> <![CDATA[<400> 54]]> gaagtgcagc tcgtggagtc gggcggaggt ctggtgcagc ccggaggaag cctgcgcctg 60 tcatgcaccg ccagcgggtt ctcgctttcc tcctacgcca tgacctgggt cagacaggca 120 ccgggaaagg gcctcgaatg gattggcatt atctatgcgg gtggcagccc ttcctacgcc 180 tcctgggcta aagggcggtt caccatctcg cgcgactcct ccaagaacac ggtgtacttg 240 caaatgaact cactgagggc cgaggacact gcggtgtact actgtgcccg gggaactgga 300 gataccgtgt acacctactt taacatctgg ggccagggaa ccctggtcac tgtctcgagc 360 <![CDATA[<210> 55]]> <![CDATA[<211> 447]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH4重鏈(IgG4P)]]> <![CDATA[<400> 55]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Ile Ile Tyr Ala Gly Gly Ser Pro Ser Tyr Ala Ser Trp Ala Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Ser Ser Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Gly Thr Gly Asp Thr Val Tyr Thr Tyr Phe Asn Ile Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys 435 440 445 <![CDATA[<210> 56]]> <![CDATA[<211> 1341]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH4重鏈(IgG4P)]]> <![CDATA[<400> 56]]> gaagtgcagc tcgtggagtc gggcggaggt ctggtgcagc ccggaggaag cctgcgcctg 60 tcatgcaccg ccagcgggtt ctcgctttcc tcctacgcca tgacctgggt cagacaggca 120 ccgggaaagg gcctcgaatg gattggcatt atctatgcgg gtggcagccc ttcctacgcc 180 tcctgggcta aagggcggtt caccatctcg cgcgactcct ccaagaacac ggtgtacttg 240 caaatgaact cactgagggc cgaggacact gcggtgtact actgtgcccg gggaactgga 300 gataccgtgt acacctactt taacatctgg ggccagggaa ccctggtcac tgtctcgagc 360 gcttctacaa agggcccatc cgtcttcccc ctggcgccct gctccaggag cacctccgag 420 agcacagccg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 480 tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 540 ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacgaagacc 600 tacacctgca acgtagatca caagcccagc aacaccaagg tggacaagag agttgagtcc 660 aaatatggtc ccccatgccc accatgccca gcacctgagt tcctgggggg accatcagtc 720 ttcctgttcc ccccaaaacc caaggacact ctcatgatct cccggacccc tgaggtcacg 780 tgcgtggtgg tggacgtgag ccaggaagac cccgaggtcc agttcaactg gtacgtggat 840 ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagttcaa cagcacgtac 900 cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaacggcaa ggagtacaag 960 tgcaaggtct ccaacaaagg cctcccgtcc tccatcgaga aaaccatctc caaagccaaa 1020 gggcagcccc gagagccaca ggtgtacacc ctgcccccat cccaggagga gatgaccaag 1080 aaccaggtca gcctgacctg cctggtcaaa ggcttctacc ccagcgacat cgccgtggag 1140 tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 1200 gacggctcct tcttcctcta cagcaggcta accgtggaca agagcaggtg gcaggagggg 1260 aatgtcttct catgctccgt gatgcatgag gctctgcaca accactacac acagaagagc 1320 ctctccctgt ctctgggtaa a 1341 <![CDATA[<210> 57]]> <![CDATA[<211> 120]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH6 V區]]> <![CDATA[<400> 57]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Ile Ile Tyr Ala Gly Gly Ser Pro Ser Tyr Ala Ser Trp Ala Lys 50 55 60 Gly Arg Phe Thr Ile Ser Lys Asp Ser 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 Arg Gly Thr Gly Asp Thr Val Tyr Thr Tyr Phe Asn Ile Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <![CDATA[<210> 58]]> <![CDATA[<211> 360]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH6 V區]]> <![CDATA[<400> 58]]> gaagtgcagc tcgtggagtc gggcggaggt ctggtgcagc ccggaggaag cctgcgcctg 60 tcatgcaccg ccagcgggtt ctcgctttcc tcctacgcca tgacctgggt cagacaggca 120 ccgggaaagg gcctcgaatg gattggcatt atctatgcgg gtggcagccc ttcctacgcc 180 tcctgggcta aagggcggtt caccatctcg aaggactcct ccaagaacac gctgtacttg 240 caaatgaact cactgagggc cgaggacact gcggtgtact actgtgcccg gggaactgga 300 gataccgtgt acacctactt taacatctgg ggccagggaa ccctggtcac tgtctcgagc 360 <![CDATA[<210> 59]]> <![CDATA[<211> 447]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172]]>gH6重鏈(IgG4P) <![CDATA[<400> 59]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Ile Ile Tyr Ala Gly Gly Ser Pro Ser Tyr Ala Ser Trp Ala Lys 50 55 60 Gly Arg Phe Thr Ile Ser Lys Asp Ser 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 Arg Gly Thr Gly Asp Thr Val Tyr Thr Tyr Phe Asn Ile Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys 435 440 445 <![CDATA[<210> 60]]> <![CDATA[<211> 1341]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH6重鏈(IgG4P)]]> <![CDATA[<400> 60]]> gaagtgcagc tcgtggagtc gggcggaggt ctggtgcagc ccggaggaag cctgcgcctg 60 tcatgcaccg ccagcgggtt ctcgctttcc tcctacgcca tgacctgggt cagacaggca 120 ccgggaaagg gcctcgaatg gattggcatt atctatgcgg gtggcagccc ttcctacgcc 180 tcctgggcta aagggcggtt caccatctcg aaggactcct ccaagaacac gctgtacttg 240 caaatgaact cactgagggc cgaggacact gcggtgtact actgtgcccg gggaactgga 300 gataccgtgt acacctactt taacatctgg ggccagggaa ccctggtcac tgtctcgagc 360 gcttctacaa agggcccatc cgtcttcccc ctggcgccct gctccaggag cacctccgag 420 agcacagccg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 480 tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 540 ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacgaagacc 600 tacacctgca acgtagatca caagcccagc aacaccaagg tggacaagag agttgagtcc 660 aaatatggtc ccccatgccc accatgccca gcacctgagt tcctgggggg accatcagtc 720 ttcctgttcc ccccaaaacc caaggacact ctcatgatct cccggacccc tgaggtcacg 780 tgcgtggtgg tggacgtgag ccaggaagac cccgaggtcc agttcaactg gtacgtggat 840 ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagttcaa cagcacgtac 900 cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaacggcaa ggagtacaag 960 tgcaaggtct ccaacaaagg cctcccgtcc tccatcgaga aaaccatctc caaagccaaa 1020 gggcagcccc gagagccaca ggtgtacacc ctgcccccat cccaggagga gatgaccaag 1080 aaccaggtca gcctgacctg cctggtcaaa ggcttctacc ccagcgacat cgccgtggag 1140 tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 1200 gacggctcct tcttcctcta cagcaggcta accgtggaca agagcaggtg gcaggagggg 1260 aatgtcttct catgctccgt gatgcatgag gctctgcaca accactacac acagaagagc 1320 ctctccctgt ctctgggtaa a 1341 <![CDATA[<210> 61]]> <![CDATA[<211>]]> 447 <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH6重鏈(IgG4P F234A L235A)]]> <![CDATA[<400> 61]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Ile Ile Tyr Ala Gly Gly Ser Pro Ser Tyr Ala Ser Trp Ala Lys 50 55 60 Gly Arg Phe Thr Ile Ser Lys Asp Ser 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 Arg Gly Thr Gly Asp Thr Val Tyr Thr Tyr Phe Asn Ile Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys 435 440 445 <![CDATA[<210> 62]]> <![CDATA[<211> 1341]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH6重鏈(IgG4P F234A L235A)]]> <![CDATA[<400> 62]]> gaagtgcagc tcgtggagtc gggcggaggt ctggtgcagc ccggaggaag cctgcgcctg 60 tcatgcaccg ccagcgggtt ctcgctttcc tcctacgcca tgacctgggt cagacaggca 120 ccgggaaagg gcctcgaatg gattggcatt atctatgcgg gtggcagccc ttcctacgcc 180 tcctgggcta aagggcggtt caccatctcg aaggactcct ccaagaacac gctgtacttg 240 caaatgaact cactgagggc cgaggacact gcggtgtact actgtgcccg gggaactgga 300 gataccgtgt acacctactt taacatctgg ggccagggaa ccctggtcac tgtctcgagc 360 gcttctacaa agggcccatc cgtcttcccc ctggcgccct gctccaggag cacctccgag 420 agcacagccg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 480 tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 540 ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacgaagacc 600 tacacctgca acgtagatca caagcccagc aacaccaagg tggacaagag agttgagtcc 660 aaatatggtc ccccatgccc accatgccca gcacctgaag ccgcgggggg accgtcagtc 720 ttcctgttcc ccccaaaacc caaggacact ctcatgatct cccggacccc tgaggtcacg 780 tgcgtggtgg tggacgtgag ccaggaagac cccgaggtcc agttcaactg gtacgtggat 840 ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagttcaa cagcacgtac 900 cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaacggcaa ggagtacaag 960 tgcaaggtct ccaacaaagg cctcccgtcc tccatcgaga aaaccatctc caaagccaaa 1020 gggcagcccc gagagccaca ggtgtacacc ctgcccccat cccaggagga gatgaccaag 1080 aaccaggtca gcctgacctg cctggtcaaa ggcttctacc ccagcgacat cgccgtggag 1140 tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 1200 gacggctcct tcttcctcta cagcaggcta accgtggaca agagcaggtg gcaggagggg 1260 aatgtcttct catgctccgt gatgcatgag gctctgcaca accactacac acagaagagc 1320 ctctccctgt ctctgggtaa a 1341 <![CDATA[<210> 63]]> <![CDATA[<211> 450]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH6重鏈(IgG1)]]> <![CDATA[<400> 63]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Ile Ile Tyr Ala Gly Gly Ser Pro Ser Tyr Ala Ser Trp Ala Lys 50 55 60 Gly Arg Phe Thr Ile Ser Lys Asp Ser 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 Arg Gly Thr Gly Asp Thr Val Tyr Thr Tyr Phe Asn Ile Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 225 230 235 240 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 245 250 255 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 260 265 270 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 290 295 300 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 325 330 335 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 340 345 350 Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu 355 360 365 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 370 375 380 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 405 410 415 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 Gly Lys 450 <![CDATA[<210> 64]]> <![CDATA[<211> 1350]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH6重鏈(IgG1)]]> <![CDATA[<400> 64]]> gaagtgcagc tcgtggagtc gggcggaggt ctggtgcagc ccggaggaag cctgcgcctg 60 tcatgcaccg ccagcgggtt ctcgctttcc tcctacgcca tgacctgggt cagacaggca 120 ccgggaaagg gcctcgaatg gattggcatt atctatgcgg gtggcagccc ttcctacgcc 180 tcctgggcta aagggcggtt caccatctcg aaggactcct ccaagaacac gctgtacttg 240 caaatgaact cactgagggc cgaggacact gcggtgtact actgtgcccg gggaactgga 300 gataccgtgt acacctactt taacatctgg ggccagggaa ccctggtcac tgtctcgagc 360 gcttctacaa agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 420 ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 480 tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 540 ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 600 tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagaa agttgagccc 660 aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga 720 ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 780 gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 840 tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 900 agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 960 gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 1020 aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggatgag 1080 ctgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 1140 gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 1200 ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 1260 cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 1320 cagaagagcc tctccctgtc tccgggtaaa 1350 <![CDATA[<210> 65]]> <![CDATA[<211> 450]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH6重鏈(IgG1 L234A L235A)]]> <![CDATA[<400> 65]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Ile Ile Tyr Ala Gly Gly Ser Pro Ser Tyr Ala Ser Trp Ala Lys 50 55 60 Gly Arg Phe Thr Ile Ser Lys Asp Ser 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 Arg Gly Thr Gly Asp Thr Val Tyr Thr Tyr Phe Asn Ile Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly 225 230 235 240 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 245 250 255 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 260 265 270 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 290 295 300 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 325 330 335 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 340 345 350 Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu 355 360 365 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 370 375 380 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 405 410 415 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 Gly Lys 450 <![CDATA[<210> 66]]> <![CDATA[<211> 1350]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH6重鏈(IgG1 L234A L235A)]]> <![CDATA[<400> 66]]> gaagtgcagc tcgtggagtc gggcggaggt ctggtgcagc ccggaggaag cctgcgcctg 60 tcatgcaccg ccagcgggtt ctcgctttcc tcctacgcca tgacctgggt cagacaggca 120 ccgggaaagg gcctcgaatg gattggcatt atctatgcgg gtggcagccc ttcctacgcc 180 tcctgggcta aagggcggtt caccatctcg aaggactcct ccaagaacac gctgtacttg 240 caaatgaact cactgagggc cgaggacact gcggtgtact actgtgcccg gggaactgga 300 gataccgtgt acacctactt taacatctgg ggccagggaa ccctggtcac tgtctcgagc 360 gcttctacaa agggcccctc cgtgttcccg ctcgctccat catcgaagtc taccagcgga 420 ggcactgcgg ctctcggttg cctcgtgaag gactacttcc cggagccggt gaccgtgtcg 480 tggaacagcg gagccctgac cagcggggtg cacacctttc cggccgtctt gcagtcaagc 540 ggcctttact ccctgtcatc agtggtgact gtcccgtcca gctcattggg aacccaaacc 600 tacatctgca atgtgaatca caaacctagc aacaccaagg ttgacaagaa agtcgagccc 660 aaatcgtgtg acaagactca cacttgtccg ccgtgcccgg cacccgaagc cgcaggaggt 720 cccagcgtct ttctgttccc tccaaagccg aaagacacgc tgatgatctc ccgcaccccg 780 gaggtcactt gcgtggtcgt ggacgtgtca catgaggacc cagaggtgaa gttcaattgg 840 tacgtggatg gcgtcgaagt ccacaatgcc aaaactaagc ccagagaaga acagtacaat 900 tcgacctacc gcgtcgtgtc cgtgctcacg gtgttgcatc aggattggct gaacgggaag 960 gaatacaagt gcaaagtgtc caacaaggcg ctgccggcac cgatcgagaa aactatctcc 1020 aaagcgaagg gacagcctag ggaacctcaa gtctacacgc tgccaccatc acgggatgaa 1080 ctgactaaga atcaagtctc actgacttgt ctggtgaagg ggttttaccc tagcgacatt 1140 gccgtggagt gggaatccaa cggccagcca gagaacaact acaagactac ccctccagtg 1200 ctcgactcgg atggatcgtt cttcctttac tcgaagctca ccgtggataa gtcccggtgg 1260 cagcagggaa acgtgttctc ctgctcggtg atgcatgaag ccctccataa ccactatacc 1320 caaaagtcgc tgtccctgtc gccgggaaag 1350 <![CDATA[<210> 67]]> <![CDATA[<211> 120]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH8 V區]]> <![CDATA[<400> 67]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Ile Ile Tyr Ala Gly Gly Ser Pro Ser Tyr Ala Ser Trp Ala Lys 50 55 60 Gly Arg Phe Thr Ile Ser Lys Asp Ser Ser Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Gly Thr Gly Asp Thr Val Tyr Thr Tyr Phe Asn Ile Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <![CDATA[<210> 68]]> <![CDATA[<211> 360]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH8 V區]]> <![CDATA[<400> 68]]> gaagtgcagc tcgtggagtc gggcggaggt ctggtgcagc ccggaggaag cctgcgcctg 60 tcatgcgctg ccagcgggtt ctcgctttcc tcctacgcca tgacctgggt cagacaggca 120 ccgggaaagg gcctcgaatg gattggcatt atctatgcgg gtggcagccc ttcctacgcc 180 tcctgggcta aagggcggtt caccatctcg aaggactcct ccaagaacac ggtgtacttg 240 caaatgaact cactgagggc cgaggacact gcggtgtact actgtgcccg gggaactgga 300 gataccgtgt acacctactt taacatctgg ggccagggaa ccctggtcac tgtctcgagc 360 <![CDATA[<210> 69]]> <![CDATA[<211> 447]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH8重鏈(IgG4P)]]> <![CDATA[<400> 69]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Ile Ile Tyr Ala Gly Gly Ser Pro Ser Tyr Ala Ser Trp Ala Lys 50 55 60 Gly Arg Phe Thr Ile Ser Lys Asp Ser Ser Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Gly Thr Gly Asp Thr Val Tyr Thr Tyr Phe Asn Ile Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys 435 440 445 <![CDATA[<210> 70]]> <![CDATA[<211> 1341]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH8重鏈(IgG4P)]]> <![CDATA[<400> 70]]> gaagtgcagc tcgtggagtc gggcggaggt ctggtgcagc ccggaggaag cctgcgcctg 60 tcatgcgctg ccagcgggtt ctcgctttcc tcctacgcca tgacctgggt cagacaggca 120 ccgggaaagg gcctcgaatg gattggcatt atctatgcgg gtggcagccc ttcctacgcc 180 tcctgggcta aagggcggtt caccatctcg aaggactcct ccaagaacac ggtgtacttg 240 caaatgaact cactgagggc cgaggacact gcggtgtact actgtgcccg gggaactgga 300 gataccgtgt acacctactt taacatctgg ggccagggaa ccctggtcac tgtctcgagc 360 gcttctacaa agggcccatc cgtcttcccc ctggcgccct gctccaggag cacctccgag 420 agcacagccg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 480 tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 540 ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacgaagacc 600 tacacctgca acgtagatca caagcccagc aacaccaagg tggacaagag agttgagtcc 660 aaatatggtc ccccatgccc accatgccca gcacctgagt tcctgggggg accatcagtc 720 ttcctgttcc ccccaaaacc caaggacact ctcatgatct cccggacccc tgaggtcacg 780 tgcgtggtgg tggacgtgag ccaggaagac cccgaggtcc agttcaactg gtacgtggat 840 ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagttcaa cagcacgtac 900 cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaacggcaa ggagtacaag 960 tgcaaggtct ccaacaaagg cctcccgtcc tccatcgaga aaaccatctc caaagccaaa 1020 gggcagcccc gagagccaca ggtgtacacc ctgcccccat cccaggagga gatgaccaag 1080 aaccaggtca gcctgacctg cctggtcaaa ggcttctacc ccagcgacat cgccgtggag 1140 tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 1200 gacggctcct tcttcctcta cagcaggcta accgtggaca agagcaggtg gcaggagggg 1260 aatgtcttct catgctccgt gatgcatgag gctctgcaca accactacac acagaagagc 1320 ctctccctgt ctctgggtaa a 1341 <![CDATA[<210> 71]]> <![CDATA[<211> 120]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH9 V區]]> <![CDATA[<400> 71]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Ile Ile Tyr Ala Gly Gly Ser Pro Ser Tyr Ala Ser Trp Ala Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Gly Thr Gly Asp Thr Val Tyr Thr Tyr Phe Asn Ile Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <![CDATA[<210> 72]]> <![CDATA[<211> 360]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH9 V區]]> <![CDATA[<400> 72]]> gaagtgcagc tcgtggagtc gggcggaggt ctggtgcagc ccggaggaag cctgcgcctg 60 tcatgcgctg ccagcgggtt ctcgctttcc tcctacgcca tgacctgggt cagacaggca 120 ccgggaaagg gcctcgaatg gattggcatt atctatgcgg gtggcagccc ttcctacgcc 180 tcctgggcta aagggcggtt caccatctcg cgcgacaatt ccaagaacac ggtgtacttg 240 caaatgaact cactgagggc cgaggacact gcggtgtact actgtgcccg gggaactgga 300 gataccgtgt acacctactt taacatctgg ggccagggaa ccctggtcac tgtctcgagc 360 <![CDATA[<210> 73]]> <![CDATA[<211> 447]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH9重鏈(IgG4P)]]> <![CDATA[<400> 73]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Ile Ile Tyr Ala Gly Gly Ser Pro Ser Tyr Ala Ser Trp Ala Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Gly Thr Gly Asp Thr Val Tyr Thr Tyr Phe Asn Ile Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys 435 440 445 <![CDATA[<210> 74]]> <![CDATA[<211> 1341]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH9重鏈(IgG4P)]]> <![CDATA[<400> 74]]> gaagtgcagc tcgtggagtc gggcggaggt ctggtgcagc ccggaggaag cctgcgcctg 60 tcatgcgctg ccagcgggtt ctcgctttcc tcctacgcca tgacctgggt cagacaggca 120 ccgggaaagg gcctcgaatg gattggcatt atctatgcgg gtggcagccc ttcctacgcc 180 tcctgggcta aagggcggtt caccatctcg cgcgacaatt ccaagaacac ggtgtacttg 240 caaatgaact cactgagggc cgaggacact gcggtgtact actgtgcccg gggaactgga 300 gataccgtgt acacctactt taacatctgg ggccagggaa ccctggtcac tgtctcgagc 360 gcttctacaa agggcccatc cgtcttcccc ctggcgccct gctccaggag cacctccgag 420 agcacagccg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 480 tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 540 ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacgaagacc 600 tacacctgca acgtagatca caagcccagc aacaccaagg tggacaagag agttgagtcc 660 aaatatggtc ccccatgccc accatgccca gcacctgagt tcctgggggg accatcagtc 720 ttcctgttcc ccccaaaacc caaggacact ctcatgatct cccggacccc tgaggtcacg 780 tgcgtggtgg tggacgtgag ccaggaagac cccgaggtcc agttcaactg gtacgtggat 840 ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagttcaa cagcacgtac 900 cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaacggcaa ggagtacaag 960 tgcaaggtct ccaacaaagg cctcccgtcc tccatcgaga aaaccatctc caaagccaaa 1020 gggcagcccc gagagccaca ggtgtacacc ctgcccccat cccaggagga gatgaccaag 1080 aaccaggtca gcctgacctg cctggtcaaa ggcttctacc ccagcgacat cgccgtggag 1140 tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 1200 gacggctcct tcttcctcta cagcaggcta accgtggaca agagcaggtg gcaggagggg 1260 aatgtcttct catgctccgt gatgcatgag gctctgcaca accactacac acagaagagc 1320 ctctccctgt ctctgggtaa a 1341 <![CDATA[<210> 75]]> <![CDATA[<211> 120]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH10 V區]]> <![CDATA[<400> 75]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Ile Ile Tyr Ala Gly Gly Ser Pro Ser Tyr Ala Ser Trp Ala Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Ser 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 Arg Gly Thr Gly Asp Thr Val Tyr Thr Tyr Phe Asn Ile Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <![CDATA[<210> 76]]> <![CDATA[<211> 360]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH10 V區]]> <![CDATA[<400> 76]]> gaagtgcagc tcgtggagtc gggcggaggt ctggtgcagc ccggaggaag cctgcgcctg 60 tcatgcgctg ccagcgggtt ctcgctttcc tcctacgcca tgacctgggt cagacaggca 120 ccgggaaagg gcctcgaatg gattggcatt atctatgcgg gtggcagccc ttcctacgcc 180 tcctgggcta aagggcggtt caccatctcg cgcgactcct ccaagaacac gctgtacttg 240 caaatgaact cactgagggc cgaggacact gcggtgtact actgtgcccg gggaactgga 300 gataccgtgt acacctactt taacatctgg ggccagggaa ccctggtcac tgtctcgagc 360 <![CDATA[<210> 77]]> <![CDATA[<211> 447]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH10重鏈(IgG4P)]]> <![CDATA[<400> 77]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Ile Ile Tyr Ala Gly Gly Ser Pro Ser Tyr Ala Ser Trp Ala Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Ser 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 Arg Gly Thr Gly Asp Thr Val Tyr Thr Tyr Phe Asn Ile Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys 435 440 445 <![CDATA[<210> 78]]> <![CDATA[<211> 1341]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH10重鏈(IgG4P)]]> <![CDATA[<400> 78]]> gaagtgcagc tcgtggagtc gggcggaggt ctggtgcagc ccggaggaag cctgcgcctg 60 tcatgcgctg ccagcgggtt ctcgctttcc tcctacgcca tgacctgggt cagacaggca 120 ccgggaaagg gcctcgaatg gattggcatt atctatgcgg gtggcagccc ttcctacgcc 180 tcctgggcta aagggcggtt caccatctcg cgcgactcct ccaagaacac gctgtacttg 240 caaatgaact cactgagggc cgaggacact gcggtgtact actgtgcccg gggaactgga 300 gataccgtgt acacctactt taacatctgg ggccagggaa ccctggtcac tgtctcgagc 360 gcttctacaa agggcccatc cgtcttcccc ctggcgccct gctccaggag cacctccgag 420 agcacagccg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 480 tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 540 ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacgaagacc 600 tacacctgca acgtagatca caagcccagc aacaccaagg tggacaagag agttgagtcc 660 aaatatggtc ccccatgccc accatgccca gcacctgagt tcctgggggg accatcagtc 720 ttcctgttcc ccccaaaacc caaggacact ctcatgatct cccggacccc tgaggtcacg 780 tgcgtggtgg tggacgtgag ccaggaagac cccgaggtcc agttcaactg gtacgtggat 840 ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagttcaa cagcacgtac 900 cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaacggcaa ggagtacaag 960 tgcaaggtct ccaacaaagg cctcccgtcc tccatcgaga aaaccatctc caaagccaaa 1020 gggcagcccc gagagccaca ggtgtacacc ctgcccccat cccaggagga gatgaccaag 1080 aaccaggtca gcctgacctg cctggtcaaa ggcttctacc ccagcgacat cgccgtggag 1140 tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 1200 gacggctcct tcttcctcta cagcaggcta accgtggaca agagcaggtg gcaggagggg 1260 aatgtcttct catgctccgt gatgcatgag gctctgcaca accactacac acagaagagc 1320 ctctccctgt ctctgggtaa a 1341 <![CDATA[<210> 79]]> <![CDATA[<211> 120]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH11 V區]]> <![CDATA[<400> 79]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Ile Ile Tyr Ala Gly Gly Ser Pro Ser Tyr Ala Ser Trp Ala Lys 50 55 60 Gly Arg Phe Thr Ile Ser Lys 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 Arg Gly Thr Gly Asp Thr Val Tyr Thr Tyr Phe Asn Ile Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <![CDATA[<210> 80]]> <![CDATA[<211> 360]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH11 V區]]> <![CDATA[<400> 80]]> gaagtgcagc tcgtggagtc gggcggaggt ctggtgcagc ccggaggaag cctgcgcctg 60 tcatgcgctg ccagcgggtt ctcgctttcc tcctacgcca tgacctgggt cagacaggca 120 ccgggaaagg gcctcgaatg gattggcatt atctatgcgg gtggcagccc ttcctacgcc 180 tcctgggcta aagggcggtt caccatctcg aaggacaatt ccaagaacac gctgtacttg 240 caaatgaact cactgagggc cgaggacact gcggtgtact actgtgcccg gggaactgga 300 gataccgtgt acacctactt taacatctgg ggccagggaa ccctggtcac tgtctcgagc 360 <![CDATA[<210> 81]]> <![CDATA[<211> 447]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH11重鏈(IgG4P)]]> <![CDATA[<400> 81]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Ile Ile Tyr Ala Gly Gly Ser Pro Ser Tyr Ala Ser Trp Ala Lys 50 55 60 Gly Arg Phe Thr Ile Ser Lys 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 Arg Gly Thr Gly Asp Thr Val Tyr Thr Tyr Phe Asn Ile Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys 435 440 445 <![CDATA[<210> 82]]> <![CDATA[<211> 1341]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH11重鏈(IgG4P)]]> <![CDATA[<400> 82]]> gaagtgcagc tcgtggagtc gggcggaggt ctggtgcagc ccggaggaag cctgcgcctg 60 tcatgcgctg ccagcgggtt ctcgctttcc tcctacgcca tgacctgggt cagacaggca 120 ccgggaaagg gcctcgaatg gattggcatt atctatgcgg gtggcagccc ttcctacgcc 180 tcctgggcta aagggcggtt caccatctcg aaggacaatt ccaagaacac gctgtacttg 240 caaatgaact cactgagggc cgaggacact gcggtgtact actgtgcccg gggaactgga 300 gataccgtgt acacctactt taacatctgg ggccagggaa ccctggtcac tgtctcgagc 360 gcttctacaa agggcccctc cgtgttccct ctggcccctt gctcccggtc cacctccgag 420 tctaccgccg ctctgggctg cctggtcaag gactacttcc ccgagcccgt gacagtgtcc 480 tggaactctg gcgccctgac ctccggcgtg cacaccttcc ctgccgtgct gcagtcctcc 540 ggcctgtact ccctgtcctc cgtcgtgacc gtgccctcct ccagcctggg caccaagacc 600 tacacctgta acgtggacca caagccctcc aacaccaagg tggacaagcg ggtggaatct 660 aagtacggcc ctccctgccc cccctgccct gcccctgaat ttctgggcgg accttccgtg 720 ttcctgttcc ccccaaagcc caaggacacc ctgatgatct cccggacccc cgaagtgacc 780 tgcgtggtgg tggacgtgtc ccaggaagat cccgaggtcc agttcaattg gtacgtggac 840 ggcgtggaag tgcacaatgc caagaccaag cccagagagg aacagttcaa ctccacctac 900 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 960 tgcaaggtgt ccaacaaggg cctgccctcc agcatcgaaa agaccatctc caaggccaag 1020 ggccagcccc gcgagcccca ggtgtacacc ctgcccccta gccaggaaga gatgaccaag 1080 aaccaggtgt ccctgacctg tctggtcaag ggcttctacc cctccgacat tgccgtggaa 1140 tgggagtcca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggacagc 1200 gacggctcct tcttcctgta ctctcggctg accgtggaca agtcccggtg gcaggaaggc 1260 aacgtcttct cctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtcc 1320 ctgtccctga gcctgggcaa g 1341 <![CDATA[<210> 83]]> <![CDATA[<211> 447]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH11重鏈(IgG4P F234A L235A)]]> <![CDATA[<400> 83]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Ile Ile Tyr Ala Gly Gly Ser Pro Ser Tyr Ala Ser Trp Ala Lys 50 55 60 Gly Arg Phe Thr Ile Ser Lys 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 Arg Gly Thr Gly Asp Thr Val Tyr Thr Tyr Phe Asn Ile Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys 435 440 445 <![CDATA[<210> 84]]> <![CDATA[<211> 1341]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH11重鏈(IgG4P F234A L235A)]]> <![CDATA[<400> 84]]> gaagtgcagc tcgtggagtc gggcggaggt ctggtgcagc ccggaggaag cctgcgcctg 60 tcatgcgctg ccagcgggtt ctcgctttcc tcctacgcca tgacctgggt cagacaggca 120 ccgggaaagg gcctcgaatg gattggcatt atctatgcgg gtggcagccc ttcctacgcc 180 tcctgggcta aagggcggtt caccatctcg aaggacaatt ccaagaacac gctgtacttg 240 caaatgaact cactgagggc cgaggacact gcggtgtact actgtgcccg gggaactgga 300 gataccgtgt acacctactt taacatctgg ggccagggaa ccctggtcac tgtctcgagc 360 gcttctacaa agggcccatc cgtcttcccc ctggcgccct gctccaggag cacctccgag 420 agcacagccg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 480 tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 540 ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacgaagacc 600 tacacctgca acgtagatca caagcccagc aacaccaagg tggacaagag agttgagtcc 660 aaatatggtc ccccatgccc accatgccca gcacctgaag ccgcgggggg accgtcagtc 720 ttcctgttcc ccccaaaacc caaggacact ctcatgatct cccggacccc tgaggtcacg 780 tgcgtggtgg tggacgtgag ccaggaagac cccgaggtcc agttcaactg gtacgtggat 840 ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagttcaa cagcacgtac 900 cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaacggcaa ggagtacaag 960 tgcaaggtct ccaacaaagg cctcccgtcc tccatcgaga aaaccatctc caaagccaaa 1020 gggcagcccc gagagccaca ggtgtacacc ctgcccccat cccaggagga gatgaccaag 1080 aaccaggtca gcctgacctg cctggtcaaa ggcttctacc ccagcgacat cgccgtggag 1140 tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 1200 gacggctcct tcttcctcta cagcaggcta accgtggaca agagcaggtg gcaggagggg 1260 aatgtcttct catgctccgt gatgcatgag gctctgcaca accactacac acagaagagc 1320 ctctccctgt ctctgggtaa a 1341 <![CDATA[<210> 85]]> <![CDATA[<211> 450]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH11重鏈(IgG1)]]> <![CDATA[<400> 85]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Ile Ile Tyr Ala Gly Gly Ser Pro Ser Tyr Ala Ser Trp Ala Lys 50 55 60 Gly Arg Phe Thr Ile Ser Lys 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 Arg Gly Thr Gly Asp Thr Val Tyr Thr Tyr Phe Asn Ile Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 225 230 235 240 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 245 250 255 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 260 265 270 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 290 295 300 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 325 330 335 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 340 345 350 Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu 355 360 365 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 370 375 380 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 405 410 415 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 Gly Lys 450 <![CDATA[<210> 86]]> <![CDATA[<211> 1350]]> <![CDATA[<212> DN]]>A <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH11重鏈(IgG1)]]> <![CDATA[<400> 86]]> gaagtgcagc tcgtggagtc gggcggaggt ctggtgcagc ccggaggaag cctgcgcctg 60 tcatgcgctg ccagcgggtt ctcgctttcc tcctacgcca tgacctgggt cagacaggca 120 ccgggaaagg gcctcgaatg gattggcatt atctatgcgg gtggcagccc ttcctacgcc 180 tcctgggcta aagggcggtt caccatctcg aaggacaatt ccaagaacac gctgtacttg 240 caaatgaact cactgagggc cgaggacact gcggtgtact actgtgcccg gggaactgga 300 gataccgtgt acacctactt taacatctgg ggccagggaa ccctggtcac tgtctcgagc 360 gcttctacaa agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 420 ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 480 tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 540 ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 600 tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagaa agttgagccc 660 aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga 720 ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 780 gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 840 tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 900 agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 960 gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 1020 aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggatgag 1080 ctgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 1140 gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 1200 ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 1260 cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 1320 cagaagagcc tctccctgtc tccgggtaaa 1350 <![CDATA[<210> 87]]> <![CDATA[<211> 450]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH11重鏈(IgG1 L234A L235A)]]> <![CDATA[<400> 87]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Ile Ile Tyr Ala Gly Gly Ser Pro Ser Tyr Ala Ser Trp Ala Lys 50 55 60 Gly Arg Phe Thr Ile Ser Lys 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 Arg Gly Thr Gly Asp Thr Val Tyr Thr Tyr Phe Asn Ile Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly 225 230 235 240 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 245 250 255 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 260 265 270 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 290 295 300 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 325 330 335 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 340 345 350 Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu 355 360 365 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 370 375 380 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 405 410 415 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 Gly Lys 450 <![CDATA[<210> 88]]> <![CDATA[<211> 1350]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH11重鏈(IgG1 L234A L235A)]]> <![CDATA[<400> 88]]> gaagtgcagc tcgtggagtc gggcggaggt ctggtgcagc ccggaggaag cctgcgcctg 60 tcatgcgctg ccagcgggtt ctcgctttcc tcctacgcca tgacctgggt cagacaggca 120 ccgggaaagg gcctcgaatg gattggcatt atctatgcgg gtggcagccc ttcctacgcc 180 tcctgggcta aagggcggtt caccatctcg aaggacaatt ccaagaacac gctgtacttg 240 caaatgaact cactgagggc cgaggacact gcggtgtact actgtgcccg gggaactgga 300 gataccgtgt acacctactt taacatctgg ggccagggaa ccctggtcac tgtctcgagc 360 gcttctacaa agggcccctc cgtgttcccg ctcgctccat catcgaagtc taccagcgga 420 ggcactgcgg ctctcggttg cctcgtgaag gactacttcc cggagccggt gaccgtgtcg 480 tggaacagcg gagccctgac cagcggggtg cacacctttc cggccgtctt gcagtcaagc 540 ggcctttact ccctgtcatc agtggtgact gtcccgtcca gctcattggg aacccaaacc 600 tacatctgca atgtgaatca caaacctagc aacaccaagg ttgacaagaa agtcgagccc 660 aaatcgtgtg acaagactca cacttgtccg ccgtgcccgg cacccgaagc cgcaggaggt 720 cccagcgtct ttctgttccc tccaaagccg aaagacacgc tgatgatctc ccgcaccccg 780 gaggtcactt gcgtggtcgt ggacgtgtca catgaggacc cagaggtgaa gttcaattgg 840 tacgtggatg gcgtcgaagt ccacaatgcc aaaactaagc ccagagaaga acagtacaat 900 tcgacctacc gcgtcgtgtc cgtgctcacg gtgttgcatc aggattggct gaacgggaag 960 gaatacaagt gcaaagtgtc caacaaggcg ctgccggcac cgatcgagaa aactatctcc 1020 aaagcgaagg gacagcctag ggaacctcaa gtctacacgc tgccaccatc acgggatgaa 1080 ctgactaaga atcaagtctc actgacttgt ctggtgaagg ggttttaccc tagcgacatt 1140 gccgtggagt gggaatccaa cggccagcca gagaacaact acaagactac ccctccagtg 1200 ctcgactcgg atggatcgtt cttcctttac tcgaagctca ccgtggataa gtcccggtgg 1260 cagcagggaa acgtgttctc ctgctcggtg atgcatgaag ccctccataa ccactatacc 1320 caaaagtcgc tgtccctgtc gccgggaaag 1350 <![CDATA[<210> 89]]> <![CDATA[<211> 120]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH12 V區]]> <![CDATA[<400> 89]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Ile Ile Tyr Ala Gly Gly Ser Pro Ser Tyr Ala Ser Trp Ala 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 Arg Gly Thr Gly Asp Thr Val Tyr Thr Tyr Phe Asn Ile Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <![CDATA[<210> 90]]> <![CDATA[<211> 360]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH12 V區]]> <![CDATA[<400> 90]]> gaagtgcagc tcgtggagtc gggcggaggt ctggtgcagc ccggaggaag cctgcgcctg 60 tcatgcgctg ccagcgggtt ctcgctttcc tcctacgcca tgacctgggt cagacaggca 120 ccgggaaagg gcctcgaatg gattggcatt atctatgcgg gtggcagccc ttcctacgcc 180 tcctgggcta aagggcggtt caccatctcg cgcgacaatt ccaagaacac gctgtacttg 240 caaatgaact cactgagggc cgaggacact gcggtgtact actgtgcccg gggaactgga 300 gataccgtgt acacctactt taacatctgg ggccagggaa ccctggtcac tgtctcgagc 360 <![CDATA[<210> 91]]> <![CDATA[<211> 447]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH12重鏈(IgG4P)]]> <![CDATA[<400> 91]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Ile Ile Tyr Ala Gly Gly Ser Pro Ser Tyr Ala Ser Trp Ala 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 Arg Gly Thr Gly Asp Thr Val Tyr Thr Tyr Phe Asn Ile Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys 435 440 445 <![CDATA[<210> 92]]> <![CDATA[<211> 1341]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH12重鏈(IgG4P)]]> <![CDATA[<400> 92]]> gaagtgcagc tcgtggagtc gggcggaggt ctggtgcagc ccggaggaag cctgcgcctg 60 tcatgcgctg ccagcgggtt ctcgctttcc tcctacgcca tgacctgggt cagacaggca 120 ccgggaaagg gcctcgaatg gattggcatt atctatgcgg gtggcagccc ttcctacgcc 180 tcctgggcta aagggcggtt caccatctcg cgcgacaatt ccaagaacac gctgtacttg 240 caaatgaact cactgagggc cgaggacact gcggtgtact actgtgcccg gggaactgga 300 gataccgtgt acacctactt taacatctgg ggccagggaa ccctggtcac tgtctcgagc 360 gcttctacaa agggcccatc cgtcttcccc ctggcgccct gctccaggag cacctccgag 420 agcacagccg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 480 tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 540 ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacgaagacc 600 tacacctgca acgtagatca caagcccagc aacaccaagg tggacaagag agttgagtcc 660 aaatatggtc ccccatgccc accatgccca gcacctgagt tcctgggggg accatcagtc 720 ttcctgttcc ccccaaaacc caaggacact ctcatgatct cccggacccc tgaggtcacg 780 tgcgtggtgg tggacgtgag ccaggaagac cccgaggtcc agttcaactg gtacgtggat 840 ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagttcaa cagcacgtac 900 cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaacggcaa ggagtacaag 960 tgcaaggtct ccaacaaagg cctcccgtcc tccatcgaga aaaccatctc caaagccaaa 1020 gggcagcccc gagagccaca ggtgtacacc ctgcccccat cccaggagga gatgaccaag 1080 aaccaggtca gcctgacctg cctggtcaaa ggcttctacc ccagcgacat cgccgtggag 1140 tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 1200 gacggctcct tcttcctcta cagcaggcta accgtggaca agagcaggtg gcaggagggg 1260 aatgtcttct catgctccgt gatgcatgag gctctgcaca accactacac acagaagagc 1320 ctctccctgt ctctgggtaa a 1341 <![CDATA[<210> 93]]> <![CDATA[<211> 120]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH26 V區]]> <![CDATA[<400> 93]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Ile Ile Tyr Ala Gly Gly Ser Pro Ser Tyr Ala Ser Trp Ala Lys 50 55 60 Gly Arg Phe Thr Ile Ser Lys Asp Asn Ser Ser 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 Arg Gly Thr Gly Asp Thr Val Tyr Thr Tyr Phe Asn Ile Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <![CDATA[<210> 94]]> <![CDATA[<211> 360]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH26 V區]]> <![CDATA[<400> 94]]> gaagtgcagc tcgtggagtc gggcggaggt ctggtgcagc ccggaggaag cctgcgcctg 60 tcatgcgctg ccagcgggtt ctcgctttcc tcctacgcca tgacctgggt cagacaggca 120 ccgggaaagg gcctcgaatg gattggcatt atctatgcgg gtggcagccc ttcctacgcc 180 tcctgggcta aagggcggtt caccatctcg aaggacaatt ccagcaacac gctgtacttg 240 caaatgaact cactgagggc cgaggacact gcggtgtact actgtgcccg gggaactgga 300 gataccgtgt acacctactt taacatctgg ggccagggaa ccctggtcac tgtctcgagc 360 <![CDATA[<210> 95]]> <![CDATA[<211> 447]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH26重鏈(hIgG4P)]]> <![CDATA[<400> 95]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Ile Ile Tyr Ala Gly Gly Ser Pro Ser Tyr Ala Ser Trp Ala Lys 50 55 60 Gly Arg Phe Thr Ile Ser Lys Asp Asn Ser Ser 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 Arg Gly Thr Gly Asp Thr Val Tyr Thr Tyr Phe Asn Ile Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys 435 440 445 <![CDATA[<210> 96]]> <![CDATA[<211> 1341]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH26重鏈(hIgG4P)]]> <![CDATA[<400> 96]]> gaagtgcagc tcgtggagtc gggcggaggt ctggtgcagc ccggaggaag cctgcgcctg 60 tcatgcgctg ccagcgggtt ctcgctttcc tcctacgcca tgacctgggt cagacaggca 120 ccgggaaagg gcctcgaatg gattggcatt atctatgcgg gtggcagccc ttcctacgcc 180 tcctgggcta aagggcggtt caccatctcg aaggacaatt ccagcaacac gctgtacttg 240 caaatgaact cactgagggc cgaggacact gcggtgtact actgtgcccg gggaactgga 300 gataccgtgt acacctactt taacatctgg ggccagggaa ccctggtcac tgtctcgagc 360 gcttctacaa agggcccatc cgtcttcccc ctggcgccct gctccaggag cacctccgag 420 agcacagccg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 480 tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 540 ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacgaagacc 600 tacacctgca acgtagatca caagcccagc aacaccaagg tggacaagag agttgagtcc 660 aaatatggtc ccccatgccc accatgccca gcacctgagt tcctgggggg accatcagtc 720 ttcctgttcc ccccaaaacc caaggacact ctcatgatct cccggacccc tgaggtcacg 780 tgcgtggtgg tggacgtgag ccaggaagac cccgaggtcc agttcaactg gtacgtggat 840 ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagttcaa cagcacgtac 900 cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaacggcaa ggagtacaag 960 tgcaaggtct ccaacaaagg cctcccgtcc tccatcgaga aaaccatctc caaagccaaa 1020 gggcagcccc gagagccaca ggtgtacacc ctgcccccat cccaggagga gatgaccaag 1080 aaccaggtca gcctgacctg cctggtcaaa ggcttctacc ccagcgacat cgccgtggag 1140 tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 1200 gacggctcct tcttcctcta cagcaggcta accgtggaca agagcaggtg gcaggagggg 1260 aatgtcttct catgctccgt gatgcatgag gctctgcaca accactacac acagaagagc 1320 ctctccctgt ctctgggtaa a 1341 <![CDATA[<210> 97]]> <![CDATA[<211> 120]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH48 V區]]> <![CDATA[<400> 97]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Ile Ile Tyr Ala Gly Gly Ser Pro Ser Tyr Ala Ser Trp Ala Lys 50 55 60 Gly Arg Phe Thr Ile Ser Lys Asp Asn Ser Gln 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 Arg Gly Thr Gly Asp Thr Val Tyr Thr Tyr Phe Asn Ile Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <![CDATA[<210> 98]]> <![CDATA[<211> 360]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH48 V區]]> <![CDATA[<400> 98]]> gaagtgcagc tcgtggagtc gggcggaggt ctggtgcagc ccggaggaag cctgcgcctg 60 tcatgcgctg ccagcgggtt ctcgctttcc tcctacgcca tgacctgggt cagacaggca 120 ccgggaaagg gcctcgaatg gattggcatt atctatgcgg gtggcagccc ttcctacgcc 180 tcctgggcta aagggcggtt caccatctcg aaggacaatt cccagaacac gctgtacttg 240 caaatgaact cactgagggc cgaggacact gcggtgtact actgtgcccg gggaactgga 300 gataccgtgt acacctactt taacatctgg ggccagggaa ccctggtcac tgtctcgagc 360 <![CDATA[<210> 99]]> <![CDATA[<211> 447]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH48重鏈(hIgG4P)]]> <![CDATA[<400> 99]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Ile Ile Tyr Ala Gly Gly Ser Pro Ser Tyr Ala Ser Trp Ala Lys 50 55 60 Gly Arg Phe Thr Ile Ser Lys Asp Asn Ser Gln 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 Arg Gly Thr Gly Asp Thr Val Tyr Thr Tyr Phe Asn Ile Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys 435 440 445 <![CDATA[<210> 100]]> <![CDATA[<211> 1341]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH48重鏈(hIgG4P)]]> <![CDATA[<400> 100]]> gaagtgcagc tcgtggagtc gggcggaggt ctggtgcagc ccggaggaag cctgcgcctg 60 tcatgcgctg ccagcgggtt ctcgctttcc tcctacgcca tgacctgggt cagacaggca 120 ccgggaaagg gcctcgaatg gattggcatt atctatgcgg gtggcagccc ttcctacgcc 180 tcctgggcta aagggcggtt caccatctcg aaggacaatt cccagaacac gctgtacttg 240 caaatgaact cactgagggc cgaggacact gcggtgtact actgtgcccg gggaactgga 300 gataccgtgt acacctactt taacatctgg ggccagggaa ccctggtcac tgtctcgagc 360 gcttctacaa agggcccatc cgtcttcccc ctggcgccct gctccaggag cacctccgag 420 agcacagccg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 480 tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 540 ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacgaagacc 600 tacacctgca acgtagatca caagcccagc aacaccaagg tggacaagag agttgagtcc 660 aaatatggtc ccccatgccc accatgccca gcacctgagt tcctgggggg accatcagtc 720 ttcctgttcc ccccaaaacc caaggacact ctcatgatct cccggacccc tgaggtcacg 780 tgcgtggtgg tggacgtgag ccaggaagac cccgaggtcc agttcaactg gtacgtggat 840 ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagttcaa cagcacgtac 900 cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaacggcaa ggagtacaag 960 tgcaaggtct ccaacaaagg cctcccgtcc tccatcgaga aaaccatctc caaagccaaa 1020 gggcagcccc gagagccaca ggtgtacacc ctgcccccat cccaggagga gatgaccaag 1080 aaccaggtca gcctgacctg cctggtcaaa ggcttctacc ccagcgacat cgccgtggag 1140 tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 1200 gacggctcct tcttcctcta cagcaggcta accgtggaca agagcaggtg gcaggagggg 1260 aatgtcttct catgctccgt gatgcatgag gctctgcaca accactacac acagaagagc 1320 ctctccctgt ctctgggtaa a 1341 <![CDATA[<210> 101]]> <![CDATA[<211> 120]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH49 V區]]> <![CDATA[<400> 101]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Ile Ile Tyr Ala Gly Gly Ser Pro Ser Tyr Ala Ser Trp Ala Lys 50 55 60 Gly Arg Phe Thr Ile Ser Lys Asp Asn Ser Glu 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 Arg Gly Thr Gly Asp Thr Val Tyr Thr Tyr Phe Asn Ile Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <![CDATA[<210> 102]]> <![CDATA[<211> 360]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH49 V區]]> <![CDATA[<400> 102]]> gaagtgcagc tcgtggagtc gggcggaggt ctggtgcagc ccggaggaag cctgcgcctg 60 tcatgcgctg ccagcgggtt ctcgctttcc tcctacgcca tgacctgggt cagacaggca 120 ccgggaaagg gcctcgaatg gattggcatt atctatgcgg gtggcagccc ttcctacgcc 180 tcctgggcta aagggcggtt caccatctcg aaggacaatt ccgagaacac gctgtacttg 240 caaatgaact cactgagggc cgaggacact gcggtgtact actgtgcccg gggaactgga 300 gataccgtgt acacctactt taacatctgg ggccagggaa ccctggtcac tgtctcgagc 360 <![CDATA[<210> 103]]> <![CDATA[<211> 447]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH49重鏈(hIgG4P)]]> <![CDATA[<400> 103]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Ile Ile Tyr Ala Gly Gly Ser Pro Ser Tyr Ala Ser Trp Ala Lys 50 55 60 Gly Arg Phe Thr Ile Ser Lys Asp Asn Ser Glu 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 Arg Gly Thr Gly Asp Thr Val Tyr Thr Tyr Phe Asn Ile Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys 435 440 445 <![CDATA[<210> 104]]> <![CDATA[<211> 1341]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 12172gH49重鏈(hIgG4P)]]> <![CDATA[<400> 104]]> gaagtgcagc tcgtggagtc gggcggaggt ctggtgcagc ccggaggaag cctgcgcctg 60 tcatgcgctg ccagcgggtt ctcgctttcc tcctacgcca tgacctgggt cagacaggca 120 ccgggaaagg gcctcgaatg gattggcatt atctatgcgg gtggcagccc ttcctacgcc 180 tcctgggcta aagggcggtt caccatctcg aaggacaatt ccgagaacac gctgtacttg 240 caaatgaact cactgagggc cgaggacact gcggtgtact actgtgcccg gggaactgga 300 gataccgtgt acacctactt taacatctgg ggccagggaa ccctggtcac tgtctcgagc 360 gcttctacaa agggcccatc cgtcttcccc ctggcgccct gctccaggag cacctccgag 420 agcacagccg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 480 tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 540 ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacgaagacc 600 tacacctgca acgtagatca caagcccagc aacaccaagg tggacaagag agttgagtcc 660 aaatatggtc ccccatgccc accatgccca gcacctgagt tcctgggggg accatcagtc 720 ttcctgttcc ccccaaaacc caaggacact ctcatgatct cccggacccc tgaggtcacg 780 tgcgtggtgg tggacgtgag ccaggaagac cccgaggtcc agttcaactg gtacgtggat 840 ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagttcaa cagcacgtac 900 cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaacggcaa ggagtacaag 960 tgcaaggtct ccaacaaagg cctcccgtcc tccatcgaga aaaccatctc caaagccaaa 1020 gggcagcccc gagagccaca ggtgtacacc ctgcccccat cccaggagga gatgaccaag 1080 aaccaggtca gcctgacctg cctggtcaaa ggcttctacc ccagcgacat cgccgtggag 1140 tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 1200 gacggctcct tcttcctcta cagcaggcta accgtggaca agagcaggtg gcaggagggg 1260 aatgtcttct catgctccgt gatgcatgag gctctgcaca accactacac acagaagagc 1320 ctctccctgt ctctgggtaa a 1341 <![CDATA[<210> 105]]> <![CDATA[<211> 107]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類IGKV1-9 IGKJ4受體構架]]> <![CDATA[<400> 105]]> Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Ser Tyr Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <![CDATA[<210> 106]]> <![CDATA[<211> 321]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類IGKV1-9 IGKJ4受體構架]]> <![CDATA[<400> 106]]> gacatccagt tgacccagtc tccatccttc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc gggccagtca gggcattagc agttatttag cctggtatca gcaaaaacca 120 gggaaagccc ctaagctcct gatctatgct gcatccactt tgcaaagtgg ggtcccatca 180 aggttcagcg gcagtggatc tgggacagaa ttcactctca caatcagcag cctgcagcct 240 gaagattttg caacttatta ctgtcaacag cttaatagtt accctctcac tttcggcgga 300 gggaccaagg tggagatcaa a 321 <![CDATA[<210> 107]]> <![CDATA[<211> 112]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類IGHV3-66 IGHJ4受體構架]]> <![CDATA[<400> 107]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Ser Asn 20 25 30 Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Val Ile Tyr Ser Gly Gly Ser Thr 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 Arg Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 100 105 110 <![CDATA[<210> 108]]> <![CDATA[<211> 336]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類IGHV3-66 IGHJ4受體構架]]> <![CDATA[<400> 108]]> gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctggatt caccgtcagt agcaactaca tgagctgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtctcagtt atttatagcg gtggtagcac atactacgca 180 gactccgtga agggcagatt caccatctcc agagacaatt ccaagaacac gctgtatctt 240 caaatgaaca gcctgagagc cgaggacacg gctgtgtatt actgtgcgag atactttgac 300 tactggggcc aaggaaccct ggtcaccgtc tcctca 336 <![CDATA[<210> 109]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1 W]]>T 01_WT_3A <![CDATA[<400> 109]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys 20 25 30 Phe Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met 35 40 45 Pro Lys Thr Leu Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp 100 105 110 Arg Ile Arg Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 110]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體02_6]]> <![CDATA[<400> 110]]> Met Glu Leu Arg Ala Ala Ala Lys Leu Thr Glu Glu Lys Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys 20 25 30 Phe Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met 35 40 45 Pro Lys Thr Leu Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp 100 105 110 Arg Ile Arg Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 111]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體03_6_7]]> <![CDATA[<400> 111]]> Met Glu Leu Arg Ala Ala Ala Ala Leu Thr Glu Glu Lys Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys 20 25 30 Phe Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met 35 40 45 Pro Lys Thr Leu Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp 100 105 110 Arg Ile Arg Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 112]]> <![CDATA[<211> 121]]> <![CDATA[<212> ]]>PRT <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體04_6_7_9]]> <![CDATA[<400> 112]]> Met Glu Leu Arg Ala Ala Ala Ala Leu Ala Glu Glu Lys Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys 20 25 30 Phe Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met 35 40 45 Pro Lys Thr Leu Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp 100 105 110 Arg Ile Arg Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 113]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體05_7_8_9]]> <![CDATA[<400> 113]]> Met Glu Leu Arg Ala Ala Thr Ala Ala Ala Glu Glu Lys Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys 20 25 30 Phe Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met 35 40 45 Pro Lys Thr Leu Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp 100 105 110 Arg Ile Arg Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 114]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體06_9_10_111]]> <![CDATA[<400> 114]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Ala Ala Glu Lys Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys 20 25 30 Phe Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met 35 40 45 Pro Lys Thr Leu Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Ala 100 105 110 Arg Ile Arg Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 115]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體07_9_10_11]]> <![CDATA[<400> 115]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Ala Ala Ala Lys Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys 20 25 30 Phe Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met 35 40 45 Pro Lys Thr Leu Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp 100 105 110 Arg Ile Arg Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 116]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體08_10_11_12]]> <![CDATA[<400> 116]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Thr Ala Ala Ala Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys 20 25 30 Phe Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met 35 40 45 Pro Lys Thr Leu Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp 100 105 110 Arg Ile Arg Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 117]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體09_11_12_13]]> <![CDATA[<400> 117]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Ala Ala Ala Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys 20 25 30 Phe Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met 35 40 45 Pro Lys Thr Leu Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp 100 105 110 Arg Ile Arg Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 118]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體10_16_118_119]]> <![CDATA[<400> 118]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu 1 5 10 15 Ala Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys 20 25 30 Phe Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met 35 40 45 Pro Lys Thr Leu Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp 100 105 110 Arg Ile Arg Leu Val Val Ala Ala Glu 115 120 <![CDATA[<210> 119]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體11_19_20_85]]> <![CDATA[<400> 119]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu 1 5 10 15 Lys Glu Gly Ala Ala Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys 20 25 30 Phe Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met 35 40 45 Pro Lys Thr Leu Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Ala Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp 100 105 110 Arg Ile Arg Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 120]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體12_22_24_26]]> <![CDATA[<400> 120]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Ala Val Ala Cys Ala Tyr Thr Leu Glu Lys 20 25 30 Phe Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met 35 40 45 Pro Lys Thr Leu Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp 100 105 110 Arg Ile Arg Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 121]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體13_24_26_28]]> <![CDATA[<400> 121]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Ala Cys Ala Tyr Ala Leu Glu Lys 20 25 30 Phe Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met 35 40 45 Pro Lys Thr Leu Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp 100 105 110 Arg Ile Arg Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 122]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體14_26_28_29]]> <![CDATA[<400> 122]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Lys Cys Ala Tyr Ala Ala Glu Lys 20 25 30 Phe Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met 35 40 45 Pro Lys Thr Leu Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp 100 105 110 Arg Ile Arg Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 123]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體15_28_29_30]]> <![CDATA[<400> 123]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Ala Ala Ala Lys 20 25 30 Phe Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met 35 40 45 Pro Lys Thr Leu Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp 100 105 110 Arg Ile Arg Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 124]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體16_29_30_31]]> <![CDATA[<400> 124]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Ala Ala Ala 20 25 30 Phe Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met 35 40 45 Pro Lys Thr Leu Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp 100 105 110 Arg Ile Arg Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 125]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體17_31_32_35]]> <![CDATA[<400> 125]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Ala 20 25 30 Ala Ala Ser Ala Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met 35 40 45 Pro Lys Thr Leu Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp 100 105 110 Arg Ile Arg Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 126]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體18_30_34]]> <![CDATA[<400> 126]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Ala Lys 20 25 30 Phe Ala Ala Ser Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met 35 40 45 Pro Lys Thr Leu Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp 100 105 110 Arg Ile Arg Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 127]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體19_34_35_57]]> <![CDATA[<400> 127]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys 20 25 30 Phe Ala Ala Ala Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met 35 40 45 Pro Lys Thr Leu Ala Cys Thr Glu Arg Ala Ser Lys Asn Ser His Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp 100 105 110 Arg Ile Arg Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 128]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體20_35_36_56]]> <![CDATA[<400> 128]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys 20 25 30 Phe Ala Ser Ala Ala Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met 35 40 45 Pro Lys Thr Leu Ala Cys Thr Glu Ala Pro Ser Lys Asn Ser His Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp 100 105 110 Arg Ile Arg Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 129]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體21_40_49_50]]> <![CDATA[<400> 129]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys 20 25 30 Phe Ala Ser Ser Gln Lys Ala Trp Ala Ile Ile Arg Asp Gly Glu Met 35 40 45 Pro Ala Ala Leu Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp 100 105 110 Arg Ile Arg Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 130]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體22_43_44_47]]> <![CDATA[<400> 130]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys 20 25 30 Phe Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Ala Ala Gly Glu Ala 35 40 45 Pro Lys Thr Leu Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp 100 105 110 Arg Ile Arg Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 131]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體23_43_44_45]]> <![CDATA[<400> 131]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys 20 25 30 Phe Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Ala Ala Ala Glu Met 35 40 45 Pro Lys Thr Leu Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp 100 105 110 Arg Ile Arg Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 132]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體24_44_45_46]]> <![CDATA[<400> 132]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys 20 25 30 Phe Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Arg Ala Ala Ala Met 35 40 45 Pro Lys Thr Leu Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp 100 105 110 Arg Ile Arg Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 133]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體25_45_46_47]]> <![CDATA[<400> 133]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys 20 25 30 Phe Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Arg Asp Ala Ala Ala 35 40 45 Pro Lys Thr Leu Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp 100 105 110 Arg Ile Arg Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 134]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體26_43_46_47]]> <![CDATA[<400> 134]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys 20 25 30 Phe Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Ala Asp Gly Ala Ala 35 40 45 Pro Lys Thr Leu Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp 100 105 110 Arg Ile Arg Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 135]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體27_47_48_49]]> <![CDATA[<400> 135]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys 20 25 30 Phe Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Ala 35 40 45 Ala Ala Thr Leu Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp 100 105 110 Arg Ile Arg Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 136]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體28_47_49_50]]> <![CDATA[<400> 136]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys 20 25 30 Phe Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Ala 35 40 45 Pro Ala Ala Leu Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp 100 105 110 Arg Ile Arg Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 137]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體29_49_50_53]]> <![CDATA[<400> 137]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys 20 25 30 Phe Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met 35 40 45 Pro Ala Ala Leu Ala Ala Thr Glu Arg Pro Ser Lys Asn Ser His Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp 100 105 110 Arg Ile Arg Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 138]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體30_50_53_55]]> <![CDATA[<400> 138]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys 20 25 30 Phe Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met 35 40 45 Pro Lys Ala Leu Ala Ala Thr Ala Arg Pro Ser Lys Asn Ser His Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp 100 105 110 Arg Ile Arg Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 139]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體31_55_56_57]]> <![CDATA[<400> 139]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys 20 25 30 Phe Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met 35 40 45 Pro Lys Thr Leu Ala Cys Thr Ala Ala Ala Ser Lys Asn Ser His Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp 100 105 110 Arg Ile Arg Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 140]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體32_34_56_57]]> <![CDATA[<400> 140]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys 20 25 30 Phe Ala Ala Ser Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met 35 40 45 Pro Lys Thr Leu Ala Cys Thr Glu Ala Ala Ser Lys Asn Ser His Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp 100 105 110 Arg Ile Arg Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 141]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體33_57_59_60]]> <![CDATA[<400> 141]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys 20 25 30 Phe Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met 35 40 45 Pro Lys Thr Leu Ala Cys Thr Glu Arg Ala Ser Ala Ala Ser His Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp 100 105 110 Arg Ile Arg Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 142]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體34_59_60_61]]> <![CDATA[<400> 142]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys 20 25 30 Phe Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met 35 40 45 Pro Lys Thr Leu Ala Cys Thr Glu Arg Pro Ser Ala Ala Ala His Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp 100 105 110 Arg Ile Arg Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 143]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體35_60_61_62]]> <![CDATA[<400> 143]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys 20 25 30 Phe Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met 35 40 45 Pro Lys Thr Leu Ala Cys Thr Glu Arg Pro Ser Lys Ala Ala Ala Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp 100 105 110 Arg Ile Arg Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 144]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體36_61_62_63]]> <![CDATA[<400> 144]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys 20 25 30 Phe Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met 35 40 45 Pro Lys Thr Leu Ala Cys Thr Glu Arg Pro Ser Lys Asn Ala Ala Ala 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp 100 105 110 Arg Ile Arg Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 145]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體37_62_63_64]]> <![CDATA[<400> 145]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys 20 25 30 Phe Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met 35 40 45 Pro Lys Thr Leu Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser Ala Ala 50 55 60 Ala Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp 100 105 110 Arg Ile Arg Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 146]]> <![CDATA[<211> 121]]> <![CDATA[<212> ]]>PRT <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體38_63_64_65]]> <![CDATA[<400> 146]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys 20 25 30 Phe Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met 35 40 45 Pro Lys Thr Leu Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Ala 50 55 60 Ala Ala Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp 100 105 110 Arg Ile Arg Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 147]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體39_64_65_66]]> <![CDATA[<400> 147]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys 20 25 30 Phe Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met 35 40 45 Pro Lys Thr Leu Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro 50 55 60 Ala Ala Ala Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp 100 105 110 Arg Ile Arg Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 148]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體40_60_74_76]]> <![CDATA[<400> 148]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys 20 25 30 Phe Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met 35 40 45 Pro Lys Thr Leu Ala Cys Thr Glu Arg Pro Ser Lys Ala Ser His Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Ala His Ala His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp 100 105 110 Arg Ile Arg Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 149]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體41_60_75_76]]> <![CDATA[<400> 149]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys 20 25 30 Phe Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met 35 40 45 Pro Lys Thr Leu Ala Cys Thr Glu Arg Pro Ser Lys Ala Ser His Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr Ala Ala His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp 100 105 110 Arg Ile Arg Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 150]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體42_60_76_77]]> <![CDATA[<400> 150]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys 20 25 30 Phe Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met 35 40 45 Pro Lys Thr Leu Ala Cys Thr Glu Arg Pro Ser Lys Ala Ser His Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Ala Ala Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp 100 105 110 Arg Ile Arg Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 151]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體43_28_76_77]]> <![CDATA[<400> 151]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Ala Leu Glu Lys 20 25 30 Phe Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met 35 40 45 Pro Lys Thr Leu Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Ala Ala Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp 100 105 110 Arg Ile Arg Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 152]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體44_28_77_78]]> <![CDATA[<400> 152]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Ala Leu Glu Lys 20 25 30 Phe Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met 35 40 45 Pro Lys Thr Leu Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp Ala Ala Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp 100 105 110 Arg Ile Arg Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 153]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體45_96_109_111]]> <![CDATA[<400> 153]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys 20 25 30 Phe Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met 35 40 45 Pro Lys Thr Leu Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Ala Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Ala Phe Ala 100 105 110 Arg Ile Arg Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 154]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體46_98_100_109]]> <![CDATA[<400> 154]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys 20 25 30 Phe Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met 35 40 45 Pro Lys Thr Leu Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Ala Ile Ala Gln Pro Pro Lys Glu Pro His Met Ala Phe Asp 100 105 110 Arg Ile Arg Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 155]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體47_35_100_102]]> <![CDATA[<400> 155]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys 20 25 30 Phe Ala Ser Ala Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met 35 40 45 Pro Lys Thr Leu Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Ala Gln Ala Pro Lys Glu Pro His Met Leu Phe Asp 100 105 110 Arg Ile Arg Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 156]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體48_102_103_104]]> <![CDATA[<400> 156]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys 20 25 30 Phe Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met 35 40 45 Pro Lys Thr Leu Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Ala Ala Ala Glu Pro His Met Leu Phe Asp 100 105 110 Arg Ile Arg Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 157]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體49_103_104_105]]> <![CDATA[<400> 157]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys 20 25 30 Phe Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met 35 40 45 Pro Lys Thr Leu Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Ala Ala Ala Pro His Met Leu Phe Asp 100 105 110 Arg Ile Arg Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 158]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體50_]]>104_105_106 <![CDATA[<400> 158]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys 20 25 30 Phe Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met 35 40 45 Pro Lys Thr Leu Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Pro Ala Ala Ala His Met Leu Phe Asp 100 105 110 Arg Ile Arg Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 159]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體51_105_106_107]]> <![CDATA[<400> 159]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys 20 25 30 Phe Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met 35 40 45 Pro Lys Thr Leu Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Pro Lys Ala Ala Ala Met Leu Phe Asp 100 105 110 Arg Ile Arg Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 160]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體52_106_107_108]]> <![CDATA[<400> 160]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys 20 25 30 Phe Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met 35 40 45 Pro Lys Thr Leu Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Pro Lys Glu Ala Ala Ala Leu Phe Asp 100 105 110 Arg Ile Arg Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 161]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體53_107_108_109]]> <![CDATA[<400> 161]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys 20 25 30 Phe Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met 35 40 45 Pro Lys Thr Leu Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro Ala Ala Ala Phe Asp 100 105 110 Arg Ile Arg Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 162]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體54_109_110_111]]> <![CDATA[<400> 162]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys 20 25 30 Phe Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met 35 40 45 Pro Lys Thr Leu Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Ala Ala Ala 100 105 110 Arg Ile Arg Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 163]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體55_11_113_114]]> <![CDATA[<400> 163]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Ala Lys Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys 20 25 30 Phe Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met 35 40 45 Pro Lys Thr Leu Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp 100 105 110 Arg Ala Ala Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 164]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體56_10_12_114]]> <![CDATA[<400> 164]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Thr Ala Glu Ala Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys 20 25 30 Phe Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met 35 40 45 Pro Lys Thr Leu Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp 100 105 110 Arg Ile Ala Leu Val Val Thr Leu Glu 115 120 <![CDATA[<210> 165]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體57_118_119_120]]> <![CDATA[<400> 165]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu 1 5 10 15 Lys Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys 20 25 30 Phe Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met 35 40 45 Pro Lys Thr Leu Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp 100 105 110 Arg Ile Arg Leu Val Val Ala Ala Ala 115 120 <![CDATA[<210> 166]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體58_16_119_120]]> <![CDATA[<400> 166]]> Met Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu 1 5 10 15 Ala Glu Gly Gln Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys 20 25 30 Phe Ala Ser Ser Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met 35 40 45 Pro Lys Thr Leu Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro 50 55 60 Val Gln Val Gly Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu 65 70 75 80 Leu Arg Val Arg Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr 85 90 95 Gln Cys Val Ile Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp 100 105 110 Arg Ile Arg Leu Val Val Thr Ala Ala 115 120 <![CDATA[<210> 167]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1 WT 01_WT_2A]]> <![CDATA[<400> 167]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 168]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體02_2_3]]> <![CDATA[<400> 168]]> Ala Ala Ala Ala Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 169]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體03_3_4]]> <![CDATA[<400> 169]]> Ala Ala Thr Ala Ala Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 170]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體04_4_5]]> <![CDATA[<400> 170]]> Ala Ala Thr Lys Ala Ala Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 171]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體05_5_104]]> <![CDATA[<400> 171]]> Ala Ala Thr Lys Leu Ala Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Ala Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 172]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體06_5_106]]> <![CDATA[<400> 172]]> Ala Ala Thr Lys Leu Ala Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Ala Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 173]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體07_5_107]]> <![CDATA[<400> 173]]> Ala Ala Thr Lys Leu Ala Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Ala Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 174]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體08_7_9]]> <![CDATA[<400> 174]]> Ala Ala Thr Lys Leu Thr Glu Ala Lys Ala Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 175]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體09_7_107]]> <![CDATA[<400> 175]]> Ala Ala Thr Lys Leu Thr Glu Ala Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Ala Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 176]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體10_8_10]]> <![CDATA[<400> 176]]> Ala Ala Thr Lys Leu Thr Glu Glu Ala Tyr Ala Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 177]]> <![CDATA[<211> 117]]> <![CDATA[<212> PR]]>T <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體11_11_12]]> <![CDATA[<400> 177]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Ala Ala Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 178]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體12_12_13]]> <![CDATA[<400> 178]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Ala Ala Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 179]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體13_12_15]]> <![CDATA[<400> 179]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Ala Glu Gly Ala 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 180]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體14_13_85]]> <![CDATA[<400> 180]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Ala Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Ala Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 181]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體15_16_81]]> <![CDATA[<400> 181]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Ala Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Ala Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 182]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TRE]]>M1突變體16_20_75 <![CDATA[<400> 182]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Ala Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Ala Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 183]]> <![CDATA[<211> 117]]> <![CDATA[<212>]]> PRT <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體17_24_25]]> <![CDATA[<400> 183]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Ala Ala Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 184]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體18_24_26]]> <![CDATA[<400> 184]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Ala Leu Ala Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 185]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體19_24_27]]> <![CDATA[<400> 185]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Ala Leu Glu Ala Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 186]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體20_25_26]]> <![CDATA[<400> 186]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Ala Ala Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 187]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體21_26_27]]> <![CDATA[<400> 187]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Ala Ala Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 188]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體22_30_31]]> <![CDATA[<400> 188]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ala Ala 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 189]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體23_30_53]]> <![CDATA[<400> 189]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ala Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Ala Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 190]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體24_37_38]]> <![CDATA[<400> 190]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ala Ala Arg Asp Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 191]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體25_37_39]]> <![CDATA[<400> 191]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ala Ile Ala Asp Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 192]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體26_37_45]]> <![CDATA[<400> 192]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ala Ile Arg Asp Gly Glu Met Pro Ala Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 193]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體27_37_47]]> <![CDATA[<400> 193]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ala Ile Arg Asp Gly Glu Met Pro Lys Thr Ala 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 194]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體28_38_44]]> <![CDATA[<400> 194]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ala Arg Asp Gly Glu Met Ala Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 195]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體29_38_90]]> <![CDATA[<400> 195]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ala Arg Asp Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Ala Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 196]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體30_42]]>_43 <![CDATA[<400> 196]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Ala Ala Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 197]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體31_42_45]]> <![CDATA[<400> 197]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Ala Met Pro Ala Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 198]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體32_43_44]]> <![CDATA[<400> 198]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Ala Ala Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 199]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體33_43_101]]> <![CDATA[<400> 199]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Ala Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Ala Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 200]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體34_44_45]]> <![CDATA[<400> 200]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Ala Ala Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 201]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體35_45_47]]> <![CDATA[<400> 201]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Ala Thr Ala 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 202]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體36_47_65]]> <![CDATA[<400> 202]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Ala 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ala Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 203]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體37_51_55]]> <![CDATA[<400> 203]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Ala Arg Pro Ser Ala Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 204]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體38_56_57]]> <![CDATA[<400> 204]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Ala Ala His Pro Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 205]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體39_58_59]]> <![CDATA[<400> 205]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser Ala Ala Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 206]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體40_59_60]]> <![CDATA[<400> 206]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Ala Ala Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 207]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體41_59_61]]> <![CDATA[<400> 207]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Ala Val Ala Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 208]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體42_59_66]]> <![CDATA[<400> 208]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Ala Val Gln Val Gly 50 55 60 Arg Ile Ala Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 209]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體43_60_61]]> <![CDATA[<400> 209]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Ala Ala Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 210]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體44_60_62]]> <![CDATA[<400> 210]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Ala Gln Ala Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 211]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體45_61_62]]> <![CDATA[<400> 211]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Ala Ala Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 212]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體46_61_66]]> <![CDATA[<400> 212]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Ala Val Gly 50 55 60 Arg Ile Ala Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 213]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體47_62_65]]> <![CDATA[<400> 213]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Ala Gly 50 55 60 Arg Ala Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 214]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體48_65_66]]> <![CDATA[<400> 214]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ala Ala Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 215]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體49_66_81]]> <![CDATA[<400> 215]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ile Ala Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Ala Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 216]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體50_72_73]]> <![CDATA[<400> 216]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Ala Ala Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 217]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體51_73_75]]> <![CDATA[<400> 217]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp Ala Gly Ala Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 218]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體52_81_82]]> <![CDATA[<400> 218]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Ala Ala Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 219]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體53_85_86]]> <![CDATA[<400> 219]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Ala Ala Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 220]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體54_98_99]]> <![CDATA[<400> 220]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Ala Ala Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 221]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體55_99_100]]> <![CDATA[<400> 221]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Ala Ala Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 222]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體56_100_101]]> <![CDATA[<400> 222]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Ala Ala Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 223]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體57_101_102]]> <![CDATA[<400> 223]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Ala Ala His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 224]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體58_102_103]]> <![CDATA[<400> 224]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Ala Ala Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 225]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體59_103_104]]> <![CDATA[<400> 225]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro Ala Ala Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 226]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體60_104_106]]> <![CDATA[<400> 226]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Ala Leu Ala Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 227]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體61_106_107]]> <![CDATA[<400> 227]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Ala Ala Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 228]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體62_8_10_112]]> <![CDATA[<400> 228]]> Ala Ala Thr Lys Leu Thr Glu Glu Ala Tyr Ala Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Ala Val Thr Lys Gly 115 <![CDATA[<210> 229]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體63_37_39_40]]> <![CDATA[<400> 229]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ala Ile Ala Ala Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 230]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體64_40]]> <![CDATA[<400> 230]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Ala Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Val Val Thr Lys Gly 115 <![CDATA[<210> 231]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體65_112]]> <![CDATA[<400> 231]]> Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln 1 5 10 15 Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser 20 25 30 Gln Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu 35 40 45 Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly 50 55 60 Arg Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg 65 70 75 80 Met Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile 85 90 95 Tyr Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu 100 105 110 Ala Val Thr Lys Gly 115 <![CDATA[<210> 232]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1 WT 01_WT_1A]]> <![CDATA[<400> 232]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 233]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體02_1]]> <![CDATA[<400> 233]]> Ala Ala Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 234]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體03_2]]> <![CDATA[<400> 234]]> Ala Thr Ala Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 235]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體04_4]]> <![CDATA[<400> 235]]> Ala Thr Lys Leu Ala Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 236]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類]]>TREM1突變體05_5 <![CDATA[<400> 236]]> Ala Thr Lys Leu Thr Ala Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 237]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體06_6]]> <![CDATA[<400> 237]]> Ala Thr Lys Leu Thr Glu Ala Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 238]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體07_7]]> <![CDATA[<400> 238]]> Ala Thr Lys Leu Thr Glu Glu Ala Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 239]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體08_8]]> <![CDATA[<400> 239]]> Ala Thr Lys Leu Thr Glu Glu Lys Ala Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 240]]> <![CDATA[<21]]>1> 116]]> <br/><![CDATA[<212> PRT]]> <br/><![CDATA[<213> 人工序列]]> <br/> <br/><![CDATA[<220>]]> <br/><![CDATA[<223> 人類TREM1突變體09_9]]> <br/> <br/><![CDATA[<400> 240]]> <br/> <br/><![CDATA[Ala Thr Lys Leu Thr Glu Glu Lys Tyr Ala Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 241]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體10_11]]> <![CDATA[<400> 241]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Ala Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 242]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體11_14]]> <![CDATA[<400> 242]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Ala Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 243]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體12_17]]> <![CDATA[<400> 243]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Ala Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 244]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體13_19]]> <![CDATA[<400> 244]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Ala Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 245]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體14_21]]> <![CDATA[<400> 245]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Ala Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 246]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體15_23]]> <![CDATA[<400> 246]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Ala Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 247]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體16_24]]> <![CDATA[<400> 247]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Ala Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 248]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體17_25]]> <![CDATA[<400> 248]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Ala Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 249]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體18_26]]> <![CDATA[<400> 249]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Ala Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 250]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體19_29]]> <![CDATA[<400> 250]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ala Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 251]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體20_30]]> <![CDATA[<400> 251]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ala Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 252]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體21_38]]> <![CDATA[<400> 252]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Ala Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 253]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體22_39]]> <![CDATA[<400> 253]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Ala Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 254]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體23_41]]> <![CDATA[<400> 254]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Ala Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 255]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體24_42]]> <![CDATA[<400> 255]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Ala Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 256]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體25_44]]> <![CDATA[<400> 256]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Ala Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 257]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體26_45]]> <![CDATA[<400> 257]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Ala Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 258]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體27_50]]> <![CDATA[<400> 258]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Ala Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 259]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體28_51]]> <![CDATA[<400> 259]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Ala Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 260]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體29_52]]> <![CDATA[<400> 260]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Ala Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 261]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體30_54]]> <![CDATA[<400> 261]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Ala Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 262]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體31_55]]> <![CDATA[<400> 262]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Ala Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 263]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體32_56]]> <![CDATA[<400> 263]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ala His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 264]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體33_57]]> <![CDATA[<400> 264]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser Ala Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 265]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體34_58]]> <![CDATA[<400> 265]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Ala Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 266]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體35_59]]> <![CDATA[<400> 266]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Ala Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 267]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體36_60]]> <![CDATA[<400> 267]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Ala Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 268]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體37_61]]> <![CDATA[<400> 268]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Ala Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 269]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體38_63]]> <![CDATA[<400> 269]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Ala 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 270]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體39_65]]> <![CDATA[<400> 270]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ala Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 271]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體40_71]]> <![CDATA[<400> 271]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Ala His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 272]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體41_72]]> <![CDATA[<400> 272]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp Ala Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 273]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體42_78]]> <![CDATA[<400> 273]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Ala Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 274]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體43_80]]> <![CDATA[<400> 274]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Ala Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 275]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體44_81]]> <![CDATA[<400> 275]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Ala Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 276]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體45_83]]> <![CDATA[<400> 276]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Ala Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 277]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體46_84]]> <![CDATA[<400> 277]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Ala Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 278]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體47_85]]> <![CDATA[<400> 278]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Ala Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 279]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體48_87]]> <![CDATA[<400> 279]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ala Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 280]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體49_95]]> <![CDATA[<400> 280]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Ala 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 281]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體50_97]]> <![CDATA[<400> 281]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Ala Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 282]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體51_98]]> <![CDATA[<400> 282]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Ala Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 283]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體52_99]]> <![CDATA[<400> 283]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Ala Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 284]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體53_100]]> <![CDATA[<400> 284]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Ala Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 285]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體54_101]]> <![CDATA[<400> 285]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Ala His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 286]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體55_102]]> <![CDATA[<400> 286]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro Ala Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 287]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體56_103]]> <![CDATA[<400> 287]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Ala Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 288]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體57_104]]> <![CDATA[<400> ]]> 288 Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Ala Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 289]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體58_106]]> <![CDATA[<400> 289]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Ala Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 290]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體59_109]]> <![CDATA[<400> 290]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Ala Leu Val 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 291]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體60_111]]> <![CDATA[<400> 291]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Ala 100 105 110 Val Thr Leu Glu 115 <![CDATA[<210> 292]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體61_113]]> <![CDATA[<400> 292]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Ala Leu Glu 115 <![CDATA[<210> 293]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體62_114]]> <![CDATA[<400> 293]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Ala Glu 115 <![CDATA[<210> 294]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類TREM1突變體63_115]]> <![CDATA[<400> 294]]> Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys Glu Gly Gln Thr 1 5 10 15 Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe Ala Ser Ser Gln 20 25 30 Lys Ala Trp Gln Ile Ile Arg Asp Gly Glu Met Pro Lys Thr Leu Ala 35 40 45 Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gln Val Gly Arg 50 55 60 Ile Ile Leu Glu Asp Tyr His Asp His Gly Leu Leu Arg Val Arg Met 65 70 75 80 Val Asn Leu Gln Val Glu Asp Ser Gly Leu Tyr Gln Cys Val Ile Tyr 85 90 95 Gln Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg Ile Arg Leu Val 100 105 110 Val Thr Leu Ala 115
Claims (33)
- 一種與人類TREM1結合之抗體,其包含: 輕鏈可變區,該輕鏈可變區包含: 包含SEQ ID NO:11之CDR-L1, 包含SEQ ID NO:12之CDR-L2,及 包含SEQ ID NO:13之CDR-L3; 以及重鏈可變區,該重鏈可變區包含: 包含SEQ ID NO:14之CDR-H1, 包含SEQ ID NO:15之CDR-H2,及 包含SEQ ID NO:16之CDR-H3。
- 如請求項1之抗體,其中該抗體抑制或減弱TREM1與其天然配位體中之一或多者之結合。
- 如請求項1或請求項2之抗體,其中該抗體抑制或減弱TREM1與PGLYRP1之結合。
- 如請求項1至3中任一項之抗體,其中該抗體對於人類TREM1之解離平衡常數(KD)小於600 pM。
- 如請求項1至4中任一項之抗體,其中該抗體結合於TREM1上不同於PGLYRP1之位點。
- 如請求項1至5中任一項之抗體,其中該抗體結合於人類TREM1之抗原決定基,該抗原決定基包含人類TREM1 (SEQ ID NO: 1)之殘基E26、E27、K28、Y29、E30、L31、K32。
- 如請求項1至5中任一項之抗體,其中該抗體結合於人類TREM1之抗原決定基,該抗原決定基包含選自人類TREM1 (SEQ ID NO: 1)之E26、E27、K28、Y29、E30、L31、K32、Q35、T36、D38、K40、D42、R97、D127、T134及G136之五個或更多個殘基,由在該抗體與TREM1之間小於4Å接觸距離的距離處所測定。
- 如請求項7之抗體,其中該結合使用X射線結晶學測定。
- 如請求項1至8中任一項之抗體,其中該輕鏈可變區包含SEQ ID NO:29中給出之序列。
- 如請求項1至9中任一項之抗體,其中該重鏈可變區包含SEQ ID NO:79中給出之序列。
- 如請求項1至8中任一項之抗體,其中該輕鏈可變區包含SEQ ID NO: 29中給出之序列或與其至少90%一致之序列;且該重鏈可變區包含SEQ ID NO: 79中給出之序列或與其至少90%一致之序列。
- 如請求項1之抗體,其中各CDR含有至多三個胺基酸取代,且其中此類胺基酸取代為保守性。
- 如請求項1之抗體,其中該輕鏈可變區及該重鏈可變區之其餘部分分別與SEQ ID No: 29及79具有至少90%一致性。
- 如請求項1至13中任一項之抗體,其中該抗體為抗體片段。
- 如請求項14之抗體,其中該抗體片段為Fab、Fab'、F(ab') 2、Fv、dsFv、scFv或dsscFv。
- 如請求項1至13中任一項之抗體,其中該抗體為全長抗體。
- 如請求項16之抗體,其中該抗體為IgG1、IgG1 LALA、IgG4、IgG4P或IgG4P FALA。
- 如請求項16之抗體,其中該抗體為IgG4P,其包含有包含SEQ ID NO: 31中給出之序列的輕鏈及包含SEQ ID NO: 81中給出之序列的重鏈。
- 如請求項1至8中任一項之抗體,其中該抗體為IgG4P且其中該輕鏈及該重鏈之其餘部分分別與SEQ ID NO:31及81具有至少90%一致性或相似性。
- 一種會與如請求項1之抗體交叉競爭結合於TREM1抗原決定基之抗體,該抗原決定基包含人類TREM1 (SEQ ID NO: 1)之殘基E26、E27、K28、Y29、E30、L31、K32及Q35。
- 一種會與人類TREM1之抗原決定基結合的IgG4P抗體,該抗原決定基包含人類TREM1 (SEQ ID NO: 1)之殘基E26、E27、K28、Y29、E30、L31、K32及Q35。
- 一種經分離之聚核苷酸,其編碼如請求項1至21中任一項之抗體。
- 一種表現載體,其攜載如請求項22之聚核苷酸。
- 一種宿主細胞,其包含如請求項23所定義之載體。
- 一種產生如請求項1至21中任一項之抗體之方法,其包含在允許產生該抗體之條件下培養如請求項24之宿主細胞,及回收所產生之該抗體。
- 一種醫藥組合物,其包含如請求項1至21中任一項之抗體及醫藥學上可接受之佐劑或載劑。
- 如請求項1至21中任一項之抗體或如請求項26所定義之醫藥組合物,其用於藉由療法治療人體或動物體之方法中。
- 如請求項1至21中任一項之抗體或如請求項26所定義之醫藥組合物,其用作藥劑。
- 一種如請求項1至21中任一項之抗體或如請求項26之醫藥組合物的用途,其用於製造藥劑。
- 如請求項1至21中任一項之抗體或如請求項26之醫藥組合物,其用於治療神經病症。
- 一種治療或預防神經病症之方法,其包含向有需要之患者投與治療有效量之如請求項1至21中任一項之抗體或如請求項26所定義之醫藥組合物。
- 一種如請求項1至21中任一項之抗體或如請求項26之醫藥組合物的用途,其用於製造供治療神經病症用之藥劑。
- 如請求項30之抗體或醫藥組合物、如請求項31之方法或如請求項32之用途,其中該神經病症為肌肉萎縮性脊髓側索硬化症(ALS)或阿茲海默氏病(Alzheimer's disease)。
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JP2024516305A (ja) | 2024-04-12 |
AR125732A1 (es) | 2023-08-09 |
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KR20240004694A (ko) | 2024-01-11 |
BR112023022844A2 (pt) | 2024-01-23 |
CN117642428A (zh) | 2024-03-01 |
WO2022233764A1 (en) | 2022-11-10 |
AU2022268545A9 (en) | 2023-11-16 |
CA3218933A1 (en) | 2022-11-10 |
IL308100A (en) | 2023-12-01 |
AU2022268545A1 (en) | 2023-11-02 |
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