TW202309092A - 靶向dll3和pd—1的組合療法之給藥方案 - Google Patents
靶向dll3和pd—1的組合療法之給藥方案 Download PDFInfo
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Abstract
本發明提供一種治療DLL3陽性癌症或SCLC之方法,該方法包括向有需要的受試者投與抗DLL3藥劑和抗PD-1抗體。還揭露了該抗DLL3藥劑的階梯給藥。
Description
本申請關於靶向DLL3和PD-1的組合療法的劑量和投與以治療癌症。
δ樣3(DLL3)係一種1型跨膜蛋白和非經典Notch配位基。DLL3係開發T細胞療法的有希望的靶標,因為它在神經內分泌腫瘤的細胞表面高表現,並且在正常組織中的定位最少,主要是細胞質定位(Owen等人, J Hematol Oncol. [血液與腫瘤學雜誌], 12:61 (2019))。小細胞肺癌(SCLC)係神經內分泌癌,其中DLL3差異表現。使用免疫組織化學(IHC),85%的SCLC腫瘤對DLL3(模式與膜性表現和細胞質表現一致)染色陽性。相比之下,在正常腦、胰島和垂體中用胞質染色模式檢測到低水平的DLL3蛋白表現(Saunders等人, Sci Transl Med. [科學轉化醫學] 7:302ra136 (2015))。
SCLC係侵襲形式的肺癌,預後差且治療選擇有限,並代表約10%-15%的肺癌。數十年來,存活率仍然很低,只有5%的SCLC患者存活五年,這在很大程度上是由於缺乏新的療法來對抗這種形式的肺癌。SCLC之特徵係神經內分泌分化、生長分數高、倍增時間快和廣泛轉移病灶的早期建立。大約三分之一的患者表現為局限期疾病。大多數患者表現為廣泛期疾病,定義為腫瘤只存在於胸部的一側,並且其適合於單一的輻射場。該等期影響了可利用的治療方案,其中局限期疾病用化療和輻射治療,而廣泛期疾病僅用化療治療。
SCLC患者通常對目前的一線療法(包括依託泊苷和順鉑)響應良好,但化學抗性疾病總是很快復發,對於此目前沒有可用的治療選擇。復發性難治性情況的預後非常差,具有快速的疾病進展和少於六個月的短期中值存活期。患有擴展性疾病SCLC的患者發展為抗藥性並在診斷後10到12個月的中值時間時死於疾病。
AMG 757係雙特異性T細胞接合劑(BiTE®)分子,靶向癌細胞上的DLL3和T細胞上的CD3。它係為治療神經內分泌癌,例如SCLC而開發的。AMG 757正在一項治療SCLC的臨床試驗中進行評估。
派姆單抗(pembrolizumab,Keytruda®)和納武單抗(nivolumab,Opdivo®)係針對計畫性細胞死亡-1(PD-1)的抗體。兩者均已在美國獲批用於治療在基於鉑的化療和至少一種其他療法線後出現進展的轉移性SCLC患者。然而,批准係基於相對較低的緩解率(派姆單抗為19%,納武單抗為12%)。評估納武單抗作為二線或維持療法的研究未能達到其主要終點(Reck等人, Annals of Oncology.[腫瘤學年鑒] 29:x39-x43 (2018))。
對於開發治療SCLC的療法,存在未滿足的醫療需求。
基於本文提供的揭露內容,熟悉該項技術者將認知到或者僅使用常規實驗就能夠確定本文所述之本發明之特定實施方式的許多等同物。此類等同物旨在由以下實施方式(E)所涵蓋。
E1:一種治療DLL3陽性癌症之方法,該方法包括向有需要的受試者投與抗DLL3藥劑和抗PD-1抗體,其中該抗DLL3藥劑以0.3 mg至30 mg或3 mg至100 mg的劑量每兩週一次投與,並且其中該PD-1抗體以約480 mg的劑量每四週一次投與。
E2:一種治療DLL3陽性癌症之方法,該方法包括向有需要的受試者投與抗DLL3藥劑和抗PD-1抗體,其中該抗DLL3藥劑根據以下計畫以28天的週期投與:a) 第1週期第1天的第一劑量0.3 mg或1 mg,b) 第1週期第8天的第二劑量,和c) 第1週期第15天的第三劑量,和e) 從第2週期第1天開始並且之後每兩週一次的一或多個後續劑量,並且其中第二、第三和後續劑量相同,各自為0.3 mg至30 mg或3 mg至100 mg,並且高於第一劑量,並且其中抗PD-1抗體以480 mg的劑量每四週一次投與。
E3:如E1或E2所述之方法,其中該抗DLL3陽性癌症係小細胞肺癌(SCLC)。
E4:如E1-E3中任一項所述之方法,其中該抗DLL3陽性癌症係復發性/難治性(RR)SCLC或廣泛性疾病(ED)SCLC。
E5:如E1-E4中任一項所述之方法,其中該抗DLL3藥劑係雙特異性T細胞接合抗原結合多肽,其包含兩個結合結構域:第一結構域與人DLL3結合,並且第二結構域與人CD3結合。
E6:如E4所述之方法,其中該DLL3結合結構域與包含在SEQ ID NO: 29的胺基酸序列內的人DLL3的表位結合。
E7:如E5或E6所述之方法,其中該DLL3結合結構域包含 (a) 重鏈可變區(VH),該重鏈可變區包含:(i) VH互補性決定區1(CDR-H1),其包含SEQ ID NO: 1的胺基酸序列;(ii) CDR-H2,其包含SEQ ID NO: 2的胺基酸序列;以及 (iii) CDR-H3,其包含SEQ ID NO: 3的胺基酸序列;和 (b) 輕鏈可變區(VL),該輕鏈可變區包含:(i) VL互補性決定區1(CDR-L1),其包含SEQ ID NO: 4的胺基酸序列;(ii) CDR-L2,其包含SEQ ID NO: 5的胺基酸序列;以及 (iii) CDR-L3,其包含SEQ ID NO: 6的胺基酸序列。
E8:如E5-E7中任一項所述之方法,其中該DLL3結合結構域包含:(1) 包含SEQ ID NO: 7之胺基酸序列的VH和包含SEQ ID NO: 8之胺基酸序列的VL,或 (2) 包含SEQ ID NO: 11之胺基酸序列的VH和包含SEQ ID NO: 12之胺基酸序列的VL。
E9:如E5-E8中任一項所述之方法,其中該DLL3結合結構域的VH和VL藉由連接子連接以形成單鏈Fv(scFv)。
E10:如E9所述之方法,其中該連接子包含選自SEQ ID NO: 42-50中任一個的序列。
E11: 如E9或E10所述之方法,其中該連接子包含(Gly4Ser)x,其中x係1或更大的整數(例如1、2、3或4)。
E12:如E5-E11中任一項所述之方法,其中該DLL3結合結構域包含SEQ ID NO: 9或SEQ ID NO: 13的胺基酸序列。
E13:如E5-E12中任一項所述之方法,其中該CD3結合結構域包含:(a) VH,其包含:包含SEQ ID NO: 18之胺基酸序列的CDR-H1,包含SEQ ID NO: 19之胺基酸序列的CDR-H2,和包含SEQ ID NO: 20之胺基酸序列的CDR-H3;和VL,其包含:包含SEQ ID NO: 15之胺基酸序列的CDR-L1,包含SEQ ID NO: 16之胺基酸序列的CDR-L2,以及包含SEQ ID NO: 17之胺基酸序列的CDR-L3。
E14:如E5-E13中任一項所述之方法,其中該CD3結合結構域包含:包含SEQ ID NO: 21之胺基酸序列的VH和包含SEQ ID NO: 22之胺基酸序列的VL。
E15:如E13或E14所述之方法,其中該CD3結合結構域的VH和VL藉由連接子連接以形成單鏈Fv(scFv)。
E16:如E15所述之方法,其中該連接子包含選自SEQ ID NO: 42-50中任一個的序列。
E17:如E15或E16所述之方法,其中該連接子包含(Gly4Ser)x,其中x係1或更大的整數(例如1、2、3或4)。
E18:如E13-E17中任一項所述之方法,其中該CD3結合結構域包含SEQ ID NO: 23的胺基酸序列。
E19:如E5-E18中任一項所述之方法,其中該DLL3結合結構域和該CD3結合結構域藉由連接子連接。
E20:如E19所述之方法,其中該連接子係包含選自SEQ ID NO: 42-50中任一個的序列的肽連接子。
E21:如E19或E20所述之方法,其中該連接子係包含(Gly4Ser)x的肽連接子,其中x係1或更大的整數(例如,1、2、3或4)。
E22:如E5-E21中任一項所述之方法,該抗DLL3藥劑係雙特異性T細胞接合抗原結合多肽,其包含DLL3結合結構域和CD3結合結構域。該DLL3結合結構域包含 (a) 重鏈可變區(VH),該重鏈可變區包含:(i) VH互補性決定區1(CDR-H1),其包含SEQ ID NO: 1的胺基酸序列;(ii) CDR-H2,其包含SEQ ID NO: 2的胺基酸序列;以及 (iii) CDR-H3,其包含SEQ ID NO: 3的胺基酸序列;和 (b) 輕鏈可變區(VL),該輕鏈可變區包含:(i) VL互補性決定區1(CDR-L1),其包含SEQ ID NO: 4的胺基酸序列;(ii) CDR-L2,其包含SEQ ID NO: 5的胺基酸序列;以及 (iii) CDR-L3,其包含SEQ ID NO: 6的胺基酸序列。該CD3結合結構域包含 (a) VH,其包含:(i) 包含SEQ ID NO: 18之胺基酸序列的CDR-H1,(ii) 包含SEQ ID NO: 19之胺基酸序列的CDR-H2,和 (iii) 包含SEQ ID NO: 20之胺基酸序列的CDR-H3;和 (b) VL,其包含:(i) 包含SEQ ID NO: 15之胺基酸序列的CDR-L1,(ii) 包含SEQ ID NO: 16之胺基酸序列的CDR-L2,以及 (iii) 包含SEQ ID NO: 17之胺基酸序列的CDR-L3。
E23:如E5-E22中任一項所述之方法,該DLL3結合結構域包含含有SEQ ID NO: 7之胺基酸序列的VH和含有SEQ ID NO: 8之胺基酸序列的VL,並且該CD3結合結構域包含含有SEQ ID NO: 21之胺基酸序列的VH和含有SEQ ID NO: 22之胺基酸序列的VL。
E24:如E5-E22中任一項所述之方法,該DLL3結合結構域包含含有SEQ ID NO: 11之胺基酸序列的VH和含有SEQ ID NO: 12之胺基酸序列的VL,並且該CD3結合結構域包含含有SEQ ID NO: 21之胺基酸序列的VH和含有SEQ ID NO: 22之胺基酸序列的VL。
E25:如E5-E23中任一項所述之方法,其中該DLL3結合結構域包含SEQ ID NO: 9的胺基酸並且該CD3結合結構域包含SEQ ID NO: 23的胺基酸。
E26:如E5-E21或E24中任一項所述之方法,該DLL3結合結構域包含SEQ ID NO: 13的胺基酸並且該CD3結合結構域包含SEQ ID NO: 23的胺基酸。
E27:如E25所述之方法,其中該抗DLL3藥劑包含SEQ ID NO: 10的胺基酸序列。
E28:如E27所述之方法,其中該抗DLL3藥劑包含SEQ ID NO: 14的胺基酸序列。
E29:如E5-E28中任一項所述之方法,其中該抗DLL3藥劑進一步包含延長或增強該抗DLL3藥劑之血清半衰期的第三結構域。
E30:如E29所述之方法,其中該第三結構域包含選自SEQ ID NO: 51-58中任一個的胺基酸序列。
E31:如E5-E22、E24、E26、E28-E30中任一項所述之方法,其中該抗DLL3藥劑包含SEQ ID NO: 27或59的胺基酸。
E32:如E5-E31中任一項所述之方法,其中該抗PD-1抗體包含 (a) VH,其包含:(i) 包含SEQ ID NO: 32之胺基酸序列的CDR-H1,(ii) 包含SEQ ID NO: 33之胺基酸序列的CDR-H2,(iii) 包含SEQ ID NO: 34之胺基酸序列的CDR-H3;和 (b) VL,其包含:(i) 包含SEQ ID NO: 35之胺基酸序列的CDR-L1,(ii) 包含SEQ ID NO: 36之胺基酸序列的CDR-L2,(iii) 包含SEQ ID NO: 37之胺基酸序列的CDR-L3。
E33:如E5-E32中任一項所述之方法,其中該抗PD-1抗體包含含有SEQ ID NO: 38之胺基酸序列的VH和含有SEQ ID NO: 39之胺基酸序列的VL。
E34:如E5-E33中任一項所述之方法,其中該抗PD-1抗體包含重鏈(HC)和輕鏈(LC),該重鏈包含EQ ID NO: 40的胺基酸序列並且該輕鏈包含SEQ ID NO: 41的胺基酸序列。
E35:如E1或E3-E34中任一項所述之方法,其中該抗DLL3藥劑以以下劑量每兩週一次投與:約0.3 mg至約30 mg、約1 mg至約30 mg、約3 mg至約30 mg或約10 mg至約30 mg。
E36:如E35所述之方法,其中該抗DLL3藥劑以約0.3 mg、1 mg、3 mg、10 mg、25 mg或30 mg的劑量每兩週一次投與。
E37:如E1或E3-E34中任一項所述之方法,其中該抗DLL3藥劑以以下劑量每兩週一次投與:約3 mg至約100 mg、約10 mg至約100 mg或約30 mg至約100 mg。
E38:如E37所述之方法,其中該抗DLL3藥劑以約3 mg,10 mg、25 mg、30 mg、50 mg、75 mg或100 mg的劑量每兩週一次投與。
E39:如E2-E34中任一項所述之方法,其中該抗DLL3藥劑的第二劑量、第三劑量和後續劑量各自是約0.3 mg至約30 mg、約1 mg至約30 mg、約3 mg至約30 mg或約10 mg至約30 mg。
E40:如E39中任一項所述之方法,其中該抗DLL3藥劑的第二劑量、第三劑量和後續劑量各自是約0.3 mg、1 mg、3 mg、10 mg、25 mg或30 mg的劑量。
E41:如E2-E34中任一項所述之方法,其中該抗DLL3藥劑的第二劑量、第三劑量和後續劑量各自是約3 mg至約100 mg、約10 mg至約100 mg、或約30 mg至約100 mg。
E42:如E41所述之方法,其中該抗DLL3藥劑的第二劑量、第三劑量和後續劑量各自是約3 mg,10 mg、25 mg、30 mg、50 mg、75 mg或100 mg的劑量。
E43:如E1或E3-E38中任一項所述之方法,其中在28天週期的第1天和第15天投與該抗DLL3藥劑,並且在28天週期的第1天、第8天或第15天投與該抗PD-1抗體。
E44:如E43所述之方法,其中在28天週期的第一週期中的第1天、第8天或第15天投與該抗PD-1抗體,並且然後在從第二週期開始的第1天或第15天及之後投與。
E45:如E2-E34或E39-E42中任一項所述之方法,其中在28天週期的第1週期中的第1天、第8天或第15天投與該抗PD-1抗體,並且然後在從第二週期開始的第1天或第15天及之後投與。
E46:如E44或E45所述之方法,其中a) 如果在第一週期的第1天或第8天投與該抗PD-1抗體,則在從第二週期開始的第1天及之後投與該抗體,或b) 如果在第一週期的第15天投與該抗PD-1抗體,則在第2週期的第15天及之後投與該抗體。
E47:如E1-E46中任一項所述之方法,其中該方法進一步包括向該受試者投與一或多種另外治療劑。
E48:如E47所述之方法,其中該一或多種另外治療劑係皮質類固醇(例如地塞米松)、鹽水或托珠單抗(tocilizumab)。
E49:如E47或E48中任一項所述之方法,其中在其中投與該抗DLL3藥劑的第一週期中將該一或多種另外治療劑投與給該受試者。
E50:如E1-E50中任一項所述之方法,其中該抗DLL3藥劑藉由以下過程製備,在該過程中,在允許該抗DLL3藥劑表現的條件下培養包含編碼如E5-E31中任一項所述之抗DLL3藥劑的核酸的宿主細胞並且然後從細胞培養物中回收表現的抗DLL3藥劑,並且其中該抗PD-1抗體藉由以下過程製備,在該過程中,在允許該抗PD-1抗體表現的條件下培養包含編碼如E32-E34中任一項所述之抗PD-1抗體的核酸的宿主細胞並且然後從細胞培養物中回收表現的抗PD-1抗體
E51:如E1-E50中任一項所述之方法,其中該受試者係人。
E52:一種抗DLL3藥劑和抗PD-1抗體,其用於在如實施方式E1-E51中任一項所述之方法中使用。
E53:一種抗DLL3藥劑和抗PD-1抗體,其用於在治療DLL3陽性癌症(例如SCLC)中使用,其中該抗DLL3藥劑和該抗PD-1抗體如實施方式E1-E51中任一項所述投與。
E54:抗DLL3藥劑和抗PD-1抗體用於製備用於治療SCLC的藥物之用途,其中製備該藥物以如實施方式E1-E51中任一項所述投與。
E55:抗DLL3藥劑和抗PD-1抗體在製備用於治療DLL3陽性癌症的藥物中之用途,其中該抗DLL3藥劑和該抗PD-1抗體如實施方式E1-E51中任一項所述投與。
優先權
本申請要求2021年5月10日提交的美國臨時申請案號63/186,569之權益,將其內容特此藉由引用以其全文併入。
以ASCII文字文件提交序列表
以下以ASCII文字文件提交的內容係藉由引用以其整體併入本文中:序列表之電腦可讀形式(CRF)(文件案名:A-2789-US-PSP_Sequence Listing_ST25,創建日期:2021年5月10日,大小:123,111位元組)。
AMG 757係開發用於治療SCLC的半衰期延長的BiTE®(雙特異性T細胞銜接子)分子。AMG 757的活性需要同時結合至靶細胞(DLL3
+細胞)和T細胞兩者。AMG 757的藥理作用係藉由先前引發的細胞毒性CD8
+或CD4
+T淋巴細胞的特異性重定向來介導以殺傷DLL3
+細胞。AMG 757正在SCLC受試者之首次人體研究中進行評估(研究20160323),發現從每兩週一次(Q2W)0.3 mg的劑量水平開始具有抗腫瘤活性,並且在劑量高達100 mg Q2W時具有可接受的安全性。
AMG 404係完全人抗體,以高親和力結合人PD-1,並阻斷該受體與其配位基、計畫性死亡配位基1(PD-L1)和計畫性死亡配位基2(PD-L2)相互作用的能力。AMG 404正在實性瘤受試者之1期研究(研究20180143)中進行評估,並被發現對實性瘤有效。
最近啟動了多項臨床試驗,用於使用PD1/PDL1抑制劑與其他抗癌劑組合治療小細胞肺癌。參見例如NCT04702880和NCT04256421(SKYSCRAPER-02)。然而,最近宣佈的SKYSCRAPER-02試驗失敗凸顯了將PD1/PDL1抑制劑與其他抗癌劑組合治療這種難以治療的癌症的不確定性。在靶向這種腫瘤類型方面仍然存在高度未滿足的需求和持續的挑戰。
與單獨的AMG 757相比,AMG 757和抗PD-1抗體的組合增加了表現DLL3的腫瘤細胞的T細胞介導的重定向裂解(美商安進公司研究報告R20190104)。人們認為,腫瘤微環境中PD1/PDL1之上調係對BiTE療法產生抗性的機制,而抗PD1療法治療可能會減輕這種抗性。
如本文所揭露和舉例說明的,使用靶向DLL3的藥劑(例如,AMG 757)和PD-1的藥劑(例如,派姆單抗或AMG 404)進行了1期臨床研究以治療SCLC。
1. 定義
本文揭露的一些示例性雙特異性抗DLL3藥劑(例如BiTE®分子)係雙特異性T細胞接合抗原結合多肽。該等多肽係包含兩個結合結構域的重組蛋白,每個結構域衍生自全長抗體的抗原結合片段。這種抗原結合片段保留了特異性結合抗原的能力(較佳的是具有基本相同的結合親和力)。抗原結合片段之實例包括 (i) Fab片段,由VL、VH、CL和CH1結構域組成的單價片段;(ii) F(ab')
2片段,其係包含由二硫橋在鉸鏈區連接的兩個Fab片段的雙價片段;(iii) 由VH和CH1結構域組成的Fd片段;(iv) 由抗體單臂的VL和VH結構域組成的Fv片段,以及 (v) dAb片段(Ward等人, 1989 Nature [自然] 341: 544-546),其由VH結構域組成。此外,雖然Fv片段的兩個結構域VL和VH係由單獨的基因編碼的,但是可以使用重組方法將這兩個結構域藉由使它們能夠形成為單一蛋白鏈的合成連接子來相連,其中VL區和VH區配對形成單價分子(被稱為單鏈Fv(scFv);參見例如,Bird等人Science [科學] 242: 423- 426 (1988)和Huston等人, 1988, Proc. Natl. Acad. Sci. USA [美國科學院院報] 85: 5879-5883。
「可變結構域」係指抗體輕鏈(VL)的可變區域或抗體重鏈(VH)的可變區域,無論是單獨的還是組合的。如本領域所知,重鏈和輕鏈的可變區域各自由被三個互補性決定區(CDR)連接的四個框架區(FR)組成,並且有助於抗體的抗原結合位點的形成。
序列表中提供了靶向DLL3和PD-1的示例性藥劑的「互補決定區」(CDR)。可以根據Kabat、Chothia、Kabat和Chothia的累積、AbM、contact、North和/或構象定義或本領域眾所周知的任何CDR測定方法來定義CDR。參見,例如,Kabat等人, 1991, Sequences of Proteins of Immunological Interest [免疫學目的蛋白的序列], 第5版 (hypervariable regions [高變區]);Chothia等人, 1989, Nature [自然] 342:877-883 (structural loop structures [結構環結構])。CDR的AbM定義係Kabat和Chothia之間的折衷方案,並使用了牛津大學分子公司(Oxfbrd Molecular)的AbM抗體建模軟體(Accelerys®)。可以使用本領域眾所周知的方法來確定構成CDR的特定抗體中胺基酸殘基的特性。
術語「治療」包括預防性和/或治療性治療。如果在病症的臨床表現之前投與,則認為該治療係預防性的。治療性治療包括,例如,改善或降低疾病的嚴重程度,或縮短疾病的長度。此外,術語「治療」以及與之相關的詞語不一定隱含100%或完全治療。更確切些,存在本領域中普通技術者認為具有潛在益處或治療作用的不同程度的治療。在此方面,本揭露內容的癌症治療方法可提供任何量或任何水平的治療。此外,由本揭露內容的方法提供的治療可包括治療所治療癌症的一或多種病狀或症狀或體征。由本揭露內容的方法提供的治療還可涵蓋減緩癌症的進展。例如,該等方法可藉由增強T細胞活性或針對癌症的免疫反應,減少腫瘤或癌症生長,減少腫瘤細胞轉移,增加腫瘤或癌細胞的細胞死亡等而治療癌症。在示例性方面中,方法借助於延遲癌症發作或復發1天、2天、4天、6天、8天、10天、15天、30天、兩個月、4個月、6個月、1年、2年、4年或更長時間而進行治療。在示例性方面中,該等方法借助於增加受試者之存活而治療。在各個方面,由本揭露之方法提供的治療提供根據實性瘤緩解評估標準(RECIST)或其他類似標準的治療性緩解。RECIST係由美國國家癌症研究所、加拿大國家癌症研究所臨床試驗組和歐洲癌症研究和治療組織共同建立的一組評估腫瘤和/或癌細胞的進展、穩定化或響應性的標準。根據RECIST,在評估(例如,臨床試驗)的開始測量某些腫瘤,以為與用藥物治療後作比較提供基線。Eisenhauer等人, Eur J Cancer [歐洲癌症雜誌] 45:228-247 (2009)和Litière等人, Journal of Clinical Oncology [臨床腫瘤學雜誌] 37(13):1102-1110 (2019) DOI: 10.1200/JCO.18.01100發表了腫瘤的緩解評定和評估標準。在各種情況下,本揭露之方法提供的治療提供根據修改的RECIST腫瘤緩解評估的治療性緩解,如下:
因此,本文提供了用於以下的方法:減緩受試者中DLL3陽性癌症的進展,增強受試者中針對DLL3陽性癌症的T細胞活性或免疫反應,減少受試者中DLL3陽性腫瘤或DLL3陽性癌症的生長,減少受試者中DLL3陽性腫瘤細胞的轉移,增加受試者中DLL3陽性腫瘤或癌細胞的細胞死亡,延遲受試者中DLL3陽性癌症的發作或復發和/或增加受試者之存活。此外,還提供了治療DLL3陽性癌症以在受試者中提供根據修改的RECIST1.1的完全緩解(CR)、部分緩解(PR)或疾病穩定(SD)之方法。在各個方面,該方法包括向受試者投與根據本揭露之抗DLL3藥劑和抗PD-1抗體。例如,在各個方面,該方法包括投與包含SEQ ID NO: 13和23之胺基酸序列的抗DLL3藥劑和包含SEQ ID NO: 38和39之胺基酸序列的抗PD-1抗體,其中抗DLL3藥劑以0.3 mg至30 mg或3 mg至100 mg的劑量每兩週一次投與,並且其中抗PD-1抗體以480 mg的劑量每四週一次投與。在各種情況下,抗DLL3藥劑根據以下計畫以28天的週期投與:a) 第1週期第1天的第一劑量0.3 mg或1 mg,b) 第1週期第8天的第二劑量,c) 第1週期第15天的第三劑量,和d) 從第2週期第1天開始並且之後每兩週一次的一或多個後續劑量,其中第二、第三和後續劑量相同,各自為0.3 mg至30 mg或3 mg至100 mg,並且高於第一劑量,並且其中抗PD-1抗體以480 mg的劑量每四週一次投與。在各個方面,該方法包括投與包含SEQ ID NO: 13和23之胺基酸序列的抗DLL3藥劑和監管機構(例如FDA或EMA)批准的抗PD-1抗體,其中抗DLL3藥劑以0.3 mg至30 mg或3 mg至100 mg的劑量每兩週一次投與,並且其中抗PD-1抗體以監管機構批准的劑量投與。
「約」或「大約」與可測量的數值變量結合使用時,指變量的指示值和變量的所有值,該等值在指示值的實驗誤差範圍內(例如,在平均值的95%信賴間隔內)或指示值的 ± 10%,以較大者為準。數位範圍包括定義該範圍的數位。
「第一階梯劑量」當與投與抗DLL3藥劑以治療癌症(例如,SCLC)相關使用時,係指抗DLL3藥劑在階梯劑量計畫或方案中的初始劑量。通常,第一階梯劑量等於或低於觀察到第一劑量效應(例如,細胞介素釋放綜合症(CRS))時的劑量。如本領域所知,可藉由對安全性和藥物動力學數據的建模和模擬來確定第一階梯劑量。例如,第一階梯劑量可為抗DLL3藥劑的最大耐受劑量(MTD),其中未觀察到CRS或低於某個等級(例如,2級)的CRS。
「目標劑量」當關於用於治療癌症(例如SCLC)的抗DLL3藥劑的投與時,係指達到抗DLL3藥劑的目標效應(例如,改善或降低SCLC的嚴重程度,或縮短SCLC的長度)的劑量。
「階梯劑量」當與投與抗DLL3藥劑以治療癌症(例如,SCLC)相關使用時,係指階梯劑量計畫或方案中高於先前投與抗DLL3藥劑劑量的劑量。階梯劑量包括從第一階梯劑量增加達到目標劑量的一或多個劑量。
2. 靶向 DLL3 的藥劑
DLL3係一種非典型Notch配位基,主要在胚胎發育過程中(在體節發生過程中起作用)表現。DLL3在正常組織的高爾基體中積累(Geffers等人, J Cell Biol. [細胞生物學雜誌]178:465-476 (2007))。藉由分析DLL3在28例SCLC腫瘤和一大批正常組織中的差異表現,DLL3被鑒定為腫瘤相關抗原和係基於T細胞治療的引人注目的靶標(研究123658)。
人DLL3蛋白包含八個胞外結構域:訊息肽、N-末端、DSL、EGF1、EGF2、EGF3、EGF4、EGF5和EGF6。人DLL3、EGF3結構域、EGF4結構域以及組合的EGF3和EGF4結構域的胺基酸序列在序列表中分別顯示為SEQ ID NO: 28、29、30和31。
靶向DLL3的示例性藥劑係結合DLL3和CD3的雙特異性T細胞接合抗原結合多肽,例如BiTE®分子。BiTE®分子係由兩個柔性連接的結合結構域製成的重組蛋白,每個結構域都源自抗體。BiTE®分子的一個結合結構域對腫瘤相關表面抗原(例如DLL3)係特異性的;第二結合結構域對CD3(T細胞上的T細胞受體複合物的亞基)具有特異性。藉由其特定設計,BiTE®抗體構建體獨特地適合於將T細胞與靶細胞暫態連接,並且同時強有力地激活T細胞對靶細胞的固有細胞溶解潛力。參見例如,WO 99/54440、WO 2005/040220、和WO 2008/119567。
因此,在一些實施方式中,所描述的靶向DLL3的藥劑包含兩個結合結構域:第一結構域與DLL3(較佳的是人DLL3)結合,並且第二結構域與CD3(較佳的是人CD3)結合。較佳的是,第一結構域與包含在SEQ ID NO: 31的胺基酸序列內的DLL3的表位結合。更較佳的是,第一結構域與包含在SEQ ID NO: 29的胺基酸序列內的DLL3的表位結合。
在某些實施方式中,DLL3結合結構域包含 (a) 重鏈可變區(VH),該重鏈可變區包含:(i) VH互補性決定區1(CDR-H1),其包含SEQ ID NO: 1的胺基酸序列;(ii) CDR-H2,其包含SEQ ID NO: 2的胺基酸序列;以及 (iii) CDR-H3,其包含SEQ ID NO: 3的胺基酸序列;和 (b) 輕鏈可變區(VL),該輕鏈可變區包含:(i) VL互補性決定區1(CDR-L1),其包含SEQ ID NO: 4的胺基酸序列;(ii) CDR-L2,其包含SEQ ID NO: 5的胺基酸序列;以及 (iii) CDR-L3,其包含SEQ ID NO: 6的胺基酸序列。
在某些實施方式中,DLL3結合結構域包含:包含SEQ ID NO: 7之胺基酸序列的VH和包含SEQ ID NO: 8之胺基酸序列的VL。在某些較佳的實施方式中,DLL3結合結構域包含:包含SEQ ID NO: 11之胺基酸序列的VH和包含SEQ ID NO: 12之胺基酸序列的VL。
在一些實施方式中,VH和VL藉由連接子連接以形成單鏈Fv(scFv)。在一些實施方式中,連接子係包含選自SEQ ID NO: 42-50中任一個的序列的肽連接子。在一些實施方式中,連接子係GS連接子,例如Gly-Gly-Gly-Gly-Ser(G4S,SEQ ID NO: 43)或其聚合物,即(Gly4Ser)x,其中x係1或更大的整數(例如,2或3)(例如,SEQ ID NO: 49、50)。
在某些實施方式中,DLL3結合結構域包含SEQ ID NO: 9的胺基酸序列。在某些較佳的實施方式中,DLL3結合結構域包含SEQ ID NO: 13的胺基酸序列。
在某些實施方式中,CD3結合結構域包含:(a) VH,其包含:包含SEQ ID NO: 18之胺基酸序列的CDR-H1,包含SEQ ID NO: 19之胺基酸序列的CDR-H2,和包含SEQ ID NO: 20之胺基酸序列的CDR-H3;和VL,其包含:包含SEQ ID NO: 15之胺基酸序列的CDR-L1,包含SEQ ID NO: 16之胺基酸序列的CDR-L2,以及包含SEQ ID NO: 17之胺基酸序列的CDR-L3。
在某些實施方式中,CD3結合結構域包含:包含SEQ ID NO: 21之胺基酸序列的VH和包含SEQ ID NO: 22之胺基酸序列的VL。在一些實施方式中,VH和VL藉由連接子連接以形成單鏈Fv(scFv)。在一些實施方式中,連接子係包含選自SEQ ID NO: 42-50中任一個的序列的肽連接子。在一些實施方式中,連接子係GS連接子,例如Gly-Gly-Gly-Gly-Ser(G4S,SEQ ID NO: 43)或其聚合物,即(Gly4Ser)x,其中x係1或更大的整數(例如,2或3)。
在某些實施方式中,CD3結合結構域包含SEQ ID NO: 23的胺基酸序列。
在某些實施方式中,DLL3結合結構域和CD3結合結構域藉由連接子連接。在一些實施方式中,連接子係包含選自SEQ ID NO: 42-50中任一個的序列的肽連接子。在一些實施方式中,連接子係GS連接子,例如Gly-Gly-Gly-Gly-Ser(G4S,SEQ ID NO: 43)或其聚合物,即(Gly4Ser)x,其中x係1或更大的整數(例如,2或3)。
在某些實施方式中,本文公開的抗DLL3藥劑包含兩個結構域。第一結構域與DLL3(較佳的是人DLL3)結合並且包含 (a) 重鏈可變區(VH),該重鏈可變區包含:(i) VH互補性決定區1(CDR-H1),其包含SEQ ID NO: 1的胺基酸序列;(ii) CDR-H2,其包含SEQ ID NO: 2的胺基酸序列;以及 (iii) CDR-H3,其包含SEQ ID NO: 3的胺基酸序列;和 (b) 輕鏈可變區(VL),該輕鏈可變區包含:(i) VL互補性決定區1(CDR-L1),其包含SEQ ID NO: 4的胺基酸序列;(ii) CDR-L2,其包含SEQ ID NO: 5的胺基酸序列;以及 (iii) CDR-L3,其包含SEQ ID NO: 6的胺基酸序列。第二結構域與CD3(較佳的是人CD3)結合並且包含 (a) VH,該VH包含:(i) 包含SEQ ID NO: 18之胺基酸序列的CDR-H1,(ii) 包含SEQ ID NO: 19之胺基酸序列的CDR-H2,和 (iii) 包含SEQ ID NO: 20之胺基酸序列的CDR-H3;和 (b) VL,其包含:(i) 包含SEQ ID NO: 15之胺基酸序列的CDR-L1,(ii) 包含SEQ ID NO: 16之胺基酸序列的CDR-L2,以及 (iii) 包含SEQ ID NO: 17之胺基酸序列的CDR-L3。
在某些實施方式中,本文所述之抗DLL3藥劑包含兩個結構域:(a) 第一結構域與DLL3(較佳的是人DLL3)結合並且包含:包含SEQ ID NO: 7之胺基酸序列的VH和包含SEQ ID NO: 8之胺基酸序列的VL;和 (b) 第二結構域與CD3(較佳的是人CD3)結合並且包含:包含SEQ ID NO: 21之胺基酸序列的VH和包含SEQ ID NO: 22之胺基酸序列的VL。在某些較佳的實施方式中,本文所述之抗DLL3藥劑包含兩個結構域:(a) 第一結構域與DLL3(較佳的是人DLL3)結合並且包含:包含SEQ ID NO: 11之胺基酸序列的VH和包含SEQ ID NO: 12之胺基酸序列的VL;和 (b) 第二結構域與CD3(較佳的是人CD3)結合並且包含:包含SEQ ID NO: 21之胺基酸序列的VH和包含SEQ ID NO: 22之胺基酸序列的VL。
在某些實施方式中,本文所述之抗DLL3藥劑包含兩個結構域:(a) 第一結構域與DLL3(較佳的是人DLL3)結合並且包含SEQ ID NO: 9的胺基酸序列,(b) 第二結構域與CD3(較佳的是人CD3)結合並且包含SEQ ID NO: 23的胺基酸序列。在某些實施方式中,本文所述之抗DLL3藥劑包含兩個結構域:(a) 第一結構域與DLL3(較佳的是人DLL3)結合並且包含SEQ ID NO: 13的胺基酸序列,(b) 第二結構域與CD3(較佳的是人CD3)結合並且包含SEQ ID NO: 23的胺基酸序列。
在某些實施方式中,本文所述之抗DLL3藥劑包含SEQ ID NO: 10的胺基酸序列。在某些實施方式中,本文所述之抗DLL3藥劑包含SEQ ID NO: 14的胺基酸序列。
在某些實施方式中,本文所述之抗DLL3藥劑進一步包含延長或增強抗DLL3藥劑之血清半衰期的第三結構域。在某些實施方式中,第三結構域包含由連接子連接的兩個多肽,每個肽包含人IgG的鉸鏈、CH2和CH3結構域。在某些實施方式中,第三結構域按N端至C端的順序包含:鉸鏈-CH2-CH3-連接子-鉸鏈-CH2-CH3。在一些實施方式中,連接子係GS連接子,例如Gly-Gly-Gly-Gly-Ser(G4S,SEQ ID NO: 43)或其聚合物,即(Gly4Ser)x,其中x係1或更大的整數(例如,6)。在某些實施方式中,第三結構域包含選自SEQ ID NO: 51-58中任一個的胺基酸序列。
在某些實施方式中,DLL3結合結構域和CD3結合結構域藉由第一連接子連接以形成肽,該肽藉由第二連接子連接到第三結構域。在某些實施方式中,第一連接子係肽連接子,其包含選自SEQ ID NO: 42-50中任一個的序列,並且第二連接子包含選自SEQ ID NO: 42、43、45、46、47、49和50中任一個的序列。在一些實施方式中,第一連接子係GS連接子,例如Gly-Gly-Gly-Gly-Ser(G4S,SEQ ID NO: 42)或其聚合物,即(Gly4Ser)x,其中x係1或更大的整數(例如,2或3)並且第二連接子包含選自SEQ ID NO: 42、43、45、46、47、49和50中任一個的序列。
在某些實施方式中,本文所述之抗DLL3藥劑包含三個結構域:(a) 第一結構域與DLL3(較佳的是人DLL3)結合並且包含SEQ ID NO: 9的胺基酸序列,(b) 第二結構域與CD3(較佳的是人CD3)結合並且包含SEQ ID NO: 23的胺基酸序列以及 (c) 第三結構域包含選自SEQ ID NO: 51-58中任一個的胺基酸序列。在某些實施方式中,本文所述之抗DLL3藥劑包含三個結構域:(a) 第一結構域與DLL3(較佳的是人DLL3)結合並且包含SEQ ID NO: 13的胺基酸序列,(b) 第二結構域與CD3(較佳的是人CD3)結合並且包含SEQ ID NO: 23的胺基酸序列以及 (c) 第三結構域包含選自SEQ ID NO: 51-58中任一個的胺基酸序列。在某些實施方式中,本文所述之抗DLL3藥劑包含SEQ ID NO: 27的胺基酸序列。在某些實施方式中,本文所述之抗DLL3藥劑包含SEQ ID NO: 59的胺基酸序列。
本文所述之抗DLL3藥劑可以藉由本領域已知的重組DNA技術產生。例如,抗DLL3藥劑可以藉由這樣的方法產生,其中包含編碼本文所述抗DLL3藥劑的核酸的宿主細胞(例如,中國倉鼠卵巢細胞)在允許抗DLL3表現的條件下培養然後從細胞培養物中回收表現的抗DLL3藥劑。在各種實施方式中,抗DLL3藥劑係塔拉他單抗(tarlatamab)(國際藥物非專利名稱(INN):建議的INN:清單123,WHO藥物資訊34(2): 395-397 (2020)),也稱為AMG 757。塔拉他單抗係免疫球蛋白scFv-scFv-scFc,抗[智人DLL3(δ樣配位基3)]和抗[智人CD3E(CD3ε,Leu-4)],單株抗體單鏈(scFv)2-scFc,雙特異性;IG單鏈scFv-scFv-scFc,抗DLL3和抗CD3E(1-982)[scFv-VH-V- κ 抗DLL3(1-241)[VH(智人IGHV4-59*01 G49 > C(44)(96.9%)-(IGHD)-IGHJ4*01(100%))CDR-IMGT [8.7.12](26-33.51-57.96-107)(1-118)-15-mer三(四甘胺醯-絲胺醯)連接子(119-133)-V-KAPPA(智人IGKV3-20*01(91.7%)-IGKJ2*01 Q120 > C(234)(90.9%))CDRIMGT [7.3.9](160-166.184-186.223-231)(134-241)] -6-mer絲胺醯-四甘胺醯-絲胺醯連接子(242-247)-scFv-VH-V-λ antiCD3E(248-496)[VH(小家鼠IGHV10-1*02(91.9%)-(IGHD)-IGHJ3*01(86.7%)/智人IGHV3-73*01(87.0%)-(IGHD)-IGHJ5*01(100%))CDR-IMGT [8.10.16](273- 280.298-307.346-361)(248-372)-15-mer-三(四甘胺醯-絲胺醯)連接子(373-387)-V-LAMBDA(智人IGLV7-43*01(85.1%)-IGLJ3*02(100%))CDR-IMGT [9.3.9](413-421.439- 441.478-486)(388-496)] -4-mer-四甘胺醯連接子(497-500)- scFc(h-CH2-CH3)-(h-CH2-CH3)(501-982)[智人IGHG1*03 h-CH2-CH3,nG1m1(鉸鏈 6-15(501-510),CH2 R83 > C(572),N84.4 > G(577),V85 > C(582)(511-620),CH3 E12(636),M14(638)(621-725),CHS > del)(501-725)-30-mer六(四甘胺醯-絲胺醯)連接子(726-755)-智人IGHG1*03 h-CH2-CH3,nG1m1(鉸鏈 6-15(756-765),CH2 R83 > C(827),N84.4 > G(832),V85 > C(837)(766-875),CH3 E12(891),M14(893)(876-980),CHS(981-982))(756-982)]],非糖基化,由中國倉鼠卵巢(CHO)細胞產生;免疫調節劑,抗腫瘤藥。
3. 靶向 PD-1 的藥劑
計畫性細胞死亡蛋白1(PD-1),也稱為CD279、SLEB2和hSLE1,係跨膜蛋白,表現於活化的T細胞、自然殺手細胞(NK)和B淋巴細胞、巨噬細胞、樹突狀細胞(DC)和單核細胞上。值得注意的是,PD-1在腫瘤特異性T細胞上高度表現(Han等人, Am J Cancer Res [美國癌症研究雜誌] 10(3): 727-742 (2020))。PD-1與B7蛋白家族成員、PD-1配位基1(PD-L1;也稱為CD279和B7-H1)和PD-1配位基2(也稱為PD-L2、CD273和B7-DC)結合。PD-L1在T細胞和B細胞、巨噬細胞和樹突狀細胞上組成型表現,而PD-L2表現通常僅限於活化的DC和巨噬細胞(Xing等人, Oncoimmunology [腫瘤免疫學] 7(3): e1356144 (2017)(doi: 10.1080/2162402X.2017.1356144))。PD-1抑制適應性和先天性免疫反應。PD-1/PD-L1軸與癌症中T細胞免疫反應的抑制有關。已在臨床上在許多實性瘤適應症中證實此路徑的拮抗劑。PD-1抑制劑納武單抗、派姆單抗和西米普利單抗(cemiplimab)以及PD-L1抑制劑阿特珠單抗(atezolizumab)、阿維魯單抗(avelumab)和德瓦魯單抗(durvalumab)靶向PD-1/PD-L1通路,並且每一種都已獲得美國食品藥品監督管理局(FDA)和/或歐洲藥品管理局(EMA)批准用於治療各種癌症。靶向PD-1的其他示例性藥劑包括替雷利珠單抗(tislelizumab)、多星單抗(dostarlimab)、筆普利單抗(penpulimab)、信迪利單抗(sintilimab)、特瑞普利單抗(toripalimab)、多星單抗(dostarlimab)、卡瑞利珠單抗(camrelizumab)、津貝利單抗(zimberelimab)和普羅戈利單抗(prolgolimab)。在某些實施方式中,可用於本文揭露的治療的PD-1靶向劑係納武單抗、派姆單抗、塞米普利單抗(cemiplimab)、替雷利珠單抗、多星單抗、筆普利單抗、信迪利單抗、特瑞普利單抗、多星單抗、卡瑞利珠單抗、津貝利單抗或普羅戈利單抗。在某些實施方式中,PD-1靶向劑係納武單抗,派姆單抗、塞米普利單抗、替雷利珠單抗或信迪利單抗。在某些實施方式中,PD-1靶向劑係納武單抗或派姆單抗。
靶向PD-1的其他示例性藥劑包括國際公開案號WO2019/140196(其全部內容藉由引用併入本文)中描述的PD-1抗原結合蛋白(例如,抗PD-1抗體、其抗原結合抗體片段,和抗PD-1抗體蛋白產物)。在示例性方面,PD-1抗原結合蛋白結合人PD-1,其具有在美國國家生物技術資訊中心(NCBI)參考序號NP_005009.2或SEQ ID NO: 60中描述的胺基酸序列,或其由SEQ ID NO: 60的胺基酸21-288代表的成熟形式(例如,缺乏訊息肽)。在示例性方面,PD-1抗原結合蛋白結合食蟹猴PD-1,其具有NCBI參考序號NP_001271065.1或SEQ ID NO: 61中描述的胺基酸序列,或其成熟形式。在示例性實例中,PD-1抗原結合蛋白與人PD-1和食蟹猴PD-1兩者結合。在示例性實施方式中,抗PD-1抗體包含SEQ ID NO: 32-37的胺基酸序列。在示例性實施方式中,抗PD-1抗體包含SEQ ID NO: 32-37的六個CDR胺基酸序列。在示例性實施方式中,抗PD-1抗體包含SEQ ID NO: 32的重鏈(HC)互補決定區(CDR)1胺基酸序列、SEQ ID NO: 33的HC CDR2胺基酸序列、SEQ ID NO: 34的HC CDR3胺基酸序列、SEQ ID NO: 35的輕鏈(LC)CDR1胺基酸序列、SEQ ID NO: 36的LC CDR2胺基酸序列和SEQ ID NO: 37的LC CDR3胺基酸序列。在某些實施方式中,抗PD-1抗體包含PD-1結合結構域,該PD-1結合結構域包含 (a) 重鏈可變區(VH),該重鏈可變區包含:(i) VH互補性決定區1(CDR-H1),其包含SEQ ID NO: 32的胺基酸序列;(ii) CDR-H2,其包含SEQ ID NO: 33的胺基酸序列;以及 (iii) CDR-H3,其包含SEQ ID NO: 34的胺基酸序列;和 (b) 輕鏈可變區(VL),該輕鏈可變區包含:(i) VL互補性決定區1(CDR-L1),其包含SEQ ID NO: 35的胺基酸序列;(ii) CDR-L2,其包含SEQ ID NO: 36的胺基酸序列;以及 (iii) CDR-L3,其包含SEQ ID NO: 37的胺基酸序列。在某些實施方式中,PD-1結合結構域包含:包含SEQ ID NO: 38之胺基酸序列的VH和包含SEQ ID NO: 39之胺基酸序列的VL。在某些實施方式中,抗PD-1抗體包含:包含SEQ ID NO: 38之胺基酸序列的VH和包含SEQ ID NO: 39之胺基酸序列的VL。在某些較佳的實施方式中,抗PD-1抗體包含:包含SEQ ID NO: 40之胺基酸序列的HC和包含SEQ ID NO: 41之胺基酸序列的LC。在各種情況下,抗PD-1抗體係澤魯伐利單抗(zeluvalimab)(國際藥物非專利名稱(INN):建議的INN:清單124,WHO藥物資訊34(4): 929-1102 (2020)),也稱為AMG 404。澤魯伐利單抗係免疫球蛋白G1-κ,抗[智人PDCD1(計畫性細胞死亡1,PD-1,PD1,CD279)],包含γ1重鏈的單株抗體(1-450)[VH(智人IGHV3-23*03(92.8%)-(IGHD)-IGHJ3*01(92.3%))CDR-IMGT [8.8.13](26-33.50-58.97-109)(1-120)- 智人IGHG1*03v,G1m3 > G1m17,nG1m1(CH1 R120 > K(217)(121-218),鉸鏈 1-15(219-233),CH2 R83 > C (295),N84.4 > G (300),V85 > C (305) (234- 343),CH3 E12 (359),M14 (361) (344-448),CHS (449- 450)) (121-450)],(223-214')-與κ輕鏈(1'-214') [V-KAPPA (H智人IGKV1-12*01 (96.8%) -IGKJ4*01 (100%)) CDR-IMGT [6.3.9](27- 32.50-52.89-97) (1'-107') -智人IGKC*01 (100%),Km3 A45.1 (153),V101 (191) (108'-214')]的二硫化物;二聚體(229-229'':232-232'')-雙二硫化物,在中國倉鼠卵巢(CHO)細胞中產生,非糖基化免疫調節劑,抗腫瘤藥。
3. 使用靶向 DLL3 和 PD-1 的藥劑的給藥方案
本文揭露了治療DLL3陽性癌症之方法,該方法包括向有需要的受試者投與靶向DLL3和PD-1的藥劑的組合。靶向DLL3的藥劑包括本文揭露的抗DLL3藥劑,靶向PD-1的藥劑包括本文揭露的抗PD-1抗體。在一個實施方式中,本文揭露了治療DLL3陽性癌症之方法,該方法包括向有需要的受試者投與抗DLL3藥劑和抗PD-1抗體的組合,其中抗DLL3藥劑以約0.3 mg至約30 mg或約3 mg至約100 mg的劑量每兩週一次投與。在各種實施方式中,抗PD-1抗體係納武單抗、派姆單抗、澤魯伐利單抗(zeluvalimab)、或替雷利珠單抗。在某些實施方式中,DLL3陽性癌症係小細胞肺癌(SCLC)。在某些實施方式中,SCLC係復發性/難治性SCLC(RR SCLC)或廣泛性疾病SCLC(ED SCLC)。在某些實施方式中,受試者係患有SCLC(例如,RR SCLC或ED SCLC)的人。在某些實施方式中,SCLC在至少一種先前的基於鉑的治療後在受試者中復發。
在某些實施方式中,抗DLL3藥劑以如下劑量每兩週一次投與:約0.3 mg至約30 mg、約1 mg至約30 mg、約3 mg至約30 mg或約10 mg至約30 mg。在某些實施方式中,抗DLL3藥劑以約0.3 mg、1 mg、3 mg、10 mg、25 mg或30 mg的劑量每兩週一次投與。
在某些實施方式中,抗DLL3藥劑以如下劑量每兩週一次投與:約3 mg至約100 mg、約10 mg至約100 mg或約30 mg至約100 mg。在某些實施方式中,抗DLL3藥劑以約3 mg,10 mg、25 mg、30 mg、50 mg、75 mg或100 mg的劑量每兩週一次投與。
抗DLL3藥劑可由任何合適的方式投與,包括腸胃外、肺內、鼻內和/或病灶內投與。腸胃外投與包括肌肉內、靜脈內、動脈內、腹膜內或皮下投與。在一些實施方式中,抗DLL3藥劑藉由靜脈內(IV)輸注(例如短靜脈內輸注(大約60分鐘)),每兩週一次投與。
在其中以上述劑量投與抗DLL3藥劑的一些實施方式中,抗PD-1抗體係澤魯伐利單抗並且抗PD-1抗體以480 mg劑量每四週一次投與。在某些實施方式中,抗DLL3藥劑和澤魯伐利單抗以28天的週期投與,並且兩種藥劑都可以在第1週期的第1天投與。為了減輕AMG 757的第一劑量效應(例如,細胞介素釋放綜合症(CRS))的可能風險(在第1週期第1天組合抗PD-1抗體可能會加劇這種效應),抗PD-1抗體可在第1週期第8天或第15天投與。因此,在某些實施方式中,抗DLL3藥劑在28天週期的第1天和第15天投與,並且抗PD-1抗體在28天週期的第1天、第8天或第15天投與。
在此類28天週期給藥方案的某些實施方式中,抗DLL3藥劑在第1天和第15天投與,澤魯伐利單抗在第1週期的第1天、第8天或第15天投與,然後在從第2週期開始的第1天或第15天及之後投與。在此類實施方式中,如果在第1週期的第1天或第8天投與澤魯伐利單抗,則在從第2週期開始的第1天及之後投與該抗體;可替代地,如果在第1週期的第15天投與澤魯伐利單抗,則在從第2週期開始的第15天及之後投與該抗體。
其他已知的抗PD-1抗體(例如,派姆單抗和納武單抗)也可以在本文揭露的方法中與抗DLL3藥劑組合使用。當組合使用時,該等其他抗PD-1抗體的劑量和方案與監管機構(例如FDA)批准的相同。例如,如實例1中所述,在SCLC患者的臨床研究中,抗DLL3藥劑與派姆單抗聯合使用,其中派姆單抗以200 mg的劑量每三週投與。因此,在其中以上述劑量投與抗DLL3藥劑的一些實施方式中,抗PD-1抗體係派姆單抗並且抗PD-1抗體以200 mg劑量每三週一次投與。在其中以上述劑量投與抗DLL3藥劑的一些實施方式中,抗PD-1抗體係納武單抗並且抗PD-1抗體以240 mg劑量每兩週一次投與。在其中以上述劑量投與抗DLL3藥劑的一些實施方式中,抗PD-1抗體係替雷利珠單抗並且抗PD-1抗體以200 mg劑量每三週一次投與。
在其中每兩週一次投與抗DLL3藥劑和每三週一次投與抗PD-1抗體的實施方式中,抗PD-1抗體可以在第1週期的第15天開始,以儘量最小化第一劑量效應(例如,CRS)。因此,在某些實施方式中,其中投與抗DLL3藥劑和抗PD-1抗體的第一週期係28天的週期,抗DLL3藥劑在第1天和第15天投與並且抗PD-1抗體在第15天投與,此後,每兩週一次投與抗DLL3藥劑,並且每三週一次投與抗PD-1抗體。
抗PD-1抗體可以藉由任何合適的方式投與,包括腸胃外。在一些實施方式中,取決於抗體藉由每兩週一次、每三週一次或每四週一次靜脈內IV輸注來投與抗PD-1抗體。
如本文所用,「組合療法」或「與...組合」係指除了一種治療方式(例如,抗PD-1抗體)之外還投與另一種治療方式(例如,抗DLL3藥劑)。因此,「組合療法」或「與...組合」係指在將一種治療方式投與給個體(例如,患有SCLC的人)之前、期間或之後投與另一種治療方式。然而,組合療法不包括在一種治療方式的投與結束和另一種治療方式開始之間已經過去28天或更長時間的情況。
3.1 階梯給藥
由於其作用機制,受試者在初始輸注AMG 757後可能處於第一劑量效應(例如CRS)的風險增加,與抗PD-1抗體組合可能會加劇這種風險。為了減輕風險,可以實施階梯給藥方案。例如,如果受試者經歷第一劑量效應(例如,CRS),則可確定並實施不超過觀察到CRS事件的劑量的適當的第一劑量。也可以確定和實施一或多個階梯劑量,直到達到目標劑量。該等劑量和給藥計畫能以對於AMG 757可用的新出現的藥物動力學和安全性數據和資訊為指導。
下表顯示了28天週期中抗DLL3藥劑(例如,AMG 757)的示例性階梯給藥計畫(僅第1週期),此後每兩週一次投與抗DLL3藥劑。
[表1]. 示例性單和多階梯給藥計畫(僅第1週期)
*:此後每2週以與第15天的相同劑量投與AMG 757
**:根據當前研究以及正在進行的FIH研究(20160323)中新出現的藥物動力學、藥效學和安全性數據,在兩階梯給藥中在第4天的階梯劑量(選項1)或在三階梯給藥中在第8天的階梯劑量可以等於目標劑量。
抗 DLL3 藥劑( AMG 757 ) | 第 1 天 | 第 4 天 | 第 8 天 | 第 15 天 * |
一階梯 | 第一階梯劑量 | N/A | 階梯劑量 (等於目標劑量) | 目標劑量 |
兩階梯 (選項1) | 第一階梯劑量 | 階梯劑量** | 階梯劑量 (等於目標劑量) | 目標劑量 |
兩階梯 (選項2) | 第一階梯劑量 | N/A | 階梯劑量 | 階梯劑量 (等於目標劑量) |
三階梯 | 第一階梯劑量 | 階梯劑量 | 階梯劑量** | 階梯劑量 (等於目標劑量) |
因此,本文揭露了治療DLL3陽性癌症之方法,該方法包括向有需要的受試者投與抗DLL3藥劑和抗PD-1抗體,其中抗DLL3藥劑根據階梯給藥計畫(例如上面表1中列出的那些)投與。抗PD-1抗體可為納武單抗、派姆單抗、澤魯伐利單抗或替雷利珠單抗。例如,在對AMG 757實施階梯給藥方案的各種實施方式中,抗PD-1抗體係澤魯伐利單抗並以480 mg的劑量每四週一次投與。
在某些實施方式中,根據一階梯給藥計畫投與抗DLL3藥劑。在此類實施方式中,本文揭露了治療DLL3陽性癌症之方法,該方法包括向有需要的受試者投與抗DLL3藥劑和抗PD-1抗體,其中抗DLL3藥劑根據以下計畫以28天的週期投與:a) 第1週期第1天的第一劑量約0.3 mg或1 mg,b) 第1週期第8天的第二劑量,c) 第1週期第15天的第三劑量,和d) 從第2週期第1天開始並且之後每兩週一次的一或多個後續劑量,並且其中第二劑量、第三劑量和後續劑量相同,各自為約0.3 mg至約30 mg或約3 mg至約100 mg,並且高於第一劑量。在一些實施方式中,抗PD-1抗體係澤魯伐利單抗並且以約480 mg的劑量每四週一次投與。在一些實施方式中,抗PD-1抗體係以監管機構批准的劑量/方案投與的納武單抗、派姆單抗或替雷利珠單抗。
在其中根據一階梯給藥計畫投與抗DLL3藥劑的某些實施方式中,抗DLL3藥劑的第一劑量係約0.3 mg或1 mg,第二劑量、第三劑量和後續劑量各自為:約0.3 mg至約30 mg、約1 mg至約30 mg、約3 mg至約30 mg或約10 mg至約30 mg。在某些實施方式中,抗DLL3藥劑的第一劑量係約0.3 mg,第二劑量、第三劑量和後續劑量各自是約1 mg、3 mg、10 mg、25 mg或30 mg。在某些實施方式中,抗DLL3藥劑的第一劑量係約1 mg,第二劑量、第三劑量和後續劑量各自是約3 mg、10 mg、25 mg或30 mg。
在其中根據一階梯給藥計畫投與抗DLL3藥劑的某些實施方式中,抗DLL3藥劑的第一劑量係約0.3 mg或1 mg,第二劑量、第三劑量和後續劑量各自是約3 mg至約100 mg、約10 mg至約100 mg或約30 mg至約100 mg。在某些實施方式中,第一劑量係約0.3 mg,第二劑量、第三劑量和後續劑量各自是約1 mg,10 mg,25 mg、30 mg、50 mg、75 mg或100 mg。在某些實施方式中,第一劑量係約1 mg,第二劑量、第三劑量和後續劑量各自是約10 mg,25 mg、30 mg、50 mg、75 mg或100 mg。
在某些實施方式中,抗PD-1抗體係澤魯伐利單抗並且在第1週期的第1天、第8天或第15天投與,然後在從第2週期開始的第1天或第15天及之後投與。如果在第1週期的第1天或第8天投與抗PD-1抗體,則在從第2週期開始的第1天及之後投與該抗體。可替代地,如果在第1週期的第15天投與澤魯伐利單抗,則在第2週期的第15天及之後投與該抗體。
在某些實施方式中,根據兩階梯給藥計畫投與抗DLL3藥劑。因此,本文揭露了治療DLL3陽性癌症之方法,該方法包括向有需要的受試者投與抗DLL3藥劑和抗PD-1抗體,其中抗DLL3藥劑根據下面的計畫I或計畫II以28天的週期投與,抗PD-1抗體以480 mg劑量每四週一次投與,並且其中
計畫I:a) 第1週期第1天的第一劑量(第一階梯劑量)0.3 mg或1 mg,b) 第1週期第4天的第二劑量(階梯劑量),c) 第1週期第8天的第三劑量(階梯劑量,等於目標劑量),d) 第1週期第15天的第四劑量(目標劑量),和e) 從第2週期第1天開始並且之後每兩週一次的一或多個後續劑量(目標劑量),並且其中第二劑量高於第一劑量,第三劑量、第四劑量及後續劑量相同,各自是約0.3 mg至30 mg或3 mg至100 mg,且高於第二劑量。或
計畫II:a) 第1週期第1天的第一劑量(第一階梯劑量)0.3 mg或1 mg,b) 第1週期第8天的第二劑量(階梯劑量),c) 第1週期第15天的第三劑量(階梯劑量,等於目標劑量),和c) 從第2週期第1天開始並且之後每兩週一次的一或多個後續劑量(目標劑量),並且其中第二劑量高於第一劑量,第三劑量及後續劑量相同,各自是約0.3 mg至30 mg或3 mg至100 mg,且高於第二劑量。
在某些實施方式中,如果認為藥物動力學和安全性數據令人滿意,則上述計畫I的第1週期第4天的階梯劑量可以高於或等於目標劑量。但是,沒有階梯劑量或目標劑量超過100 mg的量。相信這樣的給藥計畫係有益的,因為它們可以導致改善的PD活性(例如,有助於快速達到所需的血清AMG 757水平)。
在某些實施方式中,本文公開了治療DLL3陽性癌症之方法,該方法包括向需要的受試者投與抗DLL3藥劑,其中根據三階梯給藥計畫投與抗DLL3藥劑。在此類實施方式中,本文揭露了治療DLL3陽性癌症之方法,該等方法包括向有需要的受試者投與抗DLL3藥劑和抗PD-1抗體,其中所述抗DLL3藥劑根據以下計畫以28天的週期投與:a) 第1週期第1天的第一劑量(第一階梯劑量)約0.3 mg或1 mg,b) 第1週期第4天的第二劑量(階梯劑量),c) 第1週期第8天的第三劑量(階梯劑量),d) 第1週期第15天的第四劑量(階梯劑量,等於目標劑量),和e) 從第2週期第1天開始並且之後每兩週一次的一或多個後續劑量(目標劑量),並且其中第二劑量高於第一劑量,第三劑量高於第二劑量,第四劑量和後續劑量相同,各自是約0.3 mg至約30 mg或約3 mg至約100 mg,並且高於第三劑量,並且其中抗PD-1抗體係以上述劑量和計畫投與的納武單抗、派姆單抗、澤盧瓦利單抗或替雷利珠單抗。在某些實施方式中,抗PD-1抗體係澤魯伐利單抗並且以約480 mg的劑量每四週一次投與。在其他實施方式中,抗PD-1抗體係派姆單抗並且以200 mg的劑量每三週一次投與。
在某些實施方式中,如果認為藥物動力學和安全性數據令人滿意,則上述三階梯給藥方案的第1週期第8天的階梯劑量可以等於目標劑量。相信這樣的給藥計畫係有益的,因為它們有助於快速達到所需的血清AMG 757水平。
抗DLL3藥劑和抗PD-1抗體可由任何合適的方式投與,包括腸胃外、肺內、鼻內和/或病灶內投與。腸胃外投與包括肌肉內、靜脈內、動脈內、腹膜內或皮下投與。在一些實施方式中,抗DLL3藥劑藉由IV輸注投與,並且抗PD-1抗體藉由IV輸注投與。
在某些實施方式中,DLL3陽性癌症係小細胞肺癌(SCLC)。在某些實施方式中,SCLC係復發性/難治性SCLC(RR SCLC)或廣泛性疾病SCLC(ED SCLC)。在某些實施方式中,受試者係患有SCLC,例如,RR SCLC或ED SCLC的人。在某些實施方式中,SCLC在至少一種先前的基於鉑的化療後在受試者中復發。
3.2 另外的治療劑
在一些實施方式中,本文揭露的方法進一步包括使用一或多種另外治療劑來預防、降低或減輕與投與抗DLL3藥劑和抗PD-1抗體相關的副作用的風險。與使用抗DLL3藥劑相關的主要副作用係CRS。可用於預防、降低或減輕CRS風險的一或多種另外治療劑包括皮質類固醇(例如,地塞米松)、液體(例如,鹽水)、依那西普(例如,Enbrel)和抗IL6抗體(例如,托珠單抗或司妥昔單抗(siltuximab))。可以在AMG 757的所有第1週期劑量(包括所有階梯劑量)之前藉由IV投與地塞米松,可以在第1週期的所有AMG 757劑量後IV投與鹽水(例如1升),並且可以根據需要(例如,受試者對IV流體無響應性)投與抗IL6抗體(托珠單抗或司妥昔單抗)。地塞米松的示例性劑量包括8 mg/投與(最大24 mg/天)。托珠單抗的示例性劑量包括8 mg/kg(不超過800 mg)。CRS之症狀包括發燒、噁心、疲勞、頭痛、肌痛、乏力,並且也可以使用可用於治療該等症狀的治療劑(例如,用於發燒的乙醯胺酚/醋胺酚)。
抗PD-1抗體投與後之不良事件可能包括免疫相關不良反應,該等不良反應可能在第一治療劑量後不久至最後一個治療劑量後幾個月發生。與抗PD-1抗體相關的免疫相關不良反應包括肺炎、結腸炎/腹瀉、免疫介導的肝炎、腎上腺功能不全、腎炎和腎功能不全、腦病、皮疹、甲狀腺功能減退、甲狀腺功能亢進和糖尿病。一或多種用於預防、降低或減輕此類免疫相關不良反應(例如,肺炎、結腸炎/腹瀉、免疫介導的肝炎、腎上腺功能不全、腎炎和腎功能不全、腦病、皮疹、甲狀腺功能減退、甲狀腺功能亢進和糖尿病中的一或多種)的另外治療劑包括皮質類固醇(例如,普賴蘇、氫化皮質酮和地塞米松)、胰島素療法(用於糖尿病)、甲狀腺激素補充劑(用於甲狀腺功能減退)和β-阻斷劑(例如,針對甲狀腺功能亢進的阿替洛爾(atenolol)、普萘洛爾(propranolol))。
因此,在某些實施方式中,本文揭露的方法進一步包括投與一或多種選自皮質類固醇(例如,強體松、氫化皮質酮和地塞米松)、液體(鹽水)、抗IL-6抗體(例如,托珠單抗或司妥昔單抗)、胰島素療法、甲狀腺激素補充劑和β-阻斷劑(例如,阿替洛爾、普萘洛爾)的另外治療劑。在某些實施方式中,該等方法進一步包括投與一或多種選自皮質類固醇(例如地塞米松)、液體(鹽水)和托珠單抗或司妥昔單抗的另外治療劑。在某些實施方式中,皮質類固醇、液體和抗IL-6抗體(例如,托珠單抗或司妥昔單抗)中的一或多種在其中投與AMG 757的第1週期中投與。
在其中投與一或多種另外治療劑的任何一種方法的某些實施方式中,受試者係人。
4.
製品
本文公開了包含如下的製品:(a) 包含抗DLL3藥劑的容器;和 (b) 包裝插頁,其中載有藉由將抗DLL3藥劑(例如AMG 757)與抗PD-1抗體(例如派姆單抗或AMG 404)組合投與來治療受試者之DLL3陽性癌症(或治療SCLC)的說明書,其中說明書指定抗DLL3藥劑以約0.3 mg至約30 mg或約3 mg至約100 mg(或本文揭露的任何劑量範圍)的劑量每兩週一次投與於受試者,例如在28天週期的第1天和第15天。在某些實施方式中,製品進一步包括包含抗PD-1抗體的容器。
說明書還可以指定抗DLL3藥劑按照以下計畫以28天的週期投與:a) 第1週期第1天的第一劑量0.3 mg或1 mg,b) 第1週期第8天的第二劑量,c) 第1週期第15天的第三劑量,和d) 從第2週期第1天開始並且之後每兩週一次的一或多個後續劑量,第二劑量、第三劑量和後續劑量相同,各自是0.3 mg至30 mg或3 mg至100 mg(或本文揭露的任何劑量範圍),並且為高於第一劑量。
說明書還可以指定抗PD-1抗體在28天週期的第1天、第8天或第15天投與,例如抗PD-1抗體在第1週期的第1天,第8天或第15天投與,然後在從第2週期開始的第1天或第15天以及之後投與。說明書還可以指定,如果在第1週期的第1天或第8天投與抗PD-1抗體,則在從週期開始的第1天及之後投與該抗體;可替代地,如果在第1週期的第15天投與抗PD-1抗體,則在從週期開始的第15天及之後投與該抗體。
除了抗DLL3藥劑和抗PD-1抗體外,說明書還可以進一步指定將一或多種治療劑投與於受試者。一或多種治療劑可以選自皮質類固醇(例如,地塞米松、強體松、氫化皮質酮)、鹽水、依那西普和抗IL6抗體(托珠單抗或司妥昔單抗)。在某些實施方式中,說明書指定地塞米松、鹽水和抗IL6抗體(托珠單抗或司妥昔單抗)中的一或多種在其中投與抗DLL3藥劑的第一週期中投與。在某些實施方式中,說明書指定了地塞米松在投與抗DLL3藥劑的第一週期中進一步投與(例如,在抗DLL3藥劑的第1週期給藥前藉由靜脈內投與)。
5.
受試者
在當前揭露的方法的各種情況下,受試者係人受試者。在示例性實例中,人受試者患有小細胞肺癌(SCLC),視需要,組織學或細胞學證實的SCLC。在各個方面,人係患有SCLC的男性或女性和/或大於或等於18歲。在示例性方面,人受試者已經用基於鉑的化療治療。在示例性方面,人受試者具有視需要在至少一種基於鉑的化療後進展或復發的RR SCLC。在示例性實例中,人受試者具有0-1的東部腫瘤協作組(ECOG)表現狀態(Oken等人, Am J Clin Oncol [美國臨床腫瘤學雜誌] 5: 649-655 (1982)。在各個方面,人受試者具有一或多種已被治療的腦轉移瘤。在各個方面,基於鉑的化療包括卡鉑或順鉑、鉑-依託泊苷或鉑-伊立替康。
6.
癌症
在各個方面,藉由目前揭露的方法治療的癌症係DLL3陽性癌症。在各種情況下,藉由目前揭露的方法治療的癌症係小細胞肺癌(SCLC)。在示例性方面,SCLC係組織學或細胞學證實的SCLC。視需要,SCLC可藉由修改的實性瘤緩解標準(RECIST)1.1測量,其中可測量的病灶包括 (a) 具有清晰邊界的非結節病灶,其可以在軸向平面的一個維度中準確且連續地測量(最長直徑 ≥ 10 mm,藉由磁共振成像/電腦斷層掃描(MRI/CT)測量,掃描切片厚度 ≤ 5 mm)和/或 (b) 根據MRI/CT垂直於長軸(短軸)的最長直徑 ≥ 15mm的結節病灶,和/或排除單純性囊腫、胸膜/心包積液和腹水。
實例
實例1 AMG 757與派姆單抗組合在患有SCLC的受試者中的安全性、耐受性、PK和抗腫瘤活性
在患有SCLC的受試者中使用AMG 757與派姆單抗組合進行了一項臨床研究。該研究之主要目標係評估AMG 757當與派姆單抗組合投與時的安全性和耐受性,並確定AMG 757與派姆單抗組合投與時的最大耐受劑量(MTD)或推薦的2期劑量(RP2D)。該研究之次要目標係表徵AMG 757當與派姆單抗組合投與時的PK,並評估AMG 757與派姆單抗體組合投與時的初步抗腫瘤活性。
下表總結了關鍵的合格標準
關鍵的納入標準 | 關鍵的排除標準 |
男性或女性 ≥ 18歲,患有經組織學或細胞學證實的小細胞肺癌(SCLC) | AMG 757的第一劑量前的過去2年內的其他惡性腫瘤病史,其中排除 |
至少一種基於鉑的化療後進展或復發的RR SCLC | AMG 757之第一劑量的28天內的大型手術 |
東部腫瘤協作組(ECOG)表現狀態為0-2 | 抗癌療法前:任何先前的抗癌療法和第一劑量的AMG 757之間必須至少經過28天 |
具有經治療的腦轉移的受試者只要符合定義的標準就符合資格 | |
如方案中定義的充分的器官功能 |
AMG 757的起始劑量為每兩週一次0.1 mg IV。AMG 757的劑量遞增如下:0.1 mg、0.3 mg、1 mg、3 mg、10 mg、30 mg和100 mg通過IV每兩週一次。派姆單抗的劑量固定為每3週200 mg IV。在第1週期第15天投與第一劑量的派姆單抗。
截至2022年4月,8名受試者接受了AMG 757和派姆單抗的組合治療。受試者接受每3週派姆單抗200 mg IV給藥,每2週AMG 757 IV 0.1 mg(N=5)或0.3 mg(N=3)。在8名受試者中,3名受試者達到作為最佳總體緩解的疾病穩定,客觀緩解率為0%,疾病控制率為37.5%。一名研究受試者在2020年6月AMG 757的第一劑量後繼續接受治療22個月,疾病穩定。
所有受試者都經歷了至少一種治療中出現的不良事件,其中最常見的是5/8(62.5%)的疲勞。一名受試者(0.3 mg AMG 757)經歷了與治療相關之目的不良事件(等級 ≥ 3 CRS)。沒有受試者有導致治療中止的一或多種治療中出現的不良事件。在受試者中探索的劑量下,沒有記錄到針對組合的致命不良事件。
實例3 研究評估AMG 757與AMG 404組合在患有SCLC的受試者中的安全性和功效
目標和終點
下表總結了本研究(研究20200439)之目標和終點。
研究設計
目標 | 終點 |
主要 | |
評估AMG 757與AMG 404組合的安全性、耐受性和推薦的2期目標劑量 | 劑量限制毒性(DLT)、治療中出現的和與治療相關的不良事件、生命徵象的變化、心電圖(ECG)和臨床實驗室測試 |
次要 | |
評估AMG 757與AMG 404組合的抗腫瘤活性 | 根據修改的實性瘤緩解評估標準(RECIST)v1.1的客觀緩解(OR)、緩解持續時間(DOR)、疾病控制率(DCR)、無進展存活(PFS)和總存活(OS)。 |
表徵AMG 757與AMG 404組合的藥物動力學(PK) | PK參數包括但不限於給藥間隔內的最大血清濃度(Cmax)、最小血清濃度(Cmin)和濃度-時間曲線下面積(AUC) |
探索性 | |
評估治療前後血液中的蛋白質、核酸和細胞生物標誌物 | 血液中的蛋白質、核酸和細胞生物標誌物的變化 |
評估腫瘤組織中基線靶蛋白表現、腫瘤微環境特徵和臨床益處 之關係 | 基線時腫瘤組織中的細胞表面蛋白表現(例如,DLL3、PD-L1) 和腫瘤浸潤淋巴細胞狀態 |
評估AMG 757和AMG 404的免疫性 | 抗AMG 757抗體和抗AMG 404抗體形成的發生率 |
研究20200439係一項1b期、多中心、開放標籤研究,評估AMG 757與AMG 404組合在患有SCLC的受試者中的安全性、耐受性、PK、PD和功效。該研究由劑量探索(第1部分)和劑量擴展(第2部分)組成。
該研究的劑量探索部分使用改良毒性概率區間(mTPI-2)設計估計了AMG 757與AMG 404組合的推薦的2期目標劑量。在達到MTD之前,可以根據新出現的安全性、功效和藥效學數據來鑒定組合RP2D。
在整個研究過程中,AMG 404以每28天(± 3天)480 mg的劑量作為短期IV輸注(30分鐘)投與。AMG 757的起始劑量比正在進行的FIH研究(研究20160323)中確定的推薦的2期目標劑量低1個劑量水平。研究20160323中的計畫劑量水平為0.003 mg、0.01 mg、0.03 mg、0.1 mg、0.3 mg、1 mg、3 mg、10 mg、30 mg和100 mg。在這項組合研究中,AMG 757的最高計畫目標劑量不超過100 mg。
為減輕CRS的風險並潛在地優化AMG 757的PD活性,將階梯給藥方法作為初始給藥計畫的一部分實施。根據研究20160323中選擇的推薦2期目標劑量和相關給藥計畫,實施以下階梯給藥計畫之一:一階梯、兩階梯(選項1或選項2)或三階梯。從第1週期第1天開始,以480 mg的劑量投與AMG 404。基於新出現的安全性數據,可以調整給藥計畫以允許在第1週期第8天或第1週期第15天最初投與AMG 404。根據在第1週期的哪一天投與AMG 404,從第2週期開始,從第2週期第1天或第2週期第15天開始每4週投與AMG 404(注意,如果AMG 404最初在第1週期第8天投與,則第1週期第8天和第2週期第1天劑量之間有21天的間隔)。
第1部分可能包括以下一或多個計畫劑量水平的AMG 757與固定劑量的AMG 404組合(見圖1):
• 劑量隊列水平1:從第1週期第1天開始,AMG 757(以低於推薦的2期目標劑量1個劑量水平,IV Q2W投與(階梯給藥)與AMG 404(每4週(Q4W)480 mg IV)組合投與
• 劑量隊列水平2:從第1週期第1天開始,AMG 757(以推薦的2期目標劑量,IV Q2W投與(階梯給藥)與AMG 404(Q4W 480 mg IV)組合投與
• 劑量隊列水平-1:從第1週期第8天開始,AMG 757(以低於推薦的2期目標劑量1個劑量水平,IV Q2W投與(階梯給藥)與AMG 404(480 mg IV Q4W(如果不能很好地耐受劑量隊列水平1))組合投與
• 劑量隊列水平-2:從第1週期第15天開始,AMG 757(以低於推薦的2期目標劑量1個劑量水平,IV Q2W投與(階梯給藥)與AMG 404(480 mg IV Q4W(如果不能很好地耐受劑量隊列水平-1))組合投與
• 劑量隊列水平-3:從第1週期第15天開始,AMG 757(以低於推薦的2期目標劑量2個劑量水平,IV Q2W投與(階梯給藥)與AMG 404(480 mg IV Q4W(如果不能很好地耐受劑量隊列水平-2))組合投與
根據新出現的PK、PD和安全性數據,可以探索替代(中間)劑量隊列水平(包括在第1週期調整AMG404投與日期之前調整AMG 757的劑量,作為DLRM遞減推薦的一部分),或一或多個替代給藥計畫(包括AMG 757的另外階梯給藥策略)。
劑量遞增/遞減推薦以mTPI-2模型(Guo等人, 2017)為指導,目標毒性概率為30%,等效毒性區間為(25%,33%),過量給藥概率為95%。β(1, 1)用作先驗分佈。
階梯給藥:在開始AMG 757治療期間,受試者可能具有增加的細胞介素釋放綜合症風險。據信,最佳推薦的2期目標劑量可能需要對階梯給藥方法進行修改。此外,為了優化AMG 757和AMG 404的PD活性,可能需要對階梯給藥方法進行修改。
階梯給藥計畫總結如下。按照基於新出現的安全性和PD數據的DLRT建議,劑量計畫可以適合於包括一或多種以下的措施:
• 一階梯給藥,涉及第1天的第一階梯劑量,隨後係第8天的階梯劑量(等於目標劑量)和第15天然後Q2W的目標劑量。
• 兩階梯給藥(選項1),涉及第1天的第一階梯劑量,隨後係第4天的階梯劑量,第8天的階梯劑量(等於目標劑量)和第15天然後Q2W的目標劑量。
• 兩階梯給藥(選項2),涉及第1天的第一階梯劑量,隨後係第8天的階梯劑量,第15天的階梯劑量(等於目標劑量)和在C2D1然後Q2W的目標劑量。
• 三階梯給藥,涉及第1天的第一階梯劑量,隨後係第4天的階梯劑量,第8天的階梯劑量,第15天的階梯劑量(等於目標劑量)和在C2D1然後Q2W的目標劑量。
如果認為PK、PD和安全性數據令人滿意,則上述選項1的第1週期第4天的階梯劑量可以高於或等於目標劑量。但是,沒有階梯劑量或目標劑量超過100 mg的量。
第2部分(劑量擴展):完成研究的第1部分後,在第2部分開始招募,以確認所選劑量的安全性和耐受性,並進一步評估AMG 757與AMG 404組合之功效。
表2總結了20200439的合格標準
[表2] 關鍵的合格標準
關鍵的納入標準 | 關鍵的排除標準 |
在至少1種基於鉑的方案後進展或復發的 ≥ 18歲的患有組織學或細胞學確認的SCLC的男性或女性 | 其他醫學病症:包括過去2年內的其他惡性腫瘤病史(具有例外),其他醫學病症:包括過去2年內其他惡性腫瘤的病史(具有例外),AMG 757的第一劑量的28天內的大型手術,未治療的或症狀性的腦轉移和軟腦膜疾病,經歷過復發性2級肺炎或嚴重或危及生命的免疫介導的不良事件或輸注相關反應(包括在使用免疫腫瘤藥劑治療期間導致永久停藥的反應)的參與者,任何免疫相關結腸炎的病史。如果存在充分治療和臨床恢復的證據並且自診斷結腸炎後觀察至少3個月的間隔則允許感染性結腸炎,有間質性肺疾病或活動性非感染性肺炎證據的參與者,在AMG 757的第一劑量前7天內診斷為免疫缺乏或正在接受全身性類固醇療法或任何其他形式的免疫抑制療法,實體器官移植的病史,垂體炎或垂體功能障礙的病史,過去2年內需要全身性治療(替代療法除外)的活動性自體免疫性疾病或在研究期間需要免疫抑制療法的任何其他疾病。允許患有不需要免疫抑制治療的I型糖尿病、白癜風、牛皮癬、甲狀腺功能減退或甲狀腺功能亢進的參與者 |
具有根據修改的實性瘤緩解評估標準(RECIST)1.1可測量的疾病的受試者 | |
東部腫瘤協作組(ECOG)表現狀態為0-1 | 方案中定義的先前/伴隨療法:包括抗PD1或抗PDL1抗體療法,任何先前的抗癌療法和第一劑量的AMG 757之間必須至少經過28天 以下情況除外:接受過先前化療的參與者必須在AMG 757的第一劑量之前至少14天已經完成,並且所有與治療相關的毒性均消退至 ≤ 1級。 之前接受姑息性放療的參與者必須在AMG 757的第一劑量之前至少7天已經完成 |
具有經治療的腦轉移的受試者只要符合定義的標準就符合資格 | 方案中定義的先前/伴隨臨床研究經驗 |
如方案中定義的充分的器官功能 |
截至2022年4月,在本研究中,5名受試者接受了AMG 757 10 mg Q2W的1階梯給藥治療和AMG 404 480 mg Q4W治療。兩名受試者有未確認的部分緩解,一名完成了6個週期的治療,另一名完成了2個週期的治療。其餘受試者處於治療的第1週期。沒有受試者出現大於2級的治療中出現的不良事件。一名受試者發生了5級事件,該事件是由於潛在疾病且與治療無關。沒有受試者有導致治療中止的一或多種治療中出現的不良事件。
根據在說明書內引用的參考文獻的教導,將最徹底地理解本說明書。在說明書內的實施方式提供了本發明之實施方式的展示,並且不應構成對本發明範圍的限制。技術者很容易認識到,本發明涵蓋了很多其他實施方式。在本揭露中引用的所有公開物、專利和序列藉由引用以其全部內容進行結合。藉由引用併入的材料在一定程度上與本說明書發生衝突或不一致時,本說明書將替代任何此類材料。在此的任何參考文獻的引用都不是承認此類參考文獻係本發明之先前技術。
熟悉該項技術者僅使用常規實驗就將認識到或能夠確定本文所述之本發明之特定實施方式的許多等效物。此類等效實施方式意在由以下實施方式涵蓋。
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[圖1]顯示了實例2中舉例說明的臨床研究中的AMG 757和AMG 404劑量水平。
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<![CDATA[<110> 美商安進公司(Amgen Inc.)]]> <![CDATA[<120> 靶向DLL3和PD-1的組合療法之給藥方案]]> <![CDATA[<130> A-2789-US-PSP]]> <![CDATA[<160> 61 ]]> <![CDATA[<170> PatentIn 3.5版]]> <![CDATA[<210> 1]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 1]]> Ser Tyr Tyr Trp Ser 1 5 <![CDATA[<210> 2]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 2]]> Tyr Val Tyr Tyr Ser Gly Thr Thr Asn Tyr Asn Pro Ser Leu Lys Ser 1 5 10 15 <![CDATA[<210> 3]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 3]]> Ile Ala Val Thr Gly Phe Tyr Phe Asp Tyr 1 5 10 <![CDATA[<210> 4]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 4]]> Arg Ala Ser Gln Arg Val Asn Asn Asn Tyr Leu Ala 1 5 10 <![CDATA[<210> 5]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 5]]> Gly Ala Ser Ser Arg Ala Thr 1 5 <![CDATA[<210> 6]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 6]]> Gln Gln Tyr Asp Arg Ser Pro Leu Thr 1 5 <![CDATA[<210> 7]]> <![CDATA[<211> 118]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 7]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr 20 25 30 Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Val Tyr Tyr Ser Gly Thr Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu 65 70 75 80 Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Ser Ile Ala Val Thr Gly Phe Tyr Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <![CDATA[<210> 8]]> <![CDATA[<211> 108]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 8]]> Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Val Thr Leu Ser Cys Arg Ala Ser Gln Arg Val Asn Asn Asn 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asp Arg Ser Pro 85 90 95 Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <![CDATA[<210> 9]]> <![CDATA[<211> 241]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 9]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr 20 25 30 Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Val Tyr Tyr Ser Gly Thr Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu 65 70 75 80 Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Ser Ile Ala Val Thr Gly Phe Tyr Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu 130 135 140 Ser Leu Ser Pro Gly Glu Arg Val Thr Leu Ser Cys Arg Ala Ser Gln 145 150 155 160 Arg Val Asn Asn Asn Tyr Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln 165 170 175 Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile 180 185 190 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 195 200 205 Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln 210 215 220 Tyr Asp Arg Ser Pro Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile 225 230 235 240 Lys <![CDATA[<210> 10]]> <![CDATA[<211> 496]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 10]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr 20 25 30 Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Val Tyr Tyr Ser Gly Thr Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu 65 70 75 80 Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Ser Ile Ala Val Thr Gly Phe Tyr Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu 130 135 140 Ser Leu Ser Pro Gly Glu Arg Val Thr Leu Ser Cys Arg Ala Ser Gln 145 150 155 160 Arg Val Asn Asn Asn Tyr Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln 165 170 175 Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile 180 185 190 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 195 200 205 Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln 210 215 220 Tyr Asp Arg Ser Pro Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile 225 230 235 240 Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly 245 250 255 Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser 260 265 270 Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro 275 280 285 Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn 290 295 300 Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser 305 310 315 320 Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys 325 330 335 Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly 340 345 350 Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val 355 360 365 Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 370 375 380 Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser 385 390 395 400 Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val 405 410 415 Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala 420 425 430 Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro 435 440 445 Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu 450 455 460 Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp 465 470 475 480 Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 485 490 495 <![CDATA[<210> 11]]> <![CDATA[<211> 118]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 11]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr 20 25 30 Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu Trp Ile 35 40 45 Gly Tyr Val Tyr Tyr Ser Gly Thr Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu 65 70 75 80 Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Ser Ile Ala Val Thr Gly Phe Tyr Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <![CDATA[<210> 12]]> <![CDATA[<211> 108]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 12]]> Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Val Thr Leu Ser Cys Arg Ala Ser Gln Arg Val Asn Asn Asn 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asp Arg Ser Pro 85 90 95 Leu Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile Lys 100 105 <![CDATA[<210> 13]]> <![CDATA[<211> 241]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 13]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr 20 25 30 Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu Trp Ile 35 40 45 Gly Tyr Val Tyr Tyr Ser Gly Thr Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu 65 70 75 80 Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Ser Ile Ala Val Thr Gly Phe Tyr Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu 130 135 140 Ser Leu Ser Pro Gly Glu Arg Val Thr Leu Ser Cys Arg Ala Ser Gln 145 150 155 160 Arg Val Asn Asn Asn Tyr Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln 165 170 175 Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile 180 185 190 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 195 200 205 Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln 210 215 220 Tyr Asp Arg Ser Pro Leu Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile 225 230 235 240 Lys <![CDATA[<210> 14]]> <![CDATA[<211> 496]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 14]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr 20 25 30 Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu Trp Ile 35 40 45 Gly Tyr Val Tyr Tyr Ser Gly Thr Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu 65 70 75 80 Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Ser Ile Ala Val Thr Gly Phe Tyr Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu 130 135 140 Ser Leu Ser Pro Gly Glu Arg Val Thr Leu Ser Cys Arg Ala Ser Gln 145 150 155 160 Arg Val Asn Asn Asn Tyr Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln 165 170 175 Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile 180 185 190 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 195 200 205 Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln 210 215 220 Tyr Asp Arg Ser Pro Leu Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile 225 230 235 240 Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly 245 250 255 Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser 260 265 270 Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro 275 280 285 Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn 290 295 300 Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser 305 310 315 320 Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys 325 330 335 Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly 340 345 350 Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val 355 360 365 Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 370 375 380 Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser 385 390 395 400 Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val 405 410 415 Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala 420 425 430 Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro 435 440 445 Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu 450 455 460 Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp 465 470 475 480 Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 485 490 495 <![CDATA[<210> 15]]> <![CDATA[<211> 14]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 15]]> Gly Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn 1 5 10 <![CDATA[<210> 16]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 16]]> Gly Thr Lys Phe Leu Ala Pro 1 5 <![CDATA[<210> 17]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 17]]> Val Leu Trp Tyr Ser Asn Arg Trp Val 1 5 <![CDATA[<210> 18]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 18]]> Lys Tyr Ala Met Asn 1 5 <![CDATA[<210> 19]]> <![CDATA[<211> 19]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 19]]> Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser 1 5 10 15 Val Lys Asp <![CDATA[<210> 20]]> <![CDATA[<211> 14]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 20]]> His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr 1 5 10 <![CDATA[<210> 21]]> <![CDATA[<211> 125]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 21]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp 50 55 60 Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr 65 70 75 80 Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp 100 105 110 Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 125 <![CDATA[<210> 22]]> <![CDATA[<211> 109]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 22]]> Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly 1 5 10 15 Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly 20 25 30 Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly 35 40 45 Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe 50 55 60 Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val 65 70 75 80 Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn 85 90 95 Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <![CDATA[<210> 23]]> <![CDATA[<211> 249]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 23]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp 50 55 60 Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr 65 70 75 80 Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp 100 105 110 Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly 115 120 125 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val 130 135 140 Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu 145 150 155 160 Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn 165 170 175 Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly 180 185 190 Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu 195 200 205 Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp 210 215 220 Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe 225 230 235 240 Gly Gly Gly Thr Lys Leu Thr Val Leu 245 <![CDATA[<210> 24]]> <![CDATA[<211> 984]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 24]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr 20 25 30 Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Val Tyr Tyr Ser Gly Thr Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu 65 70 75 80 Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Ser Ile Ala Val Thr Gly Phe Tyr Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu 130 135 140 Ser Leu Ser Pro Gly Glu Arg Val Thr Leu Ser Cys Arg Ala Ser Gln 145 150 155 160 Arg Val Asn Asn Asn Tyr Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln 165 170 175 Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile 180 185 190 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 195 200 205 Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln 210 215 220 Tyr Asp Arg Ser Pro Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile 225 230 235 240 Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly 245 250 255 Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser 260 265 270 Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro 275 280 285 Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn 290 295 300 Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser 305 310 315 320 Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys 325 330 335 Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly 340 345 350 Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val 355 360 365 Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 370 375 380 Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser 385 390 395 400 Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val 405 410 415 Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala 420 425 430 Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro 435 440 445 Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu 450 455 460 Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp 465 470 475 480 Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 485 490 495 Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 500 505 510 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 515 520 525 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 530 535 540 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 545 550 555 560 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr 565 570 575 Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp 580 585 590 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 595 600 605 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 610 615 620 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys 625 630 635 640 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 645 650 655 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 660 665 670 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 675 680 685 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 690 695 700 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 705 710 715 720 Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly 725 730 735 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 740 745 750 Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala 755 760 765 Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 770 775 780 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 785 790 795 800 Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val 805 810 815 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln 820 825 830 Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln 835 840 845 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala 850 855 860 Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 865 870 875 880 Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr 885 890 895 Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 900 905 910 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr 915 920 925 Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 930 935 940 Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe 945 950 955 960 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 965 970 975 Ser Leu Ser Leu Ser Pro Gly Lys 980 <![CDATA[<210> 25]]> <![CDATA[<211> 982]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 25]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr 20 25 30 Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Val Tyr Tyr Ser Gly Thr Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu 65 70 75 80 Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Ser Ile Ala Val Thr Gly Phe Tyr Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu 130 135 140 Ser Leu Ser Pro Gly Glu Arg Val Thr Leu Ser Cys Arg Ala Ser Gln 145 150 155 160 Arg Val Asn Asn Asn Tyr Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln 165 170 175 Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile 180 185 190 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 195 200 205 Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln 210 215 220 Tyr Asp Arg Ser Pro Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile 225 230 235 240 Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly 245 250 255 Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser 260 265 270 Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro 275 280 285 Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn 290 295 300 Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser 305 310 315 320 Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys 325 330 335 Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly 340 345 350 Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val 355 360 365 Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 370 375 380 Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser 385 390 395 400 Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val 405 410 415 Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala 420 425 430 Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro 435 440 445 Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu 450 455 460 Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp 465 470 475 480 Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 485 490 495 Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 500 505 510 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 515 520 525 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 530 535 540 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 545 550 555 560 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr 565 570 575 Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp 580 585 590 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 595 600 605 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 610 615 620 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys 625 630 635 640 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 645 650 655 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 660 665 670 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 675 680 685 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 690 695 700 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 705 710 715 720 Leu Ser Leu Ser Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 725 730 735 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 740 745 750 Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 755 760 765 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 770 775 780 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 785 790 795 800 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 805 810 815 Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly 820 825 830 Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp 835 840 845 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 850 855 860 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 865 870 875 880 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 885 890 895 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 900 905 910 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 915 920 925 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 930 935 940 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 945 950 955 960 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 965 970 975 Ser Leu Ser Pro Gly Lys 980 <![CDATA[<210> 26]]> <![CDATA[<211> 984]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 26]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr 20 25 30 Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu Trp Ile 35 40 45 Gly Tyr Val Tyr Tyr Ser Gly Thr Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu 65 70 75 80 Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Ser Ile Ala Val Thr Gly Phe Tyr Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu 130 135 140 Ser Leu Ser Pro Gly Glu Arg Val Thr Leu Ser Cys Arg Ala Ser Gln 145 150 155 160 Arg Val Asn Asn Asn Tyr Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln 165 170 175 Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile 180 185 190 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 195 200 205 Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln 210 215 220 Tyr Asp Arg Ser Pro Leu Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile 225 230 235 240 Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly 245 250 255 Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser 260 265 270 Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro 275 280 285 Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn 290 295 300 Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser 305 310 315 320 Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys 325 330 335 Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly 340 345 350 Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val 355 360 365 Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 370 375 380 Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser 385 390 395 400 Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val 405 410 415 Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala 420 425 430 Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro 435 440 445 Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu 450 455 460 Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp 465 470 475 480 Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 485 490 495 Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 500 505 510 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 515 520 525 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 530 535 540 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 545 550 555 560 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr 565 570 575 Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp 580 585 590 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 595 600 605 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 610 615 620 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys 625 630 635 640 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 645 650 655 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 660 665 670 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 675 680 685 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 690 695 700 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 705 710 715 720 Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly 725 730 735 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 740 745 750 Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala 755 760 765 Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 770 775 780 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 785 790 795 800 Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val 805 810 815 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln 820 825 830 Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln 835 840 845 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala 850 855 860 Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 865 870 875 880 Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr 885 890 895 Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 900 905 910 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr 915 920 925 Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 930 935 940 Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe 945 950 955 960 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 965 970 975 Ser Leu Ser Leu Ser Pro Gly Lys 980 <![CDATA[<210> 27]]> <![CDATA[<211> 982]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 27]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr 20 25 30 Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu Trp Ile 35 40 45 Gly Tyr Val Tyr Tyr Ser Gly Thr Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu 65 70 75 80 Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Ser Ile Ala Val Thr Gly Phe Tyr Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu 130 135 140 Ser Leu Ser Pro Gly Glu Arg Val Thr Leu Ser Cys Arg Ala Ser Gln 145 150 155 160 Arg Val Asn Asn Asn Tyr Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln 165 170 175 Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile 180 185 190 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 195 200 205 Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln 210 215 220 Tyr Asp Arg Ser Pro Leu Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile 225 230 235 240 Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly 245 250 255 Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser 260 265 270 Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro 275 280 285 Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn 290 295 300 Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser 305 310 315 320 Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys 325 330 335 Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly 340 345 350 Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val 355 360 365 Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 370 375 380 Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser 385 390 395 400 Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val 405 410 415 Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala 420 425 430 Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro 435 440 445 Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu 450 455 460 Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp 465 470 475 480 Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 485 490 495 Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 500 505 510 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 515 520 525 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 530 535 540 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 545 550 555 560 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr 565 570 575 Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp 580 585 590 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 595 600 605 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 610 615 620 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys 625 630 635 640 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 645 650 655 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 660 665 670 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 675 680 685 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 690 695 700 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 705 710 715 720 Leu Ser Leu Ser Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 725 730 735 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 740 745 750 Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 755 760 765 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 770 775 780 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 785 790 795 800 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 805 810 815 Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly 820 825 830 Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp 835 840 845 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 850 855 860 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 865 870 875 880 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 885 890 895 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 900 905 910 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 915 920 925 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 930 935 940 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 945 950 955 960 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 965 970 975 Ser Leu Ser Pro Gly Lys 980 <![CDATA[<210> 28]]> <![CDATA[<211> 618]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 28]]> Met Val Ser Pro Arg Met Ser Gly Leu Leu Ser Gln Thr Val Ile Leu 1 5 10 15 Ala Leu Ile Phe Leu Pro Gln Thr Arg Pro Ala Gly Val Phe Glu Leu 20 25 30 Gln Ile His Ser Phe Gly Pro Gly Pro Gly Pro Gly Ala Pro Arg Ser 35 40 45 Pro Cys Ser Ala Arg Leu Pro Cys Arg Leu Phe Phe Arg Val Cys Leu 50 55 60 Lys Pro Gly Leu Ser Glu Glu Ala Ala Glu Ser Pro Cys Ala Leu Gly 65 70 75 80 Ala Ala Leu Ser Ala Arg Gly Pro Val Tyr Thr Glu Gln Pro Gly Ala 85 90 95 Pro Ala Pro Asp Leu Pro Leu Pro Asp Gly Leu Leu Gln Val Pro Phe 100 105 110 Arg Asp Ala Trp Pro Gly Thr Phe Ser Phe Ile Ile Glu Thr Trp Arg 115 120 125 Glu Glu Leu Gly Asp Gln Ile Gly Gly Pro Ala Trp Ser Leu Leu Ala 130 135 140 Arg Val Ala Gly Arg Arg Arg Leu Ala Ala Gly Gly Pro Trp Ala Arg 145 150 155 160 Asp Ile Gln Arg Ala Gly Ala Trp Glu Leu Arg Phe Ser Tyr Arg Ala 165 170 175 Arg Cys Glu Pro Pro Ala Val Gly Thr Ala Cys Thr Arg Leu Cys Arg 180 185 190 Pro Arg Ser Ala Pro Ser Arg Cys Gly Pro Gly Leu Arg Pro Cys Ala 195 200 205 Pro Leu Glu Asp Glu Cys Glu Ala Pro Leu Val Cys Arg Ala Gly Cys 210 215 220 Ser Pro Glu His Gly Phe Cys Glu Gln Pro Gly Glu Cys Arg Cys Leu 225 230 235 240 Glu Gly Trp Thr Gly Pro Leu Cys Thr Val Pro Val Ser Thr Ser Ser 245 250 255 Cys Leu Ser Pro Arg Gly Pro Ser Ser Ala Thr Thr Gly Cys Leu Val 260 265 270 Pro Gly Pro Gly Pro Cys Asp Gly Asn Pro Cys Ala Asn Gly Gly Ser 275 280 285 Cys Ser Glu Thr Pro Arg Ser Phe Glu Cys Thr Cys Pro Arg Gly Phe 290 295 300 Tyr Gly Leu Arg Cys Glu Val Ser Gly Val Thr Cys Ala Asp Gly Pro 305 310 315 320 Cys Phe Asn Gly Gly Leu Cys Val Gly Gly Ala Asp Pro Asp Ser Ala 325 330 335 Tyr Ile Cys His Cys Pro Pro Gly Phe Gln Gly Ser Asn Cys Glu Lys 340 345 350 Arg Val Asp Arg Cys Ser Leu Gln Pro Cys Arg Asn Gly Gly Leu Cys 355 360 365 Leu Asp Leu Gly His Ala Leu Arg Cys Arg Cys Arg Ala Gly Phe Ala 370 375 380 Gly Pro Arg Cys Glu His Asp Leu Asp Asp Cys Ala Gly Arg Ala Cys 385 390 395 400 Ala Asn Gly Gly Thr Cys Val Glu Gly Gly Gly Ala His Arg Cys Ser 405 410 415 Cys Ala Leu Gly Phe Gly Gly Arg Asp Cys Arg Glu Arg Ala Asp Pro 420 425 430 Cys Ala Ala Arg Pro Cys Ala His Gly Gly Arg Cys Tyr Ala His Phe 435 440 445 Ser Gly Leu Val Cys Ala Cys Ala Pro Gly Tyr Met Gly Ala Arg Cys 450 455 460 Glu Phe Pro Val His Pro Asp Gly Ala Ser Ala Leu Pro Ala Ala Pro 465 470 475 480 Pro Gly Leu Arg Pro Gly Asp Pro Gln Arg Tyr Leu Leu Pro Pro Ala 485 490 495 Leu Gly Leu Leu Val Ala Ala Gly Val Ala Gly Ala Ala Leu Leu Leu 500 505 510 Val His Val Arg Arg Arg Gly His Ser Gln Asp Ala Gly Ser Arg Leu 515 520 525 Leu Ala Gly Thr Pro Glu Pro Ser Val His Ala Leu Pro Asp Ala Leu 530 535 540 Asn Asn Leu Arg Thr Gln Glu Gly Ser Gly Asp Gly Pro Ser Ser Ser 545 550 555 560 Val Asp Trp Asn Arg Pro Glu Asp Val Asp Pro Gln Gly Ile Tyr Val 565 570 575 Ile Ser Ala Pro Ser Ile Tyr Ala Arg Glu Val Ala Thr Pro Leu Phe 580 585 590 Pro Pro Leu His Thr Gly Arg Ala Gly Gln Arg Gln His Leu Leu Phe 595 600 605 Pro Tyr Pro Ser Ser Ile Leu Ser Val Lys 610 615 <![CDATA[<210> 29]]> <![CDATA[<211> 40]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 29]]> Ser Gly Val Thr Cys Ala Asp Gly Pro Cys Phe Asn Gly Gly Leu Cys 1 5 10 15 Val Gly Gly Ala Asp Pro Asp Ser Ala Tyr Ile Cys His Cys Pro Pro 20 25 30 Gly Phe Gln Gly Ser Asn Cys Glu 35 40 <![CDATA[<210> 30]]> <![CDATA[<211> 37]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 3]]>0 Arg Val Asp Arg Cys Ser Leu Gln Pro Cys Arg Asn Gly Gly Leu Cys 1 5 10 15 Leu Asp Leu Gly His Ala Leu Arg Cys Arg Cys Arg Ala Gly Phe Ala 20 25 30 Gly Pro Arg Cys Glu 35 <![CDATA[<210> 31]]> <![CDATA[<211> 78]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 31]]> Ser Gly Val Thr Cys Ala Asp Gly Pro Cys Phe Asn Gly Gly Leu Cys 1 5 10 15 Val Gly Gly Ala Asp Pro Asp Ser Ala Tyr Ile Cys His Cys Pro Pro 20 25 30 Gly Phe Gln Gly Ser Asn Cys Glu Lys Arg Val Asp Arg Cys Ser Leu 35 40 45 Gln Pro Cys Arg Asn Gly Gly Leu Cys Leu Asp Leu Gly His Ala Leu 50 55 60 Arg Cys Arg Cys Arg Ala Gly Phe Ala Gly Pro Arg Cys Glu 65 70 75 <![CDATA[<210> 32]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 32]]> Ser Tyr Asp Met Ser 1 5 <![CDATA[<210> 33]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 33]]> Leu Ile Ser Gly Gly Gly Ser Gln Thr Tyr Tyr Ala Glu Ser Val Lys 1 5 10 15 Gly <![CDATA[<210> 34]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 34]]> Pro Ser Gly His Tyr Phe Tyr Ala Met Asp Val 1 5 10 <![CDATA[<210> 35]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 35]]> Arg Ala Ser Gln Gly Ile Ser Asn Trp Leu Ala 1 5 10 <![CDATA[<210> 36]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 36]]> Ala Ala Ser Ser Leu Gln Ser 1 5 <![CDATA[<210> 37]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 37]]> Gln Gln Ala Glu Ser Phe Pro His Thr 1 5 <![CDATA[<210> 38]]> <![CDATA[<211> 120]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 38]]> Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Leu Ile Ser Gly Gly Gly Ser Gln Thr Tyr Tyr Ala Glu Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Ser Pro Ser Gly His Tyr Phe Tyr Ala Met Asp Val Trp Gly Gln 100 105 110 Gly Thr Thr Val Thr Val Ser Ser 115 120 <![CDATA[<210> 39]]> <![CDATA[<211> 107]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 39]]> Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Asn Trp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Phe Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Glu Ser Phe Pro His 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <![CDATA[<210> 40]]> <![CDATA[<211> 450]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 40]]> Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Leu Ile Ser Gly Gly Gly Ser Gln Thr Tyr Tyr Ala Glu Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Ser Pro Ser Gly His Tyr Phe Tyr Ala Met Asp Val Trp Gly Gln 100 105 110 Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro 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 Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg 290 295 300 Cys 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 Glu Glu Met 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> 41]]> <![CDATA[<211> 213]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 41]]> Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Asn Trp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Phe Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Glu Ser Phe Pro His 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu 210 <![CDATA[<210> 42]]> <![CDATA[<211>]]> 4 <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 42]]> Gly Gly Gly Gly 1 <![CDATA[<210> 43]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 43]]> Gly Gly Gly Gly Ser 1 5 <![CDATA[<210> 44]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 44]]> Gly Gly Gly Gly Gln 1 5 <![CDATA[<210> 45]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 45]]> Ser Gly Gly Gly Gly Ser 1 5 <![CDATA[<210> 46]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 46]]> Pro Gly Gly Gly Gly Ser 1 5 <![CDATA[<210> 47]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 47]]> Pro Gly Gly Asp Gly Ser 1 5 <![CDATA[<210> 48]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 48]]> Gly Gly Gly Gly Ser Gly Gly Gly Ser 1 5 <![CDATA[<210> 49]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 49]]> Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1 5 10 <![CDATA[<210> ]]> 50 <![CDATA[<211> 15]]> <![CDATA[<212> PR]]>T <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 50]]> Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1 5 10 15 <![CDATA[<210> 51]]> <![CDATA[<211> 484]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 51]]> Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr 65 70 75 80 Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 130 135 140 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 225 230 235 240 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 245 250 255 Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 260 265 270 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 275 280 285 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 290 295 300 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 305 310 315 320 Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly Ser Thr 325 330 335 Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 340 345 350 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 355 360 365 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 370 375 380 Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val 385 390 395 400 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 405 410 415 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 420 425 430 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 435 440 445 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 450 455 460 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 465 470 475 480 Ser Pro Gly Lys <![CDATA[<210> 52]]> <![CDATA[<211> 480]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 52]]> Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr 65 70 75 80 Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 130 135 140 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 225 230 235 240 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp 245 250 255 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 260 265 270 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 275 280 285 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 290 295 300 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 305 310 315 320 Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg 325 330 335 Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 340 345 350 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 355 360 365 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 370 375 380 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 385 390 395 400 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 405 410 415 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 420 425 430 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 435 440 445 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 450 455 460 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 465 470 475 480 <![CDATA[<210> 53]]> <![CDATA[<211> 484]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 53]]> Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 130 135 140 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 225 230 235 240 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 245 250 255 Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 260 265 270 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 275 280 285 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 290 295 300 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 305 310 315 320 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 325 330 335 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 340 345 350 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 355 360 365 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 370 375 380 Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val 385 390 395 400 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 405 410 415 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 420 425 430 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 435 440 445 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 450 455 460 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 465 470 475 480 Ser Pro Gly Lys <![CDATA[<210> 54]]> <![CDATA[<211> 480]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 54]]> Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 130 135 140 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 225 230 235 240 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp 245 250 255 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 260 265 270 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 275 280 285 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 290 295 300 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 305 310 315 320 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 325 330 335 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 340 345 350 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 355 360 365 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 370 375 380 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 385 390 395 400 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 405 410 415 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 420 425 430 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 435 440 445 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 450 455 460 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 465 470 475 480 <![CDATA[<210> 55]]> <![CDATA[<211> 484]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 55]]> Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 130 135 140 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 225 230 235 240 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 245 250 255 Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 260 265 270 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 275 280 285 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 290 295 300 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 305 310 315 320 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr 325 330 335 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 340 345 350 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 355 360 365 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 370 375 380 Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val 385 390 395 400 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 405 410 415 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 420 425 430 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 435 440 445 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 450 455 460 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 465 470 475 480 Ser Pro Gly Lys <![CDATA[<210> 56]]> <![CDATA[<211> 480]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 56]]> Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 130 135 140 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 225 230 235 240 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp 245 250 255 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 260 265 270 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 275 280 285 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 290 295 300 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 305 310 315 320 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg 325 330 335 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 340 345 350 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 355 360 365 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 370 375 380 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 385 390 395 400 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 405 410 415 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 420 425 430 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 435 440 445 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 450 455 460 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 465 470 475 480 <![CDATA[<210> 57]]> <![CDATA[<211> 484]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 57]]> Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 130 135 140 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 225 230 235 240 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 245 250 255 Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 260 265 270 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 275 280 285 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 290 295 300 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 305 310 315 320 Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Asn Ser Thr 325 330 335 Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 340 345 350 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 355 360 365 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 370 375 380 Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val 385 390 395 400 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 405 410 415 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 420 425 430 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 435 440 445 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 450 455 460 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 465 470 475 480 Ser Pro Gly Lys <![CDATA[<210> 58]]> <![CDATA[<211> 480]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 58]]> Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 130 135 140 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 225 230 235 240 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp 245 250 255 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 260 265 270 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 275 280 285 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 290 295 300 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 305 310 315 320 Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 325 330 335 Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 340 345 350 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 355 360 365 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 370 375 380 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 385 390 395 400 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 405 410 415 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 420 425 430 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 435 440 445 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 450 455 460 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 465 470 475 480 <![CDATA[<210> 59]]> <![CDATA[<211> 981]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 59]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr 20 25 30 Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu Trp Ile 35 40 45 Gly Tyr Val Tyr Tyr Ser Gly Thr Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu 65 70 75 80 Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Ser Ile Ala Val Thr Gly Phe Tyr Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu 130 135 140 Ser Leu Ser Pro Gly Glu Arg Val Thr Leu Ser Cys Arg Ala Ser Gln 145 150 155 160 Arg Val Asn Asn Asn Tyr Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln 165 170 175 Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile 180 185 190 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 195 200 205 Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln 210 215 220 Tyr Asp Arg Ser Pro Leu Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile 225 230 235 240 Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly 245 250 255 Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser 260 265 270 Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro 275 280 285 Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn 290 295 300 Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser 305 310 315 320 Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys 325 330 335 Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly 340 345 350 Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val 355 360 365 Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 370 375 380 Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser 385 390 395 400 Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val 405 410 415 Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala 420 425 430 Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro 435 440 445 Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu 450 455 460 Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp 465 470 475 480 Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 485 490 495 Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 500 505 510 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 515 520 525 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 530 535 540 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 545 550 555 560 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr 565 570 575 Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp 580 585 590 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 595 600 605 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 610 615 620 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys 625 630 635 640 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 645 650 655 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 660 665 670 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 675 680 685 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 690 695 700 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 705 710 715 720 Leu Ser Leu Ser Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 725 730 735 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 740 745 750 Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 755 760 765 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 770 775 780 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 785 790 795 800 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 805 810 815 Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly 820 825 830 Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp 835 840 845 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 850 855 860 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 865 870 875 880 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 885 890 895 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 900 905 910 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 915 920 925 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 930 935 940 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 945 950 955 960 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 965 970 975 Ser Leu Ser Pro Gly 980 <![CDATA[<210> 60]]> <![CDATA[<211> 268]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的肽]]> <![CDATA[<400> 60]]> Pro Gly Trp Phe Leu Asp Ser Pro Asp Arg Pro Trp Asn Pro Pro Thr 1 5 10 15 Phe Ser Pro Ala Leu Leu Val Val Thr Glu Gly Asp Asn Ala Thr Phe 20 25 30 Thr Cys Ser Phe Ser Asn Thr Ser Glu Ser Phe Val Leu Asn Trp Tyr 35 40 45 Arg Met Ser Pro Ser Asn Gln Thr Asp Lys Leu Ala Ala Phe Pro Glu 50 55 60 Asp Arg Ser Gln Pro Gly Gln Asp Cys Arg Phe Arg Val Thr Gln Leu 65 70 75 80 Pro Asn Gly Arg Asp Phe His Met Ser Val Val Arg Ala Arg Arg Asn 85 90 95 Asp Ser Gly Thr Tyr Leu Cys Gly Ala Ile Ser Leu Ala Pro Lys Ala 100 105 110 Gln Ile Lys Glu Ser Leu Arg Ala Glu Leu Arg Val Thr Glu Arg Arg 115 120 125 Ala Glu Val Pro Thr Ala His Pro Ser Pro Ser Pro Arg Pro Ala Gly 130 135 140 Gln Phe Gln Thr Leu Val Val Gly Val Val Gly Gly Leu Leu Gly Ser 145 150 155 160 Leu Val Leu Leu Val Trp Val Leu Ala Val Ile Cys Ser Arg Ala Ala 165 170 175 Arg Gly Thr Ile Gly Ala Arg Arg Thr Gly Gln Pro Leu Lys Glu Asp 180 185 190 Pro Ser Ala Val Pro Val Phe Ser Val Asp Tyr Gly Glu Leu Asp Phe 195 200 205 Gln Trp Arg Glu Lys Thr Pro Glu Pro Pro Val Pro Cys Val Pro Glu 210 215 220 Gln Thr Glu Tyr Ala Thr Ile Val Phe Pro Ser Gly Met Gly Thr Ser 225 230 235 240 Ser Pro Ala Arg Arg Gly Ser Ala Asp Gly Pro Arg Ser Ala Gln Pro 245 250 255 Leu Arg Pro Glu Asp Gly His Cys Ser Trp Pro Leu 260 265 <![CDATA[<210> 61]]> <![CDATA[<211> 288]]> <![CDATA[<21]]>2> PRT]]> <br/><![CDATA[<213> 人工序列]]> <br/> <br/><![CDATA[<220>]]> <br/><![CDATA[<223> 合成的肽]]> <br/> <br/><![CDATA[<400> 61]]> <br/> <br/><![CDATA[Met Gln Ile Pro Gln Ala Pro Trp Pro Val Val Trp Ala Val Leu Gln 1 5 10 15 Leu Gly Trp Arg Pro Gly Trp Phe Leu Glu Ser Pro Asp Arg Pro Trp 20 25 30 Asn Ala Pro Thr Phe Ser Pro Ala Leu Leu Leu Val Thr Glu Gly Asp 35 40 45 Asn Ala Thr Phe Thr Cys Ser Phe Ser Asn Ala Ser Glu Ser Phe Val 50 55 60 Leu Asn Trp Tyr Arg Met Ser Pro Ser Asn Gln Thr Asp Lys Leu Ala 65 70 75 80 Ala Phe Pro Glu Asp Arg Ser Gln Pro Gly Gln Asp Cys Arg Phe Arg 85 90 95 Val Thr Arg Leu Pro Asn Gly Arg Asp Phe His Met Ser Val Val Arg 100 105 110 Ala Arg Arg Asn Asp Ser Gly Thr Tyr Leu Cys Gly Ala Ile Ser Leu 115 120 125 Ala Pro Lys Ala Gln Ile Lys Glu Ser Leu Arg Ala Glu Leu Arg Val 130 135 140 Thr Glu Arg Arg Ala Glu Val Pro Thr Ala His Pro Ser Pro Ser Pro 145 150 155 160 Arg Pro Ala Gly Gln Phe Gln Ala Leu Val Val Gly Val Val Gly Gly 165 170 175 Leu Leu Gly Ser Leu Val Leu Leu Val Trp Val Leu Ala Val Ile Cys 180 185 190 Ser Arg Ala Ala Gln Gly Thr Ile Glu Ala Arg Arg Thr Gly Gln Pro 195 200 205 Leu Lys Glu Asp Pro Ser Ala Val Pro Val Phe Ser Val Asp Tyr Gly 210 215 220 Glu Leu Asp Phe Gln Trp Arg Glu Lys Thr Pro Glu Pro Pro Ala Pro 225 230 235 240 Cys Val Pro Glu Gln Thr Glu Tyr Ala Thr Ile Val Phe Pro Ser Gly 245 250 255 Leu Gly Thr Ser Ser Pro Ala Arg Arg Gly Ser Ala Asp Gly Pro Arg 260 265 270 Ser Pro Arg Pro Leu Arg Pro Glu Asp Gly His Cys Ser Trp Pro Leu 275 280 285
Claims (18)
- 一種治療患有小細胞肺癌(SCLC)的受試者之方法,該方法包括向有需要的受試者投與包含SEQ ID NO: 13和23之胺基酸序列的抗DLL3藥劑、和抗PD-1抗體,其中該抗DLL3藥劑以0.3 mg至30 mg或3 mg至100 mg的劑量每兩週一次投與,並且其中該SCLC在至少一種先前的基於鉑的化療後在該受試者中復發。
- 如請求項1所述之方法,其中該抗DLL3藥劑以1 mg至30 mg的劑量每兩週一次投與。
- 如請求項1或2所述之方法,其中該抗DLL3藥劑以3 mg、10 mg、25 mg或30 mg的劑量每兩週一次投與。
- 如請求項1所述之方法,其中該抗DLL3藥劑以10 mg至100 mg的劑量每兩週一次投與。
- 如請求項1或4所述之方法,其中該抗DLL3藥劑以10 mg、25 mg、30 mg、50 mg、75 mg或100 mg的劑量每兩週一次投與。
- 如請求項1-5中任一項所述之方法,其中該抗DLL3藥劑在28天週期的第1天和第15天投與。
- 如請求項6所述之方法,其中該抗PD-1抗體係納武單抗、派姆單抗或澤魯伐利單抗。
- 如請求項7所述之方法,其中該抗PD-1抗體係派姆單抗,並且其中該派姆單抗以200 mg的劑量每三週一次投與。
- 如請求項7所述之方法,其中該抗PD-1抗體係納武單抗,並且其中該納武單抗以240 mg的劑量每兩週一次投與。
- 如請求項7所述之方法,其中該抗PD-1抗體係澤魯伐利單抗,並且其中該澤魯伐利單抗以480 mg的劑量每三週一次投與。
- 如請求項8所述之方法,其中如果派姆單抗和該抗DLL3藥劑兩者在同一天投與,則派姆單抗在該抗DLL3藥劑之前投與。
- 如請求項1-11中任一項所述之方法,該方法進一步包括向該受試者投與一或多種另外治療劑。
- 如請求項12所述之方法,其中該一或多種另外治療劑係皮質類固醇、鹽水或托珠單抗。
- 如請求項13所述之方法,其中該皮質類固醇係地塞米松。
- 如請求項11-14中任一項所述之方法,其中該一或多種另外治療劑在其中投與該抗DLL3藥劑的第1週期中投與。
- 如請求項1-15中任一項所述之方法,其中該基於鉑的化療係鉑-依託泊苷療法。
- 如請求項1-16中任一項所述之方法,其中藉由靜脈內輸注投與該抗DLL3藥劑。
- 如請求項1-17中任一項所述之方法,其中該受試者係人。
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